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Minerals are supplemented routinely to dairy cows during the dry period to prevent metabolic issues postpartum. However, limited information exists on the impacts of mineral supplementation on colostrum carotenoids. This study aimed to determine the effects of prepartum supplementation with three micro-nutrients; inorganic selenium (INORG), organic selenium (ORG) or rumen-protected choline (RPC) on the carotenoid content of bovine colostrum and transition milk (TM) from pasture-based dairy cows. A total of 57 (12 primiparous and 45 multiparous) Holstein-Friesian (HF) and HF × Jersey (JEX) cows were supplemented daily for 49 ± 12.9 d before calving. Colostrum samples were collected from all cows immediately postpartum and TM one to five (TM1-TM5) were collected from a sub-set of 15 cows (five per treatment group) at each consecutive milking postpartum. Carotenoid concentration was determined using ultra-high performance liquid chromatography - diode array detection (UHPLC-DAD). With the use of transmittance, the colour index and colour parameters a *, b * and L * were used to determine colour variations over this period. Prepartum supplementation did not have a significant effect on colostrum β-carotene concentration or colour. Positive correlations between β-carotene and colour parameter b * ( R 2 = 0.671; P < 0.001) and β-carotene and colour index ( R 2 = 0.560; P < 0.001) were observed. Concentrations of β-carotene were highest in colostrum (1.34 μg/g) and decreased significantly with each milking postpartum (TM5 0.31 μg/g). Breed had a significant effect on colostrum colour with JEX animals producing a greater b * colostrum than HF animals ( P = 0.030). Primiparous animals produced colostrum with the weakest colour compared to second or ≥third parity animals ( P = 0.042). Despite statistical increases in the b * parameter in colostrum from JEX cows and multiparous cows, β-carotene concentrations did not significantly increase suggesting that other factors may influence colostrum colour. The b * parameter may be used as an indicator for estimating carotenoid concentrations in colostrum and TM, particularly when assessed via transmittance spectroscopy.

BACKGROUNDAn HIV-1 DNA vaccine composed of 7 highly conserved, structurally important elements (conserved elements, CE) of p24Gag was tested in a phase I randomized, double-blind clinical trial (HVTN 119, NCT03181789) in people without HIV. DNA vaccination of CE prime/CE+p55Gag boost was compared with p55Gag.METHODSTwo groups (n = 25) received 4 DNA vaccinations (CE/CE+p55Gag or p55Gag) by intramuscular injection/electroporation, including IL-12 DNA adjuvant. The placebo group (n = 6) received saline. Participants were followed for safety and tolerability. Immunogenicity was assessed for T cell and antibody responses.RESULTSBoth regimens were safe and generally well tolerated. The p24CE vaccine was immunogenic and significantly boosted by CE+p55Gag (64% CD4+, P = 0.037; 42% CD8+, P = 0.004). CE+p55Gag induced responses to 5 of 7 CE, compared with only 2 CE by p55Gag DNA, with a higher response to CE5 in 30% of individuals (P = 0.006). CE+p55Gag induced significantly higher CD4+ CE T cell breadth (0.68 vs. 0.22 CE; P = 0.029) and a strong trend for overall T cell breadth (1.14 vs. 0.52 CE; P = 0.051). Both groups developed high cellular and humoral responses. p24CE vaccine-induced CD4+ CE T cell responses correlated (P = 0.007) with p24Gag antibody responses.CONCLUSIONThe CE/CE+p55Gag DNA vaccine induced T cell responses to conserved regions in p24Gag, increasing breadth and epitope recognition throughout p55Gag compared with p55Gag DNA. Vaccines focusing immune responses by priming responses to highly conserved regions could be part of a comprehensive HIV vaccine strategy.TRIAL REGISTRATIONClinical Trials.gov NCT03181789FUNDINGHVTN, NIAID/NIH.

Encounters between animals occur when animals are close in space and time. Encounters are important in many ecological processes including sociality, predation and disease transmission. Despite this, there is little theory regarding the spatial distribution of encounters and no formal framework to relate environmental characteristics to encounters. The probability of encounter could be estimated with resource selection functions (RSFs) by comparing locations where encounters occurred to available locations where they may have occurred, but this estimate is complicated by the hierarchical nature of habitat selection. We developed a method to relate resources to the relative probability of encounter based on a scale-integrated habitat selection framework. This framework integrates habitat selection at multiple scales to obtain an appropriate estimate of availability for encounters. Using this approach, we related encounter probabilities to landscape resources. The RSFs describe habitat associations at four scales, home ranges within the study area, areas of overlap within home ranges, locations within areas of overlap, and encounters compared to other locations, which can be combined into a single scale-integrated RSF. We apply this method to intraspecific encounter data from two species: white-tailed deer (Odocoileus virginianus) and elk (Cervus elaphus) and interspecific encounter data from a two-species system of caribou (Rangifer tarandus) and coyote (Canis latrans). Our method produced scale-integrated RSFs that represented the relative probability of encounter. The predicted spatial distribution of encounters obtained based on this scale-integrated approach produced distributions that more accurately predicted novel encounters than a naïve approach or any individual scale alone. Our results highlight the importance of accounting for the conditional nature of habitat selection in estimating the habitat associations of animal encounters as opposed to 'naïve' comparisons of encounter locations with general availability. This method has direct relevance for testing hypotheses about the relationship between habitat and social or predator-prey behaviour and generating spatial predictions of encounters. Such spatial predictions may be vital for understanding the distribution of encounters driving disease transmission, predation rates and other population and community-level processes., (© 2024 The Author(s). Journal of Animal Ecology © 2024 British Ecological Society.)

Background: PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia., Methods: Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks., Results: The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight., Conclusions: These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted., Trial Registration: Clinicaltrials.gov identifier: NCT03055338., Competing Interests: Declaration of competing interest Mukai, Lupinacci, Snow-adami, Voss, Smith, and Egan are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA (MSD) and own stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Marder has acted as a consultant for MSD., (Copyright © 2024. Published by Elsevier B.V.)

Tracheobronchomalacia (TBM) is a progressive weakening of the airways, leading to collapse and dyspnoea. TBM can be misdiagnosed when multiple chronic conditions accompany it. Tracheobronchoplasty (TBP) is indicated for severe symptomatic TBM, diagnosed by bronchoscopy and CT thorax. We report the case of a patient who underwent tracheal resection and reconstruction for continuing dyspnoea post argon therapy, TBP and a failure to tolerate extracorporeal membrane oxygenation-assisted Y-stent insertion. Relevant background history includes asthma, sleep apnoea, reflux, cardiomyopathy and a high body mass index. Bronchoscopy postreconstruction showed patent airways. Airway reconstruction was a viable management option for this patient's TBM. TBP is a treatment option for TBM. In this case, tracheal resection was required to sustain benefit. In addition, surveillance bronchoscopies will be carried out every year., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals' 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.

Background: HIV subtypes B and C together account for around 60% of HIV-1 cases worldwide. We evaluated the safety and immunogenicity of a subtype B DNA vaccine prime followed by a subtype C viral vector boost., Methods: Fourteen healthy adults received DNA plasmid encoding HIV-1 subtype B nef/tat/vif and env (n = 11) or placebo (n = 3) intramuscularly (IM) via electroporation (EP) at 0, 1, and 3 months, followed by IM injection of recombinant vesicular stomatitis virus encoding subtype C Env or placebo at 6 and 9 months. Participants were assessed for safety, tolerability of EP, and Env-specific T-cell and antibody responses., Results: EP was generally well tolerated, although some device-related adverse events did occur, and vaccine reactogenicity was mild to moderate. The vaccine stimulated Env-specific CD4 + T-cell responses in greater than 80% of recipients, and CD8 + T-cell responses in 30%. Subtype C Env-specific IgG binding antibodies (bAb) were elicited in all vaccine recipients, and antibody-dependent cell-mediated cytotoxicity (ADCC) responses to vaccine-matched subtype C targets in 80%. Negligible V1/V2 and neutralizing antibody (nAb) responses were detected., Conclusions: This prime/boost regimen was safe and tolerable, with some device-related events, and immunogenic. Although immunogenicity missed targets for an HIV vaccine, the DNA/rVSV platform may be useful for other applications., Clinicaltrials: gov: NCT02654080., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The following authors declare no conflicts of interest: MT, MDM, JE, DCM, JMJ, ME, DKC, GJW, GDT, GF, SK, ER, ME, TL, RX, SL. MA and MP are employed by NIAID but had no role in the funding decisions or grant oversight. DH is a full-time employee of Ichor Medical Systems, Inc. and receives a salary and equity for this work. SCDR reports funding from NIH, Bill & Melinda Gates Foundation for the work. IF gets research support from Moderna, Janssen, Pfizer and Sanofi, and is a consultant for Gilead, GlaxoSmithKline and Merck., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: None declared.

Background: Delay of progression from prodromal Alzheimer's disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized., Objective: To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR)., Methods: We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) the participant's CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression., Results: 581/1,451 (40%) participants had changes triggering adjudication and most (83%) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria., Conclusion: A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful.

Purpose: The BACE inhibitor verubecestat was previously found to reduce amyloid load as assessed by 18 F-flutemetamol positron emission tomography (PET) composite cortical standard uptake value ratio (SUVr) in patients with mild-to-moderate Alzheimer's disease (AD) in a substudy of the EPOCH trial. Here, we report on additional analyses relevant to the EPOCH PET data, to help inform on the use of PET for assessing amlyloid load in AD clinical trials., Procedures: The analyses addressed (1) identification of an optimal 18 F-flutemetamol reference region, (2) determination of the threshold to characterize the magnitude of the longitudinal change, and (3) the impact of partial volume correction (PVC). Pons and subcortical white matter were evaluated as reference regions. The SUVr cutoffs and final reference region choice were determined using 162 18 F-flutemetamol PET scans from the AIBL dataset. 18 F-flutemetamol SUVrs were computed at baseline and at Week 78 in EPOCH participants who received verubecestat 12 mg (n = 14), 40 mg (n = 20), or placebo (n = 20). Drug effects on amyloid load were computed using either Meltzer (MZ), or symmetric geometric transfer matrix (SGTM) PVC and compared to uncorrected data., Results: The optimal subcortical white matter and pons SUVr cutoffs were determined to be 0.69 and 0.62, respectively. The effect size to detect longitudinal change was higher for subcortical white matter (1.20) than pons (0.45). Hence, subcortical white matter was used as the reference region for the EPOCH PET substudy. In EPOCH, uncorrected baseline SUVr values correlated strongly with MZ PVC (r 2  = 0.94) and SGTM PVC (r 2  = 0.92) baseline SUVr values, and PVC did not provide improvement for evaluating treatment effects on amyloid load at Week 78. No change from baseline was observed in the placebo group at Week 78, whereas a 0.02 and a 0.04 decrease in SUVr were observed in the 12 mg and 40 mg arms, with the latter representing a 22% reduction in the amyloid load above the detection threshold., Conclusions: Treatment-related 18 F-flutemetamol longitudinal changes in AD clinical trials can be quantified using a subcortical white matter reference region without PVC., Clinical Trial Registration: clinicaltrials.gov NCT01739348., (© 2022. World Molecular Imaging Society.)

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine "MARVAC" consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines., Competing Interests: T.W.G. holds U.S. patent number 7,635,485 issued to US Government, U.S. patent number 7,838,658 issued to Arbutus Biopharma, U.S. patent number 8,017,130 issued to US Government, U.S. patent number 8,716,464 issued to Arbutus Biopharma, and U.S. patent number 8,796,013 issued to Boston University. N.J.S. has a patent for Chimpanzee Adenoviral vector-based filovirus vaccines (for use in humans) with royalties paid to GlaxoSmithKline Biologicals. K.L.W. is a stockholder of Emergent BioSolutions. R.Z. holds a patent for “Methods and compositions for inducing protective immunity against Marburg virus infection”. All other authors declare no conflict of interest. The conclusions in this report are those of the authors and do not necessarily represent the official position of the U.S. Centers for Disease Control and Prevention.

Background: Marburg virus (MARV), an Ebola-like virus, remains an eminent threat to public health as demonstrated by its high associated mortality rate (23-90%) and recent emergence in West Africa for the first time. Although a recombinant vesicular stomatitis virus (rVSV)-based vaccine (Ervebo) is licensed for Ebola virus disease (EVD), no approved countermeasures exist against MARV. Results from clinical trials indicate Ervebo prevents EVD in 97.5-100% of vaccinees 10 days onwards post-immunization., Methodology/findings: Given the rapid immunogenicity of the Ervebo platform against EVD, we tested whether a similar, but highly attenuated, rVSV-based Vesiculovax vector expressing the glycoprotein (GP) of MARV (rVSV-N4CT1-MARV-GP) could provide swift protection against Marburg virus disease (MVD). Here, groups of cynomolgus monkeys were vaccinated 7, 5, or 3 days before exposure to a lethal dose of MARV (Angola variant). All subjects (100%) immunized one week prior to challenge survived; 80% and 20% of subjects survived when vaccinated 5- and 3-days pre-exposure, respectively. Lethality was associated with higher viral load and sustained innate immunity transcriptional signatures, whereas survival correlated with development of MARV GP-specific antibodies and early expression of predicted NK cell-, B-cell-, and cytotoxic T-cell-type quantities., Conclusions/significance: These results emphasize the utility of Vesiculovax vaccines for MVD outbreak management. The highly attenuated nature of rVSV-N4CT1 vaccines, which are clinically safe in humans, may be preferable to vaccines based on the same platform as Ervebo (rVSV "delta G" platform), which in some trial participants induced vaccine-related adverse events in association with viral replication including arthralgia/arthritis, dermatitis, and cutaneous vasculitis., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The rVSV vector described in this manuscript is the subject of a patent licensed to Auro Vaccines. C.G., T.E.H., M.A.E., J.H.E., and D.M. are paid employees of Auro Vaccines, LLC. Auro Vaccines in-licenses a portfolio of patents previously obtained from Wyeth to support the development of Vesiculovax vectors as vaccines against hemorrhagic fever viruses. The other authors have declared that no competing interests exist.

Antibody affinity maturation is a critical step in development of functional antiviral immunity; however, accurate measurement of affinity maturation of polyclonal serum antibody responses to particulate antigens such as virions is challenging. We describe a novel avidity assay employing biolayer interferometry and dengue virus-like particles. After validation using anti-dengue monoclonal antibodies, the assay was used to assess avidity of antibody responses to a tetravalent dengue vaccine candidate (TAK-003) in children, adolescents, and adults during two phase 2 clinical trials conducted in dengue-endemic regions. Vaccination increased avidity index and avidity remained high through 1 year postvaccination. Neutralizing antibody titers and avidity index did not correlate overall; however, a correlation was observed between neutralizing antibody titer and avidity index in those subjects with the highest degree of antibody affinity maturation. Therefore, vaccination with TAK-003 stimulates polyclonal affinity maturation and functional antibody responses, including neutralizing antibodies., Clinical Trials Registration: NCT01511250 and NCT02302066., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. To enable inclusion of DBS data in population PK analyses, a conversion algorithm for calculating plasma-equivalent concentrations (accounting for DBS sample instability) was developed using paired (time-matched) plasma and DBS data from the EPOCH study. Verubecestat population PK models developed from pooled phase 1/1b and EPOCH data using either (1) plasma-only data or (2) plasma and plasma-equivalent concentrations (calculated from non-paired DBS samples) yielded similar results. The algorithm robustness was demonstrated using DBS data from paired samples from the APECS study and comparison between plasma and plasma-equivalent concentrations. The population PK model was updated with APECS data (both plasma and, if no plasma sample available, plasma equivalents). The results demonstrated similar PK in the two phase 3 populations and exposures consistent with expectations from phase 1 data. This case study illustrates challenges with employing new sampling techniques in large, global trials and describes lessons learned., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: As robust dengue-specific CD4+ and CD8+ T cell responses are essential for protective immunity, we assessed cell-mediated immune (CMI) responses to a DENV-2-based dengue tetravalent vaccine candidate (TAK-003) in adolescents living in Panama, a dengue-endemic country., Methods: Peripheral blood mononuclear cells were collected from a subset of 67 participants ≥ 10 years old included in a phase 2 clinical trial of TAK-003 (Clinicaltrials.gov: NCT02302066). Following stimulation with dengue peptides, the frequency, magnitude, and cross-reactivity of the CD8+ and CD4+ T cell IFN-γ, TNF-α and IL-2 responses were assessed by flow cytometry., Results: Intracellular cytokine staining identified NS1, NS3, and NS5 as the most common non-structural (NS) targets of the CD4+ T-cell response (IFN-γ+); NS3 and NS5 were the main NS targets of the CD8+ T cell response (IFN-γ+). Both CD4+ and CD8+ T-cell responses were multi-functional (IFN-γ + TNF-α + IL-2+) and cross-reactive against DENV-1, -3, and -4 serotypes. Similar responses were seen in all CMI assessments irrespective of participant baseline status for dengue neutralizing antibodies and T cells., Conclusions: TAK-003 elicited cross-reactive, multi-functional CD4+ and CD8+ T-cell responses, irrespective of dengue pre-exposure., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: VT, AB, DW, and HD are currently employed by Takeda. MAE was employed by Takeda during the study (current affiliation: AuroVaccines). RG, FC, GLR, and XSL received funding to perform the trial, the testing and/or the data analysis., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Auro Vaccines LLC has developed a protein vaccine to prevent disease from Nipah and Hendra virus infection that employs a recombinant soluble Hendra glycoprotein (HeV-sG) adjuvanted with aluminum phosphate. This vaccine is currently under clinical evaluation in a Phase 1 study. The Benefit-Risk Assessment of VAccines by TechnolOgy Working Group (BRAVATO; ex-V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of protein vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of such a vaccine platform. The structured and standardized assessment provided by the template may also help contribute to improved public acceptance and communication of licensed protein vaccines., 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 © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We performed exploratory analyses of retinal thickness data from a clinical trial of the AβPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer's disease (AD)., Objective: To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy., Methods: Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo., Results: Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson's r values≤0.23, p-values < 0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant., Conclusion: BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline., Trial Registration: Clinicaltrials.gov NCT01739348 (registered December 3, 2012; https://clinicaltrials.gov/ct2/show/NCT01739348).

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported., Methods: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding., Results: Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency., Discussion: In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement., (© 2020 the Alzheimer's Association.)

Background: The safety and immunogenicity of a highly attenuated recombinant vesicular stomatitis virus (rVSV) expressing HIV-1 gag (rVSVN4CT1-HIV-1gag1) was shown in previous phase 1 clinical studies. An rVSV vector expressing Ebola virus glycoprotein (EBOV-GP) in place of HIV-1 gag (rVSVN4CT1-EBOVGP1) showed single-dose protection from lethal challenge with low passage Ebola virus in non-human primates. We aimed to evaluate the safety and immunogenicity of the rVSVN4CT1-EBOVGP1 vaccine in healthy adults., Methods: We did a randomised double-blind, placebo-controlled, phase 1 dose-escalation study at a single clinical site (Optimal Research) in Melbourne, FL, USA. Eligible participants were healthy men and non-pregnant women aged 18-60 years, with a body-mass index (BMI) of less than 40 kg/m 2 , no history of filovirus infection, VSV infection, or receipt of rVSV in previous studies, and who had not visited regions where Ebola virus outbreaks have occurred. Three cohorts were enrolled to assess a low (2·5 × 10 4 plaque forming units [PFU]), intermediate (2 × 10 5 PFU), or high dose (1·8 × 10 6 PFU) of the vaccine. Participants within each cohort were randomly allocated (10:3) to receive vaccine or placebo by intramuscular injection in a homologous prime and boost regimen, with 4 weeks between doses. All syringes were masked with syringe sleeves; participants and study site staff were not blinded to dose level but were blinded to active vaccine and placebo. The primary outcomes were safety and tolerability; immunogenicity, assessed as GP-specific humoral immune response (at 2 weeks after each dose) and cellular immune response (at 1 and 2 weeks after each dose), was a secondary outcome. All randomised participants were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, NCT02718469., Findings: Between Dec 22, 2015, and Sept 15, 2016, 39 individuals (18 [46%] men and 21 [54%] women, mean age 51 years [SD 10]) were enrolled, with ten participants receiving the vaccine and three participants receiving placebo in each of three cohorts. One participant in the intermediate dose cohort was withdrawn from the study because of a diagnosis of invasive ductal breast carcinoma 24 days after the first vaccination, which was considered unrelated to the vaccine. No severe adverse events were observed. Solicited local adverse events occurred in ten (26%) of 39 participants after the first dose and nine (24%) of 38 participants after the second dose; the events lasted 3 days or less, were predominantly injection site tenderness (17 events) and injection site pain (ten events), and were either mild (19 events) or moderate (ten events) in intensity. Systemic adverse events occurred in 13 (33%) of 39 participants after the first dose and eight (21%) of 38 participants after the second dose; the events were mild (45 events) or moderate (11 events) in severity, and the most common events were malaise or fatigue (13 events) and headache (12 events). Arthritis and maculopapular, vesicular, or purpuric rash distal to the vaccination site(s) were not reported. A GP-specific IgG response was detected in all vaccine recipients after two doses (and IgG response frequency was 100% after a single high dose), and an Ebola virus neutralising response was detected in 100% of participants in the high-dose cohort., Interpretation: The rVSVN4CT1-EBOVGP1 vaccine was well tolerated at all dose levels tested and was immunogenic despite a high degree of attenuation. The combined safety and immunogenicity profile of the rVSVN4CT1-EBOVGP1 vaccine vector support phase 1-2 clinical evaluation., Funding: US Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense: Joint Project Manager for Chemical, Biological, Radiological and Nuclear Medical., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Dengue virus (DENV) can cause life-threatening disease characterized by endothelial dysfunction and vascular leakage. DENV nonstructural protein 1 (NS1) induces human endothelial hyperpermeability and vascular leak in mice, and NS1 vaccination confers antibody-mediated protective immunity. We evaluated the magnitude, cross-reactivity, and functionality of NS1-specific IgG antibody responses in sera from a phase 2 clinical trial of Takeda's live-attenuated tetravalent dengue vaccine candidate (TAK-003)., Methods: We developed an enzyme-linked immunosorbent assay to measure anti-DENV NS1 IgG in sera from DENV-naive or preimmune subjects pre- and postvaccination with TAK-003 and evaluated the functionality of this response using in vitro models of endothelial permeability., Results: TAK-003 significantly increased DENV-2 NS1-specific IgG in naive individuals, which cross-reacted with DENV-1, -3, and -4 NS1 to varying extents. NS1-induced endothelial hyperpermeability was unaffected by prevaccination serum from naive subjects but was variably inhibited by serum from preimmune subjects. After TAK-003 vaccination, all samples from naive and preimmune vaccinees completely abrogated DENV-2 NS1-induced hyperpermeability and cross-inhibited hyperpermeability induced by DENV-1, -3, and -4 NS1. Inhibition of NS1-induced hyperpermeability correlated with NS1-specific IgG concentrations. Postvaccination sera also prevented NS1-induced degradation of endothelial glycocalyx components., Conclusion: We provide evidence for functional NS1-specific IgG responses elicited by a candidate dengue vaccine., Clinical Trials Registration: NCT01511250., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Verubecestat, a BACE1 inhibitor that reduces Aβ levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH., Methods: EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically. The trial was terminated due to futility close to its scheduled completion. Of 1957 participants who were randomized and took treatment, 652 were assigned to verubecestat 12 mg, 652 to verubecestat 40 mg, and 653 to placebo. Adverse events and relevant laboratory, vital sign, and ECG findings were assessed., Results: Verubecestat 12 mg and 40 mg were associated with an increase in the percentage of participants reporting adverse events versus placebo (89 and 92% vs. 82%), although relatively few participants discontinued treatment due to adverse events (8 and 9% vs. 6%). Adverse events that were increased versus placebo included falls and injuries, suicidal ideation, weight loss, sleep disturbance, rash, and hair color change. Most were mild to moderate in severity. Treatment differences in suicidal ideation emerged within the first 3 months but did not appear to increase after 6 months. In contrast, treatment differences in falls and injuries continued to increase over time., Conclusions: Verubecestat was associated with increased risk for several types of adverse events. Falls and injuries were notable for progressive increases over time. While the mechanisms underlying the increased adverse events are unclear, they may be due to BACE inhibition and should be considered in future clinical development programs of BACE1 inhibitors., Trial Registration: ClinicalTrials.gov NCT01739348 , registered on 29 November 2012.

The purpose of this study was to examine the impact of a variety of supplemental feeds on the composition and quality of milk in a pasture-based dairy system. Four pasture-supplemented feeding systems were compared: Group 1 supplementation with 16% crude protein parlour concentrate (CONC); Group 2 supplementation with palm kernel expeller plus parlour concentrate (PKE); Group 3 supplemented with soya hulls plus parlour concentrate (SOYA); Group 4 was supplemented with molassed beet pulp plus parlour concentrate (BEET). Supplemental feeding system was demonstrated to have a significant effect on the size of native casein micelles and the gelation properties of milks. While CONC feeding produced significantly higher casein micelle size, gel strength (Young's Modulus) was significantly negatively correlated with casein micelle size. Supplemental feeding system had a significant effect on a number of fatty acids (FA) and indices derived therefrom, including total saturated and unsaturated fatty acids, de novo produced FA, omega 3, and omega 6 FA. The volatile profile of milks was also affected by supplemental feed choice, whereby multivariate analysis demonstrated that the CONC diet was distinctly different to that of the PALM, SOYA, and BEET milks. Multivariate analysis demonstrated that it is possible to distinguish milks from different pasture-supplemented feeding systems by their FA profile.

Background: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease., Methods: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function., Results: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group., Conclusions: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: The addition of plasmid cytokine adjuvants, electroporation, and live attenuated viral vectors may further optimize immune responses to DNA vaccines in heterologous prime-boost combinations. The objective of this study was to test the safety and tolerability of a novel prime-boost vaccine regimen incorporating these strategies with different doses of IL-12 plasmid DNA adjuvant., Methods: In a phase 1 study, 88 participants received an HIV-1 multiantigen (gag/pol, env, nef/tat/vif) DNA vaccine (HIV-MAG, 3000 μg) co-administered with IL-12 plasmid DNA adjuvant at 0, 250, 1000, or 1500 μg (N = 22/group) given intramuscularly with electroporation (Ichor TriGrid™ Delivery System device) at 0, 1 and 3 months; followed by attenuated recombinant vesicular stomatitis virus, serotype Indiana, expressing HIV-1 Gag (VSV-Gag), 3.4 ⊆ 107 plaque-forming units (PFU), at 6 months; 12 others received placebo. Injections were in both deltoids at each timepoint. Participants were monitored for safety and tolerability for 15 months., Results: The dose of IL-12 pDNA did not increase pain scores, reactogenicity, or adverse events with the co-administered DNA vaccine, or following the VSV-Gag boost. Injection site pain and reactogenicity were common with intramuscular injections with electroporation, but acceptable to most participants. VSV-Gag vaccine often caused systemic reactogenicity symptoms, including a viral syndrome (in 41%) of fever, chills, malaise/fatigue, myalgia, and headache; and decreased lymphocyte counts 1 day after vaccination., Conclusions: HIV-MAG DNA vaccine given by intramuscular injection with electroporation was safe at all doses of IL-12 pDNA. The VSV-Gag vaccine at this dose was associated with fever and viral symptoms in some participants, but the vaccine regimens were safe and generally well-tolerated., Trial Registration: Clinical Trials.gov NCT01578889., Competing Interests: The authors have read the journal policy and the authors of this manuscript have the following competing interests: MAA is employed by the National Institute of Allergy and Infectious Diseases (NIAID), the study sponsor. MLE, SSL, NKK, GJW, HVNT, IF, MES, KWC, BSP, JHE, MJM and CMH are recipients of NIAID funding, and this publication is a result of activities funded by NIAID. MAA is not involved with the process of funding these awards, nor in their administration of scientific aspects and, in accordance with NIAID policies, is deferred from decisions regarding funding of coauthors for a requisite period. TEL, DKC, JHE, RX, and AOS are employees and stakeholders of Profectus BioSciences, Inc. DKC is the principal author/inventor on a patent for the rVSVN4CT1 vector. At the time the study was conducted, MAE was an employee and stakeholder of Profectus BioSciences, Inc. and is now an employee of Takeda Pharmaceuticals, which has no affiliation with the study. DH is an employee and stakeholder of Ichor Medical Systems, Inc. IF serves on advisory boards for Gilead Sciences and ViiV Healthcare. HVNT has received research grant funding from Merck & Co. These affiliations do not alter our adherence to PLOS ONE policies on sharing data and materials.

Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study-derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.

Background: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer's disease., Methods: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function)., Results: A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group., Conclusions: Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).

Introduction: We evaluated the selective M1 muscarinic positive allosteric modulator, MK-7622, as adjunctive cognitive enhancing therapy in individuals with Alzheimer's disease., Methods: A randomized, double-blind, proof-of-concept trial was performed. Participants with mild-to-moderate Alzheimer's disease, being treated with an acetylcholinesterase inhibitor, were randomized 1:1 to 45 mg of MK-7622 or placebo for 24 weeks. Endpoints included the mean change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 11 ) at 12 weeks and Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory at 24 weeks., Results: Two hundred forty participants were randomized. The trial was stopped for futility after meeting prospectively defined stopping criteria. MK-7622 did not improve cognition at 12 weeks (group difference in ADAS-Cog 11 : 0.18 [95% confidence interval: -1.0 to 1.3]) or function at 24 weeks (group difference in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory: 0.06 [95% confidence interval: -2.4 to 2.5]). More participants taking MK-7622 discontinued study medication because of adverse events than those taking placebo (16% vs 6%) and who experienced cholinergically related adverse events (21% vs 8%)., Discussion: MK-7622 (45 mg) does not improve cognition or function when used as adjunctive therapy in mild-to-moderate Alzheimer's disease.

Previous studies demonstrated that a single intramuscular (i.m.) dose of an attenuated recombinant vesicular stomatitis virus (rVSV) vector (VesiculoVax vector platform; rVSV-N4CT1) expressing the glycoprotein (GP) from the Mayinga strain of Zaire ebolavirus (EBOV) protected nonhuman primates (NHPs) from lethal challenge with EBOV strains Kikwit and Makona. Here, we studied the immunogenicities of an expanded range of attenuated rVSV vectors expressing filovirus GP in mice. Based on data from those studies, an optimal attenuated trivalent rVSV vector formulation was identified that included rVSV vectors expressing EBOV, Sudan ebolavirus (SUDV), and the Angola strain of Marburg marburgvirus (MARV) GPs. NHPs were vaccinated with a single dose of the trivalent formulation, followed by lethal challenge 28 days later with each of the three corresponding filoviruses. At day 14 postvaccination, a serum IgG response specific for all three GPs was detected in all the vaccinated macaques. A modest and balanced cell-mediated immune response specific for each GP was also detected in a majority of the vaccinated macaques. No matter the level of total GP-specific immune response detected postvaccination, all the vaccinated macaques were protected from disease and death following lethal challenge with each of the three filoviruses. These findings indicate that vaccination with a single dose of attenuated rVSV-N4CT1 vectors each expressing a single filovirus GP may provide protection against the filoviruses most commonly responsible for outbreaks of hemorrhagic fever in sub-Saharan Africa. IMPORTANCE The West African Ebola virus Zaire outbreak in 2013 showed that the disease was not only a regional concern, but a worldwide problem, and highlighted the need for a safe and efficacious vaccine to be administered to the populace. However, other endemic pathogens, like Ebola virus Sudan and Marburg, also pose an important health risk to the public and therefore require development of a vaccine prior to the occurrence of an outbreak. The significance of our research was the development of a blended trivalent filovirus vaccine that elicited a balanced immune response when administered as a single dose and provided complete protection against a lethal challenge with all three filovirus pathogens., (Copyright © 2018 American Society for Microbiology.)

Despite substantial clinical benefits, complete eradication of HIV has not been possible using antiretroviral therapy (ART) alone. Strategies that can either eliminate persistent viral reservoirs or boost host immunity to prevent rebound of virus from these reservoirs after discontinuation of ART are needed; one possibility is therapeutic vaccination. We report the results of a randomized, placebo-controlled trial of a therapeutic vaccine regimen in patients in whom ART was initiated during the early stage of HIV infection and whose immune system was anticipated to be relatively intact. The objectives of our study were to determine whether the vaccine was safe and could induce an immune response that would maintain suppression of plasma viremia after discontinuation of ART. Vaccinations were well tolerated with no serious adverse events but produced only modest augmentation of existing HIV-specific CD4 + T cell responses, with little augmentation of CD8 + T cell responses. Compared with placebo, the vaccination regimen had no significant effect on the kinetics or magnitude of viral rebound after interruption of ART and no impact on the size of the HIV reservoir in the CD4 + T cell compartment. Notably, 26% of subjects in the placebo arm exhibited sustained suppression of viremia (<400 copies/ml) after treatment interruption, a rate of spontaneous suppression higher than previously reported. Our findings regarding the degree and kinetics of plasma viral rebound after ART interruption have potentially important implications for the design of future trials testing interventions aimed at achieving ART-free control of HIV infection., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The HIV Vaccine Trials Network (HVTN) 087 vaccine trial assessed the effect of increasing doses of pIL-12 (interleukin-12 delivered as plasmid DNA) adjuvant on the immunogenicity of an HIV-1 multiantigen (MAG) DNA vaccine delivered by electroporation and boosted with a vaccine comprising an attenuated vesicular stomatitis virus expressing HIV-1 Gag (VSV-Gag). We randomized 100 healthy adults to receive placebo or 3 mg HIV-MAG DNA vaccine (ProfectusVax HIV-1 gag / pol or ProfectusVax nef / tat / vif , env ) coadministered with pIL-12 at 0, 250, 1,000, or 1,500 μg intramuscularly by electroporation at 0, 1, and 3 months followed by intramuscular inoculation with 3.4 × 10 7 PFU VSV-Gag vaccine at 6 months. Immune responses were assessed after the prime and boost and 6 months after the last vaccination. High-dose pIL-12 increased the magnitude of CD8 + T-cell responses postboost compared to no pIL-12 ( P = 0.02), while CD4 + T-cell responses after the prime were higher in the absence of pIL-12 than with low- and medium-dose pIL-12 ( P ≤ 0.05). The VSV boost increased Gag-specific CD4 + and CD8 + T-cell responses in all groups ( P < 0.001 for CD4 + T cells), inducing a median of four Gag epitopes in responders. Six to 9 months after the boost, responses decreased in magnitude, but CD8 + T-cell response rates were maintained. The addition of a DNA prime dramatically improved responses to the VSV vaccine tested previously in the HVTN 090 trial, leading to broad epitope targeting and maintained CD8 + T-cell response rates at early memory. The addition of high-dose pIL-12 given with a DNA prime by electroporation and boosted with VSV-Gag increased the CD8 + T-cell responses but decreased the CD4 + responses. This approach may be advantageous in reshaping the T-cell responses to a variety of chronic infections or tumors. (This study has been registered at ClinicalTrials.gov under registration no. NCT01578889.)., (Copyright © 2017 American Society for Microbiology.)

Introduction: Changes in cerebrospinal fluid (CSF) tau and amyloid β (Aβ)42 accompany development of Alzheimer's brain pathology. Robust tau and Aβ42 immunoassays were developed to establish a tau/Aβ42 cutoff distinguishing mild-to-moderate Alzheimer's disease (AD) subjects from healthy elderly control (HC) subjects., Methods: A CSF tau/Aβ42 cutoff criteria was chosen, which distinguished the groups and maximized concordance with amyloid PET. Performance was assessed using an independent validation cohort., Results: A tau/Aβ42 = 0.215 cutoff provided 94.8% sensitivity and 77.7% specificity. Concordance with PET visual reads was estimated at 86.9% in a ∼50% PET positive population. In the validation cohort, the cutoff demonstrated 78.4% sensitivity and 84.9% specificity to distinguish the AD and HC populations., Discussion: A tau/Aβ42 cutoff with acceptable sensitivity and specificity distinguished HC from mild-to-moderate AD subjects and maximized concordance to brain amyloidosis. The defined cutoff demonstrated that CSF analysis may be useful as a surrogate to imaging assessment of AD pathology.

β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials., (Copyright © 2016, American Association for the Advancement of Science.)

Background: Therapeutic vaccination is being studied in eradication and "functional cure" strategies for HIV-1. The Profectus Biosciences multiantigen (MAG) HIV-1 DNA vaccine encodes HIV-1 Gag/Pol, Nef/Tat/Vif, and Envelope, and interleukin-12 (IL-12) and is delivered by electroporation combined with intramuscular injection (IM-EP)., Methods: Sixty-two HIV-1-infected patients on antiretroviral therapy (plasma HIV-1 RNA levels ≤ 200 copies/mL; CD4(+) T-cell counts ≥ 500 cells/mm(3)) were randomly allocated 5:1 to receive vaccine or placebo. At weeks 0, 4, and 12, 4 consecutive cohorts received 3000 μg HIV MAG pDNA with 0, 50, 250, or 1000 μg of IL-12 pDNA by IM-EP. A fifth cohort received HIV MAG pDNA and 1000 μg of IL-12 pDNA by standard IM injection., Results: CD4(+) T cells expressing IL-2 in response to Gag and Pol and interferon-γ responses to Gag, Pol, and Env increased from baseline to week 14 in the low-dose (50-μg) IL-12 arm vs. placebo (P < 0.05; intracellular cytokine staining). The total increase in the IL-2-expressing CD4 T-cell responses to any antigen was also higher in the low-dose IL-12 arm vs. placebo (P = 0.04). Cytokine responses by CD8 T cells to HIV antigens were not increased in any vaccine arm relative to placebo., Conclusions: HIV-1 MAG/low-dose IL-12 DNA vaccine delivered by IM-EP augmented CD4(+) but not CD8(+) T-cell responses to multiple HIV-1 antigens.

Previously, recombinant vesicular stomatitis virus (rVSV) pseudotypes expressing Ebolavirus glycoproteins (GPs) in place of the VSV G protein demonstrated protection of nonhuman primates from lethal homologous Ebolavirus challenge. Those pseudotype vectors contained no additional attenuating mutations in the rVSV genome. Here we describe rVSV vectors containing a full complement of VSV genes and expressing the Ebola virus (EBOV) GP from an additional transcription unit. These rVSV vectors contain the same combination of attenuating mutations used previously in the clinical development pathway of an rVSV/human immunodeficiency virus type 1 vaccine. One of these rVSV vectors (N4CT1-EBOVGP1), which expresses membrane-anchored EBOV GP from the first position in the genome (GP1), elicited a balanced cellular and humoral GP-specific immune response in mice. Guinea pigs immunized with a single dose of this vector were protected from any signs of disease following lethal EBOV challenge, while control animals died in 7-9 days. Subsequently, N4CT1-EBOVGP1 demonstrated complete, single-dose protection of 2 macaques following lethal EBOV challenge. A single sham-vaccinated macaque died from disease due to EBOV infection. These results demonstrate that highly attenuated rVSV vectors expressing EBOV GP may provide safer alternatives to current EBOV vaccines., (© The Author 2015. 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: Strategies to enhance the immunogenicity of DNA vaccines in humans include i) co-administration of molecular adjuvants, ii) intramuscular administration followed by in vivo electroporation (IM/EP) and/or iii) boosting with a different vaccine. Combining these strategies provided protection of macaques challenged with SIV; this clinical trial was designed to mimic the vaccine regimen in the SIV study., Methods: Seventy five healthy, HIV-seronegative adults were enrolled into a phase 1, randomized, double-blind, placebo-controlled trial. Multi-antigenic HIV (HIVMAG) plasmid DNA (pDNA) vaccine alone or co-administered with pDNA encoding human Interleukin 12 (IL-12) (GENEVAX IL-12) given by IM/EP using the TriGrid Delivery System was tested in different prime-boost regimens with recombinant Ad35 HIV vaccine given IM., Results: All local reactions but one were mild or moderate. Systemic reactions and unsolicited adverse events including laboratory abnormalities did not differ between vaccine and placebo recipients. No serious adverse events (SAEs) were reported. T cell and antibody response rates after HIVMAG (x3) prime-Ad35 (x1) boost were independent of IL-12, while the magnitude of interferon gamma (IFN-γ) ELISPOT responses was highest after HIVMAG (x3) without IL-12. The quality and phenotype of T cell responses shown by intracellular cytokine staining (ICS) were similar between groups. Inhibition of HIV replication by autologous T cells was demonstrated after HIVMAG (x3) prime and was boosted after Ad35. HIV specific antibodies were detected only after Ad35 boost, although there was a priming effect with 3 doses of HIVMAG with or without IL-12. No anti-IL-12 antibodies were detected., Conclusion: The vaccines were safe, well tolerated and moderately immunogenic. Repeated administration IM/EP was well accepted. An adjuvant effect of co-administered plasmid IL-12 was not detected., Trial Registration: ClinicalTrials.gov NCT01496989.

Background.  We report the first-in-human safety and immunogenicity evaluation of a highly attenuated, replication-competent recombinant vesicular stomatitis virus (rVSV) human immunodeficiency virus (HIV)-1 vaccine. Methods.  Sixty healthy, HIV-1-uninfected adults were enrolled in a randomized, double-blinded, placebo-controlled dose-escalation study. Groups of 12 participants received rVSV HIV-1 gag vaccine at 5 dose levels (4.6 × 10(3) to 3.4 × 10(7) particle forming units) (N = 10/group) or placebo (N = 2/group), delivered intramuscularly as bilateral injections at 0 and 2 months. Safety monitoring included VSV cultures from blood, urine, saliva, and swabs of oral lesions. Vesicular stomatitis virus-neutralizing antibodies, T-cell immunogenicity, and HIV-1 specific binding antibodies were assessed. Results.  Local and systemic reactogenicity symptoms were mild to moderate and increased with dose. No severe reactogenicity or product-related serious adverse events were reported, and all rVSV cultures were negative. All vaccine recipients became seropositive for VSV after 2 vaccinations. gag-specific T-cell responses were detected in 63% of participants by interferon-γ enzyme-linked immunospot at the highest dose post boost. Conclusions.  An attenuated replication-competent rVSV gag vaccine has an acceptable safety profile in healthy adults. This rVSV vector is a promising new vaccine platform for the development of vaccines to combat HIV-1 and other serious human diseases.

Background: Pain after arthroscopic shoulder surgery is often severe, and establishing a pain treatment regimen that does not delay discharge can be challenging. The reported ability of ketamine to prevent opioid-induced hyperalgesia has not been investigated in this particular setting., Methods: 300 adult patients scheduled for shoulder arthroscopy under general anesthesia were recruited for this observational clinical trial and were allotted to either receive 1mg/kg IV bolus of ketamine before surgery (ketamine group, KG) or to a control group (CG) without ketamine. NRS pain scores were obtained on the operative day and on postoperative days 1 and 2 and compared between groups. Secondary variables were blood pressure, heart rate, process times, satisfaction with the anesthetic and unwanted effects., Results: Pain severity did not differ significantly between the groups at any time. Propofol injection rate and cumulative dose were higher in the KG. Heart rates and blood pressures were similar. Time to emergence and time in PACU were longer and vomiting was more frequent in patients given ketamine., Conclusion: Preoperative low-dose ketamine added to a general anesthetic does not reduce perioperative pain after outpatient shoulder arthroscopy. It increases procedural times and the incidence of PONV.

Background: In this study, we sought to determine whether a simplified ultrasound measurement of the largest transverse diameter, using a standard ultrasound machine, could be used to diagnose postoperative urinary retention (POUR). This method may replace expensive bladder volume measuring devices or a more complex ultrasound procedure (involving the measurement of 3 bladder diameters)., Methods: Patients at risk of POUR if unable to void after orthopedic surgery were evaluated in the postanesthesia care unit before discharge. Bladder diameter was first measured using a portable ultrasound device (Vscan®; GE Healthcare, Wauwatosa, WI). An automated evaluation of bladder volume was then performed (Bladderscan® BVI 3000; Diagnostic Ultrasound, Redmond, WA). Finally, when a bladder catheterization was performed, the actual urinary volume was measured. The main outcome was a bladder volume ≥600 mL as measured using the automated ultrasound scanner (Bladderscan BVI 3000) or by catheterization. Correlations between bladder volumes and diameter were studied and receiver operating characteristic curves were constructed to determine the performance in predicting a bladder volume ≥600 mL. A "gray zone" approach was developed because a single cutoff value may not always be clinically significant., Results: One hundred patients were included and underwent a Bladderscan measurement. Urinary volume after catheterization was obtained in 49 patients. A significant correlation was found between the largest transverse diameter and urinary volumes assessed by the 2 methods (Bladderscan and catheterization). Pearson correlation coefficients were r = 0.80 (95% confidence interval [CI], 0.72-0.86; P < 0.001) and r = 0.79 (95% CI, 0.65-0.88; P < 0.001), respectively. The area under the receiver operating characteristic curves for the prediction of a bladder volume ≥600 mL were 0.94 (95% CI, 0.88-0.98) and 0.91 (95% CI, 0.79-0.97), respectively, for urinary volumes assessed by Bladderscan and catheterization. The optimal cutoff value was 9.7 cm for both methods. The gray zone was narrow, ranging from 9.7 to 10.7 cm thus limiting inconclusive measurements., Conclusions: A simple ultrasound measurement of the largest transverse bladder diameter seemed to be helpful to exclude or confirm POUR.

The family Filoviridae contains three genera, Ebolavirus (EBOV), Marburg virus, and Cuevavirus. Some members of the EBOV genus, including Zaire ebolavirus (ZEBOV), can cause lethal haemorrhagic fever in humans. During 2014 an unprecedented ZEBOV outbreak occurred in West Africa and is still ongoing, resulting in over 10,000 deaths, and causing global concern of uncontrolled disease. To meet this challenge a rapid-acting vaccine is needed. Many vaccine approaches have shown promise in being able to protect nonhuman primates against ZEBOV. In response to the current ZEBOV outbreak several of these vaccines have been fast tracked for human use. However, it is not known whether any of these vaccines can provide protection against the new outbreak Makona strain of ZEBOV. One of these approaches is a first-generation recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing the ZEBOV glycoprotein (GP) (rVSV/ZEBOV). To address safety concerns associated with this vector, we developed two candidate, further-attenuated rVSV/ZEBOV vaccines. Both attenuated vaccines produced an approximately tenfold lower vaccine-associated viraemia compared to the first-generation vaccine and both provided complete, single-dose protection of macaques from lethal challenge with the Makona outbreak strain of ZEBOV.

A guiding principle for HIV vaccine design has been that cellular and humoral immunity work together to provide the strongest degree of efficacy. However, three efficacy trials of Ad5-vectored HIV vaccines showed no protection. Transmission was increased in two of the trials, suggesting that this vaccine strategy elicited CD4+ T-cell responses that provide more targets for infection, attenuating protection or increasing transmission. The degree to which this problem extends to other HIV vaccine candidates is not known. Here, we show that a gp120-CD4 chimeric subunit protein vaccine (full-length single chain) elicits heterologous protection against simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) acquisition in three independent rhesus macaque repeated low-dose rectal challenge studies with SHIV162P3 or SIVmac251. Protection against acquisition was observed with multiple formulations and challenges. In each study, protection correlated with antibody-dependent cellular cytotoxicity specific for CD4-induced epitopes, provided that the concurrent antivaccine T-cell responses were minimal. Protection was lost in instances when T-cell responses were high or when the requisite antibody titers had declined. Our studies suggest that balance between a protective antibody response and antigen-specific T-cell activation is the critical element to vaccine-mediated protection against HIV. Achieving and sustaining such a balance, while enhancing antibody durability, is the major challenge for HIV vaccine development, regardless of the immunogen or vaccine formulation.

DNA encoded adjuvants are well known for increasing the magnitude of cellular and/or humoral immune responses directed against vaccine antigens. DNA adjuvants can also tune immune responses directed against vaccine antigens to better protect against infection of the target organism. Two potent DNA adjuvants that have unique abilities to tune immune responses are the catalytic A1 domains of Cholera Toxin (CTA1) and Heat-Labile Enterotoxin (LTA1). Here, we have characterized the adjuvant activities of CTA1 and LTA1 using HIV and SIV genes as model antigens. Both of these adjuvants enhanced the magnitude of antigen-specific cellular immune responses on par with those induced by the well-characterized cytokine adjuvants IL-12 and GM-CSF. CTA1 and LTA1 preferentially enhanced cellular responses to the intracellular antigen SIVmac239-gag over those for the secreted HIVBaL-gp120 antigen. IL-12, GM-CSF and electroporation did the opposite suggesting differences in the mechanisms of actions of these diverse adjuvants. Combinations of CTA1 or LTA1 with IL-12 or GM-CSF generated additive and better balanced cellular responses to both of these antigens. Consistent with observations made with the holotoxin and the CTA1-DD adjuvant, CTA1 and LTA1 evoked mixed Th1/Th17 cellular immune responses. Together, these results show that CTA1 and LTA1 are potent DNA vaccine adjuvants that favor the intracellular antigen gag over the secreted antigen gp120 and evoke mixed Th1/Th17 responses against both of these antigens. The results also indicate that achieving a balanced immune response to multiple intracellular and extracellular antigens delivered via DNA vaccination may require combining adjuvants that have different and complementary mechanisms of action.

Unlabelled: In previous work, a prototypic recombinant vesicular stomatitis virus Indiana serotype (rVSIV) vector expressing simian immunodeficiency virus (SIV) gag and human immunodeficiency virus type 1 (HIV-1) env antigens protected nonhuman primates (NHPs) from disease following challenge with an HIV-1/SIV recombinant (SHIV). However, when tested in a stringent NHP neurovirulence (NV) model, this vector was not adequately attenuated for clinical evaluation. For the work described here, the prototypic rVSIV vector was attenuated by combining specific G protein truncations with either N gene translocations or mutations (M33A and M51A) that ablate expression of subgenic M polypeptides, by incorporation of temperature-sensitive mutations in the N and L genes, and by deletion of the VSIV G gene to generate a replicon that is dependent on trans expression of G protein for in vitro propagation. When evaluated in a series of NHP NV studies, these attenuated rVSIV variants caused no clinical disease and demonstrated a very significant reduction in neuropathology compared to wild-type VSIV and the prototypic rVSIV vaccine vector. In spite of greatly increased in vivo attenuation, some of the rVSIV vectors elicited cell-mediated immune responses that were similar in magnitude to those induced by the much more virulent prototypic vector. These data demonstrate novel approaches to the rational attenuation of VSIV NV while retaining vector immunogenicity and have led to identification of an rVSIV N4CT1gag1 vaccine vector that has now successfully completed phase I clinical evaluation., Importance: The work described in this article demonstrates a rational approach to the attenuation of vesicular stomatitis virus neurovirulence. The major attenuation strategy described here will be most likely applicable to other members of the Rhabdoviridae and possibly other families of nonsegmented negative-strand RNA viruses. These studies have also enabled the identification of an attenuated, replication-competent rVSIV vector that has successfully undergone its first clinical evaluation in humans. Therefore, these studies represent a major milestone in the development of attenuated rVSIV, and likely other vesiculoviruses, as a new vaccine platform(s) for use in humans., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Background: Little information is available on the titration of morphine postoperatively in children. This observational study describes the technique in terms of the bolus dose, the number of boluses required, the time to establish analgesia, and side effects noted., Methods: Morphine was administered if pain score (VAS or FLACC) was >30. Patients weighing less than 45 kg received a 50 μg·kg(-1) bolus of morphine with subsequent boluses of 25 μg kg(-1) as required. Patients weighing over 45 kg received boluses of 2 mg. Pain and Ramsay scores were recorded up to 90 min after the end of the titration and any side effect or complication was noted. Data are presented as the median [interquartile Q1-Q3 range]., Results: Overall, 103 children were studied. The median age was 4.2 years [0.8-12.2 years]. The median weight was 15.5 kg [8.2-35.0 kg]. The protocol was effective for pain control with a significant decrease in pain scores over time. The median pain score (VAS or FLACC) was 70 [50-80] prior to the initial bolus and 0 [0-10] 90 min after the last bolus. Median Ramsay score was 1 [1-2] before the initial bolus administration and 4 [2-4] at 90 min. The median total dose of morphine was 100 [70-140] μg·kg(-1) , and the median number of boluses was 3 [2-5]. Side effects were observed in 17% of cases. No serious complications were observed., Conclusions: Our study of morphine titration for children shows that our protocol was effective for pain control with a significant decrease in pain scores over time. No serious complications were encountered. More studies on larger cohorts of patients are needed to confirm the efficacy and safety of this protocol., (© 2013 John Wiley & Sons Ltd.)

Previous studies of perceptual category learning in patients with schizophrenia generally demonstrate impaired perceptual category learning; however, traditional cognitive studies have often failed to address the relationship of different cortical regions to perceptually based category learning and judgments in healthy participants and patients with schizophrenia. In the present study, perceptual category learning was examined in 26 patients with schizophrenia and 25 healthy participants using a dot-pattern category learning task. In the training phase, distortions of a prototypical dot pattern were presented. In the test phase, participants were shown the prototype, low and high distortions of the prototype, and random dot patterns. Participants were required to indicate whether the presented dot pattern was a member of the category of dot-patterns previously presented during the study phase. Patients with schizophrenia displayed an impaired ability to make judgments regarding marginal members of novel, perceptually based categories relative to healthy participants. Category judgment also showed opposite patterns of strong, significant correlations with behavioral measures of prefrontal cortex function in patients relative to healthy participants. These results suggest that impaired judgments regarding novel, perceptually based category membership may be due to abnormal prefrontal cortex function in patients with schizophrenia.

Studies of patients with Parkinson's disease receiving dopamimetics report conflicting evidence for early learning of probabilistic cue-outcome associations that elicits frontal-striatal activity. Previous studies of probabilistic association learning in patients with schizophrenia administered antipsychotics have displayed conflicting evidence for normal and abnormal learning. The role of dopaminergic treatment (dopamimetic versus dopamine antagonistic) effects on probabilistic association learning in these diseases that directly impact the dopamine system is not fully understood. The current study examined the effects of dopaminergic therapies on probabilistic association learning in 13 patients with schizophrenia and 8 patients with Parkinson's disease under two conditions: after withdrawal from dopaminergic treatment and following administration of appropriate dopaminergic treatment. Medication order was counterbalanced in both groups. Patients with Parkinson's disease failed to demonstrate any significant improvement over 150 trials, under both conditions (receiving or withdrawn from dopamimetics). Patients with schizophrenia withdrawn from antipsychotics displayed significant improvement during later trials only. These results demonstrate an effect of dopamine (DA) signaling on probabilistic association learning in that: (1) dopamine replacement therapy in Parkinson's disease is insufficient to significantly improve probabilistic association learning and (2) DA receptor blockade impairs and removal of DA receptor blockade significantly improves frontal-striatal-dependent probabilistic association learning in schizophrenia, which is a novel finding and is opposite to the effects shown following removal of DA receptor blockade on other cognitive domains reported previously., Competing Interests: All authors have declared that there are no biomedical financial interests or potential conflicts of interest., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Background: Current antipsychotic treatments have little impact on the cognitive deficits associated with schizophrenia. It has been proposed that agents which promote histamine release may enhance cognition. We evaluated whether the H3 inverse agonist MK-0249 might improve cognitive deficits in patients with schizophrenia., Methods: Outpatients (N=55) with schizophrenia between ages 21 and 55 who were clinically stable, experienced no more than mild to moderate overall symptoms (PANSS score total 36-75), and were taking a stable dose of antipsychotic medication were randomized to MK-0249 10mg and placebo in a multi-center, randomized, double-blind, 2-period (4-weeks per period), cross-over study. The primary efficacy endpoint was the mean change from baseline at 4-weeks of treatment in the total cognitive score on the Brief Assessment of Cognition in Schizophrenia (BACS) Battery. Other assessments of cognition were also performed., Results: A total of 46 patients completed the study. MK-0249 10mg did not demonstrate a statistically significant difference compared to placebo in the mean change from baseline in the total cognitive score on the BACS battery after 4-weeks of treatment (-0.1, 95% CI: -2.3, 2.1) or with regard to secondary measures of attention/processing speed, episodic memory, or working memory after 4-weeks of treatment. The incidence of adverse events was greater during the MK-0249 treatment period (25/52 patients, 48.1%) compared to the placebo treatment period (15/51 patients, 29.4%)., Conclusion: MK-0249 10mg once daily was not superior to placebo in the treatment of cognitive impairment in patients with schizophrenia after 4-weeks. (Clinicaltrials.gov: NCT00506077)., (Copyright © 2013 Elsevier B.V. All rights reserved.)