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Synthesis and Activity of 6â€³-Deoxy-6â€³-thio-Î±-GalCer and Peptide Conjugates. - Organic letters
A major challenge in the development of highly defined synthetic vaccines is the codelivery of vaccine components (i.e., antigen and adjuvant) to secondary lymphoid tissue to induce optimal immune responses. This problem can be addressed by synthesizing vaccines that comprise peptide antigens covalently attached to glycolipid adjuvants through biologically cleavable linkers. Toward this, a strategy utilizing previously unreported 6â€³-deoxy-6â€³-thio analogues of Î±-GalCer that can undergo chemoselective conjugation with peptide antigens is described. Administration of these conjugate vaccines leads to enhanced priming of antigen specific T cells. This simple vaccine design is broadly applicable to multiple disease indications such as cancer and infectious disease.
2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American - Stroke; a journal of cerebral circulation
The aim of this guideline is to provide a focused update of the current recommendations for the endovascular treatment of acute ischemic stroke. When there is overlap, the recommendations made here supersede those of previous guidelines.This focused update analyzes results from 8 randomized, clinical trials of endovascular treatment and other relevant data published since 2013. It is not intended to be a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that justifies changes in current recommendations. Members of the writing committee were appointed by the American Heart Association/American Stroke Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association/American Stroke Association Manuscript Oversight Committee. Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statement Oversight Committee and Stroke Council Leadership Committee.Evidence-based guidelines are presented for the selection of patients with acute ischemic stroke for endovascular treatment, for the endovascular procedure, and for systems of care to facilitate endovascular treatment.Certain endovascular procedures have been demonstrated to provide clinical benefit in selected patients with acute ischemic stroke. Systems of care should be organized to facilitate the delivery of this care.Â© 2015 American Heart Association, Inc.
ILC2s and T cells cooperate to ensure maintenance of M2 macrophages for lung immunity against hookworms. - Nature communications
Defining the immune mechanisms underlying protective immunity to helminth infection remains an important challenge. Here we report that lung CD4(+) T cells and Group 2 innate lymphoid cells (ILC2s) work in concert to block Nippostrongylus brasiliensis (Nb) development in the parenchyma within 48â€‰h in mice. Immune-damaged larvae have a striking morphological defect that is dependent on the expansion of IL-13-producing ILC2 and CD4(+) T cells, and the activation of M2 macrophages. This T-cell requirement can be bypassed by administration of IL-2 or IL-33, resulting in expansion of IL-13-producing ILC2s and larval killing. Depletion of ILC2s inhibits larval killing in IL-2-treated mice. Our results broaden understanding of ILC2's role in immunity to helminths by demonstrating that they not only act as alarmin sensors, but can also be sustained by CD4(+) T cells, ensuring both the prompt activation and the maintenance of IL-13-dependent M2 macrophage immunity in the lung.
The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial: an adaptive trial design case study. - Trials
The 'Adaptive Designs Accelerating Promising Trials into Treatments (ADAPT-IT)' project is a collaborative effort supported by the National Institutes of Health (NIH) and United States Food & Drug Administration (FDA) to explore how adaptive clinical trial design might improve the evaluation of drugs and medical devices. ADAPT-IT uses the National Institute of Neurologic Disorders & Stroke-supported Neurological Emergencies Treatment Trials (NETT) network as a 'laboratory' in which to study the development of adaptive clinical trial designs in the confirmatory setting. The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial was selected for funding by the NIH-NINDS at the start of ADAPT-IT and is currently an ongoing phase III trial of tight glucose control in hyperglycemic acute ischemic stroke patients. Within ADAPT-IT, a Bayesian adaptive Goldilocks trial design alternative was developed.The SHINE design includes response adaptive randomization, a sample size re-estimation, and monitoring for early efficacy and futility according to a group sequential design. The Goldilocks design includes more frequent monitoring for predicted success or futility and a longitudinal model of the primary endpoint. Both trial designs were simulated and compared in terms of their mean sample size and power across a range of treatment effects and success rates for the control group.As simulated, the SHINE design tends to have slightly higher power and the Goldilocks design has a lower mean sample size. Both designs were tuned to have approximately 80% power to detect a difference of 25% versus 32% between control and treatment, respectively. In this scenario, mean sample sizes are 1,114 and 979 for the SHINE and Goldilocks designs, respectively.Two designs were brought forward, and both were evaluated, revised, and improved based on the input of all parties involved in the ADAPT-IT process. However, the SHINE investigators were tasked with choosing only a single design to implement and ultimately elected not to implement the Goldilocks design. The Goldilocks design will be retrospectively executed upon completion of SHINE to later compare the designs based on their use of patient resources, time, and conclusions in a real world setting.ClinicalTrials.gov NCT01369069 June 2011.
Increasing access to sexual health care for rural and regional young people: Similarities and differences in the views of young people and service providers. - The Australian journal of rural health
This study aims to describe the views of sexual health service providers on access issues for young people and consider them together with the views of young people themselves.A cross-sectional mixed-methods study design involving semi-structured interviews with health service providers and an electronic survey with young people.Four towns in rural and regional Queensland, Australia.A total of 32 service providers: 9 sexual health nurses, 8 general practitioners, 6 school-based youth health nurses, 5 sexual health educators, 2 Australian Aboriginal health workers and 2 youth workers. There were 391 young people who participated in the Young People's Survey.Themes generated from interviews with service providers and quantitative data from young people addressing access to sexual and reproductive health (SRH) services for rural and regional young people.Service providers frequently identified structural barriers, confidentiality and lack of awareness of SRH services as barriers for young people seeking SRH care. Young people also reported that structural factors such as transport, cost and service operating hours were important; however, they placed greater value on personal attributes of service providers, particularly welcoming and non-judgemental attitudes.Health service policy and training focused on attitudinal qualities of individual service providers may improve access to SRH services for young people. Selective staff recruitment and professional development are important to increase sensitivity to youth issues. Promotion of non-judgemental and confidential care may also improve access for youth.Â© 2015 National Rural Health Alliance Inc.
Young people. - Sexual health
Background Young people in regional and rural Queensland have difficulty accessing sexual and reproductive health (SRH) services. Young people's views regarding barriers and enablers for accessing SRH services and markers of quality are largely unknown. Methods: Young people's perceptions regarding SRH services are explored through a cross-sectional study via eight reference group meetings and an electronic survey in four sites: Atherton Tablelands, Rockhampton, Toowoomba and Townsville. The survey, developed in consultation with young people, was administered online and face to face using tablet computers. Data from 391 rural and regional participants was precoded for bivariate comparisons involving ?2 and confidence interval (CI) tests. Results: The most valued markers of quality in SRH services defined by young people all related to staff characteristics. Young people preferred services where staff were friendly (87.3%; 95% CI: 83.8-90.8%), easy to talk to (91.4%; 95% CI: 88.5-94.3%), good listeners (95.4%; 95% CI: 93.2-97.6%) and did not judge them (90.5%; 95% CI: 87.4-93.6%). A model of SRH service delivery encompassed within general health services was highly valued by 58.9% (95% CI 53.7-64.1%). However, 36.2% (95% CI: 31.4-41.0%) preferred to seek care from SRH specialist services. Conclusions: Service provision can be improved by training, and retaining friendly, attentive and non-judgemental staff. A model of service provision that includes general health care and provides sexual health services may increase the acceptability and accessibility of SRH services among youth. Additionally, our study highlights the need for choice between general and specialist SRH services.
Impact of selection strategies on representation of underserved populations and intention to practise: international findings. - Medical education
Socially accountable medical schools aim to reduce health inequalities by training workforces responsive to the priority health needs of underserved communities. One key strategy involves recruiting students from underserved and unequally represented communities on the basis that they may be more likely to return and address local health priorities. This study describes the impacts of different selection strategies of medical schools that aspire to social accountability on the presence of students from underserved communities in their medical education programmes and on student practice intentions.A cross-sectional questionnaire was administered to students starting medical education in five institutions with a social accountability mandate in five different countries. The questionnaire assessed students' background characteristics, rurality of background, and practice intentions (location, discipline of practice and population to be served). The results were compared with the characteristics of students entering medical education in schools with standard selection procedures, and with publicly available socio-economic data.The selection processes of all five schools included strategies that extended beyond the assessment of academic achievement. Four distinct strategies were identified: the quota system; selection based on personal attributes; community involvement, and school marketing strategies. Questionnaire data from 944 students showed that students at the five schools were more likely to be of non-urban origin, of lower socio-economic status and to come from underserved groups. A total of 407 of 810 (50.2%) students indicated an intention to practise in a non-urban area after graduation and the likelihood of this increased with increasing rurality of primary schooling (p = 0.000). Those of rural origin were statistically less likely to express an intention to work abroad (p = 0.003).Selection strategies to ensure that members of underserved communities can pursue medical careers can be effective in achieving a fair and equitable representation of underserved communities within the student body. Such strategies may contribute to a diverse medical student body with strong intentions to work with underserved populations.Â© 2014 John Wiley & Sons Ltd.
A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy. - Nature chemical biology
Epitope-based peptide vaccines encompass minimal immunogenic regions of protein antigens to allow stimulation of precisely targeted adaptive immune responses. However, because efficacy is largely determined by the functional status of antigen-presenting cells (APCs) that acquire and present peptides to cells of the adaptive immune system, adjuvant compounds are needed to enhance immunogenicity. We present here a vaccine consisting of an allergen-derived peptide conjugated to a prodrug of the natural killer-like T (NKT) cell agonist Î±-galactosylceramide, which is highly effective in reducing inflammation in a mouse model of allergic airway inflammation. Unlike other peptide-adjuvant conjugates that directly activate APCs through pattern recognition pathways, this vaccine encourages third-party interactions with NKT cells to enhance APC function. Therapeutic efficacy was correlated with marked increases in the number and functional activity of allergen-specific cytotoxic T lymphocytes (CTLs), leading to suppression of immune infiltration into the lungs after allergen challenge in sensitized hosts.
Readmissions after cardiac surgery: experience of the National Institutes of Health/Canadian Institutes of Health research cardiothoracic surgical trials network. - The Annals of thoracic surgery
Readmissions are a common problem in cardiac surgery. The goal of this study was to examine the frequency, timing, and associated risk factors for readmission after cardiac operations.A 10-center cohort study prospectively enrolled 5,158 adult cardiac surgical patients (5,059 included in analysis) to assess risk factors for infection after cardiac operations. Data were also collected on all-cause readmissions occurring within 65 days after the operation. Major outcomes included the readmission rate stratified by procedure type, cause of readmission, length of readmission stay, and discharge disposition after readmission. Multivariable Cox regression was used to determine risk factors for time to first readmission.The overall rate of readmission was 18.7% (number of readmissions, 945). When stratified by the most common procedure type, readmission rates were isolated coronary artery bypass grafting, 14.9% (nÂ = 248); isolated valve, 18.3% (nÂ = 337); and coronary artery bypass grafting plus valve, 25.0% (nÂ = 169). The three most common causes of first readmission within 30 days were infection (17.1% [nÂ = 115]), arrhythmia (17.1% [nÂ = 115]), and volume overload (13.5% [nÂ = 91]). More first readmissions occurred within 30 days (80.6% [nÂ = 672]) than after 30 days (19.4% [nÂ = 162]), and 50% of patients were readmitted within 22 days from the index operation. The median length of stay during the first readmission was 5 days. Discharge in 15.8% of readmitted patients (nÂ = 128) was to a location other than home. Baseline patient characteristics associated with readmission included female gender, diabetes mellitus on medication, chronic obstructive pulmonary disease, elevated creatinine, lower hemoglobin, and longer operation time. More complex surgical procedures were associated with an increased risk of readmission compared with the coronary artery bypass grafting group.Nearly 1 of 5 patients who undergo cardiac operations require readmission, an outcome with significant health and economic implications. Management practices to avert in-hospital infections, reduce postoperative arrhythmias, and avoid volume overload offer important targets for quality improvement.Copyright Â© 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
An investigation of chlorine ligands in transition-metal complexes via Â³âµCl solid-state NMR and density functional theory calculations. - Inorganic chemistry
Chlorine ligands in a variety of diamagnetic transition-metal (TM) complexes in common structural motifs were studied using (35)Cl solid-state NMR (SSNMR), and insight into the origin of the observed (35)Cl NMR parameters was gained through first-principles density functional theory (DFT) calculations. The WURST-CPMG pulse sequence and the variable-offset cumulative spectrum (VOCS) methods were used to acquire static (35)Cl SSNMR powder patterns at both standard (9.4 T) and ultrahigh (21.1 T) magnetic field strengths, with the latter affording higher signal-to-noise ratios (S/N) and reduced experimental times (i.e., <1 h). Analytical simulations were performed to extract the (35)Cl electric field gradient (EFG) tensor and chemical shift (CS) tensor parameters. It was found that the chlorine ligands in various bonding environments (i.e., bridging, terminal-axial, and terminal-equatorial) have drastically different (35)Cl EFG tensor parameters, suggesting that (35)Cl SSNMR is ideal for characterizing chlorine ligands in TM complexes. A detailed localized molecular orbital (LMO) analysis was completed for NbCl5. It was found that the contributions of individual molecular orbitals must be considered to fully explain the observed EFG parameters, thereby negating simple arguments based on comparison of bond lengths and angles. Finally, we discuss the application of (35)Cl SSNMR for the structural characterization of WCl6 that has been grafted onto a silica support material. The resulting tungsten-chloride surface species is shown to be structurally distinct from the parent compound.
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