Bergknox6409

Eosinophilic asthma and nasal polyposis are hallmarks of aspirin-exacerbated respiratory disease (AERD), and IL-5 inhibition has been shown to provide therapeutic benefit. However, IL-5Rα is expressed on many cells in addition to eosinophils, and the mechanisms by which IL-5 inhibition leads to clinical benefit in eosinophilic asthma and nasal polyposis are unlikely to be due exclusively to antieosinophil effects.

We sought to identify the mechanisms by which anti-IL-5 treatment with mepolizumab improves respiratory inflammation in AERD.

The clinical characteristics, circulating granulocytes, nasal scraping transcripts, eosinophilic cationic protein, tryptase, and antibody levels, and urinary and nasal eicosanoid levels were measured for 18 subjects with AERD who were taking mepolizumab and compared with those of 18 matched subjects with AERD who were not taking mepolizumab.

Subjects taking mepolizumab had significantly fewer peripheral blood eosinophils and basophils, and those cells that remained ha of inflammatory eicosanoids and upregulates tight junction-associated nasal epithelial cell transcripts, likely due to decreased IL-5 signaling on tissue mast cells, eosinophils, and epithelial cells. These direct effects on multiple relevant immune cells contribute to the mechanism of benefit afforded by mepolizumab.

Managing severe asthma during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is challenging, particularly due to safety concerns regarding the use of systemic corticosteroids and biologics.

We sought to determine the association between biologics or systemic corticosteroids use and PCR positivity for SARS-CoV-2 and coronavirus disease 2019 (COVID-19) outcomes among asthmatic patients.

We used the computerized database of Clalit Health Services, the largest health care provider in Israel, to identify all asthmatic adult patients who underwent PCR testing for SARS-CoV-2, between March 1, 2020, and December 7, 2020. Acohort approach was used to assess the association between biologics use and steroids treatment and COVID-19 severity and 90-day mortality.

Overall, 8,242 of 80,602 tested asthmatic patients had positive PCR testing result for SARS-CoV-2. Both biologics and systemic corticosteroids were not associated with increased risk of SARS-CoV-2 infection. Multivariate analysassociated with increased risk of SARS-CoV-2 infection. In contrast, systemic corticosteroids are an independent risk factor for worst COVID-19 severity and all-cause mortality. Our findings underscore the risk of recent or current exposure to systemic corticosteroids in asthmatic patients infected with SARS-CoV-2.

Identification of biomarkers associated with immune-mediated diseases in 22q11.2 deletion syndrome is an evolving field.

We sought to use a carefully phenotyped cohort to study immune parameters associated with autoimmunity and atopy in 22q11.2 deletion syndrome to define biomarkers associated with immune-mediated disease in this syndrome.

Chart review validated autoimmune disease and atopic condition diagnoses. Laboratory data were extracted for each subcohort and plotted according to age. Arandom-effects model was used to define statistical significance.

CD19, CD4, and CD4/45RA lymphocyte populations were not different from the general cohort for patients with atopic conditions. CD4/45RA T cells were significantly lower in the subjects with immune thrombocytopenia compared with the general cohort, and CD4 T-cell counts were lower in patients with autoimmune thyroid disease.

The mechanisms of autoimmunity in cytopenias may be distinct from those of solid-organ autoimmunity in 22q11.2 deletion syndrome. This study identifies potential biomarkers for risk stratification among commonly obtained laboratory studies.

The mechanisms of autoimmunity in cytopenias may be distinct from those of solid-organ autoimmunity in 22q11.2 deletion syndrome. This study identifies potential biomarkers for risk stratification among commonly obtained laboratory studies.The selective cytotoxicity of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) to cancer cells but not to normal cells makes it an attractive candidate for cancer therapeutics. However, the disadvantages of TRAIL such as physicochemical instability and short half-life limit its further clinical applications. In this study, TRAIL was encapsulated into a novel anti-angiogenic nanocomplex for both improved drug distribution at the tumor site and enhanced anti-tumor efficacy. A nanocomplex was prepared firstly by entrapping TRAIL into PEG-low molecular weight heparin-taurocholate conjugate (LHT7), which is previously known as a potent angiogenesis inhibitor. Then, protamine was added to make a stable form of nanocomplex (PEG-LHT7/TRAIL/Protamine) by exerting electrostatic interactions. We found that entrapping TRAIL into the nanocomplex significantly improved both pharmacokinetic properties and tumor accumulation rate without affecting the tumor selective cytotoxicity of TRAIL. Furthermore, the anti-tumor efficacy of nanocomplex was highly augmented (73.77±4.86%) compared to treating with only TRAIL (18.49 ± 19.75%), PEG-LHT7/Protamine (47.84 ± 14.20%) and co-injection of TRAIL and PEG-LHT7/Protamine (56.26 ± 9.98%). Histological analysis revealed that treatment with the nanocomplex showed both anti-angiogenic efficacy and homogenously induced cancer cell apoptosis, which suggests that accumulated TRAIL and LHT7 in tumor tissue exerted their anti-tumor effects synergistically. Based on this study, we suggest that PEG-LHT7/Protamine complex is an effective nanocarrier of TRAIL for enhancing drug distribution as well as improving anti-tumor efficacy by exploiting the synergistic mechanism of anti-angiogenesis.Pancreatic islet replacement therapy is an advanced choice for severe cases of type I diabetes. Nevertheless, extensive host immune response toward islet grafts remains a huge challenge for long-term graft function, and a lack of islet donors further increases the difficulties associated with upscaling this therapy. Mounting evidence suggests local delivery of immunosuppressive agents provides a feasible means of enhancing graft-protection. Among many immunosuppressants, tacrolimus (FK506) is one of the most potent interleukin-2 (IL-2)-mediated T-cell proliferation blockers. Here, we reported the effect of locally-delivered FK506-releasing PLGA microspheres (FK506-M) combined with polyethylene glycol (PEG)-based islet surface modification on xenogeneic islet survival in C57BL/6 mouse model. FK506-M was prepared using an emulsion method to a particle size of 10-40 μm and released FK506 over 40 days in vitro. Around 80% of the initial dose of FK506-M stably localized near transplanted islets, as observed under a bioimaging instrument and by immunofluorescence staining of islet grafts. Interestingly, FK506-M at very low-doses (equivalent to 150 to 2400 ng FK506 per recipient) was found to inhibit the infiltration of immune cells into grafts and reduce serum IL-1β levels, thereby improving graft survival times dose-dependently. The PEGylation of islets alone was not enough to protect islets from early rejection. However, combined treatment with FK506-M additively prolonged xenograft survival. In conclusion, this study describes a safe, effective approach for translating a systemic exposure-free local drug delivery into clinical trials of islet transplantation.Chikungunya nephropathy is an uncommon etiology of acute kidney injury, associated with the mosquito-borne chikungunya arbovirus (CHIKV). The very limited number of pathologic reports to date have only involved postmortem analyses. We here report 5 cases of acute kidney injury for which kidney biopsies were performed in patients with confirmed acute CHIKV infection, during the recent outbreak of chikungunya disease in the French West Indies. The patients ranged from 42 to 76 years of age. All of the patients developed kidney injury, 3 of whom required short-term dialysis and underwent a kidney biopsy. Analysis of kidney biopsies revealed 2 main histopathologic patterns acute interstitial nephritis with predominant lymphoid inflammation and acute tubular injury. Epithelioid granulomas were observed in 2 cases. There were no glomerular lesions, except in biopsies from 2 patients, including 1 with a previous known primary focal segmental glomerulosclerosis. E64d CHIKV antigen immunofluorescence microscopy revealed staining in tubular cells. In all of the cases, the short-term outcome was favorable, with recovery of kidney function.

Prior studies of patients receiving maintenance hemodialysis have shown that, on average, BP measured predialysis is higher than BP measured at home. We hypothesized that a subset of hemodialysis patients has BPs, when measured at home, that are higher than when measured predialysis. Further, we hypothesized that this subgroup of patients has a higher prevalence of left ventricular hypertrophy.

Prospective cohort.

97 hypertensive hemodialysis patients enrolled in the Blood Pressure in Dialysis Study (BID), a randomized trial of comparing target predialysis BP <140/90 to 155-165/90 mm Hg.

Differences between predialysis and next day home systolic BP measured >6 times over one year.

Left ventricular mass index (LVMI) by cardiac magnetic resonance imaging.

A hierarchical clustering analysis divided patients into 3 clusters based on the average and variability of differences in systolic predialysis and home BP. Clusters were compared with respect to clinical factors and LVMI.

Mean (95% CI) differences between predialysis and home systolic BP were 19.1 (17.0, 21.1) for Cluster 1 ('home lower'), 3.7 (1.6, 5.8) for Cluster 2 ('home and predialysis similar'), and -9.7 (-12.0, -7.4) mm Hg for Cluster 3 ('home higher'). Systolic BP declined during dialysis in Clusters 1 and 2 but increased in Cluster 3. Interdialytic weight gains did not differ. After adjusting for sex and treatment arm, LVMI was higher in Cluster 3 than in Clusters 1 and 2 (differences in means of 10.6 (SE 4.96, p=0.04) and 12.0 (SE 5.08, p=0.02) gm/m

, respectively).

Limited statistical power.

Nearly one-third of participants had home BPs higher than predialysis BPs. These patients had LVMI higher than those with similar or lower BPs at home indicating that their BP may have been undertreated.

Nearly one-third of participants had home BPs higher than predialysis BPs. These patients had LVMI higher than those with similar or lower BPs at home indicating that their BP may have been undertreated.

The burden of financial hardship among individuals with chronic kidney disease (CKD) has not been extensively studied. Therefore, we describe the scope and determinants of financial hardship among a nationally representative sample of adults with CKD.

Cross-sectional.

Nonelderly adults with CKD from the 2014-2018 National Health Interview Survey.

Sociodemographic and clinical characteristics.

Financial hardship based on medical bills and consequences of financial hardship (high financial distress, food insecurity, cost-related medication nonadherence, delayed/forgone care due to cost). Financial hardship was categorized into 3 levels no financial hardship, financial hardship but able to pay bills, and unable to pay bills at all. Financial hardship was then modeled in 2 different ways (1) any financial hardship (regardless of ability to pay) versus no financial hardship and (2) inability to pay bills versus no financial hardship and financial hardship but able to pay bills.

Nationally representative estimates of financial hardship from medical bills were computed.