Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model.

Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor (IFNR) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.

JAK1 Inhibition Blocks Lethal Immune Hypersensitivity in a Mouse Model of Down Syndrome.

Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.

Undergraduate nursing and midwifery student's attitudes to mental illness.

Aim: To explore levels of stigma in students of all fields of nursing and midwifery at different years and examine the impact of exposure to people with mental illness. Design: A cross-sectional survey was used. Methods: The Community Attitudes to Mental Illness questionnaire was administered to all branches of student nurses (adult health, mental health, child health and learning disability) and midwives in all three years in one Higher Education Institution (HEI) in Scotland. Results: Mental health nursing students scored significantly better on all stigma subscales. Stigma worsened with a little professional exposure to people with mental illness but then improved with increasing exposure. Both personal exposure and professional exposure to people with mental illness change perceptions. The professional results follow a J-curve. Current plans for cross-field experience involving short or virtual placements during student nurse training are likely to worsen stigma rather than improve it.

Genomic and phenotypic evolution of Escherichia coli in a novel citrate-only resource environment.

Evolutionary innovations allow populations to colonize new ecological niches. We previously reported that aerobic growth on citrate (Cit+) evolved in an Escherichia coli population during adaptation to a minimal glucose medium containing citrate (DM25). Cit+ variants can also grow in citrate-only medium (DM0), a novel environment for E. coli. To study adaptation to this niche, we founded two sets of Cit+ populations and evolved them for 2500 generations in DM0 or DM25. The evolved lineages acquired numerous parallel mutations, many mediated by transposable elements. Several also evolved amplifications of regions containing the maeA gene. Unexpectedly, some evolved populations and clones show apparent declines in fitness. We also found evidence of substantial cell death in Cit+ clones. Our results thus demonstrate rapid trait refinement and adaptation to the new citrate niche, while also suggesting a recalcitrant mismatch between E. coli physiology and growth on citrate.

Operating Room Clinicians' Attitudes and Perceptions of a Pediatric Surgical Safety Checklist at 1 Institution.

BACKGROUND: Despite mounting evidence that use of surgical checklists improves patient morbidity and mortality, compliance among surgical teams in executing required elements of checklists has been low. Recognizing that clinicians' receptivity is a major determinant of checklist use, we conducted a survey to investigate how mandated use of a surgical checklist impacts its operating room clinicians' attitudes about and perceptions of operating room safety, efficiency, teamwork, and prevention of medical errors. METHODS: Operating room clinicians at 1 pediatric hospital were surveyed on their attitudes and perception of the novel Pediatric Surgical Safety Checklist and the impact the checklist had on efficiency, teamwork, and prevention of medical errors 1 year after its implementation. The survey responses were compared and classified by multidisciplinary perioperative clinical staff. RESULTS: Most responses reflected positive attitudes toward checklist use. The respondents felt that the checklist reduced complications and errors and improved patient safety, communication among team members, teamwork in complex procedures, and efficiency in the operating room. Many operating room staff also reported that checklist use had prevented or averted an error or a complication. Perceptions varied according to perioperative clinical discipline, reflecting differences in perspectives. For example, the nurses perceived a higher rate of consent-related errors and site marking errors than did the physicians; the surgeons reported more antibiotic timing and equipment errors than did others. CONCLUSIONS: The surgical staff at 1 pediatric hospital who responded viewed the novel Pediatric Surgical Safety Checklist as potentially beneficial to operative patient safety by improving teamwork and communication, reducing errors, and improving efficiency. Responses varied by discipline, indicating that team members view the checklist from different perspectives.

Dry eye modulates the expression of toll-like receptors on the ocular surface.

We aimed to determine if toll-like receptor (TLR) expression is modulated in response to dry eye-associated conditions and in dry eye syndrome (DES). Primary human corneal epithelial cells (HCEC), an SV40 HCEC cell line or a normal human conjunctival epithelial cell line (IOBA-NHC) were cultured under hyperosmolar stress (HOS) (400-500 mOsm/kg) or with DES associated cytokines (IL-1α/ß, TNFα or TGFß) at concentrations ranging from 1 to 1000 ng/ml for up to 24 h. Epithelial cells were harvested from a human cornea organ culture model following 24 h of desiccation. Conjunctival impression cytology samples were harvested from subjects with DES and age and gender-matched normal subjects. TLR4, TLR5 or TLR9 mRNA or protein was examined by quantitative RT-PCR, western blotting or flow cytometry. TLR functionality was evaluated in terms of addition of TLR agonists and quantitation of secreted inflammatory cytokines by the use of ELISA and Luminex assays. In SV40 HCEC, HOS significantly increased TLR4 by 8.18 fold, decreased TLR9 by 0.58 fold, but had no effect on TLR5 mRNA expression. TLR4 and TLR9 protein were decreased by 67.7% and 72% respectively. TLR4 mRNA was also significantly up-regulated by up to 9.70 and 3.36 fold in primary HCEC and IOBA-NHC respectively. DES associated cytokines had no effect on TLR4, TLR5 and TLR9 expression. In response to desiccation, TLR4 and TLR5 mRNA were significantly up-regulated by 4.81 and 2.51 fold respectively, while TLR9 mRNA was down-regulated by 0.86 fold in HCEC. A similar trend for TLR4 and TLR9 protein was observed. TLR9 mRNA was significantly down-regulated by almost 59.5% in DES subjects. In conclusion, changes in TLR expression occur in dry eye and could have an important role in ocular surface susceptibility to inflammation and infection.

Variation in practice and resource utilization associated with the diagnosis and management of appendicitis at freestanding children's hospitals: implications for value-based comparative analysis.

OBJECTIVE: To characterize the scope and magnitude of practice variation associated with the diagnosis and treatment of appendicitis at freestanding children's hospitals. BACKGROUND: Variation in care has been associated with poor outcomes and is believed to be a key driver of excess health care spending. METHODS: Retrospective cohort study of 13,328 patients treated with appendicitis at 34 children's hospitals (9/2010-9/2011). Patients were divided into complicated and uncomplicated cohorts and examined for interhospital variation in the use of diagnostic imaging (computed tomography or ultrasonography), laboratory tests, parenteral nutrition (PN), peripherally inserted central catheters (PICC), and hospital cost. The number and distribution of statistical outliers were calculated for all measures. RESULTS: Significant variation was found for all measures, including a 3.5-fold difference in preoperative imaging (aggregate rate: 49.0%, range across hospitals: 21.2%-73.5%, P < 0.001) and a 5-fold difference in preoperative laboratory utilization (aggregate median: 2 tests/encounter, range: 1-5 tests/encounter, P < 0.001). For patients with complicated appendicitis, we characterized a 12-fold difference in postoperative imaging (aggregate rate: 19.4%, range: 4.9%-61.6%, P < 0.001), a 48-fold difference in PICC lines (aggregate rate: 18.9%, range: 1.7%-81.8%, P < 0.001), and a 100-fold difference in PN utilization (aggregate rate: 9.3%, range: 0.4%-42.0%, P < 0.001). Median hospital cost differed 4-fold for patients with uncomplicated disease (aggregate median: $6804, range: $4200-$16,796, P < 0.001) and 4.6-fold for patients with complicated disease (aggregate median: $13,138, range: $5419-$24,779, P < 0.001). Statistical outliers on the basis of high and low utilization were identified for all measures. CONCLUSIONS: Significant variation exists in practice, resource utilization, and treatment-related cost associated with the management of appendicitis at freestanding children's hospitals. Value-based measures are needed for benchmarking and to prioritize collaborative quality improvement efforts.

Hospital readmission after management of appendicitis at freestanding children's hospitals: contemporary trends and financial implications.

INTRODUCTION: The purpose of this study was to characterize epidemiologic trends and cost implications of hospital readmission after treatment of pediatric appendicitis. METHODS: We conducted a 5-year retrospective cohort analysis of 30-day readmission rates for 52,054 patients admitted with appendicitis at 38 children's hospitals participating in the Pediatric Health Information System database. Patients were categorized as "uncomplicated" (postoperative length of stay [LOS] ≤ 2 days) or "complicated" (LOS ≥ 3 days and ≥ 4 consecutive days of antibiotics) and analyzed for demographic data, treatment received during the index admission, readmission rates, and excess LOS and hospital-related costs attributable to readmission encounters. RESULTS: The aggregate 30-day readmission rate was 8.7%, and this varied significantly by disease severity and management approach (uncomplicated appendectomy, 5.6%; complicated appendectomy, 12.8%; drainage, 22.6%; antibiotics only, 24.6%; P < .0001). The median hospital cost per case attributable to readmission was $3401 (reflecting a 44% relative increase in cumulative treatment-related cost), and this varied significantly by disease severity and management approach (uncomplicated appendectomy, $1946 [31% relative increase]; complicated appendectomy, $6524 [53% increase]; drainage, $6827 [48% increase]; antibiotics only, $5835 [58% increase]; P < .0001). CONCLUSION: In freestanding children's hospitals, readmission after treatment of pediatric appendicitis is a relatively common and costly occurrence. Collaborative efforts are needed to characterize patient, treatment, and hospital-related risk factors as a basis for developing preventative strategies.