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Copper is a trace element that plays an essential role in neurodevelopment and neurologic function. Acquired copper deficiency has a range of neurologic manifestations, with myelopathy being the most common association. We describe here the clinical, radiologic, histopathologic, and toxicologic findings of a rabbit with malnutrition, neurodegeneration, and suspected copper deficiency. A stray, adult female dwarf rabbit cross (Oryctolagus cuniculus) in poor body condition developed ataxia and pelvic limb weakness progressing to lateral recumbency and urine retention. The clinical findings suggested multifocal brainstem disease with right-sided central vestibular involvement; however, microscopic examination identified thoracic and lumbosacral spinal cord myelopathy. Differentials for the spinal cord changes included neurodegenerative disease, nutritional deficiency, neurotoxin, trauma to the lumbosacral region, and ischemia. Hepatic copper levels were suboptimal at 18 ppm dry weight (RI: 24-150 ppm dry weight). While speculative, copper-deficiency myelopathy is a treatable cause of non-compressive myelopathy that may occur in this species.
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OBJECTIVE: Evidence for necrotising otitis externa (NOE) diagnosis and management is limited, and outcome reporting is heterogeneous. International best practice guidelines were used to develop consensus diagnostic criteria and a core outcome set (COS). METHODS: The study was pre-registered on the Core Outcome Measures in Effectiveness Trials (COMET) database. Systematic literature review identified candidate items. Patient-centred items were identified via a qualitative study. Items and their definitions were refined by multidisciplinary stakeholders in a two-round Delphi exercise and subsequent consensus meeting. RESULTS: The final COS incorporates 36 items within 12 themes: Signs and symptoms; Pain; Advanced Disease Indicators; Complications; Survival; Antibiotic regimes and side effects; Patient comorbidities; Non-antibiotic treatments; Patient compliance; Duration and cessation of treatment; Relapse and readmission; Multidisciplinary team management.Consensus diagnostic criteria include 12 items within 6 themes: Signs and symptoms (oedema, otorrhoea, granulation); Pain (otalgia, nocturnal otalgia); Investigations (microbiology [does not have to be positive], histology [malignancy excluded], positive CT and MRI); Persistent symptoms despite local and/or systemic treatment for at least two weeks; At least one risk factor for impaired immune response; Indicators of advanced disease (not obligatory but mut be reported when present at diagnosis). Stakeholders were unanimous that there is no role for secondary, graded, or optional diagnostic items. The consensus meeting identified themes for future research. CONCLUSION: The adoption of consensus-defined diagnostic criteria and COS facilitates standardised research reporting and robust data synthesis. Inclusion of patient and professional perspectives ensures best practice stakeholder engagement.
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BACKGROUND: In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). HYPOTHESIS/OBJECTIVES: To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. ANIMALS: Twelve neurologically affected QH foals and the dams. METHODS: Genomic DNA was isolated and pedigrees were manually constructed. RESULTS: All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma-glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0-18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE: EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs <1 month of age in North America that is etiologically distinct from other clinically similar neurological disorders. Once the causative variant for EJSCA is validated, carriers can be identified through genetic testing to inform breeding decisions.
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Doenças dos Cavalos , Linhagem , Animais , Cavalos , Doenças dos Cavalos/genética , Doenças dos Cavalos/patologia , Masculino , Feminino , América do Norte , Ataxias Espinocerebelares/veterinária , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Doenças do Sistema Nervoso/veterinária , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologiaRESUMO
BACKGROUND: Using community-engaged research may result in interventions that reduce infant oral health disparities in underserved populations. OBJECTIVE: Develop community partnerships to create a sustainable infant oral health program that meets specific community-identified needs and provides an interprofessional education experience. METHODS: Partnering with the Homewood Community Engagement Center, researchers engaged and surveyed key community partners to assess the need for an infant oral health invention. LESSONS LEARNED: Community-identified organizing principles and barriers became the framework for, "Healthy Teeth, Healthy Me," a community-driven infant oral health program. Barriers, like access to care, were addressed with community-specific solutions like agreements with local dental clinical for referrals. CONCLUSIONS: Community partnerships can be leveraged to develop oral health programs that fit specific community needs and provide resources to families at greatest risk for child dental caries. Community engagement can be used to modify the intervention to meet oral health needs of other vulnerable communities.
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Pesquisa Participativa Baseada na Comunidade , Saúde Bucal , Humanos , Pesquisa Participativa Baseada na Comunidade/organização & administração , Lactente , Acessibilidade aos Serviços de Saúde/organização & administração , Cárie Dentária/prevenção & controle , Promoção da Saúde/organização & administração , Promoção da Saúde/métodos , Desenvolvimento de Programas , Relações Comunidade-InstituiçãoRESUMO
Violence against women (VAW) affects almost 1 in 3 women and can lead to short and long-term adverse health outcomes. The health sector is an important entry point to respond to VAW. Globally, countries have committed to eliminating VAW through the SDGs and WHO Member States have endorsed a Global Plan of Action on Violence, which asks countries to provide comprehensive health services to VAW survivors. To track progress and establish a baseline for the Global Plan of Action on Violence, WHO developed a VAW Policies Database to assess how countries are addressing VAW in health and multisectoral policies. This paper presents findings from 15 select indicators related to the existence of VAW-related policies and the inclusion of health services for survivors in policies in line with WHO recommendations. Results show that while 80% of countries have multisectoral VAW policies in place, only 34% have national health policies that include VAW response and/or prevention as a strategic priority, and 48% have clinical guidelines for the health sector response. Policies were analysed to identify inclusion of WHO-recommended VAW health services: 75% of countries' policies mention provision of first-line support; while 50% or fewer of countries mention clinical enquiry to identify intimate partner violence, post-rape care services, or mental health assessment, referral and treatment. The high-income countries group had the lowest proportion of countries that specified each of the above-mentioned health services in policies. Findings show that more efforts are needed to raise the awareness of ministries of health about the public health impact of VAW and the importance of including VAW in health policies. Where policies exist, many are not aligned with WHO-recommendations. Policy dialogues should be conducted with governments on how to better align their VAW policies with internationally-agreed, evidence-based standards, and to implement them through programmes and services.
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Tooth decay is the most common chronic disease in children, and children often see their primary care practitioners more frequently than dentists (Adjaye-Gbewonyo and Black 2019-2020; National Center for Health Statistics 2019-2020). This Infant Oral Health Education Program included two online training sessions for trainees in social work, nursing, medicine, and dentistry. Trainees were assessed on anticipated changes to their practice related to children's oral health. During the first training session, trainees received a lecture on infant oral health, and then discussed a case study in interprofessional groups to reinforce the content. Trainees in medicine and nursing completed training to receive Medicaid reimbursement for performing preventive oral health services. The second training session was profession specific with tailored instructions in the form of videos, as well as a demonstration on fluoride varnish application. Of the 78 trainees (22 social work, 4 pediatric nurse practitioner, 38 pediatric medicine residents, and 14 pediatric dentistry residents), 91% (n=70) reported that they were introduced to at least one new health information resource or tool. Four-fifths of the eligible trainees (n=16/20, 80%) who completed the evaluation had fulfilled the State's requirements to receive Medicaid reimbursement for performing preventive oral health services. Three-fourths of trainees (n=22/29, 75%) reported that they are likely to promote children's oral health in future clinical practice. Trainees from all four professions provided positive feedback about the content.
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Ligands for the serotonin 2B receptor (5-HT2B) have shown potential to treat pulmonary arterial hypertension in preclinical models but cannot be used in humans because of predicted off-target neurological effects. The aim of this study was to develop novel systemically restricted compounds targeting 5-HT2B. Here, we show that mice treated with VU6047534 had decreased RVSP compared with control treatment in both the prevention and intervention studies using Sugen-hypoxia. VU6047534 is a novel 5-HT2B partial agonist that is peripherally restricted and able to both prevent and treat Sugen-hypoxia-induced pulmonary arterial hypertension. We have synthesized and characterized a structurally novel series of 5-HT2B ligands with high potency and selectivity for the 5-HT2B receptor subtype. Next-generation 5-HT2B ligands with similar characteristics, and predicted to be systemically restricted in humans, are currently advancing to investigational new drug-enabling studies.
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Salmonella infection causes epidemic death in wild songbirds, with potential to spread to humans. In February 2021, public health officials in Oregon and Washington, USA, isolated a strain of Salmonella enterica serovar Typhimurium from humans and a wild songbird. Investigation by public health partners ultimately identified 30 illnesses in 12 states linked to an epidemic of Salmonella Typhimurium in songbirds. We report a multistate outbreak of human salmonellosis associated with songbirds, resulting from direct handling of sick and dead birds or indirect contact with contaminated birdfeeders. Companion animals might have contributed to the spread of Salmonella between songbirds and patients; the outbreak strain was detected in 1 ill dog, and a cat became ill after contact with a wild bird. This outbreak highlights a One Health issue where actions like regular cleaning of birdfeeders might reduce the health risk to wildlife, companion animals, and humans.
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Intoxicação Alimentar por Salmonella , Salmonelose Animal , Aves Canoras , Humanos , Animais , Estados Unidos/epidemiologia , Cães , Salmonella typhimurium , Salmonelose Animal/epidemiologia , Intoxicação Alimentar por Salmonella/epidemiologia , Animais Selvagens , Surtos de Doenças , OregonRESUMO
Diffuse midline glioma (DMG) is a childhood brain tumor with an extremely poor prognosis. Chimeric antigen receptor (CAR) T cell therapy has recently demonstrated some success in DMG, but there may a need to target multiple tumor-specific targets to avoid antigen escape. We developed a second-generation CAR targeting an HLA-A∗02:01 restricted histone 3K27M epitope in DMG, the target of previous peptide vaccination and T cell receptor-mimics. These CAR T cells demonstrated specific, titratable, binding to cells pulsed with the H3.3K27M peptide. However, we were unable to observe scFv binding, CAR T cell activation, or cytotoxic function against H3.3K27M+ patient-derived models. Despite using sensitive immunopeptidomics, we could not detect the H3.3K27M26-35-HLA-A∗02:01 peptide on these patient-derived models. Interestingly, other non-mutated peptides from DMG were detected bound to HLA-A∗02:01 and other class I molecules, including a novel HLA-A3-restricted peptide encompassing the K27M mutation and overlapping with the H3 K27M26-35-HLA-A∗02:01 peptide. These results suggest that targeting the H3 K27M26-35 mutation in context of HLA-A∗02:01 may not be a feasible immunotherapy strategy because of its lack of presentation. These findings should inform future investigations and clinical trials in DMG.
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This paper presents methodological reflections from the development of the World Health Organization (WHO) Violence against Women (VAW) Policies Database (hereinafter referred to as 'the Database') to inform future efforts to create similar public health policy databases for government accountability. Using the WHO Global Plan of Action on Violence accountability measures as a starting point, the Database was developed over a 2-year period in consultation with a reference group. A subset of indicators was piloted before finalization of a full list and the structure of the Database. Available VAW policies from 194 WHO Member States were reviewed by a team of consultants, who conducted content analysis and data entry. A 'Manual and User Guide' was developed to record decisions related to the processes for developing the Database. This guide was used to draw out key reflections in relation to policy indicators, inclusion criteria for policy documents, languages and analysis, quality assurance and sustainability. The process of developing the Database evolved iteratively in response to many factors, including the content of policies and the specificities of policy-making in each jurisdiction. Pragmatic decisions about the number of indicators and the types of policies to review were informed by pilot tests across a range of geographies. Standardization of analysis and data entry was ensured through the provision of in-depth guidance for researchers, and regular and open communication within the team was key to quality assurance. Online translation services enabled a review of policy documents in most languages. Documentation of the methodology ensured that others could replicate processes with fidelity in the future. Despite complexities, it is possible to develop a sound methodology for analysing the content of policy documents in a manner that yields findings that are useful in holding governments accountable for the commitments to address VAW and other public health issues in policy.
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Formulação de Políticas , Violência , Feminino , Humanos , Organização Mundial da Saúde , Política Pública , Saúde PúblicaRESUMO
Background: Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) of the thalamus and spinal cord are rare but devastating high-grade glial tumors of childhood with no curative treatment. Despite aggressive treatment attempts the prognosis has remained poor. Chimeric antigen receptor (CAR) T cell therapy has been identified as a promising new approach in the treatment of DMG tumors; however, additional targets are urgently required given known tumor heterogeneity and the prospect of antigen escape of this cancer. Methods: Using cell surface mass spectrometry, we detected high HER2 cell surface protein across a panel of patient-derived DIPG cells, thereby identifying an existing CAR T cell therapy for use in DIPG. Primary human T cells were transduced to express a second-generation HER2 CAR and interrogated for efficacy against patient-derived DIPG cells. Results: HER2 CAR T cells demonstrated potent and antigen-specific cytotoxicity and cytokine secretion when co-cultured with patient-derived DIPG cells. Furthermore, HER2 CAR T cells provided a significant regression in intracranial DIPG xenograft tumors. Conclusions: HER2 CAR T cells are already in clinic development and are well tolerated in pediatric patients. Here we provide strong preclinical evidence for the inclusion of DIPG patients in future pediatric CNS tumor HER2 CAR T cell clinical trials.
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Disease caused by the archetypical amdoparvovirus (APV), Aleutian mink disease virus (AMDV), has been well studied, but APV infections in other carnivores are poorly understood. Skunk amdoparvovirus (SKAV), one of a handful of newly discovered APVs, is apparently species-specific in striped skunks (Mephitis mephitis) and has a high prevalence across North America. We have evaluated the infection status and viral tissue distribution in a cohort of 26 free-ranging California skunks from a single rehabilitation facility who were euthanized due to poor prognosis for recovery from neurologic disease. SKAV was detected in the majority of this cohort, and virus was associated with a spectrum of lesions including tubulointerstitial nephritis, meningoencephalitis, myocarditis, and arteritis. Affected tissue and patterns of inflammation were partially overlapping with those of AMDV infection but were notably distinct in the kidney.
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Meningoencefalite , Miocardite , Animais , Mephitidae , Inflamação/veterinária , Meningoencefalite/veterinária , Miocardite/veterinária , VisonRESUMO
Objectives: Glioblastoma is a highly aggressive and fatal brain malignancy, and effective targeted therapies are required. The combination of standard treatments including surgery, chemotherapy and radiotherapy is not curative. Chimeric antigen receptor (CAR) T cells are known to cross the blood-brain barrier, mediating antitumor responses. A tumor-expressed deletion mutant of the epidermal growth factor receptor (EGFRvIII) is a robust CAR T cell target in glioblastoma. Here, we show our de novo generated, high-affinity EGFRvIII-specific CAR; GCT02, demonstrating curative efficacy in human orthotopic glioblastoma models. Methods: The GCT02 binding epitope was predicted using Deep Mutational Scanning (DMS). GCT02 CAR T cell cytotoxicity was investigated in three glioblastoma models in vitro using the IncuCyte platform, and cytokine secretion with a cytometric bead array. GCT02 in vivo functionality was demonstrated in two NSG orthotopic glioblastoma models. The specificity profile was generated by measuring T cell degranulation in response to coculture with primary human healthy cells. Results: The GCT02 binding location was predicted to be located at a shared region of EGFR and EGFRvIII; however, the in vitro functionality remained exquisitely EGFRvIII specific. A single CAR T cell infusion generated curative responses in two orthotopic models of human glioblastoma in NSG mice. The safety analysis further validated the specificity of GCT02 for mutant-expressing cells. Conclusion: This study demonstrates the preclinical functionality of a highly specific CAR targeting EGFRvIII on human cells. This CAR could be an effective treatment for glioblastoma and warrants future clinical investigation.
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OBJECTIVE: We aimed to examine associations between the oral, fecal, and mucosal microbiome communities and adenoma formation. SUMMARY BACKGROUND DATA: Data are limited regarding the relationships between microbiota and preneoplastic colorectal lesions. METHODS: Individuals undergoing screening colonoscopy were prospectively enrolled and divided into adenoma and nonadenoma formers. Oral, fecal, nonadenoma and adenoma-adjacent mucosa were collected along with clinical and dietary information. 16S rRNA gene libraries were generated using V4 primers. DADA2 processed sequence reads and custom R-scripts quantified microbial diversity. Linear regression identified differential taxonomy and diversity in microbial communities and machine learning identified adenoma former microbial signatures. RESULTS: One hundred four subjects were included, 46% with adenomas. Mucosal and fecal samples were dominated by Firmicutes and Bacteroidetes whereas Firmicutes and Proteobacteria were most abundant in oral communities. Mucosal communities harbored significant microbial diversity that was not observed in fecal or oral communities. Random forest classifiers predicted adenoma formation using fecal, oral, and mucosal amplicon sequence variant (ASV) abundances. The mucosal classifier reliably diagnosed adenoma formation with an area under the curve (AUC) = 0.993 and an out-of-bag (OOB) error of 3.2%. Mucosal classifier accuracy was strongly influenced by five taxa associated with the family Lachnospiraceae, genera Bacteroides and Marvinbryantia, and Blautia obeum. In contrast, classifiers built using fecal and oral samples manifested high OOB error rates (47.3% and 51.1%, respectively) and poor diagnostic abilities (fecal and oral AUC = 0.53). CONCLUSION: Normal mucosa microbial abundances of adenoma formers manifest unique patterns of microbial diversity that may be predictive of adenoma formation.
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Adenoma , Microbioma Gastrointestinal , Humanos , Bactérias/genética , RNA Ribossômico 16S/genética , Adenosina Desaminase , Peptídeos e Proteínas de Sinalização Intercelular , Fezes/microbiologia , Adenoma/diagnóstico , Adenoma/microbiologiaRESUMO
BACKGROUND: Microbial dysbiosis has been closely linked with colorectal cancer development. However, data is limited regarding the relationship of the mucosal microbiome, adenomatous polyps and dietary habits. Understanding these associations may elucidate pathways for risk stratification according to diet. RESULTS: Patients undergoing screening colonoscopy were included in our prospective, single center study and divided into adenoma or no adenoma cohorts. Oral, fecal, and mucosal samples were obtained. Microbial DNA was extracted, and amplicon libraries generated using primers for the 16S rRNA gene V4 region. Patient and dietary information was collected. Of 104 participants, 44% presented with polyps, which were predominantly tubular adenomas (87%). Adenoma formation and multiple patient dietary and lifestyle characteristics were associated with mucosal microbiome diversity. Lifestyle factors included age, body mass index, adenoma number, and dietary consumption of red meats, processed meats, vegetables, fruit, grain, fermented foods and alcohol. CONCLUSION: In this study we showed associations between dietary habits, adenoma formation and the mucosal microbiome. These early findings suggest that ongoing research into diet modification may help reduce adenoma formation and subsequently the development of CRC.
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Vascular anomalies, both vascular tumors and vascular malformations, can occur in isolation or as part of syndromes including those which feature phenotypic overgrowth. To update what is known about vascular anomalies associated with overgrowth, PubMed was searched for "overgrowth syndromes and vascular anomalies or malformations." PubMed, OMIM, and the Rare Disease Database also were searched for specific diagnoses. We review individual overgrowth syndromes, provide a case-based approach to the clinical, radiographic, pathologic, and genetic basis for diagnosis, to complications of both the vascular anomalies and the overgrowth, and emphasize the need for a multidisciplinary approach to care.
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Malformações Vasculares , Humanos , Síndrome , Malformações Vasculares/diagnóstico , Malformações Vasculares/genética , Malformações Vasculares/terapiaRESUMO
Aspergillus nidulans snxA, an ortholog of Saccharomyces cerevisiae Hrb1/Gbp2 messenger RNA shuttle proteins, is-in contrast to budding yeast-involved in cell cycle regulation, in which snxA1 and snxA2 mutations as well as a snxA deletion specifically suppress the heat sensitivity of mutations in regulators of the CDK1 mitotic induction pathway. snxA mutations are strongly cold sensitive, and at permissive temperature snxA mRNA and protein expression are strongly repressed. Initial attempts to identify the causative snxA mutations revealed no defects in the SNXA protein. Here, we show that snxA1/A2 mutations resulted from an identical chromosome I-II reciprocal translocation with breakpoints in the snxA first intron and the fourth exon of a GYF-domain gene, gyfA. Surprisingly, a gyfA deletion and a reconstructed gyfA translocation allele suppressed the heat sensitivity of CDK1 pathway mutants in a snxA+ background, demonstrating that 2 unrelated genes, snxA and gyfA, act through the CDK1-CyclinB axis to restrain the G2-M transition, and for the first time identifying a role in G2-M regulation for a GYF-domain protein. To better understand snxA1/A2-reduced expression, we generated suppressors of snxA cold sensitivity in 2 genes: (1) loss of the abundant nucleolar protein Nsr1/nucleolin bypassed the requirement for snxA and (2) loss of the Set2 histone H3 lysine36 (H3K36) methyltransferase or a nonmethylatable histone H3K36L mutant rescued hypomorphic snxA mutants by restoring full transcriptional proficiency, indicating that methylation of H3K36 acts normally to repress snxA transcription. These observations are in line with known Set2 functions in preventing excessive and cryptic transcription of active genes.
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Aspergillus nidulans , Proteínas de Saccharomyces cerevisiae , Aspergillus nidulans/genética , Aspergillus nidulans/metabolismo , Regulação Fúngica da Expressão Gênica , Histona Metiltransferases/genética , Histona Metiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Lisina/metabolismo , RNA Mensageiro , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Transcrição GênicaRESUMO
In collaboration with the American College of Veterinary Pathologists.