A transient convection–diffusion equation is considered, which particularly arises in optimization problems for the asymmetric flow field-flow fractionation (AF4) process. A time-dependent ...generalization of the monotone edge-averaged finite element (EAFE) scheme is used to obtain a stable discretization in the convection-dominated regime. New error estimates are proved for this scheme and a comparison with the popular SUPG method is presented. Numerical experiments demonstrate that the EAFE method is more suitable for problems where boundary layers are formed.
•We consider transient convection–diffusion equation with dominating convection.•The model has an application in optimal control of the asymmetric flow field-flow fractionation process.•For a stable discretization we propose a monotone edge-averaged finite element (EAFE) scheme.•EAFE is generalized to a time-dependent case and a new error estimate is proved.•We present numerical results for comparison with a popular SUPG method.
Contemporary analyses of the distribution of heart failure (HF) patients by groups of ejection fraction are not available or are limited to hospitalized patients. Our objective was to quantify the ...per-person and system level clinical burden of a broad population of HF patients.
We studied 16,516 patients with a new HF diagnosis recorded in the electronic medical record of a U.S. integrated delivery system between 2005 and 2017. We used the diagnosis date as the index date and the nearest echocardiogram result to classify patients as HFrEF (n = 2,430), HFmrEF (n = 1,646), HFpEF (n = 12,440) and followed them through 2019 for major clinical outcomes (all-cause mortality, HF hospitalizations HHF, all-cause hospitalizations, incident chronic kidney disease CKD, progression of eGFR category, progression of CKD, incident type 2 diabetes T2D, and progression to insulin use). We compared age and sex adjusted incidence rates and rate ratios of the outcomes between the HF types.
Incidence rates for most outcomes were significantly higher among patients with HFrEF compared with HFpEF. HHF was 59 % greater, mortality 31 % greater, and CKD incidence 55 % greater, (p < 0.001 for all comparisons). However, the larger size of the HFpEF group generated 4.7–6.7 times as many total outcomes.
Regardless of subtype, the presence of HF was associated with poor clinical outcomes. Incidence rates were higher for HFrEF than HFpEF, but as the latter represented 75% of the study population, HFpEF caused a greater overall burden on the health care system, reflecting the high unmet need of target therapies for HFpEF.
This paper presents estimates of the convergence rate and complexity of an algebraic multilevel preconditioner based on piecewise constant coarse vector spaces applied to the graph Laplacian. A bound ...is derived on the energy norm of the projection operator onto any piecewise constant vector space, which results in an estimate of the two-level convergence rate where the coarse level graph is obtained by matching. The two-level convergence of the method is then used to establish the convergence of an algebraic multilevel iteration that uses the two-level scheme recursively. On structured grids, the method is proved to have convergence rate ≈ (1 - 1/log n) and O(n log n) complexity for each cycle, where n denotes the number of unknowns in the given problem. Numerical results of the algorithm applied to various graph Laplacians are reported. It is also shown that all the theoretical estimates derived for matching can be generalized to the case of aggregates containing more than two vertices.
Soil organisms, as recorded by trace fossils in paleosols of the Willwood Formation, Wyoming, show significant body-size reductions and increased abundances during the Paleocene-Eocene Thermal ...Maximum (PETM). Paleobotanical, paleopedologic, and oxygen isotope studies indicate high temperatures during the PETM and sharp declines in precipitation compared with late Paleocene estimates. Insect and oligochaete burrows increase in abundance during the PETM, suggesting longer periods of soil development and improved drainage conditions. Crayfish burrows and molluscan body fossils, abundant below and above the PETM interval, are significantly less abundant during the PETM, likely because of drier floodplain conditions and lower water tables. Burrow diameters of the most abundant ichnofossils are 30-46% smaller within the PETM interval. As burrow size is a proxy for body size, significant reductions in burrow diameter suggest that their tracemakers were smaller bodied. Smaller body sizes may have resulted from higher subsurface temperatures, lower soil moisture conditions, or nutritionally deficient vegetation in the high-CO₂ atmosphere inferred for the PETM. Smaller soil fauna co-occur with dwarf mammal taxa during the PETM; thus, a common forcing mechanism may have selected for small size in both above- and below-ground terrestrial communities. We predict that soil fauna have already shown reductions in size over the last 150 years of increased atmospheric CO₂ and surface temperatures or that they will exhibit this pattern over the next century. We retrodict also that soil fauna across the Permian-Triassic and Triassic-Jurassic boundary events show significant size decreases because of similar forcing mechanisms driven by rapid global warming.
Glioblastoma (GBM) is the most malignant neoplasm with predominant astrocytic differentiation and the most frequent primary brain tumor of the adult. Here, we investigated 170 human GBM specimens ...deriving from 162 patients, as well as 66 healthy control tissue specimens deriving from 27 patients, and analyzed the amount of 5-hydroxymethylcytosine (5hmC) in GBMs compared to normal brain and tumor infiltration zones. Additionally, we correlated the amount of 5hmC with two different proliferation markers, Ki67 and H3S10p. Genetic characterization of GBMs enabled us to analyze the effect of isocitrate dehydrogenase 1 (
IDH1
) mutations, O6-methylguanin-DNA-methyltransferase (MGMT) promoter methylation, and loss of heterozygosity of chromosome 1p and 19q (LOH1p/19q) on 5hmC amount. We found that GBMs show a tremendous loss of 5hmC, and we observed that even the infiltration zones show reduced amounts of 5hmC. Interestingly, the amount of 5hmC was inversely proportional to the two investigated proliferation markers, Ki67 and H3S10p. Correlation of 5hmC amount and molecular genetic markers of GBMs showed that there are no correlations of 5hmC amount and
IDH1
mutations, MGMT promoter methylation, and LOH1p/19q. Furthermore, we evaluated the intratumoral distribution of 5hmC in compact and infiltrating areas and found that the quantification of the 5hmC amount is a useful tool in evaluation of tumor infiltration. In summary, our data emphasize that GBMs show a disturbed hydroxymethylome that is disrupted by
IDH1
independent pathways, and that loss of 5hmC shows astonishing intratumoral heterogeneity.
Plain Radiography of the spine (PROTS) is utilized in many forms of healthcare including the chiropractic profession; however, the literature reflects conflicting opinions regarding utilization and ...value. Despite being an essential part of Evidence-Based Practice (EBP), few studies assess Doctors of Chiropractic (DCs) clinical opinions and experience regarding the utilization of (PROTS) in practice. In this study, DCs were surveyed regarding utilization of PROTS in practice. The survey was administered to an estimated 50,000 licensed DCs by email. A total of 4301 surveys were completed, of which 3641 were United States (US) DCs. The Clinician Opinion and Experience on Chiropractic Radiography (COECR) scale was designed to analyze survey responses. This valid and reliable scale demonstrated good internal consistency using confirmatory factor analysis and the Rasch model. Survey responses show that 73.3% of respondents utilize PROTS in practice and 26.7% refer patients out for PROTS. Survey responses show that, among US DCs, 91.9% indicate PROTS has value beyond identification of pathology, 86.7% indicate that PROTS is important regarding biomechanical analysis of the spine, 82.9% indicate that PROTS is vital to practice, 67.4% indicate that PROTS aids in measuring outcomes, 98.6% indicate the opinion that PROTS presents very low to no risk to patients, and 93.0% indicate that sharing clinical findings from PROTS studies with patients is beneficial to clinical outcomes. The results of the study indicated that based on clinical experience, the majority of DCs find PROTS to be vital to practice and valuable beyond the identification of red flags.
Background
To minimize the risk of progressive multifocal leucoencephalopathy (PML), treatment with natalizumab is often stopped after 2 years, but evidence upon rebound of disease activity is ...limited and controversial.
Objective
To evaluate effects of natalizumab discontinuation on clinical disease activity within twelve months after cessation.
Methods
We retrospectively analyzed data of 201 patients with MS who discontinued natalizumab between 2007 and 2012. Mean change scores of annualized relapse rate (ARR) and expanded disability status scale (EDSS) were calculated for detection of rebound disease activity after twelve months.
Results
Natalizumab exposure did not exceed 2 years in 50.2% of patients, and the most common reasons for discontinuation were a long treatment period and concern of PML (56%). A total of 11.9% experienced a rebound phenomenon within twelve months. Mean ARR prenatalizumab was lower (P = 0.001, 95% CI −1.0–0.000) and treatment response to natalizumab poorer (P < 0.001, 95% CI 0.4–1.3) in patients with rebound compared to those without, but rebound was not associated with brief exposure to natalizumab (P = 0.159, 95% CI −9.3–1.5). 86.1% of patients switched to another therapy. Patients without rebound were found more often in the group starting an alternative treatment early (P = 0.013).
Conclusion
Our data suggest that rebound of MS disease activity affects a subgroup of patients (11.9%), especially those with low disease activity before natalizumab therapy and a longer treatment gap after its withdrawal.
The aim of this study was to investigate the incidence, risk factors, and outcome of venous thromboembolism (VTE) following anterior cruciate ligament (ACL) reconstruction in a nationwide cohort.
All ...ACL reconstructions, primary and revision, that were recorded in the Swedish Knee Ligament Register (SKLR) between 2006 and 2013 were linked with data from the Swedish National Board of Health and Welfare. The incidence of VTE was determined by entries between the day of surgery until 90 days postoperatively based on diagnosis codes and the prescription of anticoagulants. Risk factors, outcome, and the use of thromboprophylaxis were analyzed. Descriptive statistics with multivariate analysis were used to describe the findings.
The cohort consisted of 26 014 primary and revision ACL reconstructions. There were 89 deep venous thromboses (DVTs) and 12 pulmonary emboli (PEs) with a total of 95 VTEs (0.4 %). Six patients with a PE had a simultaneous DVT. The only independent risk factor for VTE was age greater than or equal to 40 years (odds ratio 2.31, 95% confidence interval 1.45 to 3.70; p < 0.001). Thromboprophylaxis was prescribed to 9461 patients (36%) and was equally distributed between those with and those without a VTE (37.9% vs 36.4%). All patient-reported outcome measures (PROMs) one and two years postoperatively were significantly lower in those with VTE.
The incidence of VTE following ACL reconstruction is 0.4%, and the only significant risk factor is age. Patients with VTE had worse postoperative clinical outcome than patients without VTE. We recommend against the routine use of thromboprophylaxis, but it should be considered in older patients.
Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that hypoxia inducible factor-1α ...(HIF-1α) induces EBV's latent-to-lytic switch and identified several HIF-1α-stabilizing drugs that induce this viral reactivation. Here, we tested three classes of these drugs for preferential killing of the EBV-positive gastric cancer AGS-Akata cell line compared to its matched EBV-negative AGS control. We observed preferential killing with iron chelators Deferoxamine (DFO); Deferasirox (DFX) and a prolyl hydroxylase inhibitor (BAY 85-3934 (Molidustat)), but not with a neddylation inhibitor MLN4924 (Pevonedistat). DFO and DFX also induced preferential killing of the EBV-positive gastric cancer AGS-BDneo and SNU-719 cell lines. Preferential killing was enhanced when low-dose DFX (10 μM) was combined with the antiviral prodrug ganciclovir. DFO and DFX induced lytic EBV reactivation in approximately 10% of SNU-719 and 20-30% of AGS-Akata and AGS-BDneo cells. However, neither DFO nor DFX significantly induced synthesis of lytic EBV proteins in xenografts grown in NSG mice from AGS-Akata cells above the level observed in control-treated mice. Therefore, these FDA-approved iron chelators are less effective than gemcitabine at promoting EBV reactivation in vivo despite their high specificity and efficiency in vitro.
PDF
