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Complementary and alternative medicine (CAM) has gained popularity as a naturalistic approach to managing menopausal symptoms. This evidence-based article reviews recent studies on the use of CAM for menopause and aims to provide insights into the effectiveness, safety, and potential benefits of various CAM modalities. The article focuses on the biological domain, which includes supplements, botanicals, nutrition, homeopathy, and aromatherapy. Black cohosh and red clover are 2 of the most common botanicals used for managing menopausal symptoms. However, their efficacy and safety remain controversial and further research is needed to elucidate their precise mechanisms of action., Competing Interests: Disclosure I, M.J. Smith-Francis, hereby affirm that I have no commercial or financial conflicts of interest to declare relevant to the subject matter discussed herein., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The cattle industry contributes to Uganda's agricultural output. It faces challenges that include theft and parentage ascertainment. These challenges can benefit from recent molecular genomics and bioinformatics technologies., Objectives: We employed genomic analyses to establish potential ownership of a group of nine cattle that were being claimed by two farmers in Uganda. We investigated the genetic relationship of Ugandan cattle with regional indigenous breeds as well as exotic breeds that are currently present in Uganda. In addition, we investigated regions that are likely to be under selection in the Ugandan cattle., Methods: Hair samples were collected from seven and two animals from farmers A and B, respectively. They were genotyped for 53,218 Single Nucleotide Polymorphism markers. To establish genetic relationships between the sampled animals, we performed genomic analyses including, principal component analysis (PCA), hierarchical clustering analysis and identity by state/descent. We also performed admixture and runs of homozygosity analyses to assess the ancestry composition and identify regions potentially under selection in Ugandan cattle, respectively., Results: The seven animals from Farmer A were genetically close to each other but showed minimal relationship with the disputed animals. The two animals from Farmer B were genetically distant from each other but showed greater similarity to four of the disputed animals. Four of the disputed animals showed great dissimilarity from the animals of both farmers. Comparison of these with the reference breeds revealed minimal European exotic genetic introgression into these animals, but rather high similarity to the Sheko. Results also revealed high homozygosity in the major histocompatibility complex regions., Conclusions: Our results demonstrate the use of currently available genomic tools to empirically establish the ownership of cattle; these could be scaled up as a resourceful and viable tool that could be employed to support conflict resolution where reliable livestock identification is unavailable., (© 2023 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Porcine reproductive and respiratory syndrome virus (PRRSV) remains a leading cause of economic loss in pig farming worldwide. Existing commercial vaccines, all based on modified live or inactivated PRRSV, fail to provide effective immunity against the highly diverse circulating strains of both PRRSV-1 and PRRSV-2. Therefore, there is an urgent need to develop more effective and broadly active PRRSV vaccines. In the absence of neutralizing antibodies, T cells are thought to play a central role in controlling PRRSV infection. Herpesvirus-based vectors are novel vaccine platforms capable of inducing high levels of T cells against encoded heterologous antigens. Therefore, the aim of this study was to assess the immunogenicity and efficacy of an attenuated herpesvirus-based vector (bovine herpesvirus-4; BoHV-4) expressing a fusion protein comprising two well-characterized PRRSV-1 T-cell antigens (M and NSP5). Prime-boost immunization of pigs with BoHV-4 expressing the M and NSP5 fusion protein (vector designated BoHV-4-M-NSP5) induced strong IFN-γ responses, as assessed by ELISpot assays of peripheral blood mononuclear cells (PBMC) stimulated with a pool of peptides representing PRRSV-1 M and NSP5. The responses were closely mirrored by spontaneous IFN-γ release from unstimulated cells, albeit at lower levels. A lower frequency of M and NSP5 specific IFN-γ responding cells was induced following a single dose of BoHV-4-M-NSP5 vector. Restimulation using M and NSP5 peptides from PRRSV-2 demonstrated a high level of cross-reactivity. Vaccination with BoHV-4-M-NSP5 did not affect viral loads in either the blood or lungs following challenge with the two heterologous PRRSV-1 strains. However, the BoHV-4-M-NSP5 prime-boost vaccination showed a marked trend toward reduced lung pathology following PRRSV-1 challenge. The limited effect of T cells on PRRSV-1 viral load was further examined by analyzing local and circulating T-cell responses using intracellular cytokine staining and proliferation assays. The results from this study suggest that vaccine-primed T-cell responses may have helped in the control of PRRSV-1 associated tissue damage, but had a minimal, if any, effect on controlling PRRSV-1 viral loads. Together, these results indicate that future efforts to develop effective PRRSV vaccines should focus on achieving a balanced T-cell and antibody response., Competing Interests: Authors BS-B, MH, HB, and VF are employed by the company ECO Animal Health, London, UK. Authors JR, YW, SH, TM, JS, and MJ in part are employed by the company The Vaccine Group, Plymouth, UK. Author MF was employed by BioVacc Consulting Ltd. 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. The authors declare that project was funded by ECO Animal Health. The authors declare that this study received funding from ECO Animal Health, who contributed to the design and coordination of the study., (Copyright © 2023 de Brito, Holtham, Roser, Saunders, Wezel, Henderson, Mauch, Sanz-Bernardo, Frossard, Bernard, Lean, Nunez, Gubbins, Suárez, Davison, Francis, Huether, Benchaoui, Salt, Fowler, Jarvis and Graham.)

After introduction of faecal multiplex PCR that includes targets for stx1 and stx2 genes, we found stx genes were detected in 120 specimens from 111 patients over a 31-month period from 2018-2020 from a total of 14,179 separate tests performed. The proportion of stx1 only vs stx2 only vs stx1 and stx2 was 35%, 22% and 42%, respectively. There were 54 specimens which were culture positive, with 33 different serotypes identified, the predominant serotype being O157:H7 (19%). Eighty-two patients had clinical data available; we found a high rate of fever (35%), bloody diarrhoea (34%), acute kidney injury (27%), hospital admission (80%) and detection of faecal co-pathogens (23%). Only one patient developed haemolytic uraemic syndrome. We found no significant association with stx genotype and any particular symptom or complication. We found a significant association of serotypes O157:H7 and O26:H11 with bloody stool, but no significant association with any other symptom or complication., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

While over 95% of the population has reported experiencing extreme stress or trauma, females of reproductive age develop stress-induced neuropsychiatric disorders at twice the rate of males. This suggests that ovarian hormones may facilitate neural processes that increase stress susceptibility and underlie the heightened rates of these disorders, like depression and anxiety, that result from stress exposure in females. However, there is contradicting evidence in the literature regarding estrogen's role in stress-related behavioral outcomes. Estrogen signaling through estrogen receptor beta (ERβ) has been traditionally thought of as anxiolytic, but recent studies suggest estrogen exhibits distinct effects in the context of stress. Furthermore, ERβ is found abundantly in many stress-sensitive brain loci, including the central amygdala (CeA), in which transcription of the vital stress hormone, corticotropin releasing factor (CRF), can be regulated by an estrogen response element. Therefore, these experiments sought to identify the role of CeA ERβ activity during stress on behavioral outcomes in naturally cycling, adult, female Sprague-Dawley rats. Rats were exposed to an ethological model of vicarious social stress, witness stress (WS), in which they experienced the sensory and psychological aspects of an aggressive social defeat encounter between two males. Following WS, rats exhibited stress-induced anxiety-like behaviors in the marble burying taskand brain analysis revealed increased ERβ and CRF specifically within the CeA following exposure to stress cues. Subsequent experiments were designed to target this receptor in the CeA using microinjections of the ERβ antagonist, PHTPP, prior to each stress session. During WS, estrogen signaling through ERβ was responsible for the behavioral sensitization to repeated social stress. Sucrose preference, acoustic startle, and marble burying tasks determined that blocking ERβ in the CeA during WS prevented the development of depressive-, anxiety-like, and hypervigilant behaviors. Additionally, brain analysis revealed a long-term decrease of intra-CeA CRF expression in PHTPP-treated rats. These experiments indicate that ERβ signaling in the CeA, likely through its effects on CRF, contributes to the development of negative valence behaviors that result from exposure to repeated social stress in female rats., Competing Interests: None., (© 2023 The Authors. Published by Elsevier Inc.)

High-risk neuroblastoma (NB) accounts for 15% of all pediatric cancer deaths. Refractory disease for high-risk NB patients is attributed to chemotherapy resistance and immunotherapy failure. The poor prognosis for high-risk NB patients demonstrates an unmet medical need for the development of new, more efficacious therapeutics. CD38 is an immunomodulating protein that is expressed constitutively on natural killer (NK) cells and other immune cells in the tumor microenvironment (TME). Furthermore, CD38 over expression is implicated in propagating an immunosuppressive milieu within the TME. Through virtual and physical screening, we have identified drug-like small molecule inhibitors of CD38 with low micromolar IC 50 values. We have begun to explore structure activity relationships for CD38 inhibition through derivatization of our most effective hit molecule to develop a new compound with lead-like physicochemical properties and improved potency. We have demonstrated that our derivatized inhibitor, compound 2, elicits immunomodulatory effects in NK cells by increasing cell viability by 190 ± 36% in multiple donors and by significantly increasing interferon gamma. Additionally, we have illustrated that NK cells exhibited enhanced cytotoxicity toward NB cells (14% reduction of NB cells over 90 minutes) when given a combination treatment of our inhibitor and the immunocytokine ch14.18-IL2. Herein we describe the synthesis and biological evaluation of small molecule CD38 inhibitors and demonstrate their potential utility as a novel approach to NB immunotherapy. These compounds represent the first examples of small molecules that stimulate immune function for the treatment of cancer., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The animal-human interface has played a central role in advances made in vaccinology for the past two centuries. Many traditional veterinary vaccines were developed by growing, attenuating, inactivating and fractioning the pathogen of interest. While such approaches have been very successful, we have reached a point where they have largely been exhausted and alternative approaches are required. Furthermore, although subunit vaccines have enhanced safety profiles and created opportunities for combined discrimination between vaccinated and infected animal (DIVA) approaches, their functionality has largely been limited to diseases that can be controlled by humoral immunity until very recently. We now have a new generation of adjuvants and delivery systems that can elicit CD4 + T cells and/or CD8 +  T cell responses in addition to high-titre antibody responses. We review the current vaccine platform technologies, describe their roles in veterinary vaccinology and discuss how knowledge of their mode of action allows informed decisions on their deployment with wider benefits for One Health., 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 © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The threat posed by zoonotic diseases and other livestock pathogens has never been greater, and thus we must do all we can to learn from experience in order to tackle emerging disease threats. The process of developing a new veterinary vaccine involves the generation of a specific set of data in order to meet the strict product licencing requirements of regulatory approval bodies around the globe. As a result, it is important that those embarking on the development of a vaccine using either conventional or novel platform technologies understand these regulations. In addition, there are a number of specific requirements that one needs to take into consideration when developing a product specifically for the commercial poultry market. This paper briefly outlines the veterinary vaccine development process in general and then explores how this process can be accelerated. It also recognizes the "One Health" lessons that can be learnt from the recent rapid development of vaccines to tackle the COVID-19 pandemic and acknowledges the important measures that regulatory authorities have taken in the creation of an environment to facilitate the licencing of new vaccine platform technologies.

Corynebacterium macginleyi has long been associated with ocular infections and has more recently been rarely implicated in systemic infections. There is a paucity of literature regarding the rate of C. macginleyi co-infection with other bacterial and viral pathogens and regarding the incidence of C. macginleyi infection in the paediatric population. In this study, we report 30 isolates of C. macginleyi of ocular origin from 26 patients, identified using matrix-assisted laser desorption ionisation-time of flight mass spectrometry (MALDI-TOF MS). The rates of co-isolation with bacterial and viral pathogens were 62% (n=16/26) and 39% (n=5/13), respectively, in this study. Of these, 13 patients had molecular testing performed as requested by treating clinicians for either the Chlamydia trachomatis/Neisseria gonorrhoeae PCR or herpes/enterovirus/adenovirus multiplex PCR. All isolates tested susceptible to linezolid, vancomycin and ciprofloxacin, with variable resistance to tetracycline, clindamycin and penicillin using EUCAST breakpoints., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Real-world evidence (RWE) is an emerging scientific discipline which is being increasingly utilized for decision making on prescription-only medicines. However, there has been little focus to date on the application of RWE within the nonprescription sector. This paper reviews the existing and potential applications of RWE for nonprescription medicines, using the nonprescription medicine life cycle as a framework for discussion. Relevant sources of real-world data (RWD) are reviewed and compared with those available for prescribed medicines. Existing life-cycle data gaps are identified where RWE is required or where use of RWE can complement data from randomized controlled trials. Published RWE examples relating to nonprescription medicines are summarized, and potential relevant future sources of RWD discussed. Challenges and limitations to the use of RWE on nonprescription medicines are discussed, and recommendations made to promote optimal and appropriate use of RWE in this sector. Overall, RWE currently plays a key role in specific phases of the nonprescription medicine life cycle, including reclassification and postmarketing safety surveillance. The increasing availability of patient-generated health data is likely to further increase the utilization of RWE to aid decision making on nonprescription medicines., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Since the initial use of vaccination in the eighteenth century, our understanding of human and animal immunology has greatly advanced and a wide range of vaccine technologies and delivery systems have been developed. The COVID-19 pandemic response leveraged these innovations to enable rapid development of candidate vaccines within weeks of the viral genetic sequence being made available. The development of vaccines to tackle emerging infectious diseases is a priority for the World Health Organization and other global entities. More than 70% of emerging infectious diseases are acquired from animals, with some causing illness and death in both humans and the respective animal host. Yet the study of critical host-pathogen interactions and the underlying immune mechanisms to inform the development of vaccines for their control is traditionally done in medical and veterinary immunology 'silos'. In this Perspective, we highlight a 'One Health vaccinology' approach and discuss some key areas of synergy in human and veterinary vaccinology that could be exploited to accelerate the development of effective vaccines against these shared health threats., (© 2021. Springer Nature Limited.)

Adenovirus vectored vaccines have entered global use during the COVID-19 pandemic, and are in development for multiple other human and veterinary applications. An attraction of the technology is the suitability of the vaccines for storage at 2-8 °C for months. Widely used COVID-19 vaccine ChAdOx1 nCoV-19 (University of Oxford/AstraZeneca) is based on a species E simian adenovirus. Species E simian serotypes have been used in a wide range of other development programs, but the stability of such vectors has not been extensively described in the peer-reviewed literature. Here, we explore the stability of two candidate vaccines based on two species E serotypes: a Rift Valley fever vaccine based upon the ChAdOx1 vector (Y25 serotype) used in ChAdOx1 nCoV-19, and a rabies vaccine based upon a ChAdOx2 vector (AdC68 serotype). We describe each vector's stability in liquid and lyophilised formulations using in vitro and in vivo potency measurements. Our data support the suitability of liquid formulations of these vectors for storage at 2-8 °C for up to 1 year, and potentially for nonrefrigerated storage for a brief period during last-leg distribution (perhaps 1-3 days at 20 °C-the precise definition of acceptable last-leg storage conditions would require further product-specific data). Depending upon the level of inprocess potency loss that is economically acceptable, and the level of instorage loss that is compatible with maintenance of acceptable end-of-storage potency, a previously reported lyophilised formulation may enable longer term storage at 20 °C or storage for a number of days at 30 °C.

The ectoenzyme CD38 is highly expressed on the surface of mature immune cells, where they are a marker for cell activation, and also on the surface of multiple tumor cells such as multiple myeloma (MM). CD38-targeted monoclonal antibodies (MABs) such as daratumumab and isatuximab bind to CD38 and promote cancer cell death by stimulating the antitumor immune response. Although MABs are achieving unprecedented success in a percentage of cases, high rates of resistance limit their efficacy. Formation of the immunosuppressive intermediate adenosine is a major route by which this resistance is mediated. Thus there is an urgent need for small molecule agents that boost the immune response in T-cells. Importantly, CD38 is a dual-function enzyme, serving as a hydrolase and a nicotinamide adenine dinucleotide (NAD + ) cyclase, and both of these activities promote immunosuppression. We have employed virtual and physical screening to identify novel compounds that are selective for either the hydrolase or the cyclase activity of CD38, and have demonstrated that these compounds activate T cells in vitro . We are currently optimizing these inhibitors for use in immunotherapy. These small molecule inhibitors of the CD38-hydrolase or cyclase activity can serve as chemical probes to determine the mechanism by which CD38 promotes resistance to MAB therapy, and could become novel and effective therapeutic agents that produce immunostimulatory effects. Our studies have identified the first small molecule inhibitors of CD38 specifically for use as immunostimulants., Competing Interests: None of the authors of this manuscript have any conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Rapid detection and isolation of coronavirus disease 2019 (COVID-19) patients is the only means of reducing hospital transmission. We describe the impact of implementation of on-site severe acute respiratory coronavirus virus 2 (SARS-CoV-2) reverse-transcription polymerase chain reaction (RT-PCR) testing on reducing turnaround time, isolation duration, pathology test ordering, and antibiotic use in patients who do not have COVID-19.

Unprecedented one-step C[double bond, length as m-dash]C bond cleavage leading to opening of the buckybowl (π-bowl), that could provide access to carbon-rich structures with previously inaccessible topologies, is reported; highlighting the possibility to implement drastically different synthetic routes to π-bowls in contrast to conventional ones applied for polycyclic aromatic hydrocarbons. Through theoretical modeling, we evaluated the mechanistic pathways feasible for π-bowl planarization and factors that could affect such a transformation including strain and released energies. Through employment of Marcus theory, optical spectroscopy, and crystallographic analysis, we estimated the possibility of charge transfer and electron coupling between "open" corannulene and a strong electron acceptor such as 7,7,8,8-tetracyanoquinodimethane. Alternative to a one-pot solid-state corannulene "unzipping" route, we reported a nine-step solution-based approach for preparation of novel planar "open" corannulene-based derivatives in which electronic structures and photophysical profiles were estimated through the energies and isosurfaces of the frontier natural transition orbitals., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Trichomonas vaginalis (TV) infection is the leading cause of non-viral sexually transmitted infection (STI) globally and is endemic in rural and remote Australia. However, current accurate prevalence data for TV in urban Australia are scarce as TV is not a notifiable infection outside of the Northern Territory (NT). This study evaluated Australian guidelines for TV testing and determined TV prevalence among patients at a large urban public hospital in Melbourne, Australia. A retrospective analysis of genitourinary samples screened for STIs by multiplex polymerase chain reaction (MPCR) between May 2017 and April 2019 was performed. A total of 7155 results (5064 females) were included in the analysis. A prevalence for TV of 1.7% (n=123) was found, which was higher than Neisseria gonorrhoeae (1.4%, n=103) but less than Chlamydia trachomatis (5%, n=358). The highest rate of TV (3%) was found in females aged 30-44 years (n = 48). Routine MPCR improved TV detection almost six-fold compared with clinician request based testing. Current targeted testing guidelines for TV were inadequate for case finding in an urban setting, and clinical request among symptomatic patients was rare. MPCR testing provides a comprehensive testing strategy for curable STI, and removes the need for clinical suspicion of TV. Implementation of MPCR for STI screening can improve TV detection in populations not normally suspected to be at risk and therefore potentially reduce disease transmission or complications associated with undiagnosed infection., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Epidemiology and pharmacoepidemiology frequently employ Real-World Data (RWD) from healthcare teams to inform research. These data sources usually include signs, symptoms, tests, and treatments, but may lack important information such as the patient's diet or adherence or quality of life. By harnessing digital tools a new fount of evidence, Patient (or Citizen/Person) Generated Health Data (PGHD), is becoming more readily available. This review focusses on the advantages and considerations in using PGHD for pharmacoepidemiological research. New and corroborative types of data can be collected directly from patients using digital devices, both passively and actively. Practical issues such as patient engagement, data linking, validation, and analysis are among important considerations in the use of PGHD. In our ever increasingly patient-centric world, PGHD incorporated into more traditional Real-Word data sources offers innovative opportunities to expand our understanding of the complex factors involved in health and the safety and effectiveness of disease treatments. Pharmacoepidemiologists have a unique role in realizing the potential of PGHD by ensuring that robust methodology, governance, and analytical techniques underpin its use to generate meaningful research results., (© 2020 John Wiley & Sons Ltd.)

Background: In the context of the pandemic, the rapid emergency use authorisation of diagnostic assays for SARS-CoV-2 has meant there are few peer-reviewed published studies of clinical performance of commercial assays., Aims: To evaluate the clinical performance of AusDiagnostics respiratory multiplex tandem PCR assay including SARS-CoV-2., Methods: We reviewed the results following implementation of AusDiagnostics respiratory multiplex tandem PCR assay including SARS-CoV-2, and compared with an in-house RT-PCR assay at our State Reference Laboratory., Results: Initial validation using AusDiagnostics coronavirus multiplex tandem PCR assay including SARS-CoV-2 demonstrated good concordance with the State Reference Laboratory. After implementing the AusDiagnostics respiratory multiplex tandem PCR assay including SARS-CoV-2, we tested 7839 samples. 127 samples in which SARS-CoV-2 was detected using the AusDiagnostics assay were referred for testing at the State Reference Laboratory, with concordant results in 118/127 (92.9%) of samples. After resolution of discrepancies, 125/127 (98.4%) of AusDiagnostics results were determined to be true positive results. Out of 7839 samples tested for SARS-CoV-2 during this period, only 2 tests (0.02%) were indeterminate results., Conclusion: The AusDiagnostics respiratory MT-PCR assay is a reliable assay for detection of SARS-CoV-2., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

The UK Government recognised the importance of vaccines in the control of new emerging disease threats and in 2015 established the UK Vaccine Network to focus on specific areas of need. One of these was the understanding of what is involved in the development of a new vaccine and what are the potential bottlenecks to a rapid response in the face of an epidemic such as Ebola, MERS and more recently COVID-19. A Working Group was established to initially produce a Vaccine Development Process Map for a Human Vaccine. However, in view of the importance of animal wellbeing and the significant impact of diseases with Zoonotic potential, a similar Map has been created outlining the Veterinary Vaccine Development Process. This paper describes the production of that Map and covers the process from the generation of a Target Product Profile (TPP) through Discovery and Feasibility, and on to Product Development and Registration., 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., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Rift Valley fever virus (RVFV) is a zoonotic mosquito-borne virus that was first discovered in Kenya in 1930 and has since spread to become endemic in much of Africa and the Arabian Peninsula. Rift Valley fever (RVF) causes recurrent outbreaks of febrile illness associated with high levels of mortality and poor outcomes during pregnancy-including foetal malformations, spontaneous abortion and stillbirths-in livestock, and associated with miscarriage in humans. No vaccines are available for human use and those licensed for veterinary use have potential drawbacks, including residual virulence that may contraindicate their use in pregnancy. To address this gap, we previously developed a simian adenovirus vectored vaccine, ChAdOx1 RVF, that encodes RVFV envelope glycoproteins. ChAdOx1 RVF is fully protective against RVF in non-pregnant livestock and is also under development for human use. Here, we now demonstrate that when administered to pregnant sheep and goats, ChAdOx1 RVF is safe, elicits high titre RVFV neutralizing antibody, and provides protection against viraemia and foetal loss, although this protection is not as robust for the goats. In addition, we provide a description of RVFV challenge in pregnant goats and contrast this to the pathology observed in pregnant sheep. Together, our data further support the ongoing development of ChAdOx1 RVF vaccine for use in livestock and humans., Competing Interests: Competing interestsS.C.G. and A.V.S.H. are co-founders of, consultants to and shareholders in Vaccitech Ltd., which is developing ChAdOx1-vectored vaccines. The remaining authors declare no competing interests., (© The Author(s) 2019.)

Introduction: Geographic visualizations have been used to understand disease since the nineteenth century. We developed a software that creates simple visualizations which can be used as a decision support tool for pre-hospital acute stroke transportation planning. In this study, we test the usability of this software to improve user experience and assess the interpretability of the visualizations it produces as it relates to planning and optimizing stroke systems of care. Materials and Methods: Healthcare practitioners and administrators working within the acute stroke system in Alberta, Canada were invited to participate. Participants were randomized to either the geographic visualization or 2-D temporospatial diagrams. Using a standardized script participants were asked to complete tasks and interpret the visualizations produced by the software. The computer screen and audio were recorded. Recordings were transcribed verbatim and analyzed using inductive thematic analyses. The number of errors made and time to task completion were also analyzed. Results: Eighteen participants (8 physicians, 5 healthcare administrators, 3 paramedics, and 2 nurses) were enrolled. Mean age was 41.22 years (SD: 10.55) and 8 participants were female. It took users a mean of 1.59 min (SD: 0.71) to complete all 10 tasks for the geographic visualizations and a mean of 1.08 min (SD: 0.33) to complete all 15 tasks for the 2-D temporospatial diagrams. Map users made a median of 2 errors (IQR: 4), 2-D temporospatial diagram users also made a median of 2 errors (IQR: 1.5). All but one map user correctly interpreted all maps, only three of the eight 2-D temporospatial diagram correctly interpreted all diagrams. In the qualitative analysis three common themes were identified: comments on the user interface, comments on the visualization tool(s), and suggestions for improvement. Most study participants mentioned that the software would be useful in their work. Conclusions: Healthcare professional from several different aspects of stroke care see geographic visualizations in transport decision making to be a useful tool. The software demonstrated high usability. However, several suggestions were made to improve user experience as well as additional features which could be developed and become the subject of future studies.

Importance: Ischemic stroke with large-vessel occlusion can be treated with alteplase and/or endovascular therapy; however, the administration of each treatment is time sensitive., Objective: To identify the optimal triage and transport strategy: direct to the endovascular center (mothership) or immediate alteplase treatment followed by transfer to the endovascular center (drip and ship), for all patients with suspected large-vessel occlusion stroke., Design Setting, and Participants: This was a theoretical, conditional probability modeling study. Existing data from clinical trials of stroke treatment were used for model generation. The study was conducted from February 1, 2017, to March 1, 2018., Main Outcomes and Measures: The time-dependent efficacy of alteplase and endovascular therapy and the accuracy of large-vessel occlusion screening tools were modeled to estimate the probability of positive outcome (modified Rankin Scale score, 0-1 at 90 days) for both the drip-and-ship and mothership transport strategies. Based from onset to treatment, the strategy that estimates the greatest probability of excellent outcome is determined in several different scenarios., Results: The patient's travel time from both thrombolysis and endovascular therapy centers, speed of treatment, and positive predictive value of the screening tool affect whether the drip-and-ship or mothership strategy estimates best outcomes. With optimal treatment times (door-to-needle time: 30 minutes; door-in-door-out time: 50 minutes; door-to-groin-puncture time: 60 minutes [mothership], 30 minutes [drip and ship]), both options estimate similar outcomes when the centers are 60 minutes or less apart. However, with increasing travel time between the 2 centers (90 or 120 minutes), drip and ship is favored if the patient would have to travel past the thrombolysis center to reach the endovascular therapy center or if the patient would arrive outside the alteplase treatment time window in the mothership scenario. Holding other variables constant, if treatment times are slow at the thrombolysis center (door-to-needle time: 60 minutes; door-in-door-out time: 120 minutes), the area where mothership estimates the best outcomes expands, especially when the 2 centers are close together (60 minutes apart or less). The area where mothership estimates the best outcome also expands as the positive predictive value of the screening tool increases., Conclusions and Relevance: This study suggests that decision making for prehospital transport can be modeled using existing clinical trial data and that these models can be dynamically adapted to changing realities. Based on current median treatment times to realize the full benefit of endovascular therapy on a population level, the study findings suggest that delivery of the treatment should be regionally centralized. The study modeling suggests that transport decision making is context specific and the radius of superiority of the transport strategy changes based on treatment times at both centers, transport times, and the triaging tool used.

Aim: This hospital network-based retrospective observational study aimed to describe the prevalence and seasonality of paediatric and adult viral respiratory pathogens and their rates of co-infections, following the introduction of a rapid multiplex molecular diagnostic assay., Methods: All nasopharyngeal samples tested in patients presenting to Monash Health, Melbourne, Australia, from August 2009 to July 2015 by means of multiplex tandem polymerase chain reaction using the Respiratory Pathogen 12Plex kit (AusDiagnostics) were included in the analysis., Results: There were 28 729 patient samples analysed after duplicate samples were excluded. Positive results were twice as likely in paediatrics, 7573/11 491 (65.9%), compared to adults, 5410/17 238 (31.4%). Co-infection was more frequent in paediatrics, 1642/7573 (21.7% of positives), compared to adults 299/5410 (5.5%). Adenovirus had a high prevalence as a co-infection, 639/990 (64.5%), in paediatrics. Testing frequency increased by 179% in the paediatric group and by 949% for adults over the 6 years of observation., Conclusions: This study demonstrated a significant difference in the positive detection rate of pathogens and co-infections between the population groups. Adenovirus had a surprisingly high prevalence as a co-infection, especially in paediatric patients. Over the study period, rapid uptake of the test was observed, especially in adults. This raises concerns about how we can ensure that testing remains rational and is able to be provided in a cost-effective manner in the future., (© 2018 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a reliable tool for bacterial identification. This study compared the Bruker MALDI-TOF BioTyper MS (MBT) and 16S rRNA gene sequencing for the identification of Actinomyces and Actinotignum spp. The MBT identified 68/77 (88.3%) of Actinomyces isolates to the genus-level and 44/77 (57.1%) of Actinomyces isolates to the species-level using the manufacturer's identification criteria. The MBT did not yield reliable identification for only 1/77 (1.3%) and generated no identification for 8/77 (10.4%) of the isolates. No misidentifications were found. Discordance at the species level was observed for eight isolates. Overall, the MBT demonstrated good concordance with the 16S rRNA gene sequencing with the exception of the closely related species A. naeslundii, A. viscosus and A. oris. A variety of Actinomyces spp. were isolated from orocervicofacial/dental specimens, but only a limited number of species were isolated from urine or intra-abdominal specimens. This study confirms the utility of MBT in the identification of Actinomyces spp. and describes the diversity and anatomic niche of species in human clinical specimens from various body sites., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This brief review discusses some recent advances in vaccine technologies with particular reference to their application within veterinary medicine. It highlights some of the key inactivated/killed approaches to vaccination, including natural split-product and subunit vaccines, recombinant subunit and protein vaccines, and peptide vaccines. It also covers live/attenuated vaccine strategies, including modified live marker/differentiating infected from vaccinated animals vaccines, live vector vaccines, and nucleic acid vaccines., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In 2013, the librarians at a small academic health sciences library reevaluated their mission, vision, and strategic plan to expand their roles. The school was transitioning to a new pedagogical culture and a new building designed to emphasize interprofessional education and active learning methodologies. Subsequent efforts to implement the new strategic plan resulted in the librarians joining curriculum committees and other institutional initiatives, such as an Active Learning Task Force, and participating in faculty development workshops. This participation has increased visibility and led to new roles and opportunities for librarians.

Bacteroides pyogenes is part of the normal oral flora of domestic animals. There is one previous report of human infection, with B. pyogenes bacteremia following a cat bite (Madsen 2011). We report seven severe human infections where B. pyogenes was identified by Bruker matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDTI-TOF MS), but not by VITEK MS and was misidentified by VITEK ANC card., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

In Drosophila, P-element transposition causes mutagenesis and genome instability during hybrid dysgenesis. The P-element 31-bp terminal inverted repeats (TIRs) contain sequences essential for transposase cleavage and have been implicated in DNA repair via protein-DNA interactions with cellular proteins. The identity and function of these cellular proteins were unknown. Biochemical characterization of proteins that bind the TIRs identified a heterodimeric basic leucine zipper (bZIP) complex between an uncharacterized protein that we termed "Inverted Repeat Binding Protein (IRBP) 18" and its partner Xrp1. The reconstituted IRBP18/Xrp1 heterodimer binds sequence-specifically to its dsDNA-binding site within the P-element TIRs. Genetic analyses implicate both proteins as critical for repair of DNA breaks following transposase cleavage in vivo. These results identify a cellular protein complex that binds an active mobile element and plays a more general role in maintaining genome stability., Competing Interests: The authors declare no conflict of interest.

This study provides the first robust data that the antibody response of dogs vaccinated with Nobivac® Rabies vaccine stored for several months at high temperatures (up to 30°C) is not inferior to that of dogs vaccinated with vaccine stored under recommended cold-chain conditions (2-8°C). A controlled and randomized non-inferiority study was carried out comparing the four-week post vaccination serological responses of Tanzanian village dogs inoculated with vaccine which had been stored at elevated temperatures for different periods of time with those of dogs vaccinated with the same product stored according to label recommendations. Specifically, the neutralizing antibody response following the use of vaccine which had been stored for up to six months at 25°C or for three months at 30°C was not inferior to that following the use of cold-chain stored vaccine. These findings provide reassurance that the vaccine is likely to remain efficacious even if exposed to elevated temperatures for limited periods of time and, under these circumstances, it can safely be used and not necessarily destroyed or discarded. The availability of thermotolerant vaccines has been an important factor in the success of several disease control and elimination programs and could greatly increase the capacity of rabies vaccination campaigns to access hard to reach communities in Africa and Asia. We have not confirmed a 3-year duration of immunity for the high temperature stored vaccine, however because annual re-vaccination is usually practiced for dogs presented for vaccination during campaigns in Africa and Asia this should not be a cause for concern. These findings will provide confidence that, for rabies control and elimination programs using this vaccine in low-income settings, more flexible delivery models could be explored, including those that involve limited periods of transportation and storage at temperatures higher than that currently recommended., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mannheimia spp. are veterinary pathogens that can cause mastitis and pneumonia in domestic cattle and sheep. While Mannheimia glucosida can be found as normal flora in oral and respiratory mucosa in sheep, there have been no reported cases of human infection with this organism., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

We report a case of Acanthamoeba encephalitis diagnosed from an antemortem brain biopsy specimen, where the organism was first isolated in mycobacterial liquid medium and first identified by using a sequence generated by a commercial panfungal sequencing assay. We correlate susceptibility results with clinical outcome., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Eggerthella lenta is an emerging pathogen that has been underrecognized due to historical difficulties with phenotypic identification. Until now, its pathogenicity, antimicrobial susceptibility profile, and optimal treatment have been poorly characterized. In this article, we report the largest cohort of patients with E. lenta bacteremia to date and describe in detail their clinical features, microbiologic characteristics, treatment, and outcomes. We identified 33 patients; the median age was 68 years, and there was no gender predominance. Twenty-seven patients (82%) had serious intra-abdominal pathology, often requiring a medical procedure. Of those who received antibiotics (28/33, 85%), the median duration of treatment was 21.5 days. Mortality from all causes was 6% at 7 days, 12% at 30 days, and 33% at 1 year. Of 26 isolates available for further testing, all were identified as E. lenta by both commercially available matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) systems, and none were found to harbor a vanA or vanB gene. Of 23 isolates which underwent susceptibility testing, all were susceptible to amoxicillin-clavulanate, cefoxitin, metronidazole, piperacillin-tazobactam, ertapenem, and meropenem, 91% were susceptible to clindamycin, 74% were susceptible to moxifloxacin, and 39% were susceptible to penicillin., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

We compared the identification of Clostridium species using mass spectrometry by two different Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) platforms (Bruker MS and Vitek MS) against 16S rRNA sequencing as the reference standard. We then examined the impact of different sample preparations and (on one of those platforms) age of bacterial colonial growth on the performance of the MALDI-TOF MS systems. We identified 10 different species amongst the 52 isolates by 16S rRNA sequencing, with Clostridium perfringens the most prevalent (n=30). Spectrometric analysis using Vitek MS correctly speciated 47/52 (90.4%) isolates and was not affected by the sample preparation used. Performance of the Bruker MS was dependent on sample preparation with correct speciation obtained for 36 of 52 (69.2%) isolates tested using the Direct Transfer [DT] protocol, but all 52 (100%) isolates were correctly speciated using either an Extended Direct Transfer [EDT] or a Full Formic Extraction [EX] protocol. We then examined the effect of bacterial colonial growth age on the performance of Bruker MS and found substantial agreement in speciation using DT (Kappa=0.62, 95% CI: 0.46-0.75), almost perfect agreement for EDT (Kappa=0.94, 95% CI: 0.86-1.00) and exact agreement for EX (Kappa=1.00) between different days., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: We identified 12 patients with Clostridium difficile infection between July 2011 and March 2012 from whom an unusual C. difficile strain was isolated. This strain had a single-nucleotide deletion of the tcdC gene at position 117 and binary toxin genes, which are characteristic of the hypervirulent ribotype (RT) 027 strain., Methods: A retrospective cohort study of 12 patients infected with C. difficile RT244 and 24 patients infected with non-RT244/non-RT027 strains matched for place of diagnosis and time of collection of specimen was performed. We performed whole-genome sequencing to understand the relationship of the RT244 strain to other C. difficile strains and further understand its virulence potential., Results: Clostridium difficile RT244 was associated with more severe disease and a higher mortality rate. Phylogenomic analysis using core genome single-nucleotide polymorphisms showed that RT244 is in the same genetic clade (clade 2) as RT027 but is distinct from all RT027 strains. The pathogenicity locus of the RT244 strain encodes a variant toxin B, and this was confirmed by demonstration of Clostridium sordellii-like cytopathic effect on Vero cells. Toxin B production in culture supernatants was lower than that seen with a RT027 strain., Conclusions: Our findings demonstrate the pathogenic potential of this RT244 C. difficile strain and emphasize the importance of ongoing surveillance for emergent strains., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: Gestational diabetes mellitus (GDM) is a strong risk factor for the development of diabetes. We assessed the impact of a 1-year intensive follow-up demonstration program, using direct nurse and outreach worker case management, aimed at increasing compliance with postpartum oral glucose tolerance testing (OGTT)., Study Design: During the year of implementation, a nurse or bilingual outreach worker contacted patients to encourage attendance at their scheduled postpartum 2-h 75-g OGTT and assisted in overcoming obstacles to testing. All patients with GDM seen in our specialty clinic the previous year served as a control group for comparison., Results: One hundred eighty-one patients treated during the year prior to implementation were compared to the 207 in the demonstration program. Baseline characteristics were similar in both groups. After the program's implementation, postpartum OGTT adherence increased from 43.1 to 59.4 % (p < 0.01, hazard ratio 1.59; 95 % confidence interval 1.20-2.12). Had the program been in place the previous year, we calculated that 12 additional cases of diabetes or prediabetes would have been detected, increasing the total number from 33 to 45 such cases., Conclusion: Implementation of direct nurse and outreach worker case management leads to a modest, but important increase in adherence to postpartum OGTT testing.

The etiology of culture-negative septic arthritis is poorly characterised in persons infected with human immunodeficiency virus (HIV). New molecular methods may assist in the investigation of culture-negative infections of sterile sites, including septic arthritis. We describe the first case of septic arthritis due to the cause of rat bite fever (RBF), Streptobacillus moniliformis, confirmed by 16S rRNA sequence analysis, in a patient with newly diagnosed HIV infection.

Vaccination of poultry against coccidiosis caused by the Eimeria species is almost entirely based upon varied formulations of live parasites. The recent development of a series of protocols that support genetic complementation by transfection in Eimeria now provides an opportunity to utilise live anticoccidial vaccines to deliver additional vaccinal antigens. The capacity of Eimeria tenella to express an exogenous antigen and induce an immune response during in vivo infection which is protective against subsequent bacterial challenge has been tested here using the anti-Campylobacter jejuni vaccine candidate CjaA. Using restriction enzyme mediated integration (REMI) a transgenic E. tenella population expressing CjaA and the fluorescent reporter mCitrine has been developed. Vaccination of specific pathogen free chickens by single or multiple oral inoculation of E. tenella-CjaA oocysts induced 91% and 86% immune protection against C. jejuni challenge compared with unvaccinated and wild-type E. tenella vaccinated controls (p<0.001). Increasing vaccination number had no significant influence on the magnitude of protection. These results support the hypothesis that eimerian parasites can be developed as multivalent vaccine vectors and encourage the extension of these studies., (Copyright © 2012 Elsevier Ltd. All rights reserved.)