Targeting STING oligomerization with small-molecule inhibitors.

Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. dsDNA activates cGAS to generate cGAMP, which binds and activates STING triggering a conformational change, oligomerization, and the IRF3- and NFκB-dependent transcription of type I Interferons (IFNs) and inflammatory cytokines, as well as the activation of autophagy. Aberrant activation of STING is now linked to a growing number of both rare as well as common chronic inflammatory diseases. Here, we identify and characterize a potent small-molecule inhibitor of STING. This compound, BB-Cl-amidine inhibits STING signaling and production of type I IFNs, IFN-stimulated genes (ISGs) and NFκB-dependent cytokines, but not other pattern recognition receptors. In vivo, BB-Cl-amidine alleviated pathology resulting from accrual of cytosolic DNA in Trex-1 mutant mice. Mechanistically BB-Cl-amidine inhibited STING oligomerization through modification of Cys148. Collectively, our work uncovers an approach to inhibit STING activation and highlights the potential of this strategy for the treatment of STING-driven inflammatory diseases.

Report card on access to rural health care in Canada.

INTRODUCTION: Canadians living in rural communities continue to experience challenges in accessing rural health care. The Rural Road Map for Action (RRM) was developed in February 2017 and provides a guiding framework for a coordinated, pan-Canadian approach to physician rural work force planning and improved access to rural health care. METHODS: The Rural Road Map Implementation Committee (RRMIC) was formed in February 2018 to support the implementation of the RRM. The RRMIC was co-sponsored by the College of Family Physicians of Canada and the Society of Rural Physicians of Canada and had a broad membership that deliberately crossed sectors supporting the RRM's social accountability vision. RESULTS: In April 2021, the \"Rural Road Map: Report Card on Access to HealthCare in Rural Canada\" was discussed at a Society of Rural Physicians of Canada national forum. Next steps included: focusing on equitable access to rural health care service delivery; enhancing rural physician resource planning including national medical licensure and the adoption of more effective strategies for rural physician recruitment and retention; improving access to rural specialty care; supporting the work of the National Consortium on Indigenous Medical Education; and developing metrics as useful tools to facilitate change in rural health care, social accountability in medical education and provisions for supporting the delivery of virtual health care. DISCUSSION: Collaborative partnerships and commitments from all key stakeholders will be critical to addressing national and regional health work force needs. No one sector alone can fix the inequitable health care realities of people living in rural communities in Canada.

Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling molecules.

Hepatocyte nuclear factor 4 α (HNF4A) is a highly conserved nuclear receptor that has been associated with ulcerative colitis. In mice, HNF4A is indispensable for the maintenance of intestinal homeostasis, yet the underlying mechanisms are poorly characterized. Here, we demonstrate that the expression of HNF4A in intestinal epithelial cells (IECs) is required for the proper development and composition of the intraepithelial lymphocyte (IEL) compartment. HNF4A directly regulates expression of immune signaling molecules including butyrophilin-like (Btnl) 1, Btnl6, H2-T3, and Clec2e that control IEC-IEL crosstalk. HNF4A selectively enhances the expansion of natural IELs that are TCRγδ+ or TCRαß+CD8αα+ to shape the composition of IEL compartment. In the small intestine, HNF4A cooperates with its paralog HNF4G, to drive expression of immune signaling molecules. Moreover, the HNF4A-BTNL regulatory axis is conserved in human IECs. Collectively, these findings underscore the importance of HNF4A as a conserved transcription factor controlling IEC-IEL crosstalk and suggest that HNF4A maintains intestinal homeostasis through regulation of the IEL compartment.

Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells.

Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. We sought to delineate the functional role of STING in intestinal inflammation. Increased STING expression was a feature of intestinal inflammation in mice with colitis and in humans afflicted with inflammatory bowel disease. Mice bearing an allele rendering STING constitutively active exhibited spontaneous colitis and dysbiosis, as well as progressive chronic intestinal inflammation and fibrosis. Bone marrow chimera experiments revealed STING accumulation in intestinal macrophages and monocytes as the initial driver of inflammation. Depletion of Gram-negative bacteria prevented STING accumulation in these cells and alleviated intestinal inflammation. STING accumulation occurred at the protein rather than transcript level, suggesting post-translational stabilization. We found that STING was ubiquitinated in myeloid cells, and this K63-linked ubiquitination could be elicited by bacterial products, including cyclic di-GMP. Our findings suggest a positive feedback loop wherein dysbiosis foments the accumulation of STING in intestinal myeloid cells, driving intestinal inflammation.

Succination inactivates gasdermin D and blocks pyroptosis.

Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.

Team-Based Intervention to Reduce the Impact of Nonactionable Alarms in an Adult Intensive Care Unit.

BACKGROUND: Nonactionable alarms comprise over 70% of alarms and contribute a threat to patient safety. Few studies have reported approaches to translate and sustain these interventions in clinical settings. PURPOSE: This study tested whether an interprofessional team-based approach can translate and implement effective alarm reduction interventions in the adult intensive care unit. METHODS: The study was a prospective, cohort, pre- and postdesign with repeated measures at baseline (preintervention) and post-phase I and II intervention periods. The settings for the most prevalent nonactionable arrhythmia and bedside parameter alarms were adjusted during phases I and II, respectively. RESULTS: The number of total alarms was reduced by 40% over a 14-day period after both intervention phases were implemented. The most prevalent nonactionable parameter alarms decreased by 47% and arrhythmia alarms decreased by 46%. CONCLUSIONS: It is feasible to translate and sustain system-level alarm management interventions addressing alarm fatigue using an interprofessional team-based approach.

Satellite-based time-series of sea-surface temperature since 1981 for climate applications.

A climate data record of global sea surface temperature (SST) spanning 1981-2016 has been developed from 4 × 1012 satellite measurements of thermal infra-red radiance. The spatial area represented by pixel SST estimates is between 1 km2 and 45 km2. The mean density of good-quality observations is 13 km-2 yr-1. SST uncertainty is evaluated per datum, the median uncertainty for pixel SSTs being 0.18 K. Multi-annual observational stability relative to drifting buoy measurements is within 0.003 K yr-1 of zero with high confidence, despite maximal independence from in situ SSTs over the latter two decades of the record. Data are provided at native resolution, gridded at 0.05° latitude-longitude resolution (individual sensors), and aggregated and gap-filled on a daily 0.05° grid. Skin SSTs, depth-adjusted SSTs de-aliased with respect to the diurnal cycle, and SST anomalies are provided. Target applications of the dataset include: climate and ocean model evaluation; quantification of marine change and variability (including marine heatwaves); climate and ocean-atmosphere processes; and specific applications in ocean ecology, oceanography and geophysics.

Experiences of parenting and clinical intervention for mothers affected by personality disorder: a pilot qualitative study combining parent and clinician perspectives.

BACKGROUND: Evidence-based parenting programmes are recommended for the treatment of child mental health difficulties. Families with complex psychosocial needs show poorer retention and outcomes when participating in standard parenting programmes. The Helping Families Programme (HFP) is a 16-week community-based parenting intervention designed to meet the needs of these families, including families with parental personality disorder. This study aimed to explore the help seeking and participatory experiences of parents with a diagnosis of personality disorder. It further aimed to examine the acceptability of referral and intervention processes for the HFP from the perspectives of (i) clinicians referring into the programme; and (ii) referred parents. METHOD: Semi-structured interviews were conducted with parents recruited to receive HFP (n = 5) as part of a research case series and the referring NHS child and adolescent mental health service (CAMHS) clinicians (n = 5). Transcripts were analysed using Interpretive Phenomenological Analysis. RESULTS: Four themes were identified for parents: (i) the experience of parenthood, (ii) being a parent affected by personality disorder, (iii) experience of the intervention, and (iv) qualities of helping. Three themes emerged for clinicians: (i) challenges of addressing parental need, (ii) experience of engaging parents with personality disorders and (iii) limited involvement during HFP. Comparison of parent and clinician themes led to the identification of two key interlinked themes: (i) concerns prior to receiving the intervention, and (ii) the challenges of working together without a mutual understanding. CONCLUSIONS: This pilot study identifies potentially significant challenges of working with parents affected by personality disorder and engaging them in HFP and other similar interventions. Results have important wider clinical implications by highlighting potential barriers to engagement and participation and providing insights on how these barriers might be overcome. Findings have been used to inform the referral and intervention processes of a pilot RCT and further intervention development.

Lifestyle, attitudes and needs of uncured XDR-TB patients living in the communities of South Africa: a qualitative study.

OBJECTIVE: Patient-level data are required to inform strategies interrupting transmission and default in patients with extensively drug-resistant TB (XDR-TB) to improve models of care and identify potential routes of transmission. We therefore explored the experiences, lifestyle, attitudes and needs of patients with uncured XDR-TB, who failed or interrupted therapy, living without treatment in the community. METHODS: We conducted in-depth interviews with 12 community-based patients from South Africa. Family members were interviewed when patients were unavailable. Interviews were analysed using inductive thematic analysis. RESULTS: The thematic experiences identified from the interviews were as follows: (i) living with but not being cured of XDR-TB, (ii) altered lifestyle in the community, (iii) experiences with community health care, (iv) local community members, and (v) wants and needs. Patients identified mistrust in health care, futility of treatment regimens, a need for a purpose in life and subsistence as major concerns. Restriction of living in the community for patients whose treatment had failed resulted in self-imposed isolation. Defaulters focused more on the never-ending drug regimen and bad experiences with health care contributing to non-adherence. Family members emphasised an under-recognised experience of unforeseen burden, obligation, worry and discomfort. Lack of knowledge and lack of concern about transmission was evident. CONCLUSION: Current models of care are not adequately meeting the needs of patients with uncured XDR-TB and relatives. These data inform the need for community-based palliative care, vocational facilities to improve economic opportunities, home-based infection control and improved psychosocial support to increase patient adherence, reduce transmission, provide income and relieve the burden on family members.

Male and non-English-speaking patients with fracture have poorer knowledge of osteoporosis.

BACKGROUND: Prior fracture is a strong independent risk factor for subsequent fracture. To date, few studies have examined the level of osteoporosis knowledge specifically in the population of patients who have sustained a fracture. This study was designed to assess the knowledge of osteoporosis among patients who sustained a fracture and who were forty years of age or older, as well as to identify what social factors and health and fracture characteristics determine the level of osteoporosis knowledge in this population. METHODS: Patients who had sustained a fracture and were attending fracture clinics at two Toronto hospitals were identified and invited to fill out a questionnaire during their visit. This questionnaire included questions that could be answered by checking "true," "false," or "don't know" and that were designed to assess the patient's knowledge of osteoporosis. The questionnaire also included questions about the respondent's background. RESULTS: Of 259 patients identified as eligible for the study, 204 (78.8%) agreed to participate. The mean number of correct responses was 16.5 (55%) out of thirty responses. Variables significantly associated with greater numbers of correct responses were female sex, English as a first language, being currently employed, exercising regularly, and having received information from a health-care provider or from a newspaper or magazine. CONCLUSIONS: The level of osteoporosis knowledge was fairly low among the surveyed patients, indicating that more education is needed. This study also highlighted certain characteristics (i.e., male sex, English as a second language, being unemployed, and not exercising) that are associated with a lower level of knowledge. Our results can help target certain groups for osteoporosis educational initiatives, especially ethnic groups whose first language is not English, so as to appropriately reduce the risk of future fractures in this high-risk population.

Factors associated with hypertension awareness, treatment, and control in Dallas County, Texas.

BACKGROUND: Hypertension (HTN) control rates in the United States remain lower in black than white persons, particularly before 65 years of age. Potential sociocultural factors have not been sufficiently addressed. METHODS: We analyzed data from structured interviews and blood pressure measurements in a population-based sample of 1514 hypertensive (1194 non-Hispanic black and 320 non-Hispanic white) subjects aged 18 to 64 years in Dallas County, Texas, from 2000 to 2002 to identify sociocultural factors associated with low rates of HTN control. We calculated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) using multivariate logistic regression. RESULTS: Awareness, treatment, and control of HTN were negatively associated with a common perception of good health, with aORs (95% CIs) of 0.37 (0.27-0.50) for awareness, 0.47 (0.36-0.62) for treatment, and 0.66 (0.51-0.86) for control. They were positively associated with having a regular physician, with aORs (95% CIs) of 3.81 (2.86-5.07) for awareness, 8.36 (5.95-11.74) for treatment, and 5.23 (3.30-8.29) for control. Among untreated hypertensive subjects, lack of perceived need for a regular physician was associated with perceived good health (aOR [95% CI], 2.2 [1.2-4.0]), male gender (aOR [95% CI], 2.4 [1.4-4.1]), and black race/ethnicity (aOR [95% CI], 2.1 [1.0-4.4]). The HTN outcomes were unrelated to perceived racism or lay beliefs about the causes, consequences, and treatment of HTN. CONCLUSIONS: Among young to middle-aged hypertensive subjects, a perception of good health and the lack of perceived need for a regular physician remain major factors associated with untreated and uncontrolled HTN at the community level-particularly among black men. These factors merit greater emphasis in professional education and public health programs on HTN.

Barbershops as hypertension detection, referral, and follow-up centers for black men.

Barbershops constitute potential sites for community health promotion programs targeting hypertension (HTN) in black men, but such programs have not been evaluated previously. Here we conducted 2 nonrandomized feasibility studies to determine whether an enhanced intervention program of continuous blood pressure (BP) monitoring and peer-based health messaging in a barbershop lowers BP more than standard screening and health education (study 1) and can be implemented by barbers rather than research personnel (study 2). In study 1, we measured changes in HTN treatment and BP in regular barbershop customers with poorly controlled HTN assigned for 8 months to either an enhanced intervention group (n=36) or a contemporaneous comparison group (n=27). Groups were similar at baseline. BP fell by 16+/-3/9+/-2 mm Hg in the enhanced intervention group but was unchanged in the comparison group (P<0.0001, adjusted for age and body mass index). HTN treatment and control increased from 47% to 92% (P<0.001) and 19% to 58% (P<0.001), respectively, in the enhanced intervention group, whereas both remained unchanged in the comparison group. In study 2, barbers were trained to administer the enhanced intervention continuously for 14 months to the entire adult black male clientele (n=321) in 1 shop. Six barbers recorded 8953 BP checks during 11 066 haircuts, thus demonstrating a high degree of intervention fidelity. Furthermore, among 107 regular customers with HTN, treatment and control increased progressively with increasing intervention exposure (P<0.01). Taken together, these data suggest that black-owned barbershops can be transformed into effective HTN detection, referral, and follow-up centers. Further research is warranted.

Effects of papaya seed extract and benzyl isothiocyanate on vascular contraction.

To investigate their potentially toxic effects on mammalian vascular smooth muscle, pentane extracts of papaya seeds and the chief active ingredient in the extracts, benzyl isothiocyanate (BITC), were tested for their effects on the contraction of strips of dog carotid artery. BITC and the papaya seed extract caused relaxation when added to tissue strips that had been pre-contracted with phenylephrine (PE). Incubation of the tissue with papaya seed extract or BITC caused inhibition of contraction when the strips were subsequently contracted with KCl or PE. This relaxation and inhibition of contraction did not appear to be endothelium-dependent, as endothelium-denuded rings showed the same degree of relaxation or inhibition of contraction in response to the preparations/drugs as those with the endothelium intact. The effects of both BITC and the extract were irreversible, i.e., the tissue did not recover to normal contractile ability after extensive washing. Exposure of the tissue to the papaya seed extract caused slower relaxation of the tissue, compared to controls, both after contraction with PE and subsequent addition of carbachol (CCh), and after contraction with KCl and then washing. Calcium imaging studies using cultured endothelial cells showed strong influxes of Ca2+ into the cells in response to addition of the papaya seed extract. We conclude that these extracts, when present in high concentration, are cytotoxic by increasing the membrane permeability to Ca2+, and that the vascular effects of papaya seed extracts are consistent with the notion that BITC is the chief bio-active ingredient.