Macromolecular modeling and design in Rosetta: recent methods and frameworks.

The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at http://www.rosettacommons.org.

Using cfDNA and ctDNA as Oncologic Markers: A Path to Clinical Validation.

The detection of circulating tumor DNA (ctDNA) in liquid biopsy samples as an oncological marker is being used in clinical trials at every step of clinical management. As ctDNA-based liquid biopsy kits are developed and used in clinics, companies work towards increased convenience, accuracy, and cost over solid biopsies and other oncological markers. The technology used to differentiate ctDNA and cell-free DNA (cfDNA) continues to improve with new tests and methodologies being able to detect down to mutant allele frequencies of 0.001% or 1/100,000 copies. Recognizing this development in technology, the FDA has recently given pre-market approval and breakthrough device designations to multiple companies. The purpose of this review is to look at the utility of measuring total cfDNA, techniques used to differentiate ctDNA from cfDNA, and the utility of different ctDNA-based liquid biopsy kits using relevant articles from PubMed, clinicaltrials.gov, FDA approvals, and company newsletters. Measuring total cfDNA could be a cost-effective, viable prognostic marker, but various factors do not favor it as a monitoring tool during chemotherapy. While there may be a place in the clinic for measuring total cfDNA in the future, the lack of standardization means that it is difficult to move forward with large-scale clinical validation studies currently. While the detection of ctDNA has promising standardized liquid biopsy kits from various companies with large clinical trials ongoing, their applications in screening and minimal residual disease can suffer from lower sensitivity. However, researchers are working towards solutions to these issues with innovations in technology, multi-omics, and sampling. With great promise, further research is needed before liquid biopsies can be recommended for everyday clinical management.

Two-Year Costs and Quality in the Comprehensive Primary Care Initiative.

BACKGROUND: The 4-year, multipayer Comprehensive Primary Care Initiative was started in October 2012 to determine whether several forms of support would produce changes in care delivery that would improve the quality and reduce the costs of care at 497 primary care practices in seven regions across the United States. Support included the provision of care-management fees, the opportunity to earn shared savings, and the provision of data feedback and learning support. METHODS: We tracked changes in the delivery of care by practices participating in the initiative and used difference-in-differences regressions to compare changes over the first 2 years of the initiative in Medicare expenditures, health care utilization, claims-based measures of quality, and patient experience for Medicare fee-for-service beneficiaries attributed to initiative practices and a group of matched comparison practices. RESULTS: During the first 2 years, initiative practices received a median of $115,000 per clinician in care-management fees. The practices reported improvements in approaches to the delivery of primary care in areas such as management of the care of high-risk patients and enhanced access to care. Changes in average monthly Medicare expenditures per beneficiary did not differ significantly between initiative and comparison practices when care-management fees were not taken into account (-$11; 95% confidence interval [CI], -$23 to $1; P=0.07; negative values indicate less growth in spending at initiative practices) or when these fees were taken into account ($7; 95% CI, -$5 to $19; P=0.27). The only significant differences in other measures were a 3% reduction in primary care visits for initiative practices relative to comparison practices (P<0.001) and changes in two of the six domains of patient experience--discussion of decisions regarding medication with patients and the provision of support for patients taking care of their own health--both of which showed a small improvement in initiative practices relative to comparison practices (P=0.006 and P<0.001, respectively). CONCLUSIONS: Midway through this 4-year intervention, practices participating in the initiative have reported progress in transforming the delivery of primary care. However, at this point these practices have not yet shown savings in expenditures for Medicare Parts A and B after accounting for care-management fees, nor have they shown an appreciable improvement in the quality of care or patient experience. (Funded by the Department of Health and Human Services, Centers for Medicare and Medicaid Services; ClinicalTrials.gov number, NCT02320591.).

Maryland's Global Hospital Budgets--Preliminary Results from an All-Payer Model.

In the first year of Maryland's experiment in setting all-payer rates for hospital services, costs were contained and the quality of care improved, though the state still has high rates of hospital admissions and per capita spending for Medicare patients.

The Roles of Cost and Quality Information in Medicare Advantage Plan Enrollment Decisions: an Observational Study.

BACKGROUND: To facilitate informed decision-making in the Medicare Advantage marketplace, the Centers for Medicare & Medicaid Services publishes plan information on the Medicare Plan Finder website, including costs, benefits, and star ratings reflecting quality. Little is known about how beneficiaries weigh costs versus quality in enrollment decisions. OBJECTIVE: We aimed to assess associations between publicly reported Medicare Advantage plan attributes (i.e., costs, quality, and benefits) and brand market share and beneficiaries' enrollment decisions. DESIGN, SETTING, PARTICIPANTS: We performed a nationwide, beneficiary-level cross-sectional analysis of 847,069 beneficiaries enrolling in Medicare Advantage for the first time in 2011. MAIN MEASURES: Matching beneficiaries with their plan choice sets, we used conditional logistic regression to estimate associations between plan attributes and enrollment to assess the proportion of enrollment variation explained by plan attributes and willingness to pay for quality. KEY RESULTS: Relative to the total variation explained by the model, the variation in plan choice explained by premiums (25.7 %) and out-of-pocket costs (11.6 %) together explained nearly three times as much as quality ratings (13.6 %), but brand market share explained the most variation (35.3 %). Further, while beneficiaries were willing to pay more in total annual combined premiums and out-of-pocket costs for higher-rated plans (from $4,154.93 for 2.5-star plans to $5,698.66 for 5-star plans), increases in willingness to pay diminished at higher ratings, from $549.27 (95 %CI: $541.10, $557.44) for a rating increase from 2.5 to 3 stars to $68.22 (95 %CI: $61.44, $75.01) for an increase from 4.5 to 5 stars. Willingness to pay varied among subgroups: beneficiaries aged 64-65 years were more willing to pay for higher-rated plans, while black and rural beneficiaries were less willing to pay for higher-rated plans. CONCLUSIONS: While beneficiaries prefer higher-quality and lower-cost Medicare Advantage plans, marginal utility for quality diminishes at higher star ratings, and their decisions are strongly associated with plans' brand market share.

Association Between Hospital Participation in a Medicare Bundled Payment Initiative and Payments and Quality Outcomes for Lower Extremity Joint Replacement Episodes.

IMPORTANCE: Bundled Payments for Care Improvement (BPCI) is a voluntary initiative of the Centers for Medicare & Medicaid Services to test the effect of holding an entity accountable for all services provided during an episode of care on episode payments and quality of care. OBJECTIVE: To evaluate whether BPCI was associated with a greater reduction in Medicare payments without loss of quality of care for lower extremity joint (primarily hip and knee) replacement episodes initiated in BPCI-participating hospitals that are accountable for total episode payments (for the hospitalization and Medicare-covered services during the 90 days after discharge). DESIGN, SETTING, AND PARTICIPANTS: A difference-in-differences approach estimated the differential change in outcomes for Medicare fee-for-service beneficiaries who had a lower extremity joint replacement at a BPCI-participating hospital between the baseline (October 2011 through September 2012) and intervention (October 2013 through June 2015) periods and beneficiaries with the same surgical procedure at matched comparison hospitals. EXPOSURE: Lower extremity joint replacement at a BPCI-participating hospital. MAIN OUTCOMES AND MEASURES: Standardized Medicare-allowed payments (Medicare payments), utilization, and quality (unplanned readmissions, emergency department visits, and mortality) during hospitalization and the 90-day postdischarge period. RESULTS: There were 29 441 lower extremity joint replacement episodes in the baseline period and 31 700 in the intervention period (mean [SD] age, 74.1 [8.89] years; 65.2% women) at 176 BPCI-participating hospitals, compared with 29 440 episodes in the baseline period (768 hospitals) and 31 696 episodes in the intervention period (841 hospitals) (mean [SD] age, 74.1 [8.92] years; 64.9% women) at matched comparison hospitals. The BPCI mean Medicare episode payments were $30 551 (95% CI, $30 201 to $30 901) in the baseline period and declined by $3286 to $27 265 (95% CI, $26 838 to $27 692) in the intervention period. The comparison mean Medicare episode payments were $30 057 (95% CI, $29 765 to $30 350) in the baseline period and declined by $2119 to $27 938 (95% CI, $27 639 to $28 237). The mean Medicare episode payments declined by an estimated $1166 more (95% CI, -$1634 to -$699; P < .001) for BPCI episodes than for comparison episodes, primarily due to reduced use of institutional postacute care. There were no statistical differences in the claims-based quality measures, which included 30-day unplanned readmissions (-0.1%; 95% CI, -0.6% to 0.4%), 90-day unplanned readmissions (-0.4%; 95% CI, -1.1% to 0.3%), 30-day emergency department visits (-0.1%; 95% CI, -0.7% to 0.5%), 90-day emergency department visits (0.2%; 95% CI, -0.6% to 1.0%), 30-day postdischarge mortality (-0.1%; 95% CI, -0.3% to 0.2%), and 90-day postdischarge mortality (-0.0%; 95% CI, -0.3% to 0.3%). CONCLUSIONS AND RELEVANCE: In the first 21 months of the BPCI initiative, Medicare payments declined more for lower extremity joint replacement episodes provided in BPCI-participating hospitals than for those provided in comparison hospitals, without a significant change in quality outcomes. Further studies are needed to assess longer-term follow-up as well as patterns for other types of clinical care.

The Patient Protection and Affordable Care Act: opportunities for prevention and public health.

The Patient Protection and Affordable Care Act, which was enacted by the US Congress in 2010, marks the greatest change in US health policy since the 1960s. The law is intended to address fundamental problems within the US health system, including the high and rising cost of care, inadequate access to health insurance and health services for many Americans, and low health-care efficiency and quality. By 2019, the law will bring health coverage--and the health benefits of insurance--to an estimated 25 million more Americans. It has already restrained discriminatory insurance practices, made coverage more affordable, and realised new provisions to curb costs (including tests of new health-care delivery models). The new law establishes the first National Prevention Strategy, adds substantial new funding for prevention and public health programmes, and promotes the use of recommended clinical preventive services and other measures, and thus represents a major opportunity for prevention and public health. The law also provides impetus for greater collaboration between the US health-care and public health systems, which have traditionally operated separately with little interaction. Taken together, the various effects of the Patient Protection and Affordable Care Act can advance the health of the US population.

Opportunities for quality measurement to improve the value of care for patients with multiple chronic conditions.

Quality measurement efforts have not historically focused on patients with multiple chronic conditions (MCCs), despite them comprising one quarter of the population and two thirds of health care spending. The Patient Protection and Affordable Care Act (ACA) creates several mechanisms for the Centers for Medicare & Medicaid Services (CMS) to transform quality measurement into an organized enterprise designed to support clinicians caring for this vulnerable population. This article highlights 3 emerging policy opportunities for CMS to guide public and private quality measurement efforts for patients with MCCs. First, it discusses infusing an MCC framework into measure development to promote patient-centered, as opposed to single-disease-specific, performance measurement. Second, it describes the importance of using common performance measures for individual clinicians, hospitals, and communities to accelerate meaningful improvement in the prevention and management of chronic conditions across local populations. Finally, the need for longitudinal measurement as a foundation for sustained quality improvement is presented. The ACA's expansion of insurance access and portability necessitates collaborative alignment of chronic condition quality measurement efforts between public and private programs to develop a high-value lifelong health system.

Association of Pioneer Accountable Care Organizations vs traditional Medicare fee for service with spending, utilization, and patient experience.

IMPORTANCE: The Pioneer Accountable Care Organization (ACO) Model aims to drive health care organizations to reduce expenditures while improving quality for fee-for-service (FFS) Medicare beneficiaries. OBJECTIVE: To determine whether FFS beneficiaries aligned with Pioneer ACOs had smaller increases in spending and utilization than other FFS beneficiaries while retaining similar levels of care satisfaction in the first 2 years of the Pioneer ACO Model. DESIGN, SETTING, AND PARTICIPANTS: Participants were FFS Medicare beneficiaries aligned with 32 ACOs (n = 675,712 in 2012; n = 806,258 in 2013) and a comparison group of alignment-eligible beneficiaries in the same markets (n = 13,203,694 in 2012; n = 12,134,154 in 2013). Analyses comprised difference-in-differences multivariable regression with Oaxaca-Blinder reweighting to model expenditure and utilization outcomes over a 2-year performance period (2012-2013) and 2-year baseline period (2010-2011) as well as adjusted analyses of Consumer Assessment of Healthcare Providers & Systems (CAHPS) survey responses among random samples of beneficiaries in Pioneer ACOs (n = 13,097), FFS (n = 116,255), or Medicare Advantage (n = 203,736) for 2012 care. EXPOSURES: Beneficiary alignment with a Pioneer ACO in 2012 or 2013. MAIN OUTCOMES AND MEASURES: Medicare spending, utilization, and CAHPS domain scores. RESULTS: Total spending for beneficiaries aligned with Pioneer ACOs in 2012 or 2013 increased from baseline to a lesser degree relative to comparison populations. Differential changes in spending were approximately -$35.62 (95% CI, -$40.12 to -$31.12) per-beneficiary-per-month (PBPM) in 2012 and -$11.18 (95% CI, -$15.84 to -$6.51) PBPM in 2013, which amounted to aggregate reductions in increases of approximately -$280 (95% CI, -$315 to -$244) million in 2012 and -$105 (95% CI, -$148 to -$61) million in 2013. Inpatient spending showed the largest differential change of any spending category (-$14.40 [95% CI, -$17.31 to -$11.49] PBPM in 2012; -$6.46 [95% CI, -$9.26 to -$3.66] PBPM in 2013). Changes in utilization of physician services, emergency department, and postacute care followed a similar pattern. Compared with other Medicare beneficiaries, ACO-aligned beneficiaries reported higher mean scores for timely care (77.2 [ACO] vs 71.2 [FFS] vs 72.7 [MA]) and for clinician communication (91.9 [ACO] vs 88.3 [FFS] vs 88.7 [MA]). CONCLUSIONS AND RELEVANCE: In the first 2 years of the Pioneer ACO Model, beneficiaries aligned with Pioneer ACOs, as compared with general Medicare FFS beneficiaries, exhibited smaller increases in total Medicare expenditures and differential reductions in utilization of different health services, with little difference in patient experience.

Polyploidy in Cancer: Causal Mechanisms, Cancer-Specific Consequences, and Emerging Treatments.

Drug resistance is the major determinant for metastatic disease and fatalities, across all cancers. Depending on the tissue of origin and the therapeutic course, a variety of biological mechanisms can support and sustain drug resistance. Although genetic mutations and gene silencing through epigenetic mechanisms are major culprits in targeted therapy, drug efflux and polyploidization are more global mechanisms that prevail in a broad range of pathologies, in response to a variety of treatments. There is an unmet need to identify patients at risk for polyploidy, understand the mechanisms underlying polyploidization, and to develop strategies to predict, limit, and reverse polyploidy thus enhancing efficacy of standard-of-care therapy that improve better outcomes. This literature review provides an overview of polyploidy in cancer and offers perspective on patient monitoring and actionable therapy.

Aurkin-A, a TPX2-aurora a small molecule inhibitor disrupts Alisertib-induced polyploidy in aggressive diffuse large B cell lymphoma.

Chemotherapy induced polyploidy is a mechanism of inherited drug resistance resulting in an aggressive disease course in cancer patients. Alisertib, an Aurora Kinase A (AK-A) ATP site inhibitor, induces cell cycle disruption resulting in polyaneuploidy in Diffuse Large B Cell Lymphoma (DLBCL). Propidium iodide flow cytometry was utilized to quantify alisertib induced polyploidy in U2932 and VAL cell lines. In U2932 cells, 1µM alisertib generated 8n+ polyploidy in 48% of the total cell population after 5 days of treatment. Combination of Aurkin A an AK-A/TPX2 site inhibitor, plus alisertib disrupted alisertib induced polyploidy in a dose-dependent manner with associated increased apoptosis. We generated a stable FUCCI U2932 cell line expressing Geminin-clover (S/G2/M) and cdt1-mKO (G1), to monitor cell cycle progression. Using this system, we identified alisertib induces polyploidy through endomitosis, which was eliminated with Aurkin A treatment. In a VAL mouse xenograft model, we show polyploidy generation in alisertib treated mice versus vehicle control or Aurkin A. Aurkin A plus alisertib significantly reduced polyploidy to vehicle control levels. Our in vitro and in vivo studies show that Aurkin A synergizes with alisertib and significantly decreases the alisertib dose needed to disrupt polyploidy while increasing apoptosis in DLBCL cells.