Antibiotic use in early life subsequently impairs MAIT cell-mediated immunity.

Mucosal-associated invariant T (MAIT) cells are predominantly located in barrier tissues where they rapidly respond to pathogens and commensals by recognizing microbial derivatives of riboflavin synthesis. Early-life exposure to these metabolites imprints the abundance of MAIT cells within tissues, so we hypothesized that antibiotic use during this period may abrogate their development. We identified antibiotics that deplete riboflavin-synthesizing commensals and revealed an early period of susceptibility during which antibiotic administration impaired MAIT cell development. The reduction in MAIT cell abundance rendered mice more susceptible to pneumonia, while MAIT cell-deficient mice were unaffected by early-life antibiotics. Concomitant administration of a riboflavin-synthesizing commensal during antibiotic treatment was sufficient to restore MAIT cell development and immunity. Our work demonstrates that transient depletion of riboflavin-synthesizing commensals in early life can adversely affect responses to subsequent infections.

Latent pathway-based Bayesian models to identify intervenable factors of racial disparities in breast cancer stage at diagnosis.

PURPOSE: We built Bayesian Network (BN) models to explain roles of different patient-specific factors affecting racial differences in breast cancer stage at diagnosis, and to identify healthcare related factors that can be intervened to reduce racial health disparities. METHODS: We studied women age 67-74 with initial diagnosis of breast cancer during 2006-2014 in the National Cancer Institute's SEER-Medicare dataset. Our models included four measured variables (tumor grade, hormone receptor status, screening utilization and biopsy delay) expressed through two latent pathways-a tumor biology path, and health-care access/utilization path. We used various Bayesian model assessment tools to evaluate these two latent pathways as well as each of the four measured variables in explaining racial disparities in stage-at-diagnosis. RESULTS: Among 3,010 Black non-Hispanic (NH) and 30,310 White NH breast cancer patients, respectively 70.2% vs 76.9% were initially diagnosed at local stage, 25.3% vs 20.3% with regional stage, and 4.56% vs 2.80% with distant stage-at-diagnosis. Overall, BN performed approximately 4.7 times better than Classification And Regression Tree (CART) (Breiman L, Friedman JH, Stone CJ, Olshen RA. Classification and regression trees. CRC press; 1984) in predicting stage-at-diagnosis. The utilization of screening mammography is the most prominent contributor to the accuracy of the BN model. Hormone receptor (HR) status and tumor grade are useful for explaining racial disparity in stage-at diagnosis, while log-delay in biopsy impeded good prediction. CONCLUSIONS: Mammography utilization had a significant effect on racial differences in breast cancer stage-at-diagnosis, while tumor biology factors had less impact. Biopsy delay also aided in predicting local and regional stages-at-diagnosis for Black NH women but not for white NH women.

The use of indocyanine green (ICYG) angiography intraoperatively to evaluate gastric conduit perfusion during esophagectomy: does it impact surgical decision-making?

BACKGROUND: Ischemia is known to be a major contributor for anastomotic leaks and indocyanine green (ICYG) fluorescence angiography has been utilized to assess perfusion. Experienced esophageal surgeons have clinically assessed the gastric conduit with acceptable outcomes for years. We sought to examine the impact of ICYG in a surgeon's decision-making during esophagectomy. METHODS: We queried a prospectively maintained database to identify patients who underwent robotic esophagectomy. Time to initial perfusion, time to maximum perfusion, and residual ischemia were measured and used as a guide to resection of residual stomach. During esophagectomy the surgeon identified the anticipated line of ischemic demarcation (LOD) prior to ICYG injection. The distance between the surgeon's LOD and ICYG LOD was measured. RESULTS: We identified 312 patients who underwent robotic esophagectomy, 251 without ICYG and 61 with ICGY. There were no differences in age, sex, race, body mass index, histology, stage, or neoadjuvant therapy use between groups. The incidence of anastomotic leak did not differ between groups (non-ICYG, 5.2% vs. ICYG, 6.6%), p = 0.67. The initial perfusion time was ≥ 10 s and max perfusion was > 25 s in all the patients in the ICYG that developed anastomotic leaks. All patients were noted to have at least 1 cm of residual gastric ischemia. Fifteen patients underwent independent surgeon evaluation of the ischemic LOD prior to ICYG. Differential distances were noted in 12 (80%) patients with a mean distance between surgical line of demarcation and ICYG LOD of 0.77 cm. CONCLUSION: While the implementation of ICYG during esophagectomy demonstrates no significant improvements in anastomotic leak rates compared to historical controls, surgeon's decision-making is impacted in 80% of cases resulting in additional resection of the gastric conduit. Elevated times to initial perfusion and maximum perfusion were associated with increased gastric ischemia and anastomotic leaks.

Gut microbiota gestalt.

The pathogenicity of disease-associated microbes varies widely between individuals. In this issue of Cell Host & Microbe, Rice et al. demonstrate that interactions between intestinal commensals reciprocally modulate the host immune response to each microbe, ameliorating the inflammation caused by one and dampening antibody responses to the other.

COVID-19-Associated Middle Ear Myoclonus in a 10-Year-Old Male.

Middle ear myoclonus is a rare condition attributed to abnormal, repetitive contractions of the middle ear muscles including the tensor tympani and/or stapedius muscles. This condition generates objective tinnitus that is characterized by a "clicking" noise that is audible to both the patient and an outside observer. No specific pathophysiologic process has been identified as the cause of middle ear myoclonus, making its diagnosis and treatment challenging. In this report, we present a presumptive case of COVID-19-associated middle ear myoclonus in a 10-year-old male.

Synthetic glycans control gut microbiome structure and mitigate colitis in mice.

Relative abundances of bacterial species in the gut microbiome have been linked to many diseases. Species of gut bacteria are ecologically differentiated by their abilities to metabolize different glycans, making glycan delivery a powerful way to alter the microbiome to promote health. Here, we study the properties and therapeutic potential of chemically diverse synthetic glycans (SGs). Fermentation of SGs by gut microbiome cultures results in compound-specific shifts in taxonomic and metabolite profiles not observed with reference glycans, including prebiotics. Model enteric pathogens grow poorly on most SGs, potentially increasing their safety for at-risk populations. SGs increase survival, reduce weight loss, and improve clinical scores in mouse models of colitis. Synthetic glycans are thus a promising modality to improve health through selective changes to the gut microbiome.

Rural-Urban Differences in Breast Cancer Stage at Diagnosis.

Purpose: To analyze the extent to which rural-urban differences in breast cancer stage at diagnosis are explained by factors including age, race, tumor grade, receptor status, and insurance status. Methods: Using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 18 database, analysis was performed using data from women aged 50-74 diagnosed with breast cancer between the years 2013 and 2016. Patient rurality of residence was coded according to SEER's Rural-Urban Continuum Code 2013: Large Urban (RUCC 1), Small Urban (RUCC 2,3), and Rural (RUCC 4,5,6,7,8,9). Stage at diagnosis was coded according to SEER's Combined Summary Stage 2000 (2004+) criteria: Localized (0,1), Regional (2,3,4,5), and Distant (7). Descriptive statistics were analyzed, and variations were tested for across rural-urban categories using Kruskall-Wallis and Kendall's tau-b tests. Additionally, odds ratios (ORs) and 95% confidence intervals for the three ordinal levels of rural-urban residence were calculated while adjusting for other independent variables using ordinal logistic regression. Results: The rural residence category showed the largest proportion of women diagnosed with distant stage breast cancer. Additionally, we determined that patients with residence in both large and small urban areas had statistically significantly lower odds of higher stage diagnosis compared to rural patients even after controlling for age, race, tumor grade, receptor status, and insurance status. Conclusions: Rural women with breast cancer show small but statistically significant disparities in stage-at-diagnosis. Further research is needed to understand local area variation in these disparities across a wide range of rural communities, and to identify the most effective interventions to eliminate these disparities.

'I'm not interested in research; i'm interested in services': How to better health and social services for transgender women living with and affected by HIV.

This paper presents results of a research priority setting process focused on trans women living with and affected by HIV across Canada. It features data from semi-structured interviews and focus groups conducted with a diverse group of 76 trans women in five urban centers across the country on how they have navigated health and social service programming within their geographic context. The results focus on the structure and types of services. Respondents offered simple, yet creative ways to address barriers to vital services based on their individual and collective experiences. Notably, participants stressed the need for 1) trans-friendly and trans-specific services, 2) integrated health services, and aid in navigating complex, overlapping systems, and 3) comprehensive community-based services. They also suggest employing trans women as care coordinators or case managers in order to foster more trans-friendly environments and empower community members. We identify concrete ways to improve health and social services at the level of service delivery and program design, as well as recommendations for future participatory research. We close with an interrogation of trans people, and trans women living with and affected by HIV in particular, as 'hard to reach' populations.

Implementation and evaluation of the 'Transgender Education for Affirmative and Competent HIV and Healthcare (TEACHH)' provider education pilot.

BACKGROUND: Transgender (trans) women face constrained access to gender-affirming HIV prevention and care. This is fueled in part by the convergence of limited trans knowledge and competency with anti-trans and HIV-related stigmas among social and healthcare providers. To advance gender-affirming HIV service delivery we implemented and evaluated 'Transgender Education for Affirmative and Competent HIV and Healthcare (TEACHH)'. This theoretically-informed community-developed intervention aimed to increase providers' gender-affirming HIV prevention and care knowledge and competency and reduce negative attitudes and biases among providers towards trans women living with and/or affected by HIV. METHODS: Healthcare and social service providers and providers in-training (e.g., physicians, nurses, social workers) working with trans women living with and/or affected by HIV (n = 78) participated in a non-randomized multi-site pilot study evaluating TEACHH with a pre-post-test design. Pre- and post-intervention surveys assessed participant characteristics, intervention feasibility (e.g., workshop completion rate) and acceptability (e.g., willingness to attend another training). Paired sample t-tests were conducted to assess pre-post intervention differences in perceived competency, attitudes/biases, and knowledge to provide gender-affirming HIV care to trans women living with HIV and trans persons. RESULTS: The intervention was feasible (100% workshop completion) and acceptable (91.9% indicated interest in future gender-affirming HIV care trainings). Post-intervention scores indicated significant improvement in: 1) knowledge, attitudes/biases and perceived competency in gender-affirming HIV care (score mean difference (MD) 8.49 (95% CI of MD: 6.12-10.86, p < 0.001, possible score range: 16-96), and 2) knowledge, attitudes/biases and perceived competency in gender-affirming healthcare (MD = 3.21; 95% CI of MD: 1.90-4.90, p < 0.001, possible score range: 9-63). Greater change in outcome measures from pre- to post-intervention was experienced by those with fewer trans and transfeminine clients served in the past year, in indirect service roles, and having received less prior training. CONCLUSIONS: This brief healthcare and social service provider intervention showed promise in improving gender-affirming provider knowledge, perceived competency, and attitudes/biases, particularly among those with less trans and HIV experience. Scale-up of TEACHH may increase access to gender-affirming health services and HIV prevention and care, increase healthcare access, and reduce HIV disparities among trans women. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT04096053 ).

Naïve Bayesian network-based contribution analysis of tumor biology and healthcare factors to racial disparity in breast cancer stage-at-diagnosis.

BACKGROUND: Variation in breast cancer stage at initial diagnosis (including racial disparities) is driven both by tumor biology and healthcare factors. METHODS: We studied women age 67-74 with initial diagnosis of breast cancer from 2006 through 2014 in the SEER-Medicare database. We extracted variables related to tumor biology (histologic grade and hormone receptor status) and healthcare factors (screening mammography [SM] utilization and time delay from mammography to diagnostic biopsy). We used naïve Bayesian networks (NBNs) to illustrate the relationships among patient-specific factors and stage-at-diagnosis for African American (AA) and white patients separately. After identifying and controlling confounders, we conducted counterfactual inference through the NBN, resulting in an unbiased evaluation of the causal effects of individual factors on the expected utility of stage-at-diagnosis. An NBN-based decomposition mechanism was developed to evaluate the contributions of each patient-specific factor to an actual racial disparity in stage-at-diagnosis. 2000 bootstrap samples from our training patients were used to compute the 95% confidence intervals (CIs) of these contributions. RESULTS: Using a causal-effect contribution analysis, the relative contributions of each patient-specific factor to the actual racial disparity in stage-at-diagnosis were as follows: tumor grade, 45.1% (95% CI: 44.5%, 45.8%); hormone receptor status, 5.0% (4.5%, 5.4%); mammography utilization, 23.1% (22.4%, 24.0%); and biopsy delay 26.8% (26.1%, 27.3%). CONCLUSION: The modifiable mechanisms of mammography utilization and biopsy delay drive about 49.9% of racial difference in stage-at-diagnosis, potentially guiding more targeted interventions to eliminate cancer outcome disparities. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13755-021-00165-5.

A qualitative exploration of barriers to HIV prevention, treatment and support: Perspectives of transgender women and service providers.

Transgender (trans) women experience barriers to access to HIV care, which result in their lower engagement in HIV prevention, treatment and support relative to cisgender people living with HIV. Studies of trans women's barriers to HIV care have predominantly focused on perspectives of trans women, while barriers are most often described at provider, organisation and/or systems levels. Comparing perspectives of trans women and service providers may promote a shared vision for achieving health equity. Thus, this qualitative study utilised focus groups and semi-structured interviews conducted 2018-2019 to understand barriers and facilitators to HIV care from the perspectives of trans women (n = 26) and service providers (n = 10). Barriers endorsed by both groups included: (a) anticipated and enacted stigma and discrimination in the provision of direct care, (b) lack of provider knowledge of HIV care needs for trans women, (c) absence of trans-specific services/organisations and (d) cisnormativity in sexual healthcare. Facilitators included: (a) provision of trans-positive trauma-informed care, (b) autonomy and choice for trans women in selecting sexual health services and (c) models for trans-affirming systems change. Each theme had significant overlap, yet nuanced perspective, between trans women and service providers. Specific recommendations to improve HIV care access for trans women are discussed. These recommendations can be used by administrators and service providers alike to work collaboratively with trans women to reduce barriers and facilitators to HIV care and ultimately to achieve health equity for trans women.

'Transgender Education for Affirmative and Competent HIV and Healthcare (TEACHH)': protocol of community-based intervention development and a non-randomised multisite pilot study with pre-post test design in Canada.

INTRODUCTION: Educational workshops are a promising strategy to increase healthcare providers' ability to provide gender-affirming care for transgender (trans) people. This strategy may also reduce healthcare providers' stigma towards trans people and people living with HIV. There is less evidence, however, of educational workshops that address HIV prevention and care among trans women. This protocol details development and pilot testing of the Transgender Education for Affirmative and Competent HIV and Healthcare intervention that aims to increase gender-affirming HIV care knowledge and perceived competency, and to reduce negative attitudes/biases, among providers. METHODS AND ANALYSIS: This community-based research (CBR) project involves intervention development and implementation of a non-randomised multisite pilot study with pre-post test design. First, we conducted a qualitative formative phase involving focus groups with 30 trans women and individual interviews with 12 providers to understand HIV care access barriers for trans women and elicit feedback on a proposed workshop. Second, we will pilot test the intervention with 90-150 providers (n=30-50×3 in-person settings). For pilot studies, primary outcomes include feasibility (eg, completion rate) and acceptability (eg, workshop satisfaction). Secondary preintervention and postintervention outcomes, assessed directly preceding and following the workshop, include perceived competency, attitudes/biases towards trans women with HIV, and knowledge needed to provide gender-affirming HIV care. Primary outcomes will be summarised as frequencies and proportions (categorical variables). We will conduct paired-sample t-tests to explore the direction of preintervention and postintervention differences for secondary outcomes. ETHICS AND DISSEMINATION: This study has been approved by the University of Toronto HIV Research Ethics Board (Protocol Number: 00036238). Study findings will be disseminated through community forums with trans women and service providers; manuscripts submitted to peer reviewed journals; and conferences. Findings will inform a larger CBR research agenda to remove barriers to engagement in HIV prevention/care among trans women across Canada. TRIAL REGISTRATION NUMBER: NCT04096053; Pre-results.

Protein misfolding in neurodegenerative diseases: implications and strategies.

A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse. Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease, including synthesis, chaperone-assisted folding and trafficking, and degradation via the proteasome and autophagy pathways. Other therapies, like mTOR inhibitors and activators of the heat shock response, can rebalance the entire proteostatic network. However, there are major challenges that impact the development of novel therapies, including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response. A notable development is the creation of collaborative ecosystems that include patients, clinicians, basic and translational researchers, foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent, reverse or delay the progression of neurodegenerative proteinopathies.

Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies.

Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable.

Biology of vascular malformations of the brain.

BACKGROUND AND PURPOSE: This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation, sporadic brain arteriovenous malformation, and the arteriovenous malformations of hereditary hemorrhagic telangiectasia. Summary of Review- The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene. CONCLUSIONS: Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these.

Curing epilepsy: progress and future directions.

During the past decade, substantial progress has been made in delineating clinical features of the epilepsies and the basic mechanisms responsible for these disorders. Eleven human epilepsy genes have been identified and many more are now known from animal models. Candidate targets for cures are now based upon newly identified cellular and molecular mechanisms that underlie epileptogenesis. However, epilepsy is increasingly recognized as a group of heterogeneous syndromes characterized by other conditions that co-exist with seizures. Cognitive, emotional and behavioral co-morbidities are common and offer fruitful areas for study. These advances in understanding mechanisms are being matched by the rapid development of new diagnostic methods and therapeutic approaches. This article reviews these areas of progress and suggests specific goals that once accomplished promise to lead to cures for epilepsy.

National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards.

BACKGROUND AND PURPOSE: One in 3 individuals will experience a stroke, dementia or both. Moreover, twice as many individuals will have cognitive impairment short of dementia as either stroke or dementia. The commonly used stroke scales do not measure cognition, while dementia criteria focus on the late stages of cognitive impairment, and are heavily biased toward the diagnosis of Alzheimer disease. No commonly agreed standards exist for identifying and describing individuals with cognitive impairment, particularly in the early stages, and especially with cognitive impairment related to vascular factors, or vascular cognitive impairment. METHODS: The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to recommend minimum, common, clinical and research standards for the description and study of vascular cognitive impairment. RESULTS: The results of these discussions are reported herein. CONCLUSIONS: The development of common standards represents a first step in a process of use, validation and refinement. Using the same standards will help identify individuals in the early stages of cognitive impairment, will make studies comparable, and by integrating knowledge, will accelerate the pace of progress.

Genetics of vascular cognitive impairment: the opportunity and the challenges.

BACKGROUND AND PURPOSE: This review considers the current state of knowledge of genetic factors underlying vascular cognitive impairment (VCI). SUMMARY OF REVIEW: We argue here that genes conferring susceptibility to VCI must be of 2 nonmutually exclusive classes: (1) genes that confer susceptibility to cerebrovascular disease, and (2) genes that determine brain tissue responses to cerebrovascular disease (ie, render parenchymal tissue more or less susceptible to injury or able to repair itself after injury). Although some progress has been made in identifying genes of the first class, little has been done to explore genes of the second class. Evidence for the existence of such genes is presented. We discuss the advantages and disadvantages of different forms of cerebrovascular disease for studying these genes, and different study designs that might be used. CONCLUSIONS: The most critical challenge for genetic studies of VCI is to identify quantifiable phenotypes that can be reliably and effectively determined in large samples of subjects.