Croup during the Coronavirus Disease 2019 Omicron Variant Surge.

We conducted a retrospective review of medical records of patients with croup seen during the coronavirus disease 2019 pandemic. Approximately 50% underwent testing for severe acute respiratory syndrome coronavirus 2. During the Delta wave, 2.8% of those tested were positive for severe acute respiratory syndrome coronavirus 2; this increased to 48.2% during the Omicron wave, demonstrating a strong correlation between the Omicron variant and croup.

Suppressors of cytokine signaling 2 and 3 diametrically control macrophage polarization.

Suppressors of cytokine signaling (SOCS) are important regulators of lipopolysaccharide (LPS) and cytokine responses but their role in macrophage polarization is unknown. We have shown here that myeloid-restricted Socs3 deletion (Socs3(Lyz2cre)) resulted in resistance to LPS-induced endotoxic shock, whereas Socs2(-/-) mice were highly susceptible. We observed striking bias toward M2-like macrophages in Socs3(Lyz2cre) mice, whereas the M1-like population was enriched in Socs2(-/-) mice. Adoptive transfer experiments showed that responses to endotoxic shock and polymicrobial sepsis were transferable and macrophage dependent. Critically, this dichotomous response was associated with enhanced regulatory T (Treg) cell recruitment by Socs3(Lyz2cre) cells, whereas Treg cell recruitment was absent in the presence of Socs2(-/-) macrophages. In addition, altered polarization coincided with enhanced interferon-gamma (IFN-γ)-induced signal transducer and activator of transcription-1 (STAT1) activation in Socs2(-/-) macrophages and enhanced interleukin-4 (IL-4) plus IL-13-induced STAT6 phosphorylation in Socs3(Lyz2cre) macrophages. SOCS, therefore, are essential controllers of macrophage polarization, regulating inflammatory responses.

MicroRNA-302d targets IRF9 to regulate the IFN-induced gene expression in SLE.

Systemic lupus erythematosus (SLE) is a complex disease targeting multiple organs as a result of overactivation of the type I interferon (IFN) system, a feature currently being targeted by multiple biologic therapies against IFN-α. We have identified an estrogen-regulated microRNA, miR-302d, whose expression is decreased in SLE patient monocytes and identify its target as interferon regulatory factor (IRF)-9, a critical component of the transcriptional complex that regulates expression of interferon-stimulated genes (ISGs). In keeping with the reduced expression of miR-302d in SLE patient monocytes, IRF9 levels were increased, as was expression of a number of ISGs including MX1 and OAS1. In vivo evaluation revealed that miR-302d protects against pristane-induced inflammation in mice by targeting IRF9 and hence ISG expression. Importantly, patients with enhanced disease activity have markedly reduced expression of miR-302d and enhanced IRF9 and ISG expression, with miR-302d negatively correlating with IFN score. Together these findings identify miR-302d as a key regulator of type I IFN driven gene expression via its ability to target IRF9 and regulate ISG expression, underscoring the importance of non-coding RNA in regulating the IFN pathway in SLE.

Healthicization and Lay Knowledge About Eating Practices in Two African American Communities.

In this manuscript, we expand upon sociological research in lay knowledge about health and healthicization by examining socially mediated ways in which 40 African American adults in two communities acquired information about eating practices. Participants employed a variety of socially informed information-seeking strategies. Many, but not all, used socially prescribed sources exhorting them to maximize their own health and reported an amalgam of experiences concerning their interpretation of healthist messages. Participants variously accepted messages about healthy eating or engaged in strategies of micro-resistance that decentered and/or reinterpreted health promotion discourse. Furthermore, participants used emic community-based resources including those that prioritized familial engagement over individual responsibility in eating practices or that drew upon alternative health practices. We discuss the implications our work has for further research on healthicization and lay knowledge about eating practices, in which community members are actively engaged in meaning-making within local socio-structural contexts.

Asymmetric Isothiourea-Catalysed Formal [3+2] Cycloadditions of Ammonium Enolates with Oxaziridines.

A highly enantioselective Lewis base-catalysed formal [3+2] cycloaddition of ammonium enolates and oxaziridines to give stereodefined oxazolidin-4-ones in high yield is described. Employing an enantioenriched oxaziridine in this process leads to a matched/mis-matched effect with the isothiourea catalyst and allowed the synthesis of either syn- or anti-stereodefined oxazolidin-4-ones in high d.r., yield and ee. Additionally, the oxazolidin-4-one products have been derivatised to afford functionalised enantioenriched building blocks.

The association of cytokines with disease activity and damage scores in systemic lupus erythematosus patients.

OBJECTIVE: The aim of this study was to explore the role of cytokines in the pathogenesis of SLE in a genetically homogeneous Caucasian SLE patient population. METHODS: Serum levels of the following cytokines were determined by ELISA in SLE patients (diagnosed as per ACR diagnostic criteria): IL-1ß, IL-10, IL-12p70 and TNF-α. Demographic data, disease activity as per the SLEDAI and damage scores (SLICC) at the 5-year follow-up were calculated. RESULTS: Enhanced production of TNF-α, IL-1 and IL-10 were observed in SLE patients compared with controls. A strong positive correlation was seen between levels of IL-12p70 and IL-10. In addition, IL-10, TNF-α and IL-1 demonstrated a significant relationship with disease activity. Interestingly, elevated levels of IL-10 were observed in SLE patients with CNS involvement while patients with elevated levels of TNF-α were more likely to have renal involvement and sustain damage over the follow-up period. Additionally, the ratio of all cytokines assayed to IL-12p70 levels were significantly higher in SLE patients when compared with controls, with an association seen between damage accrual and the IL-1ß/IL-12p70 ratio (r = 0.431, P = 0.003), IL-10/IL-12p70 ratio (r = 0.351, P = 0.018) and TNF-α/IL-12p70 ratio (r = 0.33, P = 0.028). When the respective ratios were analysed for organ-specific disease, significant differences were observed for the IL-1ß/IL-12p70 ratio (0.79 vs 0.47, P = 0.036), IL-10/IL-12p70 ratio (4.29 vs 1.87, P = 0.018) and TNF-α/IL-12p70 ratio (7.49 vs 5.21, P = 0.018) with respect to renal involvement. CONCLUSION: Increased levels of a number of immunomodulatory cytokines relative to IL-12p70 in this Caucasian SLE patient population are seen in patients with renal involvement and are associated with increased accrual of damage at the 5-year follow-up.

Isothiourea-catalyzed asymmetric synthesis of ß-lactams and ß-amino esters from arylacetic acid derivatives and N-sulfonylaldimines.

The isothiourea HBTM-2.1 (5 mol %) catalyzes the asymmetric formal [2 + 2] cycloaddition of both arylacetic acids (following activation with tosyl chloride) and preformed 2-arylacetic anhydrides with N-sulfonylaldimines, generating stereodefined 2,3-diaryl-ß-amino esters (after ring-opening) and 3,4-diaryl-anti-ß-lactams, respectively, with high diastereocontrol (up to >95:5 dr) and good to excellent enantiocontrol. Deprotection of the N-tosyl substituent within the ß-lactam framework was possible without racemization by treatment with SmI2.

Organocatalytic Michael addition-lactonisation of carboxylic acids using α,ß-unsaturated trichloromethyl ketones as α,ß-unsaturated ester equivalents.

Isothiourea HBTM-2.1 catalyses the Michael addition-lactonisation of 2-aryl and 2-alkenylacetic acids and α,ß-unsaturated trichloromethyl ketones. Ring-opening of the resulting dihydropyranones and subsequent alcoholysis of the CCl3 ketone with an excess of methanol gives a range of diesters in high diastereo- and enantioselectivity (up to 95 : 5 dr and >99% ee). Sequential addition of two different nucleophiles to a dihydropyranone gives the corresponding differentially substituted diacid derivative.

Elevated B lymphocyte stimulator levels are associated with increased damage in an Irish systemic lupus erythematosus cohort.

OBJECTIVE: The overall aim of this study is to identify clinical and serological features that are associated with B lymphocyte stimulator (BLyS) elevation in a homogeneous Caucasian SLE population and thereby identify patients who are most likely to benefit from BLyS blockade. METHODS: Patients with SLE (as per ACR criteria) were recruited. Clinical history, disease activity measures and laboratory measures of disease were recorded. BLyS levels were determined by ELISA. RESULTS: BLyS elevation was defined as being higher than the 95th percentile of BLyS levels measured in controls. Patients were divided into two groups: those with elevated BLyS levels (group 1, n = 23) and those with normal BLyS levels (group 2, n = 22). Elevated BLyS levels were significantly associated with patients of younger age and shorter disease duration. In keeping with previous reports, patients with elevated BLyS levels had more active disease (SLEDAI 5.1 vs 0.86, P < 0.001); however, our analysis also demonstrates that BLyS elevation was significantly associated with increased organ damage at 5-year follow-up [Systemic Lupus International Collaborating Clinics/ACR Damage Index (SLICC/ACR DI) 0.53 vs 0.13, P = 0.012]. Furthermore, the presence of Sm autoantibody significantly predicted elevated BLyS levels in a Caucasian population. BLyS levels were significantly higher in those with musculoskeletal involvement, malar rash, renal disease and evidence of immunological activity. CONCLUSION: BLyS blockade may be most beneficial if introduced early in the course of disease in young Caucasian patients presenting with renal, musculoskeletal and skin disease in an effort to reduce long-term damage.

Enhanced interferon regulatory factor 3 binding to the interleukin-23p19 promoter correlates with enhanced interleukin-23 expression in systemic lupus erythematosus.

OBJECTIVE: To examine the role of interferon regulatory factor 3 (IRF-3) in the regulation of interleukin-23 (IL-23) production in patients with systemic lupus erythematosus (SLE). METHODS: Bone marrow-derived macrophages were isolated from both wild-type and IRF3(-/-) C57BL/6 mice. These cells were stimulated with the Toll-like receptor 3 (TLR-3) agonist poly(I-C), and IL-23p19 cytokine levels were analyzed by enzyme-linked immunosorbent assay. IRF-3 binding to the IL-23p19 gene promoter region in monocytes from patients with SLE and healthy control subjects was analyzed by chromatin immunoprecipitation (ChIP) assay. Luciferase reporter gene assays were performed to identify key drivers of IL-23p19 promoter activity. TANK-binding kinase 1 (TBK-1) protein levels were determined by Western blotting. RESULTS: ChIP assays demonstrated that IRF-3 was stably bound to the human IL-23p19 promoter in monocytes; this association increased following TLR-3 stimulation. Patients with SLE demonstrated increased levels of IRF-3 bound to the IL-23p19 promoter compared with control subjects, which correlated with enhanced IL-23p19 production in monocytes from patients with SLE. Investigations of the TLR-3-driven responses in monocytes from patients with SLE revealed that TBK-1, which is critical for regulating IRF-3 activity, was hyperactivated in both resting and TLR-3-stimulated cells. CONCLUSION: Our results demonstrate for the first time that patients with SLE display enhanced IL-23p19 expression as a result of hyperactivation of TBK-1, resulting in increased binding of IRF-3 to the promoter. These findings provide novel insights into the molecular pathogenesis of SLE and the potential role for TLR-3 in driving this response.

Defects in acute responses to TLR4 in Btk-deficient mice result in impaired dendritic cell-induced IFN-γ production by natural killer cells.

This study defines a critical role for Btk in regulating TLR4-induced crosstalk between antigen presenting cells (APCs) and natural killer (NK) cells. Reduced levels of IL-12, IL-18 and IFN-γ were observed in Btk-deficient mice and ex vivo generated macrophages and dendritic cells (DCs) following acute LPS administration, whilst enhanced IL-10 production was observed. In addition, upregulation of activation markers and antigen presentation molecules on APCs was also impaired in the absence of Btk. APCs, by virtue of their ability to produce IL-12 and IL-18, are strong inducers of NK-derived IFN-γ. Co-culture experiments demonstrate that Btk-deficient DCs were unable to drive wild-type or Btk-deficient NK cells to induce IFN-γ production, whereas these responses could be restored by exogenous administration of IL-12 and IL-18. Thus Btk is a critical regulator of APC-induced NK cell activation by virtue of its ability to regulate IL-12 and IL-18 production in response to acute LPS administration.

Genetics of SLE: functional relevance for monocytes/macrophages in disease.

Genetic studies in the last 5 years have greatly facilitated our understanding of how the dysregulation of diverse components of the innate immune system contributes to pathophysiology of SLE. A role for macrophages in the pathogenesis of SLE was first proposed as early as the 1980s following the discovery that SLE macrophages were defective in their ability to clear apoptotic cell debris, thus prolonging exposure of potential autoantigens to the adaptive immune response. More recently, there is an emerging appreciation of the contribution both monocytes and macrophages play in orchestrating immune responses with perturbations in their activation or regulation leading to immune dysregulation. This paper will focus on understanding the relevance of genes identified as being associated with innate immune function of monocytes and macrophages and development of SLE, particularly with respect to their role in (1) immune complex (IC) recognition and clearance, (2) nucleic acid recognition via toll-like receptors (TLRs) and downstream signalling, and (3) interferon signalling. Particular attention will be paid to the functional consequences these genetic associations have for disease susceptibility or pathogenesis.

Electronic Screening for Adolescent Risk Behaviors in the Emergency Department: A Randomized Controlled Trial.

INTRODUCTION: In this study we aimed to assess the impact of an electronic health assessment with individualized feedback for risk behaviors in adolescents seeking care in a pediatric emergency department (ED). METHODS: We conducted a randomized control trial using a tablet-based screening program with a study population of adolescents in a busy pediatric ED. The intervention group received the screening program with individualized feedback. The control group received the screening program without feedback. All participants received one-day and three-month follow-up surveys to assess behaviors and attitudes toward health behaviors. RESULTS: A total of 296 subjects were enrolled and randomized. There was no difference in changes in risky behaviors between the control and experimental groups. A higher proportion of participants in the intervention groups reported that the screener changed the way they thought about their health at one-day follow-up (27.0%, 36/133) compared to the control group (15.5%, 20/129, P = .02). CONCLUSION: This study successfully tested a multivariable electronic health screener in a real-world setting of a busy pediatric ED. The tool did not significantly change risky health behaviors in the adolescent population screened. However, our finding that the intervention changed adolescents' perceptions of their health opens a door to the continued development of electronic interventions to screen for and target risk behaviors in adolescents in the ED setting.

A randomized controlled trial of simulation-based mastery learning to teach the extended focused assessment with sonography in trauma.

BACKGROUND: Mastery learning has gained popularity for training residents in procedural skills due to its demonstrated superiority over traditional methods. However, no studies have compared the efficacy of traditional versus mastery learning methods in residency point-of-care ultrasound education. We hypothesized that mastery learning would improve residents' skills in performing the extended focused assessment with sonography in trauma (eFAST). METHODS: All first-year emergency medicine (EM) resident physicians at a single university hospital underwent a crossover randomized controlled trial to receive mastery-learning eFAST training either at the beginning of the academic year or 6 months into intern year. Participants were taught using a checklist validated by a panel of experts using Mastery Angoff methods and were given feedback on missed tasks until each trainee completed the eFAST with a minimum passing standard (MPS). Our primary outcome was technical proficiency between the two groups for eFAST examinations performed in the emergency department during the academic year. RESULTS: Sixteen interns were enrolled; eight were randomized to each group. The group that received mastery training at the beginning of the year had mean clinical eFAST proficiency scores above the MPS in the first two quarters of the academic year, while the control group did not. Once the control group underwent eFAST mastery training at the midpoint of the year, both groups had mean proficiency scores above the MPS for the remainder of the year. CONCLUSION: Simulation-based mastery learning is an effective method of teaching the eFAST examination. This training during intern orientation conferred early proficiency in clinical performance of eFAST among EM residents. This difference in proficiency was no longer present after the control group received mastery learning education halfway through the academic year.

Evaluation of an Emergency Department High-risk Bruising Screening Protocol.

OBJECTIVES: The objective of this study was to describe the outcomes of implementing a high-risk bruise screening pathway in a pediatric emergency department (ED). METHODS: A retrospective observational study was performed of children aged 0 to <48 months who presented to the ED between December 1, 2016, and April 1, 2019, and had bruising that is high-risk for physical abuse on a nurse screening examination. A high-risk bruise was defined as any bruise if aged <6 months or a bruise to the torso, ears, or neck if aged 6 to <48 months. Records of children with provider-confirmed high-risk bruising were reviewed. RESULTS: Of the 49 726 age-eligible children presenting to the ED, 43 771 (88%) were screened for bruising. Seven hundred eighty-three (1.8%) of those children had positive screen results and 163 (0.4%) had provider-confirmed high-risk bruising. Of the 8635 infants aged <6 months who were screened, 48 (0.6%) had high-risk bruising and 24 of 48 (50%) were classified as cases of likely or definite abuse. Skeletal surveys were performed in 29 of 48 (60%) infants, and 11 of 29 (38%) had occult fracture. Of the 35 136 children aged 6 to <48 months who were screened, 115 of 35 136 (0.3%) had high-risk bruising and 32 of 115 (28%) were classified as cases of likely or definite abuse. CONCLUSIONS: High-risk bruising was rarely present. When infants aged <6 months were evaluated per recommendations, occult fracture was identified in one-third of patients. The screening pathway could help other institutions identify occult injuries in pediatric ED patients.

miR-744-5p contributes to ocular inflammation in patients with primary Sjogrens Syndrome.

In primary Sjögren's syndrome (pSS) the exocrine glands become infiltrated with lymphocytes instigating severe damage to the salivary and lacrimal glands causing dry eyes and dry mouth. Previous investigations have suggested that dysregulated localized and systemic inflammation contributes to the development and pathogenesis of pSS. A miR microarray performed in primary human conjunctival epithelial cells (PECs) demonstrated significant differences in miR expression at the ocular surface between pSS patients and healthy controls. MicroRNA-744-5p (miR-744-5p) was identified as being of particular interest, as its top predicted target is Pellino3 (PELI3), a known negative regulator of inflammation. Validation studies confirmed that miR-744-5p expression is significantly increased in PECs from pSS patients, whilst PELI3 was significantly reduced. We validated the miR-744 binding site in the 3' untranslated region (UTR) of PELI3 and demonstrated that increasing PELI3 levels with a miR-744-5p antagomir in an inflammatory environment resulted in reduced levels of IFN dependent chemokines Rantes (CCL5) and CXCL10. These results reveal a novel role for miR-744-5p in mediating ocular inflammation via Pellino3 expression in pSS patients and suggest that miR-744-5p may be a potential therapeutic target for the management of severe dry eye disease and ocular inflammation in pSS patients.

The effects of sedentary behaviour interventions on work-related productivity and performance outcomes in real and simulated office work: A systematic review.

This review examined the impact of environmental, behavioral, and combined interventions to reduce occupational sedentary behaviour on work performance and productivity outcomes. Productivity outcomes were defined as variables assessing work-related tasks (e.g., typing, mouse), whereas performance outcomes were categorized as any variables assessing cognition that did not mimic work-related tasks. Nine databases were searched for articles published up to January 2018. Sixty-three studies were identified that met the inclusion criteria: 45 examined a productivity outcome (i.e., typing, mouse, work-related tasks, and absenteeism), 38 examined a performance outcome (i.e., memory, reading comprehension, mathematics, executive function, creativity, psychomotor function, and psychobiological factors), and 30 examined a self-reported productivity/performance outcome (i.e., presenteeism or other self-reported outcome). Overall, standing interventions do not appear to impact productivity/performance outcomes, whereas walking and cycling interventions demonstrate mixed null/negative associations for productivity outcomes. Hence, standing interventions to reduce occupational sedentary behaviour could be implemented without negatively impacting productivity/performance outcomes.

Systemic IL-1ß production as a consequence of corneal HSV-1 infection-contribution to the development of herpes simplex keratitis.

This study sought to identify potential therapeutic targets in herpes simplex keratitis (HSK) patients with active and inactive infection by investigating peripheral cytokine production. Peripheral blood mononuclear cells (PBMCs) and serum were prepared from healthy controls and HSK patients during active infection or following treatment (inactive infection). Serum antibody titres were determined by ELISA. Protein expression levels were analysed by Western blot. Cytokine levels were determined by multiplex ELISA. Active corneal herpes simplex virus type 1 (HSV-1) infection resulted in significantly elevated peripheral levels of IL-1ß in HSK patients compared to healthy controls, and remained significantly increased following treatment. Elevated production of IL-1ß in inactive patients was associated with significantly increased levels of IRF3 and STAT1, key proteins involved in promoting anti-viral immune responses. Our data suggest that inflammation persists beyond the period that it is clinically evident and that enhanced peripheral production of IL-1ß may have implications for HSV-1 viral clearance in active and inactive HSK patients.

IL-16/miR-125a axis controls neutrophil recruitment in pristane-induced lung inflammation.

Severe lung inflammation and alveolar hemorrhage can be life-threatening in systemic lupus erythematosus (SLE) patients if not treated early and aggressively. Neutrophil influx is the driver key of this pathology, but little is known regarding the molecular events regulating this recruitment. Here, we uncover a role for IL-16/mir-125a in this pathology and show not only that IL-16 is a target for miR-125a but that reduced miR-125a expression in SLE patients associates with lung involvement. Furthermore, in the pristane model of acute "SLE-like" lung inflammation and alveolar hemorrhage, we observed reduced pulmonary miR-125a and enhanced IL-16 expression. Neutrophil infiltration was markedly reduced in the peritoneal lavage of pristane-treated IL-16-deficient mice and elevated following i.n. delivery of IL-16. Moreover, a miR-125a mimic reduced pristane-induced IL-16 expression and neutrophil recruitment and rescued lung pathology. Mechanistically, IL-16 acts directly on the pulmonary epithelium and markedly enhances neutrophil chemoattractant expression both in vitro and in vivo, while the miR-125a mimic can prevent this. Our results reveal a role for miR-125a/IL-16 in regulating lung inflammation and suggest this axis may be a therapeutic target for management of acute lung injury in SLE.