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1.  KUD773, a phenylthiazole derivative, displays anticancer activity in human hormone-refractory prostate cancers through inhibition of tubulin polymerization and anti-Aurora A activity 
Background
Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment. An approach to inhibit HRPC growth and ultimately to kill cancers is highly demanded.
Results
KUD773 induced the anti-proliferative effect and subsequent apoptosis in PC-3 and DU-145 (two HRPC cell lines); whereas, it showed less active in normal prostate cells. Further examination showed that KUD773 inhibited tubulin polymerization and induced an increase of mitotic phosphoproteins and polo-like kinase 1 (PLK1) phosphorylation, indicating a mitotic arrest of the cell cycle through an anti-tubulin action. The kinase assay demonstrated that KUD773 inhibited Aurora A activity. KUD773 induced an increase of Cdk1 phosphorylation at Thr161 (a stimulatory phosphorylation site) and a decrease of phosphorylation at Tyr15 (an inhibitory phosphorylation site), suggesting the activation of Cdk1. The data were substantiated by an up-regulation of cyclin B1 (a Cdk1 partner). Furthermore, KUD773 induced the phosphorylation and subsequent down-regulation of Bcl-2 and activation of caspase cascades.
Conclusions
The data suggest that KUD773 induces apoptotic signaling in a sequential manner. It inhibits tubulin polymerization associated with an anti-Aurora A activity, leading to Cdk1 activation and mitotic arrest of the cell cycle that in turn induces Bcl-2 degradation and a subsequent caspase activation in HRPCs.
doi:10.1186/s12929-014-0107-x
PMCID: PMC4304192  PMID: 25563361
Hormone-refractory prostate cancer; Phenylthiazole derivative; Tubulin depolymerization; Aurora A kinase; Mitochondria-involved apoptosis
2.  Do Medicare Advantage Plans Select Enrollees in Higher Margin Clinical Categories? 
Journal of health economics  2013;32(6):10.1016/j.jhealeco.2013.09.003.
The CMS-HCC risk adjustment system for Medicare Advantage (MA) plans calculates weights, which are effectively relative prices, for beneficiaries with different observable characteristics. To do so it uses the relative amounts spent per beneficiary with those characteristics in Traditional Medicare (TM). For multiple reasons one might expect relative amounts in MA to differ from TM, thereby making some beneficiaries more profitable to treat than others. Much of the difference comes from differences in how TM and MA treat different diseases or diagnoses. Using data on actual medical spending from two MA-HMO plans, we show that the weights calculated from MA costs do indeed differ from those calculated using TM spending. One of the two plans (Plan 1) is more typical of MA-HMO plans in that it contracts with independent community providers, while the other (Plan 2) is vertically integrated with care delivery. We calculate margins, or Average Revenue/Average Cost, for Medicare beneficiaries in the two plans who have one of 48 different combinations of medical conditions. The two plans’ margins for these 48 conditions are correlated (r=0.39, p<0.01). Both plans have margins that are more positive for persons with conditions that are managed by primary care physicians and where medical management can be effective. Conversely they have lower margins for persons with conditions that tend to be treated by specialists with greater market power than primary care physicians and for acute conditions where little medical management is possible. The two plan’s margins among beneficiaries with different observable characteristics vary over a range of 160 and 98 percentage points, respectively, and thus would appear to offer substantial incentive for selection by HCC. Nonetheless, we find no evidence of overrepresentation of beneficiaries in high margin HCC’s in either plan. Nor, using the margins from Plan 1, the more typical plan, do we find evidence of overrepresentation of high margin HCC’s in Medicare more generally. These results do not permit a conclusion on overall social efficiency, but we note that selection according to margin could be socially efficient. In addition, our findings suggest there are omitted interaction terms in the risk adjustment model that Medicare currently uses.
doi:10.1016/j.jhealeco.2013.09.003
PMCID: PMC3855666  PMID: 24308879
Selection; risk adjustment; Medicare
3.  The Combination Effects of LiCl and the Active Leflunomide Metabolite, A771726, on Viral-Induced Interleukin 6 Production and EV-A71 Replication 
PLoS ONE  2014;9(11):e111331.
Enterovirus 71 (EV-A71) is a neurotropic virus that can cause severe complications involving the central nervous system. No effective antiviral therapeutics are available for treating EV-A71 infection and drug discovery efforts are rarely focused to target this disease. Thus, the main goal of this study was to discover existing drugs with novel indications that may effectively inhibit EV-A71 replication and the inflammatory cytokines elevation. In this study, we showed that LiCl, a GSK3β inhibitor, effectively suppressed EV-A71 replication, apoptosis and inflammatory cytokines production (Interleukin 6, Interleukin-1β) in infected cells. Furthermore, LiCl and an immunomodular agent were shown to strongly synergize with each other in suppressing EV-A71 replication. The results highlighted potential new treatment regimens in suppressing sequelae caused by EV-A71 replication.
doi:10.1371/journal.pone.0111331
PMCID: PMC4239034  PMID: 25412347
4.  Epstein-Barr Virus BALF3 Has Nuclease Activity and Mediates Mature Virion Production during the Lytic Cycle 
Journal of Virology  2014;88(9):4962-4975.
ABSTRACT
Epstein-Barr virus (EBV) lytic replication involves complex processes, including DNA synthesis, DNA cleavage and packaging, and virion egress. These processes require many different lytic gene products, but the mechanisms of their actions remain unclear, especially for DNA cleavage and packaging. According to sequence homology analysis, EBV BALF3, encoded by the third leftward open reading frame of the BamHI-A fragment in the viral genome, is a homologue of herpes simplex virus type 1 UL28. This gene product is believed to possess the properties of a terminase, such as nucleolytic activity on newly synthesized viral DNA and translocation of unit length viral genomes into procapsids. In order to characterize EBV BALF3, the protein was produced by and purified from recombinant baculoviruses and examined in an enzymatic reaction in vitro, which determined that EBV BALF3 acts as an endonuclease and its activity is modulated by Mg2+, Mn2+, and ATP. Moreover, in EBV-positive epithelial cells, BALF3 was expressed and transported from the cytoplasm into the nucleus following induction of the lytic cycle, and gene silencing of BALF3 caused a reduction of DNA packaging and virion release. Interestingly, suppression of BALF3 expression also decreased the efficiency of DNA synthesis. On the basis of these results, we suggest that EBV BALF3 is involved simultaneously in DNA synthesis and packaging and is required for the production of mature virions.
IMPORTANCE Virus lytic replication is essential to produce infectious virions, which is responsible for virus survival and spread. This work shows that an uncharacterized gene product of the human herpesvirus Epstein-Barr virus (EBV), BALF3, is expressed during the lytic cycle. In addition, BALF3 mediates an endonucleolytic reaction and is involved in viral DNA synthesis and packaging, leading to influence on the production of mature virions. According to sequence homology and physical properties, the lytic gene product BALF3 is considered a terminase in EBV. These findings identify a novel viral gene with an important role in contributing to a better understanding of the EBV life cycle.
doi:10.1128/JVI.00063-14
PMCID: PMC3993834  PMID: 24554665
5.  Insurance Coverage & Whither Thou Goest for Health Information in 2012 
Medicare & Medicaid Research Review  2014;4(4):mmrr2014-004-04-b01.
Objective
Examine use of the Internet (eHealth) and mobile health (mHealth) technologies by privately insured, publicly insured (Medicare/Medicaid), or uninsured U.S. adults in 2012.
Data Source
Pew Charitable Trust telephone interviews of a nationally representative, random sample of 3,014 adult U.S. residents, age 18+.
Methods
Estimate health information seeking behavior overall and by segment (i.e., insurance type), then, adjust estimates for individual traits, clinical need, and technology access using logistic regression.
Results
Most respondents prefer offline to online (Internet) health information sources; over half across all segments use the Internet. More respondents communicate with providers offline compared with online. Most self-reported Internet users use online tools for health information, with privately insured respondents more likely to use new technologies. Unadjusted use rates differ across segments. Medicaid beneficiaries are more likely than the privately insured to share health information online, and Medicare beneficiaries are more likely than the privately insured to text with health professionals. After adjustment, these differences were minimal (e.g., Medicare beneficiaries had odds similar to the privately insured of online physician consultations), or the direction of the association reversed (e.g., Medicaid beneficiaries had greater odds than the privately insured of online physician consultations versus lower odds before adjustment).
Discussion
Few adults report eHealth or mHealth use in 2012. Use levels appear unevenly distributed across insurance types, which could be mostly attributed to differences in individual traits and/or need. As out-of-pocket costs of medical care increases, consumers may increasingly turn to these generally free electronic health tools.
doi:10.5600/mmrr.004.04.b01
PMCID: PMC4222715  PMID: 25383242
Medicare; Medicaid; private insurance; eHealth; mHealth; health insurance; technology; surveys; interviews
6.  COBRA ARRA Subsidies: Was the Carrot Enticing Enough? 
Health Services Research  2012;47(5):1980-1998.
Objective
To help preserve continuity of health insurance coverage during the recent recession, the American Recovery and Reinvestment Act provided a 65 percent Consolidated Omnibus Budget Reconciliation Act (COBRA) premium subsidy for workers laid off in 2008–2010. We examined COBRA enrollment levels with the subsidy and the health, access, and financial consequences of enrollment decisions.
Study Design/Data Collection
Telephone interviews linked with health system databases for 561 respondents who were laid off in 2009 and eligible for the COBRA subsidy (80 percent response rate).
Principal Findings
Overall, 38 percent reported enrolling in COBRA and 54 percent reported having some gaps in insurance coverage since being laid off. After adjustments, we found that those who had higher cost-sharing, who had higher incomes, were older, or were sicker were more likely to enroll in COBRA. COBRA enrollees less frequently reported access problems or that their health suffered because of poor access, but they reported greater financial stress due to health care spending.
Conclusion
Despite the substantial subsidy, a majority of eligible individuals did not enroll in COBRA, and many reported insurance coverage gaps. Nonenrollees reported more access problems and that their health worsened. Without a mandate, subsidies may need to be widely publicized and larger to encourage health insurance enrollment among individuals who suffer a negative income shock.
doi:10.1111/j.1475-6773.2012.01409.x
PMCID: PMC3513614  PMID: 22515835
Premium subsidy; COBRA; individual mandate; care access
7.  Anatomical characterization of athetotic and spastic cerebral palsy using an atlas-based analysis 
Purpose
To analyze diffusion tensor imaging (DTI) in two types of cerebral palsy (CP): the athetotic-type and the spastic-type, using an atlas-based anatomical analysis of the entire brain, and to investigate whether these images have unique anatomical characteristics that can support functional diagnoses.
Methods
We retrospectively analyzed the DTI of seven children with athetotic-type, 11 children with spastic-type, and 20 healthy control children, all age-matched. The severity of motor dysfunction was evaluated with the Gross Motor Function Classification System (GMFCS). The images were normalized using a linear transformation, followed by large deformation diffeomorphic metric mapping. For 205 parcellated brain areas, the volume, fractional anisotropy, and mean diffusivity were measured. Principal component analysis (PCA) was performed for the Z scores of these parameters.
Result
The GMFCS scores in athetotic-type were significantly higher than those in spastic-type (p<0.001). PCA extracted anatomical components that comprised the two types of CP, as well as the severity of motor dysfunction. In the athetotic group, the abnormalities were more severe than in the spastic group. In the spastic group, significant changes were concentrated in the lateral ventricle and periventricular structures.
Conclusion
Our results quantitatively delineated anatomical characteristics that reflected the functional findings in two types of CP.
doi:10.1002/jmri.23931
PMCID: PMC3749241  PMID: 23737247
cerebral palsy; diffusion tensor imaging; atlas-based analysis; principal component analysis
8.  Acute lesions that impair affective empathy 
Brain  2013;136(8):2539-2549.
Functional imaging studies of healthy participants and previous lesion studies have provided evidence that empathy involves dissociable cognitive functions that rely on at least partially distinct neural networks that can be individually impaired by brain damage. These studies converge in support of the proposal that affective empathy—making inferences about how another person feels—engages at least the following areas: prefrontal cortex, orbitofrontal gyrus, anterior insula, anterior cingulate cortex, temporal pole, amygdala and temporoparietal junction. We hypothesized that right-sided lesions to any one of these structures, except temporoparietal junction, would cause impaired affective empathy (whereas bilateral damage to temporoparietal junction would be required to disrupt empathy). We studied 27 patients with acute right hemisphere ischaemic stroke and 24 neurologically intact inpatients on a test of affective empathy. Acute impairment of affective empathy was associated with infarcts in the hypothesized network, particularly temporal pole and anterior insula. All patients with impaired affective empathy were also impaired in comprehension of affective prosody, but many patients with impairments in prosodic comprehension had spared affective empathy. Patients with impaired affective empathy were older, but showed no difference in performance on tests of hemispatial neglect, volume of infarct or sex distribution compared with patients with intact affective empathy.
doi:10.1093/brain/awt177
PMCID: PMC3722353  PMID: 23824490
empathy; stroke; emotion perception; magnetic resonance imaging; prosody
9.  Adverse Clinical Events Among Medicare Beneficiaries Using Antipsychotic Drugs: Linking Health Insurance Benefits and Clinical Needs 
Medical care  2013;51(7):614-621.
Objective
Medicare Part D provides formulary protections for antipsychotics, but does not exempt these drugs from cost-sharing. We investigated the impact of Part D coverage on antipsychotic drug spending, adherence, and clinical outcomes among beneficiaries with varying indications for use.
Methods
We conducted a historical cohort study of Medicare Advantage beneficiaries who received antipsychotic drugs, with diagnoses of schizophrenia or bipolar disorder, or no mental health diagnoses (N=10,190). Half had a coverage gap; half had no gap because of low-income subsidies. Using fixed effects regression models, we examined changes in spending and adherence as beneficiaries experienced cost-sharing increases after reaching the gap. We examined changes in hospitalizations and emergency department visits using proportional hazard models.
Results
Across all diagnostic groups, monthly total antipsychotic spending decreased with cost-sharing increases in the gap compared with those with no gap (e.g., schizophrenia: −$123 [−$138, −$108]), and out-of-pocket spending increased (e.g., schizophrenia: $104 [$98, $110]). Adherence similarly decreased, with the largest declines among those with schizophrenia (−20.6 percentage points [−22.3, −18.9] in proportion of days covered). Among beneficiaries with schizophrenia and bipolar disorder, hospitalizations and emergency department visit rates increased with cost-sharing increases (e.g., schizophrenia: HR=1.32 [1.06, 1.65] for all hospitalizations), but did not among subjects without mental health diagnoses. Clinical event rates did not change among beneficiaries with low income subsidies without gaps.
Conclusions
There is evidence of interruptions in antipsychotic use attributable to Part D cost-sharing. Adverse events increased among beneficiaries with approved indications for use, but not among beneficiaries without such indications.
doi:10.1097/MLR.0b013e31829019c5
PMCID: PMC3687515  PMID: 23752219
Medicare; antipsychotics; benefit design
10.  Multi-Contrast Multi-Atlas Parcellation of Diffusion Tensor Imaging of the Human Brain 
PLoS ONE  2014;9(5):e96985.
In this paper, we propose a novel method for parcellating the human brain into 193 anatomical structures based on diffusion tensor images (DTIs). This was accomplished in the setting of multi-contrast diffeomorphic likelihood fusion using multiple DTI atlases. DTI images are modeled as high dimensional fields, with each voxel exhibiting a vector valued feature comprising of mean diffusivity (MD), fractional anisotropy (FA), and fiber angle. For each structure, the probability distribution of each element in the feature vector is modeled as a mixture of Gaussians, the parameters of which are estimated from the labeled atlases. The structure-specific feature vector is then used to parcellate the test image. For each atlas, a likelihood is iteratively computed based on the structure-specific vector feature. The likelihoods from multiple atlases are then fused. The updating and fusing of the likelihoods is achieved based on the expectation-maximization (EM) algorithm for maximum a posteriori (MAP) estimation problems. We first demonstrate the performance of the algorithm by examining the parcellation accuracy of 18 structures from 25 subjects with a varying degree of structural abnormality. Dice values ranging 0.8–0.9 were obtained. In addition, strong correlation was found between the volume size of the automated and the manual parcellation. Then, we present scan-rescan reproducibility based on another dataset of 16 DTI images – an average of 3.73%, 1.91%, and 1.79% for volume, mean FA, and mean MD respectively. Finally, the range of anatomical variability in the normal population was quantified for each structure.
doi:10.1371/journal.pone.0096985
PMCID: PMC4014574  PMID: 24809486
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
23.  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
24.  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
25.  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

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