Using the relationship between brain tissue regional saturation of oxygen and mean arterial pressure to determine the optimal mean arterial pressure in patients following cardiac arrest: A pilot proof-of-concept study.

INTRODUCTION: Prospectively assess cerebral autoregulation and optimal mean arterial pressure (MAPOPT) using the dynamic relationship between MAP and regional saturation of oxygen (rSO2) using near-infrared spectroscopy. METHODS: Feasibility study of twenty patients admitted to the intensive care unit following a cardiac arrest. All patients underwent continuous rSO2 monitoring using the INVOS(®) cerebral oximeter. ICM+(®) brain monitoring software calculates the cerebral oximetry index (COx) in real-time which is a moving Pearson correlation coefficient between 30 consecutive, 10-s averaged values of MAP and correspond rSO2 signals. When rSO2 increases with increasing MAP (COx ≥0.3), cerebral autoregulation is dysfunctional. Conversely, when rSO2 remains constant or decreases with increasing MAP (COx <0.3), autoregulation is preserved. ICM+(®) fits a U-shaped curve through the COx values plotted vs. MAP. The MAPOPT is nadir of this curve. RESULTS: The median age was 59 years (IQR 54-67) and 7 of 20 were female. The cardiac arrest was caused by myocardial infarction in 12 (60%) patients. Nineteen arrests were witnessed and return of spontaneous circulation occurred in a median of 15.5min (IQR 8-33). Patients underwent a median of 30h (IQR 23-46) of monitoring. COx curves and MAPOPT were generated in all patients. The mean overall MAP and MAPOPT were 76mmHg (SD 10) and 76mmHg (SD 7), respectively. MAP was outside of 5mmHg from MAPOPT in 50% (SD 15) of the time. Out of the 7672 5-min averaged COx measurements, 1182 (15%) were at 0.3 or above, indicating absence of autoregulation. Multivariable polynomial fractional regression demonstrated an increase in COx with increasing temperature (P=0.008). CONCLUSIONS: We demonstrated the feasibility to determine a MAPOPT using cerebral oximetry in patients after cardiac arrest

Using ActionADE to create information continuity to reduce re-exposures to harmful medications: study protocol for a randomized controlled trial

Background: Repeat exposures to culprit medications are a common cause of preventable adverse drug events. Health information technologies have the potential to reduce repeat adverse drug events by improving information continuity. However, they rarely interoperate to ensure providers can view adverse drug events documented in other systems. We designed ActionADE to enable rapid documentation of adverse drug events and communication of standardized information across health sectors by integrating with legacy systems. We will leverage ActionADE’s implementation to conduct two parallel, randomized trials: patients with adverse drug reactions in the main trial and those diagnosed with non-adherence in a secondary trial. Primary objective of the main trial is to evaluate the effects of providing information continuity about adverse drug reactions on culprit medication re-dispensations over 12 months. Primary objective of the secondary trial is to evaluate the effect of providing information continuity on adherence over 12 months. Methods: We will conduct two parallel group, triple-blind randomized controlled trials in participating hospitals in British Columbia, Canada. We will enroll adults presenting to hospital with an adverse drug event to prescribed outpatient medication. Clinicians will document the adverse drug event in ActionADE. The software will use an algorithm to determine patient eligibility and allocate eligible patients to experimental or control. In the experimental arm, ActionADE will transmit information to PharmaNet, where adverse drug event information will be displayed in community pharmacies when re-dispensations are attempted. In the control arm, ActionADE will retain information in the local record. We will enroll 3600 adults with an adverse drug reaction into the main trial. The main trial’s primary outcome is re-dispensation of a culprit or same-class medication within 12 months; the secondary trial’s primary outcome will be adherence to culprit medication. Secondary outcomes include health services utilization and mortality. Discussion: These studies have the potential to guide policy decisions and investments needed to drive health information technology integrations to prevent repeat adverse drug events. We present an example of how a health information technology implementation can be leveraged to conduct pragmatic randomized controlled trials. Trial registration ClinicalTrials.gov NCT04568668 , NCT04574648 . Registered on 1 October 2020.Medicine, Faculty ofOther UBCNon UBCEmergency Medicine, Department ofPopulation and Public Health (SPPH), School ofReviewedFacult

Constructing treatment episodes from concomitant medication logs: a prospective observational study

ObjectivesTo describe an approach using concomitant medication log records for the construction of treatment episodes. Concomitant medication log records are routinely collected in clinical studies. Unlike prescription and dispensing records, concomitant medication logs collect utilisation data. Logs can provide information about drug safety and drug repurposing.DesignA prospective multicentre, multicohort observational study.SettingTwenty-one clinical sites in the USA, Europe, Israel and Australia.Participants415 subjects from the de novo cohort of the Parkinson’s Progression Markers Initiative.MethodsWe construct treatment episodes of concomitant medication use. The proposed approach treats temporal gaps as a stoppage of medication and temporal overlaps as simultaneous use or changes in dose. Log records with no temporal gaps were combined into a single treatment episode.Results5723 concomitant medication log records were used to construct 3655 treatment episodes for 65 medications. There were 405 temporal gaps representing a stoppage of medication; 985 temporal overlaps representing simultaneous regimens of the same medication and 2696 temporal overlaps representing a change in dose regimen. The median episode duration was 37 months (IQ interval: 11–73 months).ConclusionsThe proposed approach for constructing treatment episodes offers a method of estimating duration and dose of treatment from concomitant medication log records. The accompanying recommendations guide log data collection to improve their quality for drug safety and drug repurposing

Reexamining the surfaces of bone in boys and girls during adolescent growth: A 12-Year mixed longitudinal pQCT Study

We revisit Stanley Garn's theory related to sex differences in endocortical and periosteal apposition during adolescence using a 12-year mixed longitudinal study design. We used peripheral quantitative computed tomography to examine bone parameters in 230 participants (110 boys, 120 girls; aged 11.0 years at baseline). We assessed total (Tt.Ar, mm2), cortical (Ct.Ar, mm2), and medullary canal area (Me.Ar, mm2), Ct.Ar/Tt.Ar, cortical bone mineral density (Ct.BMD, mg/cm3), and polar strength-strain index (SSIp, mm3) at the tibial midshaft (50% site). We used annual measures of height and chronological age to identify age at peak height velocity (APHV) for each participant. We compared annual accrual rates of bone parameters between boys and girls, aligned on APHV using a linear mixed effects model. At APHV, boys demonstrated greater Tt.Ar (ratio = 1.27; 95% confidence interval [CI] 1.21, 1.32), Ct.Ar (1.24 [1.18, 1.30]), Me.Ar (1.31 [1.22, 1.40]), and SSIp (1.36 [1.28, 1.45]) and less Ct.Ar/Tt.Ar (0.98 [0.96, 1.00]) and Ct.BMD (0.97 [0.96, 0.97]) compared with girls. Boys and girls demonstrated periosteal bone formation and net bone loss at the endocortical surface. Compared with girls, boys demonstrated greater annual accrual rates pre-APHV for Tt.Ar (1.18 [1.02, 1.34]) and Me.Ar (1.34 [1.11, 1.57]), lower annual accrual rates pre-APHV for Ct.Ar/Tt.Ar (0.56 [0.29, 0.83]) and Ct.BMD (–0.07 [–0.17, 0.04]), and similar annual accrual rates pre-APHV for Ct.Ar (1.10 [0.94, 1.26]) and SSIp (1.14 [0.98, 1.30]). Post-APHV, boys demonstrated similar annual accrual rates for Ct.Ar/Tt.Ar (1.01 [0.71, 1.31]) and greater annual accrual rates for all other bone parameters compared with girls (ratio = 1.23 to 2.63; 95% CI 1.11 to 3.45). Our findings support those of Garn and others of accelerated periosteal apposition during adolescence, more evident in boys than girls. However, our findings challenge the notion of greater endocortical apposition in girls, suggesting instead that girls experience diminished endocortical resorption compared with boy

Prophylactic Surgery in the BRCA+ Patient: Do Women Develop Breast Cancer While Waiting?

Breast cancer susceptibility gene (BRCA) mutation carriers have an increased risk of breast cancer. Mitigation of this risk can be achieved via surveillance or prophylactic mastectomy with or without breast reconstruction. Those that choose surgery expect to reduce their chance of developing cancer. The purpose of this study was to determine the incidence of patients developing breast cancer prior to surgery and to identify modifiable contributing factors within the patient journey. This is a historical cohort study of all BRCA mutation carriers identified through the British Columbia Cancer Hereditary Cancer Program between 2000 and 2012. Patients were divided into two groups: surveillance (S) and prophylactic mastectomy with immediate breast reconstruction (PM/IBR). The incidence of cancer, time to PM/IBR and patient journeys were analyzed. A total of 333 women were identified. The time to surgery from mutation disclosure was a median of 31 (5.3, 75.7) months. During this period, 6% of patients developed breast cancer compared with a 14% incidence of breast cancer in patients choosing surveillance. The majority of time to surgery was attributed to the period between mutation disclosure and the decision to proceed with surgery. Strategies to facilitate decision-making as well as wait list prioritization and dedicated operative time should be targeted to this population to decrease the number of women developing an interval cancer prior to surgery.Medicine, Faculty ofMedical Oncology, Division ofSurgery, Department ofReviewedFacultyResearche

A systematic, concept-based method of developing the exposure measure for drug safety and effectiveness studies.

PURPOSE In drug safety and effectiveness studies based on secondary data, the choice of an appropriate exposure measure for a given outcome can be challenging. Different measures of exposure can yield different estimates of treatment effect and safety. There is a knowledge gap with respect to developing and refining measures of drug exposure, to ensure that the exposure measure addresses the study question and is suitable for statistical analysis. METHODS We present a transparent, step-by-step approach to the development of drug exposure measures involving secondary data. This approach would be of interest to students and investigators with initial training in pharmacoepidemiology. We illustrate the approach using a study about Parkinson's disease. RESULTS We described the exposure specifications according to the study question. Next, we refined the exposure measure by linking it to knowledge about four major concepts in drug safety and effectiveness studies: drug use patterns, duration, timing, and dose. We then used this knowledge to guide the ultimate choice of exposure measure: time-varying, cumulative 6-month exposure to tamsulosin (a drug used to treat prostate hyperplasia). CONCLUSIONS The proposed approach links exposure specifications to four major concepts in drug safety and effectiveness studies. Formulating subject-matter knowledge about these major concepts provides an avenue to develop the rationale and specifications for the exposure measure

Naloxone interventions in opioid overdoses: a systematic review protocol

Background: North America is in the midst of an unabated opioid overdose epidemic due to the increasing non-medical use of fentanyl and ultra-potent opioids. Naloxone is an effective antidote to opioid toxicity, yet its optimal dosing in the context of fentanyl and ultra-potent opioid overdoses remains unknown. This review aims to determine the relationship between the first empiric dose of naloxone and reversal of toxicity, adverse events, and the total cumulative dose required among patients with undifferentiated opioid overdoses and those with suspected toxicity from ultra-potent opioids. Secondary objectives include evaluating the relationship between the cumulative naloxone dose and toxicity reversal and adverse events, among patients with undifferentiated opioid overdoses and those with suspected toxicity from ultra-potent opioids. Methods: To identify studies, we will search MEDLINE, Embase, CENTRAL, DARE, CDAG, CINAHL, Science Citation Index, multiple trial registries, and the gray literature. Included studies will evaluate patients with suspected or confirmed opioid toxicity from undifferentiated opioids and ultra-potent opioids, who received an empiric and possibly additional doses of naloxone. The main outcomes of interest are the relationship between naloxone dose and toxicity reversal and adverse events. We will include controlled and non-controlled interventional studies, observational studies, case reports/series, and reports from poison control centers. We will extract data and assess study quality in duplicate with discrepancies resolved by consensus or a third party. We will use the Downs and Black and Cochrane risk of bias tools for observational and randomized controlled studies. If we find sufficient variation in dose, we will fit a random effects one-stage model to estimate a dose-response relationship. We will conduct multiple subgroup analyses, including by type of opioid used and by suspected high and low prevalence of ultra-potent opioid use based on geographic location and time of the original studies. Discussion: Our review will include the most up-to-date available data including ultra-potent opioids to inform the current response to the opioid epidemic, addressing the limitations of recent reviews. We anticipate limitations relating to study heterogeneity. We will disseminate study results widely to update overdose treatment guidelines and naloxone dosing in Take Home Naloxone programs.Medicine, Faculty ofOther UBCNon UBCEmergency Medicine, Department ofPopulation and Public Health (SPPH), School ofReviewedFacult

Canadian Optically-guided approach for Oral Lesions Surgical (COOLS) trial: study protocol for a randomized controlled trial

Background: Oral cancer is a major health problem worldwide. The 5-year survival rate ranges from 30-60%, and has remained unchanged in the past few decades. This is mainly due to late diagnosis and high recurrence of the disease. Of the patients who receive treatment, up to one third suffer from a recurrence or a second primary tumor. It is apparent that one major cause of disease recurrence is clinically unrecognized field changes which extend beyond the visible tumor boundary. We have previously developed an approach using fluorescence visualization (FV) technology to improve the recognition of the field at risk surrounding a visible oral cancer that needs to be removed and preliminary results have shown a significant reduction in recurrence rates. Method/Design This paper describes the study design of a randomized, multi-centre, double blind, controlled surgical trial, the COOLS trial. Nine institutions across Canada will recruit a total of 400 patients with oral severe dysplasia or carcinoma in situ (N = 160) and invasive squamous cell carcinoma (N = 240). Patients will be stratified by participating institution and histology grade and randomized equally into FV-guided surgery (experimental arm) or white light-guided surgery (control arm). The primary endpoint is a composite of recurrence at or 1 cm within the previous surgery site with 1) the same or higher grade histology compared to the initial diagnosis (i.e., the diagnosis used for randomization); or 2) further treatment due to the presence of severe dysplasia or higher degree of change at follow-up. This is the first randomized, multi-centre trial to validate the effectiveness of the FV-guided surgery. Discussion In this paper we described the strategies, novelty, and challenges of this unique trial involving a surgical approach guided by the FV technology. The success of the trial requires training, coordination, and quality assurance across multiple sites within Canada. The COOLS trial, an example of translational research, may result in reduced recurrence rates following surgical treatment of early-stage oral cancer with significant impacts on survival, morbidity, patients' quality of life and the cost to the health care system. Trial Registration Clinicaltrials.gov NCT01039298Dentistry, Faculty ofMedicine, Faculty ofOral Biological and Medical Sciences (OBMS), Department ofScience, Faculty ofSurgery, Department ofNon UBCReviewedFacult