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Objective: To determine the association between non-adherence to long term chronic obstructive pulmonary disease (COPD) medications and COPD related emergency department (ED) visits and hospitalizations in patients with incident COPD, utilizing time varying measures of adherence as well as accounting for time-varying confounding impacted by prior adherence., Study Design and Setting: We conducted a population-based retrospective cohort study between 2007-2017 among individuals aged 66 years and older with incident COPD using multiple linked administrative health databases from the province of Ontario, Canada. Adherence to COPD medications was measured using time varying proportion of days covered based on insurance claims for medications dispensed at community pharmacies. The parametric g-formula was used to assess the association between time-varying adherence (in the last 90-days) to COPD medications and risk of COPD related hospitalizations and ED visits while accounting for time varying confounding by COPD severity., Results: Overall, 60,251 individuals with incident COPD were included; mean age was 76 (SD 7) and 59% were male. Mean adherence over the entire follow-up was 23% (SD 0.3). There were 7248 (12%) COPD related ED visits (2.8 events per 100 person years [PY]) and 9188 (15%) COPD related hospitalizations (3.5 events per 100 PY). Compared to those with 0% 90-day adherence, those with adherence between 1-33% had a 19% decreased risk of COPD related ED visits (adjusted risk ratio[aRR]:0.81, 95% confidence interval [CI]:0.78-0.83), those with adherence between 34%-67% had a 18% decreased risk (aRR: 0.82, 95% CI: 0.77-0.85) while those with 68%-100% 90-day adherence had a 63% increased risk of COPD related ED visits (aRR: 1.63, 95% CI: 1.47-1.78). Nearly identical results were obtained for COPD specific hospitalizations., Conclusion: After accounting for time varying confounding by COPD severity, the highest time varying 90-days adherence was associated with an increased risk of both COPD related ED visits and hospitalizations compared to the lowest adherence categories. Differences in COPD severity between adherence categories, perception of need for medication management in the higher adherence categories, and potential residual confounding makes it difficult to disentangle the independent effects of adherence from the severity of the condition itself., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Certain combinations of medications can be harmful and may lead to serious adverse drug events (ADEs). Identifying potentially problematic medication clusters could help guide prescribing and/or deprescribing decisions in hospital. The aim of this study is to characterize medication prescribing patterns at hospital discharge and determine which medication clusters were associated with an increased risk of ADEs in the 30-day posthospital discharge., Methods: All residents of the province of Ontario in Canada aged 66 years or older admitted to hospital between March 2016 and February 2017 were included. Identification of medication clusters prescribed at hospital discharge was conducted using latent class analysis. Cluster identification and categorization were based on medications dispensed up to 30-day posthospitalization. Multivariable logistic regression was used to assess the potential association between membership to a particular medication cluster and ADEs postdischarge, while also evaluating other patient characteristics., Results: In total, 188 354 patients were included in the study cohort. Median age (interquartile range) was 77 (71-84) years, and patients had a median (IQR) (interquartile range [IQR]) of 9 (6-13) medications dispensed prior to admission. Within the study population, 6 separate clusters of dispensing patterns were identified: cardiovascular (14%), respiratory (26%), complex care needs (12%), cardiovascular and metabolic (15%), infection (10%), and surgical (24%). Overall, 12 680 (7%) patients had an ADE in the 30 days following discharge. After considering other patient characteristics, those belonging to the respiratory cluster had the highest risk of ADEs (adjusted odds ratio: 1.12, 95% confidence interval: 1.08-1.17) compared with all the other clusters, while those in the complex care needs cluster had the lowest risk (adjusted odds ratio: 0.82, 95% confidence interval: 0.77-0.87)., Conclusion: This study suggests that ADEs post hospital discharge can be linked with identifiable medication clusters. This information may help clinicians and researchers better understand patient populations that are more or less likely to benefit from peri-hospital discharge interventions aimed at reducing ADEs., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current immunotherapies are thus focused on the early, pre-symptomatic stage of disease, with the goal of peripheral neutralization of virus to prevent CNS infection. Here, we evaluated the therapeutic efficacy of F11, an anti-lyssavirus human monoclonal antibody (mAb), on established lyssavirus infections. We show that a single dose of F11 limits viral load in the brain and reverses disease signs following infection with a lethal dose of lyssavirus, even when administered after initiation of robust virus replication in the CNS. Importantly, we found that F11-dependent neutralization is not sufficient to protect animals from mortality, and a CD4 T cell-dependent adaptive immune response is required for successful control of infection. F11 significantly changes the spectrum of leukocyte populations in the brain, and the FcRγ-binding function of F11 contributes to therapeutic efficacy. Thus, mAb therapy can drive potent neutralization-independent T cell-mediated effects, even against an established CNS infection by a lethal neurotropic virus., (© 2023 Commonwealth of Australia and The Authors. Published under the terms of the CC BY 4.0 license. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

This study tested the hypothesis that high frequencies of natural killer (NK) cells are protective against symptomatic SARS-CoV-2 infection. Samples were utilized from the COVID-19 Health Action Response for Marines study, a prospective, observational study of SARS-CoV-2 infection in which participants were enrolled prior to infection and then serially monitored for development of symptomatic or asymptomatic infection. Frequencies and phenotypes of NK cells (CD3 - CD14 - CD19 - CD56 + ) were assessed by flow cytometry. Individuals that developed asymptomatic infections were found to have higher pre-infection frequencies of total NK cells compared to symptomatic individuals (10.61% [SD 4.5] vs 8.33% [SD 4.6], p = 0.011). Circulating total NK cells decreased over the course of infection, reaching a nadir at 4 weeks, while immature NK cells increased, a finding confirmed by multidimensional reduction analysis. These results indicate that NK cells likely play a key role in controlling the severity of clinical illness in individuals infected with SARS-CoV-2., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University of the Health Sciences, Department of the Navy, Department of Defense, the U.S. Government, nor the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. AMWM, PS, SL, RL, DLW, CWG, AGL, and EM are military Service members or employees of the U.S. Government. This work was prepared as part of their official duties. Title 17, U.S.C., §105 provides that copyright protection under this title is not available for any work of the U.S. Government. Title 17, U.S.C., §101 defines a U.S. Government work as a work prepared by a military Service member or employee of the U.S. Government as part of that person’s official duties., (© 2023 Published by Elsevier B.V.)

DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS-CoV-2 infection. The differential methylation caused by asymptomatic or mildly symptomatic infections was indistinguishable. While differential gene expression largely returned to baseline levels after the virus became undetectable, some differentially methylated sites persisted for months of follow-up, with a pattern resembling autoimmune or inflammatory disease. We leveraged these responses to construct methylation-based machine learning models that distinguished samples from pre-, during-, and postinfection time periods, and quantitatively predicted the time since infection. The clinical trajectory in the young adults and in a diverse cohort with more severe outcomes was predicted by the similarity of methylation before or early after SARS-CoV-2 infection to the model-defined postinfection state. Unlike the phenomenon of trained immunity, the postacute SARS-CoV-2 epigenetic landscape we identify is antiprotective., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Assays detecting blood transcriptome changes are studied for infectious disease diagnosis. Blood-based RNA alternative splicing (AS) events, which have not been well characterized in pathogen infection, have potential normalization and assay platform stability advantages over gene expression for diagnosis. Here, we present a computational framework for developing AS diagnostic biomarkers. Leveraging a large prospective cohort of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and whole-blood RNA sequencing (RNA-seq) data, we identify a major functional AS program switch upon viral infection. Using an independent cohort, we demonstrate the improved accuracy of AS biomarkers for SARS-CoV-2 diagnosis compared with six reported transcriptome signatures. We then optimize a subset of AS-based biomarkers to develop microfluidic PCR diagnostic assays. This assay achieves nearly perfect test accuracy (61/62 = 98.4%) using a naive principal component classifier, significantly more accurate than a gene expression PCR assay in the same cohort. Therefore, our RNA splicing computational framework enables a promising avenue for host-response diagnosis of infection., Competing Interests: A provisional patent application on this work has been submitted, and the Icahn School of Medicine at Mount Sinai and Princeton University are in discussions about licensing the technology. Z.Z., O.G.T., and S.C.S. are co-inventors of this technology and may benefit from any licensing.

Background: The development of memory B cells after asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well understood., Methods: We compared spike antibody titers, pseudovirus neutralizing antibody titers, and memory B-cell responses among SARS-CoV-2 PCR-positive Marine recruits who either reported asymptomatic or symptomatic infection., Results: Thirty-six asymptomatic participants exhibited similar spike IgG titers, spike IgA titers, and pseudovirus neutralization titers compared to 30 symptomatic participants. Pseudovirus neutralization and spike IgG titers showed significant positive correlations with frequency of memory B cells., Conclusions: Among young adults, asymptomatic SARS-CoV-2 infection induced antibody and memory B-cell responses comparable to mild symptomatic infection., Competing Interests: Potential conflicts of interest. S. C. has consulted for GSK, JP Morgan, Citi, Morgan Stanley, Avalia NZ, Nutcracker Therapeutics, University of California, California State Universities, United Airlines, Adagio, and Roche. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Male sex is a major risk factor for SARS-CoV-2 infection severity. To understand the basis for this sex difference, we studied SARS-CoV-2 infection in a young adult cohort of United States Marine recruits. Among 2,641 male and 244 female unvaccinated and seronegative recruits studied longitudinally, SARS-CoV-2 infections occurred in 1,033 males and 137 females. We identified sex differences in symptoms, viral load, blood transcriptome, RNA splicing, and proteomic signatures. Females had higher pre-infection expression of antiviral interferon-stimulated gene (ISG) programs. Causal mediation analysis implicated ISG differences in number of symptoms, levels of ISGs, and differential splicing of CD45 lymphocyte phosphatase during infection. Our results indicate that the antiviral innate immunity set point causally contributes to sex differences in response to SARS-CoV-2 infection. A record of this paper's transparent peer review process is included in the supplemental information., Competing Interests: Declaration of interests C.W.G., R.A.L., S.E.L., M.A.S., M.S.T., D.L.W., and A.G.L. are military service members or government service employees. This work was prepared as part of their official duties. Title 17, US Code §105 provides that copyright protection under this title is not available for any work of the US Government. Title 17, US code §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person’s official duties. The views expressed in the article are those of the authors and do not necessarily express the official policy and position of the US Navy, the Department of Defense, and the US Government or the institutions affiliated with the authors. O.G.T. is on the advisory board of Cell Systems., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort., Methods: Between May and November 2020, we monitored 2,469 unvaccinated, mostly male, Marine recruits prospectively during basic training. If participants tested negative for SARS-CoV-2 by quantitative polymerase chain reaction (qPCR) at the end of quarantine, they were transferred to the training site in segregated companies and underwent biweekly testing for 6 weeks. We assessed the effects of coronavirus disease 2019 (COVID-19) prevention measures on other respiratory infections with passive surveillance data, performed phylogenetic analysis, and modeled transmission dynamics and testing regimens., Results: Preventive measures were associated with drastically lower rates of other respiratory illnesses. However, among the trainees, 1,107 (44.8%) tested SARS-CoV-2-positive, with either mild or no symptoms. Phylogenetic analysis of viral genomes from 580 participants revealed that all cases but one were linked to five independent introductions, each characterized by accumulation of mutations across and within companies, and similar viral isolates in individuals from the same company. Variation in company transmission rates (mean reproduction number R 0 ; 5.5 [95% confidence interval [CI], 5.0, 6.1]) could be accounted for by multiple initial cases within a company and superspreader events. Simulations indicate that frequent rapid-report testing with case isolation may minimize outbreaks., Conclusions: Transmission of wild-type SARS-CoV-2 among Marine recruits was approximately twice that seen in the community. Insights from SARS-CoV-2 outbreak dynamics and mutations spread in a remote, congregate setting may inform effective mitigation strategies., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

SARS-CoV-2 T cell responses are associated with COVID-19 recovery, and Class I- and Class II-restricted epitopes have been identified in the spike (S), nucleocapsid (N) and membrane (M) proteins and others. This prospective COVID-19 Health Action Response for Marines (CHARM) study enabled assessment of T cell responses against S, N and M proteins in symptomatic and asymptomatic SARS-CoV-2 infected participants. At enrollment all participants were negative by qPCR; follow-up occurred biweekly and bimonthly for the next 6 weeks. Study participants who tested positive by qPCR SARS-CoV-2 test were enrolled in an immune response sub-study. FluoroSpot interferon-gamma (IFN-γ) and IL2 responses following qPCR-confirmed infection at enrollment (day 0), day 7 and 14 and more than 28 days later were measured using pools of 17mer peptides covering S, N, and M proteins, or CD4+CD8 peptide pools containing predicted epitopes from multiple SARS-CoV-2 antigens. Among 124 asymptomatic and 105 symptomatic participants, SARS-CoV-2 infection generated IFN-γ responses to the S, N and M proteins that persisted longer in asymptomatic cases. IFN-γ responses were significantly (p = 0.001) more frequent to the N pool (51.4%) than the M pool (18.9%) among asymptomatic but not symptomatic subjects. Asymptomatic IFN-γ responders to the CD4+CD8 pool responded more frequently to the S pool (55.6%) and N pool (57.1%), than the M pool (7.1%), but not symptomatic participants. The frequencies of IFN-γ responses to the S and N+M pools peaked 7 days after the positive qPCR test among asymptomatic (S pool: 22.2%; N+M pool: 28.7%) and symptomatic (S pool: 15.3%; N+M pool 21.9%) participants and dropped by >28 days. Magnitudes of post-infection IFN-γ and IL2 responses to the N+M pool were significantly correlated with IFN-γ and IL2 responses to the N and M pools. These data further support the central role of Th1-biased cell mediated immunity IFN-γ and IL2 responses, particularly to the N protein, in controlling COVID-19 symptoms, and justify T cell-based COVID-19 vaccines that include the N and S proteins., Competing Interests: The authors have declared that no competing interests exist.

Young adults infected with SARS-CoV-2 are frequently asymptomatic or develop only mild disease. Because capturing representative mild and asymptomatic cases require active surveillance, they are less characterized than moderate or severe cases of COVID-19. However, a better understanding of SARS-CoV-2 asymptomatic infections might shed light into the immune mechanisms associated with the control of symptoms and protection. To this aim, we have determined the temporal dynamics of the humoral immune response, as well as the serum inflammatory profile, of mild and asymptomatic SARS-CoV-2 infections in a cohort of 172 initially seronegative prospectively studied United States Marine recruits, 149 of whom were subsequently found to be SARS-CoV-2 infected. The participants had blood samples taken, symptoms surveyed and PCR tests for SARS-CoV-2 performed periodically for up to 105 days. We found similar dynamics in the profiles of viral load and in the generation of specific antibody responses in asymptomatic and mild symptomatic participants. A proteomic analysis using an inflammatory panel including 92 analytes revealed a pattern of three temporal waves of inflammatory and immunoregulatory mediators, and a return to baseline for most of the inflammatory markers by 35 days post-infection. We found that 23 analytes were significantly higher in those participants that reported symptoms at the time of the first positive SARS-CoV-2 PCR compared with asymptomatic participants, including mostly chemokines and cytokines associated with inflammatory response or immune activation (i.e., TNF-α, TNF-β, CXCL10, IL-8). Notably, we detected 7 analytes (IL-17C, MMP-10, FGF-19, FGF-21, FGF-23, CXCL5 and CCL23) that were higher in asymptomatic participants than in participants with symptoms; these are known to be involved in tissue repair and may be related to the control of symptoms. Overall, we found a serum proteomic signature that differentiates asymptomatic and mild symptomatic infections in young adults, including potential targets for developing new therapies and prognostic tests., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Soares-Schanoski, Sauerwald, Goforth, Periasamy, Weir, Lizewski, Lizewski, Ge, Kuzmina, Nair, Vangeti, Marjanovic, Cappuccio, Cheng, Mofsowitz, Miller, Yu, George, Zaslavsky, Bukreyev, Troyanskaya, Sealfon, Letizia and Ramos.)

We used epidemiologic and viral genetic information to identify a case of likely reinfection in an otherwise healthy, young Marine recruit enrolled in the prospective, longitudinal COVID-19 Health Action Response for Marines (CHARM) study, and we paired these findings with serological studies. This participant had a positive RT-PCR to SARS-CoV-2 upon routine sampling on study day 7, although he was asymptomatic at that time. He cleared the infection within seven days. On study day 46, he had developed symptoms consistent with COVID-19 and tested positive by RT-PCR for SARS-CoV-2 again. Viral whole genome sequencing was conducted from nares swabs at multiple time points. The day 7 sample was determined to be lineage B.1.340, whereas both the day 46 and day 49 samples were B.1.1. The first positive result for anti-SARS-CoV-2 IgM serology was collected on day 49 and for IgG on day 91. This case appears most consistent with a reinfection event. Our investigation into this case is unique in that we compared sequence data from more than just paired specimens, and we also assayed for immune response after both the initial infection and the later reinfection. These data demonstrate that individuals who have experienced an infection with SARS-CoV-2 may fail to generate effective or long-lasting immunity, similar to endemic human beta coronaviruses.

Objective: The objectives of this pilot study were (1) to assess the feasibility of a larger evaluation of Smart About Meds (SAM), a patient-centered medication management mobile application, and (2) to evaluate SAM's potential to improve outcomes of interest, including adherence to medication changes made at hospital discharge and the occurrence of adverse events., Materials and Methods: We conducted a pilot randomized controlled trial among patients discharged from internal medicine units of an academic health center between June 2019 and March 2020. Block randomization was used to randomize patients to intervention (received access to SAM at discharge) or control (received usual care). Patients were followed for 30 days post-discharge, during which app use was recorded. Pharmacy claims data were used to measure adherence to medication changes made at discharge, and physician billing data were used to identify emergency department visits and hospital readmissions during follow-up., Results: Forty-nine patients were eligible for inclusion in the study at hospital discharge (23 intervention, 26 control). In the 30 days of post-discharge, 15 (65.2%) intervention patients used the SAM app. During this period, intervention patients adhered to a larger proportion of medication changes (83.7%) than control patients (77.8%), including newly prescribed medications (72.7% vs 61.7%) and dose changes (90.9% vs 81.8%). A smaller proportion of intervention patients (8.7%) were readmitted to hospital during follow-up than control patients (15.4%)., Conclusion: The high uptake of SAM among intervention patients supports the feasibility of a larger trial. Results also suggest that SAM has the potential to enhance adherence to medication changes and reduce the risk of downstream adverse events. This hypothesis needs to be tested in a larger trial., Trial Registration: Clinicaltrials.gov, registration number NCT04676165., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Whether young adults who are infected with SARS-CoV-2 are at risk of subsequent infection is uncertain. We investigated the risk of subsequent SARS-CoV-2 infection among young adults seropositive for a previous infection., Methods: This analysis was performed as part of the prospective COVID-19 Health Action Response for Marines study (CHARM). CHARM included predominantly male US Marine recruits, aged 18-20 years, following a 2-week unsupervised quarantine at home. After the home quarantine period, upon arrival at a Marine-supervised 2-week quarantine facility (college campus or hotel), participants were enrolled and were assessed for baseline SARS-CoV-2 IgG seropositivity, defined as a dilution of 1:150 or more on receptor-binding domain and full-length spike protein ELISA. Participants also completed a questionnaire consisting of demographic information, risk factors, reporting of 14 specific COVID-19-related symptoms or any other unspecified symptom, and brief medical history. SARS-CoV-2 infection was assessed by PCR at weeks 0, 1, and 2 of quarantine and participants completed a follow-up questionnaire, which included questions about the same COVID-19-related symptoms since the last study visit. Participants were excluded at this stage if they had a positive PCR test during quarantine. Participants who had three negative swab PCR results during quarantine and a baseline serum serology test at the beginning of the supervised quarantine that identified them as seronegative or seropositive for SARS-CoV-2 then went on to basic training at Marine Corps Recruit Depot-Parris Island. Three PCR tests were done at weeks 2, 4, and 6 in both seropositive and seronegative groups, along with the follow-up symptom questionnaire and baseline neutralising antibody titres on all subsequently infected seropositive and selected seropositive uninfected participants (prospective study period)., Findings: Between May 11, 2020, and Nov 2, 2020, we enrolled 3249 participants, of whom 3168 (98%) continued into the 2-week quarantine period. 3076 (95%) participants, 2825 (92%) of whom were men, were then followed up during the prospective study period after quarantine for 6 weeks. Among 189 seropositive participants, 19 (10%) had at least one positive PCR test for SARS-CoV-2 during the 6-week follow-up (1·1 cases per person-year). In contrast, 1079 (48%) of 2247 seronegative participants tested positive (6·2 cases per person-year). The incidence rate ratio was 0·18 (95% CI 0·11-0·28; p<0·001). Among seropositive recruits, infection was more likely with lower baseline full-length spike protein IgG titres than in those with higher baseline full-length spike protein IgG titres (hazard ratio 0·45 [95% CI 0·32-0·65]; p<0·001). Infected seropositive participants had viral loads that were about 10-times lower than those of infected seronegative participants (ORF1ab gene cycle threshold difference 3·95 [95% CI 1·23-6·67]; p=0·004). Among seropositive participants, baseline neutralising titres were detected in 45 (83%) of 54 uninfected and in six (32%) of 19 infected participants during the 6 weeks of observation (ID50 difference p<0·0001)., Interpretation: Seropositive young adults had about one-fifth the risk of subsequent infection compared with seronegative individuals. Although antibodies induced by initial infection are largely protective, they do not guarantee effective SARS-CoV-2 neutralisation activity or immunity against subsequent infection. These findings might be relevant for optimisation of mass vaccination strategies., Funding: Defense Health Agency and Defense Advanced Research Projects Agency., Competing Interests: Declaration of interests DMP owned stock in Co-Diagnostics Inc during the conduct of the study. DS and FK have filed a patent regarding serological assays for SARS-CoV-2 and Icahn School of Medicine at Mount Sinai has founded a company to commercialise serological assays they developed. AGL, CG, DLW, HWC, DE, WDG, FJ, JM, EN, CKP, ESA, MS, VAS, RAL, SEL, PS, MT, and PS are military service members or government service employees. This work was prepared as part of their official duties. Title 17, US Code §105 provides that copyright protection under this title is not available for any work of the US Government. Title 17, US code §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person's official duties. The views expressed in the article are those of the authors and do not necessarily express the official policy and position of the US Navy, the Department of Defense, the US Government or the institutions affiliated with the authors. AGL, YG, SV, CG, DLW, HWC, NAK, CAB, DE, M-CG, WDG, FJ, RAL, SEL, JM, NM, CMM, PB, SM, VDN, EN, CKP, ESA, AS-S, MS, VAS, MT, PS, RPT, AB, IR, and SCS declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To outline the development of a software solution to improve medication management after hospital discharge, including its design, data sources, intrinsic features, and to evaluate the usability and the perception of use by end-users., Materials and Methods: Patients were directly involved in the development using a User Center Design (UCD) approach. We conducted usability interviews prior to hospital discharge, before a user started using the application. A technology acceptance questionnaire was administered to evaluate user self-perception after 2 weeks of use., Results: The following features were developed; pill identification, patient-friendly drug information leaflet, side effect checker, and interaction checker, adherence monitoring and alerts, weekly medication schedule, daily pill reminders, messaging service, and patient medication reviews. The usability interviews show a 98.3% total success rate for all features, severity (on a scale of 1-4) 1.4 (SD 0.79). Regarding the self-perception of use (1-7 agreement scale) the 3 highest-rated domains were: (1) perceived ease of use 5.65 (SD 2.02), (2) output quality 5.44 (SD 1.65), and (3) perceived usefulness 5.29 (SD 2.11)., Discussion: Many medication management apps solutions have been created and most of them have not been properly evaluated. SAM (Smart About Medications) includes the user perspective, integration between a province drug database and the pharmacist workflow in real time. Its features are not limited to maintaining a medication list through manual entry., Conclusion: We can conclude after evaluation that the application is usable and has been self-perceived as easy to use by end-users. Future studies are required to assess the health benefits associated with its use., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

We investigated serological responses following a SARS-CoV-2 outbreak in spring 2020 on a US Marine recruit training base. 147 participants that were isolated during an outbreak of respiratory illness were enrolled in this study, with visits approximately 6 and 10 weeks post-outbreak (PO). This cohort is comprised of young healthy adults, ages 18-26, with a high rate of asymptomatic infection or mild symptoms, and therefore differs from previously reported longitudinal studies on humoral responses to SARS-CoV-2, which often focus on more diverse age populations and worse clinical presentation. 80.9% (119/147) of the participants presented with circulating IgG antibodies against SARS-CoV-2 spike (S) receptor-binding domain (RBD) at 6 weeks PO, of whom 97.3% (111/114) remained positive, with significantly decreased levels, at 10 weeks PO. Neutralizing activity was detected in all sera from SARS-CoV-2 IgG positive participants tested (n=38) at 6 and 10 weeks PO, without significant loss between time points. IgG and IgA antibodies against SARS-CoV-2 RBD, S1, S2, and the nucleocapsid (N) protein, as well neutralization activity, were generally comparable between those participants that had asymptomatic infection or mild disease. A multiplex assay including S proteins from SARS-CoV-2 and related zoonotic and human endemic betacoronaviruses revealed a positive correlation for polyclonal cross-reactivity to S after SARS-CoV-2 infection. Overall, young adults that experienced asymptomatic or mild SARS-CoV-2 infection developed comparable humoral responses, with no decrease in neutralizing activity at least up to 10 weeks after infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.​​​​​​​​​​​​​​​​​​​​, (At least a portion of this work is authored by Carl Goforth, Dawn L. Weir, Brian L. Pike, James Regeimbal, Mark P. Simons, Michael S. Termini, Stephen Lizewski, Rhonda Lizewski, Eric D. Laing, Christopher C. Broder and Andrew G. Letizia on behalf of the U.S. Government and, as regards Goforth, Weir, Pike, Regeimbal, Simons, Termini, S. Lizewski, R. Lizewski, Laing, Broder, Letizia and the U.S. Government, is not subject to copyright protection in the United States. Foreign and other copyrights may apply.)

In a study of US Marine recruits, seroprevalence of severe acute respiratory syndrome coronavirus 2 IgG was 9.0%. Hispanic and non-Hispanic Black participants and participants from states affected earlier in the pandemic had higher seropositivity rates. These results suggest the need for targeted public health strategies among young adults at increased risk for infection.

Australian bat lyssavirus (ABLV) is a rhabdovirus that circulates in four species of pteropid bats (ABLVp) and the yellow-bellied sheath-tailed bat (ABLVs) in mainland Australia. In the three confirmed human cases of ABLV, rabies illness preceded fatality. As with rabies virus (RABV), post-exposure prophylaxis (PEP) for potential ABLV infections consists of wound cleansing, administration of the rabies vaccine and injection of rabies immunoglobulin (RIG) proximal to the wound. Despite the efficacy of PEP, the inaccessibility of human RIG (HRIG) in the developing world and the high immunogenicity of equine RIG (ERIG) has led to consideration of human monoclonal antibodies (hmAbs) as a passive immunization option that offers enhanced safety and specificity. Using a recombinant vesicular stomatitis virus (rVSV) expressing the glycoprotein (G) protein of ABLVs and phage display, we identified two hmAbs, A6 and F11, which completely neutralize ABLVs/ABLVp, and RABV at concentrations ranging from 0.39 and 6.25 µg/mL and 0.19 and 0.39 µg/mL respectively. A6 and F11 recognize overlapping epitopes in the lyssavirus G protein, effectively neutralizing phylogroup 1 lyssaviruses, while having little effect on phylogroup 2 and non-grouped diverse lyssaviruses. These results suggest that A6 and F11 could be effective therapeutic and diagnostic tools for phylogroup 1 lyssavirus infections.

Background: Mobilizing pharmacists practicing in community pharmacies as a new player in primary care has recently emerged as a cost-effective strategy for clinical consultations related to minor ailments. However, little is known about these consultations initiated by patients. The objectives of this study were to describe patient initiated consultations in community pharmacies, and to estimate the impact of these consultations on care-seeking behaviors of patients., Methods: A cross sectional study was conducted in 11 retail pharmacies in Quebec, Canada, from October until December 2017, using two data sources: 1) an application and 2) structured interviews. Pharmacists had to compile all consultations in the app during a 4 week-period. Consenting patients were interviewed on the day of the consultation and one week after. Descriptive statistics on the number of consultations were calculated, as well as on the recommendation and the experience of the patient., Results: A total number of 4994 consultations were entered in the app by 55 pharmacists, with an average of 18 consultations (SD = 7) per pharmacy per day. Of the 900 patients consented to participate to the study, 600 (67%) completed the two interviews. Pharmacists reported that they recommended another healthcare resource to patients (e.g. emergency department (ED), walk-in clinic) in only 15% of cases. In the week following the consultation, 105 (18%) patients reported that they avoided going to the ED as a result of the consultation. Patients in rural regions or consulting in a pharmacy far from a medical clinic were more likely to report avoiding an ED visit as a result of the consultation with the pharmacist., Conclusions: This study suggests that patients are seeking advice from pharmacists for a variety of health care concerns and that pharmacists are able to manage most of these consultations, with a high level of patient satisfaction., (Copyright © 2020. Published by Elsevier Inc.)

Background: The efficacy of public health measures to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been well studied in young adults., Methods: We investigated SARS-CoV-2 infections among U.S. Marine Corps recruits who underwent a 2-week quarantine at home followed by a second supervised 2-week quarantine at a closed college campus that involved mask wearing, social distancing, and daily temperature and symptom monitoring. Study volunteers were tested for SARS-CoV-2 by means of quantitative polymerase-chain-reaction (qPCR) assay of nares swab specimens obtained between the time of arrival and the second day of supervised quarantine and on days 7 and 14. Recruits who did not volunteer for the study underwent qPCR testing only on day 14, at the end of the quarantine period. We performed phylogenetic analysis of viral genomes obtained from infected study volunteers to identify clusters and to assess the epidemiologic features of infections., Results: A total of 1848 recruits volunteered to participate in the study; within 2 days after arrival on campus, 16 (0.9%) tested positive for SARS-CoV-2, 15 of whom were asymptomatic. An additional 35 participants (1.9%) tested positive on day 7 or on day 14. Five of the 51 participants (9.8%) who tested positive at any time had symptoms in the week before a positive qPCR test. Of the recruits who declined to participate in the study, 26 (1.7%) of the 1554 recruits with available qPCR results tested positive on day 14. No SARS-CoV-2 infections were identified through clinical qPCR testing performed as a result of daily symptom monitoring. Analysis of 36 SARS-CoV-2 genomes obtained from 32 participants revealed six transmission clusters among 18 participants. Epidemiologic analysis supported multiple local transmission events, including transmission between roommates and among recruits within the same platoon., Conclusions: Among Marine Corps recruits, approximately 2% who had previously had negative results for SARS-CoV-2 at the beginning of supervised quarantine, and less than 2% of recruits with unknown previous status, tested positive by day 14. Most recruits who tested positive were asymptomatic, and no infections were detected through daily symptom monitoring. Transmission clusters occurred within platoons. (Funded by the Defense Health Agency and others.)., (Copyright © 2020 Massachusetts Medical Society.)

Objective: To evaluate the hypothesis that nonadherence to medication changes made at hospital discharge is associated with an increased risk of adverse events in the 30 days postdischarge., Study Setting: Patients admitted to hospitals in Montreal, Quebec, between 2014 and 2016., Study Design: Prospective cohort study., Data Collection: Nonadherence to medication changes was measured by comparing medications dispensed in the community with those prescribed at hospital discharge. Patient, health system, and drug regimen-level covariates were measured using medical services and pharmacy claims data as well as data abstracted from the patient's hospital chart. Multivariable Cox models were used to determine the association between nonadherence to medication changes and the risk of adverse events., Principal Findings: Among 2655 patients who met our inclusion criteria, mean age was 69.5 years (SD 14.7) and 1581 (60%) were males. Almost half of patients (n = 1161, 44%) were nonadherent to at least one medication change, and 860 (32%) were readmitted to hospital, visited the emergency department, or died in the 30 days postdischarge. Patients who were not adherent to any of their medication changes had a 35% higher risk of adverse events compared to those who were adherent to all medication changes (1.41 vs 1.27 events/100 person-days, adjusted hazard ratio: 1.35, 95% CI: 1.06-1.71)., Conclusions: Almost half of all patients were not adherent to some or all changes made to their medications at hospital discharge. Nonadherence to all changes was associated with an increased risk of adverse events. Interventions addressing barriers to adherence should be considered moving forward., (© 2020 The Authors. Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Traditional mouse models of lyssavirus pathogenesis rely on euthanizing large groups of animals at various time points post-infection, processing infected tissues, and performing histological and molecular analyses to determine anatomical sites of infection. While powerful by some measures, this approach is limited by the inability to monitor disease progression in the same mice over time. In this study, we established a novel non-invasive mouse model of lyssavirus pathogenesis, which consists of longitudinal imaging of a luciferase-expressing Australian bat lyssavirus (ABLV) reporter virus. In vivo bioluminescence imaging (BLI) in mice revealed viral spread from a peripheral site of inoculation into the central nervous system (CNS), with kinetically and spatially distinct foci of replication in the footpad, spinal cord, and hindbrain. Detection of virus within the CNS was associated with onset of clinical disease. Quantification of virus-derived luminescent signal in the brain was found to be a reliable measure of viral replication, when compared to traditional molecular methods. Furthermore, we demonstrate that in vivo imaging of ABLV infection is not restricted to the use of albino strains of mice, but rather strong BLI signal output can be achieved by shaving the hair from the heads and spines of pigmented strains, such as C57BL/6. Overall, our data show that in vivo BLI can be used to rapidly and non-invasively identify sites of lyssavirus replication and to semi-quantitatively determine viral load without the need to sacrifice mice at multiple time points., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier B.V.)

Background: Admission to hospital provides the opportunity to review patient medications; however, the extent to which the safety of drug regimens changes after hospitalization is unclear., Objective: To estimate the number of potentially inappropriate medications (PIMs) prescribed to patients at hospital discharge and their association with the risk of adverse events 30 days after discharge., Design: Prospective cohort study., Setting: Tertiary care hospitals within the McGill University Health Centre Network in Montreal, Quebec, Canada., Participants: Patients from internal medicine, cardiac, and thoracic surgery, aged 65 years and older, admitted between October 2014 and November 2016., Measures: Abstracted chart data were linked to provincial health databases. PIMs were identified using AGS (American Geriatrics Society) Beers Criteria®, STOPP, and Choosing Wisely statements. Multivariable logistic regression and Cox models were used to assess the association between PIMs and adverse events., Results: Of 2,402 included patients, 1,381 (57%) were male; median age was 76 years (interquartile range [IQR] = 70-82 years); and eight discharge medications were prescribed (IQR = 2-8). A total of 1,576 (66%) patients were prescribed at least one PIM at discharge; 1,176 (49%) continued a PIM from prior to admission, and 755 (31%) were prescribed at least one new PIM. In the 30 days after discharge, 218 (9%) experienced an adverse drug event (ADE) and 862 (36%) visited the emergency department (ED), were rehospitalized, or died. After adjustment, each additional new PIM and continued community PIM were respectively associated with a 21% (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 1.01-1.45) and a 10% (OR = 1.10; 95% CI = 1.01-1.21) increased odds of ADEs. They were also respectively associated with a 13% (hazard ratio [HR] = 1.13; 95% CI = 1.03-1.26) and a 5% (HR = 1.05; 95% CI = 1.00-1.10) increased risk of ED visits, rehospitalization, and death., Conclusions: Two in three hospitalized patients were prescribed a PIM at discharge, and increasing numbers of PIMs were associated with an increased risk of ADEs and all-cause adverse events. Improving hospital prescribing practices may reduce the frequency of PIMs and associated adverse events. J Am Geriatr Soc 68:1184-1192, 2020., (© 2020 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.)

Background: In-hospital medication reconciliation has not demonstrated reductions in adverse health outcomes, possibly because patients do not follow the changes made to their preadmission medications. Our objective was to determine the incidence of and variables associated with failure to follow newly prescribed therapies, discontinued medications, and dose changes., Methods: A prospective cohort study of patients admitted to hospitals in Montreal, Quebec between 2014 and 2016 was conducted. Failure to follow medication changes 30 days post discharge was measured by comparing prescribed and dispensed medications. Multivariable logistic regression was used to determine characteristics associated with failure to follow changes., Results: Among 2655 patients, mean age was 69.5 years (SD 14.7), and 1581 (60%) were males. There were 10,068 medication changes made at hospital discharge and 24% were not followed in the 30 days post discharge. Thirty percent of dose modifications were filled at the incorrect dose, 27% of new medications were not filled, and 12% of discontinued medications were filled. A number of factors increased the risk of failure to follow medication changes, including increasing out-of-pocket medication costs (adjusted odds ratio [aOR] 1.12; 95% confidence interval [CI], 1.07-1.18), discharge to long-term care facility (aOR 2.29; 95% CI, 1.63-3.08), and not having medications dispensed prior to admission (aOR 4.67; 95% CI, 3.75-5.90)., Conclusion: One in 4 hospital medication changes was not followed post discharge. Health policy aimed at eliminating out-of-pocket medication costs and investigation of factors influencing failure to follow changes for those not dispensed medications prior to admission and for long-term care residents are important next steps to address this issue., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Adverse drug events (ADEs) account for up to 16% of emergency department (ED) visits and 7% of hospital admissions. Medication reconciliation is required for hospital accreditation because it can reduce medication discrepancies, but there is no evidence that reducing discrepancies reduces ADEs or other adverse outcomes., Objective: To evaluate whether electronic medication reconciliation reduces ADEs, medication discrepancies, and other adverse outcomes compared with usual care., Design, Setting, and Participants: This cluster randomized trial involved 3491 patients who were discharged from 2 medical units and 2 surgical units at the McGill University Health Centre, Montreal, Quebec, Canada, between October 2014 and November 2016. Data analysis took place from July 2017 to July 2019., Intervention: The RightRx intervention electronically retrieved community drugs from the provincial insurer and aligned them with in-hospital drugs to facilitate reconciliation and communication at care transitions., Main Outcomes and Measures: The primary outcome was ADEs in 30 days after discharge. Secondary outcomes included medication discrepancies, ED visits, hospital readmissions, and a composite outcome of ED visits, readmissions, and death up to 90 days after discharge., Results: Of 4656 eligible patients, 3567 (76.6%) consented to participate (2060 [57.8%] men; mean [SD] age, 69.8 [14.9] years). Overall, 76 patients died during the hospital stay, so 3491 patients were included in the analysis. There was no significant difference in the risk of ADEs between intervention and control groups (76 [4.6%] vs 73 [4.0%]; OR, 0.97; 95% CI, 0.33-1.48), ED visits (433 [26.2%] vs 488 [26.6%]; OR, 0.83; 95% CI, 0.36-1.42), hospital readmission (170 [10.3%] vs 261 [14.2%]; OR, 0.22; 95% CI, 0.06-1.14), or the composite outcome (447 [27.0%] vs 506 [27.6%]; OR, 0.75; 95% CI, 0.34-1.27) at 30 days. Medication discrepancies were significantly reduced in the intervention group compared with the control group (437 [26.4%] vs 1029 [56.0%]; OR, 0.24; 95% CI, 0.12-0.57). Changes made to community medications (OR, 1.05; 95% CI, 1.01-1.10) and new medications (OR, 1.09; 95% CI, 1.01-1.18) were significant risk factors for ADEs., Conclusions and Relevance: Electronic medication reconciliation reduced medication discrepancies but did not reduce ADEs or other adverse outcomes. Hospital accreditation should focus on interventions that reduce the risk of adverse events for patients with multiple changes to community medications., Trial Registration: ClinicalTrials.gov identifier: NCT01179867.

Over 3 million hospitalizations and 17 million ER visits occur in Canada each year. A substantial proportion of these encounters are preventable and attributable to medication non- adherence. Non-adherence to medication changes during discharge increases the risk of adverse events post-discharge. A mobile application was developed to improve medication management of post-discharge patients. A pilot randomized controlled trial was conducted to assess the application's usability and efficacy in decreasing non-adherence to medication changes made at discharge.

Bats are increasingly implicated as hosts of highly pathogenic viruses. The underlying virus⁻host interactions and cellular mechanisms that promote co-existence remain ill-defined, but physiological traits such as flight and longevity are proposed to drive these adaptations. Autophagy is a cellular homeostatic process that regulates ageing, metabolism, and intrinsic immune defense. We quantified basal and stimulated autophagic responses in black flying fox cells, and demonstrated that although black flying fox cells are susceptible to Australian bat lyssavirus (ABLV) infection, viral replication is dampened in these bat cells. Black flying fox cells tolerated prolonged ABLV infection with less cell death relative to comparable human cells, suggesting post-entry mechanisms interference with virus replication. An elevated basal autophagic level was observed and autophagy was induced in response to high virus doses. Pharmacological stimulation of the autophagy pathway reduced virus replication, indicating autophagy acts as an anti-viral mechanism. Enhancement of basal and virus-induced autophagy in bat cells connects related reports that long-lived species possess homeostatic processes that dampen oxidative stress and macromolecule damage. Exemplifying the potential that evolved cellular homeostatic adaptations like autophagy may secondarily act as anti-viral mechanisms, enabling bats to serve as natural hosts to an assortment of pathogenic viruses. Furthermore, our data suggest autophagy-inducing drugs may provide a novel therapeutic strategy for combating lyssavirus infection.

Background: There is increasing concern over the use of benzodiazepine receptor agonists (BZRAs). The objective of this study was to describe BZRA dispensations in the province of Alberta in 2015 according to age, sex and appropriateness., Methods: A population-based descriptive study of people 10 years of age or older with at least 1 BZRA dispensation in Alberta, Canada, between Jan. 1 and Dec. 31, 2015, was conducted. Prevalence of BZRA use, characteristics of BZRAs dispensations, use at the individual level and appropriateness were determined., Results: A total of 372 870 people received 2 463 585 BZRA dispensations in Alberta in 2015. Prevalence of use at the population level was 10% overall, increased with age ( p value for trend < 0.001) and was consistently highest among females. Twenty percent of patients used both Z-drugs and benzodiazepines. BZRA users had an average of 7 dispensations (standard deviation [SD] 20), 137 days of use overall (SD 123) and a maximum period of consecutive use of 90 days (SD 95). Days of consecutive use were highest among those aged 65 years or older (126 d). A total of 62 795 (17%) people used more than 1 distinct BZRA ingredient concurrently and 10% had 3 or more distinct prescribers., Interpretation: The prevalence of BZRA use was high and a substantial proportion of use appeared to be potentially inappropriate. This study supports the need for continued monitoring for the prescribing and use of these medications at the population level., Competing Interests: Competing interests: Salim Samanani reports receiving a grant from the College of Physicians & Surgeons of Alberta, during the conduct of the study. No other competing interests were declared., (Copyright 2018, Joule Inc. or its licensors.)

Aims: To evaluate the association between metformin use and heart failure (HF) exacerbation in people with type 2 diabetes (T2D) and pre-existing HF using alternative exposure models., Materials and Methods: We analysed data for patients with T2D and incident HF from a national US insurance claims database. We compared the results of several multivariable Cox models where time-varying use of metformin was modelled as: (1) current use; (2) total duration of past use; and (3) use within the past 30 days or 10 days. The outcome was defined as time to HF-related hospitalization. We then re-analysed the data using flexible weighted cumulative exposure (WCE) models., Results: A total of 7620 patients with diabetes and incident HF were analysed. The mean (SD) patient age was 54 (8) years, and 58% (n = 4440) were men. In all, 3799 individuals (50%) were exposed to metformin, and 837 HF hospitalizations (11%) occurred (mean follow-up 1.7 years). Results of conventional models suggested potential acute benefits in reducing HF exacerbation with metformin use in the past 10 days (adjusted hazard ratio [aHR] 0.76, 95% confidence interval [CI] 0.60-0.97), while WCE models, which provided a better fit for the data, suggested lack of a systematic effect (aHR 0.91, 95% CI 0.69-1.20)., Conclusions: Our results suggest that cumulative metformin exposure does not decrease the risk of HF-related exacerbation. Use of other anti-hyperglycaemic agents with proven efficacy in patients with HF should also be considered as treatment options in this population., (© 2018 John Wiley & Sons Ltd.)

Objectives: The primary objective of this study was to identify the predictors of new-onset psychological distress available in routinely collected administrative health databases for women diagnosed with breast cancer. The secondary objective was to explore whether the predictors vary based on the period of cancer care. Methods: A population-based cohort study followed 16,495 female patients with newly diagnosed breast cancer who did not experience psychological distress during the 14 months before breast cancer surgery. The incidence of psychological distress was reported overall and by type of mental health problem. Time-varying Cox proportional hazards models were developed to identify predictors of new-onset psychological distress during 2 key periods of cancer care: (1) hospital-based treatment during which women undergo treatment with breast surgery, chemotherapy, and/or radiation, and (2) 1-year transitional survivorship when women begin follow-up care. Results: The incidence of psychological distress was 16% within each period. Anxiety was present in 85.1% and 65.5% of new cases during hospital-based treatment and transitional survivorship, respectively. Predictors during both periods were younger age, receipt of axillary lymph node dissection, rheumatologic disease, and baseline menopausal symptoms, as well as new opioid dispensations, emergency department visits, and hospital contacts that occurred during follow-up. Other predictors varied based on the period of cancer care. More advanced breast cancer and type of treatment were associated with onset of psychological distress during hospital-based treatment. Psychological distress during transitional survivorship was predicted by diagnosis of localized breast disease, shorter duration of hospital-based treatment, receipt of additional hospital-based treatment in survivorship, and newly diagnosed comorbidities or symptoms. Conclusions: This study identified the predictors of new-onset psychological distress available in routinely collected administrative health databases, and showed how predictors change between hospital-based treatment and transitional survivorship periods. The results highlight the importance of developing predictive models tailored to the period of cancer care., (Copyright © 2018 by the National Comprehensive Cancer Network.)

Objective: (1) To describe the usage of medication data from the Health Information Exchange (HIE) at the health care system level in the province of Quebec; (2) To assess the accuracy of the medication list obtained from the HIE., Methods: A descriptive study was conducted utilizing usage data obtained from the Ministry of Health at the individual provider level from January 1 to December 31, 2015. Usage patterns by role, type of site, and tool used to access the HIE were investigated. The list of medications of 111 high risk patients arriving at the emergency department of an academic healthcare center was obtained from the HIE and compared with the list obtained through the medication reconciliation process., Results: There were 31 022 distinct users accessing the HIE 11 085 653 times in 2015. The vast majority of pharmacists and general practitioners accessed it, compared to a minority of specialists and nurses. The top 1% of users was responsible of 19% of access. Also, 63% of the access was made using the Viewer application, while using a certified electronic medical record application seemed to facilitate usage. Among 111 patients, 71 (64%) had at least one discrepancy between the medication list obtained from the HIE and the reference list., Conclusions: Early adopters were mostly in primary care settings, and were accessing it more frequently when using a certified electronic medical record. Further work is needed to investigate how to resolve accuracy issues with the medication list and how certain tools provide different features.

Hendra virus (HeV) and Nipah virus (NiV) are zoonotic viruses that emerged in the mid to late 1990s causing disease outbreaks in livestock and people. HeV appeared in Queensland, Australia in 1994 causing a severe respiratory disease in horses along with a human case fatality. NiV emerged a few years later in Malaysia and Singapore in 1998-1999 causing a large outbreak of encephalitis with high mortality in people and also respiratory disease in pigs which served as amplifying hosts. The key pathological elements of HeV and NiV infection in several species of mammals, and also in people, are a severe systemic and often fatal neurologic and/or respiratory disease. In people, both HeV and NiV are also capable of causing relapsed encephalitis following recovery from an acute infection. The known reservoir hosts of HeV and NiV are several species of pteropid fruit bats. Spillovers of HeV into horses continue to occur in Australia and NiV has caused outbreaks in people in Bangladesh and India nearly annually since 2001, making HeV and NiV important transboundary biological threats. NiV in particular possesses several features that underscore its potential as a pandemic threat, including its ability to infect humans directly from natural reservoirs or indirectly from other susceptible animals, along with a capacity of limited human-to-human transmission. Several HeV and NiV animal challenge models have been developed which have facilitated an understanding of pathogenesis and allowed for the successful development of both active and passive immunization countermeasures., (Published by Elsevier Ltd.)

Aims: To examine whether patients using sitagliptin at the time of an acute coronary syndrome event are at increased risk of incident heart failure compared with those not exposed., Methods: Using US claims data, people with diabetes without a history of heart failure in the 3 years before hospitalization for acute coronary syndrome were identified for the period 2004 to 2010. We used a nested case-control design, whereby cases were patients who developed incident heart failure <30 days after admission to hospital for acute coronary syndrome and were matched by age and sex with up to 10 controls with no heart failure. Subjects exposed or not exposed to sitagliptin in the 90 days before acute coronary syndrome admission were compared using conditional logistic regression after adjustment for clinical and laboratory data, healthcare utilization and propensity scores., Results: In total, 457 cases of heart failure developing de novo after diagnosis of acute coronary syndrome were matched to 4570 controls. The average age of the subjects was 55 years and 65% were male. Overall, 11 of 147 (7%) people exposed to sitagliptin developed heart failure compared with 446 of the 4880 people not exposed (9%, adjusted odds ratio 0.75, 95% CI 0.38-1.46; P=0.40). Sitagliptin exposure before acute coronary syndrome was not associated with an increased risk of death or heart failure combined (7% vs 9%, adjusted odds ratio 0.66, 95% CI 0.34-1.28)., Conclusions: In our sample of patients who are at high risk of heart failure after acute coronary syndrome, sitagliptin exposure was not associated with an increased risk of de novo heart failure., (© 2015 Diabetes UK.)

Objectives: To evaluate the impact of continuity of care and multimorbidity on health outcomes in patients with diabetes., Research Design: Using a US claims database of insured patients, we identified those with incident diabetes between 2004 and 2008 and followed them until death, disenrollment, or December 31, 2010. Continuity of care was defined using Breslau's Usual Provider of Continuity (UPC; proportion of visits to the usual or predominant provider within 2 y of diabetes diagnosis). Multivariable logistic regression was used to determine the association between UPC in the first 2 years after diabetes diagnosis and subsequent 1-year composite primary outcome of all-cause hospitalization or death in year 3 in patients with/without multimorbidity., Results: Of the 285,231 patients with incident diabetes, 74% had multimorbidity; their average age was 53 years (SD=10.5) and 49% were female. A total of 77,270 (27%) individuals had a mean UPC≥75% in the first 2 years. During year 3 of follow-up, 33,632 (12%) patients died or were hospitalized for any cause. Greater continuity of care (UPC≥75%) was associated with reduced risk of subsequent death or hospitalization [7.2% vs. 13.5%; adjusted odds ratio (aOR)=0.72; 95% CI, 0.70-0.75]. Although multimorbidity was independently associated with an increased risk of our primary composite endpoint (13.4% vs. 7.2%; aOR=1.26; 95% CI, 1.21-1.30), the association between greater continuity and better outcomes was similar in those with multimorbidity (aOR=0.71; 95% CI, 0.69-0.71) as in those without (aOR=0.75; 95% CI, 0.71-0.80)., Conclusions: In patients with incident diabetes, greater continuity of care is associated with improved outcomes, irrespective of whether or not they have multimorbidity.

The impact of multimorbidity on patients with community-acquired pneumonia has not been well characterised. Thus, our aim was to explore the relationship between multimorbidity and adverse events within 90 days of discharge. Data were prospectively collected for a population-based cohort of all adults discharged from any of the seven emergency departments (ED) or six hospitals in Edmonton (Alberta, Canada) with community-acquired pneumonia. Multivariable Cox regression models were used to examine the independent association between multimorbidity (defined as two or more chronic conditions) and subsequent 90-day mortality, hospitalisation, or ED visits after treatment of pneumonia. The cohort included 5565 patients, mean age was 57 years (SD 20), 54% were male, and 59% were treated as outpatients; 1602 (29%) patients had multimorbidity. Within 90 days, 255 (5%) patients died, 1205 (22%) were hospitalised, 1280 (23%) died or were hospitalised, and 2049 (37%) were admitted to the ED. The presence of multimorbidity was independently associated with an increased risk of death or hospitalisation within 90 days (37% vs. 17% for those without multimorbidity, adjusted hazard ratio: 1.43, 95% confidence interval: 1.26 to 1.62) as well as ED visits (45% vs. 34%, adjusted hazard ratio: 1.40, 95% confidence interval: 1.26 to 1.56). Multimorbidity was present in one-third of all patients with pneumonia in our study, and it was independently associated with death, hospitalisation, or return to ED within 90 days of discharge. Our findings suggest that multimorbidity is strongly related to prognosis and should be considered when making site-of-care decisions in the ED or deciding upon readiness for discharge., (Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Aims: Many studies have demonstrated the effectiveness of primary prevention strategies in type 2 diabetes, however, questions remain around the feasibility of high resource, intensive interventions within a healthcare setting. We report the results of a dietitian-led pre-diabetes education session targeting healthy eating and active living as strategies for weight reduction., Methods: Participants were asked to complete a baseline questionnaire prior to completing the pre-diabetes education session and were sent follow-up questionnaires at 3 and 6 months. Differences between participants at baseline, 3 and 6 months were determined using χ(2), t-tests and ANOVA., Results: Of the 211 participants asked to fill out baseline questionnaires, 45 participants completed questionnaires at baseline, 3 months and 6 months. Although we observed general trends towards improvements in diet, physical activity and weight related behaviours among the 45 completers, no significant changes were observed among participants between questionnaire periods., Conclusion: A "one-off", theory-guided group education session may be insufficient to support lifestyle modifications in the context of weight management in a pre-diabetic population. Further evaluation of the efficacy and feasibility of the PCN as a setting for lifestyle intervention is required., (Copyright © 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Objectives: The study objective was to evaluate the effects of sitagliptin in patients with type 2 diabetes (T2D) and heart failure (HF)., Background: There is uncertainty in the literature about whether dipeptidyl peptidase (DPP)-4 inhibitors cause harm in patients with HF and T2D., Methods: We analyzed data from a national commercially insured U.S. claims database. Patients with incident HF were identified from individuals with T2D initially treated with metformin or sulfonylurea and followed over time. Subjects subsequently using sitagliptin were compared with those not using sitagliptin in the 90 days before our primary outcome of all-cause hospital admission or death using a nested case-control analysis after adjustment for demographics and clinical and laboratory data. HF-specific hospital admission or death also was assessed., Results: A total of 7,620 patients with diabetes and incident HF met our inclusion criteria. Mean (SD) age was 54 years (9), and 58% (3,180) were male. Overall, 887 patients (12%) were exposed to sitagliptin therapy (521 patient years of exposure) after incident HF. Our primary composite endpoint occurred in 4,137 patients (54%). After adjustment, sitagliptin users were not at an increased risk for the primary endpoint (7.1% vs. 9.2%, adjusted odds ratio [aOR]: 0.84, 95% confidence interval [CI]: 0.69 to 1.03) or each component (hospital admission 7.5% vs. 9.2%, aOR: 0.93, 95% CI: 0.76 to 1.14; death 6.9% vs. 9.3%, aOR: 1.16, 95% CI: 0.68 to 1.97). However, sitagliptin use was associated with an increased risk of HF hospitalizations (12.5% vs. 9.0%, aOR: 1.84, 95% CI: 1.16 to 2.92)., Conclusions: Sitagliptin use was not associated with an increased risk of all-cause hospitalizations or death, but was associated with an increased risk of HF-related hospitalizations among patients with T2D with pre-existing HF., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Most patients are not treated for osteoporosis after their fragility fracture "teachable moment." Among almost 400 consecutive wrist fracture patients, we determined that better-than-average osteoporosis knowledge (adjusted odds = 2.6) and BMD testing (adjusted odds = 6.5) were significant modifiable facilitators of bisphosphonate treatment while male sex, working outside the home, and depression were major barriers., Introduction: In the year following fragility fracture, fewer than one quarter of patients are treated for osteoporosis. Although much is known regarding health system and provider barriers and facilitators to osteoporosis treatment, much less is understood about modifiable patient-related factors., Methods: Older patients with wrist fracture not treated for osteoporosis were enrolled in trials that compared a multifaceted intervention with usual care controls. Baseline data included a test of patient osteoporosis knowledge. We then determined baseline factors that independently predicted starting bisphosphonate treatment within 1 year., Results: Three hundred seventy-four patients were enrolled; mean age 64 years, 78 % women, 90 % white, and 54 % with prior fracture. Within 1 year, 86 of 374 (23 %) patients were treated with bisphosphonates. Patients who were treated had better osteoporosis knowledge at baseline (70 % correct vs 57 % for untreated, p < 0.001) than patients who remained untreated; conversely, untreated patients were more likely to be male, still working, and report depression. In fully adjusted models, osteoporosis knowledge was independently associated with starting bisphosphonates (adjusted OR 2.6, 95 %CI 1.3-5.3). Obtaining a BMD test (aOR 6.5, 95 %CI 3.4-12.2) and abnormal BMD results (aOR 34.5, 95 %CI 16.8-70.9) were strongly associated with starting treatment., Conclusions: The most important modifiable facilitators of osteoporosis treatment in patients with fracture were knowledge and BMD testing. Specifically targeting these two patient-level factors should improve post-fracture treatment rates.

Background: The rates and risk factors for developing recurrent pneumonia following hospitalization with community-acquired pneumonia (CAP) are poorly understood., Methods: We examined a population-based cohort of patients with CAP who survived hospital admission and who were free of pneumonia for at least 3 months. We collected clinical, functional, and medication-related information and pneumonia severity index (PSI). Using linked databases we followed patients for 5 years and captured any clinical episode of pneumonia 90 days or more post-discharge. We used Cox proportional hazards models (adjusted for age, sex, PSI, functional status, medications) to determine rates and independent correlates of recurrent pneumonia., Results: The final cohort included 2709 inpatients; 43% were 75 years or older, 34% were not fully independent, and 56% had severe pneumonia. Over 5 years of follow-up, 245 (9%; 95% confidence interval [CI], 8%-10%) patients developed recurrent pneumonia, and 156 (64%) of these episodes required hospitalization. Rate of recurrence was 3.0/100 person-years and median time to recurrence was 317 days (interquartile range, 177-569); 32 (13%) patients had 2 or more recurrences. In multivariable analyses only age >75 years (adjusted P = .047) and less than fully independent functional status (12% recurrence rate with impaired functional status vs 7% for fully independent; adjusted hazard ratio, 1.7; 95% CI, 1.3-2.2; P < .001) were significantly associated with recurrent pneumonia., Conclusions: One of 11 patients who survived CAP hospitalization had recurrent pneumonia over 5 years and those with impaired functional status were at particularly high risk. Recurrent pneumonia is common and more attention to preventive strategies at discharge and closer follow-up over the long-term seem warranted., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Rural residents face numerous barriers to healthcare access and studies suggest poorer health outcomes for rural patients. Therefore we undertook a systematic review to determine if cardiovascular medication utilization and adherence patterns differ for rural versus urban patients., Methods: A comprehensive search of major electronic datasets was undertaken for controlled clinical trials and observational studies comparing utilization or adherence to cardiovascular medications in rural versus urban adults with cardiovascular disease or diabetes. Two reviewers independently identified citations, extracted data, and evaluated quality using the STROBE checklist. Risk estimates were abstracted and pooled where appropriate using random effects models. Methods and reporting were in accordance with MOOSE guidelines., Results: Fifty-one studies were included of fair to good quality (median STROBE score 17.5). Although pooled unadjusted analyses suggested that patients in rural areas were less likely to receive evidence-based cardiovascular medications (23 studies, OR 0.88, 95% CI 0.79, 0.98), pooled data from 21 studies adjusted for potential confounders indicated no rural-urban differences (adjusted OR 1.02, 95% CI 0.91, 1.13). The high heterogeneity observed (I(2) = 97%) was partially explained by treatment setting (hospital, ambulatory care, or community-based sample), age, and disease. Adherence did not differ between urban versus rural patients (3 studies, OR 0.94, 95% CI 0.39, 2.27, I(2) = 91%)., Conclusions: We found no consistent differences in rates of cardiovascular medication utilization or adherence among adults with cardiovascular disease or diabetes living in rural versus urban settings. Higher quality evidence is needed to determine if differences truly exist between urban and rural patients in the use of, and adherence to, evidence-based medications.

Background: Australian bat lyssavirus (ABLV), a rhabdovirus of the genus Lyssavirus which circulates in both pteropid fruit bats and insectivorous bats in mainland Australia, has caused three fatal human infections, the most recent in February 2013, manifested as acute neurological disease indistinguishable from clinical rabies. Rhabdoviruses infect host cells through receptor-mediated endocytosis and subsequent pH-dependent fusion mediated by their single envelope glycoprotein (G), but the specific host factors and pathways involved in ABLV entry have not been determined., Methods: ABLV internalization into HEK293T cells was examined using maxGFP-encoding recombinant vesicular stomatitis viruses (rVSV) that express ABLV G glycoproteins. A combination of chemical and molecular approaches was used to investigate the contribution of different endocytic pathways to ABLV entry. Dominant negative Rab GTPases were used to identify the endosomal compartment utilized by ABLV to gain entry into the host cell cytosol., Results: Here we show that ABLV G-mediated entry into HEK293T cells was significantly inhibited by the dynamin-specific inhibitor dynasore, chlorpromazine, a drug that blocks clathrin-mediated endocytosis, and the actin depolymerizing drug latrunculin B. Over expression of dominant negative mutants of Eps15 and Rab5 also significantly reduced ABLV G-mediated entry into HEK293T cells. Chemical inhibitors of caveolae-dependent endocytosis and macropinocytosis and dominant negative mutants of Rab7 and Rab11 had no effect on ABLV entry., Conclusions: The predominant pathway utilized by ABLV for internalization into HEK293T cells is clathrin-and actin-dependent. The requirement of Rab5 for productive infection indicates that ABLV G-mediated fusion occurs within the early endosome compartment.

Australian bat lyssavirus (ABLV) is a recently emerged rhabdovirus of the genus lyssavirus considered endemic in Australian bat populations that causes a neurological disease in people indistinguishable from clinical rabies. There are two distinct variants of ABLV, one that circulates in frugivorous bats (genus Pteropus) and the other in insectivorous microbats (genus Saccolaimus). Three fatal human cases of ABLV infection have been reported, the most recent in 2013, and each manifested as acute encephalitis but with variable incubation periods. Importantly, two equine cases also arose recently in 2013, the first occurrence of ABLV in a species other than bats or humans. Similar to other rhabdoviruses, ABLV infects host cells through receptor-mediated endocytosis and subsequent pH-dependent fusion facilitated by its single fusogenic envelope glycoprotein (G). Recent studies have revealed that proposed rabies virus (RABV) receptors are not sufficient to permit ABLV entry into host cells and that the unknown receptor is broadly conserved among mammalian species. However, despite clear tropism differences between ABLV and RABV, the two viruses appear to utilize similar endocytic entry pathways. The recent human and horse infections highlight the importance of continued Australian public health awareness of this emerging pathogen.

Australian bat lyssavirus (ABLV) is a rhabdovirus of the lyssavirus genus capable of causing fatal rabies-like encephalitis in humans. There are two variants of ABLV, one circulating in pteropid fruit bats and another in insectivorous bats. Three fatal human cases of ABLV infection have been reported with the third case in 2013. Importantly, two equine cases also arose in 2013; the first occurrence of ABLV in a species other than bats or humans. We examined the host cell entry of ABLV, characterizing its tropism and exploring its cross-species transmission potential using maxGFP-encoding recombinant vesicular stomatitis viruses that express ABLV G glycoproteins. Results indicate that the ABLV receptor(s) is conserved but not ubiquitous among mammalian cell lines and that the two ABLV variants can utilize alternate receptors for entry. Proposed rabies virus receptors were not sufficient to permit ABLV entry into resistant cells, suggesting that ABLV utilizes an unknown alternative receptor(s)., (Published by Elsevier Inc.)

Background: There is an ongoing controversy regarding the safety and effectiveness of metformin in the setting of heart failure (HF). Therefore, we undertook a systematic review of the trial and nontrial evidence for metformin in patients with diabetes mellitus and HF., Methods and Results: We conducted a comprehensive search for controlled studies, evaluating the association between metformin and morbidity and mortality in people with diabetes mellitus and HF. Two reviewers independently identified citations, extracted data, and evaluated quality. Risk estimates were abstracted and pooled where appropriate. As measures of overall safety, we examined all-cause mortality and all-cause hospitalizations. Nine cohort studies were included; no randomized controlled trials were identified. Most (5 of 9) studies were published in 2010 and were of good quality. Metformin was associated with reduced mortality compared with controls (mostly sulfonylurea therapy): 23% versus 37% (pooled adjusted risk estimates: 0.80; 0.74-0.87; I(2)=15%; P<0.001). No increased risk was observed for metformin in those with reduced left ventricular ejection fraction (mortality pooled adjusted risk estimate: 0.91; 0.72-1.14; I(2)=0%; P=0.34), nor in those with HF and chronic kidney disease (pooled adjusted risk estimate: 0.81; 0.64-1.02; P=0.08). Metformin was associated with a small reduction in all-cause hospitalizations (pooled adjusted risk estimate: 0.93; 0.89-0.98; I(2)=0%; P=0.01). Metformin was not associated with increased risk of lactic acidosis., Conclusions: The totality of evidence indicates that metformin is at least as safe as other glucose-lowering treatments in patients with diabetes mellitus and HF and even in those with reduced left ventricular ejection fraction or concomitant chronic kidney disease. Until trial data become available, metformin should be considered the treatment of choice for patients with diabetes mellitus and HF.

Background: Canada's Common Drug Review was implemented to provide publicly funded drug plans (provincial and federal) with a transparent, rigorous and consistent approach for assessing the clinical effectiveness and cost-effectiveness of new drugs. We compared uptake of drug coverage across jurisdictions before and after the implementation of the Common Drug Review., Methods: Using the IMS Brogan formulary acceptance: monitoring and evaluation database, we identified new drug products in Canada five years before and five years after the first recommendation was made by the Common Drug Review. For each jurisdiction, we compared the proportion of drugs listed, the median time-to-listing and the agreement between the listing decisions of the drug plans and the recommendations of the Common Drug Review., Results: We identified 198 new drugs approved for use in Canada between May 26, 1999, and May 27, 2009, of which 53 had a recommendation from the Common Drug Review. The proportion of drugs listed decreased after the introduction of the Common Drug Review for all participating drug plans (81.1% to 71.3% overall [p ≤ 0.01 for all plans, with the exceptions of Ontario and Quebec [p = 0.07]). The change in median time-to-listing between the periods before and after the Common Drug Review varied by jurisdiction, ranging from a decrease of 691 days to an increase of 250 days. The change in median time-to-listing was not statistically significant for most jurisdictions, with the exceptions of Saskatchewan (increased, Mann-Whitney U test p = 0.01) and New Brunswick, Prince Edward Island, and Newfoundland and Labrador (all decreased, Mann-Whitney U test p < 0.01)., Interpretation: There was a decline in the proportion of new drugs listed after the introduction of the Common Drug Review for both participating and nonparticipating jurisdictions. The introduction of the review was associated with a decreased time-to-listing for certain smaller provinces.

The purification of highly homogeneous, phospholipase-free alpha-bungarotoxin (alpha-Bgt) from the venom of the elapid Bungarus multicinctus or from commercial samples of alpha-Bgt is described. The method combines a conventional procedure for the purification of alpha-Bgt [D. Mebs, K. Narita, S. Iwanaga, Y. Samejima, and C. Y. Lee (1972) Hoppe-Seyler's Z. Physiol. Chem. 353, 243-262] with high-resolution gel-filtration and cation-exchange chromatography steps to remove membrane-damaging, contaminating phospholipase activity. The procedure also removes contaminating radioactive peptides from commercial preparations of 125I-alpha-Bgt. Apparent homogeneity of the purified alpha-Bgt (referred to as fraction D in the text), as well as the absence of contaminating phospholipase A2 activity, is assessed by (i) polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate, (ii) gel-filtration and cation-exchange high-performance liquid chromatography, (iii) direct measurements of phospholipase A2 activity under conditions where very low enzymatic levels should be detected, (iv) lack of interference with the passive cation permeability properties of acetylcholine receptor membranes, (v) competitive inhibition of 125I-alpha-Bgt binding to the acetylcholine receptor membranes, and (vi) amino acid analysis and end-group (C- and N-terminus) determination. alpha-Bgt preparations subjected to these criteria do not exert the increase in membrane passive permeability to cations detected with other laboratory or commercial samples of alpha-Bgt. Availability of the new alpha-Bgt preparation allows for an assessment of the inertness of alpha-Bgt on lipid membrane properties while preventing cholinergic ligand binding to nicotinic acetylcholine receptor-rich membranes. These conditions are necessary for experiments requiring maintenance of the physical and phospholipid integrity of membranes.

Homogenates of rabbit heart hydrolyzed the phospholipids of autoclaved E. coli maximally at pH 7.0 with 5.0 mM added CaCl2; EDTA was a potent inhibitor. More than 70% of the homogenate phospholipase A activity was sedimented at 100 000 x g. Homogenates dialyzed to pH 3.0 had a similar pH optima, but required less than 1.0 mM added CaCl2 for optimal activity. Sulfuric acid extraction of whole heart, and other rabbit organs, solubilized a calcium-dependent phospholipase A that was maximally active at pHs 7.0 to 7.5. Myocardial extracts were as active (approx. 60 nmol/h/mg) as acid extracts from rabbit lung, liver and kidney. Phospholipase(s) A with similar properties were solubilized by acid extraction of 12-day-old chick embryo myocytes (10 nmol/h/mg). Regardless of origin, the phospholipases A were absolutely specific for release of fatty acid from the 2-acyl position of phospholipids. Activity was inhibited by (i) pretreatment with p-bromo-phenacylbromide; (ii) the anesthetics, dibucaine and chlorpromazine; and (iii) the nonsteroidal antiinflammatory agents, indomethacin, ibuprofen and meclofenamate. Aspirin and dexamethasone had little or no effect on enzymic activity.

The effects of propofol given before and during a period of profound hypotension that caused incomplete global cerebral ischaemia were investigated in anaesthetised cats. Cortical cerebral blood flow, extracellular fluid pH, potassium and calcium ion activities, and electroencephalogram were recorded. Neuropathological outcome was also assessed. Propofol-treated animals had higher cerebral blood flows than control animals after the period of hypotension (p <0.05); they also had better correction of extracellular fluid acidosis and hyperkalaemia (p <0.01) and a late improvement in calcium ion activity (p <0.05). Neuropathological outcome was not significantly different between the groups.