Association of limited English proficiency with emergency department irregular departures and return visits: A cross-sectional cohort study in the Upper Midwest between January 2018 and December 2021.

OBJECTIVES: Patients with limited English proficiency (LEP) have been shown to experience disparities in emergency department (ED) care. The objectives of this study were to examine the associations between LEP and irregular ED departures and return ED visits. METHODS: We conducted a multicenter cross-sectional analysis of 18 EDs within an integrated health system in the upper Midwest from January 1, 2018, to December 31, 2021. ED visits of pediatric and adult patients who were discharged on the index visit were included for analysis. We analyzed the association of LEP with irregular departures, 72-h and 7-day return visits, and ED disposition at the time of that return visit. Multivariable model associations were calculated using generalized estimating equations and reported as odds ratios (OR) with 95% confidence intervals (CIs). RESULTS: A total of 745,464 total ED visits were analyzed, including 27,906 (3.7%) visits among patients with LEP. The most common preferred languages among patients with LEP were Spanish (12,759; 45.7%), Somali (4978; 17.8%), and Arabic (3185; 11.4%). After multivariable adjustment there were no differences in proportions of irregular departures (OR 1.09, 95% CI 0.99-1.21), 72-h returns (OR 0.99, 95% CI 0.92-1.06), or 7-day returns (OR 0.99, 95% CI 0.93-1.05) between patients with LEP or English proficiency. Patients with LEP returning within 72 h (OR 1.19, 95% CI 1.01-1.40) and 7 days (OR 1.15, 95% CI 1.01-1.33) were more likely to be admitted to the hospital. CONCLUSIONS: After multivariable adjustment, we did not find an increased frequency of irregular ED departures or 72-h or 7-day returns among patients with LEP compared with people proficient in English. However, we did find that higher proportions of patients with LEP were admitted to the hospital at the time of the return ED visit.

Talin1 controls dendritic cell activation by regulating TLR complex assembly and signaling.

Talin critically controls integrin-dependent cell migration, but its regulatory role in skin dendritic cells (DCs) during inflammatory responses has not been investigated. Here, we show that talin1 regulates not only integrin-dependent Langerhans cell (LC) migration, but also MyD88-dependent Toll-like receptor (TLR)-stimulated DC activation. Talin1-deficient LCs failed to exit the epidermis, resulting in reduced LC migration to skin-draining lymph nodes (sdLNs) and defective skin tolerance induction, while talin1-deficient dermal DCs unexpectedly accumulated in the dermis despite their actomyosin-dependent migratory capabilities. Furthermore, talin1-deficient DCs exhibited compromised chemotaxis, NFκB activation, and proinflammatory cytokine production. Mechanistically, talin1 was required for the formation of preassembled TLR complexes in DCs at steady state via direct interaction with MyD88 and PIP5K. Local production of PIP2 by PIP5K then recruited TIRAP to the preassembled complexes, which were required for TLR signalosome assembly during DC activation. Thus, talin1 regulates MyD88-dependent TLR signaling pathways in DCs through a novel mechanism with implications for antimicrobial and inflammatory immune responses.

IRF-7 Mediates Type I IFN Responses in Endotoxin-Challenged Mice.

IRF-7 mediates robust production of type I IFN via MyD88 of the TLR9 pathway in plasmacytoid dendritic cells (pDCs). Previous in vitro studies using bone marrow-derived dendritic cells lacking either Irf7 or Irf3 have demonstrated that only IRF-3 is required for IFN-ß production in the TLR4 pathway. Here, we show that IRF-7 is essential for both type I IFN induction and IL-1ß responses via TLR4 in mice. Mice lacking Irf7 were defective in production of both IFN-ß and IL-1ß, an IFN-ß-induced pro-inflammatory cytokine, after LPS challenge. IFN-ß production in response to LPS was impaired in IRF-7-deficient macrophages, but not dendritic cells. Unlike pDCs, IRF-7 is activated by the TRIF-, but not MyD88-, dependent pathway via TBK-1 in macrophages after LPS stimulation. Like pDCs, resting macrophages constitutively expressed IRF-7 protein. This basal IRF-7 protein was completely abolished in either Ifnar1-/- or Stat1-/- macrophages, which corresponded with the loss of LPS-stimulated IFN-ß induction in these macrophages. These findings demonstrate that macrophage IRF-7 is critical for LPS-induced type I IFN responses, which in turn facilitate IL-1ß production in mice.

Ezh2 Controls Skin Tolerance through Distinct Mechanisms in Different Subsets of Skin Dendritic Cells.

Ezh2, a well-established epigenetic repressor, can down-regulate leukocyte inflammatory responses, but its role in cutaneous health remains elusive. Here we demonstrate that Ezh2 controls cutaneous tolerance by regulating Langerhans cell (LC) transmigration across the epidermal basement membrane directly via Talin1 methylation. Ezh2 deficiency impaired disassembly of adhesion structures in LCs, leading to their defective integrin-dependent emigration from the epidermis and failure in tolerance induction. Moreover, mobilization of Ezh2-deficient Langerin- dermal dendritic cells (dDCs) via high-dose treatment with a weak allergen restored tolerance, which is associated with an increased tolerogenic potential of Langerin- dDCs likely due to epigenetic de-repression of Aldh in the absence of Ezh2. Our data reveal novel roles for Ezh2 in governing LC- and dDC-mediated host protection against cutaneous allergen via distinct mechanisms.

Talin1 Methylation Is Required for Neutrophil Infiltration and Lipopolysaccharide-Induced Lethality.

Talin1, a well-established integrin coactivator, is critical for the transmigration of neutrophils across the vascular endothelium into various organs and the peritoneal cavity during inflammation. Several posttranslational modifications of talin1 have been proposed to play a role in this process. In this study, we show that trimethylation of talin1 at Lys2454 by cytosolic Ezh2 is substantially increased in murine peritoneal neutrophils upon induction of peritonitis. By reconstituting talin1-deficient mouse myeloid cells with wild-type, methyl-mimicking, or unmethylatable talin1 variants, we demonstrate that methylation of talin1 at Lys2454 is important for integrin-dependent neutrophil infiltration into the peritoneal cavity. Furthermore, we show that treatment with an Ezh2 inhibitor or reconstitution of talin1-deficient myeloid cells with unmethylatable talin1 significantly reduces the number of organ-infiltrating neutrophils and protects mice from LPS-induced mortality.

Avian influenza A (H5N1) infection with respiratory failure and meningoencephalitis in a Canadian traveller.

In an urban centre in Alberta, an otherwise healthy 28-year-old woman presented to hospital with pleuritic chest and abdominal pain after returning from Beijing, China. After several days, this was followed by headache, confusion and, ultimately, respiratory failure, coma and death. Microbiology yielded influenza A subtype H5N1 from various body sites and neuroimaging was consistent with meningoencephalitis. While H5N1 infections in humans have been reported in Asia since 1997, this is the first documented case of H5N1 influenza in the Western Hemisphere. The present case demonstrated the typical manifestation of H5N1 influenza but, for the first time, also confirmed previous suggestions from human and animal studies that H5N1 is neurotropic and can manifest with neurological symptoms and meningoencephalitis.

Dans un centre urbain de l'Alberta, une femme auparavant en santé de 28 ans s'est rendue à l'hôpital en raison d'une douleur pleurétique et abdominale à son retour de Beijing, en Chine. Quelques jours plus tard, cette douleur a été suivie de céphalées et de confusion, puis la patiente a souffert d'une insuffisance respiratoire, d'un coma et est décédée. La microbiologie de divers sièges a révélé une grippe H5N1 de sous-type A, et la neuro-imagerie a corroboré la présence d'une méningoencéphalite. Des infections par la grippe H5N1 sont signalées chez les humains depuis 1997 en Asie, mais il s'agit du premier cas démontré dans l'hémisphère occidental. Ce cas présentait la forme classique de la grippe H5N1, mais pour la première fois, il confirmait également ce que laissaient entrevoir les études sur des humains et des animaux, soit que la grippe H5N1 est neurotrope et peut se manifester par des symptômes neurologiques et une méningoencéphalite.

Applicability of the MATRICS Consensus Cognitive Battery in Singapore.

The MATRICS Consensus Cognitive Battery (MCCB) was developed to provide a reliable, valid, and standard battery for clinical trials on cognitive enhancers in schizophrenia. In this study we tested the applicability of the MCCB to Singapore's English speakers. Healthy ethnic Chinese, Malay, and Indian English speakers (N = 171) of both genders were recruited within three age groups and three levels of education to match as closely as possible the US norming sample, and were administered the MCCB. Descriptive data, T scores, age, gender, education, and ethnicity effects on performance were explored and compared with the US norming study. Age, education, and ethnicity affected the battery's composite scores, with young and highly educated participants generally outperforming the old, less-educated ones. Male participants outperformed their female counterparts in two out of seven cognitive domains. Although generally lower when compared to the US norming sample, Singaporean scores reflected the same relationship with age, education, and gender, with the exception of a substantially worse performance in the social cognition domain. Differences among the ethnic groups in Singapore-and the poorer performance measured in these groups with respect to the US sample-call for the necessity of an extended norming study in Singapore.

Cardiovascular effects of angiotensin converting enzyme inhibition or angiotensin receptor blockade in hemodialysis: a meta-analysis.

BACKGROUND AND OBJECTIVES: Cardiovascular (CV) disease causes significant morbidity and mortality among the hemodialysis (HD) population. This meta-analysis was performed to determine whether angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) reduce fatal and nonfatal CV events and left ventricular (LV) mass in patients receiving HD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Studies were identified by searching electronic databases, bibliographies, and conference proceedings. Two reviewers independently selected randomized controlled trials using ACEIs or ARBs compared with control among patients receiving HD. Studies were independently assessed for inclusion, quality, and data extraction. Random-effects models were used to estimate the pooled relative risk (RR) for CV outcomes and the weighted mean difference (WMD) for pooled change-from-baseline comparisons for LV mass for ACEI or ARB treated patients compared with control. RESULTS: Compared with control, the RR of CV events associated with ACEI or ARB use was 0.66 [95% confidence interval (CI) 0.35 to 1.25; P = 0.20]. ACEI or ARB use resulted in a statistically significant reduction in LV mass, with a WMD of 15.4 g/m(2) (95% CI 7.4 to 23.3; P < 0.001). CONCLUSIONS: Treatment with an ACEI or ARB reduced LV mass in patients receiving HD. However, their use was not associated with a statistically significant reduction in the risk of fatal and nonfatal CV events. Larger, high-quality trials in the HD population are required to determine if the effects of ACEI or ARB therapy on LV mass translate into decreased CV morbidity and mortality.

Reovirus salvage of squamous cell cancer-contaminated wounds.

PURPOSE: To assess the susceptibility of human squamous cell carcinoma to reovirus infection in vitro and in vivo using a murine model of cancer-contaminated wounds. METHODS: The University of Michigan squamous carcinoma 22B cell line was cultured and inoculated with reovirus in vitro. The effect of the reovirus was assessed with microscopy and a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. We used the previously established cancer-contaminated wound SCID mouse model to test saline and reovirus irrigation in vivo. Fifty-five mice were used; 15 were controls, 20 had immediate irrigation, and 20 had delayed irrigation. Surgical sites were assessed for palpable tumour biweekly. RESULTS: The microscopy and MTT assay both showed evidence of reovirus-mediated squamous cancer cell lysis. The control mice grew palpable tumours in 80% of the wounds. Immediate irrigation with saline delayed the onset of palpable tumour and demonstrated a persistent reduction in the rate of development of palpable tumours (p = .004 compared with controls). This effect disappeared when the saline irrigation was delayed, resulting in a tumour development rate that was not significantly different from that of the control. Wounds that were irrigated with reovirus, both immediately and delayed, did not produce palpable tumour (p < .0005 when compared with controls). CONCLUSIONS: (1) The University of Michigan squamous cell carcinoma 22B cell line is susceptible to reovirus in vitro. (2) Immediate irrigation with saline resulted in a significant delay in clinically evident tumour growth and a reduction in the rate of tumour development in the SCID mouse model. (3) The reovirus irrigation resulted in a significant reduction of tumour development in both the immediate and delayed groups in the SCID mouse model. (4) The efficacy of the reovirus irrigation in the delayed group suggests that the major mechanism of action is through a selective and specific targeting of implanted cancer cells.

Additive effect of dornase alfa and Nacystelyn on transportability and viscoelasticity of cystic fibrosis sputum.

OBJECTIVE: To investigate the effect of dornase alfa (DA), Nacystelyn (NAL) and their combination on mucociliary transportability and mucus viscoelasticity of cystic fibrosis (CF) sputum, and to assess whether the combination possesses an additive effect. DESIGN: Determination of transportability in frog palate and viscoelasticity in vitro. SETTING: Research laboratory at a medical centre. PATIENTS: Sputa from 15 patients with CF, chronically infected with Pseudomonas aeruginosa, were studied. INTERVENTIONS: Sputum samples were incubated without any drug solution as a control, and with normal saline, DA, NAL and a mixture of DA and NAL in concentrations approximating those achieved in clinical practice. RESULTS: Normal saline (10% volume) by itself had a small effect on CF sputum transportability with a mean increase of 9%, and on viscoelasticity with a mean of decrease of 0.22 log units, respectively, compared with control (incubation without saline). DA (200 nM) further increased the transportability by a mean of 35% versus saline and decreased viscoelasticity by a mean of 0.30 log units. NAL (100 M) increased the transportability by a mean of 32% and decreased viscoelasticity by a mean of 0.22 log units from the levels achieved with saline. The mixture of DA plus NAL at one-half of the above concentration of each agent produced an additional increase in the transportability, by a mean of 18%, and a further decrease in viscoelasticity, by a mean of 0.25 log units, compared with DA or NAL as a single treatment. CONCLUSIONS: The combination of DA and NAL exhibits an additive effect for both the viscoelasticity and transportability of CF sputum samples. The two agents appear to act well together in breaking down the bonding due to extracellular DNA and mucins. Clinical studies should be undertaken to see whether the additive combination at lower concentration produces the anticipated benefits of improved airway clearance and fewer side effects.