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1.  Evaluation of the Antitumor Effects of BPR1J-340, a Potent and Selective FLT3 Inhibitor, Alone or in Combination with an HDAC Inhibitor, Vorinostat, in AML Cancer 
PLoS ONE  2014;9(1):e83160.
Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment. In this study, BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD+ AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD+ AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy. Our results suggest that BPR1J-340 may be further developed in the preclinical and clinical studies as therapeutics in AML treatments.
doi:10.1371/journal.pone.0083160
PMCID: PMC3885398  PMID: 24416160
2.  Validation of an Algorithm for Categorizing the Severity of Hospital Emergency Department Visits 
Medical care  2010;48(1):10.1097/MLR.0b013e3181bd49ad.
Background
Differentiating between appropriate and inappropriate resource use represents a critical challenge in health services research. The New York University Emergency Department (NYU ED) visit severity algorithm attempts to classify visits to the ED based on diagnosis, but it has not been formally validated.
Objective
To assess the validity of the NYU algorithm. Research Design: A longitudinal study in a single integrated delivery system (IDS) from January 1999 to December 2001.
Subjects
2,257,445 commercial and 261,091 Medicare members of an IDS.
Measures
ED visits were classified as emergent, non-emergent, or intermediate severity, using the NYU ED algorithm. We examined the relationship between visit-severity and the probability of future hospitalizations and death using a logistic model with a general estimating equation (GEE) approach.
Results
Among commercially insured subjects, ED visits categorized as emergent were significantly more likely to result in a hospitalization within one-day (OR=3.37, 95% CI: 3.31–3.44) or death within 30-days (OR=2.81, 95% CI: 2.62–3.00) than visits categorized as non-emergent. We found similar results in Medicare patients and in sensitivity analyses using different probability thresholds. ED overuse for non-emergent conditions was not related to socio-economic status or insurance type.
Conclusions
The evidence presented supports the validity of the NYU ED visit severity algorithm for differentiating ED visits based on need for hospitalization and/or mortality risk; therefore, it can contribute to evidence-based policies aimed at reducing the use of the ED for non-emergencies.
doi:10.1097/MLR.0b013e3181bd49ad
PMCID: PMC3881233  PMID: 19952803
Access/Utilization of Services; Health Care Financing/Insurance; Emergency Care; NYU Algorithm; Billings
3.  Diffeomorphic Brain Mapping Based on T1-Weighted Images: Improvement of Registration Accuracy by Multi-Channel Mapping 
Purpose
To improve image registration accuracy in neurodegenerative populations.
Materials and Methods
This study used primary progressive aphasia, aged control, and young control T1-weighted images. Mapping to a template image was performed using single-channel Large Deformation Diffeomorphic Metric Mapping (LDDMM), a dual-channel method with ventricular anatomy in the second channel, and a dual-channel w/appendage method, which utilized a priori knowledge of template ventricular anatomy in the deformable atlas.
Results
Our results indicated substantial improvement in the registration accuracy over single-contrast-based brain mapping, mainly in the lateral ventricles and regions surrounding them. Dual-channel mapping significantly (p<0.001) reduced the number of misclassified lateral ventricle voxels (based on manually-defined reference) over single-channel mapping. Dual-channel (w/appendage) method further reduced (p<0.001) misclassification over dual-channel method, indicating that the appendage provides more accurate anatomical correspondence for deformation.
Conclusion
Brain anatomical mapping by shape normalization is widely used for quantitative anatomical analysis. However, in many geriatric and neurodegenerative disorders, severe tissue atrophy poses a unique challenge for accurate mapping of voxels, especially around the lateral ventricles. In this paper, we demonstrate our ability to improve mapping accuracy by incorporating ventricular anatomy in LDDMM and by utilizing a priori knowledge of ventricular anatomy in the deformable atlas.
doi:10.1002/jmri.23790
PMCID: PMC3525783  PMID: 22972747
Atlas; Ventricles; Mapping; Brain; MRI; Diffeomorphic
4.  Steps to reduce favorable risk selection in medicare advantage largely succeeded, boding well for health insurance exchanges 
Health affairs (Project Hope)  2012;31(12):2618-2628.
Managing competition among health plans that attract different risks has been a challenging policy problem. Within Medicare, the Medicare Advantage (MA) program historically attracted better risks than did Traditional Medicare (TM). This favorable selection resulted in Medicare’s paying more for persons enrolled in MA than if they had been enrolled in TM. We studied whether policies Medicare implemented in the past decade to reduce favorable selection in the MA program succeeded, in particular improved matching of reimbursement with a beneficiary’s expected cost and restricting when beneficiaries could switch from MA to TM. We found they did. Differences in predicted spending between those switching from TM to MA relative to those who remained in TM markedly narrowed, as did adjusted mortality rates. Because insurance exchanges will employ similar policies to combat selection, our results give reason for optimism about managing competition among health plans.
doi:10.1377/hlthaff.2012.0345
PMCID: PMC3535470  PMID: 23213145
5.  New Risk-Adjustment System Was Associated With Reduced Favorable Selection in Medicare Advantage 
Health affairs (Project Hope)  2012;31(12):2630-2640.
Health plans participating in the Medicare managed care program, now called Medicare Advantage, have historically attracted healthier enrollees than the traditional fee-for-service program. Medicare Advantage plans have gained financially from this favorable risk selection because until recently Medicare payments to plans were adjusted only minimally for the clinical characteristics of enrollees, such that payments systematically exceeded costs for healthier enrollees and were systematically lower than costs for sicker enrollees. To address favorable selection in Medicare Advantage, a new risk-adjustment system adjusting plan payments for clinical diagnoses was phased in from 2004 to 2007. Also, a lock-in provision was instituted in 2006 and strengthened in 2007 to limit midyear disenrollment by Medicare Advantage enrollees, particularly those experiencing health declines whose disenrollment could benefit plans financially. To determine if these reforms were associated with intended reductions in favorable selection in Medicare Advantage, we compared self-reported utilization and health for Medicare Advantage vs. traditional Medicare beneficiaries and for those who switched into or out of Medicare Advantage vs. non-switchers both before and after these reforms were implemented. In 2001-2003, differences in utilization and health between these groups suggested favorable selection in Medicare Advantage. By 2006-2007, however, most differences were substantially narrowed, indicating reduced selection. For example, Medicare Advantage enrollees reported 17.7% lower utilization than traditional Medicare enrollees in 2001-2003 but 8.1% lower in 2006-2007. Similar risk-adjustment methods may help may help mitigate incentives for Accountable Care Organizations participating in the Medicare Shared Savings Program and plans competing in health insurance exchanges to select patients with favorable clinical risks.
doi:10.1377/hlthaff.2011.1344
PMCID: PMC3538078  PMID: 23213147
6.  Using Medicare Data for Comparative Effectiveness Research – Opportunities and Challenges 
Background
With the introduction of Part D drug benefits, Medicare collects information on diagnoses, treatments, and clinical events for millions of beneficiaries. These data are a promising resource for comparative effectiveness research (CER) on treatments, benefit designs, and delivery systems.
Objectives
We explore the data available for researchers and approaches that could be used to enhance the value of Medicare data for CER.
Challenges and Opportunities
Using currently available Medicare data for CER is challenging; as with all administrative data, it is not possible to capture every factor that contributes to prescribing decisions and patients are not randomly assigned to treatments. In addition, Part D plan selection and switching may influence treatment decisions and contribute to selection bias. Exploiting certain program aspects can help address these limitations. For example, ongoing changes in Medicare or plan policies, and the random assignment of beneficiaries who receive Part D low income subsidies into plans with different formularies could yield natural experiments.
Policy implications
Refining policies around time to data release, provision of additional data elements, and linkage with greater beneficiary-level information would improve the value and usability of these data. Improving the transparency and reproduceability of findings, and potential open access to qualified stakeholders are also important policy considerations. Work is needed to reconcile data needs with current policies and goals.
Conclusions
Medicare data provides a rich resource for CER. Leveraging existing program elements combined with some administrative changes in data availability could create large datasets for evaluating treatment patterns, spending, and coverage decisions.
PMCID: PMC3705556  PMID: 21819169
Comparative effectiveness research; Medicare; prescription drugs
7.  Outpatient Electronic Health Records and the Clinical Care and Outcomes of Patients With Diabetes Mellitus 
Annals of internal medicine  2012;157(7):482-489.
Background
Physicians can receive federal payments for meaningful use of complete certified electronic health records (EHRs). Evidence is limited on how EHR use affects clinical care and outcomes.
Objective
To examine the association between use of a commercially available certified EHR and clinical care processes and disease control in patients with diabetes.
Design
Quasi-experimental design with outpatient EHR implementation sequentially across 17 medical centers. Multivariate analyses adjusted for patient characteristics, medical center, time trends, and patient-level clustering.
Setting
Kaiser Permanente Northern California, an integrated delivery system.
Patients
169 711 patients with diabetes mellitus.
Intervention
Use of a commercially available certified EHR.
Measurements
Drug treatment intensification and hemoglobin A1c (HbA1c) and low-density lipoprotein cholesterol (LDL-C) testing and values.
Results
Use of an EHR was associated with statistically significant improvements in treatment intensification after HbA1c values of 9% or greater (odds ratio, 1.10 [95% CI, 1.06 to 1.14]) or LDL-C values of 2.6 to 3.3 mmol/L (100 to 129 mg/dL) (odds ratio, 1.06 [CI, 1.03 to 1.09]); increases in 365-day retesting for HbA1c and LDL-C levels among all patients, with the most dramatic change among patients with the worst disease control (HbA1c ≥9% or LDL-C ≥3.4 mmol/L [ ≥130 mg/dL]); and decreased 90-day retesting among patients with HbA1c level less than 7% or LDL-C level less than 2.6 mmol/L (<100 mg/dL). The EHR was also associated with statistically significant reductions in HbA1c and LDL-C levels, with the largest reductions among patients with the worst control (0.06-mmol/L [2.19-mg/dL] reduction among patients with baseline LDL-C ≥3.4 mmol/L [ ≥130 mg/dL]; P < 0.001).
Limitation
The EHR was implemented in a setting with strong baseline performance on cardiovascular care quality measures.
Conclusion
Use of a commercially available, certified EHR was associated with improved drug treatment intensification, monitoring, and physiologic control among patients with diabetes, with greater improvements among patients with worse control and less testing in patients already meeting guideline-recommended glycemic and lipid targets.
Primary Funding Source
National Institute of Diabetes and Digestive and Kidney Diseases.
doi:10.7326/0003-4819-157-7-201210020-00004
PMCID: PMC3603566  PMID: 23027319
8.  The viral theory of schizophrenia revisited: Abnormal placental gene expression and structural changes with lack of evidence of H1N1 viral presence in placentae of infected mice or brains of exposed offspring 
Neuropharmacology  2011;62(3):1290-1298.
Researchers have long noted an excess of patients with schizophrenia were born during the months of January and March. This winter birth effect has been hypothesized to result either from various causes such as vitamin D deficiency (McGrath, 1999; McGrath et al., 2010), or from maternal infection during pregnancy. Infection with a number of viruses during pregnancy including influenza, and rubella are known to increase the risk of schizophrenia in the offspring (Brown, 2006). Animal models using influenza virus or PolyI:C, a viral mimic, have been able to replicate many of the brain morphological, genetic, and behavioral deficits of schizophrenia (Meyer et al., 2006, 2008a, 2009; Bitanihirwe et al. 2010; Meyer and Feldon, 2010; Short et al., 2010). Using a murine model of prenatal viral infection, our laboratory has shown that viral infection on embryonic days 9, 16, and 18 leads to abnormal expression of brain genes and brain structural abnormalities in the exposed offspring (Fatemi et al., 2005, 2008a,b, 2009a,b). The purpose of the current study was to examine gene expression and morphological changes in the placenta, hippocampus, and prefrontal cortex as a result of viral infection on embryonic day 7 of pregnancy. Pregnant mice were either infected with influenza virus [A/WSN/33 strain (H1N1)] or sham-infected with vehicle solution. At E16, placentas were harvested and prepared for either microarray analysis or for light microscopy. We observed significant, upregulation of 77 genes and significant downregulation of 93 genes in placentas. In brains of exposed offspring following E7 infection, there were changes in gene expression in prefrontal cortex (6 upregulated and 24 downregulated at P0; 5 upregulated and 14 downregulated at P56) and hippocampus (4 upregulated and 6 downregulated at P0; 6 upregulated and 13 downregulated at P56). QRT-PCR verified the direction and magnitude of change for a number of genes associated with hypoxia, inflammation, schizophrenia, and autism. Placentas from infected mice showed a number of morphological abnormalities including presence of thrombi and increased presence of immune cells. Additionally, we searched for presence of H1N1 viral-specific genes for M1/M2, NA, and NS1 in placentas of infected mice and brains of exposed offspring and found none. Our results demonstrate that prenatal viral infection disrupts structure and gene expression of the placenta, hippocampus, and prefrontal cortex potentially explaining deleterious effects in the exposed offspring without evidence for presence of viral RNAs in the target tissues.
doi:10.1016/j.neuropharm.2011.01.011
PMCID: PMC3156896  PMID: 21277874
placenta; influenza; brain; microarray; schizophrenia; viral genes
9.  Parallel Screening of Wild-Type and Drug-Resistant Targets for Anti-Resistance Neuraminidase Inhibitors 
PLoS ONE  2013;8(2):e56704.
Infection with influenza virus is a major public health problem, causing serious illness and death each year. Emergence of drug-resistant influenza virus strains limits the effectiveness of drug treatment. Importantly, a dual H275Y/I223R mutation detected in the pandemic influenza A 2009 virus strain results in multidrug resistance to current neuraminidase (NA) drugs. Therefore, discovery of new agents for treating multiple drug-resistant (MDR) influenza virus infections is important. Here, we propose a parallel screening strategy that simultaneously screens wild-type (WT) and MDR NAs, and identifies inhibitors matching the subsite characteristics of both NA-binding sites. These may maintain their potency when drug-resistant mutations arise. Initially, we analyzed the subsite of the dual H275Y/I223R NA mutant. Analysis of the site-moiety maps of NA protein structures show that the mutant subsite has a relatively small volume and is highly polar compared with the WT subsite. Moreover, the mutant subsite has a high preference for forming hydrogen-bonding interactions with polar moieties. These changes may drive multidrug resistance. Using this strategy, we identified a new inhibitor, Remazol Brilliant Blue R (RB19, an anthraquinone dye), which inhibited WT NA and MDR NA with IC50 values of 3.4 and 4.5 µM, respectively. RB19 comprises a rigid core scaffold and a flexible chain with a large polar moiety. The former interacts with highly conserved residues, decreasing the probability of resistance. The latter forms van der Waals contacts with the WT subsite and yields hydrogen bonds with the mutant subsite by switching the orientation of its flexible side chain. Both scaffolds of RB19 are good starting points for lead optimization. The results reveal a parallel screening strategy for identifying resistance mechanisms and discovering anti-resistance neuraminidase inhibitors. We believe that this strategy may be applied to other diseases with high mutation rates, such as cancer and human immunodeficiency virus type 1.
doi:10.1371/journal.pone.0056704
PMCID: PMC3577712  PMID: 23437217
10.  A Novel Aurora-A Inhibitor, BPR1K0609S1, Sensitizes Colorectal Tumor cells to 5-Fluorofracil (5-FU) Treatment 
Small synthetic compounds have been implicated in treatment of human cancers. We have synthesized a small compound, BPR1K0609S1 (hereafter, BP), which inhibits Aurora-A kinase. In the present study, we studied the mechanism of BP suppression of tumorigenesis induced by Aurora-A. Given our previous results that inactivation of p53 accelerates MMTV-Aurora-A-mediated tumorigenesis in vivo, we studied the roles of p53 pathway using the isogenic human colon carcinoma cell lines of HCT116, in which p53, Puma, Bax, p21 or Chk2 is deleted. When these isogenic cell lines are treated with BP for 48 h, accumulation of G2M phase and aneuploidy are commonly observed, and HCT116 p21(-) cells show increase in apoptosis. In xenograft assay, s.c. injection of BP efficiently inhibits tumorigenesis of HCT116 deficient for Chk2 or p21. Re-transplantation of BP-resistant tumors indicates that these resistant cells do not acquire advanced tumor growth. Significantly, 5-FU (5-fluorouracil) treatment further induces apoptosis of BP-resistant HCT116 deficient for Chk2 or Puma. These results demonstrate that p21 deficiency enhances BP-mediated suppression of tumor growth, and that BP and 5-FU can collaborate for tumor regression.
doi:10.7150/ijbs.5806
PMCID: PMC3654437  PMID: 23678290
Aurora-A; kinase inhibitors; mice xenograft; cell cycle; apoptosis
11.  Computational analysis of LDDMM for brain mapping 
One goal of computational anatomy (CA) is to develop tools to accurately segment brain structures in healthy and diseased subjects. In this paper, we examine the performance and complexity of such segmentation in the framework of the large deformation diffeomorphic metric mapping (LDDMM) registration method with reference to atlases and parameters. First we report the application of a multi-atlas segmentation approach to define basal ganglia structures in healthy and diseased kids' brains. The segmentation accuracy of the multi-atlas approach is compared with the single atlas LDDMM implementation and two state-of-the-art segmentation algorithms—Freesurfer and FSL—by computing the overlap errors between automatic and manual segmentations of the six basal ganglia nuclei in healthy subjects as well as subjects with diseases including ADHD and Autism. The high accuracy of multi-atlas segmentation is obtained at the cost of increasing the computational complexity because of the calculations necessary between the atlases and a subject. Second, we examine the effect of parameters on total LDDMM computation time and segmentation accuracy for basal ganglia structures. Single atlas LDDMM method is used to automatically segment the structures in a population of 16 subjects using different sets of parameters. The results show that a cascade approach and using fewer time steps can reduce computational complexity as much as five times while maintaining reliable segmentations.
doi:10.3389/fnins.2013.00151
PMCID: PMC3753595  PMID: 23986653
subcortical segmentation; computational anatomy; brain mapping; LDDMM
13.  Enhanced recombinant protein production and differential expression of molecular chaperones in sf-caspase-1-repressed stable cells after baculovirus infection 
BMC Biotechnology  2012;12:83.
Background
There are few studies that have examined the potential of RNA inference (RNAi) to increase protein production in the baculovirus expression vector system (BEVS). Spodoptera frugiperda (fall armyworm) (Sf)-caspase-1-repressed stable cells exhibit resistance to apoptosis and enhancement of recombinant protein production. However, the mechanism of recombinant protein augmentation in baculovirus-infected Caspase-repressed insect cells has not been elucidated.
Results
In the current study, we utilized RNAi-mediated Sf-caspase-1-repressed stable cells to clarify how the resistance to apoptosis can enhance both intracellular (firefly luciferase) and extracellular (secreted alkaline phosphatase [SEAP]) recombinant protein production in BEVS. Since the expression of molecular chaperones is strongly associated with the maximal production of exogenous proteins in BEVS, the differential expression of molecular chaperones in baculovirus-infected stable cells was also analyzed in this study.
Conclusion
The data indicated that the retention of expression of molecular chaperones in baculovirus-infected Sf-caspase-1-repressed stable cells give the higher recombinant protein accumulation.
doi:10.1186/1472-6750-12-83
PMCID: PMC3505465  PMID: 23134743
Apoptosis; Baculovirus; Chaperone; RNA interference; Sf-caspase-1
14.  Social organization of self-management support of persons with diabetes: A health systems comparison 
Objective
Identify important organizational elements for providing self-management support (SMS).
Design
Semi-structured qualitative interviews conducted in two healthcare systems.
Setting
Kaiser Permanente Northern California and the Danish Health Care System.
Subjects
36 managers and healthcare professionals in the two healthcare systems.
Main outcome measures
Elements important to providing self-management support to persons with diabetes.
Results
Healthcare professionals’ provision of SMS was influenced by healthcare system organization and their perceptions of SMS, the capability and responsibility of healthcare systems, and their roles in the healthcare organization. Enabling factors for providing SMS included: strong leadership; aligned incentives; use of an integrated health information technology (HIT) system; multidisciplinary healthcare provider teams; ongoing training for healthcare professionals; outreach; and quality goals. Barriers to providing SMS included lack of collaboration between providers and skeptical attitudes towards prevention and outreach.
Conclusions and implications
Implementation of SMS can be improved by an understanding of the elements that enhance its provision: (1) initiatives seeking to improve collaboration and integration between providers; (2) implementation of an integrated HIT system; and (3) ongoing training of healthcare professionals.
doi:10.3109/02813432.2012.704810
PMCID: PMC3443944  PMID: 22839353
Denmark; diabetes mellitus; general practice; health system; international comparison; patient education; self-management support
15.  Fixing flaws in Medicare drug coverage that prompt insurers to avoid low-income patients 
Health affairs (Project Hope)  2010;29(12):2335-2343.
Medicare assigns beneficiaries receiving low-income subsidies to plans with premiums below regional benchmarks. The number of these low premium plans fell in 2009, forcing the reassignment of 1.6 million beneficiaries. Using data from Part D plans, we found that CMS’s current risk adjustment scheme does not sufficiently compensate plans for the greater drug spending of low-income subsidy beneficiaries. Since plans can avoid these beneficiaries by raising their premiums above that of their competitors, premiums for all beneficiaries tend to rise over time. Paying more for subsidy and less for non-subsidy beneficiaries, or accounting for past drug use in the risk adjustment scheme could mitigate these perverse incentives.
doi:10.1377/hlthaff.2009.0323
PMCID: PMC3422650  PMID: 21030394
16.  Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus 
The aim of this study was to identify the antiviral mechanism of a novel compound, BPR3P0128. From a large-scale screening of a library of small compounds, BPR3P compounds were found to be potent inhibitors of influenza viral replication in Madin–Darby canine kidney (MDCK) cells. BPR3P0128 exhibited inhibitory activity against both influenza A and B viruses. The 50% inhibitory concentrations were in the range of 51 to 190 nM in MDCK cells, as measured by inhibition-of-cytopathic-effect assays. BPR3P0128 appeared to target the viral replication cycle but had no effect on viral adsorption. The inhibition of cap-dependent mRNA transcription by BPR3P0128 was more prominent with a concurrent increase in cap-independent cRNA replication in a primer extension assay, suggesting a role of BPR3P0128 in switching transcription to replication. This reduction in mRNA expression resulted from the BPR3P-mediated inhibition of the cap-dependent endoribonuclease (cap-snatching) activities of nuclear extracts containing the influenza virus polymerase complex. No inhibition of binding of 5′ viral RNA to the viral polymerase complex by this compound was detected. BPR3P0128 also effectively inhibited other RNA viruses, such as enterovirus 71 and human rhinovirus, but not DNA viruses, suggesting that BPR3P0128 targets a cellular factor(s) associated with viral PB2 cap-snatching activity. The identification of this factor(s) could help redefine the regulation of viral transcription and replication and thereby provide a potential target for antiviral chemotherapeutics.
doi:10.1128/AAC.00125-11
PMCID: PMC3264257  PMID: 21930871
17.  Improving treatment intensification to reduce cardiovascular disease risk: a cluster randomized trial 
Background
Blood pressure, lipid, and glycemic control are essential for reducing cardiovascular disease (CVD) risk. Many health care systems have successfully shifted aspects of chronic disease management, including population-based outreach programs designed to address CVD risk factor control, to non-physicians. The purpose of this study is to evaluate provision of new information to non-physician outreach teams on need for treatment intensification in patients with increased CVD risk.
Methods
Cluster randomized trial (July 1-December 31, 2008) in Kaiser Permanente Northern California registry of members with diabetes mellitus, prior CVD diagnoses and/or chronic kidney disease who were high-priority for treatment intensification: blood pressure ≥ 140 mmHg systolic, LDL-cholesterol ≥ 130 mg/dl, or hemoglobin A1c ≥ 9%; adherent to current medications; no recent treatment intensification). Randomization units were medical center-based outreach teams (4 intervention; 4 control). For intervention teams, priority flags for intensification were added monthly to the registry database with recommended next pharmacotherapeutic steps for each eligible patient. Control teams used the same database without this information. Outcomes included 3-month rates of treatment intensification and risk factor levels during follow-up.
Results
Baseline risk factor control rates were high (82-90%). In eligible patients, the intervention was associated with significantly greater 3-month intensification rates for blood pressure (34.1 vs. 30.6%) and LDL-cholesterol (28.0 vs 22.7%), but not A1c. No effects on risk factors were observed at 3 months or 12 months follow-up. Intervention teams initiated outreach for only 45-47% of high-priority patients, but also for 27-30% of lower-priority patients. Teams reported difficulties adapting prior outreach strategies to incorporate the new information.
Conclusions
Information enhancement did not improve risk factor control compared to existing outreach strategies at control centers. Familiarity with prior, relatively successful strategies likely reduced uptake of the innovation and its potential for success at intervention centers.
Trial registration
ClinicalTrials.gov Identifier NCT00517686
doi:10.1186/1472-6963-12-183
PMCID: PMC3438122  PMID: 22747998
Diabetes mellitus; Hypertension; Hyperlipidemia; Cardiovascular diseases; Clinical inertia
18.  Self-Management Support to People with Type 2 Diabetes - A comparative study of Kaiser Permanente and the Danish Healthcare System 
Background
Self-management support is considered to be an essential part of diabetes care. However, the implementation of self-management support within healthcare settings has appeared to be challenging and there is increased interest in “real world” best practice examples to guide policy efforts. In order to explore how different approaches to diabetes care and differences in management structure influence the provision of SMS we selected two healthcare systems that have shown to be comparable in terms of budget, benefits and entitlements. We compared the extent of SMS provided and the self-management behaviors of people living with diabetes in Kaiser Permanente (KP) and the Danish Healthcare System (DHS).
Methods
Self-administered questionnaires were used to collect data from a random sample of 2,536 individuals with DM from KP and the DHS in 2006–2007 to compare the level of SMS provided in the two systems and identify disparities associated with educational attainment. The response rates were 75 % in the DHS and 56 % in KP. After adjusting for gender, age, educational level, and HbA1c level, multiple linear regression analyses determined the level of SMS provided and identified disparities associated with educational attainment.
Results
Receipt of SMS varied substantially between the two systems. More people with diabetes in KP reported receiving all types of SMS and use of SMS tools compared to the DHS (p < .0001). Less than half of all respondents reported taking diabetes medication as prescribed and following national guidelines for exercise.
Conclusions
Despite better SMS support in KP compared to the DHS, self-management remains an under-supported area of care for people receiving care for diabetes in the two health systems. Our study thereby suggests opportunity for improvements especially within the Danish healthcare system and systems adopting similar SMS support strategies.
doi:10.1186/1472-6963-12-160
PMCID: PMC3441680  PMID: 22697597
Self-management support; Type 2 diabetes mellitus; Health system; International comparison
19.  Falling into the Coverage Gap: Part D Drug Costs and Adherence for Medicare Advantage Prescription Drug Plan Beneficiaries with Diabetes 
Health Services Research  2010;45(2):355-375.
Objective
To compare drug costs and adherence among Medicare beneficiaries with the standard Part D coverage gap versus supplemental gap coverage in 2006.
Data Sources
Pharmacy data from Medicare Advantage Prescription Drug (MAPD) plans.
Study Design
Parallel analyses comparing beneficiaries aged 65+ with diabetes in an integrated MAPD with a gap versus no gap (n=28,780); and in a network-model MAPD with a gap versus generic-only coverage during the gap (n=14,984).
Principal Findings
Drug spending was 3 percent (95 percent confidence interval [CI]: 1–4 percent) and 4 percent (CI: 1–6 percent) lower among beneficiaries with a gap versus full or generic-only gap coverage, respectively. Out-of-pocket expenditures were 189 percent higher (CI: 185–193 percent) and adherence to three chronic drug classes was lower among those with a gap versus no gap (e.g., odds ratio=0.83, CI: 0.79–0.88, for oral diabetes drugs). Annual out-of-pocket spending was 14 percent higher (CI: 10–17 percent) for beneficiaries with a gap versus generic-only gap coverage, but levels of adherence were similar.
Conclusions
Among Medicare beneficiaries with diabetes, having the Part D coverage gap resulted in lower total drug costs, but higher out-of-pocket spending and worse adherence compared with having no gap. Having generic-only coverage during the gap appeared to confer limited benefits compared with having no gap coverage.
doi:10.1111/j.1475-6773.2009.01071.x
PMCID: PMC2838150  PMID: 20050931
Medicare; prescription drugs; diabetes
20.  Timely detection of localized excess influenza activity in northern California across patient care, prescription, and laboratory data 
Statistics in medicine  2011;30(5):549-559.
Timely detection of clusters of localized influenza activity in excess of background seasonal levels could improve situational awareness for public health officials and health systems. However, no single data type may capture influenza activity with optimal sensitivity, specificity, and timeliness, and it is unknown which data types could be most useful for surveillance. We compared the performance of ten types of electronic clinical data for timely detection of influenza clusters throughout the 2007/08 influenza season in northern California. Kaiser Permanente Northern California generated zip code-specific daily episode counts for: influenza-like illness (ILI) diagnoses in ambulatory care (AC) and emergency departments (ED), both with and without regard to fever; hospital admissions and discharges for pneumonia and influenza; antiviral drugs dispensed (Rx); influenza laboratory tests ordered (Tests); and tests positive for influenza type A (FluA) and type B (FluB). Four credible events of localized excess illness were identified. Prospective surveillance was mimicked within each data stream using a space-time permutation scan statistic, analyzing only data available as of each day, to evaluate the ability and timeliness to detect the credible events. AC without fever and Tests signaled during all four events and, along with Rx, had the most timely signals. FluA had less timely signals. ED, hospitalizations, and FluB did not signal reliably. When fever was included in the ILI definition, signals were either delayed or missed. Although limited to one health plan, location, and year, these results can inform the choice of data streams for public health surveillance of influenza.
doi:10.1002/sim.3883
PMCID: PMC3058686  PMID: 21312219
influenza; outbreak detection; spatio-temporal analysis
21.  Quantitative Analysis of Brain Pathology Based on MRI and Brain Atlases - Applications for Cerebral Palsy 
NeuroImage  2010;54(3):1854-1861.
We have developed a new method to provide a comprehensive quantitative analysis of brain anatomy in cerebral palsy patients, which makes use of two techniques: diffusion tensor imaging and automated 3D whole brain segmentation based on our brain atlas and a nonlinear normalization technique (large-deformation diffeomorphic metric mapping). This method was applied to 13 patients and normal controls. The reliability of the automated segmentation revealed close agreement with the manual segmentation. We illustrate some potential applications for individual characterization and group comparison. This technique also provides a framework for determining the impact of various neuroanatomic features on brain functions.
doi:10.1016/j.neuroimage.2010.09.061
PMCID: PMC3008311  PMID: 20920589
22.  The Structure of Risk Adjustment for Private Plans in Medicare 
The American journal of managed care  2011;17(6 Spec No):e231-e240.
Medicare bases its risk adjustment method for Medicare Advantage (MA) plan payment on the relative costs of treating various diagnoses in traditional Medicare (TM). But there are many reasons to doubt that the relative cost of treating different diagnoses is similar between MA plans and TM, including the varying applicability of care management methods to different diagnoses and varying degrees of market power among suppliers of services to plans. We use internal cost data from a large health plan to compare its cost of treating various diagnoses with Medicare’s reimbursement. We find substantial variability across diagnoses, implying that the current risk adjustment system creates incentives for MA plans to favor beneficiaries with certain diagnoses, but no consistent relationship between the costliness of the diagnosis and the difference between reimbursement and cost.
PMCID: PMC3246270  PMID: 21756017
23.  Something is amiss in Denmark: A comparison of preventable hospitalisations and readmissions for chronic medical conditions in the Danish Healthcare system and Kaiser Permanente 
Background
As many other European healthcare systems the Danish healthcare system (DHS) has targeted chronic condition care in its reform efforts. Benchmarking is a valuable tool to identify areas for improvement. Prior work indicates that chronic care coordination is poor in the DHS, especially in comparison with care in Kaiser Permanente (KP), an integrated delivery system based in the United States. We investigated population rates of hospitalisation and readmission rates for ambulatory care sensitive, chronic medical conditions in the two systems.
Methods
Using a historical cohort study design, age and gender adjusted population rates of hospitalisations for angina, heart failure, chronic obstructive pulmonary disease, and hypertension, plus rates of 30-day readmission and mortality were investigated for all individuals aged 65+ in the DHS and KP.
Results
DHS had substantially higher rates of hospitalisations, readmissions, and mean lengths of stay per hospitalisation, than KP had. For example, the adjusted angina hospitalisation rates in 2007 for the DHS and KP respectively were 1.01/100 persons (95%CI: 0.98-1.03) vs. 0.11/100 persons (95%CI: 0.10-0.13/100 persons); 21.6% vs. 9.9% readmission within 30 days (OR = 2.53; 95% CI: 1.84-3.47); and mean length of stay was 2.52 vs. 1.80 hospital days. Mortality up through 30 days post-discharge was not consistently different in the two systems.
Conclusions
There are substantial differences between the DHS and KP in the rates of preventable hospitalisations and subsequent readmissions associated with chronic conditions, which suggest much opportunity for improvement within the Danish healthcare system. Reductions in hospitalisations also could improve patient welfare and free considerable resources for use towards preventing disease exacerbations. These conclusions may also apply for similar public systems such as the US Medicare system, the NHS and other systems striving to improve the integration of care for persons with chronic conditions.
doi:10.1186/1472-6963-11-347
PMCID: PMC3258291  PMID: 22192270
24.  BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells 
PLoS ONE  2011;6(8):e23485.
Background
Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.
Principal Findings
BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.
Conclusions and Significance
BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.
doi:10.1371/journal.pone.0023485
PMCID: PMC3160846  PMID: 21887256
25.  Generic-only Drug Coverage in the Medicare Part D Gap and Effect on Medication Cost-Cutting Behaviors for Patients with Diabetes: The Translating Research into Action for Diabetes (TRIAD) Study 
Background
Medicare Part D beneficiaries with diabetes are at risk of medication non-adherence and forgoing necessities due to cost pressures. Generic drug coverage during the Part D gap may attenuate these potentially adverse behaviors.
Objective
To examine the association between drug coverage during the gap and medication cost-cutting behaviors among insulin users and non-users.
Participants and Setting
2007 survey of Medicare Advantage Part D (MAPD) and Prescription Drug Plan (PDP) beneficiaries within a network-model health system who entered the gap by October 2006 (N=1,468, 57% response rate).
Design
The study was cross-sectional.
Measurements
The primary predictor variable was no gap coverage versus generic-only gap coverage. We examined seven cost-cutting behaviors as dependent variables, including cost-related non-adherence (CRN) to any medication. Covariates included race/ethnicity, education, health status, income, and comorbidities, as well as generic medication use in the first quarter. We constructed logistic regression models using non-response weights, to generate predicted percentages.
Results
In multivariate analyses, beneficiaries taking insulin were less likely to report CRN if they had generic-only gap coverage compared to no gap coverage (16% vs. 29%, p=0.03). No differences in CRN by type of gap coverage were seen among beneficiaries not taking insulin.
Conclusions
Medicare beneficiaries using insulin are at high risk of CRN. Generic-only coverage during the gap is associated with an attenuated risk of CRN among insulin users, possibly due to savings on other, generic medications. Future research should evaluate CRN within alternative benefit designs covering selected brand name medications, such as insulin, during the gap.
doi:10.1111/j.1532-5415.2010.02813.x
PMCID: PMC3125132  PMID: 20406312
Medicare Part D; pharmaceutical use; diabetes

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