Acidic chitinase primes the protective immune response to gastrointestinal nematodes.

Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.

The incidence of transfusion-related acute lung injury using active surveillance: A systematic review and meta-analysis.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-related mortality. A concern with passive surveillance to detect transfusion reactions is underreporting. Our aim was to obtain evidence-based estimates of TRALI incidence using meta-analysis of active surveillance studies and to compare these estimates with passive surveillance. STUDY DESIGN AND METHODS: We performed a systematic review and meta-analysis of studies reporting TRALI rates. A search of Medline and Embase by a research librarian identified studies published between January 1, 1991 and January 20, 2023. Prospective and retrospective observational studies reporting TRALI by blood component (red blood cells [RBCs], platelets, or plasma) were identified and all inpatient and outpatient settings were eligible. Adult and pediatric, as well as general and specific clinical populations, were included. Platelets and plasma must have used at least one modern TRALI donor risk mitigation strategy. A random effects model estimated TRALI incidence by blood component for active and passive surveillance studies and heterogeneity was examined using meta-regression. RESULTS: Eighty studies were included with approximately 176-million blood components transfused. RBCs had the highest number of studies (n = 66) included, followed by platelets (n = 35) and plasma (n = 34). Pooled TRALI estimates for active surveillance studies were 0.17/10,000 (95% confidence intervals [CI]: 0.03-0.43; I2 = 79%) for RBCs, 0.31/10,000 (95% CI: 0.22-0.42; I2 = <1%) for platelets, and 3.19/10,000 (95% CI: 0.09-10.66; I2 = 86%) for plasma. Studies using passive surveillance ranged from 0.02 to 0.10/10,000 among the various blood components. DISCUSSION: In summary, these estimates may improve a quantitative understanding of TRALI risk, which is important for clinical decision-making weighing the risks and benefits of transfusion.

Meta-analysis of bacterial growth characteristics in platelet components: Refining the inputs of a simulation analysis comparing the relative safety of testing strategies.

BACKGROUND: The relative safety of bacterial risk control strategies for platelets that include culture with or without rapid testing has been compared using simulation analysis. A wide range of bacterial lag and doubling times were included. However, published data on growth rates are available and these data have not been synthesized. We conducted a systematic review and meta-analysis to estimate growth rates and used these estimates to refine a comparative safety analysis of bacterial risk control strategies in the FDA guidance STUDY DESIGN AND METHODS: Data were extracted from published studies on bacterial growth rates in platelet components during storage. These data were used to estimate the practical range of growth rates. This refined the inputs for a simulation model comparing the safety of the testing strategies. RESULTS: In total, 108 growth curves for 11 different aerobic organisms were obtained. Doubling times ranged from 0.8 to 12 h, but the lower 90% range was approximately 1-5 h. The revised comparative safety simulation using the narrower 1-5-h range showed similar rankings to the prior simulation, with 48-h large-volume delayed sampling with 7-day expiration (48C-7) demonstrating the lowest-ranking relative performance at the 103 and 105 colony forming unit (CFU)/mL exposure thresholds. DISCUSSION: This was a two-step study. First, meta-analysis of published data on aerobic bacterial growth rates in stored platelets showed the vast majority of doubling times were 1-5 h. Next, an updated comparative safety simulation yielded similar results to a prior study, with 48C-7 showing the least favorable relative safety performance.

The epidemiology of transfusion-related acute lung injury: A scoping review and analysis.

BACKGROUND: The purpose of this scoping review was to identify available sources of evidence on the epidemiology of transfusion-related acute lung injury (TRALI) and whether meta-analysis on the incidence of TRALI is feasible. TRALI is a serious complication and the second leading cause of death related to blood transfusion. Estimates of the incidence of TRALI would provide a useful benchmark for research to reduce TRALI. STUDY DESIGN AND METHODS: We searched the Medline, EMBASE, and PubMed databases for publications related to the incidence of TRALI and hemovigilance. We included all studies irrespective of language or country. Both full-text articles and conference abstracts were included. Participants of the studies must all have received a blood transfusion. Reviews and case studies were excluded. RESULTS: We identified 427 articles or abstracts to include for review. More than half were abstracts, and the majority were published after 2010. Reported TRALI definitions varied, but only 27.2% of studies reported any definition for TRALI. TRALI rates were reported using different denominators, such as per blood unit (54.1%), patient (34.4%), and transfusion episode (14.8%). Study populations and contexts were mostly general (75.6% and 80.3%, respectively). There was also variation in study design with most being observational (90.6%) and only 13.1% of all studies used modern donor restriction policies. DISCUSSION: There was substantial variation in reporting in studies on TRALI incidence. Meta-analysis of TRALI rates may be feasible in specific circumstances where reporting is clear. Future studies should clearly report key items, such as a TRALI definition.

Bacterial culture time to detection in platelet components: An evidence synthesis and estimation of detection failures.

BACKGROUND: Non-pathogen reduction platelet bacterial risk control strategies in the US FDA guidance include at least one culture. Almost all of these strategies have a culture hold time of ≥12 h. Studies have reported time to detection (TTD) of bacterial cultures inoculated with bacteria from contaminated platelets, but these data and estimates of risk associated with detection failures have not been synthesized. METHODS: We performed a literature search to identify studies reporting TTD for samples obtained from spiked platelet components. Using extracted data, regression analysis was used to estimate TTD for culture bottles at different inoculum sizes. Detection failures were defined as events in which contaminated components are transfused to a patient. We then used published data on time of transfusion (ToT) to estimate the risk of detection failures in practice. RESULTS: The search identified 1427 studies, of which 16 were included for analysis. TTD data were available for 16 different organisms, including 14 in aerobic cultures and 11 in anaerobic cultures. For inocula of 1 colony forming unit (CFU), the average TTD for aerobic organisms was 19.2 h while it was 24.9 h in anaerobic organisms, but there was substantial overall variation. A hold time of 12 versus 24 h had minimal effect for most organisms. CONCLUSION: TTD variation occurs between bacterial species and within a particular species. Under typical inventory management, the relative contribution of culture detection failures is much smaller than the residual risk from sampling failures. Increasing the hold period beyond 12 h has limited value.

The effect of community water fluoridation on dental caries in children and young people in England: an ecological study.

BACKGROUND: The protective effect of community water fluoridation (CWF) against dental caries may be modified by secular changes in health behaviour. We aimed to determine the contemporary association between fluoride in public water supplies (PWS) and dental caries indicators and inequalities in England. METHODS: We estimated exposure to CWF and PWS fluoride concentrations from national monitoring data, using Geographic Information Systems and water supply boundaries, categorizing mean period exposure into <0.1, 0.1-<0.2, 0.2-<0.4, 0.4-<0.7 and ≥0.7 mg/l. We used area-level health outcome and confounder data in multivariable regression models to determine the association between fluoride and caries outcomes and calculated preventive fractions using these coefficients. RESULTS: The odds of caries and of severe caries in 5-year-olds fell with increasing fluoride concentration in all SES quintiles (P < 0.001 to P = 0.003). There was a negative trend between increasing fluoride concentration and dental extractions (P < 0.001). Compared to PWS with <0.2 mg/l, CWF prevented 17% (95% confidence interval (CI): 5-27%) to 28% (95% CI: 24-32%) of caries (high-low SES) and 56% (95% CI: 25-74%) of dental extractions. The association between fluoride concentration and caries prevalence/severity varied by socioeconomic status (SES) (P < 0.001). CONCLUSIONS: Exposure to fluoride in PWS appears highly protective against dental caries and reduces oral health inequalities.

The incremental benefit of anaerobic culture for controlling bacterial risk in platelets: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Septic transfusion reactions are a principal cause of transfusion-related mortality. The frequency of detectable bacterial contamination is greater in platelets compared to other blood components because platelets are stored at room temperature. Most strategies outlined in the September 2019 FDA guidance require both aerobic culture (AC) and anaerobic culture (AnC) testing. We performed a systematic review and meta-analysis in an effort to provide the best available estimate of the effectiveness of AnC. MATERIALS AND METHODS: Our analysis was performed according to published guidelines. Broad and context-specific meta-analyses of bacterial detection rates in platelets by AnC were performed to assess the practical effectiveness of AnC as a risk control measure. RESULTS: Seven studies with a total of 1 767 014 tested platelet components were included for analysis. With exclusion of positives due to Cutibacterium/Propionibacterium species and redundancy due to AC results, AnC detected 0·06 contamination events per thousand (EPT) components tested, twofold lower than the AC (0·12 EPT). CONCLUSION: Excluding Cutibacterium/Propionibacterium species, AnC detects occasional bacterial contamination events that are not detected by AC (~1 in 17 000 platelet components).

Residual bacterial detection rates after primary culture as determined by secondary culture and rapid testing in platelet components: A systematic review and meta-analysis.

BACKGROUND: Primary culture alone was a bacterial risk control strategy intended to facilitate interdiction of contaminated platelets (PLTs). A September 2019 FDA guidance includes secondary testing options to enhance safety. Our objective was to use meta-analysis to determine residual contamination risk after primary culture using secondary culture and rapid testing. STUDY DESIGN AND METHODS: A December 2019 literature search identified articles on PLT bacterial detection rates using primary culture and a secondary testing method. We used meta-analysis to estimate secondary testing detection rates after a negative primary culture. We evaluated collection method, sample volume, sample time, and study date as potential sources of heterogeneity. RESULTS: The search identified 6102 articles; 16 were included for meta-analysis. Of these, 12 used culture and five used rapid testing as a secondary testing method. Meta-analysis was based on a total of 103 968 components tested by secondary culture and 114 697 by rapid testing. The residual detection rate using secondary culture (DRSC ) was 0.93 (95% CI, 0.24-0.6) per 1000 components, while residual detection rate using rapid testing (DRRT ) was 0.09 (95% CI, 0.01-0.25) per 1000 components. Primary culture detection rate was the only statistically significant source of heterogeneity. CONCLUSION: We evaluated bacterial detection rates after primary culture using rapid testing and secondary culture. These results provide a lower and upper bound on real-world residual clinical risk because these methods are designed to detect high-level exposures or any level of exposure, respectively. Rapid testing may miss some harmful exposures and secondary culture may identify some clinically insignificant exposures.

Bacterial contamination rate of platelet components by primary culture: a systematic review and meta-analysis.

BACKGROUND: Platelets have the highest bacterial contamination risk of all blood components, and septic transfusion reactions remain a problem. A good estimate of contamination rates could provide information about residual risk and inform optimal testing strategies. We performed a systematic review and meta-analysis of platelet contamination rates by primary culture. STUDY DESIGN AND METHODS: A literature search in December 2019 identified articles on platelet contamination rates using primary culture. We used meta-analysis to estimate the overall rate of contamination and meta-regression to identify heterogeneity. We studied the following sources of heterogeneity: collection method, sample volume, positivity criteria, and study date. Contamination rate estimates were obtained for apheresis (AP), platelet rich plasma (PRP), and buffy coat (BC) collection methods. RESULTS: The search identified 6102 studies, and 22 were included for meta-analysis. Among these 22 studies, there were 21 AP cohorts (4,072,022 components), 4 PRP cohorts (138,869 components), and 15 BC cohorts (1,474,679 components). The overall mean contamination rate per 1000 components was 0.51 (95% CI: 0.38-0.67) including AP (0.23, 95% CI: 0.18-0.28), PRP, (0.38, 95% CI: 0.15-0.70), and BC (1.12, 95% CI: 0.51-1.96). There was considerable variability within each collection method. Sample volume, positivity criteria, and publication year were significant sources of heterogeneity. CONCLUSION: The bacterial contamination rate of platelets by primary culture is 1 in 1961. AP and PRP components showed a lower contamination rate than BC components. There is clinically significant between-study variability for each method. Larger sample volumes increased sensitivity, and bacterial contamination rates have decreased over time.

The comparative safety of bacterial risk control strategies for platelet components: a simulation study.

BACKGROUND: Bacterial contamination of platelets is a problem that can lead to harmful septic transfusion reactions. The US Food and Drug Administration published a guidance in September 2019 detailing several permissible risk control strategies. Our objective was to compare the safety of each bacterial testing strategy for apheresis platelets. STUDY DESIGN AND METHODS: We used simulation to compare safety of the nine risk control strategies involving apheresis platelet testing. The primary outcome was the risk of exposure. An exposure event occurred if a patient received platelets exceeding a specific contamination threshold (>0, 103 , and 105 colony-forming units (CFU/mL). We generated a range of bacterial contamination scenarios (inoculum size, doubling time, lag time) and compared risk of exposure for each policy in each contamination scenario. We then computed the average risk difference over all scenarios. RESULTS: At the 0 CFU/mL exposure threshold, two-step policies that used secondary culture ranked best (all top three), while single-step 24-hour culture with 3-day expiration ranked last (ninth). This latter policy performed well (median rank of 1) at both the 103 and 105 CFU/mL thresholds, but 48-hour culture with 7-day expiration performed relatively poorly. At these higher thresholds, median ranks of two-step policies that used secondary culture were again top three. Two-step policies that used rapid testing improved at the higher (105 CFU/mL) harm threshold, with median rankings between 1 and 5. CONCLUSION: Two-step policies that used secondary culture were generally safer than single-step policies. Performance of two-step policies that used rapid testing depended on the CFU per milliter threshold of exposure used.

Fibroblast-specific integrin-alpha V differentially regulates type 17 and type 2 driven inflammation and fibrosis.

Fibroproliferative diseases affect a significant proportion of the world's population. Despite this, core mechanisms driving organ fibrosis of diverse etiologies remain ill defined. Recent studies suggest that integrin-alpha V serves as a master driver of fibrosis in multiple organs. Although diverse mechanisms contribute to the progression of fibrosis, TGF-ß and IL-13 have emerged as central mediators of fibrosis during type 1/type 17, and type 2 polarized inflammatory responses, respectively. To investigate if integrin-alpha V interactions or signaling is critical to the development of type 2 fibrosis, we analyzed fibroblast-specific integrin-alpha V knockout mice in three type 2-driven inflammatory disease models. While we confirmed a role for integrin-alpha V in type 17-associated fibrosis, integrin-alpha V was not critical to the development of type 2-driven fibrosis. Additionally, our studies support a novel mechanism through which fibroblasts, via integrin-alpha V expression, are capable of regulating immune polarization. We show that when integrin-alpha V is deleted on fibroblasts, initiation of type 17 inflammation is inhibited leading to a deregulation of type 2 inflammation. This mechanism is most evident in a model of severe asthma, which is characterized by a mixed type 2/type 17 inflammatory response. Together, these findings suggest dual targeting of integrin-alpha V and type 2 pathways may be needed to ameliorate fibrosis and prevent rebound of opposing pro-fibrotic and inflammatory mechanisms. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

(1→3)-ß-D-glucan testing for the detection of invasive fungal infections in immunocompromised or critically ill people.

BACKGROUND: Invasive fungal infections (IFIs) are life-threatening opportunistic infections that occur in immunocompromised or critically ill people. Early detection and treatment of IFIs is essential to reduce morbidity and mortality in these populations. (1→3)-ß-D-glucan (BDG) is a component of the fungal cell wall that can be detected in the serum of infected individuals. The serum BDG test is a way to quickly detect these infections and initiate treatment before they become life-threatening. Five different versions of the BDG test are commercially available: Fungitell, Glucatell, Wako, Fungitec-G, and Dynamiker Fungus. OBJECTIVES: To compare the diagnostic accuracy of commercially available tests for serum BDG to detect selected invasive fungal infections (IFIs) among immunocompromised or critically ill people. SEARCH METHODS: We searched MEDLINE (via Ovid) and Embase (via Ovid) up to 26 June 2019. We used SCOPUS to perform a forward and backward citation search of relevant articles. We placed no restriction on language or study design. SELECTION CRITERIA: We included all references published on or after 1995, which is when the first commercial BDG assays became available. We considered published, peer-reviewed studies on the diagnostic test accuracy of BDG for diagnosis of fungal infections in immunocompromised people or people in intensive care that used the European Organization for Research and Treatment of Cancer (EORTC) criteria or equivalent as a reference standard. We considered all study designs (case-control, prospective consecutive cohort, and retrospective cohort studies). We excluded case studies and studies with fewer than ten participants. We also excluded animal and laboratory studies. We excluded meeting abstracts because they provided insufficient information. DATA COLLECTION AND ANALYSIS: We followed the standard procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened studies, extracted data, and performed a quality assessment for each study. For each study, we created a 2 × 2 matrix and calculated sensitivity and specificity, as well as a 95% confidence interval (CI). We evaluated the quality of included studies using the Quality Assessment of Studies of Diagnostic Accuracy-Revised (QUADAS-2). We were unable to perform a meta-analysis due to considerable variation between studies, with the exception of Candida, so we have provided descriptive statistics such as receiver operating characteristics (ROCs) and forest plots by test brand to show variation in study results. MAIN RESULTS: We included in the review 49 studies with a total of 6244 participants. About half of these studies (24/49; 49%) were conducted with people who had cancer or hematologic malignancies. Most studies (36/49; 73%) focused on the Fungitell BDG test. This was followed by Glucatell (5 studies; 10%), Wako (3 studies; 6%), Fungitec-G (3 studies; 6%), and Dynamiker (2 studies; 4%). About three-quarters of studies (79%) utilized either a prospective or a retrospective consecutive study design; the remainder used a case-control design. Based on the manufacturer's recommended cut-off levels for the Fungitell test, sensitivity ranged from 27% to 100%, and specificity from 0% to 100%. For the Glucatell assay, sensitivity ranged from 50% to 92%, and specificity ranged from 41% to 94%. Limited studies have used the Dynamiker, Wako, and Fungitec-G assays, but individual sensitivities and specificities ranged from 50% to 88%, and from 60% to 100%, respectively. Results show considerable differences between studies, even by manufacturer, which prevented a formal meta-analysis. Most studies (32/49; 65%) had no reported high risk of bias in any of the QUADAS-2 domains. The QUADAS-2 domains that had higher risk of bias included participant selection and flow and timing. AUTHORS' CONCLUSIONS: We noted considerable heterogeneity between studies, and these differences precluded a formal meta-analysis. Because of wide variation in the results, it is not possible to estimate the diagnostic accuracy of the BDG test in specific settings. Future studies estimating the accuracy of BDG tests should be linked to the way the test is used in clinical practice and should clearly describe the sampling protocol and the relationship of time of testing to time of diagnosis.

The association of inpatient blood utilization and diagnosis-related group weight: implications for risk-adjusted benchmarking.

BACKGROUND: Risk-adjusted benchmarking could be useful to compare blood utilization between hospitals or individual groups, such as physicians, while accounting for differences in patient complexity. The aim of this study was to analyze the association of red blood cell (RBC) use and diagnosis-related group (DRG) weights across all inpatient hospital stays to determine the suitability of using DRGs for between-hospital risk-adjusted benchmarking. Specific hierarchical organizational units (surgical vs. nonsurgical patients, departments, and physicians) were also evaluated. STUDY DESIGN AND METHODS: We studied blood use among all adult inpatients, and within organizational units, over 4 years (May 2014 to March 2018) at an academic center. Number of RBCs transfused, all patient refined (APR)-DRGs, and other variables were captured over entire hospital stays. We used multilevel generalized linear modeling (zero-inflated negative binomial) to study the relationship between RBC utilization and APR-DRG. RESULTS: A total of 97,955 hospital stays were evaluated and the median APR-DRG weight was 1.2. The association of RBCs transfused and APR-DRG weight was statistically significant at all hierarchical levels (incidence rate ratio = 1.22; p < 0.001). The impact of APR-DRG on blood use, measured by the incidence rate ratio, demonstrated an association at the all-patient and surgical levels, at several department and physician levels, but not at the medical patient level. The relationship between RBCs transfused and APR-DRG varied across organizational units. CONCLUSION: Number of RBCs transfused was associated with APR-DRG weight at multiple hierarchical levels and could be used for risk-adjusted benchmarking in those contexts. The relationship between RBC use and APR-DRG varied across organizational units.

Burden of respiratory abnormalities in microwave popcorn and flavouring manufacturing workers.

OBJECTIVES: Diacetyl, a butter flavour compound used in food and flavouring production, is a respiratory toxin. We characterised the burden of respiratory abnormalities in workers at popcorn and flavouring manufacturing facilities that used diacetyl as evaluated through US National Institute for Occupational Safety and Health (NIOSH) health hazard evaluations. METHODS: We performed analyses describing the number and percentage of current and former workers from popcorn and flavouring manufacturing facilities where NIOSH administered a respiratory health questionnaire and spirometry testing who met case definitions of suspected flavouring-related lung disease. Case definitions were pathologist reported: lung biopsy pathology report stating supportive of/consistent with constrictive bronchiolitis or bronchiolitis obliterans; probable: obstructive/mixed spirometric pattern with forced expiratory volume in 1 s (FEV1) <60% predicted; possible: obstructive/mixed spirometric pattern with FEV1 ≥60% or any spirometric restriction; symptoms only: normal spirometry plus exertional dyspnoea or usual cough. RESULTS: During 2000-2012, NIOSH collected questionnaire and spirometry data on 1407 workers (87.0% current, 13.0% former) at nine facilities in eight states. After applying case definitions, 4 (0.3%) were classified as pathologist reported, 48 (3.4%) as probable, 234 (16.6%) as possible and 404 (28.7%) as symptoms only. The remaining 717 (51.0%) workers had normal spirometry without exertional dyspnoea or usual cough. Seven of 11 workers with biopsies did not meet the pathologist-reported case definition, although four met probable and three met possible. CONCLUSIONS: This approach demonstrates the substantial burden of respiratory abnormalities in these workers. A similar approach could quantify the burden of respiratory abnormalities in other industries that use diacetyl.

Incomplete deletion of IL-4Rα by LysM(Cre) reveals distinct subsets of M2 macrophages controlling inflammation and fibrosis in chronic schistosomiasis.

Mice expressing a Cre recombinase from the lysozyme M-encoding locus (Lyz2) have been widely used to dissect gene function in macrophages and neutrophils. Here, we show that while naïve resident tissue macrophages from IL-4Rαf(lox/delta)LysM(Cre) mice almost completely lose IL-4Rα function, a large fraction of macrophages elicited by sterile inflammatory stimuli, Schistosoma mansoni eggs, or S. mansoni infection, fail to excise Il4rα. These F4/80(hi)CD11b(hi) macrophages, in contrast to resident tissue macrophages, express lower levels of Lyz2 explaining why this population resists LysM(Cre)-mediated deletion. We show that in response to IL-4 and IL-13, Lyz2(lo)IL-4Rα(+) macrophages differentiate into an arginase 1-expressing alternatively-activated macrophage (AAM) population, which slows the development of lethal fibrosis in schistosomiasis. In contrast, we identified Lyz2(hi)IL-4Rα(+) macrophages as the key subset of AAMs mediating the downmodulation of granulomatous inflammation in chronic schistosomiasis. Our observations reveal a limitation on using a LysMCre mouse model to study gene function in inflammatory settings, but we utilize this limitation as a means to demonstrate that distinct populations of alternatively activated macrophages control inflammation and fibrosis in chronic schistosomiasis.

miR-182 and miR-10a are key regulators of Treg specialisation and stability during Schistosome and Leishmania-associated inflammation.

A diverse suite of effector immune responses provide protection against various pathogens. However, the array of effector responses must be immunologically regulated to limit pathogen- and immune-associated damage. CD4(+)Foxp3(+) regulatory T cells (Treg) calibrate immune responses; however, how Treg cells adapt to control different effector responses is unclear. To investigate the molecular mechanism of Treg diversity we used whole genome expression profiling and next generation small RNA sequencing of Treg cells isolated from type-1 or type-2 inflamed tissue following Leishmania major or Schistosoma mansoni infection, respectively. In-silico analyses identified two miRNA "regulatory hubs" miR-10a and miR-182 as critical miRNAs in Th1- or Th2-associated Treg cells, respectively. Functionally and mechanistically, in-vitro and in-vivo systems identified that an IL-12/IFNγ axis regulated miR-10a and its putative transcription factor, Creb. Importantly, reduced miR-10a in Th1-associated Treg cells was critical for Treg function and controlled a suite of genes preventing IFNγ production. In contrast, IL-4 regulated miR-182 and cMaf in Th2-associed Treg cells, which mitigated IL-2 secretion, in part through repression of IL2-promoting genes. Together, this study indicates that CD4(+)Foxp3(+) cells can be shaped by local environmental factors, which orchestrate distinct miRNA pathways preserving Treg stability and suppressor function.

Graduate Medical Education in Pathology: A Scoping Review.

CONTEXT.­: Pathologists have produced a substantial body of literature on graduate medical education (GME). However, this body of literature is diverse and has not yet been characterized. OBJECTIVE.­: To chart the concepts, research methods, and publication patterns of studies on GME in pathology. DATA SOURCES.­: This was a systematic scoping review covering all literature produced since 1980 in the PubMed and Embase databases. CONCLUSIONS.­: Research on GME in pathology is evenly dispersed across educational topics. This body of literature would benefit from research based on theory, stronger study designs, and studies that can provide evidence to support decisions on educational policies.

IL-10 blocks the development of resistance to re-infection with Schistosoma mansoni.

Despite effective chemotherapy to treat schistosome infections, re-infection rates are extremely high. Resistance to reinfection can develop, however it typically takes several years following numerous rounds of treatment and re-infection, and often develops in only a small cohort of individuals. Using a well-established and highly permissive mouse model, we investigated whether immunoregulatory mechanisms influence the development of resistance. Following Praziquantel (PZQ) treatment of S. mansoni infected mice we observed a significant and mixed anti-worm response, characterized by Th1, Th2 and Th17 responses. Despite the elevated anti-worm response in PBMC's, liver, spleen and mesenteric lymph nodes, this did not confer any protection from a secondary challenge infection. Because a significant increase in IL-10-producing CD4(+)CD44(+)CD25(+)GITR(+) lymphocytes was observed, we hypothesised that IL-10 was obstructing the development of resistance. Blockade of IL-10 combined with PZQ treatment afforded a greater than 50% reduction in parasite establishment during reinfection, compared to PZQ treatment alone, indicating that IL-10 obstructs the development of acquired resistance. Markedly enhanced Th1, Th2 and Th17 responses, worm-specific IgG1, IgG2b and IgE and circulating eosinophils characterized the protection. This study demonstrates that blocking IL-10 signalling during PZQ treatment can facilitate the development of protective immunity and provide a highly effective strategy to protect against reinfection with S. mansoni.

Markers of upper airway inflammation associated with microbial exposure and symptoms in occupants of a water-damaged building.

BACKGROUND: Water damage in buildings has been associated with reports of upper airway inflammation among occupants. METHODS: This survey included a questionnaire, allergen skin testing, nasal nitric oxide, and nasal lavage on 153 participants. We conducted exposure assessments of 297 workstations and analyzed collected dust for fungi, endotoxin, and (1 → 3)-ß-D-glucan to create floor-specific averages. RESULTS: Males had higher levels of nasal inflammatory markers, and females reported more symptoms. ECP, IL-8, and MPO were significantly associated with nasal symptoms, flu-like achiness, or chills. Fungi and glucan were positively associated with blowing out thick mucus. Endotoxin was significantly associated with ECP in overall models, and with ECP, IL-8, MPO, and neutrophils among non-atopic females. CONCLUSIONS: In this study, we documented an association between endotoxin and nasal inflammatory markers among office workers. The results of our study suggest that a non-allergic response may contribute to symptoms occurring among occupants in this water-damaged building.

Th1-driven immune reconstitution disease in Mycobacterium avium-infected mice.

Following antiretroviral therapy, a significant proportion of HIV(+) patients with mycobacterial coinfections develop a paradoxical, poorly understood inflammatory disease termed immune reconstitution inflammatory syndrome (IRIS). Here, we show that Mycobacterium avium-infected T cell-deficient mice injected with CD4 T cells also develop an immune reconstitution disease (IRD) manifesting as weight loss, impaired lung function, and rapid mortality. This form of IRD requires Ag recognition and interferonγ production by the donor CD4 T cells and correlates with marked alterations in blood and tissue CD11b(+) myeloid cells. Interestingly, disease is associated with impaired, rather than augmented, T-cell expansion and function and is not strictly dependent on lymphopenia-induced T-cell proliferation. Instead, our findings suggest that mycobacterial-associated IRIS results from a heightened sensitivity of infected lymphopenic hosts to the detrimental effects of Ag-driven CD4 T-cell responses.