A Direct Elliptic Solver Based on Hierarchically Low-rank Schur Complements

A parallel fast direct solver for rank-compressible block tridiagonal linear systems is presented. Algorithmic synergies between Cyclic Reduction and Hierarchical matrix arithmetic operations result in a solver with $O(N \log^2 N)$ arithmetic complexity and $O(N \log N)$ memory footprint. We provide a baseline for performance and applicability by comparing with well known implementations of the $\mathcal{H}$-LU factorization and algebraic multigrid with a parallel implementation that leverages the concurrency features of the method. Numerical experiments reveal that this method is comparable with other fast direct solvers based on Hierarchical Matrices such as $\mathcal{H}$-LU and that it can tackle problems where algebraic multigrid fails to converge

ACR Accreditation for Utah Valley Hospital’s Radiation Oncology Center

Becoming an accredited clinic through the American College of Radiology (ACR) and their Radiation Oncology Practice Accreditation (ROPA) program will provide third-party evaluation of patient care to ensure the best treatment possible for patients. Talk of getting ACR accreditation has occurred in the past for Utah Valley Hospital/American Fork Hospital, but at the time it was seen as something that did not provide sufficient value vs. the cost. The recent One Intermountain restructuring is intended to unify all of the Intermountain Healthcare radiation oncology centers in Utah so the Radiation Oncology Director has set the goal that all Intermountain radiation oncology programs will be accredited. Intermountain Medical Center (IMC) and Dixie Regional Medical Center (DRMC) are currently ACR accredited and can be used as model programs. I started with an in-depth examination of our department’s workflow, documentation, and policies in order to determine where improvements to meet ACR accreditation standards could be made. I followed this up by working on implementing some of these improvements throughout the clinic and made sure they become routine and a standard in the department. An analysis of Dixie Regional Medical Center and Intermountain Medical Center’s ACR documents was performed to provide a baseline of an accredited-ACR program. Finally, a comprehensive checklist of everything that will need to be changed or implemented was presented in order to provide guidance for the future

Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.

BACKGROUND: An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. METHODS: We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). RESULTS: At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. CONCLUSIONS: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48

Potent CRISPR-Cas9 inhibitors from Staphylococcus genomes.

Anti-CRISPRs (Acrs) are small proteins that inhibit the RNA-guided DNA targeting activity of CRISPR-Cas enzymes. Encoded by bacteriophage and phage-derived bacterial genes, Acrs prevent CRISPR-mediated inhibition of phage infection and can also block CRISPR-Cas-mediated genome editing in eukaryotic cells. To identify Acrs capable of inhibiting Staphylococcus aureus Cas9 (SauCas9), an alternative to the most commonly used genome editing protein Streptococcus pyogenes Cas9 (SpyCas9), we used both self-targeting CRISPR screening and guilt-by-association genomic search strategies. Here we describe three potent inhibitors of SauCas9 that we name AcrIIA13, AcrIIA14, and AcrIIA15. These inhibitors share a conserved N-terminal sequence that is dispensable for DNA cleavage inhibition and have divergent C termini that are required in each case for inhibition of SauCas9-catalyzed DNA cleavage. In human cells, we observe robust inhibition of SauCas9-induced genome editing by AcrIIA13 and moderate inhibition by AcrIIA14 and AcrIIA15. We also find that the conserved N-terminal domain of AcrIIA13-AcrIIA15 binds to an inverted repeat sequence in the promoter of these Acr genes, consistent with its predicted helix-turn-helix DNA binding structure. These data demonstrate an effective strategy for Acr discovery and establish AcrIIA13-AcrIIA15 as unique bifunctional inhibitors of SauCas9

Secukinumab versus adalimumab for psoriatic arthritis: comparative effectiveness up to 48 weeks using a matching-adjusted indirect comparison

Secukinumab and adalimumab are approved for adults with active psoriatic arthritis (PsA). In the absence of direct randomized controlled trial (RCT) data, matching-adjusted indirect comparison can estimate the comparative effectiveness in anti-tumor necrosis factor (TNF)-naïve populations. Individual patient data from the FUTURE 2 RCT (secukinumab vs. placebo; N = 299) were adjusted to match baseline characteristics of the ADEPT RCT (adalimumab vs. placebo; N = 313). Logistic regression determined adjustment weights for age, body weight, sex, race, methotrexate use, psoriasis affecting ≥ 3% of body surface area, Psoriasis Area and Severity Index score, Health Assessment Questionnaire Disability Index score, presence of dactylitis and enthesitis, and previous anti-TNF therapy. Recalculated secukinumab outcomes were compared with adalimumab outcomes at weeks 12 (placebo-adjusted), 16, 24, and 48 (nonplacebo-adjusted). After matching, the effective sample size for FUTURE 2 was 101. Week 12 American College of Rheumatology (ACR) response rates were not significantly different between secukinumab and adalimumab. Week 16 ACR 20 and 50 response rates were higher for secukinumab 150 mg than for adalimumab (P = 0.017, P = 0.033), as was ACR 50 for secukinumab 300 mg (P = 0.030). Week 24 ACR 20 and 50 were higher for secukinumab 150 mg than for adalimumab (P = 0.001, P = 0.019), as was ACR 20 for secukinumab 300 mg (P = 0.048). Week 48 ACR 20 was higher for secukinumab 150 and 300 mg than for adalimumab (P = 0.002, P = 0.027), as was ACR 50 for secukinumab 300 mg (P = 0.032). In our analysis, patients with PsA receiving secukinumab were more likely to achieve higher ACR responses through 1 year (weeks 16-48) than those treated with adalimumab. Although informative, these observations rely on a subgroup of patients from FUTURE 2 and thus should be considered interim until the ongoing head-to-head RCT EXCEED can validate these findings. Novartis Pharma AG

Gravitational Properties of Monopole Spacetimes Near the Black Hole Threshold

Although nonsingular spacetimes and those containing black holes are qualitatively quite different, there are continuous families of configurations that connect the two. In this paper we use self-gravitating monopole solutions as tools for investigating the transition between these two types of spacetimes. We show how causally distinct regions emerge as the black hole limit is achieved, even though the measurements made by an external observer vary continuously. We find that near-critical solutions have a naturally defined entropy, despite the absence of a true horizon, and that this has a clear connection with the Hawking-Bekenstein entropy. We find that certain classes of near-critical solutions display naked black hole behavior, although they are not truly black holes at all. Finally, we present a numerical simulation illustrating how an incident pulse of matter can induce the dynamical collapse of a monopole into an extremal black hole. We discuss the implications of this process for the third law of black hole thermodynamics.Comment: 23 pages, 4 figures RevTe

Herbal therapy for treating rheumatoid arthritis (review)

Background Herbal medicine interventions have been identified as having potential benefit in the treatment of rheumatoid arthritis (RA). Objectives To update an existing systematic (Cochrane) review of herbal therapies in RA. Search methods We searched electronic databases Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, AMED, CINAHL, Web of Science, Dissertation Abstracts (1996 to 2009), unrestricted by language, and the WHO International Clinical Trials Registry Platform in October 2010. Selection criteria Randomised controlled trials of herbal interventions compared with placebo or active controls in RA. Data collection and analysis Two authors selected trials for inclusion, assessed risk of bias and extracted data. Main results Twelve new studies were added to the update, a total of 22 studies were included. Evidence from seven studies indicate potential benefits of gamma linolenic acid (GLA) from evening primrose oil, borage seed oil, or blackcurrent seed oil, in terms of reduced pain intensity (mean difference (MD) ‐32.83 points, 95% confidence interval (CI) ‐56.25 to ‐9.42,100 point pain scale); improved disability (MD ‐15.75% 95% CI ‐27.06 to ‐4.44%); and an increase in adverse events (GLA 20% versus placebo 3%), that was not statistically different (relative risk 4.24, 95% CI 0.78 to 22.99). Three studies compared Tripterygium wilfordii (thunder god vine) to placebo and one to sulfasalazine and indicated improvements in some outcomes, but data could not be pooled due to differing interventions, comparisons and outcomes. One study reported serious side effects with oral Tripterygium wilfordii Hook F. In the follow‐up studies, all side effects were mild to moderate and resolved after the intervention ceased. Two studies compared Phytodolor® N to placebo but poor reporting limited data extraction. The remaining studies each considered differing herbal interventions. Authors' conclusions Several herbal interventions are inadequately justified by single studies or non‐comparable studies in the treatment of rheumatoid arthritis. There is moderate evidence that oils containing GLA (evening primrose, borage, or blackcurrant seed oil) afford some benefit in relieving symptoms for RA, while evidence for Phytodolor® N is less convincing.Tripterygium wilfordii products may reduce some RA symptoms, however, oral use may be associated with several side effects. Many trials of herbal therapies are hampered by research design flaws and inadequate reporting. Further investigation of each herbal therapy is warranted, particularly via well designed, fully powered, confirmatory clinical trials that use American College of Rheumatology improvement criteria to measure outcomes and report results according to CONSORT guidelines

Time-variability in the Interstellar Boundary Conditions of the Heliosphere: Effect of the Solar Journey on the Galactic Cosmic Ray Flux at Earth

During the solar journey through galactic space, variations in the physical properties of the surrounding interstellar medium (ISM) modify the heliosphere and modulate the flux of galactic cosmic rays (GCR) at the surface of the Earth, with consequences for the terrestrial record of cosmogenic radionuclides. One phenomenon that needs studying is the effect on cosmogenic isotope production of changing anomalous cosmic ray fluxes at Earth due to variable interstellar ionizations. The possible range of interstellar ram pressures and ionization levels in the low density solar environment generate dramatically different possible heliosphere configurations, with a wide range of particle fluxes of interstellar neutrals, their secondary products, and GCRs arriving at Earth. Simple models of the distribution and densities of ISM in the downwind direction give cloud transition timescales that can be directly compared with cosmogenic radionuclide geologic records. Both the interstellar data and cosmogenic radionuclide data are consistent with cloud transitions during the Holocene, with large and assumption-dependent uncertainties. The geomagnetic timeline derived from cosmic ray fluxes at Earth may require adjustment to account for the disappearance of anomalous cosmic rays when the Sun is immersed in ionized gas.Comment: Submitted to Space Sciences Review