Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

BACKGROUND: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits. METHODS: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. RESULTS: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. CONCLUSIONS: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

Racism as a public health issue in environmental health disparities and environmental justice: working toward solutions.

BACKGROUND: Environmental health research in the US has shown that racial and ethnic minorities and members of low-socioeconomic groups, are disproportionately burdened by harmful environmental exposures, in their homes, workplace, and neighborhood environments that impact their overall health and well-being. Systemic racism is a fundamental cause of these disproportionate exposures and associated health effects. To invigorate and inform current efforts on environmental justice and to raise awareness of environmental racism, the National Institute of Environmental Health Sciences (NIEHS) hosted a workshop where community leaders, academic researchers, and NIEHS staff shared perspectives and discussed ways to inform future work to address health disparities. OBJECTIVES: To share best practices learned and experienced in partnerships between academic researchers and communities that are addressing environmental racism across the US; and to outline critical needs and future actions for NIEHS, other federal agencies, and anyone who is interested in conducting or funding research that addresses environmental racism and advances health equity for all communities. DISCUSSION: Through this workshop with community leaders and researchers funded by NIEHS, we learned that partnerships between academics and communities hold great promise for addressing environmental racism; however, there are still profound obstacles. To overcome these barriers, translation of research into plain language and health-protective interventions is needed. Structural changes are also needed in current funding mechanisms and training programs across federal agencies. We also learned the importance of leveraging advances in technology to develop creative solutions that can protect public health.

Screening for hypertension in adults: protocol for evidence reviews to inform a Canadian Task Force on Preventive Health Care guideline update.

PURPOSE: To inform updated recommendations by the Canadian Task Force on Preventive Health Care on screening in a primary care setting for hypertension in adults aged 18 years and older. This protocol outlines the scope and methods for a series of systematic reviews and one overview of reviews. METHODS: To evaluate the benefits and harms of screening for hypertension, the Task Force will rely on the relevant key questions from the 2021 United States Preventive Services Task Force systematic review. In addition, a series of reviews will be conducted to identify, appraise, and synthesize the evidence on (1) the association of blood pressure measurement methods and future cardiovascular (CVD)-related outcomes, (2) thresholds for discussions of treatment initiation, and (3) patient acceptability of hypertension screening methods. For the review of blood pressure measurement methods and future CVD-related outcomes, we will perform a de novo review and search MEDLINE, Embase, CENTRAL, and APA PsycInfo for randomized controlled trials, prospective or retrospective cohort studies, nested case-control studies, and within-arm analyses of intervention studies. For the thresholds for discussions of treatment initiation review, we will perform an overview of reviews and update results from a relevant 2019 UK NICE review. We will search MEDLINE, Embase, APA PsycInfo, and Epistemonikos for systematic reviews. For the acceptability review, we will perform a de novo systematic review and search MEDLINE, Embase, and APA PsycInfo for randomized controlled trials, controlled clinical trials, and observational studies with comparison groups. Websites of relevant organizations, gray literature sources, and the reference lists of included studies and reviews will be hand-searched. Title and abstract screening will be completed by two independent reviewers. Full-text screening, data extraction, risk-of-bias assessment, and GRADE (Grading of Recommendations Assessment, Development and Evaluation) will be completed independently by two reviewers. Results from included studies will be synthesized narratively and pooled via meta-analysis when appropriate. The GRADE approach will be used to assess the certainty of evidence for outcomes. DISCUSSION: The results of the evidence reviews will be used to inform Canadian recommendations on screening for hypertension in adults aged 18 years and older. SYSTEMATIC REVIEW REGISTRATION: This protocol is registered on PROSPERO and is available on the Open Science Framework (osf.io/8w4tz).

Beyond Sterilization: A Comprehensive Review on the Safety and Efficacy of Opportunistic Salpingectomy as a Preventative Strategy for Ovarian Cancer.

Ovarian cancer (OC) is Canada's third most common gynecological cancer, with an estimated 3000 new cases and 1950 deaths projected in 2022. No effective screening has been found to identify OC, especially the most common subtype, high-grade serous carcinoma (HGSC), at an earlier, curable stage. In patients with hereditary predispositions such as BRCA mutations, the rates of HGSC are significantly elevated, leading to the use of risk-reducing salpingo-oophorectomy as the key preventative intervention. Although surgery has been shown to prevent HGSC in high-risk women, the associated premature menopause has adverse long-term sequelae and mortality due to non-cancer causes. The fact that 75% of HGSCs are sporadic means that most women diagnosed with HGSC will not have had the option to avail of either screening or prevention. Recent research suggests that the fimbrial distal fallopian tube is the most likely origin of HGSC. This has led to the development of a prevention plan for the general population: opportunistic salpingectomy, the removal of both fallopian tubes. This article aims to compile and review the studies evaluating the effect of opportunistic salpingectomy on surgical-related complications, ovarian reserve, cost, and OC incidence when performed along with hysterectomy or instead of tubal ligation in the general population.

"When there is no money, that is when I vomit blood": the domino effect and the unfettered lethal exploitation of Black labor on Dominican sugar plantations.

BACKGROUND: In this article, I utilize the concept of the Plantationocene as an analytical framework to generate a holistic and historical understanding of the present-day struggles of a mostly Haitian migrant workforce on sugar plantations in the Dominican Republic. METHODS: Inspired by Paul Farmer's methodology, I combine political economy, history, and ethnography approaches to interpret the experiences of sugarcane cutters across historical and contemporary iterations of colonial, post-colonial, and neo-colonial practices over the course of five centuries. RESULTS: My findings elucidate the enduring power of capitalism, implicating corporate and state elites, as the structural scaffolding for acts of racialized violence that condition the life-and-death circumstances of Black laborers on Caribbean plantations to this day. Although today's sugarcane cutters may suffer differently than their enslaved or wage labor ancestors on the plantation, I argue that an unfettered racialized pattern of lethal exploitation is sustained through the structural violence of neoliberalism that links present conditions with the colonial past. CONCLUSIONS: Ultimately, this paper contributes understandings of the plantationocene's enduring effects in the global south by demonstrating how imperialist arrangements of capitalism are not a distant memory from the colonial past but instead are present yet hidden and obscured while relocated and reanimated overseas to countries like the Dominican Republic, where American capitalists still exploit Black bodies for profit and power.

Recommendations on screening for primary prevention of fragility fractures.

BACKGROUND: Fragility fractures are a major health concern for older adults and can result in disability, admission to hospital and long-term care, and reduced quality of life. This Canadian Task Force on Preventive Health Care (task force) guideline provides evidence-based recommendations on screening to prevent fragility fractures in community-dwelling individuals aged 40 years and older who are not currently on preventive pharmacotherapy. METHODS: We commissioned systematic reviews on benefits and harms of screening, predictive accuracy of risk assessment tools, patient acceptability and benefits of treatment. We analyzed treatment harms via a rapid overview of reviews. We further examined patient values and preferences via focus groups and engaged stakeholders at key points throughout the project. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to determine the certainty of evidence for each outcome and strength of recommendations, and adhered to Appraisal of Guidelines for Research and Evaluation (AGREE), Guidelines International Network and Guidance for Reporting Involvement of Patients and the Public (GRIPP-2) reporting guidance. RECOMMENDATIONS: We recommend "risk assessment-first" screening for prevention of fragility fractures in females aged 65 years and older, with initial application of the Canadian clinical Fracture Risk Assessment Tool (FRAX) without bone mineral density (BMD). The FRAX result should be used to facilitate shared decision-making about the possible benefits and harms of preventive pharmacotherapy. After this discussion, if preventive pharmacotherapy is being considered, clinicians should request BMD measurement using dual-energy x-ray absorptiometry (DXA) of the femoral neck, and re-estimate fracture risk by adding the BMD T-score into FRAX (conditional recommendation, low-certainty evidence). We recommend against screening females aged 40-64 years and males aged 40 years and older (strong recommendation, very low-certainty evidence). These recommendations apply to community-dwelling individuals who are not currently on pharmacotherapy to prevent fragility fractures. INTERPRETATION: Risk assessment-first screening for females aged 65 years and older facilitates shared decision-making and allows patients to consider preventive pharmacotherapy within their individual risk context (before BMD). Recommendations against screening males and younger females emphasize the importance of good clinical practice, where clinicians are alert to changes in health that may indicate the patient has experienced or is at higher risk of fragility fracture.

Objective and self-reported evidence of dextromethorphan antitussive efficacy in children, aged 6-11 years, with acute cough due to the common cold.

OBJECTIVE: To determine objective and subjective endpoints most suitable for evaluating antitussive efficacy of dextromethorphan hydrobromide (DXM) in children. Spontaneous resolution of acute cough and large placebo effects are impediments to evaluating antitussive efficacy. Another impediment is paucity of age-appropriate, validated cough assessment tools. METHODS: This was a multiple-dose, double-blind, placebo-controlled, randomized, pilot clinical study in children, aged 6-11 years, with cough due to the common cold. Eligible subjects met entry criteria and qualified by completing a run-in period where coughs were recorded with a cough monitor after they were dosed with sweet syrup. They were subsequently randomized to receive DXM or placebo over 4 days. Coughs were recorded during the initial 24 h; subjective assessments of cough severity and frequency were self-reported daily during treatment. RESULTS: Data from 128 evaluable subjects (67 DXM; 61 placebo) were analyzed. Total coughs over 24-hours (primary endpoint) and cough frequency during daytime were reduced by 21.0% and 25.5%, respectively, with DXM relative to placebo. Also, greater reductions in cough severity and frequency were self-reported with DXM. These findings were statistically significant and medically relevant. No effects were detected between treatments for nighttime cough rates or impact of cough on sleep. Multiple doses of DXM and placebo were generally well-tolerated. CONCLUSION: Evidence of DXM antitussive efficacy was shown in children using objective and subjective assessment tools validated in pediatric populations. Diurnal variation of cough frequency over 24 h reduced the assay sensitivity needed to detect treatment differences at nighttime, as coughs/hour decreased during sleep for both groups.

Recommandations sur le dépistage pour la prévention primaire des fractures de fragilisation.

CONTEXTE: Les fractures de fragilisation sont un important problème de santé chez les adultes âgés et peuvent entraîner des incapacités, des hospitalisations et le placement en établissement de soins de longue durée, en plus de nuire à la qualité de vie. La présente ligne directrice du Groupe d'étude canadien sur les soins de santé préventifs (le Groupe d'étude) formule des recommandations fondées sur des données probantes au sujet du dépistage pour la prévention des fractures de fragilisation chez les personnes âgées de 40 ans et plus vivant dans la collectivité qui ne sont pas sous traitement pharmacologique préventif. MÉTHODES: Nous avons commandé des revues systématiques sur les bénéfices et les préjudices du dépistage, l'exactitude prédictive des outils d'évaluation du risque, les bénéfices du traitement, ainsi que l'acceptabilité de celui-ci par les patients. Nous avons analysé les préjudices des traitements au moyen d'un examen rapide de revues systématiques. Nous avons en outre analysé les valeurs et les préférences des patients par l'entremise de groupes de discussion et auprès d'intervenants mobilisés à certains moments clés, tout au long du projet. Nous avons utilisé l'approche méthodologique GRADE (Grading of Recommendations, Assessment, Development and Evaluation) afin de déterminer la certitude des données probantes pour chacune des issues cliniques ainsi que la force des recommandations, et nous avons appliqué les lignes directrices de l'instrument AGREE (Appraisal of Guidelines for Research and Evaluation), du Guidelines International Network (GIN) et du guide de rédaction Guidance for Reporting Involvement of Patients and the Public (GRIPP 2). RECOMMANDATIONS: Nous recommandons un dépistage débutant par une estimation du risque pour la prévention des fractures de fragilisation chez les femmes de 65 ans et plus. Le dépistage se fait d'abord au moyen de l'outil canadien FRAX, qui mesure le risque de fracture, sans densité minérale osseuse (DMO). Le score FRAX devrait guider la prise de décision partagée entourant les bénéfices et les préjudices potentiels de la pharmacothérapie préventive. Après cette discussion, si une pharmacothérapie préventive est envisagée, les médecins devraient demander une mesure de la DMO par absorptiométrie à rayons X biphotonique (DEXA) du col du fémur, puis réévaluer le risque de fracture en intégrant le score T de la DMO au score FRAX (recommandation conditionnelle, données de faible certitude). Nous ne recommandons pas le dépistage chez les femmes de 40­64 ans et les hommes de 40 ans et plus (recommandation forte, données de très faible certitude). Ces recommandations s'appliquent aux personnes vivant dans la collectivité qui ne sont pas sous pharmacothérapie pour la prévention des fractures de fragilisation. INTERPRÉTATION: Le dépistage débutant par une estimation du risque chez les femmes de 65 ans et plus facilite la prise de décision partagée et permet aux patientes d'envisager la pharmacothérapie préventive en fonction de leur propre risque (avant DMO). Le fait de ne pas recommander le dépistage chez les hommes et les femmes plus jeunes rappelle l'importance des bonnes pratiques cliniques, en vertu desquelles les médecins doivent demeurer à l'affût de tout changement de l'état de santé des personnes qui pourrait indiquer qu'elles ont subi une fracture de fragilisation ou pourraient y être plus sujettes.

Vascular Endothelial Growth Factor A Contributes to Increased Mammalian Respiratory Epithelial Permeability Induced by Pasteurella multocida Infection.

Pasteurella multocida infection can cause significant zoonotic respiratory problems in both humans and animals, but little is known about the mechanisms used by P. multocida to invade and cross the mammalian respiratory barrier. In this study, we investigated the influence of P. multocida infection on the dysfunction of the respiratory epithelial barrier. In vivo tests in mouse infection models demonstrated that P. multocida infection significantly increased epithelial permeability and increased the expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in murine tracheae and lungs. In murine lung epithelial cell (MLE-12) models, P. multocida infection decreased the expression of tight junctions (ZO-1) and adherens junctions (ß-catenin and E-cadherin) proteins but induced the activation of hypoxia-inducible factor 1α (HIF-1α) and VEGFA signaling. When the expression of HIF-1α is suppressed, the induction of VEGFA and ZO-1 expression by P. multocida infection is decreased. We also found that intervention of HIF-1α and VEGFA signaling affected infection outcomes caused by respiratory bacteria in mouse models. Most importantly, we demonstrate that P. multocida infection increases the permeability of human respiratory epithelial cells and that this process is associated with the activation of HIF-1α and VEGFA signaling and likely contributes to the pathogenesis of P. multocida infection in humans. IMPORTANCE The mammalian respiratory epithelium forms the first line of defense against infections with P. multocida, an important zoonotic respiratory pathogen. In this study, we found that P. multocida infection increased respiratory epithelial permeability and promoted the induction of the HIF-1α-VEGFA axis in both mouse and murine cell models. Similar findings were also demonstrated in human respiratory epithelial cells. The results from this study provide important knowledge about the pathogenesis of P. multocida causing infections in both animals and humans.

"Letting die" by design: Asylum seekers' lived experience of postcolonial necropolitics.

Although the United States has been a nation of immigrants since its founding, the massive number of asylum seekers arriving at the US-Mexico Border is a relatively new phenomenon that requires attention and study. This paper describes the lived experience of three asylum seekers, demonstrating how physical and mental health are structured by US policies and politics. The in-depth accounts are informed by participant observation and policy analysis of humanitarian, non-governmental organizations advocating for asylum seekers. We focus on health and geographical trajectories using the triple trauma paradigm that includes trauma in the country of origin, trauma incurred during transit/flight, and the trauma of arrival and relocation/resettlement in the host country. We suggest that a form of necropower, understood as processes exacerbating the potentiality for death, is embedded in the structure of the US asylum apparatus.

Two Bordetella bronchiseptica attenuated vaccine candidates confer protection against lethal challenge with B. Bronchiseptica and Pasteurella multocida toxin in mouse models.

Dermonecrotic toxin (DNT) is an important bacterial virulence factor produced by the zoonotic pathogens Bordetella bronchiseptica and Pasteurella multocida. This study aims to explore the possibility of expressing different fragments of P. multocida toxin (PMT) in the chromosome of attenuated B. bronchiseptica to generate single-component mucosal vaccine candidates. To achieve this, a 954-bp fragment (basepairs 301 âˆ¼ 1254) of the B. bronchiseptica aroA gene was replaced with an N-terminal, 930-bp fragment (basepairs 1-930; PMTN) or a C-terminal, 900-bp fragment (base pairs 2959 âˆ¼ 3858; PMTC) of the PMT encoding gene toxA. The resulting strains, denoted as Bb-PMTN or Bb-PMTC, expressed PMTN and PMTC, as evidenced by ELISA using polyclonal against full-length of PMT. Phenotypical analyses revealed that Bb-PMTN and Bb-PMTC grew much slower than wild type strains in tryptic soy broth. These strains also displayed significantly decreased 161-fold-virulence compared to the wildtype strains in mouse models. Intranasal immunization of Bb-PMTN and Bb-PMTC in mice induced high levels of antibodies against B. bronchiseptica and PMT, as well as IFN-γ and IL-10 in mouse sera, and most importantly, high titers of sIgA in mouse lungs. Vaccination with these two engineering strains provided 100% protection of mice against lethal challenge with B. bronchiseptica and 80%∼100% protection against lethal challenge with PMT, with Bb-PMTN exhibiting 1.25-fold greater immunogenic efficacy over Bb-PMTC. This study highlights the use of B. bronchiseptica attenuated strains as live mucosal vectors to deliver heterologous antigens.

Implementation of an ED surge management platform: a study protocol.

BACKGROUND: Emergency departments (EDs) around the world are struggling with long wait times and overcrowding. To address these issues, a quality improvement program called SurgeCon was created to improve ED efficiency and patient satisfaction. This paper presents a framework for managing and evaluating the implementation of an ED surge management platform. Our framework builds on the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to structure our approach and the Consolidated Framework for Implementation Research (CFIR) to guide our choice of outcome variables and scalability. METHODS: Four hospital EDs will receive the SurgeCon quality improvement intervention. Using a stepped wedge cluster design, each ED will be randomized to one of four start dates. Data will be collected before, during, and after the implementation of the intervention. RE-AIM will be used to guide the assessment of SurgeCon, and guided by CFIR, we will measure ED key performance indicators (KPI), patient-reported outcomes, and implementation outcomes related to SurgeCon's scalability, adaptability, sustainability, and overall costs. Participants in this study consist of patients who visit any of the four selected EDs during the study period, providers/staff, and health system managers. A mixed-methods approach will be utilized to evaluate implementation outcomes. DISCUSSION: This study will provide important insight into the implementation and evaluation techniques to enhance uptake and benefits associated with an ED surge-management platform. The proposed framework bridges research and practice by involving researchers, practitioners, and patients in the implementation and evaluation process, to produce an actionable framework that others can follow. We anticipate that the implementation approach would be generalizable to program implementations in other EDs. TRIAL REGISTRATION: • Name of the registry: ClinicalTrials.gov • Trial registration number: NCT04789902 • Date of registration: 03/10/2021.

Families' healthcare experiences for children with inherited metabolic diseases: protocol for a mixed methods cohort study.

INTRODUCTION: Children with inherited metabolic diseases (IMDs) often have complex and intensive healthcare needs and their families face challenges in receiving high-quality, family centred health services. Improvement in care requires complex interventions involving multiple components and stakeholders, customised to specific care contexts. This study aims to comprehensively understand the healthcare experiences of children with IMDs and their families across Canada. METHODS AND ANALYSIS: A two-stage explanatory sequential mixed methods design will be used. Stage 1: quantitative data on healthcare networks and encounter experiences will be collected from 100 parent/guardians through a care map, 2 baseline questionnaires and 17 weekly diaries over 5-7 months. Care networks will be analysed using social network analysis. Relationships between demographic or clinical variables and ratings of healthcare experiences across a range of family centred care dimensions will be analysed using generalised linear regression. Other quantitative data related to family experiences and healthcare experiences will be summarised descriptively. Ongoing analysis of quantitative data and purposive, maximum variation sampling will inform sample selection for stage 2: a subset of stage 1 participants will participate in one-on-one videoconference interviews to elaborate on the quantitative data regarding care networks and healthcare experiences. Interview data will be analysed thematically. Qualitative and quantitative data will be merged during analysis to arrive at an enhanced understanding of care experiences. Quantitative and qualitative data will be combined and presented narratively using a weaving approach (jointly on a theme-by-theme basis) and visually in a side-by-side joint display. ETHICS AND DISSEMINATION: The study protocol and procedures were approved by the Children's Hospital of Eastern Ontario's Research Ethics Board, the University of Ottawa Research Ethics Board and the research ethics boards of each participating study centre. Findings will be published in peer-reviewed journals and presented at scientific conferences.

Family Experiences with Care for Children with Inherited Metabolic Diseases in Canada: A Cross-Sectional Survey.

BACKGROUND AND OBJECTIVE: Children with inherited metabolic diseases often require complex and highly specialized care. Patient and family-centered care can improve health outcomes that are important to families. This study aimed to examine experiences of family caregivers (parents/guardians) of children diagnosed with inherited metabolic diseases with healthcare to inform strategies to improve those experiences. METHODS: A cross-sectional mailed survey was conducted of family caregivers recruited from an ongoing cohort study. Participants rated their healthcare experiences during their child's visits to five types of healthcare settings common for inherited metabolic diseases: the metabolic clinic, the emergency department, hospital inpatient units, the blood laboratory, and the pharmacy. Participants provided narrative descriptions of any memorable negative or positive experiences. RESULTS: There were 248 respondents (response rate 49%). Caregivers were generally very or somewhat satisfied with the care provided at each care setting. Appropriate treatment, provider knowledge, provider communication, and care coordination were deemed essential aspects of satisfaction with care by the majority of participants across many settings. Memorable negative experiences were reported by 8-22% of participants, varying by setting. Among participants who reported memorable negative experiences, contributing factors included providers' demeanor, lack of communication, lack of involvement of the family, and disregard of an emergency protocol letter provided by the family. CONCLUSIONS: While caregivers' satisfaction with care for children with inherited metabolic diseases was high, we identified gaps in family-centered care and factors contributing to negative experiences that are important to consider in the future development of strategies to improve pediatric care for inherited metabolic diseases.

When numbers eclipse narratives: a cultural-political critique of the 'ethical' impacts of short-term experiences in global health in Dominican Republic bateyes.

With the rising demand for short-term experiences in global health (STEGH) is an ever-increasing volume of literature that focuses attention on ethics and ethical concerns, such as the effects of STEGH on host populations. Such concerns have driven the development of ethical principles and guidelines, with discussions and debates largely centred around normative questions of positive/negative and benefit/harm for us/them. Using a critical medical humanities lens, this paper blurs these dichotomous framings and offers a more complex understanding of the effects and effectiveness of STEGH on hosts. I explore STEGH that send volunteers from North American universities to the Dominican Republic to participate in service-learning activities aimed at improving the lives of impoverished Haitian migrants living in bateyes I address the following questions: What perspectives about the impacts of interventions on host communities manifest through STEGH? What tensions emerge through interactions among diverse stakeholders related to those perspectives, and with what effects? Drawing together critical theory and ethnography, I examined the perspectives of three stakeholder groups: student and faculty volunteers, host organisation staff, and hosts in batey communities. Data collected from observations and interviews were counterposed; I analysed interactions and interplay between stakeholders. My findings revealed conflicts around an emergent theme: counting efforts, or volunteers' proclivity for numerical evidence of impactful STEGH for hosts. With attention on power relations, I argue that a preoccupation with quantifiable evidence eclipsed and erased the lived realities of hosts, thereby blocking a fully ethical engagement. These sociopolitical effects, often overlooked in conventional ethics assessments, are no less harmful and may reinforce rather than reduce inequalities that the global health movement seeks to eliminate. My study offers a compelling case for how the critical medical humanities lend critical insights in the name of improving global health.

Insertion-trigger residues differentially modulate endosomal escape by cytotoxic necrotizing factor toxins.

The cellular specificity, potency, and modular nature of bacterial protein toxins enable their application for targeted cytosolic delivery of therapeutic cargo. Efficient endosomal escape is a critical step in the design of bacterial toxin-inspired drug delivery (BTIDD) vehicles to avoid lysosomal degradation and promote optimal cargo delivery. The cytotoxic necrotizing factor (CNF) family of modular toxins represents a useful model for investigating cargo-delivery mechanisms due to the availability of many homologs with high sequence identity, their flexibility in swapping domains, and their differential activity profiles. Previously, we found that CNFy is more sensitive to endosomal acidification inhibitors than CNF1 and CNF2. Here, we report that CNF3 is even less sensitive than CNF1/2. We identified two amino acid residues within the putative translocation domain (E374 and E412 in CNFy, Q373 and S411 in CNF3) that differentiate between these two toxins. Swapping these corresponding residues in each toxin changed the sensitivity to endosomal acidification and efficiency of cargo-delivery to be more similar to the other toxin. Results suggested that trafficking to the more acidic late endosome is required for cargo delivery by CNFy but not CNF3. This model was supported by results from toxin treatment of cells in the presence of NH4Cl, which blocks endosomal acidification, and of small-molecule inhibitors EGA, which blocks trafficking to late endosomes, and ABMA, which blocks endosomal escape and trafficking to the lysosomal degradative pathway. These findings suggest that it is possible to fine-tune endosomal escape and cytosolic cargo delivery efficiency in designing BTIDD platforms.

Recovery of microbial community profile information hidden in chimeric sequence reads.

The next frontier in the field of microbiome studies is identification of all microbes present in the microbiome and accurate determination of their abundance such that microbiome profiles can serve as reliable assessments of health or disease status. PCR-based 16S rRNA gene sequencing and metagenome shotgun sequencing technologies are the prevailing approaches used in microbiome analyses. Each poses a number of technical challenges associated with PCR amplification, sample availability, and cost of processing and analysis. In general, results from these two approaches rarely agree completely with each other. Here, we compare these methods utilizing a set of vaginal swab and lavage specimens from a cohort of 42 pregnant women collected for a pilot study exploring the effect of the vaginal microbiome on preterm birth. We generated the microbial community profiles from the sequencing reads of the V3V4 and V4V5 regions of the 16S rRNA gene in the vaginal swab and lavage samples. For a subset of the vaginal samples from 12 subjects, we also performed metagenomic shotgun sequencing analysis and compared the results obtained from the PCR-based sequencing methods. Our findings suggest that sample composition and complexity, particularly at the species level, are major factors that must be considered when analyzing and interpreting microbiome data. Our approach to sequence analysis includes consideration of chimeric reads, by using our chimera-counting BlastBin program, and enables recovery of microbial content information generated during PCR-based sequencing methods, such that the microbial profiles more closely resemble those obtained from metagenomic read-based approaches.

Anticipating the primary care role in genomic medicine: expectations of genetics health professionals.

Our purpose was to explore genetics health professionals' (GHPs) expectations of primary care providers' (PCPs) role in genomic medicine now and in the future. Focus groups/interviews were conducted with GHPs in Ontario, Canada. Recordings were transcribed and analysed using qualitative descriptive analysis. Five focus groups (6 clinical geneticists, 24 genetic counselors, 1 nurse, 4 laboratory staff, 3 genetics program administrators) and 3 interviews (nurses) were conducted. GHPs described a key role for PCPs in genomic medicine that could be enhanced if GHPs and PCPs worked together more effectively, making better use of GHPs as a scarce specialist resource, improving PCP knowledge and awareness of genomics, and increasing GHPs' understanding of primary care practice and how to provide PCPs meaningful education and support. Health system change is needed to facilitate the GHP/PCP relationship and improve care. This might include: PCPs ordering more genetic tests independently or with GHP guidance prior to GHP consultations, genomic expertise in primary care clinics or GHPs being accessible through buddy systems or virtually through telemedicine or electronic consultation, and developing educational materials and electronic decision support for PCPs. Our findings highlight need for change in delivering genomic medicine, which requires building the relationship between GHPs and PCPs, and creating new service delivery models to meet future needs.