Desensitization of NMDA channels requires ligand binding to both GluN1 and GluN2 subunits to constrict the pore beside the activation gate.

N-methyl-D-aspartate (NMDA) receptor channels are activated by glutamate (or NMDA) and glycine. The channels also undergo desensitization, which denotes decreased channel availability, after prolonged exposure to the activating ligands. Glycine apparently has a paradoxical negative effect on desensitization, as the increase in ambient glycine in concentrations required for channel activation would increase sustained NMDA receptor currents. We hypothesized that this classical "glycine-dependent desensitization" could be glycine-dependent activation in essence. By performing electrophysiological recordings and biophysical analyses with rat brain NMDA receptors heterogeneously expressed in Xenopus laevis oocytes, we characterized that the channel opened by "only" NMDA (in nominally glycine-free condition probably with the inevitable nanomolar glycine) would undergo a novel form of deactivation rather than desensitization, and is thus fully available for subsequent activation. Moreover, external tetrapentylammonium ions (TPentA), tetrabutylammonium ions, and tetrapropylammonium ions (TPA, in higher concentrations) block the pore and prohibit channel desensitization with a simple "foot-in-the-door" hindrance effect. TpentA and TPA have the same voltage dependence but show different flow dependence in binding affinity, revealing a common binding site at an electrical distance of ~0.7 from the outside yet differential involvement of the flux-coupling region in the external pore mouth. The smaller tetraethylammonium ion and the larger tetrahexylammonium and tetraheptylammonium ions may block the channel but could not affect desensitization. We conclude that NMDA receptor desensitization requires concomitant binding of both glycine and glutamate, and thus movement of both GluN1 and GluN2 subunits. Desensitization gate itself embodies a highly restricted pore reduction with a physical distance of ~4 Å from the charged nitrogen atom of bound tetraalkylammonium ions, and is located very close to the activation gate in the bundle-crossing region in the external pore vestibule.

Quadrivalent human papillomavirus vaccination in girls and the risk of autoimmune disorders: the Ontario Grade 8 HPV Vaccine Cohort Study.

BACKGROUND: Despite demonstrated effectiveness in real-world settings, concerns persist regarding the safety of the quadrivalent human papillomavirus (HPV4) vaccine. We sought to assess the risk of autoimmune disorders following HPV4 vaccination among grade 8 girls eligible for Ontario's school-based HPV vaccination program. METHODS: We undertook a population-based retrospective cohort study using Ontario's administrative health and vaccination databases from 2007 to 2013. The self-controlled case series method was used to compare the rate of a composite end point of autoimmune disorders diagnosed during days 7-60 post-vaccination ("exposed" follow-up) to that at any other time ("unexposed"). The analysis was repeated to assess the effect of a history of immune-mediated diseases and time since vaccination. We also conducted an exploratory analysis of individual autoimmune disorders. Rate ratios and 95% confidence intervals (CIs) were estimated using conditional Poisson regression, adjusted for age, seasonality, concomitant vaccinations and infections. RESULTS: The study cohort consisted of 290 939 girls aged 12-17 years who were eligible for vaccination between 2007 and 2013. There was no significant risk for developing an autoimmune disorder following HPV4 vaccination (n = 681; rate ratio 1.12, 95% CI 0.85-1.47), and the association was unchanged by a history of immune-mediated disorders and time since vaccination. Exploratory analyses of individual autoimmune disorders found no significant risks, including for Bell palsy (n = 65; rate ratio 1.73, 95% CI 0.77-3.89), optic neuritis (n = 67; rate ratio 1.57, 95% CI 0.74-3.33) and Graves disease (n = 47; rate ratio 1.55, 95% CI 0.92-2.63). INTERPRETATION: We did not observe an increased risk of autoimmune disorders following HPV4 vaccination among teenaged girls. These findings should reassure parents and health care providers.

Concurrent prescriptions for opioids and benzodiazepines and risk of opioid overdose: protocol for a retrospective cohort study using linked administrative data.

INTRODUCTION: Opioid overdoses have increased substantially over the last 20 years, with over 400 000 deaths in North America. While opioid prescribing has been a target of research, benzodiazepine and opioid co-intoxication has emerged as a potential risk factor. Our aim was to assess the risk of opioid overdose associated with concurrent use of opioids and benzodiazepines relative to opioids alone. METHODS AND ANALYSIS: A retrospective cohort study will be conducted using medical claims data from adult residents of Montréal, Canada. We will create a cohort of new users of opioids (ie, no opioid dispensations in prior year) in 2000-2014 from people with at least 2 years of continuous health insurance. Those with any diagnosis or hospitalisation for cancer or palliative care in the 2 years before their first opioid dispensation will be excluded. On each person-day of follow-up, exposure status will be classified into one of four mutually exclusive categories: (1) opioid-only, (2) benzodiazepine-only, (3) both opioid and benzodiazepine (concurrent use) or (4) neither. Opioid overdose will be measured using diagnostic codes documented in the hospital discharge abstract database, physician billing claims from emergency department visits and death records. Using a marginal structural Cox proportional hazards model, we will compare the hazard of overdose during intervals of concurrent opioid and benzodiazepine use to intervals of opioid use alone, adjusted for sociodemographics, medical and psychiatric comorbidities, and substance use disorders. ETHICS AND DISSEMINATION: This study is approved by the McGill Faculty of Medicine Institutional Review Board and the Commission d'access à l'information (Québec privacy commission). Results will be relevant to clinicians, policymakers and other researchers interested in co-prescribing practices of opioids and benzodiazepines. Study findings will be disseminated at relevant conferences and published in biomedical and epidemiological peer-reviewed journals.

Democracy and Mobility: A preliminary analysis of global adherence to non-pharmaceutical interventions for COVID-19.

In the absence of vaccines or therapeutics, and with cases of COVID-19 continuing to grow each day, most countries are relying on non-pharmaceutical interventions (NPIs) to reduce the spread of SARS-CoV-2. The goal of NPIs - decreasing mobility in order to decrease contact - comes with competing socioeconomic costs and incentives that are not well-understood. Using Google's Community Mobility data, we visualized changes in mobility and explored the effect of economic, social, and governmental factors on mobility via regression. We found decreases in mobility for all movement categories except in residential areas; these changes corresponded strongly with country-specific outbreak trajectory. Mobility increased with GDP per capita, though this relationship varied among movement categories. Finally, countries with more authoritarian governments were more responsive with respect to mobility changes as local case counts increased; however, these countries were also less likely to report mobility data to Google. These preliminary findings suggest that country-specific outbreak trajectory, GDP per capita, and democracy index may be important indicators in assessing a given population's adherence to NPIs.

Network analysis of cases with methicillin-resistant Staphylococcus aureus and controls in a large tertiary care facility.

BACKGROUND: Despite increased awareness of infection control precautions, methicillin-resistant Staphylococcus aureus (MRSA) still spreads through patients and contaminated objects, causing a substantial burden of illness and cost. Our objective was to define risk factors for contracting MRSA in a tertiary health care facility using a historic case-control study and to validate health care network changes during pre-outbreak and outbreak periods. METHODS: We conducted a case-control study using secondary data on hospitalizations where infected or colonized cases were compared with matched controls who tested negative by age, sex, and campus over 1 year. Social networks of all cases and controls were built from links joining patients to rooms, roommates, and health care providers over time. RESULTS: Matched controls were similar to cases in comorbidity, lengths of stay, mortality, and number of roommates, rooms, and health care providers. As expected, the number of rooms and roommates increased in the outbreak by more than 50%. A timed animation of the network at one campus identified potential source patients linked to 2 rooms and many roommates, after which cases connected to those same rooms proliferated. CONCLUSIONS: Only the network animation over time revealed possible transmission of MRSA through the network, rather than attributes measured in the traditional case control study.

A Novel Neuroscience Intermediate-Level Care Unit Model: Retrospective Analysis of Impact on Patient Flow and Safety.

BACKGROUND AND PURPOSE: Neurointensive care units have been shown to improve patient outcomes across a variety of neurological and neurosurgical conditions. However, the efficacy of less resource-intensive intermediate-level care units to deliver similar care has not been well studied. The purpose of this study is to evaluate the impact of neurocritical specialist comanagement on patient flow and safety in a neuroscience intermediate-level care unit. METHODS: Our intervention consisted of the addition of a physician with critical care experience as well as training in neurology, anesthesiology, or intensive care to a neuroscience intermediate-level care unit to comanage patients alongside neurology and neurosurgery staff during weekday daytime hours. A retrospective analysis was performed on prospectively collected data pertaining to all patients admitted to the unit over a 3-year period, 1 year before our intervention and 2 years after. Patient statistics including wait times to admission, length of stay (LOS), and mortality were reviewed. RESULTS: Following the intervention, there were significant reductions in wait times to unit admission from both the emergency department and postanesthetic care unit, as well as reductions in the average LOS. No significant safety concerns were identified. CONCLUSION: This study has demonstrated that the optimization of a neuroscience intermediate-level care unit involving comanagement of patients by a neurocritical specialist can reduce wait times to admission and lengths of stay, with preserved safety outcomes.

Epidemiology of recurrent traumatic brain injury in the general population: A systematic review.

OBJECTIVE: To comprehensively assess recurrent traumatic brain injury (rTBI) risk and risk factors in the general population. METHODS: We systematically searched MEDLINE, EMBASE, and the references of included studies until January 16, 2017, for general population observational studies reporting rTBI risk or risk factors. Estimates were not meta-analyzed due to significant methodologic heterogeneity between studies, which was evaluated using meta-regression. RESULTS: Twenty-two studies reported recurrence risk and 11 reported on 27 potential risk factors. rTBI risk was heterogeneous and varied from 0.43% (95% confidence interval [CI] 0.19%-0.67%) to 41.92% (95% CI 34.43%-49.40%), with varying follow-up periods (3 days-55 years). Median time to recurrence ranged from 0.5 to 3.8 years. In studies where cases were ascertained from multiple points of care, at least 5.50% (95% CI 4.80%-6.30%) of patients experienced a recurrence after a 1-year follow-up. Studies that used administrative data/self-report surveys to ascertain cases tended to report higher risk. Risk factors measured at time of index traumatic brain injury (TBI) that were significantly associated with rTBI in more than one study were male sex, prior TBI before index case, moderate or severe TBI, and alcohol intoxication. Risk factors reported in a single study that were significantly associated with rTBI were epilepsy, not seeking medical care, and multiple factors indicative of low socioeconomic status. CONCLUSIONS: rTBI is an important contributor to the general population TBI burden. Certain risk factors can help identify individuals at higher risk of these repeated injuries. However, higher quality research that improves on rTBI surveillance methodology is needed.

Time is of the essence: an observational time-motion study of internal medicine residents while they are on duty.

BACKGROUND: The effects of changes to resident physician duty hours need to be measureable. This time-motion study was done to record internal medicine residents' workflow while on duty and to determine the feasibility of capturing detailed data using a mobile electronic tool. METHODS: Junior and senior residents were shadowed by a single observer during six-hour blocks of time, covering all seven days. Activities were recorded in real-time. Eighty-nine activities grouped into nine categories were determined a priori. RESULTS: A total of 17,714 events were recorded, encompassing 516 hours of observation. Time was apportioned in the following categories: Direct Patient Care (22%), Communication (19%), Personal tasks (15%), Documentation (14%), Education (13%), Indirect care (11%), Transit (6%), Administration (0.6%), and Non-physician tasks (0.4%). Nineteen percent of the education time was spent in self-directed learning activities. Only 9% of the total on duty time was spent in the presence of patients. Sixty-five percent of communication time was devoted to information transfer. A total of 968 interruptions were recorded which took on average 93.5 seconds each to service. CONCLUSION: Detailed recording of residents' workflow is feasible and can now lead to the measurement of the effects of future changes to residency training. Education activities accounted for 13% of on-duty time.

Variations in Resource Intensity and Cost Among High Users of the Emergency Department.

OBJECTIVES: High users of emergency department (ED) services are often identified by number of visits per year, with little exploration of the distribution/pattern of visits over time. The purpose of this study was to examine patient- and encounter-level factors and costs related to periods of short-term resource intensity among high users of the ED within a tertiary care teaching facility. METHODS: We identified all adults with at least three visits to the Ottawa Hospital ED within a 1-year period from April 1, 2012, to March 31, 2013. Within this high-user cohort, we then measured intensity of use by calculating average daily visit rates to identify individuals with a cluster of ED visits. Those with at least three ED visits/7 days at any point during follow-up were considered patients with clustered ED use (i.e., a period of short-term resource intensity). Detailed clinical and administrative data were used to compare patient- and encounter-level characteristics and cost profiles between the clustered and nonclustered groups. Analyses were repeated using varying cut points to define high users (at least five and at least eight visits per year). RESULTS: Of the 16,153 patients identified as high ED users during the study period, 13.5% had their visits clustered within a short period of time. These clustered users were more likely to be homeless, to require psychiatric services, and to leave without being seen by a physician and less likely to be admitted to the hospital. Approximately one in three (31.2%) high ED users with clustered visits returned for the same medical problem (namely pain-related disorders, shortness of breath, and cellulitis) within a 1-week period. Similar trends were observed when the high-user cohort was restricted to those with at least five and at least eight ED visits/year. Finally, patients with short-term intensity periods had lower direct and indirect costs per encounter than those without. CONCLUSIONS: Using a novel methodology that accounts for both number and intensity of ED encounters over time, we were able to identify specific subpopulations of high ED users. Further work is required to determine if this methodology has utility for targeting care pathways within this heterogeneous and high-risk patient group.

Quantification of in vivo doxorubicin transport from PLGA millirods in thermoablated rat livers.

The objective of this research was to quantify the key parameters governing the drug transport processes in radiofrequency (RF) thermoablated and non-ablated liver tissues. Experimentally, doxorubicin-containing polymer millirods were implanted in the ablated rat livers and spatial distribution of doxorubicin was measured by fluorescence imaging from 1 to 96 h after millirod implantation. At all time points, doxorubicin had significantly higher tissue penetration and retention in ablated tissues than in non-ablated tissues. A mathematical model was developed to quantitatively describe the transport processes in ablated and non-ablated rat livers. Based on the experimental data and mathematical models, the optimal estimates of apparent drug diffusivities in ablated and non-ablated tissues were 1.1 x 10(-7) and 6.7 x 10(-7) cm(2) s(-1), respectively, and the apparent drug elimination rate coefficient was 9.6 x 10(-4) s(-1) in non-ablated tissues. Results from this study contribute to the fundamental understanding of in vivo drug transport in liver tissues and provide the quantitative parameters for the rational design of polymer millirods for liver cancer treatment.

Model analysis of tissue responses to transient and chronic heating.

Thermal models are used to analyze responses of muscle and lung tissue to transient (30-45 min) and chronic (4-7 week) heating in vivo. The general bioheat model, which describes one-dimensional temperature dynamics, incorporates heat conductance and perfusion. In general, perfusion changes with time and distance from a heated surface. One of the main objectives of this study was to analyze long-term perfusion change, which reflects tissue adaptation associated with angiogenesis. The database for these models was obtained using heated disks implanted in calves for up to seven weeks. Tissue temperature distributions were obtained repeatedly from thermistors protruding 1 to 10 mm from the heated disk surface. The perfusion parameter was estimated from the transient experiments at least several times each week by nonlinear, least-squares fitting of the model predicted temperature to the measured temperature response. Chronic heating at a heat flux 0.08 W/cm2 caused perfusion of muscle tissue to increase with postimplant day (PID). Under the same conditions, lung tissue perfusion increased with chronic heating from early to late PID, but less than that for muscle tissue. During chronic heating above 42 degrees C and below 50 degrees C, a decrease in tissue temperature is associated with higher perfusion that develops with time. Over seven weeks, perfusion of muscle tissue near the heated disk surface increased by about 70% at 0.08 W/cm2 and 40% at 0.06 W/cm2. Furthermore, the model can be used to predict tissue and perfusion changes continuously over weeks for heat fluxes around 0.08 W/cm2.