A HIV-1 Gp41 Peptide-Liposome Vaccine Elicits Neutralizing Epitope-Targeted Antibody Responses in Healthy Individuals.

Background: HIV-1 vaccine development is a global health priority. Broadly neutralizing antibodies (bnAbs) which target the HIV-1 gp41 membrane-proximal external region (MPER) have some of the highest neutralization breadth. An MPER peptide-liposome vaccine has been found to expand bnAb precursors in monkeys. Methods: The HVTN133 phase 1 clinical trial (NCT03934541) studied the MPER-peptide liposome immunogen in 24 HIV-1 seronegative individuals. Participants were recruited between 15 July 2019 and 18 October 2019 and were randomized in a dose-escalation design to either 500 mcg or 2000 mcg of the MPER-peptide liposome or placebo. Four intramuscular injections were planned at months 0, 2, 6, and 12. Results: The trial was stopped prematurely due to an anaphylaxis reaction in one participant ultimately attributed to vaccine-associated polyethylene glycol. The immunogen induced robust immune responses, including MPER+ serum and blood CD4+ T-cell responses in 95% and 100% of vaccinees, respectively, and 35% (7/20) of vaccine recipients had blood IgG memory B cells with MPER-bnAb binding phenotype. Affinity purification of plasma MPER+ IgG demonstrated tier 2 HIV-1 neutralizing activity in two of five participants after 3 immunizations. Conclusions: MPER-peptide liposomes induced gp41 serum neutralizing epitope-targeted antibodies and memory B-cell responses in humans despite the early termination of the study. These results suggest that the MPER region is a promising target for a candidate HIV vaccine.

'A blessing and a burden': Exploring posttraumatic growth in doctors with acquired invisible disability-An interpretative phenomenological analysis.

OBJECTIVES: Qualitative studies of the relationship between acquired invisible disability (AcqID) and posttraumatic growth (PTG) are scant, especially in the context of healthcare professionals. This study aimed to explore in-depth accounts of the lived experience of PTG in doctors with AcqID arising from physical illness with cognitive dysfunction. DESIGN: Five doctors who had been diagnosed in the last decade with a physical illness with cognitive dysfunction resulting in an AcqID, and who self-reported at least one feature of PTG participated in this qualitative research study. METHODS: Semi-structured interviews were used to collect data, which were analysed using interpretative phenomenological analysis. RESULTS: This study recognized that AcqID supported a process of PTG for participants. Three superordinate themes were apparent across the sample: identity (The human left behind), self (Acceptance of the disabled self), and rebirth (The phoenix rises from the ashes). Human connection, service as a value, and the role of the body were found to be key facilitators of PTG in these participants. This study offers new perspectives on cognitive-embodied appreciation in facilitating PTG in doctors with AcqID. CONCLUSIONS: While the participants perceived AcqID with cognitive dysfunction to be a trauma, they also experienced PTG, Corporeal PTG and a new considered domain, Cognitive-Embodied PTG. The unrealised potential of PTG can be harnessed if doctors with disability are viewed as assets to the medical profession, and diversity is promoted through the provision of appropriate support. Thus, there is potential to cultivate a flourishing, inclusive, and compassionate culture within medicine.

An Inter-Institutional Collaboration to "Make Teaching Matter": The Teaching Academy of the Consortium of West Region Colleges of Veterinary Medicine.

Veterinary medical education is a relatively small community with limited numbers of institutions, people, and resources widely dispersed geographically. The problems faced, however, are large-and not very different from the problems faced by (human) medical education. As part of an effort to share resources and build a community of practice around common issues, five colleges in the westernmost region of the United States came together to form a regional inter-institutional consortium. This article describes the processes by which the consortium was formed and the initiation of its first collaborative endeavor, an inter-institutional medical/biomedical teaching academy (the Regional Teaching Academy, or RTA). We report outcomes, including the successful launch of three RTA initiatives, and the strategies that have been considered key to the academy's success. These include strong support from the consortium deans, including an ongoing financial commitment, a dedicated part-time Executive Coordinator, regular face-to-face meetings that supplement virtual meetings, an organization-wide biennial conference, an effective organizational structure, and a core group of dedicated leaders and RTA Fellows. The western consortium and RTA share these processes, insights, and outcomes to provide a model upon which other colleges of veterinary medicine can build to further leverage inter-institutional collaboration.

An Inter-Institutional External Peer-Review Process to Evaluate Educators at Schools of Veterinary Medicine.

Despite its fundamental importance, the educational mission of most schools of veterinary medicine receives far less recognition and support than the missions of research and discovery. This disparity is evident in promotion and tenure processes. Despite the frequent assertion that education is every college's core mission, there is a broad consensus that faculty are promoted primarily on the basis of meeting expectations relative to publications and grant funding. This expectation is evident in the promotion packets faculty are expected to produce and the criteria by which those packets are reviewed. Among the outcomes is increasing difficulty in hiring and retaining faculty, including young clinicians and basic scientists who are drawn to academic institutions because of the opportunity to teach. The Regional Teaching Academy (RTA) of the West Region Consortium of Colleges of Veterinary Medicine initiated an inter-institutional collaboration to address the most important obstacles to recognizing and rewarding teaching in its five member colleges. Working from the medical education literature, the RTA developed an Educator's Promotion Dossier, workshops to train promotion applicants, and an external review process. Initial use has shown that the reviews are efficient and complete. Administrators have expressed strong support for the product, a letter of external review that is returned to a promotion applicant's home institution. The overall result is an evidence-based, structured process by which teaching-intensive faculty can more fully document their achievements in teaching and educational leadership and a more rigorous external review process by which member colleges can assess quality, impact, and scholarly approach.

Assessing Cat Flea Microbiomes in Northern and Southern California by 16S rRNA Next-Generation Sequencing.

Flea-borne diseases (FBDs) impact both human and animal health worldwide. Because adult fleas are obligately hematophagous and can harbor potential pathogens, fleas act as ectoparasites of vertebrates, as well as zoonotic disease vectors. Cat fleas (Ctenocephalides felis) are important vectors of two zoonotic bacterial genera listed as priority pathogens by the National Institute of Allergy and Infectious Diseases (NIAID-USA): Bartonella spp. and Rickettsia spp., causative agents of bartonelloses and rickettsioses, respectively. In this study, we introduce the first microbiome analysis of C. felis samples from California, determining the presence and abundance of relevant pathogenic genera by characterizing the cat flea microbiome through 16S rRNA next-generation sequencing (16S-NGS). Samples from both northern (NoCal) and southern (SoCal) California were assessed to expand current knowledge regarding FBDs in the state. We identified Rickettsia and Bartonella, as well as the endosymbiont Wolbachia, as the most abundant genera, followed by less abundant taxa. In comparison to our previous study screening Californian cat fleas for rickettsiae using PCR/digestion/sequencing of the ompB gene, the 16S-NGS approach applied herein showed a 95% level of agreement in detecting Rickettsia spp. There was no overall difference in microbiome diversity between NoCal and SoCal samples. Bacterial taxa identified by 16S-NGS in this study may help to improve epidemiological investigations, pathogen surveillance efforts, and clinical diagnostics of FBDs in California and elsewhere.

Integrating Genomic Data Sets for Knowledge Discovery: An Informed Approach to Management of Captive Endangered Species.

Many endangered captive populations exhibit reduced genetic diversity resulting in health issues that impact reproductive fitness and quality of life. Numerous cost effective genomic sequencing and genotyping technologies provide unparalleled opportunity for incorporating genomics knowledge in management of endangered species. Genomic data, such as sequence data, transcriptome data, and genotyping data, provide critical information about a captive population that, when leveraged correctly, can be utilized to maximize population genetic variation while simultaneously reducing unintended introduction or propagation of undesirable phenotypes. Current approaches aimed at managing endangered captive populations utilize species survival plans (SSPs) that rely upon mean kinship estimates to maximize genetic diversity while simultaneously avoiding artificial selection in the breeding program. However, as genomic resources increase for each endangered species, the potential knowledge available for management also increases. Unlike model organisms in which considerable scientific resources are used to experimentally validate genotype-phenotype relationships, endangered species typically lack the necessary sample sizes and economic resources required for such studies. Even so, in the absence of experimentally verified genetic discoveries, genomics data still provides value. In fact, bioinformatics and comparative genomics approaches offer mechanisms for translating these raw genomics data sets into integrated knowledge that enable an informed approach to endangered species management.

Detection of Rickettsia Species in Fleas Collected from Cats in Regions Endemic and Nonendemic for Flea-Borne Rickettsioses in California.

Rickettsia typhi, transmitted by rat fleas, causes most human flea-borne rickettsioses worldwide. Another rickettsia, Rickettsia felis, found in cat fleas, Ctenocephalides felis, has also been implicated as a potential human pathogen. In the continental United States, human cases of flea-borne rickettsioses are reported primarily from the southern regions of Texas and California where the cat flea is considered the principal vector. In California, more than 90% of locally acquired human cases are reported from suburban communities within Los Angeles and Orange counties despite the almost ubiquitous presence of cat fleas and their hosts throughout the state. The objective of this study is to assess the presence and infection rate of Rickettsia species in cat fleas from selected endemic and nonendemic regions of California. Cat fleas were collected from cats in Los Angeles County (endemic region) and Sacramento and Contra Costa counties (nonendemic region). Sequencing of 17 amplicons confirmed the presence of R. felis in both the endemic and non-endemic regions with a calculated maximum likelihood estimation of 131 and 234 per 1000 fleas, respectively. R. typhi was not detected in any flea pools. Two R. felis-like genotypes were also detected in fleas from Los Angeles County; Genotype 1 was detected in 1 flea pool and Genotype 2 was found in 10 flea pools. Genotype 1 was also detected in a single flea pool from Sacramento County. Results from this study show that R. felis is widespread in cat flea populations in both flea-borne rickettsioses endemic and nonendemic regions of California, suggesting that a high prevalence of this bacterium in cat fleas does not predispose to increased risk of human infection. Further studies are needed to elucidate the role of R. felis and the two R. felis-like organisms as etiologic agents of human flea-borne rickettsioses in California.

Using educational games to engage students in veterinary basic sciences.

Educational games are an example of an active learning teaching technique based on Kolb's learning cycle. We have designed multiple games to provide concrete experiences for social groups of learners in the basic sciences. "Antimicrobial Set" is a card game that illustrates global patterns in antimicrobial therapy. "SHOCK!" is a card game designed to enhance student understanding of the four types of hypersensitivity reactions. After each game is played, students undergo a structured debriefing session with faculty members to further enhance their self-reflective skills. "Foodborne Outbreak Clue" utilizes the famous Parker Brothers® board game as a means to practice skills associated with outbreak investigation and risk assessment. This game is used as a review activity and fun application of epidemiologic concepts. Anecdotal feedback from students suggests that they enjoyed the activities. Games such as these can be easily implemented in large- or small-group settings and can be adapted to other disciplines as needed.

Validation of a scenario-based assessment of critical thinking using an externally validated tool.

With medical education transitioning from knowledge-based curricula to competency-based curricula, critical thinking skills have emerged as a major competency. While there are validated external instruments for assessing critical thinking, many educators have created their own custom assessments of critical thinking. However, the face validity of these assessments has not been challenged. The purpose of this study was to compare results from a custom assessment of critical thinking with the results from a validated external instrument of critical thinking. Students from the College of Veterinary Medicine at Western University of Health Sciences were administered a custom assessment of critical thinking (ACT) examination and the externally validated instrument, California Critical Thinking Skills Test (CCTST), in the spring of 2011. Total scores and sub-scores from each exam were analyzed for significant correlations using Pearson correlation coefficients. Significant correlations between ACT Blooms 2 and deductive reasoning and total ACT score and deductive reasoning were demonstrated with correlation coefficients of 0.24 and 0.22, respectively. No other statistically significant correlations were found. The lack of significant correlation between the two examinations illustrates the need in medical education to externally validate internal custom assessments. Ultimately, the development and validation of custom assessments of non-knowledge-based competencies will produce higher quality medical professionals.

Development of a PCR assay to detect papillomavirus infection in the snow leopard.

BACKGROUND: Papillomaviruses (PVs) are a group of small, non-encapsulated, species-specific DNA viruses that have been detected in a variety of mammalian and avian species including humans, canines and felines. PVs cause lesions in the skin and mucous membranes of the host and after persistent infection, a subset of PVs can cause tumors such as cervical malignancies and head and neck squamous cell carcinoma in humans. PVs from several species have been isolated and their genomes have been sequenced, thereby increasing our understanding of the mechanism of viral oncogenesis and allowing for the development of molecular assays for the detection of PV infection. In humans, molecular testing for PV DNA is used to identify patients with persistent infections at risk for developing cervical cancer. In felids, PVs have been isolated and sequenced from oral papillomatous lesions of several wild species including bobcats, Asian lions and snow leopards. Since a number of wild felids are endangered, PV associated disease is a concern and there is a need for molecular tools that can be used to further study papillomavirus in these species. RESULTS: We used the sequence of the snow leopard papillomavirus UuPV1 to develop a PCR strategy to amplify viral DNA from samples obtained from captive animals. We designed primer pairs that flank the E6 and E7 viral oncogenes and amplify two DNA fragments encompassing these genes. We detected viral DNA for E6 and E7 in genomic DNA isolated from saliva, but not in paired blood samples from snow leopards. We verified the identity of these PCR products by restriction digest and DNA sequencing. The sequences of the PCR products were 100% identical to the published UuPV1 genome sequence. CONCLUSIONS: We developed a PCR assay to detect papillomavirus in snow leopards and amplified viral DNA encompassing the E6 and E7 oncogenes specifically in the saliva of animals. This assay could be utilized for the molecular investigation of papillomavirus in snow leopards using saliva, thereby allowing the detection of the virus in the anatomical site where oral papillomatous lesions develop during later stages of infection and disease development.

Methamphetamine and lentivirus interactions: reciprocal enhancement of central nervous system disease.

Use of methamphetamine is increasingly a significant factor for the spread of human immunodeficiency virus type 1, for in certain populations, there is a convergence of methamphetamine abuse with human immunodeficiency virus type 1 infection. Methamphetamine and human immunodeficiency virus type 1 are both individually neuropathogenic, and the neuropathology caused by these two agents occurs in overlapping brain regions. However, the biological interaction of methamphetamine with lentiviruses remains unknown. Here, we investigate the effects of simultaneous exposure of these two agents on disease progression using the feline immunodeficiency virus model. The study models the bingeing methamphetamine user with sequential and repeated episodes of use, which were interrupted by periods of abstinence. Methamphetamine exposure significantly accelerated and enhanced the severity of the feline immunodeficiency virus model-induced central nervous system functional pathology, as measured in delays in brainstem auditory evoked potentials. Reciprocally, feline immunodeficiency virus enhanced the severity of the methamphetamine-induced effects on brain monoamine neurotransmitter and dopamine transporter levels. The results of this study indicate that a dual potentiation occurred. That is, methamphetamine enhanced feline immunodeficiency virus model-induced central nervous system disease and feline immunodeficiency virus model enhanced the toxic effects of methamphetamine, heralding a significant concern for those individuals that are exposed to both agents.

Combinatorial approach to hepadnavirus-like particle vaccine design.

The particulate hepatitis core protein (HBcAg) represents an efficient carrier platform with many of the characteristics uniquely required for the delivery of weak immunogens to the immune system. Although the HBcAg is highly immunogenic, the existing HBcAg-based platform technology has a number of theoretical and practical limitations, most notably the "preexisting immunity" and "assembly" problems. To address the assembly problem, we have developed the core protein from the woodchuck hepadnavirus (WHcAg) as a new particulate carrier platform system. WHcAg appears to tolerate insertions of foreign epitopes at a greater number of positions than HBcAg. For example, both within the external loop region and outside the loop region a total of 17 insertion sites were identified on WHcAg. Importantly, the identification of an expanded number of insertion sites was dependent on additional modifications to the C terminus that appear to stabilize the various internal insertions. Indeed, 21 separate C-terminal modifications have been generated that can be used in combination with the 17 insertion sites to ensure efficient hybrid WHcAg particle assembly. This combinatorial technology is also dependent on the sequence of the heterologous insert. Therefore, the three variables of insert position, C terminus, and epitope sequence are relevant in the design of hybrid WHcAg particles for vaccine purposes.

Important emerging bacterial zoonotic infections affecting the immunocompromised.

The immunocompromised are at particular risk for infection with zoonotic diseases. Persons can be temporarily immunocompromised due to pregnancy or developmental stage (i.e. infants); longer-term or permanent states of immunosuppression can occur as a result of immunosuppressive treatment following cancer or organ transplant, or from infectious diseases, such as AIDS. The focus of this review article is on emerging bacterial zoonotic diseases that are of particular concern among the immunocompromised. Factors that affect disease emergence can include factors such as human demographics and behavior; technology and industry; economic development and land use; international travel and commerce; microbial adaptation and change; and breakdown of public health measures. The immunocompromised need to take precautions when engaging in seemingly normal activities such as food preparation; caring for companion animals; and recreational or occupational activities. The immunocompromised are not only more susceptible to infection, but often suffer more serious sequelae as a result of infection. This review article provides an overview of the major foodborne, respiratory, and vector-borne bacterial pathogens that affect the immunocompromised. The major categories of immunodeficiency are described. In addition, measures that can be taken to prevent infection, including the role of health education, are discussed.

Escalating morphine exposures followed by withdrawal in feline immunodeficiency virus-infected cats: a model for HIV infection in chronic opiate abusers.

Opiate abuse is a risk factor for human immunodeficiency virus (HIV) infection. Because the direct effects of opiates on HIV infection are difficult to determine epidemiologically, animal models of lentivirus infection are relied upon to study the effects of opiates in the absence of confounding factors. Morphine, the predominant metabolite of heroin, is used in most experimental systems examining heroin abuse. In this study, morphine treatment of feline immunodeficiency virus (FIV)-infected cats modeled a typical pattern of escalating drug use interspersed with withdrawals. Plasma cortisol levels were measured for evidence of stress associated with morphine withdrawal. In the morphine-treated cats, cortisol levels peaked at time points corresponding to morphine withdrawal and returned to baseline levels during treatment and several weeks after the final withdrawal. Morphine-treated cats displayed clear behavioral and physical signs of opiate exposure and evidence of withdrawal when the drug was stopped. Morphine-exposed cats did not experience enhanced severity of FIV-related disease; in fact, morphine demonstrated a protective effect on FIV-associated changes in brainstem auditory evoked potentials. Our research suggests that opiate exposure is unlikely to adversely affect the progression of acute lentivirus infection and might be beneficial in controlling associated neurological disease.