Fertility desires and sexual behaviours among women recovering from genital fistula repair in Eldoret, Kenya.

OBJECTIVES: The reproductive desire of women following genital fistula repair surgery is complex, varied and often not addressed, although it carries significant consequences. The aim of this study was to better understand the fertility desires and sexual behaviours of women who recently underwent surgical repair of a genital fistula. METHODS: This is a secondary analysis of a retrospective cohort study designed to assess the effectiveness of Beyond Fistula, a reintegration programme for women recovering from genital fistula surgery in Eldoret, Kenya. One hundred women who participated in the Beyond Fistula programme between 2013 and 2019 were interviewed in person regarding future fertility desire, current sexual behaviour and contraceptive use. RESULTS: Among the 79 reproductive-aged women included in this study, 63.3% reported no future desire for pregnancy. Those that desired another pregnancy were significantly younger (48.3% were 18-29 years old vs. 66.0% were 35 years old or more, p = 0.004), had fewer living children (70% had 0-2 children vs. 56% had 3 or more children, p < 0.001), and a lower level of food insecurity (27.6% reported no to marginal insecurity vs. 14%, p = 0.014). Current sexual activity was marginally different between women who did and did not desire future pregnancy (82.8% vs. 66.0%, p = 0.053). Of the 50 women in our study who did not desire pregnancy, 62.0% were sexually active and of these, only 38.7% were preventing pregnancy. Lack of knowledge and access to methods were most commonly cited as barriers to use. CONCLUSIONS: Many women recovering from genital fistula surgery do not desire pregnancy and are sexually active but are not using a method to prevent pregnancy. The potential for post-surgical reintegration programmes to address education and access to contraception is a vital and unmet need to promote reproductive empowerment in this population of women as they reestablish their lives.

Exploring the gap between refugee-background communities' needs and existing community-based physical activity programs in Australia.

Physical activity programs run by local government, public health and not-for-profit sectors are a key public health strategy for improving rates of physical activity within local communities. However, these programs are underutilized. This is especially the case among members of refugee-background communities whose participation could have far-ranging and multilevel benefits. To explore how greater engagement among refugee-background communities with these programs could be fostered in Brisbane, Queensland, Australia, a qualitative study was undertaken from the perspectives of both community-based physical activity program providers and agencies involved in delivering services to refugee-background communities. This study involved a series of semi-structured interviews with a purposive sample of personnel from agencies that work with individuals and families from refugee-background communities and organizations that provide low-cost or no-cost physical activity programs and initiatives. Reflexive thematic analysis was used to interpret meaning from these data. Three themes relating to how participation in community-based physical activity programs could be improved among refugee-background communities were identified: improving cultural safety through intersectoral collaboration; confronting constraints imposed by the broader public health policy environment; and building capacity and empowering the community to diversify the sector. The findings highlight the importance of localized, deep-level intersectoral collaborations in bridging the gap between the health and social care needs of refugee-background communities and existing physical activity programs. However, a range of systems-produced barriers to the creation of such collaborations must be addressed to enable local actors to help mitigate and address the systemic exclusion of marginalized populations from participation in broader society.

This qualitative study explored how participation in community-based physical activity programs could be improved among refugee-background communities. To do this, community-based physical activity program providers and agencies involved in delivering services to refugee-background communities in Brisbane, Queensland, Australia, were invited to participate in a semi-structured interview. Reflexive thematic analysis was then used to identify patterns and themes within the interview data. This analysis found that the cultural safety of community-based physical activity programs needs to be improved. From participants' perspectives, a good way to do this is through genuine collaboration between services providing community-based physical activity programs and those working directly with refugee-background communities. Relatedly, however, participants experienced the broader public health policy environment as increasingly bureaucratic and market orientated, where top-down models are adopted and funding is ad hoc and insecure. This environment was identified as constraining the ability of service providers and agencies to collaborate on the level required to improve cultural safety for members of refugee-background communities. Relatedly, the analysis also identified the importance of building the capacity and empowering members of refugee-background communities for diversifying the sector and increasing the participation rates of refugee-background communities in community-based physical activity programs.

Microplastic surface retention and mobility on hiking trails.

Hiking and trail running are a source of microplastic (MP) pollution on recreational trails in wilderness and conservation areas; however, the fate of MPs deposited on trails is poorly understood as MP mobility on such surfaces has not yet been examined. In this study, we simulated heavy rainfall (100 mm/h) on trail surfaces with existing MP pollution (in situ MPs) and spiked with 99 ± 2 rubber MPs (100-940 µm). Runoff was collected for 15 min and spiked and in situ MPs were quantified. Hydrological, erosional and microplastic responses were evaluated in relation to slope, bulk density, soil moisture and surface condition indicators, including amounts and types of surface cover and soil physical attributes. The MPs were largely immobile, with 85-100% of spiked MPs retained on trail surfaces. In situ MPs were detected in the trail runoff, with the majority being polyurethane, polypropylene and polyester. Microplastic movement was primarily influenced by hydrological effects, and analysis indicated the main explanatory variable was total runoff volume, followed by soil slaking. Trail sections with at least 15% herbaceous cover or a layer of loose alluvium had higher MP retention. Areas of resource accrual may be preferentially enriched, suggesting MPs from outdoor recreation may be concentrated on and adjacent to recreational trails. Microplastics deposited on trails may have long term implications for biodiversity and ecosystem functioning in wilderness and conservation areas, particularly around the trail corridor.

Arsenic and cadmium leaching in co-contaminated agronomic soil and the influence of high rainfall and amendments.

Arsenic (As) and cadmium (Cd) co-contaminate agricultural systems worldwide and threaten water resources, food security and human health. This column leaching study examined As and Cd mobility in an acidic sandy loam Alfisol soil collected from the dry zone of Sri Lankafor four co-contaminant concentration combinations (spiked and 1 year aged As at 20 & 100 mg kg-1 with co-added Cd at 3 & 20 mg kg-1) i, and under the influence of high rainfall (RF), phosphorus fertilizer (P) and lime amendments. In almost all treatments a synergistic co-contaminant adsorption effect was evident which reduced leaching of both elements, significantly in the higher spiked soil concentration treatments. The magnitude of leaching decrease varied with treatment but was greater for As due to its weaker retention in the soil. The co-sorbing effects, evident even under RF, were attributed to electrostatic sorption interactions, the formation of ternary bridging complexes and surface precipitation at higher concentrations. Liming significantly retarded mobilisation of both elements in all treatments, whereas P enhanced As leaching but suppressed Cd leaching, and both amendments moderated co-contaminant effects. An antagonistic effect of Cd on As sorption was evident in two treatments which showed increased As leaching with added Cd: the RF low spike concentration treatment, accredited to washout of stable As-Cd soluble complexes; the P high concentration treatment considered due to P disruption of As-Cd bridging complexes. This work is important for effective risk mitigation in these widely occurring co-contaminated agronomic systems, and demonstrates a strong system effect on synergistic or antagonistic co-contaminant interactions.

Trends in Diversity Related to Gender and Race in the Surgical Specialties and Subspecialties Inclusive of Oral and Maxillofacial Surgery.

Medical training in the United States has undergone multiple evolutions and maturations. The Flexner Report and its effects, written in 1910, still has significant impact on modern professional education in the medical and dental arenas. The National Academy of Medicine (Institute of Medicine) in 2003 documented the need for diversity in the health care workforce, and the Association of American Medical Colleges additionally looked at Medical Education and health care through the lens of Academic Medicine. Both these reports reflected that health care institutions, providers, educators, students, and surgical residents are mandated to improve the health of the nation.

Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets.

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR.

Resistance to antibody-drug conjugates (ADCs) has been observed in both preclinical models and clinical studies. However, mechanisms of resistance to pyrrolobenzodiazepine (PBD)-conjugated ADCs have not been well characterized and thus, this study was designed to investigate development of resistance to PBD dimer warheads and PBD-conjugated ADCs. We established a PBD-resistant cell line, 361-PBDr, by treating human breast cancer MDA-MB-361 cells with gradually increasing concentrations of SG3199, the PBD dimer released from the PBD drug-linker tesirine. 361-PBDr cells were over 20-fold less sensitive to SG3199 compared with parental cells and were cross-resistant to other PBD warhead and ADCs conjugated with PBDs. Proteomic profiling revealed that downregulation of Schlafen family member 11 (SLFN11), a putative DNA/RNA helicase, sensitizing cancer cells to DNA-damaging agents, was associated with PBD resistance. Confirmatory studies demonstrated that siRNA knockdown of SLFN11 in multiple tumor cell lines conferred reduced sensitivity to SG3199 and PBD-conjugated ADCs. Treatment with EPZ011989, an EZH2 inhibitor, derepressed SLFN11 expression in 361-PBDr and other SLFN11-deficient tumor cells, and increased sensitivity to PBD and PBD-conjugated ADCs, indicating that the suppression of SLFN11 expression is associated with histone methylation as reported. Moreover, we demonstrated that combining an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, AZD6738, with SG3199 or PBD-based ADCs led to synergistic cytotoxicity in either resistant 361-PBDr cells or cells that SLFN11 was knocked down via siRNA. Collectively, these data provide insights into potential development of resistance to PBDs and PBD-conjugated ADCs, and more importantly, inform strategy development to overcome such resistance.

Alectinib induces marked red cell spheroacanthocytosis in a near-ubiquitous fashion and is associated with reduced eosin-5-maleimide binding.

We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered standard first-line treatment for patients with ALK-rearranged advanced non-small cell lung cancer. Ninety-five percent of patients developed marked acanthocytosis, echinocytosis and/or spheroacanthocytosis, not observable with prior treatment with other ALK-inhibitors. Anaemia developed in 73% of patients (38% <100 g/L, 8% <80 g/L), though definite new haemolysis was present in only 11%. Eosin-5-maleimide binding was reduced in all assessed patients, and increased membrane cholesterol was identified in one patient assessed with lattice light sheet microscopy. We have identified a previously undescribed phenomenon whereby alectinib induces red cell membrane abnormalities in nearly all patients through an unclear, but likely ALK-independent, mechanism, resulting in mild anaemia without universal haemolysis.

Airway Elastin is increased in severe asthma and relates to proximal wall area: histological and computed tomography findings from the U-BIOPRED severe asthma study.

BACKGROUND: Airway remodelling, which may include goblet cell hyperplasia / hypertrophy, changes in epithelial integrity, accumulation of extracellular matrix components, smooth muscle hypertrophy and thickening of the lamina reticularis, is a feature of severe asthma and contributes to the clinical phenotype. OBJECTIVE: Within the U-BIOPRED severe asthma study, we have assessed histological elements of airway remodelling and their relationship to computed tomography (CT) measures of proximal airway dimensions. METHODS: Bronchial biopsies were collected from two severe asthma groups, one non-smoker (SAn, n = 28) and one current/ex-smoker (SAs/ex, n = 13), and a mild-moderate asthma group (MMA, n = 28) classified and treated according to GINA guidelines, plus a healthy control group (HC, n = 33). Movat's pentachrome technique was used to identify mucin, elastin and total collagen in these biopsies. The number of goblet cells (mucin+) was counted as a percentage of the total number of epithelial cells and the percentage mucin epithelial area measured. The percentage area of elastic fibres and total collagen within the submucosa was also measured, and the morphology of the elastic fibres classified. Participants in the asthma groups also had a CT scan to assess large airway morphometry. RESULTS: The submucosal tissue elastin percentage was higher in both severe asthma groups (16.1% SAn, 18.9% SAs/ex) compared with the HC (9.7%) but did not differ between asthma groups. There was a positive relationship between elastin and airway wall area measured by CT (n = 18-20, rho=0.544, p = 0.024), which also related to an increase in elastic fibres with a thickened lamellar morphological appearance. Mucin epithelial area and total collagen were not different between the four groups. Due to small numbers of suitable CT scans, it was not feasible to compare airway morphometry between the asthma groups. CONCLUSION: These findings identify a link between extent of elastin deposition and airway wall thickening in severe asthma.

Chemically Defined, High-Density Insect Cell-Based Expression System for Scalable AAV Vector Production.

The recombinant adeno-associated virus (AAV) vector is one of the most utilized viral vectors in gene therapy due to its robust, long-term in vivo transgene expression and low toxicity. One major hurdle for clinical AAV applications is large-scale manufacturing. In this regard, the baculovirus-based AAV production system is highly attractive due to its scalability and predictable biosafety. Here, we describe a simple method to improve the baculovirus-based AAV production using the ExpiSf Baculovirus Expression System with a chemically defined medium for suspension culture of high-density ExpiSf9 cells. Baculovirus-infected ExpiSf9 cells produced up to 5 × 1011 genome copies of highly purified AAV vectors per 1 mL of suspension culture, which is up to a 19-fold higher yield than the titers we obtained from the conventional Sf9 cell-based system. When mice were administered the same dose of AAV vectors, we saw comparable transduction efficiency and biodistributions between the vectors made in ExpiSf9 and Sf9 cells. Thus, the ExpiSf Baculovirus Expression System would support facile and scalable AAV manufacturing amenable for preclinical and clinical applications.

Development and validation of a multiplex immunoassay for the simultaneous quantification of type-specific IgG antibodies to E6/E7 oncoproteins of HPV16 and HPV18.

More than 170 types of human papilloma viruses (HPV) exist with many causing proliferative diseases linked to malignancy in indications such as cervical cancer and head and neck squamous cell carcinoma. Characterization of antibody levels toward HPV serology is challenging due to complex biology of oncoproteins, pre-existing titers to multiple HPV types, cross-reactivity, and low affinity, polyclonal responses. Using multiplex technology from MSD, we have developed an assay that simultaneously characterizes antibodies against E6 and E7 oncoproteins of HPV16 and 18, the primary drivers of HPV-associated oncogenesis. We fusion tagged our E6 and E7 proteins with MBP via two-step purification, spot-printed an optimized concentration of protein into wells of MSD 96-well plates, and assayed various cynomolgus monkey, human and HPV+ cervical cancer patient serum to validate the assay. The dynamic range of the assay covered 4-orders of magnitude and antibodies were detected in serum at a dilution up to 100,000-fold. The assay was very precise (n = 5 assay runs) with median CV of human serum samples ~ 5.3% and inter-run variability of 11.4%. The multiplex serology method has strong cross-reactivity between E6 oncoproteins from human serum samples as HPV18 E6 antigens neutralized 5 of 6 serum samples as strongly as HPV16 E6. Moderate concordance (Spearman's Rank = 0.775) was found between antibody responses against HPV16 E7 in the multiplex assay compared to standard ELISA serology methods. These results demonstrate the development of a high-throughput, multi-plex assay that requires lower sample quantity input with greater dynamic range to detect type-specific anti-HPV concentrations to E6 and E7 oncoproteins of HPV16 and 18.

IL-17-high asthma with features of a psoriasis immunophenotype.

BACKGROUND: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. OBJECTIVE: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. METHODS: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17-high and IL-13-high asthma phenotypes. RESULTS: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17-high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and ß-defensin. CONCLUSION: The IL-17-high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP-10 and MET.

BACKGROUND: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. METHODS: We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. RESULTS: Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. CONCLUSION: Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.

Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.

BACKGROUND: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. OBJECTIVE: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. METHODS: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. RESULTS: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1ß, IL-8, and IL-1ß. CONCLUSIONS: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.

A Disintegrin and A Metalloproteinase-9 (ADAM9): A Novel Proteinase Culprit with Multifarious Contributions to COPD.

INTRODUCTION: Proteinases with a disintegrin and a metalloproteinase domain (ADAMs) have not been well studied in COPD. We investigated whether ADAM9 is linked to COPD in humans and mice. METHODS: ADAM9 blood and lung levels were measured in COPD patients versus controls, and air- versus cigarette smoke (CS)-exposed wild-type (WT) mice. WT and Adam9-/- mice were exposed to air or CS for 1-6 months, and COPD-like lung pathologies were measured. RESULTS: ADAM9 staining was increased in lung epithelial cells and macrophages in smokers and even more so in COPD patients and correlated directly with pack-year smoking history and inversely with airflow obstruction and/or FEV1 % predicted. Bronchial epithelial cell ADAM9 mRNA levels were higher in COPD patients than controls and correlated directly with pack-year smoking history. Plasma, BALF and sputum ADAM9 levels were similar in COPD patients and controls. CS exposure increased Adam9 levels in WT murine lungs. Adam9-/- mice were protected from emphysema development, small airway fibrosis, and airway mucus metaplasia. CS-exposed Adam9-/- mice had reduced lung macrophage counts, alveolar septal cell apoptosis, lung elastin degradation, and shedding of VEGFR2 and EGFR in BALF samples. Recombinant ADAM9 sheds EGF and VEGF receptors from epithelial cells to reduce activation of the Akt pro-survival pathway and increase cellular apoptosis. CONCLUSIONS: ADAM9 levels are increased in COPD lungs and linked to key clinical variables. Adam9 promotes emphysema development, and large and small airway disease in mice. Inhibition of ADAM9 could be a therapeutic approach for multiple COPD phenotypes.

Fewer thromboembolic events after implementation of a venous thromboembolism risk stratification tool.

BACKGROUND: Deep venous thrombosis and pulmonary embolus are leading preventable causes of death after surgery. Venous thromboembolism (VTE) prophylaxis management guidelines, with evidenced-based recommendations, are available in the literature. However, over 40% of "at-risk" surgical patients fail to receive appropriate VTE prophylaxis. Decision support-based interventions to reduce venous thromboembolic events were explored. METHODS: A venous thromboembolic risk stratification tool embedded in the electronic medical record, Epic, linking risk category to venous thromboembolic prophylaxis order sets was created, implemented, and analyzed for general surgery patients. Logistic regression analysis was used to compare rates of venous thromboembolic events before and after the intervention, controlling for age, gender, race, body mass index, inpatient status, transfer status, elective/emergent case status, American Society of Anesthesiologists classification, and wound classification. RESULTS: Venous thromboembolic events in the preintervention and postintervention periods were 55 (1.25%) and 12 (0.64%), respectively (P = 0.033). All-cause mortality events decreased after intervention from 49 (1.12%) to 14 (0.75%; P = 0.187). Multivariable analyses show that the risk of a venous thromboembolic event after intervention was half (odds ratio = 0.532; 95% confidence interval, 0.284-0.997; P = 0.049) as likely compared to that in the preintervention period. From 2012 to 2015, our institution moved from the ninth decile (poor) to the first decile (best) for the incidence of venous thromboembolic events among 760 National Surgical Quality Improvement Program hospitals across the nation. CONCLUSIONS: Postoperative thromboembolic events decreased after implementation of a VTE risk stratification tool, linking risk category to venous thromboembolic prophylaxis order sets, embedded in the electronic medical record, Epic.

CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in TB granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells.