Publications by authors named "Alex Kiss"

235 Publications

Cardiac Rehabilitation Is Associated With Improved Long-Term Outcomes After Coronary Artery Bypass Grafting.

CJC Open 2021 Feb 12;3(2):167-175. Epub 2020 Oct 12.

Division of Cardiac Surgery, Schulich Heart Centre, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

Background: Although cardiac rehabilitation (CR) has proven to have short- and mid-term benefit in treatment of coronary artery disease, its long-term benefit in patients who have undergone coronary artery bypass grafting (CABG) is less certain. Our objective was to examine the late outcomes of patients who attended CR within the first year after CABG.

Methods: Adult CABG patients referred to Toronto Rehabilitation Institute (CR group: were referred and attended at least 1 session; No-CR group: were referred but did not attend) between January 1996 and September 2008 were identified through linkages with clinical and provincial administrative databases for comorbidities and outcome ascertainment. The primary outcome was a composite of all-cause mortality, acute myocardial infarction, stroke or repeat revascularization (major adverse cardiac and cerebrovascular events [MACCE]). The secondary outcome was all-cause mortality. Multivariable Cox proportional hazard models were used to assess the CR treatment effect, adjusting for baseline characteristics.

Results: The study cohort consisted of 5,000 patients-3,685 (73.7%) in the CR group and 1,315 (26.3%) in the No-CR group. Median referral time was 32.5 days, and follow-up was 13.1 years. The CR group patients, compared with the No-CR group, were younger (age 62.6 ± 9.6 vs 64.0 ± 10.5 years), were more likely to be male (85.0% vs 79.5%), and had fewer cardiac comorbidities. In adjusted analyses, the CR group was associated with decreased MACCE (hazard ratio 0.83, 95% confidence interval 0.75-0.91, < 0.0001) and a higher adjusted survival at 15 years (66.3% vs 60.1%, hazard ratio 0.76, 95% confidence interval 0.68-0.84, < 0.0001), as compared with the No-CR group.

Conclusions: There was a reduction in MACCE and late mortality associated with CR attendance, highlighting the importance of patient referral and participation in CR after CABG.
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http://dx.doi.org/10.1016/j.cjco.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893191PMC
February 2021

Comparison of the Analgesic Duration of 0.5% Bupivacaine With 1:200,000 Epinephrine Versus 0.5% Ropivacaine Versus 1% Ropivacaine for Low-Volume Ultrasound-Guided Interscalene Brachial Plexus Block: A Randomized Controlled Trial.

Anesth Analg 2021 Jan 15. Epub 2021 Jan 15.

From the Department of Anesthesia, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

Background: Bupivacaine and ropivacaine are the preferred long-acting local anesthetics for peripheral nerve blocks as they provide prolonged analgesia in the postoperative period. No studies have directly compared the analgesic duration of these commonly used local anesthetics in the setting of low-volume ultrasound-guided interscalene block (US-ISB). This study was designed to determine which local anesthetic and concentration provides superior analgesia (duration and quality) for low-volume US-ISB.

Methods: Sixty eligible patients scheduled for arthroscopic shoulder surgery were randomized (1:1:1) to receive US-ISB (5 mL) with 0.5% bupivacaine with 1:200,000 epinephrine, 0.5% ropivacaine, or 1% ropivacaine. All individuals were blinded including study participants, anesthesiologists, surgeons, research personnel, and statistician. All participants received a standardized general anesthetic and multimodal analgesia. The primary outcome was duration of analgesia defined as the time from the end of injection to the time that the patients reported a significant increase in pain (>3 numeric rating scale [NRS]) at the surgical site.

Results: The mean duration of analgesia for 0.5% bupivacaine with 1:200,000 epinephrine, 0.5% ropivacaine, or 1% ropivacaine was 14.1 ± 7.4, 13.8 ± 4.5, and 15.8 ± 6.3 hours, respectively (analysis of variance [ANOVA], P = .51). There were no observed differences in analgesic duration or other secondary outcomes between the 3 groups with the exception of a difference in cumulative opioid consumption up to 20h00 on the day of surgery in favor of ropivacaine 0.5% over bupivacaine of minimal clinical significance.

Conclusions: In the context of single-injection low-volume US-ISB, we have demonstrated a similar efficacy between equal concentrations of ropivacaine and bupivacaine. In addition, increasing the concentration of ropivacaine from 0.5% to 1% did not prolong the duration of US-ISB.
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http://dx.doi.org/10.1213/ANE.0000000000005373DOI Listing
January 2021

Depression and Increased Risk of Alzheimer's Dementia: Longitudinal Analyses of Modifiable Risk and Sex-Related Factors.

Am J Geriatr Psychiatry 2021 Jan 6. Epub 2021 Jan 6.

Neuropsychopharmacology Research Group (DK, RW, KLL, NH, DG), Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Psychiatry (KLL, NH, DG), University of Toronto, Toronto, Ontario, Canada.

Objective: Our understanding of why older adults with depression are at increased risk of Alzheimer's disease (AD) remains incomplete. Most adults living with AD are women, and women have a near twofold lifetime risk of depression. We examined the risk of depression upon incident AD, and how sex influences this risk.

Methods: Using the National Alzheimer's Coordinating Center database, older adults (age 50+) with normal cognition, who visited memory clinics across the United States between September 2005 and December 2019, were followed until first diagnosis of AD or loss to follow up. Multivariable survival analyses were performed to determine if recent and/or remote depression were independent risk factors for AD, if this depression-related risk exists for each sex or was moderated by sex.

Results: Six hundred and fifty-two of 10,739 enrolled participants developed AD over a median follow-up of 55.3 months. Recent depression (active within the last 2 years) was independently associated with increased risk of AD (hazard ratio [HR] = 2.0; 95%CI, 1.5-2.6) while a remote history of depression was not (HR = 1.0; 95%CI, 0.7-1.5). After stratification by sex, recent depression was an independent predictor in females (HR = 2.3; 95%CI, 1.7-3.1) but not in males (HR = 1.4; 95%CI, 0.8-2.6). No interaction between recent depression and sex was observed.

Conclusion: Only a recent history of depression was associated with higher risk of AD. This association was significant among women only, but was not moderated by sex. Future analyses should determine if these findings extend to other populations and may be explained by variable distribution of neurobiological or other modifiable risk factors between the sexes.
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http://dx.doi.org/10.1016/j.jagp.2020.12.031DOI Listing
January 2021

Machine Learning Frameworks to Predict Neoadjuvant Chemotherapy Response in Breast Cancer Using Clinical and Pathological Features.

JCO Clin Cancer Inform 2021 Jan;5:66-80

Temerty Centre for AI Research and Education in Medicine, University of Toronto, ON, Toronto, Canada.

Purpose: Neoadjuvant chemotherapy (NAC) is used to treat locally advanced breast cancer (LABC) and high-risk early breast cancer (BC). Pathological complete response (pCR) has prognostic value depending on BC subtype. Rates of pCR, however, can be variable. Predictive modeling is desirable to help identify patients early who may have suboptimal NAC response. Here, we test and compare the predictive performances of machine learning (ML) prediction models to a standard statistical model, using clinical and pathological data.

Methods: Clinical and pathological variables were collected in 431 patients, including tumor size, patient demographics, histological characteristics, molecular status, and staging information. A standard multivariable logistic regression (MLR) was developed and compared with five ML models: k-nearest neighbor classifier, random forest (RF) classifier, naive Bayes algorithm, support vector machine, and multilayer perceptron model. Model performances were measured using a receiver operating characteristic (ROC) analysis and statistically compared.

Results: MLR predictors of NAC response included: estrogen receptor (ER) status, human epidermal growth factor-2 (HER2) status, tumor size, and Nottingham grade. The strongest MLR predictors of pCR included HER2+ versus HER2- BC (odds ratio [OR], 0.13; 95% CI, 0.07 to 0.23; < .001) and Nottingham grade G3 versus G1-2 (G1-2: OR, 0.36; 95% CI, 0.20 to 0.65; < .001). The area under the curve (AUC) for the MLR was AUC = 0.64. Among the various ML models, an RF classifier performed best, with an AUC = 0.88, sensitivity of 70.7%, and specificity of 84.6%, and included the following variables: menopausal status, ER status, HER2 status, Nottingham grade, tumor size, nodal status, and presence of inflammatory BC.

Conclusion: Modeling performances varied between standard versus ML classification methods. RF ML classifiers demonstrated the best predictive performance among all models.
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http://dx.doi.org/10.1200/CCI.20.00078DOI Listing
January 2021

The Incidence of Brain Metastases Among Patients with Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

Neuro Oncol 2020 Dec 23. Epub 2020 Dec 23.

Sunnybrook Research Institute, Sunnybrook Health Sciences Centre.

Background: Patients with metastatic breast cancer (MBC) are living longer, but development of brain metastases often limits their survival. We conducted a systematic review and meta-analysis to determine the incidence of brain metastases in this patient population.

Methods: Articles published from January 2000 to January 2020 were compiled from four databases using search terms related to: breast cancer, brain metastasis, and incidence. The overall and per patient-year incidence of brain metastases were extracted from studies including patients with HER2+, triple negative, and hormone receptor (HR)+/HER2- MBC; pooled overall estimates for incidence were calculated using random effects models.

Results: 937 articles were compiled, and 25 were included in the meta-analysis. Incidence of brain metastases in patients with HER2+ MBC, triple negative MBC, and HR+/HER2- MBC was reported in 17, 6, and 4 studies, respectively. The pooled cumulative incidence of brain metastases was 31% for the HER2+ subgroup (median follow-up: 30.7 months, IQR: 24.0 - 34.0), 32% for the triple negative subgroup (median follow-up: 32.8 months, IQR: 18.5 - 40.6), and 15% among patients with HR+/HER2- MBC (median follow-up: 33.0 months, IQR: 31.9 - 36.2). The corresponding incidences per patient-year were 0.13 (95% CI: 0.10 - 0.16) for the HER2+ subgroup, 0.13 (95%CI: 0.09 - 0.20) for the triple negative subgroup, and only 0.05 (95%CI: 0.03 - 0.08) for patients with HR+/HER2- MBC.

Conclusion: There is high incidence of brain metastases among patients with HER2+ and triple negative MBC. The utility of a brain metastases screening program warrants investigation in these populations.
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http://dx.doi.org/10.1093/neuonc/noaa285DOI Listing
December 2020

Gender-Based Differences in Outcomes Among Resuscitated Patients With Out-of-Hospital Cardiac Arrest.

Circulation 2021 Feb 15;143(7):641-649. Epub 2020 Dec 15.

Rescu at the Li Ka Shing Knowledge Institute, Emergency Medicine, St. Michael's Hospital, Division of Emergency Medicine, Department of Medicine, Faculty of Medicine, Institute for Health Policy and Management (L.M.), University of Toronto, Ontario, Canada.

Background: Studies examining gender-based differences in outcomes of patients experiencing out-of-hospital cardiac arrest have demonstrated that, despite a higher likelihood of return of spontaneous circulation, women do not have higher survival.

Methods: Patients successfully resuscitated from out-of-hospital cardiac arrest enrolled in the CCC trial (Trial of Continuous or Interrupted Chest Compressions during CPR) were included. Hierarchical multivariable logistic regression models were constructed to evaluate the association between gender and survival after adjustment for age, gender, cardiac arrest rhythm, witnessed status, bystander cardiopulmonary resuscitation, episode location, epinephrine dose, emergency medical services response time, and duration of resuscitation. Do not resuscitate (DNR) and withdrawal of life-sustaining therapy (WLST) order status were used to assess whether differences in postresuscitation outcomes were modified by baseline prognosis. The analysis was replicated among ALPS trial (Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest) participants.

Results: Among 4875 successfully resuscitated patients, 1825 (37.4%) were women and 3050 (62.6%) were men. Women were older (67.5 versus 65.3 years), received less bystander cardiopulmonary resuscitation (49.1% versus 54.9%), and had a lower proportion of cardiac arrests that were witnessed (55.1% versus 64.5%) or had shockable rhythm (24.3% versus 44.6%, <0.001 for all). A significantly higher proportion of women received DNR orders (35.7% versus 32.1%, =0.009) and had WLST (32.8% versus 29.8%, =0.03). Discharge survival was significantly lower in women (22.5% versus 36.3%, <0.001; adjusted odds ratio, 0.78 [95% CI, 0.66-0.93]; =0.005). The association between gender and survival to discharge was modified by DNR and WLST order status such that women had significantly reduced survival to discharge among patients who were not designated DNR (31.3% versus 49.9%, =0.005; adjusted odds ratio, 0.74 [95% CI, 0.60-0.91]) or did not have WLST (32.3% versus 50.7%, =0.002; adjusted odds ratio, 0.73 [95% CI, 0.60-0.89]). In contrast, no gender difference in survival was noted among patients receiving a DNR order (6.7% versus 7.4%, =0.90) or had WLST (2.8% versus 2.4%, =0.93). Consistent patterns of association between gender and postresuscitation outcomes were observed in the secondary cohort.

Conclusions: Among patients resuscitated after experiencing out-of-hospital cardiac arrest, discharge survival was significantly lower in women than in men, especially among patients considered to have a favorable prognosis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050427DOI Listing
February 2021

Gender-Based Differences in Outcomes Among Resuscitated Patients With Out-of-Hospital Cardiac Arrest.

Circulation 2021 Feb 15;143(7):641-649. Epub 2020 Dec 15.

Rescu at the Li Ka Shing Knowledge Institute, Emergency Medicine, St. Michael's Hospital, Division of Emergency Medicine, Department of Medicine, Faculty of Medicine, Institute for Health Policy and Management (L.M.), University of Toronto, Ontario, Canada.

Background: Studies examining gender-based differences in outcomes of patients experiencing out-of-hospital cardiac arrest have demonstrated that, despite a higher likelihood of return of spontaneous circulation, women do not have higher survival.

Methods: Patients successfully resuscitated from out-of-hospital cardiac arrest enrolled in the CCC trial (Trial of Continuous or Interrupted Chest Compressions during CPR) were included. Hierarchical multivariable logistic regression models were constructed to evaluate the association between gender and survival after adjustment for age, gender, cardiac arrest rhythm, witnessed status, bystander cardiopulmonary resuscitation, episode location, epinephrine dose, emergency medical services response time, and duration of resuscitation. Do not resuscitate (DNR) and withdrawal of life-sustaining therapy (WLST) order status were used to assess whether differences in postresuscitation outcomes were modified by baseline prognosis. The analysis was replicated among ALPS trial (Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest) participants.

Results: Among 4875 successfully resuscitated patients, 1825 (37.4%) were women and 3050 (62.6%) were men. Women were older (67.5 versus 65.3 years), received less bystander cardiopulmonary resuscitation (49.1% versus 54.9%), and had a lower proportion of cardiac arrests that were witnessed (55.1% versus 64.5%) or had shockable rhythm (24.3% versus 44.6%, <0.001 for all). A significantly higher proportion of women received DNR orders (35.7% versus 32.1%, =0.009) and had WLST (32.8% versus 29.8%, =0.03). Discharge survival was significantly lower in women (22.5% versus 36.3%, <0.001; adjusted odds ratio, 0.78 [95% CI, 0.66-0.93]; =0.005). The association between gender and survival to discharge was modified by DNR and WLST order status such that women had significantly reduced survival to discharge among patients who were not designated DNR (31.3% versus 49.9%, =0.005; adjusted odds ratio, 0.74 [95% CI, 0.60-0.91]) or did not have WLST (32.3% versus 50.7%, =0.002; adjusted odds ratio, 0.73 [95% CI, 0.60-0.89]). In contrast, no gender difference in survival was noted among patients receiving a DNR order (6.7% versus 7.4%, =0.90) or had WLST (2.8% versus 2.4%, =0.93). Consistent patterns of association between gender and postresuscitation outcomes were observed in the secondary cohort.

Conclusions: Among patients resuscitated after experiencing out-of-hospital cardiac arrest, discharge survival was significantly lower in women than in men, especially among patients considered to have a favorable prognosis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050427DOI Listing
February 2021

Differences in demographics and outcomes based on method of consent for a randomised controlled trial on heat loss prevention in the delivery room.

Arch Dis Child Fetal Neonatal Ed 2021 Mar 24;106(2):118-124. Epub 2020 Nov 24.

Women and Babies Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Objective: Informed consent is standard in research. International guidelines allow for research without prior consent in emergent situations, such as neonatal resuscitation. Research without prior consent was incorporated in the Vermont Oxford Network Heat Loss Prevention Trial. We evaluated whether significant differences in outcomes exist based on the consent method.

Design: Subgroup analysis of infants enrolled in a randomised controlled trial conducted from 2004 to 2010.

Setting: A multicentre trial with 38 participating centres.

Participants: Infants born 24-27 weeks of gestation. 3048 infants assessed, 2231 excluded due to fetal congenital anomalies, failure to obtain consent or gestation less than 24 weeks. 817 randomised, 4 withdrew consent, total of 813 analysed.

Main Outcome Measure: The difference in mortality between consent groups.

Results: No significant differences were found in mortality at 36 weeks (80.2%, 77.4%, p=0.492) or 6 months corrected gestational age (80.7%, 79.7%, p=0.765). Infants enrolled after informed consent were more likely to have mothers who had received antenatal steroids (95.2%, 84.0%, p<0.0001). They also had significantly higher Apgar scores at 1 (5.0, 4.4, p=0.019), 5 (7.3, 6.7, p=0.025) and 10 min (7.5, 6.3, p=0.0003).

Conclusions And Relevance: Research without prior consent resulted in the inclusion of infants with different baseline characteristics than those enrolled after informed consent. There were no significant differences in mortality. Significantly higher Apgar scores in the informed consent group suggest that some of the sicker infants would have been excluded from enrolment under informed consent. Research without prior consent should be considered in neonatal resuscitation research.
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http://dx.doi.org/10.1136/archdischild-2020-319045DOI Listing
March 2021

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

J Affect Disord 2021 Feb 5;280(Pt A):140-147. Epub 2020 Nov 5.

Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jad.2020.11.004DOI Listing
February 2021

Prescribing patterns of opioids and adjunctive analgesics for patients with burn injuries.

Burns 2020 Oct 4. Epub 2020 Oct 4.

Division of Plastic and Reconstructive Surgery, University of Toronto, Toronto, Ontario, Canada; Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Electronic address:

Purpose: Large quantities of analgesics are prescribed to control pain among patients with burn injuries and may lead to chronic use and dependency. This study aimed to determine whether patients are overprescribed analgesics at discharge and to identify factors that influence prescribing patterns.

Material And Methods: A retrospective review of patient charts (n = 199) between July 1, 2015-2018 were reviewed from a registry at a single burn center. Opioid, neuropathic pain agent, acetaminophen, and ibuprofen quantities given before and at discharge were compared. Linear mixed regression models were used to identify factors that increased the amount of analgesics prescribed.

Results: On average, patients were prescribed significantly more analgesics at discharge compared to what was consumed pre-discharge (p < 0.0001). Specifically, on average, providers did not overprescribe the daily dose, but overprescribed the duration of pain medications required. For every increase in percent TBSA, 14 MEQ more opioids, 203 mg more neuropathic pain agents, 843 mg more acetaminophen, and 126 mg more ibuprofen were prescribed (p < 0.05). Surgery was a predictor for higher opioid and neuropathic pain agent prescriptions (p = 0.03), while length of stay was associated with fewer neuropathic pain agents prescribed (p = 0.04). Fewer ibuprofen were given to patients with a history of substance misuse (p = 0.01).

Conclusions: The quantity of analgesics prescribed at discharge varied widely and often prescribed for long durations of time. Standardized prescribing guidelines should be developed to optimize how analgesics are prescribed at discharge.
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http://dx.doi.org/10.1016/j.burns.2020.09.009DOI Listing
October 2020

Associations between Diet Quality and Body Composition in Young Children Born with Very Low Body Weight.

J Nutr 2020 11;150(11):2961-2968

Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.

Background: Very low birth weight (VLBW; <1500 g) infants have increased adiposity and metabolic disease risk in adulthood. Limited evidence suggests low-quality childhood diets are a predisposing risk factor. Despite this, to our knowledge no study has yet examined associations between diet quality and body composition in VLBW individuals.

Objective: The objective of this study was to determine associations between Healthy Eating Index-2010 (HEI-2010) scores and consumption of fruits/vegetables, added sugars, and macronutrients with body composition in 5.5-y-old children born VLBW. We hypothesized HEI-2010 scores were inversely associated with adiposity.

Methods: This cohort study leveraged the 5.5-y follow-up to the Donor Milk for Improved Neurodevelopmental Outcomes randomized controlled trial. From June 2016 to July 2018, participants attended a follow-up visit at The Hospital for Sick Children, Canada, or were visited in their home. All 316 surviving infants from the trial were eligible, and the caregivers of 158 children (50%; 53% male) consented to follow-up. Diet quality (HEI-2010) and usual intake of fruits/vegetables, added sugars, and macronutrients were determined from two 24-h dietary recalls (ASA24). Linear regressions evaluated associations of diet with BMI (kg/m2) and waist circumference z-scores, total fat, fat-free mass (air displacement plethysmography), and skinfolds.

Results: Mean ± SD age at follow-up was 5.7 ± 0.2 y, birth weight was 1013 ± 264 g, and gestational age was 27.9 ± 2.5 wk. Dietary data and BMI z-scores were available for all children; 123 completed air displacement plethysmography. HEI-2010 score was 58.2 ± 12.4 out of 100, and 27% of children had poor quality diets (scores ≤50). HEI-2010 scores were inversely associated with BMI z-score, but only in children with obese mothers. A 10-point increase in HEI-2010 score was associated with reduced BMI (β: -0.5 SD; 95% CI: -0.7, -0.2) and subscapular (-0.3 SD; 95% CI: -0.6, -0.06) z-scores.

Conclusions: Improving diet quality in children born VLBW with obese mothers may be an important strategy to prevent excess adiposity. This trial was registered at clinicaltrials.gov as Optimizing Mothers' Milk for Preterm Infants (OptiMoM) Program of Research: Study 1-Impact of Donor Milk at Kindergarten, NCT02759809.
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http://dx.doi.org/10.1093/jn/nxaa281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675023PMC
November 2020

HIIT the Road Jack: An Exploratory Study on the Effects of an Acute Bout of Cardiovascular High-Intensity Interval Training on Piano Learning.

Front Psychol 2020 10;11:2154. Epub 2020 Sep 10.

Rehabilitation Sciences Institute, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Pairing high-intensity interval training (HIIT) with motor skill acquisition may improve learning of some implicit motor sequences (albeit with some variability), but it is unclear if HIIT enhances learning of motor sequences. We asked whether a single bout of HIIT after non-musicians learned to play a piano melody promoted better retention of the melody than low-intensity interval training (LIIT). Further, we investigated whether HIIT facilitated transfer of learning to a new melody. We generated individualized exercise protocols by having participants ( = 25) with little musical training undergo a graded maximal exercise test (GXT) to determine their cardiorespiratory fitness (VO) and maximum power output (W). In a subsequent session, participants practiced a piano melody (skill acquisition) and were randomly assigned to a single bout of HIIT or LIIT. Retention of the piano melody was tested 1 hour, 1 day, and 1 week after skill acquisition. We also evaluated transfer to learning a new melody 1 week after acquisition. Pitch and rhythm accuracy were analyzed with linear mixed-effects modeling. HIIT did not enhance sequence-specific retention of pitch or rhythmic elements of the piano melody, but there was modest evidence that HIIT facilitated transfer to learning a new melody. We tentatively conclude that HIIT enhances explicit, task-general motor consolidation.
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http://dx.doi.org/10.3389/fpsyg.2020.02154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511539PMC
September 2020

Association between hospital outbreaks and hand hygiene: Insights from electronic monitoring.

Clin Infect Dis 2020 Sep 16. Epub 2020 Sep 16.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Hand hygiene (HH) is an important patient safety measure linked to prevention of healthcare-associated infection yet how outbreaks affect HH performance has not been formally evaluated.

Methods: A controlled interrupted time series was performed across five acute-care academic hospitals using group electronic monitoring. This system captures 100% of all hand sanitizer and soap dispenser activations via a wireless signal to a wireless hub divided by a previously validated estimate of the number of daily HH opportunities per patient bed multiplied by the hourly census of patients on the unit. Daily HH adherence 60 days prior and 90 days following outbreak on inpatient units was compared to control units not in outbreak over the same period, using a Poisson regression model adjusting for correlation within hospitals and units. Predictors of HH improvement were assessed in this multivariate model.

Results: In the 60 days prior to outbreak, units destined for outbreak had significantly lower HH adherence compared to control units (IRR of 0.91 (95% CI 0.90-0.93; p <0.0001). Following outbreak, the HH adherence among outbreak units increased above controls (IRR 1.04, 95% CI = 1.02-1.06; p <0.0001). Greater improvements were noted for outbreaks on surgical units, involving antibiotic-resistant organisms and enteric outbreaks, as well as those where healthcare workers became ill.

Conclusions: Hospital outbreaks tend to occur on units with lower HH adherence and are associated with rapid improvements in HH performance. Group electronic monitoring of HH could be used to develop novel prospective feedback interventions designed to avert hospital outbreaks.
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http://dx.doi.org/10.1093/cid/ciaa1405DOI Listing
September 2020

Mothers of Preterm Infants Have Individualized Breast Milk Microbiota that Changes Temporally Based on Maternal Characteristics.

Cell Host Microbe 2020 11 3;28(5):669-682.e4. Epub 2020 Sep 3.

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Translational Medicine Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Rogers Hixon Ontario Human Milk Bank and the Department of Pediatrics, Sinai Health, Toronto, ON M5G 1X5, Canada. Electronic address:

Mother's milk contains complex microbial communities thought to be important for colonizing a preterm infant's gastrointestinal tract. However, little is known about the microbiota in the preterm mother's milk and factors influencing its composition. We characterized the temporal dynamics of microbial communities in 490 breast milk samples from 86 mothers of preterm infants (born <1,250g) over the first 8 weeks postpartum. Highly individualized microbial communities were identified in each mother's milk that changed temporally with notable alterations in predicted microbial functions. However, pre-pregnancy BMI, delivery mode, and antibiotics were associated with changes in these microbial dynamics. Individual classes of antibiotics and their duration of exposure during prenatal and postpartum periods showed unique relationships with microbial taxa abundance and diversity in mother's milk. These results highlight the temporal complexity of the preterm mother's milk microbiota and its relationship with maternal characteristics as well as the importance of discussing antibiotic stewardship for mothers.
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http://dx.doi.org/10.1016/j.chom.2020.08.001DOI Listing
November 2020

Maternal Diet and Infant Feeding Practices Are Associated with Variation in the Human Milk Microbiota at 3 Months Postpartum in a Cohort of Women with High Rates of Gestational Glucose Intolerance.

J Nutr 2021 Feb;151(2):320-329

Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.

Background: Human milk contains a diverse community of bacteria believed to play a role in breast health and inoculation of the infant's gastrointestinal tract. The role of maternal nutrition and infant feeding practices on the human milk microbiota remains poorly understood.

Objective: Our aim was to explore the associations between maternal diet (delivery to 3 mo postpartum), infant feeding practices, and the microbial composition and predicted function in milk from women with varied metabolic status.

Methods: This was an exploratory analysis of a previously completed prospective cohort study of women with varying degrees of gestational glucose intolerance (NCT01405547). Milk samples (n = 93 mothers) were collected at 3 mo postpartum. Maternal dietary information (validated food-frequency questionnaire) and infant feeding practices (human milk exclusivity, frequency of direct breastfeeding per day) were collected. V4-16S ribosomal RNA gene sequencing (Illumina MiSeq) was conducted to determine microbiota composition.

Results: Intake of polyunsaturated fat [β estimate (SE): 0.036 (0.018), P = 0.047] and fiber from grains [0.027 (0.013), P = 0.048] were positively associated with ɑ-diversity (Shannon index) of human milk. Overall microbial composition of human milk clustered based on human milk exclusivity (weighted UniFrac R2 = 0.034, P = 0.015; Bray-Curtis R2 = 0.041, P = 0.007), frequency of direct breastfeeding per day (Bray-Curtis R2 = 0.057, P = 0.026), and maternal fiber intake from grains (Bray-Curtis R2 = 0.055, P = 0.040). Total fiber, fiber from grains, dietary fat, and infant feeding practices were also associated with a number of differentially abundant taxa. The overall composition of predicted microbial functions was associated with total fiber consumption (Bray-Curtis R2 = 0.067, P = 0.036) and human milk exclusivity (Bray-Curtis R2 = 0.041, P = 0.013).

Conclusions: Maternal consumption of fiber and fat, as well as mother's infant feeding practices, are important determinants of the human milk microbiota. Understanding whether these microbial changes impact an infant's overall health and development requires future study.
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http://dx.doi.org/10.1093/jn/nxaa248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850034PMC
February 2021

Examining the relationship between maternal body size, gestational glucose tolerance status, mode of delivery and ethnicity on human milk microbiota at three months post-partum.

BMC Microbiol 2020 07 20;20(1):219. Epub 2020 Jul 20.

Department of Nutritional Sciences, University of Toronto, Medical Sciences Building, 1 King College Circle, Toronto, ON, M5S 1A8, Canada.

Background: Few studies have examined how maternal body mass index (BMI), mode of delivery and ethnicity affect the microbial composition of human milk and none have examined associations with maternal metabolic status. Given the high prevalence of maternal adiposity and impaired glucose metabolism, we systematically investigated the associations between these maternal factors in women ≥20 years and milk microbial composition and predicted functionality by V4-16S ribosomal RNA gene sequencing (NCT01405547;  https://clinicaltrials.gov/ct2/show/NCT01405547 ). Demographic data, weight, height, and a 3-h oral glucose tolerance test were gathered at 30 (95% CI: 25-33) weeks gestation, and milk samples were collected at 3 months post-partum (n = 113).

Results: Multivariable linear regression analyses demonstrated no significant associations between maternal characteristics (maternal BMI [pre-pregnancy, 3 months post-partum], glucose tolerance, mode of delivery and ethnicity) and milk microbiota alpha-diversity; however, pre-pregnancy BMI was associated with human milk microbiota beta-diversity (Bray-Curtis R = 0.037). Women with a pre-pregnancy BMI > 30 kg/m (obese) had a greater incidence of Bacteroidetes (incidence rate ratio [IRR]: 3.70 [95% CI: 1.61-8.48]) and a reduced incidence of Proteobacteria (0.62 [0.43-0.90]) in their milk, compared to women with an overweight BMI (25.0-29.9 kg/m) as assessed by multivariable Poisson regression. An increased incidence of Gemella was observed among mothers with gestational diabetes who had an overweight BMI versus healthy range BMI (5.96 [1.85-19.21]). An increased incidence of Gemella was also observed among mothers with impaired glucose tolerance with an obese BMI versus mothers with a healthy range BMI (4.04 [1.63-10.01]). An increased incidence of Brevundimonas (16.70 [5.99-46.57]) was found in the milk of women who underwent an unscheduled C-section versus vaginal delivery. Lastly, functional gene inference demonstrated that pre-pregnancy obesity was associated with an increased abundance of genes encoding for the biosynthesis of secondary metabolites pathway in milk (coefficient = 0.0024, P < 0.1).

Conclusions: Human milk has a diverse microbiota of which its diversity and differential abundance appear associated with maternal BMI, glucose tolerance status, mode of delivery, and ethnicity. Further research is warranted to determine whether this variability in the milk microbiota impacts colonization of the infant gut.
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http://dx.doi.org/10.1186/s12866-020-01901-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372813PMC
July 2020

Reply to A Lucas and SA Abrams.

Am J Clin Nutr 2020 06;111(6):1302-1303

Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1093/ajcn/nqaa094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266681PMC
June 2020

Intensive control of hypertension and risk of Alzheimer's dementia in older adults with depression.

Int J Geriatr Psychiatry 2020 08 21;35(8):888-896. Epub 2020 Apr 21.

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Objectives: Intensive control of hypertension has been reported to decrease risk of cognitive decline. However, the effect of this in older adults with hypertension and comorbid depression is not well understood. We aim to identify whether intensive control of systolic blood pressure (BP) is associated with reduced risk of Alzheimer's dementia (AD) in a clinical population.

Methods: Using data from the National Alzheimer's Coordinating Center, we conducted survival analyses in older adults with normal cognition at baseline and treated hypertension. We also examined those with comorbid depression, to determine if intensive control of systolic BP (≤120 mmHg) was associated with reduced risk of AD.

Results: In all older adults with treated hypertension (n = 4505), 298 (6.6%) developed AD during a median follow-up duration of 4.2 years. In the comorbid depression subgroup (n = 1327), 152 (11.5%) developed AD. Intensive control of systolic BP was not significantly associated with reduced risk of AD in the overall sample (HR 1.13, 95%, 0.79-1.64). However, in the comorbid depression subgroup, intensive control of systolic BP (≤120 mmHg) was associated with increased risk of AD (HR 1.49, 95%, 1.03-2.15) compared to standard control (121-139 mmHg).

Conclusions: In a clinical population of older adults with hypertension and comorbid depression, we found that an intensive systolic BP target of ≤120 mmHg was associated with increased risk of AD. While these findings are preliminary, they suggest that a more cautious approach to hypertension treatment may be warranted in this vulnerable subgroup.
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http://dx.doi.org/10.1002/gps.5309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375011PMC
August 2020

Nutrient Enrichment of Human Milk with Human and Bovine Milk-Based Fortifiers for Infants Born <1250 g: 18-Month Neurodevelopment Follow-Up of a Randomized Clinical Trial.

Curr Dev Nutr 2019 Dec 12;3(12):nzz129. Epub 2019 Nov 12.

Department of Nutritional Sciences, University of Toronto, Toronto, Canada.

Background: Bovine milk-based fortifiers (BMBF) have been standard of care for nutrient fortification of feeds for very low birth weight (VLBW) infants, however, there is increasing use of human milk-based fortifiers (HMBF) in neonatal care despite additional costs and limited supporting data. No randomized clinical trial has followed infants fed these fortifiers after initial hospitalization.

Objective: To compare neurodevelopment in infants born weighing <1250 g fed maternal milk with supplemental donor milk and either a HMBF or BMBF.

Methods: This is a follow-up of a completed pragmatic, triple-blind, parallel group randomized clinical trial conducted in Southern Ontario between August 2014 and March 2016 (NCT02137473) with feeding tolerance as the primary outcome. Infants weighing <1250 g at birth were block randomized by an online third-party service to receive either HMBF ( = 64) or BMBF ( = 63) added to maternal milk with supplemental donor milk during hospitalization. Neurodevelopment was assessed at 18-mo corrected age using the , Third Edition. Follow-up was completed in October 2017.

Results: Of the 127 infants randomized, 109 returned for neurodevelopmental assessment. No statistically significant differences between fortifiers were identified for cognitive composite scores [adjusted mean scores 94.7 in the HMBF group and 95.9 in the BMBF group; fully adjusted mean difference, -1.1 (95% CI: -6.5 to 4.4)], language composite scores [adjusted scores 92.4 in the HMBF group and 93.1 in the BMBF; fully adjusted mean difference, -1.2 (-7.5 to 5.1)], or motor composite scores [adjusted scores 95.6 in the HMBF group and 97.7 in the BMBF; fully adjusted mean difference, -1.1 (-6.3 to 4.2)]. There was no difference in the proportion of participants that died or had neurodevelopmental impairment or disability between groups.

Conclusions: Providing HMBF compared with BMBF does not improve neurodevelopmental scores at 18-mo corrected age in infants born <1250 g otherwise fed a human milk diet. This trial was registered at clinicaltrials.gov as NCT02137473.
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http://dx.doi.org/10.1093/cdn/nzz129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053578PMC
December 2019

Nutrient Enrichment of Human Milk with Human and Bovine Milk-Based Fortifiers for Infants Born <1250 g: 18-Month Neurodevelopment Follow-Up of a Randomized Clinical Trial.

Curr Dev Nutr 2019 Dec 12;3(12):nzz129. Epub 2019 Nov 12.

Department of Nutritional Sciences, University of Toronto, Toronto, Canada.

Background: Bovine milk-based fortifiers (BMBF) have been standard of care for nutrient fortification of feeds for very low birth weight (VLBW) infants, however, there is increasing use of human milk-based fortifiers (HMBF) in neonatal care despite additional costs and limited supporting data. No randomized clinical trial has followed infants fed these fortifiers after initial hospitalization.

Objective: To compare neurodevelopment in infants born weighing <1250 g fed maternal milk with supplemental donor milk and either a HMBF or BMBF.

Methods: This is a follow-up of a completed pragmatic, triple-blind, parallel group randomized clinical trial conducted in Southern Ontario between August 2014 and March 2016 (NCT02137473) with feeding tolerance as the primary outcome. Infants weighing <1250 g at birth were block randomized by an online third-party service to receive either HMBF ( = 64) or BMBF ( = 63) added to maternal milk with supplemental donor milk during hospitalization. Neurodevelopment was assessed at 18-mo corrected age using the , Third Edition. Follow-up was completed in October 2017.

Results: Of the 127 infants randomized, 109 returned for neurodevelopmental assessment. No statistically significant differences between fortifiers were identified for cognitive composite scores [adjusted mean scores 94.7 in the HMBF group and 95.9 in the BMBF group; fully adjusted mean difference, -1.1 (95% CI: -6.5 to 4.4)], language composite scores [adjusted scores 92.4 in the HMBF group and 93.1 in the BMBF; fully adjusted mean difference, -1.2 (-7.5 to 5.1)], or motor composite scores [adjusted scores 95.6 in the HMBF group and 97.7 in the BMBF; fully adjusted mean difference, -1.1 (-6.3 to 4.2)]. There was no difference in the proportion of participants that died or had neurodevelopmental impairment or disability between groups.

Conclusions: Providing HMBF compared with BMBF does not improve neurodevelopmental scores at 18-mo corrected age in infants born <1250 g otherwise fed a human milk diet. This trial was registered at clinicaltrials.gov as NCT02137473.
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http://dx.doi.org/10.1093/cdn/nzz129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053578PMC
December 2019

Telephone-based nurse-delivered interpersonal psychotherapy for postpartum depression: nationwide randomised controlled trial.

Br J Psychiatry 2020 04;216(4):189-196

Associate Professor of Psychiatry, Department of Psychiatry, Faculty of Medicine, University of Toronto, Canada; and Morgan Firestone Psychotherapy Chair, Department of Psychiatry, Sinai Health System, Mount Sinai Hospital, Toronto, Canada.

Background: Postpartum depression and anxiety are under-addressed public health problems with numerous treatment access barriers, including insufficiently available mental health specialist providers.

Aims: To examine the effectiveness of nurse-delivered telephone interpersonal psychotherapy (IPT) for postpartum depression. Trial registration ISRCTN88987377.

Method: Postpartum women (n = 241) with major depression (on the Structured Clinical Interview for DSM-IV (SCID-I)) from 36 Canadian public health regions in rural and urban settings were randomly assigned to 12 weekly 60 min nurse-delivered telephone-IPT sessions or standard locally available care. The primary outcome was the proportion of women clinically depressed at 12 weeks post-randomisation, with masked intention-to-treat analysis. Secondary outcomes examined included comorbid anxiety, self-reported attachment and partner relationship quality.

Results: At 12 weeks, 10.6% of women in the IPT group (11/104) and 35% in the control group (35/100) remained depressed (OR = 0.22, 95% CI 0.10-0.46), with the IPT group 4.5 times less likely to be clinically depressed (SCID); 21.2% in the IPT group and 51% in the control group had an Edinburgh Postnatal Depression Scale (EPDS) score >12 (OR = 0.26, 95% CI 0.14-0.48), and attachment avoidance decreased more in the IPT group than in the control group (P = 0.02). Significant differences favoured the IPT group for comorbid anxiety and partner relationship quality at all time points, with no differences in health service or antidepressant use. None of the IPT responders relapsed by 36 weeks. Between-group SCID differences were sustained at 24 weeks, but not at 36 weeks.

Conclusions: Nurse-delivered telephone IPT is an effective treatment for diverse urban and rural women with postpartum depression and anxiety that can improve treatment access disparities.
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http://dx.doi.org/10.1192/bjp.2019.275DOI Listing
April 2020

Retrospective multicentre matched cohort study comparing safety and efficacy outcomes of intermittent-infusion versus continuous-infusion vancomycin.

J Antimicrob Chemother 2020 04;75(4):1038-1046

Division of Infectious Diseases, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Background: Patients with good renal function receiving intermittent-infusion vancomycin (IIV) may require total daily doses ≥4 g to achieve trough concentrations of 15-20 mg/L, increasing the risk of vancomycin-associated nephrotoxicity. Continuous-infusion vancomycin (CIV) may be associated with a lower risk of vancomycin-associated nephrotoxicity compared with IIV, but studies comparing safety of both dosing strategies are lacking.

Objectives: To compare the risk of nephrotoxicity with CIV versus IIV when target concentration ranges were the same with both dosing modalities.

Methods: A retrospective multicentre matched cohort study of admitted patients between 1 January 2010 and 31 December 2016 was completed. Adult patients who received ≥48 h of vancomycin with at least one steady-state vancomycin concentration were eligible. The primary outcome was to compare the rates of nephrotoxic risk and renal injury, defined by the RIFLE criteria, between CIV and IIV.

Results: Of 2136 patients who received vancomycin during the study period, 146 CIV patients were eligible and matched to 146 IIV patients. After adjustment of potential confounders, CIV was found to have a lower odds of developing nephrotoxic risk (OR 0.42, 95% CI 0.21-0.98, P = 0.025) and renal injury (OR 0.19, 95% CI 0.05-0.59, P = 0.004).

Conclusions: CIV is associated with a lower odds of nephrotoxicity compared with IIV when targeting the same concentration range and should be an alternative dosing strategy for patients who will receive prolonged therapy or require >4 g/day to achieve therapeutic levels.
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http://dx.doi.org/10.1093/jac/dkz531DOI Listing
April 2020

Lithium for Fracture Treatment (LiFT): a double-blind randomised control trial protocol.

BMJ Open 2020 01 7;10(1):e031545. Epub 2020 Jan 7.

Orthopaedic Biomechanics Lab, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Introduction: Fracture healing can fail in up to 10% of cases despite appropriate treatment. While lithium has been the standard treatment for bipolar disorder, it may also have a significant impact to increase bone healing in patients with long bone fractures. To translate this knowledge into clinical practice, a randomised clinical trial (RCT) is proposed.

Methods And Analysis: A multicentre double blind, placebo-controlled RCT is proposed to evaluate the efficacy of lithium to increase the rate and predictability of long bone fracture healing in healthy adults compared to lactose placebo treatment. 160 healthy individuals from 18 to 55 years of age presenting with shaft fractures of the femur, tibia/fibula, humerus or clavicle will be eligible. Fractures will be randomised to placebo (lactose) or treatment (300 mg lithium carbonate) group within 2 weeks of the injury. The primary outcome measure will be radiographic union defined as visible callus bridging on three of the four cortices at the fracture site using a validated radiographic union score. Secondary outcome measures will include functional assessment and pain scoring.

Ethics And Dissemination: Participant confidentiality will be maintained with publication of results. Research Ethics Board Approval: Sunnybrook Research Institute (REB # 356-2016). Health Canada Approval (HC6-24-C201560). Results of the main trial and secondary endpoints will be submitted for publication in a peer-reviewed journal and presented at conferences.

Trial Registration Number: NCT02999022.
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http://dx.doi.org/10.1136/bmjopen-2019-031545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955565PMC
January 2020

A Pilot Study Comparing Effects of Bifrontal Versus Bitemporal Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Mild Alzheimer Disease.

J ECT 2020 Sep;36(3):211-215

Neuropsychopharmacology Research Group, Hurvitz Brain Sciences Program, Sunnybrook Research Institute.

Objective: While transcranial direct current stimulation (tDCS) can enhance aspects of memory in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD), there has been wide variability in both the placement of tDCS electrodes and treatment response. This study compared the effects of bifrontal (anodal stimulation over the dorsolateral prefrontal cortices), bitemporal (anodal stimulation over the temporal cortices), and sham tDCS on cognitive performance in MCI and AD.

Methods: Seventeen patients diagnosed with MCI or mild AD received 3 sessions of anodal tDCS (bifrontal, bitemporal, 2 mA for 20 minutes; and sham) in random order. Sessions were separated by 1 week. The Alzheimer's Disease Assessment Scale-Cognitive Word Recognition Task, Alzheimer's Disease Assessment Scale-Cognitive Word Recall Task, 2-back, and Montreal Cognitive Assessment were used to assess cognition.

Results: There was a significant effect of stimulation condition on 2-back accuracy (F2,28 = 5.28 P = 0.01, ηp = 0.27), with greater improvements following bitemporal tDCS compared with both bifrontal and sham stimulations. There were no significant changes on other outcome measures following any stimulation. Adverse effects from stimulation were mild and temporary.

Conclusions: These findings demonstrate that improvements in specific memory tasks can be safely achieved after a single session of bitemporal tDCS in MCI and mild AD patients.
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http://dx.doi.org/10.1097/YCT.0000000000000639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447169PMC
September 2020

Adiposity and Fat-Free Mass of Children Born with Very Low Birth Weight Do Not Differ in Children Fed Supplemental Donor Milk Compared with Those Fed Preterm Formula.

J Nutr 2020 02;150(2):331-339

Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.

Background: Many mothers of very-low-birth-weight (VLBW) infants (<1500 g) are unable to provide sufficient breast milk, and supplemental pasteurized donor human milk (donor milk) or preterm formula is required. The composition of donor milk differs from that of mother's milk and infants fed with donor milk often exhibit slower growth during hospitalization. The long-term impact of nutrient-enriched donor milk on growth, body composition, or blood pressure is unknown.

Objective: We aimed to determine the effects of nutrient-enriched donor milk compared with preterm formula on growth, body composition, and blood pressure of children born preterm and with VLBW. Associations with in-hospital mother's milk intake were explored.

Methods: This study was a follow-up of children at 5.5-y of age who participated in a randomized controlled trial evaluating the effect of nutrient-enriched donor milk (commencing at ≥120 mL·kg-1·d-1) or preterm formula fed as a supplement when mother's milk was unavailable. The trial intervention lasted 90 d or until hospital discharge, whichever occurred first. In this follow-up investigation, differences in total body fat percentage determined by using air displacement plethysmography (primary outcome), fat-free mass, skinfold thickness, waist circumference, BMI z scores, and blood pressure] were evaluated using linear regressions.

Results: Of 316 surviving infants from the earlier trial, 158 (50%) participated in the current study (53% male). Mean ± SD birth weight and gestational age were 1013 ± 264 g and 27.9 ± 2.5 wk. The median (IQR) intervention period was 67.5 d (52.0-91.0 d). Mean ± SD age and BMI z score at follow-up were 5.7 ± 0.2 y and -0.3 ± 1.2. Supplemental nutrient-enriched donor milk, compared to preterm formula, was not associated with growth, body composition, or blood pressure. In-hospital mother's milk intake was positively associated with height z score at 5.5 y (β: 0.07; 95% CI: 0.004, 0.1; P = 0.04).

Conclusions: Supplemental nutrient-enriched donor milk and preterm formula during initial hospitalization results in comparable long-term growth and body composition in young children born VLBW. This trial was registered at clinicaltrials.gov as NCT02759809 and at isrctn.com as ISRCTN35317141.
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http://dx.doi.org/10.1093/jn/nxz234DOI Listing
February 2020

Comparison of the effects of perineural or intravenous dexamethasone on low volume interscalene brachial plexus block: a randomised equivalence trial.

Br J Anaesth 2020 01 5;124(1):84-91. Epub 2019 Oct 5.

Department of Anesthesia, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Efforts to prolong interscalene block (ISB) analgesia include the use of local anaesthetic adjuvants such as dexamethasone. Previous work showing prolonged block duration suggests that both perineural and intravenous (i.v.) routes can both prolong analgesia. The superiority of either route is controversial given the design of previous studies. As perineural dexamethasone is an off-label use, anaesthesiologists should be fully informed of the clinical differences, if any, on block duration. This study was designed to test whether perineural vs i.v. dexamethasone administration are equivalent.

Methods: We randomised 182 eligible patients scheduled for arthroscopic shoulder surgery to receive low-dose ISB (0.5% ropivacaine 5 ml) with perineural or i.v. dexamethasone 4 mg. Subjects, anaesthesiologists, and research personnel were blinded. All subjects also received a standardised general anaesthetic and multimodal analgesia. The primary outcome was duration of analgesia analysed as an equivalence outcome (2 h equivalency margin) using the two one-sided test (TOST) method.

Results: For the primary outcome, duration of analgesia, and perineural and i.v. administration of dexamethasone were not equivalent. The upper and lower bounds of the 90% confidence interval were 1 h (P=0.12) and -2.5 h (P=0.01), respectively. The observed difference in mean block duration was not clinically relevant (0.75 h longer for i.v. dexamethasone). There were no other clinically significant differences between groups.

Conclusion: In the context of low-volume ISB with ropivacaine, perineural and i.v. dexamethasone were not equivalent in terms of their effects on block duration. However, there were no clinically significant differences in outcomes, and there is no advantage of perineural over intravenous dexamethasone. WWW.CLINICALTRIALS.

Gov Registration: NCT02322242.
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http://dx.doi.org/10.1016/j.bja.2019.08.025DOI Listing
January 2020

Voriconazole prophylaxis in leukemic patients: A retrospective single-center study.

J Oncol Pharm Pract 2020 Jun 29;26(4):873-881. Epub 2019 Sep 29.

Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Background: Invasive fungal infections commonly occur in acute myeloid and lymphoblastic leukemia patients receiving chemotherapy. In these patients with acute leukemia, posaconazole prophylaxis is recommended; however, voriconazole may be a less costly alternative.

Objectives: The objective of this study was to evaluate the efficacy and safety of voriconazole prophylaxis in acute leukemia patients.

Methods: A retrospective chart review of inpatients at Sunnybrook Health Sciences Centre between 2005 and 2017 was completed. Hospitalized adult acute leukemia patients who received voriconazole prophylaxis (cases) were compared to patients who received fluconazole or no prophylaxis during chemotherapy (controls). Statistical analyses comparing baseline characteristics, safety, and efficacy outcomes between the study cohorts were completed. A posaconazole literature-based weighted mean risk was compared to the voriconazole risk of invasive fungal infection identified in this study.

Results: Of 490 acute myeloid leukemia or acute lymphoblastic leukemia patients, 83 controls and 92 cases were eligible. Case patients received an average of 24.4 ± 10.8 days of voriconazole prophylaxis. The incidence of proven or probable invasive fungal infections with voriconazole was 3.3% (3/92) versus 7.2% (6/83) in the control cohort (p > 0.05) and was comparable to the literature reported weighted incidence of invasive fungal infection with posaconazole (2.4 ± 2.1%; 95% CI 1.3%-3.4%; p > 0.05). Voriconazole was well tolerated by patients (91%; 84/91; seven discontinued due to asymptomatic elevated liver function tests).

Conclusions: Voriconazole prophylaxis was found to be safe, effective, and comparable to literature-based efficacy data for risk of invasive fungal infection with posaconazole antifungal prophylaxis in patients with acute leukemia undergoing chemotherapy and could represent a significant cost advantage.
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http://dx.doi.org/10.1177/1078155219876683DOI Listing
June 2020

Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation.

J Geriatr Psychiatry Neurol 2020 07 23;33(4):175-184. Epub 2019 Sep 23.

Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.

The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; = 6.41, = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; = 3.97, = .06), were associated with agitation severity, and TNF-α remained significantly associated ( = 3.69, = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.
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http://dx.doi.org/10.1177/0891988719874118DOI Listing
July 2020

Optimizing the growth of very-low-birth-weight infants requires targeting both nutritional and nonnutritional modifiable factors specific to stage of hospitalization.

Am J Clin Nutr 2019 12;110(6):1384-1394

Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.

Background: Data on how baseline characteristics, acuity, morbidity, and nutrition work in combination to affect the growth of very-low-birth-weight (VLBW, <1500 g) infants are limited.

Objective: We aimed to determine factors associated with in-hospital weight, length, and head circumference (HC) trajectories of VLBW infants.

Methods: VLBW infants (n = 316) from the GTA-DoMINO trial were included. Linear mixed-effects models assessed relations of baseline characteristics, acuity (at birth, across hospitalization), major morbidities, and nutrition (enteral feeding type, macronutrient/energy intakes) with changes in anthropometrics over hospitalization (days 1-8, 9-29, 30-75).

Results: Specific factors and the strength of their associations with growth depended on in-hospital time interval. Small-for-gestational-age infants experienced weight gain (4.3   g · kg-1 · d-1; 95% CI: 2.0, 6.5   g · kg-1 · d-1) during days 1-8, versus weight loss (-4.6     g · kg-1 · d-1; 95% CI: -5.6, -3.7     g · kg-1 · d-1) among appropriate-for-gestational-age infants (P < 0.001). Positive-pressure ventilation (versus oxygen/room air) was associated with slower weight (-1.8    g · kg-1 · d-1) and HC (-0.25 cm/wk) gain during days 9-29 (P < 0.001). Morbidities were negatively associated with growth after days 1-8, with patent ductus arteriosus (PDA) showing negative associations with weight (-2.7     g · kg-1 · d-1), length (-0.11 cm/wk), and HC (-0.21 cm/wk) gain during days 9-29 (P < 0.001). Macronutrient/energy intakes were associated with weight across hospitalization (P ≤ 0.01), with greater weight gain (1.3-3.0 g  ·  kg-1  ·  d-1) among infants achieving macronutrient/energy recommendations during days 9-29 and 30-75. Macronutrient/energy intakes were associated with HC during the first month (P = 0.013-0.003), with greater HC gain (0.07-0.12 cm/wk) among infants achieving protein, lipid, and energy recommendations during days 9-29.

Conclusions: Baseline characteristics, acuity, morbidity, and nutrition factors were independently associated with VLBW infant growth. A focus on achieving macronutrient/energy recommendations and improving nutrient delivery to PDA-diagnosed infants may yield improvements to their growth. This trial was registered at www.isrctn.com as ISRCTN35317141.
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http://dx.doi.org/10.1093/ajcn/nqz227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885476PMC
December 2019

Predictive Ability of a Serious Game to Identify Emergency Patients With Unrecognized Delirium.

J Am Geriatr Soc 2019 11 29;67(11):2370-2375. Epub 2019 Jul 29.

Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Ontario, Canada.

Objectives: Recognition of delirium in the emergency department (ED) is poor. Our objectives were to assess: (1) the diagnostic accuracy of the Predicting Emergency department Delirium with an Interactive Computer Tablet (PrEDICT) "serious game" to identify older ED patients with delirium compared to clinical recognition and (2) the feasibility of the PrEDICT application compared to existing tests of attention.

Design: Prospective observational study.

Setting: ED of a Canadian tertiary care center.

Participants: We included ED patients, aged 70 years and older, with a minimum 4-hour stay. We excluded anyone with critical illness, communication barriers, and visual impairment or those unable to use a computer tablet. None had prevalent delirium by ED clinicians' routine clinical assessment.

Measurements: Participants were asked to tap targets on a tablet at four difficulty levels. Time and accuracy were automatically recorded. Other measures included the Confusion Assessment Method, the Delirium Severity Index, the Digit Vigilance Test (DVT), and the Choice Reaction Test (CRT).

Results: We enrolled 203 patients. Their average age was 80.6 years, 49.8% were female, and their average ED length of stay was 15.9 hours. Sixteen subjects had clinically unrecognized delirium, and 14 of them completed the PrEDICT game (87.5%). We developed a threshold score with 100% sensitivity (95% confidence interval [CI] = 76.8%-100.0%) and 59.7% specificity (95% CI = 52.3%-66.6%) to identify patients with clinically unrecognized delirium. The area under the curve was 0.86 (95% CI = 0.77-0.94). Completion rates were 196/203 (96.6%) for the PrEDICT serious game compared to 128/203 (63.1%) for the CRT and 51/203 (25.1%) for the DVT.

Conclusion: Older ED patients were able to use our serious game, including 87.5% of those with clinically unrecognized delirium. The PrEDICT application has potential to act as a sensitive screening tool to identify older ED patients with clinically unrecognized delirium. J Am Geriatr Soc 67:2370-2375, 2019.
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http://dx.doi.org/10.1111/jgs.16095DOI Listing
November 2019