Comparison of bleeding and thrombotic outcomes in veno-venous extracorporeal membrane oxygenation: Heparin versus bivalirudin.

OBJECTIVES: We aimed to evaluate thrombotic and hemorrhagic complications with heparin versus bivalirudin use in veno-venous extracorporeal membrane oxygenation (V-V ECMO). METHODS: We performed a retrospective cohort study of adult patients placed on V-V ECMO with intravenous anticoagulation with either heparin or bivalirudin. Time to thrombotic event and major bleed were analyzed in addition to related outcomes. RESULTS: We identified 95 patients placed on V-V ECMO: 61 receiving heparin, 34 bivalirudin. The bivalirudin group had a higher rate of severe COVID-19, higher BMI, and longer ECMO duration. Despite this, bivalirudin was associated with reduced risk of thrombotic event (HR 0.14, 95% CI 0.06-0.32, p < .001) and increased average lifespan of the circuit membrane lung (16 vs. 10 days, p = 0.004). While there was no difference in major bleeding, the bivalirudin group required fewer transfusions of packed red blood cells and platelets per 100 ECMO days (means of 13 vs. 39, p = 0.004; 5 vs. 19, p = .014, respectively). Lastly, the bivalirudin group had improved survival to ECMO decannulation in univariate analysis (median OS 53 vs. 26 days, p = .015). CONCLUSIONS: In this real-world analysis of bivalirudin versus heparin, bivalirudin is a viable option for V-V ECMO and associated with lower risk of thrombotic complications and fewer transfusion requirements.

Predictors of thrombosis during VV ECMO: an analysis of 9809 patients from the ELSO registry.

Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving therapy for critically ill patients, but it carries an increased risk of thrombosis due to blood interacting with non-physiological surfaces. While the relationship between clinical variables and thrombosis remains unclear, our study aimed to identify which factors are most predictive of thrombosis. The Extracorporeal Life Support Organization Registry was queried to obtain a cohort of VV-ECMO patients aged 18 years and older from 2015 to 2019. Patients who were over 80-years-old, at the extremes of weight, who received less than 24 h of ECMO, multiple rounds of ECMO, or had missing data were excluded. Multivariate logistic regression modeling was used to assess predictors of thrombosis and mortality. A total of 9809 patients were included in the analysis, with a mean age of 47.1 ± 15.1 years and an average ECMO run time of 305 ± 353 h. Thrombosis occurred in 19.9% of the cohort, with circuit thrombosis (8.6%) and membrane lung failure (6.1%) being the most common. Multivariate analysis showed that ECMO runs over 14 days (OR: 2.62, P < 0.001) and pregnancy-related complications (OR: 1.79, P = 0.004) were associated with an increased risk of thrombosis. Risk factors for circuit thrombosis included incremental unit increases in the pump flow rate at 24 h (OR: 1.07 [1.00-1.14], P = 0.044) and specific cannulation sites. Increased body weight (OR: 1.02 [1.00-1.04], P = 0.026) and increased duration on ECMO (OR: 3.82 [3.12-4.71], P < 0.001) were predictive of membrane lung failure. Additionally, patients with thrombosis were at increased likelihood of in-hospital mortality (OR: 1.52, P < 0.001). This study identified multiple thrombotic risk factors in VV-ECMO, suggesting that future studies investigating the impact of pregnancy associated complications and ECMO flow rate on hemostasis would be illuminating.

Intermittent Versus Continuous Infusion Dosing of Intravenous Proton Pump Inhibitors for Upper Gastrointestinal Bleeding.

BACKGROUND: Proton pump inhibitor (PPI) continuous infusions or intermittent boluses are used for the treatment of upper gastrointestinal bleeding (UGIB). Intermittent boluses are easier to give and are of lower cost without affecting clinical outcomes. OBJECTIVE: To compare the rate of rebleeding between intermittent bolus and continuous infusion PPI therapy. METHODS: We performed a retrospective, multicenter review of patients with UGIB receiving either continuous or intermittent PPI therapy. During the study period, due to drug and supply shortages, each institution implemented policies preferring intermittent PPI bolus therapy. We performed bivariate and multivariable comparisons of the 2 treatment strategies, with the primary outcome of interest being incidence of rebleeding. Additional variables of interest included intensive care unit (ICU) and hospital lengths of stay, discharge disposition, and in-hospital mortality. RESULTS: Compared with intermittent bolus dosing (n = 209), patients receiving continuous infusion PPI (n = 237) were associated with a higher rate of rebleeding (33.8% vs 23.0%; P = 0.012); however, no difference was detected in multivariable analysis: adjusted odds ratio, 1.50 (95% confidence interval, 0.91-2.50). There was no difference in median hospital or ICU length of stay, discharge disposition, or in-hospital mortality. Correlatively, patients receiving continuous infusion therapy were more likely to have liver disease (29.1% vs 20.1%; P = 0.028), alcohol use disorder (28.3% vs 16.3.%; P = 0.003), history of lower gastrointestinal bleeding (6.4% vs 1.9%; P = 0.021), variceal bleeding (6.3 vs 2.4%, P = 0.045), and be admitted to the ICU (65.0% vs 32.5%, P = 0.00). CONCLUSIONS: Introduction of intermittent PPI bolus UGIB treatment via change in hospital policy was not associated with higher rates of rebleeding. However, continuous PPI therapy may have been perceived as more effective as it was used more commonly in high-risk patients.

Improvements needed to support people living and working with a rare disease in Northern Ireland: current rare disease support perceived as inadequate.

BACKGROUND: Many people living and working with rare diseases describe consistent difficulties accessing appropriate information and support. In this study an evaluation of the awareness of rare diseases, alongside related information and educational resources available for patients, their families and healthcare professionals, was conducted in 2018-2019 using an online survey and semi-structured interviews with rare disease collaborative groups (charities, voluntary and community groups) active across Northern Ireland (NI). METHODS: This study had 2 stages. Stage 1 was an online survey and stage 2 involved semi-structured interviews both with rare disease collaborative groups in Northern Ireland. The surveys and interviews were used to locate existing resources as well as identify gaps where the development of further resources would be appropriate. RESULTS: Ninety-nine rare disease collaborative groups engaged with the survey with 31 providing detailed answers. Resources such as information, communication, 'registries', online services, training and improvements to support services were queried. Excellent communication is an important factor in delivering good rare disease support. Training for health professionals was also highlighted as an essential element of improving support for those with a rare disease to ensure they approach people with these unique and challenging diseases in an appropriate way. Carers were mentioned several times throughout the study; it is often felt they are overlooked in rare disease research and more support should be in place for them. Current care/support for those with a rare disease was highlighted as inadequate. Nine semi-structured interviews were conducted with rare disease collaborative groups. Reoccurring themes included a need for more effective information and communication, training for health professionals, online presence, support for carers, and involvement in research. CONCLUSIONS: All rare disease collaborative groups agreed that current services for people living and working with a rare disease are not adequate. An important finding to consider in future research within the rare disease field is the inclusion of carers perceptions and experiences in studies. This research provides insight into the support available for rare diseases across Northern Ireland, highlights unmet needs, and suggests approaches to improve rare disease support.

Communication strategies for rare cancers: a systematic review protocol.

BACKGROUND: Rare cancers comprise almost a quarter of all cancers in Europe, and patients generally have poorer outcomes than those suffering from more common cancers. This is attributed in part to a general lack of knowledge and awareness of rare cancers. This review aims to examine the communication strategies being used throughout the world to inform on rare cancers and to highlight any opportunities for improvement. METHODS: A systematic review of literature published in English prior to November 2018 will be conducted, screening articles from the electronic databases MEDLINE, PubMed, EMBASE, Web of Science, PsycINFO, CINAHL Plus and the Cochrane Database of Systematic Reviews. Grey literature databases (GreyLit, OpenGrey) will also be searched in order to screen for any unpublished works. As well as primary literature, reference lists will be examined via forward and reverse citation screening. The review will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Titles and abstracts will first be examined for eligibility, with remaining studies undergoing a full-text screening before being included in the final review. Individual studies will be screened for bias, and a meta-analysis performed provided there is enough data. If insufficient homogenous literature exists, a narrative summary of the literature will be produced. DISCUSSION: Despite the broad topic and width of study type that will be considered, this review hopes to provide a reflective summary of the communication strategies available for people living with and working with rare cancer. It aims to reveal any gaps in the resources available, to contribute to the long-term improvement of diagnosis and management of rare cancers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018099784.

Epigenome-wide association study for Parkinson's disease.

A methylation-based EWAS on carefully phenotyped individuals with Parkinson's disease (PD) was conducted to reveal prioritised genes and pathways with statistically significant and sizable changes in PD and in the anxiety that often accompanies it. This was followed by subsequent replication of top-ranked CpG sites. Using the Infinium(®) HumanMethylation 450K beadchip (Illumina Inc., USA), twenty unique genes with a sizable difference in methylation (P(adjusted) < 0.05, Δß ≥ 0.2), after correction for multiple testing, were identified between PD and controls, while seventeen were identified between PD with anxiety and PD without anxiety. Twelve top ranked, significantly associated loci in PD were evaluated in an independent replicate population using Sequenom EpiTYPER for 219 individuals with similar phenotypes to the cross-sectional case-control discovery design. FANCC cg14115740 and TNKS2 cg11963436 show significant differential methylation between PD cases and controls using both techniques and their Δß values, which have the same direction of effect, are reasonable to warrant further investigation.

Synthesis and structure-activity analysis of diphenylpyrazolodiazene inhibitors of the HIV-1 Nef virulence factor.

HIV-1 Nef is a critical AIDS progression factor yet underexplored target for antiretroviral drug discovery. A recent high-throughput screen for pharmacological inhibitors of Nef-dependent Src-family kinase activation identified a diphenylpyrazolodiazene hit compound with submicromolar potency in HIV-1 replication assays against a broad range of primary Nef variants. This compound, known as 'B9', binds directly to Nef and inhibits its dimerization in cells as a possible mechanism of action. Here were synthesized a diverse set of B9 analogs and identified structural features essential to antiretroviral activity. Chemical modifications to each of the three rings present in the parent compound were identified that did not compromise antiviral action. These analogs will guide the development of next-generation compounds with appropriate pharmacological profiles for assessment of antiretroviral activity in vivo.

Deleterious impact of a γ-aminobutyric acid type A receptor preferring general anesthetic when used in the presence of persistent inflammation.

BACKGROUND: Experimental data suggest general anesthetics preferring γ-aminobutyric acid receptor type A may increase postoperative pain in patients with persistent inflammation. The current study was designed to begin to test this hypothesis. METHODS: Groups of rats were defined by the presence of inflammation, surgical intervention, and/or the type of general anesthetic used for a 3-h period of anesthesia. Persistent inflammation was induced with complete Freund adjuvant. The surgical intervention was a plantar incision. Three mechanistically distinct general anesthetics were used: pentobarbital, ketamine/xylazine, and isoflurane. Ongoing pain and hypersensitivity were assessed with guarding behavior analysis and the von Frey test, respectively. RESULTS: There was no influence of general anesthetic type on the magnitude or time course of recovery from postoperative hypersensitivity in the absence of persistent inflammation. However, in the presence of persistent inflammation, recovery from hypersensitivity was significantly slower in the pentobarbital group than in the ketamine/xylazine or isoflurane groups. The pentobarbital effect was significant within 3 days of surgery and persisted through the remainder of the testing period. A comparable delay in recovery was observed in pentobarbital-anesthetized inflamed rats not subjected to hind paw incision. The time to 50% recovery in the pentobarbital-treated inflamed groups was almost double that in the other groups. No differences were observed between ketamine/xylazine and isoflurane. Pentobarbital exposure did not increase guarding scores. CONCLUSIONS: These results suggest that general anesthetics preferring γ-aminobutyric acid receptor type A may have deleterious consequences when used in the presence of persistent inflammation.

Changes in Bacterial Cell and Spore Counts of Reduced-Fat Egg Products As Influenced by Pasteurization and Spray Drying.

Microbial counts of several laboratory-prepared defatted egg products and ingredients were determined. Commercial full-fat egg yolks (EY) were defatted with hexane, air dried overnight, mixed with water, homogenized, pasteurized (60°C, 5 min), and spray dried to yield a defatted egg yolk product (DEY). Egg products for scrambling (EPS) were formulated with DEY and other ingredients, processed as above, and held wet (EPS-W) or spray-dried (EPS-SD). On a dry matter basis, the log counts in colony forming units per g (log CFU/g) of EY for aerobic bacteria, yeasts and molds, and aerobic mesophilic sporeformers were low at 1.3, 1.0 and 0, respectively. For DEY these counts were 6.0, 2.4, and 4.3, respectively. These counts for DEY after pasteurization decreased by 98.6, 89.6, and 40.0%, and after spray drying decreased by 99.3, 96.1, and 83.5%, respectively, compared to the pre-pasteurization counts. For EPS-W, pasteurization reduced aerobic bacteria, yeasts and molds, and coliforms by 82.0, 86.7, and 98.7%, but did not reduce aerobic mesophilic sporeformers. Compared to pre pasteurization counts, for EPS-SD the aerobic bacteria, yeasts and molds, coliforms, and aerobic mesophilic sporeformer counts after pasteurization decreased by 99.7, 91.9, 99.3, and 50.0%, while after spray drying the count reductions were 99.9, 98.9, 99.9, and 85.8%, respectively. Microbial counts of finished products were below guidelines set by the U.S.D.A. for egg products. No Salmonella were detected in any of the ingredients or prototype products at any stage of processing. The combination treatment of pasteurization followed by spray drying significantly reduced the spore counts of DEY and EPS-SD, compared to pre-pasteurization counts.