Immunomodulatory therapy for severe influenza

Influenza A virus is a significant cause of morbidity and mortality worldwide. Severe influenza is recognized as a clinical syndrome, characterized by hyperinduction of proinflammatory cytokine production, otherwise known as hypercytokinemia or a 'cytokine storm'. Research focused on therapeutics to modulate influenza virus-induced inflammation is currently underway. In this review, we discuss the limitations of current antiviral drug treatment strategies, describe the influenza viral and host pathogenicity determinants, and present the evidence supporting the use of immunomodulatory therapy to target the host inflammatory response as a means to improve clinical outcome in severe influenza. We then review the experimental data on investigational immunomodulatory agents targeting the host inflammatory response in severe influenza, including anti-TNF therapy, statins, glucocorticoids, cyclooxygenase-2 inhibitors, macrolides, peroxisome proliferator-activated receptor agonists, AMP-activated protein kinase agonists and high mobility group box 1 antagonists. We then conclude with a rationale for the use of mesenchymal stromal (stem) cells and angiopoietin-1 therapy against deleterious influenza-induced host responses that mediate end-organ injury and dysfunction.     

Impact of hospitalist vs. non-hospitalist services on length of stay and 30-day readmission rate in hip fracture patients

Objectives: Hip fracture is a common and morbid condition, affecting a patient population with significant medical co-morbidities. A number of medical co-management models have been studied, with conflicting reports of effect on patient outcomes. Our objective was to compare outcomes for patients with hip fracture managed by hospitalist vs. non-hospitalist services at an academic medical center.

Methods: We conducted a retrospective cohort study of patients with hip fracture over 1 year, comparing those on hospitalist vs. non-hospitalist services. Outcomes included 30-day readmission and hospitalization ≤7 days, with comparison between patients admitted to hospitalist vs. non-hospitalist services. We performed multivariate analysis, adjusting for age, gender, race/ethnicity, insurance type, ASA score, and blood transfusion during hospitalization and days from admission to surgery.

Results: We identified 124 hospitalist and 53 non-hospitalist patients. In unadjusted analysis, hospitalist patients were more likely to have hospitalization ≤7 days (84.7% vs. 67.9%, p = 0.01). In adjusted analysis, hospitalist patients had lower odds of 30-day readmissions (OR 0.2, 95% CI 0.04–0.97) but no difference in odds of hospitalization ≤7 days (OR 2.1, 95% CI 0.82–5.66).

Conclusions: Patients with hip fracture managed by hospitalist vs. non-hospitalist services had lower odds of 30-day readmission after discharge. Our results suggest benefit to hospitalist co-management of hip fracture patients.     

Cortico-striatal evoked potentials in the monkey (Macaca mulatta).

A systematic study has been made of topographic organization in the striatum of evoked potentials elicited by stimulation of the cerebral cortex in unanesthetized, comatose monkeys (Macaca mulatta). Stimulation of the dorsal field of the prefrontal convexity elicited potentials primarily in rostral portions of the caudate, while stimulation of the ventral field of the prefrontal convexity elicited potentials in ventromedial areas of the putamen. Stimulation of different points on the precentral and postcentral gyri revealed a distinct somatopic organization of evoked responses in the putamen, although responsive zones in the putamen to precentral and postcentral stimulation showed almost total overlap. An overlap of responsive zones to stimulation of the dorsal prefrontal convexity and the premotor area (area 6) was found in the dorsolateral part of the rostral caudate, while a zone of overlap of responses to stimulation of the ventral prefrontal convexity and "hand" motor area of the precentral gyrus was found in the ventromedial area of the putamen near the commissural level.     

Differential response of human lung epithelial cells to fas-induced apoptosis

The Fas (CD95)/Fas ligand (CD178) system plays an important role in epithelial damage during the acute respiratory distress syndrome. The goal of this study was to determine whether proximal and distal human lung epithelial cells differ in their sensitivity to Fas ligand (rh-sFasL), and whether the response of lung epithelium to Fas ligation is modulated by proinflammatory cytokines. Although the expression of both Fas message and protein was similar in proximal and distal lung epithelial cells, only distal cells became apoptotic when exposed to serial dilutions of rh-sFasL. Stimulation with tumor necrosis factor-alpha, interleukin-1beta, or interferon-gamma significantly increased the sensitivity of proximal cells to rh-sFasL, and exposure to either tumor necrosis factor-alpha or interferon-gamma enhanced the sensitivity of distal cells to Fas ligation. These findings suggest that in normal human lungs, the responses of the epithelium to Fas ligation become more pronounced from proximal to distal locations. Furthermore, proinflammatory cytokines sensitize lung epithelium to Fas-induced death. These findings are relevant for understanding the role of the Fas/FasL system in acute lung injury, in which epithelial damage occurs primarily in distal airway and alveolar epithelium, whereas sFasL is present throughout the airspaces.     

Hyper-IgE syndrome is not associated with defects in several candidate toll-like receptor pathway genes

The genetic basis of hyper-IgE syndrome (HIES), also known as Job syndrome, a primary immunodeficiency associated with recurrent skin and pulmonary infections, is unknown. We hypothesized that HIES is due to a defect in the Toll-like receptor signaling pathway. We used a whole blood cytokine assay to compare inflammatory responses to stimulation with specific Toll-like receptor (TLR) pathway agonists in four individuals with HIES and nine healthy controls. Production of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and IL-12 was not impaired in response to stimulation with lipopolysaccharide, peptidoglycan, zymosan, lipoteichoic acid, Staphylococcus aureus, Escherichia coli, or Streptococcus pneumoniae. Interferon (IFN)-gamma was reduced in HIES subjects in response to each of these stimuli. We sequenced several candidate genes from the TLR pathway in HIES individuals to determine whether any mutations were associated with this syndrome. No novel mutations or polymorphisms were found in the coding regions of TLR1, TLR2, TLR6, MyD88, or TRAF6. In summary, although HIES individuals had an IFN-gamma secretion defect, they also produced normal levels of several TLR-regulated proinflammatory cytokines. No unique mutations or polymorphisms were observed in several candidate genes from the TLR pathway. Our studies do not support a role for a defective TLR response in HIES individuals.     

The contribution of employer characteristics to continued employment of employees with residual work capacity: evidence from register data in The Netherlands

Objectives:This study aimed to examine the contribution of employer characteristics to continued employment of employees with residual work capacity. Moreover, we examined whether the contribution of employer characteristics differs across types of employers and employees’ types of diseases.Methods:Register data on disability assessments and employment status of N=84 394 long-term sick-listed employees with residual work capacity were obtained from the Dutch Employee Insurance Agency between 2010 and 2017. The dependent variable was continued employment four months after the assessment. We linked employees to their (former) employer to measure sector, firm size, and workforce composition. The average employment outcome of all employees assessed in the same firm and year served as a proxy measure for the extent of implemented disability-related policies and practices. Using multilevel multiple regression analysis, we compared the relative contribution of employer characteristics with employees’ characteristics.Results:Employer characteristics accounted for 10% of the variability in employment outcomes. In comparison, employees’ socio-demographic and disease characteristics accounted for 13% of the variability. The prevalence of continued employment was lowest in smaller firms and construction and low-wage service-orientated sectors. Furthermore, there were sizeable differences in employment outcomes between similar employers in terms of size, sector and workforce-composition, particularly between larger firms and among employees with mental or musculoskeletal disorders compared to other diseases.Conclusions:This study shows substantial differences between employers in facilitating continued employment of employees with residual work capacity. Encouraging firms to invest more in disability-related policies and practices may result in better employment opportunities for these employees.     

Correction to: Early Colorectal Cancer Detected by Machine Learning Model Using Gender,Age, and Complete Blood Count Data

Digestive Diseases and Sciences - The article Early Colorectal Cancer Detected by Machine Learning Model Using Gender, Age, and Complete Blood Count Data, written by Mark C. Hornbrook, Ran Goshen,...