Learning from Latent Safety Threats Identified During Simulation to Improve Patient Safety.

BACKGROUND: Latent safety threats (LSTs-characteristics of design, processes, or physical environment in health care compromising patient safety) are commonly revealed during simulation-based training. Methods of collecting, analyzing, and classifying LSTs are underdeveloped and not standardized. Building on a large simulation program in one organization, the authors aimed to collect LSTs systematically and develop a taxonomy to classify them. METHODS: The authors modified the Press Ganey Healthcare Performance Improvement Failure Modes Taxonomy (HPI-FMT), a standardized framework for safety event classification in health care, and used three categories: System, Individual, and Medications. The subcategories were revised to reflect simulation LST content and promote consistent data entry into a spreadsheet. Data visualization software was used to analyze LST data and generate dashboards, graphs, and executive summaries to share across the system that depicted data for individual hospitals and outpatient areas and allowed grouping, comparisons, and trending. RESULTS: Over a year, the researchers identified 1,318 LSTs in 232 simulations across the organization-a rate of 5.7 LSTs/simulation. The top three LST subcategories were Environment/supplies/equipment (System category); Process/structure (System category); and Knowledge or unformed skill/habit (Individual category). Other important LSTs were Missing/malfunctioning supplies/equipment; Unclear or ineffective process or no process; and Unfamiliarity with supplies/equipment. When a repetitive pattern of LSTs was observed (for example, improper dantrolene use during malignant hyperthermia simulations), targeted process improvement or training was implemented. CONCLUSION: The authors developed, implemented, and refined a systematic method of collecting, analyzing, displaying LSTs, and recommending targeted process improvements or training when LST trends were noted.

Hemozoin-mediated inflammasome activation limits long-lived anti-malarial immunity.

During acute malaria, most individuals mount robust inflammatory responses that limit parasite burden. However, long-lived sterilizing anti-malarial memory responses are not efficiently induced, even following repeated Plasmodium exposures. Using multiple Plasmodium species, genetically modified parasites, and combinations of host genetic and pharmacologic approaches, we find that the deposition of the malarial pigment hemozoin directly limits the abundance and capacity of conventional type 1 dendritic cells to prime helper T cell responses. Hemozoin-induced dendritic cell dysfunction results in aberrant Plasmodium-specific CD4 T follicular helper cell differentiation, which constrains memory B cell and long-lived plasma cell formation. Mechanistically, we identify that dendritic cell-intrinsic NLRP3 inflammasome activation reduces conventional type 1 dendritic cell abundance, phagocytosis, and T cell priming functions in vivo. These data identify biological consequences of hemozoin deposition during malaria and highlight the capacity of the malarial pigment to program immune evasion during the earliest events following an initial Plasmodium exposure.

Responding and navigating racialized microaggressions in STEM.

While it is commonly thought that microaggressions are isolated incidents, microaggressions are ingrained throughout the academic research institution (Young, Anderson and Stewart 2015; Lee et al. 2020). Persons Excluded from science because of Ethnicity and Race (PEERs) frequently experience microaggressions from various academicians, including graduate students, postdocs and faculty (Asai 2020; Lee et al. 2020). Here, we elaborate on a rationale for concrete actions to cope with and diminish acts of microaggressions that may otherwise hinder the inclusion of PEERs. We encourage Science, Technology, Engineering and Mathematics (STEM) departments and leadership to affirm PEER scholar identities and promote allyship by infusing sensitivity, responsiveness and anti-bias awareness.

Extrafollicular CD4 T cell-derived IL-10 functions rapidly and transiently to support anti-Plasmodium humoral immunity.

Immunity against malaria depends on germinal center (GC)-derived antibody responses that are orchestrated by T follicular helper (TFH) cells. Emerging data show that the regulatory cytokine IL-10 plays an essential role in promoting GC B cell responses during both experimental malaria and virus infections. Here we investigated the cellular source and temporal role of IL-10, and whether IL-10 additionally signals to CD4 T-cells to support anti-Plasmodium humoral immunity. Distinct from reports of virus infection, we found that IL-10 was expressed by conventional, Foxp3-negative effector CD4 T cells and functioned in a B cell-intrinsic manner only during the first 96 hours of Plasmodium infection to support humoral immunity. The critical functions of IL-10 manifested only before the orchestration of GC responses and were primarily localized outside of B cell follicles. Mechanistically, our studies showed that the rapid and transient provision of IL-10 promoted B cell expression of anti-apoptotic factors, MHC class II, CD83, and cell-cell adhesion proteins that are essential for B cell survival and interaction with CD4 T cells. Together, our data reveal temporal features and mechanisms by which IL-10 critically supports humoral immunity during blood-stage Plasmodium infection, information that may be useful for developing new strategies designed to lessen the burden of malaria.

Patching the Leaks: Revitalizing and Reimagining the STEM Pipeline.

We identify problematic areas throughout the Science, Technology, Engineering and Mathematics (STEM) pipeline that perpetuate racial disparities in academia. Distinct ways to curtail these disparities include early exposure and access to resources, supportive mentoring networks and comprehensive training programs specifically for racially minoritized students and trainees at each career stage. These actions will revitalize the STEM pipeline.

Cutting Edge: Augmenting Muscle MHC Expression Enhances Systemic Pathogen Control at the Expense of T Cell Exhaustion.

Myocytes express low levels of MHC class I (MHC I), perhaps influencing the ability of CD8+ T cells to efficiently detect and destroy pathogens that invade muscle. Trypanosoma cruzi infects many cell types but preferentially persists in muscle, and we asked if this tissue-dependent persistence was linked to MHC expression. Inducible enhancement of skeletal muscle MHC I in mice during the first 20 d of T. cruzi infection resulted in enhanced CD8-dependent reduction of parasite load. However, continued overexpression of MHC I beyond 30 d ultimately led to a collapse of systemic parasite control associated with immune exhaustion, which was reversible in part by blocking PD-1:PD-L1 interactions. These studies demonstrate a surprisingly strong and systemically dominant effect of skeletal muscle MHC expression on maintaining T cell function and pathogen control and argue that the normally low MHC I expression in skeletal muscle is host protective by allowing for pathogen control while preventing immune exhaustion.

Highly competent, non-exhausted CD8+ T cells continue to tightly control pathogen load throughout chronic Trypanosoma cruzi infection.

Trypanosoma cruzi infection is characterized by chronic parasitism of non-lymphoid tissues and is rarely eliminated despite potent adaptive immune responses. This failure to cure has frequently been attributed to a loss or impairment of anti-T. cruzi T cell responses over time, analogous to the T cell dysfunction described for other persistent infections. In this study, we have evaluated the role of CD8+ T cells during chronic T. cruzi infection (>100 dpi), with a focus on sites of pathogen persistence. Consistent with repetitive antigen exposure during chronic infection, parasite-specific CD8+ T cells from multiple organs expressed high levels of KLRG1, but exhibit a preferential accumulation of CD69+ cells in skeletal muscle, indicating recent antigen encounter in a niche for T. cruzi persistence. A significant proportion of CD8+ T cells in the muscle also produced IFNγ, TNFα and granzyme B in situ, an indication of their detection of and functional response to T. cruzi in vivo. CD8+ T cell function was crucial for the control of parasite burden during chronic infection as exacerbation of parasite load was observed upon depletion of this population. Attempts to improve T cell function by blocking PD-1 or IL-10, potential negative regulators of T cells, failed to increase IFNγ and TNFα production or to enhance T. cruzi clearance. These results highlight the capacity of the CD8+ T cell population to retain essential in vivo function despite chronic antigen stimulation and support a model in which CD8+ T cell dysfunction plays a negligible role in the ability of Trypanosoma cruzi to persist in mice.

Th1-like Plasmodium-Specific Memory CD4+ T Cells Support Humoral Immunity.

Effector T cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for resistance to clinical malaria. To determine whether Plasmodium-specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium-specific memory CD4 T cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B cell help and protection following transfer, characteristics that are enhanced following ligation of the T cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium-specific memory CD4 T cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure.

Preterm low birth weights associated with periodontal disease in the Fiji Islands.

AIM: To determine any association between pre-term low birth weight (PTLBW) neonates and periodontal disease during the mother's pregnancy. DESIGN: A multi-centered prospective case cohort study. SETTING: Ante-natal clinics at the Colonial War Memorial and Lautoka Hospitals, Fiji from 1st January to 30th June 2004. PARTICIPANTS: 670 multiethnic pregnant women. METHODS: Participants were interviewed to identify confounding variables--medical conditions, smoking, alcohol consumption, maternal age and history of preterm birth. Oral examination was conducted and included the Community Periodontal Index of Treatment Needs (CPITN). Delivery outcome was recorded for each woman. RESULTS: The mean age of participants was 25.80 +/- 5.56 years. 1.9% (n=13) women delivered preterm babies. More than 50% of this group displayed moderate to severe periodontitis compared with 13% of women who had a normal delivery. Preterm birth was also associated with the mother having had a previous preterm birth and who was more likely to be Indo-Fijian (p < 0.01). There was no significant association with where the mother lived; however, rural women with PTLBW babies had more severe periodontal disease (p = 0.0001). CONCLUSION: There is a highly significant association between pre-term birth and moderate to severe periodontal disease (p = 0.0001).

The effects of manuka honey on plaque and gingivitis: a pilot study.

UNLABELLED: Research has shown that manuka honey has superior antimicrobial properties that can be used with success in the treatment of wound healing, peptic ulcers and bacterial gastro-enteritis. Studies have already shown that manuka honey with a high antibacterial activity is likely to be non-cariogenic. The current pilot study investigated whether or not manuka honey with an antibacterial activity rated UMF 15 could be used to reduce dental plaque and clinical levels of gingivitis. A chewable "honey leather" was produced for this trial. Thirty volunteers were randomly allocated to chew or suck either the manuka honey product, or sugarless chewing gum, for 10 minutes, three times a day, after each meal. Plaque and gingival bleeding scores were recorded before and after the 21-day trial period. Analysis of the results indicated that there were statistically highly significant reductions in the mean plaque scores (0.99 reduced to 0.65; p=0.001), and the percentage of bleeding sites (48% reduced to 17%; p=0.001), in the manuka honey group, with no significant changes in the control group. CONCLUSION: These results suggest that there may be a potential therapeutic role for manuka honey confectionery in the treatment of gingivitis and periodontal disease.

Scaling and root-planing treatment with adjunctive subgingival minocycline. A clinical pilot study over six months, of sites adjacent to and remote from the antibiotic application.

AIM: A clinical trial was performed to determine if a single dose of subgingival minocycline has (i) a clinical spillover effect at adjacent and remote sites and (ii) an adjunctive effect to scaling and root-planing. MATERIALS AND METHODS: Each of the 15 adult subjects included in the study had to present with at least two pairs of adjacent 6-9 mm pockets each pair located on adjacent teeth in an interproximal space, on opposite sides of the mouth. Each study site was required to have at least 3 mm loss of attachment. Following a baseline examination including assessments of plaque, pocket depth (PD), clinical attachment levels (CAL) and bleeding on probing (BOP), instruction in oral hygiene was given. Each subject was treated with a single episode of scaling and root-planing (SRP), of approximately 90 minutes duration using ultrasonic and hand instrumentation under local anaesthetic, if indicated. This was followed by a single application of 1 mg of minocycline in the form of Minocycline Periodontal Therapeutic System (MPTS) into one of the four sites selected at random by another clinician, who also randomly selected one of the two sites on the opposite side of the mouth to be designated the Remote site. Clinical re-examinations were performed at 3- and 6-months. RESULTS: At six months the CAL gains at the MPTS sites were statistically significantly different when compared with the Adjacent sites (P=0.04). The proportion of sites demonstrating a CAL gain (> or = 2 mm) was higher in the MPTS group (73%) compared with the Adjacent (40%) and Remote sites (53%). Periodontal therapy, (MPTS+SRP) and (SRP alone) resulted in a statistically significant reduction in mean pocket depths (P<0.01). However no statistically significant differences in pocket depths were found between treatment groups over the six months of the study. The proportion of sites demonstrating a clinically significant reduction in PD (> or = 2 mm) was higher in the MPTS sites (80%) compared with the Adjacent sites (53%) and Remote sites (53%). BOP was significantly reduced at all sites over the duration of the study except at the Adjacent sites at three months (P<0.05). CONCLUSION: No apparent clinical spillover effect of minocycline was demonstrated over the six months of the study. There was a trend for greater improvement in all clinical parameters at the MPTS sites compared with the Adjacent and Remote sites except for plaque scores. This trend needs to be examined in a study with a sufficient number of subjects to allow statistical significance.