Baseline predictors of disease severity in immune checkpoint inhibitor-induced inflammatory arthritis.

OBJECTIVES: To determine baseline risk factors for requiring immunosuppression and having persistent arthritis in patients with immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA). METHODS: Participants were adults with rheumatologist diagnosed ICI-IA. The primary outcome was requirement of conventional synthetic (cs) or biologic (b) DMARDs; other outcomes were persistence of IA > 6 months after ICI cessation and requirement of corticosteroids. Logistic regression models evaluated associations between clinical features and primary and secondary outcomes, with adjustment for potential confounders, as appropriate. RESULTS: 126 patients with ICI-IA were included; 53 patients (42%) required a csDMARD/bDMARD. In univariate logistic regressions, higher CDAI, tenosynovitis, longer symptom duration before first rheumatology visit, and longer ICI duration were significantly associated with a higher likelihood of requiring DMARDs; there was a trend toward those treated with prior chemotherapy being less likely to need DMARDs. After adjustment, tenosynovitis, longer symptom duration, and higher CDAI remained associated with requiring DMARDs, while those with prior chemotherapy were significantly less likely to require DMARDs. Combination anti-CTLA-4/PD-1 therapy and steroid use at baseline were associated with a higher risk of persistent IA. CONCLUSION: Higher levels of disease activity, tenosynovitis, and longer symptom duration prior to rheumatology referral were associated with requiring DMARDs for ICI-IA, while those treated previously with chemotherapy were less likely to require additional immunosuppression. The presence of risk factors for severe disease at baseline may indicate a role for higher initial steroid dose, earlier rheumatology referral, and adoption of immunosuppression beyond steroids to improve outcomes.

AKI Treated with Renal Replacement Therapy in Critically Ill Patients with COVID-19.

BACKGROUND: AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT). METHODS: We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients. RESULTS: A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission. CONCLUSIONS: AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission.

Filter clotting with continuous renal replacement therapy in COVID-19.

Coronavirus disease 2019 (COVID-19) appears to be associated with increased arterial and venous thromboembolic disease. These presumed abnormalities in hemostasis have been associated with filter clotting during continuous renal replacement therapy (CRRT). We aimed to characterize the burden of CRRT filter clotting in COVID-19 infection and to describe a CRRT anticoagulation protocol that used anti-factor Xa levels for systemic heparin dosing. Multi-center study of consecutive patients with COVID-19 receiving CRRT. Primary outcome was CRRT filter loss. Sixty-five patients were analyzed, including 17 using an anti-factor Xa protocol to guide systemic heparin dosing. Fifty-four out of 65 patients (83%) lost at least one filter. Median first filter survival time was 6.5 [2.5, 33.5] h. There was no difference in first or second filter loss between the anti-Xa protocol and standard of care anticoagulation groups, however fewer patients lost their third filter in the protocolized group (55% vs. 93%) resulting in a longer median third filter survival time (24 [15.1, 54.2] vs. 17.3 [9.5, 35.1] h, p = 0.04). The rate of CRRT filter loss is high in COVID-19 infection. An anticoagulation protocol using systemic unfractionated heparin, dosed by anti-factor Xa levels is reasonable approach to anticoagulation in this population.

Solubility Enhancement of a Poorly Water-Soluble Drug Using Hydrotropy and Mixed Hydrotropy-Based Solid Dispersion Techniques.

Purpose: The biopharmaceutics classification system places rosuvastatin calcium in class II has a low and fluctuating oral bioavailability. The research focus is to maximize rosuvastatin calcium solubility in water and dissolution rate by employing and combining various hydrotropic agents to make a solid dispersion using solvent evaporation techniques. Methodology. The experimental study was conducted at Duhok University, College of Pharmacy. Initially, assess rosuvastatin's solubility in hydrotropic agents including urea, mannitol, citric acid, sodium benzoate, and sodium salicylate at concentrations of 10, 20, 30, and 40% w/v. Then, various ratios of 2 and 3 hydrotropic agents were employed to reduce the concentration of each hydrotropic agent. By using a solvent evaporation procedure, solid dispersions were made. The solid dispersion powders underwent evaluation for their percentage drug content, percentage yield, solubility, dissolution test, XRD, DSC, SEM, and FTIR. For statistical analysis, GraphPad InStat Demo software was used to conduct a two-way analysis of variance (ANOVA). Results: In comparison to the pure drug, the solubility of hydrotropic solid dispersions and physical mixtures of rosuvastatin with a combination of hydrotropic agents (sodium salicylate, sodium benzoate, and urea) in the ratio of 13.33 for each increased in all formulations significantly, and all manufactured formulations' drug release ranged from 98.83 to 104.78%, indicating a noticeably higher dissolution rate. Conclusion: The concept of mixed hydrotropic solid dispersion was shown to be an original, risk-free, and cost-effective method for enhancing the bioavailability of drugs that have a low degree of solubility in water.

Prasugrel and Ticagrelor in Patients with Drug-Eluting Stents and Kidney Failure.

BACKGROUND AND OBJECTIVES: Prasugrel and ticagrelor have superior efficacy compared with clopidogrel in moderate CKD but have not been studied in kidney failure. The study objective is to determine the effectiveness and safety of prasugrel and ticagrelor in kidney failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study used United States Renal Data System data from 2012 to 2015. We identified all patients on dialysis who received a drug-eluting stent and were alive at 90 days after stent implantation. Inverse probability-weighted Cox proportional hazard models were used. Weights were estimated with propensity scores for multiple treatments. RESULTS: This cohort included 6648 patients on clopidogrel, 621 on prasugrel, and 449 on ticagrelor. A total of 3279 primary composite (cardiovascular death, myocardial infarction, or stroke) and 2120 clinically relevant bleeding events were observed. The incidence of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke at 12 months was similar across the three treatment groups. The absolute event rate in the unweighted cohort was 144 events per 100 patient-years for clopidogrel, 126 for prasugrel, and 161 for ticagrelor. For prasugrel versus clopidogrel, the weighted hazard ratio was 0.96 (95% confidence interval, 0.82 to 1.11; P=0.58). For ticagrelor versus clopidogrel, the hazard ratio was 1.00 (95% confidence interval, 0.83 to 1.20; P=0.98). A numerically higher incidence of clinically relevant bleeding was seen with prasugrel or ticagrelor compared with clopidogrel (weighted hazard ratio, 1.15; 95% confidence interval, 0.95 to 1.38 and weighted hazard ratio, 1.13; 95% confidence interval, 0.91 to 1.40, respectively). CONCLUSIONS: Prasugrel or ticagrelor does not seem to be associated with significant benefits compared with clopidogrel in patients with kidney failure treated with drug-eluting stents. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_04_02_CJN12120720.mp3.

Cardiovascular Issues Among Homeless People: An Issue that Needs Attention.

Cardiovascular disease is one of the most common causes of death with social factors increasingly recognized as determinants of cardiovascular prognosis. Homelessness, transient or chronic, may be one of the factors which predict treatment access and eventual outcomes as socially and economically disadvantaged group has high prevalence of cardiovascular risk factors such as smoking, and delayed diagnosis and poor control of other risk factors such as diabetes and hypertension. This perspective article aims to discuss the issues associated with cardiovascular disease treatment, outcomes and future directions for homeless patients.

Protocols for nuclei isolation and nuclear protein extraction from the resurrection plant Xerophyta viscosa for proteomic studies.

The plant nucleus is an important subcellular organelle but the isolation of pure and enriched nuclei from plants and subsequent extraction of nuclear proteins for proteomic studies is challenging. Here, we present protocols for nuclei isolation and nuclear protein extraction from the resurrection plant, Xerophyta viscosa, and show optimization and modification of the most critical steps.

Analysis of the nuclear proteome of the resurrection plant Xerophyta viscosa in response to dehydration stress using iTRAQ with 2DLC and tandem mass spectrometry.

Xerophyta viscosa Baker (family Velloziaceae) is a desiccation tolerant plant which survives extremes of dehydration down to 5% relative water content (RWC) and resumes full physiological activity within 80h of rehydration. The nuclear proteome of Xerophyta viscosa and its response to dehydration at 35% RWC as compared to fully hydrated plants was analysed using iTRAQ together with 2DLC and ESI-MS/MS. RWC at 35% is unique for desiccation tolerant species as it represents a distinct phase of the dehydration process where induction of late protection mechanisms are initiated. We reproducibly identified 122 proteins with confidence≥95% (ρ<0.05). In response to dehydration, 65% of the identified proteins had the same protein abundance as the hydrated, 22% were shown to be more abundant while 9.8% were less abundant. Classification of the nuclear proteins according to GO annotation showed that most proteins were part of cellular processes (77.43%) and had binding activity (85.47%) respectively. Ontological classification according to Interpro and Pfam databases categorized most nuclear proteins as part of gene regulation (21%) while the functions of the mapped proteins using MapMan showed involvement in protein synthesis (22%), degradation (9%), DNA structure (8%) and regulation (8%).