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Background: The Prospective Research In MEmory clinics (PRIME) is a three-year non-prescriptive, observational study identifying and measuring relationships among predictor and outcome variables.Methods: Patients from nine memory clinics, diagnosed with dementia or mild cognitive impairment (MCI), living in the community with <40 hours/week nursing care were divided into diagnostic groups defined at baseline as Alzheimer's disease (AD) early or late onset, frontotemporal dementia (FTD), vascular dementia (VaD), mixed (AD and VaD) and other dementia. To achieve outcome measures, baseline and change over six months in all measures by diagnostic group, and predictors of change at six months were examined.Results: Of the 970 patients enrolled, 967 were eligible for analysis. The most common disorder was AD (late onset) accounting for 46.5% of this population. Patients had an overall slight worsening on all assessment scales over the six-month period. Patients with FTD had a more marked change (decline) in cognition, function and behavior over six months compared to other diagnostic groups. However, in the regression analysis the difference was not significant between groups. Predictors of decline in Mini-Mental State Examination (MMSE) scores were not robust at six months, and longer follow-up is required. Patients with FTD were more likely to be prescribed psychotropics.Conclusion: The PRIME study is continuing and will provide important data on predictors of decline along with differences between diagnosis groups on the rate of change. [ABSTRACT FROM AUTHOR]

Objective: To collect descriptive data on the treatment of Alzheimer's disease with galantamine under naturalistic conditions.Study Design: This was a prospective, open-label, observational study.Patients: Subjects (n = 345) with mild to moderately severe dementia of the Alzheimer's type were recruited from 48 hospitals in Australia.Methods: Subjects were enrolled and received treatment with galantamine for 6 months in a clinical practice setting. Subjects were assessed at baseline and 3 and 6 months after starting treatment using the Mini-Mental State Examination (MMSE), the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [the latter only if the baseline MMSE score was at least 25]. Subjects were also assessed using an abridged Instrumental Activities of Daily Living (IADL) questionnaire that included questions on using the telephone, ability to travel more than 1km outside the home, taking medications and managing money, and an 11-item behaviour assessment scale that measured aggression, sleep disturbance, disinhibition, personality changes, irritability, depression, agitation, apathy, inertia, hallucinations and aberrant motor behaviour.Results: Of the 345 subjects who were enrolled in the study (intent-to-treat [ITT] population), 229 completed the baseline, 3- and 6-month visits (per-protocol [PP] population). The mean age of the PP population was 78.0 +/- 6.8 years. At 6 months, most PP subjects (70%) showed an increase in MMSE score compared with baseline, with a mean increase in score of 2.0 +/- 3.1 points from a baseline of 20.8 +/- 4.2 points. In the ITT population, 44% of subjects (151/345) showed an increase in MMSE after 6 months. If data were unavailable the patient was classified as a nonresponder. Of the 21 PP patients who were assessed using ADAS-cog, 18 (86%) demonstrated a decrease in the ADAS-cog score, reflecting an improvement in cognition. Of the ITT population, 33% (19/57) had a decreased ADAS-cog score after 6 months. Most PP subjects (86%) were considered responders according to the CIBIC-plus score, with 65% showing some improvement over 6 months of treatment. Of the ITT population, 54% (187/345) showed no deterioration in CIBIC-plus score after 6 months.No deterioration in IADL or behaviour assessments occurred in the majority of PP subjects over 6 months.Conclusions: In a clinical practice setting, the majority of subjects receiving galantamine who completed the study maintained their ratings of cognition, function, behaviour or global assessment over the 6-month period. [ABSTRACT FROM AUTHOR]

The dexamethasone suppression test (DST) was administered to 40 adults with severe and profound mental retardation. All participants were free from known conditions which may have given misleading results from cortisol assay. Of nine participants who showed symptoms possibly indicating depression the DST results concurred in two cases (i.e. there were two true-positives). However there were four or five (depending on criteria adopted) false-positive DST results. There did not appear to be a consistent behavioural profile for positive DST responders. With sensitivity to possible depression estimated at 22%, and a diagnostic confidence of <35%, these data do not support recommendations that the DST is useful for assisting in diagnosis of depression in this population. [ABSTRACT FROM AUTHOR]

Background: There are three possible SARS-CoV-2 post-pandemic scenarios: (i) ongoing severity, (ii) influenza-like severity, and (iii) a transition to an endemic disease with lesser morbidity similar to that of other human coronaviruses., Methods: To assess a possible evolution of the pandemic under the three scenarios, we use data from the US National Covid Cohort Collaborative, CDC COVID-NET, and CDC Fluview and from the WastewaterSCAN Dashboard. We include influenza disease and treatment response as benchmark. The US National Covid Cohort Collaborative allows the quantification of viral-specific morbidity using electronic health records from 424,165 SARS-CoV-2 cases, 53,846 influenza cases, and 199,971 uninfected control subjects from 2021-2022. Evolution of hospitalization rates is estimated from the correlation between national SARS-CoV-2 and influenza hospitalization data and viral gene copies in wastewater., Results: Our findings reveal that medically attended SARS-CoV-2 infections exhibit similar morbidity to influenza [indicative of scenario (ii)], but SARS-CoV-2 hospitalization rates are one order of magnitude lower than influenza when considering virus concentration in wastewater [indicative of scenario (iii)]. Moreover, SARS-CoV-2 displays a more favorable response to antiviral therapy., Conclusions: Our analysis confirms a rapid decline in SARS-CoV-2 morbidity as it transitions to an endemic state., Competing Interests: Competing interests: The authors declare the following competing interests: Authors are employees or contractors of Vir Biotechnology Inc., San Francisco, CA, USA., (© 2024. The Author(s).)

Background: Influenza A results in significant morbidity and mortality. VIR-2482, an engineered human monoclonal antibody with extended half-life, targets a highly conserved epitope on the stem region of influenza A hemagglutinin and may protect against seasonal and pandemic influenza., Methods: This double-blind, randomized, placebo-controlled, phase 2 study examined the safety and efficacy of VIR-2482 for seasonal influenza A illness prevention in unvaccinated healthy adults. Participants (N = 2977) were randomized 1:1:1 to receive VIR-2482 450 mg, VIR-2482 1200 mg, or placebo via intramuscular injection. Primary and secondary efficacy endpoints were the proportions of participants with reverse transcriptase-polymerase chain reaction-confirmed influenza A infection and either protocol-defined influenza-like illness (ILI) and Centers for Disease Control and Prevention-defined ILI or World Health Organization-defined ILI, respectively., Results: VIR-2482 450 mg and 1200 mg prophylaxis did not reduce the risk of protocol-defined ILI with reverse transcriptase-polymerase chain reaction-confirmed influenza A versus placebo (relative risk reduction, 3.8% [95% confidence interval (CI), -67.3 to 44.6] and 15.9% [95% CI, -49.3 to 52.3], respectively). At the 1200-mg dose, the relative risk reductions in influenza A illness were 57.2% (95% CI: -2.5 to 82.2) using Centers for Disease Control and Prevention ILI and 44.1% (95% CI: -50.5 to 79.3) using World Health Organization ILI definitions, respectively. Serum VIR-2482 levels were similar regardless of influenza status; variants with reduced VIR-2482 susceptibility were not detected. Local injection site reactions were mild and similar across groups., Conclusions: VIR-2482 1200 mg intramuscular was well tolerated but did not significantly prevent protocol-defined ILI. Secondary endpoint analyses suggest this dose may have reduced influenza A illness. Trial registration: ClinicalTrials.gov identifier, NCT05567783., Competing Interests: Potential conflicts of interest. S. K. T., D. C., D. P., M. L. A., K. B., W. W. Y., and P. S. P. are employees of Vir Biotechnology, Inc and report stock ownership in Vir Biotechnology, Inc. C. M. H. is a former employee and shareholder of Vir Biotechnology, Inc. and is a coauthor on select Vir Biotechnology, Inc. patents. J. M. and M. D. have nothing to disclose. C. F. reports receiving grant support from Vir Biotechnology, Inc. for conduct of the clinical trial. F. G. H. has received consulting fees from The University of Alabama and Krog Associates; served as a nonpaid consultant to Vir Biotechnology, Inc. and other companies involved in developing influenza therapeutics or vaccines, including Appili, Arcturus, Eradivir, Gilead, GSK, Janssen/JNJ, Fujifilm, Merck, Ridgeback, Roche/Genentech, Sanofi Pasteur, and Via Nova; is a trustee of the International Society for Influenza and other Respiratory Viruses; and has participated on a data safety monitoring board or advisory board for Imperial College London, University of Oxford, and Enanta. Cidara, Enanta, Shionogi, and Versatope have made charitable donations for Dr. Hayden's consulting time, and both Shionogi and Roche have provided meeting travel support. 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of VIR-2482 in healthy adult subjects. A phase 1, first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted. One hundred participants were allocated to four cohorts (60 mg, 300 mg, 1,200 mg, and 1,800 mg). In each cohort, participants were randomized in a 4:1 ratio (active:placebo) to receive either VIR-2482 or volume-matched placebo by gluteal intramuscular injection. Participants remained at the investigative site under observation for 48 h, and adverse events (AEs) were collected for 56 days. PK and immunogenicity were measured up to 52 weeks post-dose. VIR-2482 was well tolerated at all doses studied. The overall incidence of AEs was comparable between VIR-2482 (68.8%) and placebo (85.0%). Nineteen VIR-2482 (23.8%) and six placebo (30.0%) recipients had Grade 1 or 2 AEs that were considered to be related to the study intervention. There were no treatment-related serious AEs. Injection-site reactions (ISRs) were reported in six (7.5%) VIR-2482 recipients, while no such reactions were reported among the placebo recipients. All ISRs were Grade 1, and there was no relationship with the dose. Median VIR-2482 serum elimination half-life ranged from 56.7 to 70.6 days across cohorts. The serum area under the curve and C max were dose-proportional. Nasopharyngeal VIR-2482 concentrations were approximately 2%-5% of serum levels and were less than dose-proportional. The incidence of immunogenicity across all cohorts was 1.3%. Overall, the safety, tolerability, and pharmacokinetic profile of VIR-2482 at doses up to 1,800 mg supported its further investigation as a long-acting antibody for the prevention of influenza A illness. This study has been registered at ClinicalTrials.gov under identifier NCT04033406., Competing Interests: The following authors are Vir employees and stockholders: D.P., J.E.S., M.A., M.C.F., A.P., M.A.S., D.C., E.M., K.B., W.W.Y., and M.R. P.G. has no financial disclosures to report.

Background: We report on the safety and immunogenicity of V591, a measles vector-based SARS-CoV-2 vaccine candidate., Methods: In this multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial, healthy adults with no history of COVID-19 disease were assigned to intramuscular injection of V591 or placebo (4:1 ratio). In part 1, younger adults (18-55 years) received V591 median tissue culture infectious dose (TCID 50 )-levels of 1×10 5 or 1×10 6 or placebo, 56 days apart. In part 2, younger and older (>55 years) adults received a single dose of one of four (10 4 /10 5 /10 6 /10 7 ) or one of two (10 5 /10 6 ) V591 TCID 50 levels, respectively, or placebo., Primary Outcome: safety/tolerability. Secondary outcome: humoral immunogenicity. ClinicalTrials.gov: NCT04498247., Findings: From August-December 2020, 444 participants were screened and 263 randomised (210 V591; 53 placebo); 262 received at least one and 10 received two doses of V591 or placebo. Adverse events were experienced by 140/209 (67.0%) V591 dose-group participants and 37/53 (69.8%) placebo-group participants following injection 1; most frequent were fatigue (57 [27.3%] vs 20 [37.7%]), headache (57 [27.3%] vs 19 [35.8%]), myalgia (35 [16.7%] vs 10 [18.9%]), and injection-site pain (35 [16.7%] vs 4 [7.5%]). No deaths nor vaccine-related serious adverse events occurred. At Day 29, no anti-SARS-CoV-2 spike serum neutralising antibody and IgG-responses were identified in placebo or the three lower V591 dose-groups; responses were detected with V591 1×10 7 TCID 50 , although titres were lower than convalescent serum., Interpretation: V591 was generally well tolerated, but immunogenicity was insufficient to warrant continued development., Funding: Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA., Competing Interests: Declaration of interests WL, RTW, LH, XC, MD, JH, JL, MMcG, KR, YT, RT, DDB, WX, KR, SAS and EL are employees of Merck Sharpe & Dohme, Corp., and division of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock or hold stock options in the Company. JRS is an employee of Merck Sharpe & Dohme, Corp. and division of Merck & Co., Inc., Kenilworth, NJ, USA, holding stocks alongside stocks in various pharmaceutical and biotechnology companies and service providers, has participated on various editorial boards and committees for Society for Industrial and Applied Mathematics and is a member and participant in committees for the International Society of Pharmacometrics. KB was an employee of Merck Sharpe & Dohme, Corp., and division of Merck & Co., Inc., Kenilworth, NJ, USA until February 2021. AA was an employee of Merck Sharpe & Dohme, Corp., and division of Merck & Co., Inc., Kenilworth, NJ, USA, until September 2021. All other authors report no conflicts of interest., (Copyright © 2022 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA, The Author(s). Published by Elsevier B.V. All rights reserved.)

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS., Competing Interests: MHB has received research support, speaking engagement honoraria, advisory board honoraria and travel sponsorship from Biogen Idec, Merck, Novartis, Roche and Sanofi-Genzyme, and is a consulting neurologist for RxMx and is Research Director of the Sydney Neuroimaging Analysis Centre. MB has received travel sponsorship and honoraria from Sanofi-Genzyme, Teva, Novartis, Biogen Idec and Roche. BB has received honoraria as a board member for GlaxoSmithKline, Biogen Idec, ViiV Healthcare and Merck Serono, has received speaker honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, Abbvie, and Biogen Idec; has received travel sponsorship from Abbott and ViiV Healthcare, and has received research support funding from EI Lilly, GlaxoSmithKline, ViiV Healthcare and Merck Serono. FB has received speaker's honoraria from Biogen-Idec and EMD Serono. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis, and Sanofi-Genzyme, has received speakers honoraria from Biogen-Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme, and was the recipient of an unencumbered research grant from Biogen-Idec. HB has received honoraria for serving on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Genzyme, has received conference travel sponsorship from Novartis and Biogen Idec, has received honoraria for speaking and acting as Chair at educational events organised by Novartis, Biogen Idec, Medscape and Merck Serono, serves on steering committees for trials conducted by Biogen Idec and Novartis, is chair (honorary) of the MSBase Foundation, which has received research support from Merck Serono, Novartis, Biogen Idec, Genzyme Sanofi and CSL Biopharma and has received research support form Merck Serono. WC has been the recipient of travel sponsorship from, and provided advice to, Bayer Schering Pharma, Biogen-Idec, Novartis, Genzyme, Sanofi-Aventis, BioCSL and Merck-Serono. RD has received research funding from the National Health and Medical Research Council, MS Research Australia, Star Scientific Foundation, Pfizer Neuroscience, Tourette Syndrome Association, University of Sydney, and the Petre Foundation and has received honoraria from Biogen-Idec and Bristol-Myers Squibb as an invited speaker. MF-P has received travel sponsorship from Biogen Australia and New Zealand. RH has received honoraria, educational support and clinic funding from Novartis, Biogen Idec, Genzyme and BioCSL. AGKK has received scientific consulting fees and/or lecture honoraria from Bayer, BioCSL, Biogen-Idec, Genzyme, Lgpharma, Merck, Mitsubishi Tanabe Pharma, NeuroScientific Biopharmaceuticals, Novartis, Roche, Sanofi-Aventis, and Teva. TK has received travel sponsorship from Novartis, BioCSL, Novartis, Merck Serono and Biogen Idec, has received speaker honoraria from Biogen Idec, BioCSL, Merck Serono, Teva, Genzyme and Novartis, has received research support from Biogen Idec, Genzyme, GlaxoSmithKline, Bayer-Schering and Merck Serono, and has received scientific consulting fees from GlaxoSmithKline China, Biogen-Idec and Novartis. JK has received remuneration for advisory board activities and presentations from Bayer Healthcare, Biogen Idec, BioCSL, Genzyme and Novartis. CK has received travel support, honoraria and advisory board payments from Biogen Idec, Bayer, Genzyme, Novartis and Serono. JL-S has received unencumbered funding as well as honoraria for presentations and membership on advisory boards from Sanofi Aventis, Biogen Idec, Bayer Health Care, CSL, Genzyme, Merck Serono, Novartis Australia and Teva. RM has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, CSL, Merck-Serono, Novartis, and Sanofi-Genzyme. MM has received travel sponsorship, honoraria, trial payments, research and clinical support from Bayer Schering, Biogen Idec, BioCSL, Genzyme, Novartis, and Sanofi Aventis Genzyme. DM has received honoraria for attendance at advisory boards from Biogen-Idec and Novartis, and travel sponsorship from Bayer-Schering, Biogen-Idec, and Sanofi-Genzyme. PM has received honoraria or travel sponsorship from Novartis, Sanofi-Aventis and Biogen Idec. JP has received travel sponsorship, honoraria for presentations and membership on advisory boards from Biogen Idec and Novartis and Sanofi Aventis. JDP has received honoraria for seminars or advisory boards from Teva, Biogen, Sanofi-Genzyme, Novartis, Merck, Bayer and research grants or fellowships from Merck, Novartis, Bayer, Biogen, Sanofi-Genzyme, and Teva. SR has received honoraria for advisory consultancy from UCB and speaker's honoraria from Biogen Idec. SWR has received travel sponsorship, honoraria, trial payments, research and clinical support from Aspreva, Baxter, Bayer Schering, Biogen Idec, BioCSL, Genzyme, Novartis, Sanofi Aventis Genzyme and Servier, and is a director of Medical Safety Systems Pty Ltd. CPS has received travel sponsorship from Biogen Idec, Novartis and Bayer-Schering. IS has received remuneration for Advisory Board activities from Biogen, CSL, and Bayer Schering and educational activities with Biogen, CSL and travel sponsorship from Biogen, Novartis and Bayer Schering. JMS has received honoraria for lectures and participation in advisory boards, and travel sponsorship from Novartis, BioCSL, Genzyme, and Biogen Idec. BT has received travel sponsorship from Novartis and Bayer Schering. AV and the University of Oxford hold patents and receive royalties for antibody testing. PW and the University of Oxford hold patents for antibody assays and have received royalties, has received honoraria from Alexion, Biogen Idec F. Hoffmann-La Roche, Retrogenix, UBC and Euroimmun AG, and travel grants from the Guthy-Jackson Charitable Foundation. EW has received honoraria for participation in advisory boards from Biogen-Idec and Novartis, travel sponsorship from Biogen-Idec, Bayer-Schering and Teva and is an investigator in clinical trials funded by Biogen-Idec and Teva. The remaining 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 © 2021 Clarke, Arnett, Bukhari, Khalilidehkordi, Jimenez Sanchez, O'Gorman, Sun, Prain, Woodhall, Silvestrini, Bundell, Abernethy, Bhuta, Blum, Boggild, Boundy, Brew, Brownlee, Butzkueven, Carroll, Chen, Coulthard, Dale, Das, Fabis-Pedrini, Gillis, Hawke, Heard, Henderson, Heshmat, Hodgkinson, Kilpatrick, King, Kneebone, Kornberg, Lechner-Scott, Lin, Lynch, Macdonell, Mason, McCombe, Pereira, Pollard, Ramanathan, Reddel, Shaw, Spies, Stankovich, Sutton, Vucic, Walsh, Wong, Yiu, Barnett, Kermode, Marriott, Parratt, Slee, Taylor, Willoughby, Brilot, Vincent, Waters and Broadley.)

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis ( p < 0.001) and area postrema relapses ( P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS ( p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January ( P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD., (Copyright © 2020 Khalilidehkordi, Clarke, Arnett, Bukhari, Jimenez Sanchez, O'Gorman, Sun, Prain, Woodhall, Silvestrini, Bundell, Abernethy, Bhuta, Blum, Boggild, Boundy, Brew, Brown, Brownlee, Butzkueven, Carroll, Chen, Coulthard, Dale, Das, Fabis-Pedrini, Fulcher, Gillis, Hawke, Heard, Henderson, Heshmat, Hodgkinson, Kilpatrick, King, Kneebone, Kornberg, Lechner-Scott, Lin, Lynch, Macdonell, Mason, McCombe, Pereira, Pollard, Ramanathan, Reddel, Shaw, Spies, Stankovich, Sutton, Vucic, Walsh, Wong, Yiu, Barnett, Kermode, Marriott, Parratt, Slee, Taylor, Willoughby, Brilot, Vincent, Waters and Broadley.)

The effects of supratherapeutic doses of intravenous (IV) relebactam on duration of ventricular depolarization and subsequent repolarization were assessed in a thorough QT/corrected QT study. This was a single-dose, double-blind (relebactam only), randomized, placebo- and positive-controlled, 3-period, balanced crossover study in healthy participants. Participants received in randomized order, and separated by a washout (≥4 days), a single dose of IV relebactam 1150 mg, oral moxifloxacin 400 mg (open-label positive control), and IV placebo. Least squares mean and 2-sided 90% confidence interval for change from baseline in population-derived corrected QT intervals for relebactam, moxifloxacin, and placebo were estimated for 24 hours. The upper limit of the 90% confidence interval of all least squares mean population-derived corrected QT treatment differences from placebo was not >10 milliseconds at any time point for 24 hours. Corrected QT assay sensitivity was confirmed with moxifloxacin treatment. Analysis of electrocardiogram parameters resulted in no additional cardiac safety concerns. Overall, a supratherapeutic dose of relebactam yielded no cardiac safety events; the 1150-mg supratherapeutic dose (4.6-fold above the 250-mg therapeutic dose) was not associated with QT prolongation or other abnormal cardiodynamic parameters. This study lends additional support to relebactam's use as a β-lactamase inhibitor in antimicrobial therapy., (© 2020, The American College of Clinical Pharmacology.)

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.

Aims: Two phase 1, open-label studies were conducted to investigate the effect of renal impairment (RI) and organic anion transporter (OAT) inhibition on pharmacokinetics (PK) and safety of relebactam (REL) plus imipenem/cilastatin (IMI)., Methods: Study PN005 evaluated the PK of REL (125 mg) plus IMI (250 mg) in participants with RI vs healthy controls. Study PN019 evaluated the PK of REL (250 mg) and imipenem (500 mg; dosed as IMI) with/without probenecid (1 g; OAT inhibitor) in healthy adults., Results: Geometric mean ratios (RI/healthy matched controls) of area under the concentration-time curve from time 0 to infinity (AUC 0-∞ ; 90% confidence interval) for REL, imipenem and cilastatin increased as RI increased from mild (1.6 [1.1, 2.4], 1.4 [1.1, 1.8] and 1.6 [1.0, 2.5], respectively) to severe (4.9 [3.4, 7.0], 2.5 [1.9, 3.3] and 5.6 [3.6, 8.6], respectively). For all 3 analytes, plasma and renal clearance decreased and corresponding plasma apparent terminal half-life increased with increasing RI. Geometric mean ratios ([probenecid+IMI/REL]/[IMI/REL]) of plasma exposure for REL and imipenem were 1.24 (1.19, 1.28) and 1.16 (1.13, 1.20), respectively. The dose fraction excreted (fe) in the urine decreased progressively from mild to severe RI. Probenecid reduced renal clearance of REL and imipenem by 25 and 31%, respectively. Compared with IMI/REL, coadministration of IMI/REL with probenecid yielded lower fe for REL and imipenem. In both studies, treatment was well tolerated; there were no serious adverse events or discontinuations due to adverse events., Conclusion: RI increased plasma exposure and similarly decreased clearance of REL, imipenem and cilastatin; IMI/REL dose adjustment (fixed-ratio) will be required for patients with RI. Probenecid had no clinically meaningful impact on the PK of REL or imipenem., (© 2019 The British Pharmacological Society.)

Relebactam is a novel class A and C β-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg) and multiple-dose (50 to 625 mg every 6 h [q6h] for 7 to 14 days) escalation study with men and (ii) a single-dose (125 mg) study with women and elderly individuals. Following single- or multiple-dose intravenous administration over 30 min, plasma relebactam concentrations declined biexponentially, with a terminal half-life ( t 1/2 ) ranging from 1.35 to 1.85 h independently of the dose. Exposures increased in a dose-proportional manner across the dose range. No clinically significant differences in pharmacokinetics between men and women, or between adult and elderly participants, were observed. Urine pharmacokinetics demonstrated that urinary excretion is the major route of relebactam elimination. No drug-drug interaction between relebactam and imipenem-cilastatin was observed, and the observed t 1/2 values for relebactam, imipenem, and cilastatin were comparable, thus supporting coadministration. Relebactam administered alone or in combination with imipenem-cilastatin was well tolerated across the dose ranges studied. No serious adverse events or deaths were reported. The pharmacokinetic profile and favorable safety results supported q6h dosing of relebactam with imipenem-cilastatin in clinical treatment trials., (Copyright © 2018 Rhee et al.)

Objectives: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry., Background: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established., Methods: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases., Results: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD., Conclusions: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry., Competing Interests: Competing interests: MHB has received honoraria for participation in advisory boards and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec. MBo has received travel sponsorship and honoraria from Sanofi-Genzyme, Teva, Novartis, BiogenIdec and Roche. BJB has received honoraria as a board member for GlaxoSmithKline, Biogen Idec, ViiV Healthcare and Merck Serono, has received speaker honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, AbbVie and Biogen Idec, has received travel sponsorship from Abbott and ViiV Healthcare and has received research support funding from EIi Lilly, GlaxoSmithKline, ViiV Healthcare and Merck Serono. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer Schering Pharma, BiogenIdec, Merck Serono, Novartis and Sanofi-Genzyme, has received speaker honoraria from Biogen Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme and was the recipient of an unencumbered research grant from Biogen Idec. HB has received honoraria for serving on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Genzyme, has received conference travel sponsorship from Novartis and Biogen Idec, has received honoraria for speaking and acting as Chair at educational events organised by Novartis, Biogen Idec, Medscape and Merck Serono, serves on steering committees for trials conducted by Biogen Idec and Novartis, is chair (honorary) of the MSBase Foundation, which has received research support from Merck Serono, Novartis, Biogen Idec, Genzyme Sanofi and CSL Biopharma and has received research support form Merck Serono. WMC has been the recipient of travel sponsorship from, and provided advice to, Bayer Schering Pharma, BiogenIdec, Novartis, Genzyme, Sanofi-Aventis, BioCSL and Merck Serono. RCD has received research funding from the National Health and Medical Research Council, MS Research Australia, Star Scientific Foundation, Pfizer Neuroscience, Tourette Syndrome Association, University of Sydney and the Petre Foundation and has received honoraria from Biogen Idec and Bristol-Myers Squibb as an invited speaker. MjF-P has received travel sponsorship from Biogen Australia and New Zealand. RH has received honoraria, educational support and clinic funding from Novartis, Biogen Idec, Genzyme and BioCSL. AGK has received scientific consulting fees and/or lecture honoraria from Bayer, BioCSL, BiogenIdec, Genzyme, Merck, Novartis, Sanofi-Aventis and Teva. TJK has received travel sponsorship from Novartis, BioCSL, Novartis, Merck Serono and BiogenIdec, has received speaker honoraria from Biogen Idec, BioCSL, Merck Serono, Teva, Genzyme and Novartis, has received research support from Biogen Idec, Genzyme, GlaxoSmithKline, Bayer Schering Pharma and Merck Serono and has received scientific consulting fees from GlaxoSmithKline China, Biogen Idec and Novartis. JK has received remuneration for advisory board activities and presentations from Bayer Healthcare, Biogen Idec, BioCSL, Genzyme and Novartis. CK has received travel support, honoraria and advisory board payments from Biogen Idec, Bayer,Genzyme, Novartis and Serono. JL-S has received unencumbered funding as well as honoraria for presentations and membership on advisory boards from Sanofi-Aventis, Biogen Idec, Bayer Health Care, CSL, Genzyme, Merck Serono, Novartis Australia and Teva. RALM has received honoraria for attendance at advisory boards and travel sponsorship from Bayer Schering Pharma, Biogen Idec, CSL, Merck Serono, Novartis and Sanofi-Genzyme. MPMa has received travel sponsorship, honoraria, trial payments, research and clinical support from Bayer Schering Pharma, Biogen Idec, BioCSL, Genzyme, Novartis and Sanofi-Aventis Genzyme. DFM has received honoraria for attendance at advisory boards from Biogen Idec and Novartis, and travel sponsorship from Bayer Schering Pharma, Biogen Idec and Sanofi-Genzyme. PAMcC has received honoraria or travel sponsorship from Novartis, Sanofi-Aventis and Biogen Idec. JAP has received travel sponsorship, honoraria for presentations and membership on advisory boards from Biogen Idec and Novartis and Sanofi-Aventis. JDP has received honoraria for seminars or advisory boards from Teva, Biogen, Sanofi-Genzyme, Novartis, Merck, Bayer and research grants or fellowships from Merck, Novartis, Bayer, Biogen, Sanofi-Genzyme and Teva. SWR has received travel sponsorship, honoraria, trial payments, research and clinical support from Aspreva, Baxter, Bayer Schering Pharma, Biogen Idec, BioCSL, Genzyme, Novartis, Sanofi-Aventis Genzyme and Servier, and is a director of Medical Safety Systems Pty Ltd. CPS has received travel sponsorship from Biogen Idec, Novartis and Bayer Schering Pharma. IS has received remuneration for Advisory Board activities from Biogen, CSL and Bayer Schering Pharma and educational activities with Biogen, CSL and travel sponsorship from Biogen, Novartis and Bayer Schering Pharma. MS has received research support from Novartis, Biogen Idec and BioCSL. JSp has received honoraria for lectures and participation in advisory boards, and travel sponsorship from Novartis, BioCSL, Genzyme and Biogen Idec. BVT has received travel sponsorship from Novartis and Bayer Schering Pharma. AV and the University of Oxford hold patents and receive royalties for antibody testing. PW and the University of Oxford hold patents for antibody assays and have received royalties, has received speaker honoraria from Biogen Idec and Euroimmun AG and travel grants from the Guthy-Jackson Charitable Foundation. EW has received honoraria for participation in advisory boards from Biogen Idec and Novartis, travel sponsorship from Biogen Idec, Bayer Schering Pharma and Teva and is an investigator in clinical trials funded by Biogen Idec and Teva. DA, SBh, SBl, KB, MBr, WBr, WBu, CSB, CCM, LC, AC, CD, KD, DF, DG, SHa, APDH, SHe, SHo, SJ-S, AJK, M-WL, CL, CO’G, MPM, CS, RS, JSt, AV, SV, MWa, RJW, RCW, MWo and EMY report no disclosures., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Patients with mild cognitive impairment (MCI) are at greater risk of mortality than the general population. Comparatively little research has examined predictors of mortality in MCI and no research has examined whether time-varying variables, such as change in cognition and function, predict survival., Objective: To identify predictors of mortality in patients with MCI., Methods: 185 patients with MCI were recruited from nine memory clinics around Australia. Patients completed measures of cognition, function, and neuropsychiatric symptoms over three years. Mortality data were obtained from state registries eight years after baseline., Results: 55 (30%) patients died within this period. Older age, lower cognitive and functional ability at baseline, and greater decline in functional ability over six months predicted mortality., Conclusion: Easily measurable clinical data predict mortality in patients with MCI. Longitudinal assessment over time can provide additional information about patients' risk.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.

Background: Dementia is a terminal illness. While various baseline characteristics of patients, such as age, sex, and dementia severity, are known to predict mortality, little research has examined how changes in patients' symptoms over time predict survival. There are also limited data on patients seen in memory clinics, as opposed to other health care settings, and whether antipsychotic medications are associated with mortality in dementia once patients' demographic and clinical features are controlled for., Objective: To identify predictors of mortality in patients with dementia., Method: Of 970 patients recruited from nine memory clinics around Australia, 779 patients had dementia at baseline. Patients completed measures of dementia severity, cognition, functional ability, neuropsychiatric symptoms, caregiver burden, and medication use at baseline and at regular intervals over a three-year period. Mortality data were obtained from state registries eight years after baseline., Results: Overall, 447 (57.4%) of the patients with dementia died within the eight years. Older age, male sex, more severe dementia and functional impairment at baseline, greater decline in dementia severity and functional impairment over six months, taking a larger number of medications, and use of atypical antipsychotic medication predicted earlier mortality., Conclusions: The findings confirm that demographic and diagnostic features predict the survival of patients with dementia. Importantly, the findings indicate that changes in dementia severity and functional impairment over time predict mortality independently of baseline levels, and provide further evidence for the higher mortality risk of patients taking antipsychotic medications.

Objective: To examine prevalence and predictors of burden in caregivers of people with dementia attending memory clinics., Methods: This Prospective cohort study conducted at nine memory clinics in Australia rated 732 outpatient attendees and their primary caregivers at baseline and at 3, 6, 12, 24, and 36 months. Ratings were based on the following: dementia diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Mini-Mental State Exam, Alzheimer's Disease Assessment Scale-Cognitive, Functional Autonomy Measurement System, Neuropsychiatric Inventory, use of psychotropic and antidepressant medications, patient and caregiver resource use, and the Zarit Caregiver Burden Interview (ZBI)., Results: Half the caregivers had significantly high levels of burden, rising to 57.7% at 12 months; with moderate to severe burden rates, rising from 14.7% at baseline to 22.8% at 12 months; and mean ZBI levels rising from 22.9 at baseline to 25.5 at 6 months and 27.7 at 12 months. Caregiver predictors of 6- and 12-month burden were their neuroticism and baseline ZBI score. Patient predictors were their level of behavioral symptoms, use of antipsychotics and antidepressants, and more rapid functional decline. Other predictors (female caregiver, level of cognition and function, diagnosis of frontotemporal dementia) were not significant in regression analyses., Conclusion: Caregivers of people with dementia have high and persistent rates of burden. Identification of caregivers likely to have high levels of burden at 12 months may allow more accurate targeting of interventions., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Folate fortification of food aims to reduce the number of babies born with neural tube defects, but has been associated with cognitive impairment when vitamin B12 levels are deficient. Given the prevalence of low vitamin B12 levels among the elderly, and the global deployment of food fortification programs, investigation of the associations between cognitive impairment, vitamin B12, and folate are needed., Objective: To investigate the associations of serum vitamin B12, red cell folate, and cognitive impairment., Methods: Data were collected on 1,354 subjects in two studies investigating cognitive impairment, and from patients attending for assessment or management of memory problems in the Barwon region of south eastern Australia between 2001 and 2011. Eligible subjects who had blood measurements of vitamin B12 and red cell folate taken within six months of cognitive testing were included. Subjects with stroke or neurodegenerative diseases other than Alzheimer's disease were excluded. A Mini-Mental State Examination score of <24 was used to define impaired cognitive function., Results: Participants with low serum vitamin B12 (<250 pmol/L) and high red cell folate (>1,594 nmol/L) levels were more likely to have impaired cognitive performance (adjusted odds ratio (AOR) 3.45, 95% confidence interval (CI): 1.60-7.43, p = 0.002) when compared to participants with biochemical measurements that were within the normal ranges. Participants with high folate levels, but normal serum vitamin B12, were also more likely to have impaired cognitive performance (AOR 1.74, 95% CI: 1.03-2.95, p = 0.04)., Conclusions: High folate or folic acid supplements may be detrimental to cognition in older people with low vitamin B12 levels. This topic is of global significance due to the wide distribution of food fortification programs, so prospective studies should be a high priority.

Objective: To investigate the associations of metformin, serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes., Research Design and Methods: Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) (n=480) or mild cognitive impairment (n=187) and those who were cognitively intact (n=687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes (n=104) or impaired glucose tolerance (n=22)., Results: Participants with diabetes (n=126) had worse cognitive performance than participants who did not have diabetes (n=1,228; adjusted odds ratio 1.51 [95% CI 1.03-2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05-4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19-0.92])., Conclusions: Metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin.

Background: People with Alzheimer's disease (AD) who present with prominent frontal features such as a dysexecutive syndrome may be difficult to differentiate clinically from subjects with frontotemporal lobar degeneration (FTLD). This study was performed to improve the differential diagnosis between AD and FTLD and to better characterize the AD subgroup with greater executive dysfunction., Methods: Using a well-defined prospectively studied cohort of cognitively impaired subjects, which included those with AD and with FTLD, we nominated a frontal variant of AD (FvAD) group as those AD subjects with the lowest quartile of scores on the Frontal Assessment Battery (FAB), indicating greatest executive dysfunction, and compared them with the rest of the AD cases (whom we called the AD group) and those with FTLD across several baseline variables including cognitive, functional and behavioral scales. We also compared the changes from baseline for these three groups at 6 and 12 months. Additionally, we controlled for dementia severity by matching AD and FTLD cases on a functional scale, the SMAF, and repeated the same comparisons with these severity-matched groups., Results: The 114 FvAD subjects had a mean age of 78.1 years and Mini-mental State Examination (MMSE) scores of 16.6, and the (remaining) AD group had a mean age of 78.4 years and MMSE of 22.4. There were 30 FTLD subjects with a mean age at baseline of 70.9 years and a mean baseline MMSE of 23.4. The FvAD group was significantly more severely impaired than the other two groups on all baseline assessments except the behavioral scale, the Neuropsychiatric Inventory (NPI), where there was insignificantly less impairment than in the FTLD group. In the analysis of subjects matched at baseline for functional impairment, the FvAD and FTLD groups were not significantly different on most assessment scales although on the FAB, clock-drawing and MMSE the FvAD subjects were still significantly more impaired. These two severity-matched groups were also similar in other baseline characteristics except for older age and less psychotropic use in the FvAD group. The severity-matched FvAD group was significantly different from the AD group in almost all assessment scales. All three unmatched and matched groups declined similarly over 12 months., Conclusions: When groups were not matched for baseline severity, the use of the FAB defined a group of AD subjects with greater executive dysfunction that were distinguished from both the remainder of the AD and FTLD subjects in almost all domains except behavioral disturbance and probably were just more severely affected AD subjects. The FAB is thus more useful as a marker of dementia severity than as a scale to detect a frontal variant of AD or to distinguish AD from FTLD. Controlling for severity, however, did allow the definition of a subgroup of AD subjects that more closely resembled FTLD subjects than the remainder of the AD subjects. It is proposed that subjects with dementia presenting with greater executive impairment but without prominent behavioral symptoms are likely to have AD rather than FTLD, especially if they are quite functionally impaired. With time FTLD subjects develop increasing executive dysfunction and increasingly resemble the more severely affected AD subjects.

Objective: To determine the long-term tolerability and efficacy of donepezil in patients with vascular dementia (VaD)., Methods: International, multicentre, open-label, 30-week extension study of two 24-week, randomised, double-blind, placebo-controlled studies. Participants were ambulatory adults (59% female; mean age, 74.7 +/- 0.3) with a diagnosis of possible or probable VaD and without a diagnosis of Alzheimer's disease, who were medically stable and had completed one of two double-blind studies. All patients received donepezil 5 mg/day for the first 6 weeks, then 10 mg/day (clinician approval required). Assessments were performed at week 6 and every 12 weeks thereafter. The main outcome measure was the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-cog). Safety/tolerability measures included adverse events (AEs) and physical and laboratory evaluations., Results: Of 1219 eligible patients, 885 (72.6%) were enrolled, of which 707 (79.9%) completed the study; 127 (14.4%) patients discontinued due to AEs. A mean reduction (0.6-1.15 points) from double-blind study baseline score to week 54 (end of open-label study) on the ADAS-cog was observed for patients who received donepezil continuously for 54 weeks. ADAS-cog scores remained stable in the group that initiated donepezil treatment during the extension study. Most common donepezil-related AEs were nausea (occurring in 5.3%) and diarrhoea (8.8%); no unexpected AEs attributable to donepezil occurred., Conclusion: These data suggest that donepezil improves cognition for up to 54 weeks in patients with VaD. Patients initiating donepezil in this extension study did not perform as well on the primary outcome measure as those initiating donepezil in the double-blind study.

Introduction: The aim of this study was to compare cardiovascular autonomic nervous system function in patients with primary Sjögren's syndrome (pSS) with that in control individuals, and to correlate the findings with autonomic symptoms and the presence of exocrine secretory dysfunction., Methods: Twenty-seven female patients with pSS and 25 control individuals completed the COMPASS (Composite Autonomic Symptom Scale) self-reported autonomic symptom questionnaire. Beat-to-beat heart rate and blood pressure data in response to five standard cardiovascular reflex tests were digitally recorded using a noninvasive finger pressure cuff and heart rate variability was analyzed by Fourier spectral analysis. Analysis was performed by analysis of variance (ANOVA), multivariate ANOVA and repeated measures ANOVA, as indicated. Factor analysis was utilized to detect relationships between positive autonomic symptoms in pSS patients., Results: Multiple, mild autonomic disturbances were observed in pSS patients relating to decreased heart rate variability, decreased blood pressure variability and increased heart rate, which were most evident in response to postural change. There was a strong trend toward an association between decreased heart rate variability and increased severity of the secretomotor, orthostatic, bladder, gastroparesis and constipation self-reported autonomic symptom cluster identified in pSS patients. This symptom cluster was also associated with fatigue and reduced unstimulated salivary flow, and therefore may be an important component of the clinical spectrum of this disease., Conclusion: There was evidence of mild autonomic dysfunction in pSS as measured with both cardiovascular reflex testing and self-reported symptoms. Pathogenic autoantibodies targeting M3 muscarinic receptors remain a strong candidate for the underlying pathophysiology, but practical assays for the detection of this autoantibody remain elusive.

Early detection of Alzheimer's disease (AD) allows timely pharmacological and social interventions. Alteration in muscarinic receptor binding was evaluated with I-123 iodo-dexetimide (IDEX) in early clinical stage AD. We studied 11 mild AD patients (Folstein Minimental State Examination Score 24-27, Clinical Dementia Rating 0.5-1.0) and 10 age- and sex-matched normal subjects with SPECT brain imaging after injection of 185 MBq of IDEX and 750 MBq of 99mTc-HMPAO. Using a voxel based approach (Statistical Parametric Mapping (SPM99) software), a deficit in IDEX binding was found in the posterior cingulate cortex in the mild AD group with p (corrected)=0.06 for the most significant voxel and p=0.0003 for the voxel cluster. Region of interest (ROI) analysis confirmed the SPM99 results. SPM99 found no deficit in the HMPAO scans, suggesting that neither atrophy nor hypoperfusion were major factors in the reduced IDEX binding. This study provides further evidence of the involvement of the posterior cingulate region and of muscarinic receptors in early Alzheimer's disease and suggests that this change may precede an alteration in blood flow.

Objectives: We hypothesized that <0% residual stenosis (RS) after rescue/adjunctive percutaneous coronary intervention (PCI) following fibrinolytic administration in ST-segment elevation myocardial infarction (STEMI) would be associated with improved outcomes., Background: Prior studies have associated larger lumen diameters after PCI with reduced rates of restenosis and target vessel revascularization., Methods: Data were drawn from 748 patients with open epicardial arteries and with optimal luminal results (RS <20%) following rescue/adjunctive PCI after fibrinolytic administration in six STEMI trials. Patients were divided into two groups: 1) <0% RS and 2) 0% to 20% RS., Results: A RS <0% was associated with greater gains in lumen diameter and smaller reference diameters after PCI (p < 0.001 for each), with a trend toward less frequent Thrombolysis In Myocardial Infarction flow grade (TFG) 3. A RS <0% was associated with a greater incidence of abnormal post-PCI Thrombolysis In Myocardial Infarction myocardial perfusion grades (TMPGs) (odds ratio 2.6 [1.2 to 5.9] for TMPG 0/1/2, p = 0.02), even when the analysis was restricted to patients with post-PCI TFG 3., Conclusions: A RS <0% following rescue/adjunctive PCI after fibrinolytic therapy for STEMI was independently associated with a reduction in the frequency of normal myocardial perfusion. Potential mechanisms of this finding include greater downstream embolization, increased stimulation of arterial stretch receptors with resultant coronary vasoconstriction, and increased vessel-wall injury after PCI. These findings suggest that additional prospective studies are needed to assess optimal RS that minimizes long-term restenosis without adverse effects.

Unfavorable hemodynamics among patients with ST-elevation myocardial infarction (STEMI) have been associated with adverse clinical outcomes and may be linked to a failure to achieve complete reperfusion. We hypothesized that impaired epicardial and tissue-level perfusion after fibrinolytic therapy would be associated with adverse hemodynamics. The relationship between left ventricular end-diastolic pressure (LVEDP), baseline clinical characteristics, and angiographic findings were examined in 666 patients with STEMI treated with fibrinolytic therapy from the TIMI 14, INTEGRITI (TIMI 20), ENTIRE (TIMI 23), and FASTER (TIMI 24) trials. LVEDP was analyzed as a dichotomous variable with an elevated LVEDP defined as LVEDP >18 mmHg (median value). Higher post-fibrinolytic LVEDP was associated with age > or = 65, female gender, Killip Class II-IV on presentation, and LAD culprit location. Elevated LVEDP was associated with both a closed infarct-related artery (58.8% of TIMI Flow Grade (TFG) 0/1 with elevated LVEDP vs. 46.6% of TFG 2/3, p = 0.03) and impaired myocardial perfusion (55.7% of TIMI Myocardial Perfusion Grade (TMPG) 0/1 with elevated LVEDP vs. 43.8% of TMPG 2/3, p = 0.02). In a multivariate analysis, impaired myocardial perfusion (OR 1.7, p = 0.02), abnormal Killip Class (OR 4.8, p = 0.001), age > or = 65 (OR 1.6, p = 0.04), and female gender (OR 1.9, p = 0.01) were independently associated with elevated LVEDP. Elevated LVEDP was independently associated with a greater incidence of in-hospital (OR 11.8, p = 0.02) and 30-day congestive heart failure (OR 4.4, p = 0.02). In STEMI, angiographic indices of incomplete reperfusion are associated with an elevated LVEDP, and elevated LVEDP is associated with adverse clinical outcomes.

Clinical trials and independent reviews support the use of cholinesterase inhibitors for treating the symptoms of patients with mild to moderate Alzheimer's disease (AD). Before initiating cholinesterase inhibitor therapy, patients should be thoroughly assessed, and the diagnosis confirmed, preferably by a specialist. Compliance with cholinesterase inhibitor therapy should be monitored and the response (in global, cognitive, functional and behavioural domains) reassessed after 2-3 months of treatment. Vitamin E may be protective against AD, and therapy with 1000 IU twice daily may be considered. There is insufficient evidence to support the use of other antioxidant agents, anti-inflammatory agents, monoamine oxidase B inhibitors, folate/homocysteine or antihypertensive drugs in patients with AD, or hormone replacement therapy in affected women.

There is evidence suggesting that muscarinic cholinergic neuroreceptors (mChR) are reduced at seizure foci. Iodine-123 (I-123) iododexetimide (IDEX) single-photon emission computed tomography (SPECT) permits in vivo imaging of mChR. We assessed 23 patients with temporal lobe epilepsy (TLE) undergoing preoperative assessment. Regions of interest were placed over the amygdala, hippocampus, and lateral temporal cortex on IDEX SPECT images. Eighteen patients had unilateral TLE. In these, IDEX binding in the ipsilateral hippocampal region was reduced by 19.1 +/- 12%. This was significantly greater than blood flow asymmetry (p < 0.02 by Wilcoxon's signed-rank test). Changes were less marked in the amygdala (11.3 +/- 6.4%) and lateral cortex (7.6 +/- 12.1%). Blinded visual analysis gave correct localization in 14 (78%) patients, and hexamethylpropylenamine oxide (HMPAO) SPECT gave correct localization in 50%. MRI revealed hippocampal sclerosis in 13 (72%) patients and was normal in 5 patients. Of the latter group, four were correctly localized by IDEX. This study confirms that mChR receptors are altered in medial temporal lobe structures in TLE. IDEX SPECT appears to be superior to interictal HMPAO SPECT and complimentary to MRI for seizure focus localization.

Unlabelled: Iodine-123-iododexetimide (IDEX) has recently been used for SPECT imaging of muscarinic cholinergic neuroreceptors (mAChR) in humans. We report the human radiation dosimetry, whole-body and normal cerebral distribution of IDEX., Methods: Serial whole-body planar and brain SPECT scans were performed over 24 hr in four normal subjects. Organ activity was calculated from attenuation-corrected geometric mean counts from ROIs drawn over visible organs. Thigh activity was used for background subtraction. Organ absorbed doses and effective dose were calculated using the MIRD schema. Brain SPECT was performed 6 hr postinjection in ten normal subjects. ROIs placed over cortical and subcortical structures were used to determine brain distribution., Results: The effective dose was 24.7 microSv/MBq. An average of 54% of IDEX remained in the body background. Decay-corrected brain uptake was 6.9% of injected dose at 1 hr, 8.6% at 6 hr and 8.1% at 24 hr. Regional brain distribution showed high uptake in striatum and cortex with low activity in thalamus and cerebellum. At 6 hr, activity relative to striatum was 70% for frontal and parietal cortex, 102% for occipital cortex, 54% for thalamus and 11% for cerebellum., Conclusion: Iodine-123-IDEX produced high quality SPECT images with activity at 6 hr reflecting the known distribution of mAChR receptors. The favorable dosimetry of IDEX and high synthetic yield (50%-70%) suggest it to be a suitable agent for clinical studies.

A man with profound mental retardation and multiple topographies of severe self-injurious behavior (SIB) had been receiving contingent shock for SIB for 2 years before the study started. Shock was being delivered with a handheld shock stick (Hot Shot Sabre Six), which produced burns to the man's skin. SIB rate, without a shock contingency, was 10 responses/min. The Therapeutic Shock Device (TSD), worn by the client and remotely operated by a radio frequency signal, provided superior control of SIB (0.02 responses/min) compared with the shock stick (0.06 responses/min) without causing tissue damage. TSD treatment was introduced in a mixed multiple baseline design across times, settings, and behaviors. The client did not appear to find the TSD aversive. To the contrary, his behaviors indicated that he preferred to wear it. The TSD appeared to provide a substitute for restraint, the hypothesized reinforcer for the man's most frequent form of SIB.

We describe 2 patients with rheumatoid arthritis (RA) and inclusion body myositis (IBM). Examination and laboratory tests including muscle biopsy with frozen section and electron microscopy were performed. Both patients fulfilled diagnostic criteria for IBM, which is increasingly recognized in association with autoimmune disease. A high index of suspicion and early thorough investigation are required to diagnose IBM in patients with RA.

Magnetic Resonance Imaging was performed in two cases of suspected internal carotid artery dissection. In both cases it was possible to demonstrate the dissection. It is suggested that magnetic resonance imaging (MRI) could replace more invasive techniques in the diagnosis of this condition.

The purpose of the study was to determine whether quantitative or discriminant analysis of the electroencephalograph (EEG) would vary significantly when the same EEG was analysed by 3 different operators. EEGs on 10 healthy volunteers were recorded on the Cadwell Spectrum AT 386, using the Electrocap (10-20 system). The EEGs were analysed independently, with each operator selecting the first 48 artifact-free epochs. The results were analysed using the non-parametric Friedman two-way analysis of variance (ANOVA) for the discrimination analysis and a one-way ANOVA for the monopolar and bipolar Absolute Power raw measures. Statistical analysis of the discriminant data showed no significant differences between operators, with 7 of 10 studies yielding the same results. The remaining 3 studies were classified either as borderline or normal when analysed by different operators. Although a series of "t" tests comparing 2 operators showed most variability occurring in Absolute Power as compared with Relative Power, Power Asymmetry and Coherence, ANOVA of the raw mono- and bipolar Absolute Power measures showed no significant differences between the operators at the P = 0.05 level. Thus the differences between the operators were non-significant when comparing quantitative EEG analyses with respect to both the raw measures and the discriminant analyses.

A 40-year-old Australian Aboriginal female presented with hemoptysis in association with a right upper zone pulmonary and mediastinal mass. Several syphilitic infections in the patient had been documented during the previous 16 years. Death was due to a large hemoptysis, and autopsy revealed that the mass in the chest was a right subclavian artery aneurysm which had ruptured into the lung parenchyma.

Human adipocyte lipid-binding protein (H-ALBP) was purified from normal subcutaneous adipose tissue to greater than 98% homogeneity, utilizing a combination of acid fractionation, gel filtration, covalent chromatography on activated thiol-Sepharose 4B, and anion-exchange chromatography. Human ALBP comprised about 1% of total cytosolic protein in human adipose tissue, had a relative molecular mass of about 15 kDa, and existed as a monomer in solution. The amino terminus of H-ALBP was blocked to sequencing. When a liposome ligand delivery assay was used, H-ALBP saturably bound oleic acid with about 1 mol of ligand bound per mole of protein. Additionally, H-ALBP saturably bound retinoic acid as determined by the quenching of intrinsic tryptophan fluorescence. A full-length H-ALBP cDNA has been cloned; the sequence predicts a 649-base mRNA comprised of a 62-base 5'-noncoding region containing an 18S ribosome-binding site, a single 396-base open-reading frame, and a 191-base 3'-noncoding region. Comparative sequence analysis indicated that the 132 amino acid H-ALBP is a member of a multigene family of intracellular lipid-binding proteins and contains the consensus substrate phosphorylation sequence for tyrosyl kinases.