Prescription Drug Use under Medicare Part D: A Linear Model of Nonlinear Budget Sets.

Medicare Part D enrollees face a complicated decision: they dynamically choose prescription drug consumption in each period given difficult-to-find prices and a non-linear budget set. We use Part D claims data to estimate a flexible model of consumption that accounts for non-linear prices, dynamic responses, and salience. We use reduced form price responses from a linear regression of consumption on coverage range prices to compare performance under several models of behavior. We find small price elasticities, substantial myopia, and that salient characteristics impact consumption beyond their effect on prices. A hyperbolic discounting model with salience fits the data best.

Neuronal Pentraxin 2 predicts medial temporal atrophy and memory decline across the Alzheimer's disease spectrum.

Chronic neuroinflammation is thought to potentiate medial temporal lobe (MTL) atrophy and memory decline in Alzheimer's disease (AD). It has become increasingly important to find novel immunological biomarkers of neuroinflammation or other processes that can track AD development and progression. Our study explored which pro- or anti-inflammatory cerebrospinal fluid (CSF) biomarkers best predicted AD neuropathology over 24months. Using Alzheimer's Disease Neuroimaging Initiative data (N=285), CSF inflammatory biomarkers from mass spectrometry and multiplex panels were screened using stepwise regression, followed up with 50%/50% model retests for validation. Neuronal Pentraxin 2 (NPTX2) and Chitinase-3-like-protein-1 (C3LP1), biomarkers of glutamatergic synaptic plasticity and microglial activation respectively, were the only consistently significant biomarkers selected. Once these biomarkers were selected, linear mixed models were used to analyze their baseline and longitudinal associations with bilateral MTL volume, memory decline, global cognition, and established AD biomarkers including CSF amyloid and tau. Higher baseline NPTX2 levels corresponded to less MTL atrophy [R2=0.287, p<0.001] and substantially less memory decline [R2=0.560, p<0.001] by month 24. Conversely, higher C3LP1 modestly predicted more MTL atrophy [R2=0.083, p<0.001], yet did not significantly track memory decline over time. In conclusion, NPTX2 is a novel pro-inflammatory cytokine that predicts AD-related outcomes better than any immunological biomarker to date, substantially accounting for brain atrophy and especially memory decline. C3LP1 as the microglial biomarker, by contrast, performed modestly and did not predict longitudinal memory decline. This research may advance the current understanding of AD etiopathogenesis, while expanding early diagnostic techniques through the use of novel pro-inflammatory biomarkers, such as NPTX2. Future studies should also see if NPTX2 causally affects MTL morphometry and memory performance.

Translesion synthesis of 8,5'-cyclopurine-2'-deoxynucleosides by DNA polymerases η, ι, and ζ.

Reactive oxygen species can give rise to a battery of DNA damage products including the 8,5'-cyclo-2'-deoxyadenosine (cdA) and 8,5'-cyclo-2'-deoxyguanosine (cdG) tandem lesions. The 8,5'-cyclopurine-2'-deoxynucleosides are quite stable lesions and are valid and reliable markers of oxidative DNA damage. However, it remains unclear how these lesions compromise DNA replication in mammalian cells. Previous in vitro biochemical assays have suggested a role for human polymerase (Pol) η in the insertion step of translesion synthesis (TLS) across the (5'S) diastereomers of cdA and cdG. Using in vitro steady-state kinetic assay, herein we showed that human Pol ι and a two-subunit yeast Pol ζ complex (REV3/REV7) could function efficiently in the insertion and extension steps, respectively, of TLS across S-cdA and S-cdG; human Pol κ and Pol η could also extend past these lesions, albeit much less efficiently. Results from a quantitative TLS assay showed that, in human cells, S-cdA and S-cdG inhibited strongly DNA replication and induced substantial frequencies of mutations at the lesion sites. Additionally, Pol η, Pol ι, and Pol ζ, but not Pol κ, had important roles in promoting replication through S-cdA and S-cdG in human cells. Based on these results, we propose a model for TLS across S-cdA and S-cdG in human cells, where Pol η and/or Pol ι carries out nucleotide insertion opposite the lesion, whereas Pol ζ executes the extension step.

Accurate and efficient bypass of 8,5'-cyclopurine-2'-deoxynucleosides by human and yeast DNA polymerase η.

Reactive oxygen species (ROS), which can be produced during normal aerobic metabolism, can induce the formation of tandem DNA lesions, including 8,5'-cyclo-2'-deoxyadenosine (cyclo-dA) and 8,5'-cyclo-2'-deoxyguanosine (cyclo-dG). Previous studies have shown that cyclo-dA and cyclo-dG accumulate in cells and can block mammalian RNA polymerase II and replicative DNA polymerases. Here, we used primer extension and steady-state kinetic assays to examine the efficiency and fidelity for polymerase η to insert nucleotides opposite, and extend primer past, these cyclopurine lesions. We found that Saccharomyces cerevisiae and human polymerase η inserted 2'-deoxynucleotides opposite cyclo-dA, cyclo-dG and their adjacent 5' nucleosides at fidelities and efficiencies that were similar to those of their respective undamaged nucleosides. Moreover, the yeast enzyme exhibited similar processivity in DNA synthesis on templates housing a cyclo-dA or cyclo-dG to those carrying an unmodified dA or dG; the human polymerase, however, dissociated from the primer-template complex after inserting one or two additional nucleotides after the lesion. Pol η's accurate and efficient bypass of cyclo-dA and cyclo-dG indicates that this polymerase is likely responsible for error-free bypass of these lesions, whereas mutagenic bypass of these lesions may involve other translesion synthesis DNA polymerases. Together, our results suggested that pol η may have an additional function in cells, i.e., to alleviate the cellular burden of endogenously induced DNA lesions, including cyclo-dA and cyclo-dG.

Hospital management practices and medical device costs.

OBJECTIVE: To determine whether the variation in prices paid for cardiac medical devices was associated with management practices in cardiac units. STUDY SETTING: Cardiac units in US hospitals. STUDY DESIGN: We regressed unit prices on management practice scores and other hospital characteristics, with and without controls for device fixed effects, for the 11 top-spending cardiac device categories. DATA COLLECTION: A trusted third party that had entered into a confidentiality agreement combined de-identified medical device price data for N = 213 US hospitals from ECRI's Supply Guide benchmarking service, with survey responses regarding management practices in those hospitals' cardiac units; the resulting merged data were made available to researchers for analysis with hospital identifiers removed. N = 1980 hospitals with interventional cardiac catheterization laboratories and at least 25 annual acute myocardial infarction discharges in 2010 were eligible for inclusion; N = 648 responded to the management practices survey; N = 213 subscribed to Supply Guide and purchased at least one of 11 top cardiac medical device categories. PRINCIPAL FINDINGS: Cardiac units with better management practices paid lower prices for cardiac devices (percent decrease in price for one standard deviation increase in management score = 1.33%, 95% confidence interval 0.99-1.67). This was comparable in magnitude to the price decrease associated with a one standard deviation increase in patient volume. CONCLUSIONS: Better management practices were associated with lower device prices. This relationship is robust, but modest in magnitude. This modest magnitude is similar, though, to other events expected to lower input prices, such as transparency in the form of benchmarking information and hospital mergers.

In vitro replication studies of carboxymethylated DNA lesions with Saccharomyces cerevisiae polymerase η.

Humans are exposed to N-nitroso compounds (NOCs) both endogenously and exogenously from a number of environmental sources, and NOCs are both mutagenic and carcinogenic. After metabolic activation, some NOCs can induce carboxymethylation of nucleobases through a diazoacetate intermediate, which could give rise to p53 mutations similar to those seen in human gastrointestinal cancers. It was previously found that the growth of polymerase η-deficient human cells was inhibited by treatment with azaserine, a DNA carboxymethylation agent, suggesting the importance of this polymerase in bypassing the azaserine-induced carboxymethylated DNA lesions. In this study, we examined how carboxymethylated DNA lesions, which included N(6)-carboxymethyl-2'-deoxyadenosine (N(6)-CMdA), N(4)-carboxymethyl-2'-deoxycytidine (N(4)-CMdC), N3-carboxymethylthymidine (N3-CMdT), and O(4)-carboxymethylthymidine (O(4)-CMdT), perturbed the efficiency and fidelity of DNA replication mediated by Saccharomyces cerevisiae polymerase η (pol η). Our results from steady-state kinetic assay showed that pol η could readily bypass and extend past N(6)-CMdA and incorporated the correct nucleotides opposite the lesion and its neighboring 5'-nucleoside with high efficiency. By contrast, the polymerase could bypass N(4)-CMdC inefficiently, with substantial misincorporation of dCMP followed by dAMP, though pol η could extend past the lesion with high fidelity and efficiency when dGMP was incorporated opposite the lesion. On the other hand, yeast pol η experienced great difficulty in bypassing O(4)-CMdT and N3-CMdT, and the polymerase inserted preferentially the incorrect dGMP opposite these two DNA lesions; the extension step, nevertheless, occurred with high fidelity and efficiency when the correct dAMP was opposite the lesion, as opposed to the preferentially incorporated incorrect dGMP. These results suggest that these lesions may contribute significantly to diazoacetate-induced mutations and those in the p53 gene observed in human gastrointestinal tumors.

Physician investment in hospitals: Specialization, selection, and quality in cardiac care.

Physician ownership of hospitals involves several competing economic forces. Physician-owners may be incentivized to "cherry-pick" and treat profitable patients at their facilities. However, physician-owned hospitals are often specialized and may provide higher-quality care for well-matched patients. Using multiple identification approaches, I document no significant mortality improvement for cardiac patients treated at physician-owned hospitals. Using aggregate data on ownership to infer physician-owner preferences in a hospital choice model, my results rule out significant cherry-picking within physician-owners' patient populations. However, both facility location and a healthier overall patient population among physician-owners drive advantageous selection of patients into physician-owned hospitals.

Medical Device Firm Payments To Physicians Exceed What Drug Companies Pay Physicians, Target Surgical Specialists.

Many physicians receive payments from medical device companies that make products physicians can use or recommend. Such payments are controversial because of concerns that they might influence physicians to treat patients with devices made by the firms that make those payments, even if those devices are not optimal for patients. This issue has been studied extensively in the drug industry. Medical devices entail a greater degree of physician-industry interaction regarding treatment, training, and innovation than pharmaceuticals, and they have been less studied because of data limitations. We summarize and compare device and drug firm payment rates and magnitudes reported in Open Payments data by payment type, physician specialty, and Medicare billing amount. Relative to drug firm payments, device firm payments as a percentage of industry revenue were seven times as large; device firm payments were also more often related to product development and training and were more strongly correlated with physicians' Medicare billing amounts. Using Food and Drug Administration product approval data, we further document that top-paying firms dominate high-revenue device categories. Our results suggest that optimal policy regarding physician-industry relationships for medical devices may be very different from that for pharmaceuticals. Estimating the causal relationships between payments and device use, pricing, and innovation to inform policy makers will be possible only with greater data transparency, such as including device identifiers in medical claims.

Neuroinflammation in Alzheimer's disease: Pleiotropic roles for cytokines and neuronal pentraxins.

Neuroinflammation is a potential factor speculated to underlie Alzheimer's disease (AD) etiopathogenesis and progression. The overwhelming focus in this area of research to date has been on the chronic upregulation of pro-inflammatory cytokines to understand how neuroinflammatory mechanisms contribute to neurodegeneration. Yet, it is important to understand the pleiotropic roles of these cytokines in modulating neuroinflammation in which they cannot be labeled as a strictly "good" or "bad" biomarker phenotype. As such, biomarkers with more precise functions are needed to better understand how neuroinflammation impacts the brain in AD. Neuronal pentraxins are a concentration- dependent group of pro- or anti- inflammatory cytokines. There is contradictory evidence of these pentraxins as being both neuroprotective and potentially detrimental in AD. Potential neuroprotective examples include their ability to predict AD-related outcomes such as cognition, memory function and synaptic refinement. This review will briefly outline the basis of AD and subsequently summarize findings for neuropathological mechanisms of neuroinflammation, roles for traditional pro-and anti-inflammatory cytokines, and data found thus far on the neuronal pentraxins.

Early Medicaid Expansion Associated With Reduced Payday Borrowing In California.

We examined the impact of California's early Medicaid expansion under the Affordable Care Act on the use of payday loans, a form of high-interest borrowing used by low- and middle-income Americans. Using a data set for the period 2009-13 (roughly twenty-four months before and twenty-four months after the 2011-12 Medicaid expansion) that covered the universe of payday loans from five large payday lenders with locations around the United States, we used a difference-in-differences research design to assess the effect of the expansion on payday borrowing, comparing trends in early-expansion counties in California to those in counties nationwide that did not expand early. The early Medicaid expansion was associated with an 11 percent reduction in the number of loans taken out each month. It also reduced the number of unique borrowers each month and the amount of payday loan debt. We were unable to determine precisely how and for whom the expansion reduced payday borrowing, since to our knowledge, no data exist that directly link payday lending to insurance status. Nonetheless, our results suggest that Medicaid reduced the demand for high-interest loans and improved the financial health of American families.

Marketplace Plans With Narrow Physician Networks Feature Lower Monthly Premiums Than Plans With Larger Networks.

The introduction of health insurance Marketplaces under the Affordable Care Act has been associated with growth of restricted provider networks. The value of this plan design strategy, including its association with lower premiums, is uncertain. We used data from all silver plans offered in the 2014 health insurance exchanges in the fifty states and the District of Columbia to estimate the association between the breadth of a provider network and plan premiums. We found that within a market, for plans of otherwise equivalent design and controlling for issuer-specific pricing strategy, a plan with an extra-small network had a monthly premium that was 6.7 percent less expensive than that of a plan with a large network. Because narrow networks remain an important strategy available to insurance companies to offer lower-cost plans on health insurance Marketplaces, the success of health insurance coverage expansions may be tied to the successful implementation of narrow networks.