Serum Amyloid A Proteins Induce Pathogenic Th17 Cells and Promote Inflammatory Disease.

Lymphoid cells that produce interleukin (IL)-17 cytokines protect barrier tissues from pathogenic microbes but are also prominent effectors of inflammation and autoimmune disease. T helper 17 (Th17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naive CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, Th17 cell behaviors vary markedly according to their environment. Here, we show that SAAs additionally direct a pathogenic pro-inflammatory Th17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting Th17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.

Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element.

T helper 17 (Th17) cells regulate mucosal barrier defenses but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been elucidated, the transcriptional programs that sustain Th17 cells in vivo remain obscure. The transcription factor RORγt is critical for Th17 cell differentiation; however, it is not clear whether the closely related RORα, which is co-expressed in Th17 cells, has a distinct role. Here, we demonstrated that although dispensable for Th17 cell differentiation, RORα was necessary for optimal Th17 responses in peripheral tissues. The absence of RORα in T cells led to reductions in both RORγt expression and effector function among Th17 cells. Cooperative binding of RORα and RORγt to a previously unidentified Rorc cis-regulatory element was essential for Th17 lineage maintenance in vivo. These data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program.

Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy.

Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4+ T cells in these mice revealed impaired CD4+ T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident RORγT+FOXP3+ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT+FOXP3+ Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how RORγT+FOXP3+ Treg cells can regulate intestinal immunity while leaving systemic responses intact.

An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses.

RORγt(+) Th17 cells are important for mucosal defenses but also contribute to autoimmune disease. They accumulate in the intestine in response to microbiota and produce IL-17 cytokines. Segmented filamentous bacteria (SFB) are Th17-inducing commensals that potentiate autoimmunity in mice. RORγt(+) T cells were induced in mesenteric lymph nodes early after SFB colonization and distributed across different segments of the gastrointestinal tract. However, robust IL-17A production was restricted to the ileum, where SFB makes direct contact with the epithelium and induces serum amyloid A proteins 1 and 2 (SAA1/2), which promote local IL-17A expression in RORγt(+) T cells. We identified an SFB-dependent role of type 3 innate lymphoid cells (ILC3), which secreted IL-22 that induced epithelial SAA production in a Stat3-dependent manner. This highlights the critical role of tissue microenvironment in activating effector functions of committed Th17 cells, which may have important implications for how these cells contribute to inflammatory disease.

Characterization of Transcriptional Regulatory Networks that Promote and Restrict Identities and Functions of Intestinal Innate Lymphoid Cells.

Innate lymphoid cells (ILCs) promote tissue homeostasis and immune defense but also contribute to inflammatory diseases. ILCs exhibit phenotypic and functional plasticity in response to environmental stimuli, yet the transcriptional regulatory networks (TRNs) that control ILC function are largely unknown. Here, we integrate gene expression and chromatin accessibility data to infer regulatory interactions between transcription factors (TFs) and genes within intestinal type 1, 2, and 3 ILC subsets. We predicted the "core" TFs driving ILC identities, organized TFs into cooperative modules controlling distinct gene programs, and validated roles for c-MAF and BCL6 as regulators affecting type 1 and type 3 ILC lineages. The ILC network revealed alternative-lineage-gene repression, a mechanism that may contribute to reported plasticity between ILC subsets. By connecting TFs to genes, the TRNs suggest means to selectively regulate ILC effector functions, while our network approach is broadly applicable to identifying regulators in other in vivo cell populations.

Intestinal Helminth Infection Impairs Oral and Parenteral Vaccine Efficacy.

The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminth Heligmosomoides polygyrus bakeri alters Ag-specific Ab and cellular immune responses to oral and parenteral vaccination in mice. Oral vaccination of mice with a clinically relevant, live, attenuated, recombinant Salmonella vaccine expressing chicken egg OVA (Salmonella-OVA) induced the accumulation of activated, OVA-specific T effector cells rather than OVA-specific regulatory T cells in the GALT. Intestinal helminth infection significantly reduced Th1-skewed Ab responses to oral vaccination with Salmonella-OVA. Activated, adoptively transferred, OVA-specific CD4+ T cells accumulated in draining mesenteric lymph nodes of vaccinated mice, regardless of their helminth infection status. However, helminth infection increased the frequencies of adoptively transferred OVA-specific CD4+ T cells producing IL-4 and IL-10 in the mesenteric lymph node. Ab responses to the oral Salmonella-OVA vaccine were reduced in helminth-free mice adoptively transferred with OVA-specific CD4+ T cells harvested from mice with intestinal helminth infection. Intestinal helminth infection also significantly reduced Th2-skewed Ab responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest that vaccine-specific CD4+ T cells induced in the context of helminth infection retain durable immunomodulatory properties and may promote blunted Ab responses to vaccination. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas.

Mapping HIV prevalence in sub-Saharan Africa between 2000 and 2017.

HIV/AIDS is a leading cause of disease burden in sub-Saharan Africa. Existing evidence has demonstrated that there is substantial local variation in the prevalence of HIV; however, subnational variation has not been investigated at a high spatial resolution across the continent. Here we explore within-country variation at a 5 × 5-km resolution in sub-Saharan Africa by estimating the prevalence of HIV among adults (aged 15-49 years) and the corresponding number of people living with HIV from 2000 to 2017. Our analysis reveals substantial within-country variation in the prevalence of HIV throughout sub-Saharan Africa and local differences in both the direction and rate of change in HIV prevalence between 2000 and 2017, highlighting the degree to which important local differences are masked when examining trends at the country level. These fine-scale estimates of HIV prevalence across space and time provide an important tool for precisely targeting the interventions that are necessary to bringing HIV infections under control in sub-Saharan Africa.

Retraction Note: DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.

Change History: This Article has been retracted; see accompanying Retraction. Corrected online 20 January: In this Article, author Frank Rigo was incorrectly listed with a middle initial; this has been corrected in the online versions of the paper.

Exploring factors influencing implementation of interprofessional education in undergraduate healthcare programmes: a multiple-case study.

Interprofessional education (IPE) can help prepare future graduates to work collaboratively in healthcare teams. Using a multiple-case study approach, we explored IPE across four United Kingdom (UK) Higher Education Institutions (HEIs) to identify factors affecting IPE implementation and outcomes. For each site, educators involved with IPE were surveyed and interviewed to explore IPE implementation. To examine outcomes, students took part in focus groups and accreditation reports published by professional regulators were explored. A total of five IPE courses were surveyed, six IPE leads were interviewed, three focus groups were conducted with students, and sixteen reports were reviewed. Regulators' standards mandating IPE and directives by the Deans were the main triggers for IPE initiation. In sites where the regulator's standards were perceived by educators as non-mandating IPE, some staff were less inclined to engage with IPE initiation, which adversely affected IPE planning and delivery. Students from such sites were less satisfied with their IPE experiences and uncertain about the purpose of IPE. Senior management (i.e. Dean) commitment and support is needed to establish IPE initiatives across the institution and cultivate a collaborative culture. The presence of a collaborative culture was associated with positive feedback from regulators and students regarding IPE.

Variable Accessibility to Consumer Pricing Among Breast Cancer Operations.

BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) mandate that every US hospital provide public online pricing information for services rendered. This allows patients to compare prices across hospital systems before establishing care. The goal of this project was to evaluate hospital compliance and patient-level accessibility to price transparency for common breast cancer surgical procedures. METHODS: A sample case of a 62-year-old female with a T2N0 breast cancer was chosen. The patient would have the option of undergoing a partial mastectomy or mastectomy, both with sentinel lymph node biopsy (SLNB). Eight Massachusetts academic medical centers were evaluated. Searches were performed by authors for each hospital system and procedure using the sample case. RESULTS: Every hospital had a cost calculator on its website. The average success rate of establishing a cost for partial mastectomy, mastectomy, and SLNB was 58, 35, and 25%, respectively. The median time to reach the cost calculator tool was 32 s (range 25-37 s). In successful attempts, the median pre-insurance estimated cost of a partial mastectomy was $16,509 (range $11,776-22,169), compared with $24,541 (range $16,921-25,543) for mastectomy and $12,342 (range $4034-20,644) for SLNB. SLNB costs varied significantly across hospitals (p = 0.025), but no statistically significant difference was observed for partial mastectomy or mastectomy. CONCLUSION: Despite new regulatory requirements by CMS for increased price transparency for surgical procedures, our results demonstrate poor success rates in obtaining cost estimates and significant variability of reported hospital charges. Further efforts to improve the quality of hospital cost estimate calculators are necessary for informed decision-making for patients with breast cancer.

The Impact of Income and Social Mobility on Colorectal Cancer Outcomes and Treatment: A Cross-sectional Study.

OBJECTIVE: To determine the impact of income mobility on racial disparities in colorectal cancer. BACKGROUND: There are well-documented disparities in colorectal cancer treatment and outcomes between Black and White patients. Socioeconomic status, insurance, and other patient-level factors have been shown important, but little has been done to show the discriminatory factors that lead to these outcomes. METHODS: Data were obtained from the Surveillance Epidemiology and End-Results database for Black and White patients with colorectal cancer between 2005 and 2015. County level measures of Black (BIM) and White income mobility (WIM) were obtained from the Opportunity Atlas as a measure of intergenerational poverty and social mobility. Regression models were created to assess the relative risk of advanced stage at diagnosis (Stage IV), surgery for localized disease (Stage I/II), and cancer-specific mortality. RESULTS: There was no significant association of BIM or WIM on advanced stage at diagnosis in Black or White patients. An increase of $10,000 of BIM was associated with a 9% decrease in hazards of death for both Black (hazard ratio 0.91, 95% confidence interval 0.86,0.95) and White (0.91, 95%CI 0.90,0.93) patients, while the same increase in WIM was associated with no significant difference in hazards among Black patients (hazard ratio 0.99, 95% confidence interval 0.97,1.02). There were no predicted racial differences in hazards of death at high levels of BIM. CONCLUSIONS: Increased Black income mobility significantly improves survival for both Black and White patients. Interventions aimed at increasing economic and social mobility could significantly decrease mortality in both Black and White patients while alleviating disparities in outcomes.

Leveraging chromatin accessibility for transcriptional regulatory network inference in T Helper 17 Cells.

Transcriptional regulatory networks (TRNs) provide insight into cellular behavior by describing interactions between transcription factors (TFs) and their gene targets. The assay for transposase-accessible chromatin (ATAC)-seq, coupled with TF motif analysis, provides indirect evidence of chromatin binding for hundreds of TFs genome-wide. Here, we propose methods for TRN inference in a mammalian setting, using ATAC-seq data to improve gene expression modeling. We test our methods in the context of T Helper Cell Type 17 (Th17) differentiation, generating new ATAC-seq data to complement existing Th17 genomic resources. In this resource-rich mammalian setting, our extensive benchmarking provides quantitative, genome-scale evaluation of TRN inference, combining ATAC-seq and RNA-seq data. We refine and extend our previous Th17 TRN, using our new TRN inference methods to integrate all Th17 data (gene expression, ATAC-seq, TF knockouts, and ChIP-seq). We highlight newly discovered roles for individual TFs and groups of TFs ("TF-TF modules") in Th17 gene regulation. Given the popularity of ATAC-seq, which provides high-resolution with low sample input requirements, we anticipate that our methods will improve TRN inference in new mammalian systems, especially in vivo, for cells directly from humans and animal models.

COVID-19 Self-Test Data: Challenges and Opportunities - United States, October 31, 2021-June 11, 2022.

Self-tests* to detect current infection with SARS-CoV-2, the virus that causes COVID-19, are valuable tools that guide individual decision-making and risk reduction† (1-3). Increased self-test use (4) has likely contributed to underascertainment of COVID-19 cases (5-7), because unlike the requirements to report results of laboratory-based and health care provider-administered point-of-care COVID-19 tests,§ public health authorities do not require reporting of self-test results. However, self-test instructions include a recommendation that users report results to their health care provider so that they can receive additional testing and treatment if clinically indicated.¶ In addition, multiple manufacturers of COVID-19 self-tests have developed websites or companion mobile applications for users to voluntarily report self-test result data. Federal agencies use the data reported to manufacturers, in combination with manufacturing supply chain information, to better understand self-test availability and use. This report summarizes data voluntarily reported by users of 10.7 million self-tests from four manufacturers during October 31, 2021-June 11, 2022, and compares these self-test data with data received by CDC for 361.9 million laboratory-based and point-of-care tests performed during the same period. Overall trends in reporting volume and percentage of positive results, as well as completeness of reporting demographic variables, were similar across test types. However, the limited amount and quality of data reported from self-tests currently reduces their capacity to augment existing surveillance. Self-tests provide important risk-reduction information to users, and continued development of infrastructure and methods to collect and analyze data from self-tests could improve their use for surveillance during public health emergencies.

Exploration of changes in health-related behaviours among Saudi Arabian undergraduates in the UK.

This project is an exploratory survey of the ways in which living in the UK has affected the health-related behaviours of Saudi Arabian undergraduate students. The study identifies changes in exercise behaviours, dietary and smoking habits and experiences of stress after their move to the UK. In addition, it identifies what the students perceive to be the drivers of these changes. To achieve this, an online questionnaire was developed collecting quantitative data. This was distributed via Facebook groups specifically for Saudi students in the UK. The results demonstrate that a majority of Saudi Arabian undergraduates felt that their behaviours had become healthier since their move to the UK, mainly as a result of a more active lifestyle, derived from reduced reliance on cars, increased daily walking, and a heightened focus on health promoted by their independence, the availability of healthy foods and exposure to a more health-promoting culture. Although these results are based on a relatively small sample, they are surprising since they contradict previous studies on international students, which have generally found negative lifestyle changes during their studies, including increased stress, poorer dietary habits and a decline in physical activity. Although the exploratory nature of the study means that concrete recommendations cannot be made, it nonetheless offers an impetus for further research into how Saudi Arabian students may be encouraged to adopt healthier lifestyles while studying in the UK.

The Impact of Racial Residential Segregation on Colorectal Cancer Outcomes and Treatment.

OBJECTIVE: We sought to examine the impact of racial residential segregation on Black-White disparities in colorectal cancer diagnosis, surgical resection, and cancer-specific survival. SUMMARY BACKGROUND DATA: There are clear Black-White disparities in colorectal cancer diagnosis and treatment with equally disparate explanations for these findings, including genetics, socioeconomic factors, and health behaviors. METHODS: Data on Black and White patients with colorectal cancer were obtained from SEER between 2005 and 2015. The exposure of interest was the index of dissimilarity (IoD), a validated measure of segregation derived from 2010 Census data. Outcomes included advanced stage at diagnosis (AJCC stage IV), resection of localized disease (AJCC stage I-II), and cancer-specific survival. We used Poisson regression with robust error variance for the outcomes of interest and Cox proportional hazards were used to assess cancer-specific 5-year survival. RESULTS: Black patients had a 41% increased risk of presenting at advanced stage per IoD [risk ratio (RR) 1.41, 95% confidence intervals (CI) 1.18, 1.69] and White patients saw a 17% increase (RR 1.17, 95%CI 1.04, 1.31). Black patients were 5% less likely to undergo surgical resection (RR 0.95, 95%CI 0.90, 0.99), whereas Whites were 5% more likely (RR 1.05, 95%CI 1.03, 1.07). Black patients had 43% increased hazards of cancer-specific mortality with increasing IoD (hazard ratio (HR) 1.43, 95%CI 1.17, 1.74). CONCLUSIONS: Black patients with colorectal cancer living in more segregated counties are significantly more likely to present at advanced stage and have worse cancer-specific survival. Enduring structural racism in the form of residential segregation has strong impacts on the colorectal cancer outcomes.

DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions.

T helper 17 (TH17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORγt, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORγt partner that coordinates transcription of selective TH17 genes, and is required for TH17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORγt and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5-RORγt interaction and RORγt target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORγt complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in TH17-dependent diseases.

Minimally Invasive Management of Diverticular Disease.

Traditionally, management of complicated diverticular disease has involved open damage control operations with large definitive resections and colostomies. Studies are now showing that in a subset of patients who would typically have undergone an open Hartmann's procedure for Hinchey III/IV diverticulitis, a laparoscopic approach is equally safe, and has better outcomes. Similar patients may be good candidates for primary anastomosis to avoid the morbidity and subsequent reversal of a colostomy. While most operations for diverticulitis across the country are still performed open, there has been an incremental shift in practice toward minimally invasive approaches in the elective setting. The most recent data from large trials, most notably the SIGMA trial, found laparoscopic sigmoid colectomy is associated with fewer short-term and long-term complications, decreased pain, improvement in length of stay, and maintains better cost-effectiveness than open resections. Some studies even demonstrate that robotic sigmoid resections can maintain a similar if not more reduction in morbidity as the laparoscopic approach while still remaining cost-effective. Intraoperative approaches also factor into improving outcomes. One of the most feared complications in colorectal surgery is anastomotic leak, and many studies have sought to find ways to minimize this risk. Factors to consider to minimize incidence of leak are the creation of tension-free anastomoses, amount of contamination, adequacy of blood supply, and a patient's use of steroids. Techniques supported by data that decrease anastomotic leaks include preoperative oral antibiotic and mechanical bowel prep, intraoperative splenic flexure mobilization, low-tie ligation of the inferior mesenteric artery, and use of indocyanine green immunofluorescence to assess perfusion. In summary, the management of benign diverticular disease is shifting from open, morbid operations for a very common disease to a minimally invasive approach. In this article, we review those approaches shown to have better outcomes, greater patient satisfaction, and fewer complications.

The role of retinoic acid in tolerance and immunity.

Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology.