Predicting relative efficiency of amide bond formation using multivariate linear regression.

Amides are ubiquitous in biologically active natural products and commercial drugs. The most common strategy for introducing this functional group is the coupling of a carboxylic acid with an amine, which requires the use of a coupling reagent to facilitate elimination of water. However, the optimal reaction conditions often appear rather arbitrary to the specific reaction. Herein, we report the development of statistical models correlating measured rates to physical organic descriptors to enable the prediction of reaction rates for untested carboxylic acid/amine pairs. The key to the success of this endeavor was the development of an end-to-end data science­based workflow to select a set of coupling partners that are appropriately distributed in chemical space to facilitate statistical model development. By using a parameterization, dimensionality reduction, and clustering protocol, a training set was identified. Reaction rates for a range of carboxylic acid and primary alkyl amine couplings utilizing carbonyldiimidazole (CDI) as the coupling reagent were measured. The collected rates span five orders of magnitude, confirming that the designed training set encompasses a wide range of chemical space necessary for effective model development. Regressing these rates with high-level density functional theory (DFT) descriptors allowed for identification of a statistical model wherein the molecular features of the carboxylic acid are primarily responsible for the observed rates. Finally, out-of-sample amide couplings are used to determine the limitations and effectiveness of the model.

Changes in Quality of Care after Hospital Mergers and Acquisitions.

BACKGROUND: The hospital industry has consolidated substantially during the past two decades and at an accelerated pace since 2010. Multiple studies have shown that hospital mergers have led to higher prices for commercially insured patients, but research about effects on quality of care is limited. METHODS: Using Medicare claims and Hospital Compare data from 2007 through 2016 on performance on four measures of quality of care (a composite of clinical-process measures, a composite of patient-experience measures, mortality, and the rate of readmission after discharge) and data on hospital mergers and acquisitions occurring from 2009 through 2013, we conducted difference-in-differences analyses comparing changes in the performance of acquired hospitals from the time before acquisition to the time after acquisition with concurrent changes for control hospitals that did not have a change in ownership. RESULTS: The study sample included 246 acquired hospitals and 1986 control hospitals. Being acquired was associated with a modest differential decline in performance on the patient-experience measure (adjusted differential change, -0.17 SD; 95% confidence interval [CI], -0.26 to -0.07; P = 0.002; the change was analogous to a fall from the 50th to the 41st percentile) and no significant differential change in 30-day readmission rates (-0.10 percentage points; 95% CI, -0.53 to 0.34; P = 0.72) or in 30-day mortality (-0.03 percentage points; 95% CI, -0.20 to 0.14; P = 0.72). Acquired hospitals had a significant differential improvement in performance on the clinical-process measure (0.22 SD; 95% CI, 0.05 to 0.38; P = 0.03), but this could not be attributed conclusively to a change in ownership because differential improvement occurred before acquisition. CONCLUSIONS: Hospital acquisition by another hospital or hospital system was associated with modestly worse patient experiences and no significant changes in readmission or mortality rates. Effects on process measures of quality were inconclusive. (Funded by the Agency for Healthcare Research and Quality.).

SNAr Regioselectivity Predictions: Machine Learning Triggering DFT Reaction Modeling through Statistical Threshold.

Fast and accurate prospective predictions of regioselectivity can significantly reduce the time and resources spent on unproductive transformations in the pharmaceutical industry. Density functional theory (DFT) reaction modeling through transition state theory (TST) and machine learning (ML) methods has been widely used to predict reaction outcomes such as selectivity. However, TST reaction modeling and ML methods are either time-consuming or data-dependent. Herein, we introduce a prototype seamlessly bridging ML and TST modeling by triggering resource-intensive but much less domain-sensitive DFT calculations only on less confident ML predictions. The proposed workflow was trained and tested on both the Pfizer internal dataset and the USPTO public dataset to predict regioselectivity for SNAr reactions. Our method is accurate and fast, which achieves 96.3 and 94.7% accuracy in predicting the correct major product on Pfizer and USPTO datasets, respectively, in a fraction of conventional TST computing time.

Residual Confounding in Health Plan Performance Assessments: Evidence From Randomization in Medicaid.

BACKGROUND: Risk adjustment is used widely in payment systems and performance assessments, but the extent to which it distinguishes plan or provider effects from confounding due to patient differences is typically unknown. OBJECTIVE: To assess the degree to which risk-adjusted measures of health plan performance adequately adjust for the variation across plans that arises because of differences in patient characteristics (residual confounding). DESIGN: Comparison between plan performance estimates based on enrollees who made plan choices (observational population) and estimates based on enrollees assigned to plans (randomized population). SETTING: Natural experiment in which more than two thirds of a state's Medicaid population in 1 region was randomly assigned to 1 of 5 plans. PARTICIPANTS: 137 933 enrollees in 2013 to 2014, of whom 31.1% selected a plan and 68.9% were randomly assigned to 1 of the same 5 plans. MEASUREMENTS: Annual total spending (that is, payments to providers), primary care use, dental care use, and avoidable emergency department visits, all scored as plan-specific deviations from the "average" plan performance within each population. RESULTS: Enrollee characteristics were appreciably imbalanced across plans in the observational population, as expected, but were not in the randomized population. Annual total spending varied across plans more in the observational population (SD, $147 per enrollee) than in the randomized population (SD, $70 per enrollee) after accounting for baseline differences in the observational and randomized populations and for differences across plans. On average, a plan's spending score (its deviation from the "average" performance) in the observational population differed from its score in the randomized population by $67 per enrollee in absolute value (95% CI, $38 to $123), or 4.2% of mean spending per enrollee (P = 0.009, rejecting the null hypothesis that this difference would be expected from sampling error). The difference was reduced modestly by risk adjustment to $62 per enrollee (P = 0.012). Residual confounding was similarly substantial for most other performance measures. Further adjustment for social factors did not materially change estimates. LIMITATION: Potential heterogeneity in plan effects between the 2 populations. CONCLUSION: Residual confounding in risk-adjusted performance assessments can be substantial and should caution policymakers against assuming that risk adjustment isolates real differences in plan performance. PRIMARY FUNDING SOURCE: Arnold Ventures.

Organization and Performance of US Health Systems.

Importance: Health systems play a central role in the delivery of health care, but relatively little is known about these organizations and their performance. Objective: To (1) identify and describe health systems in the United States; (2) assess differences between physicians and hospitals in and outside of health systems; and (3) compare quality and cost of care delivered by physicians and hospitals in and outside of health systems. Evidence Review: Health systems were defined as groups of commonly owned or managed entities that included at least 1 general acute care hospital, 10 primary care physicians, and 50 total physicians located within a single hospital referral region. They were identified using Centers for Medicare & Medicaid Services administrative data, Internal Revenue Service filings, Medicare and commercial claims, and other data. Health systems were categorized as academic, public, large for-profit, large nonprofit, or other private systems. Quality of preventive care, chronic disease management, patient experience, low-value care, mortality, hospital readmissions, and spending were assessed for Medicare beneficiaries attributed to system and nonsystem physicians. Prices for physician and hospital services and total spending were assessed in 2018 commercial claims data. Outcomes were adjusted for patient characteristics and geographic area. Findings: A total of 580 health systems were identified and varied greatly in size. Systems accounted for 40% of physicians and 84% of general acute care hospital beds and delivered primary care to 41% of traditional Medicare beneficiaries. Academic and large nonprofit systems accounted for a majority of system physicians (80%) and system hospital beds (64%). System hospitals were larger than nonsystem hospitals (67% vs 23% with >100 beds), as were system physician practices (74% vs 12% with >100 physicians). Performance on measures of preventive care, clinical quality, and patient experience was modestly higher for health system physicians and hospitals than for nonsystem physicians and hospitals. Prices paid to health system physicians and hospitals were significantly higher than prices paid to nonsystem physicians and hospitals (12%-26% higher for physician services, 31% for hospital services). Adjusting for practice size attenuated health systems differences on quality measures, but price differences for small and medium practices remained large. Conclusions and Relevance: In 2018, health system physicians and hospitals delivered a large portion of medical services. Performance on clinical quality and patient experience measures was marginally better in systems but spending and prices were substantially higher. This was especially true for small practices. Small quality differentials combined with large price differentials suggests that health systems have not, on average, realized their potential for better care at equal or lower cost.

Early Effects of an Accountable Care Organization Model for Underserved Areas.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) developed the Accountable Care Organization (ACO) Investment Model (AIM) to encourage the growth of Medicare Shared Savings Program (MSSP) ACOs in rural and underserved areas. AIM provides financial support to eligible MSSP ACOs by means of prepayment of shared savings. Estimation of the performance of AIM ACOs on measures of spending and utilization in their first performance year would be useful for understanding the viability of ACOs located in these areas. METHODS: We analyzed Medicare claims and enrollment data for a group of fee-for-service beneficiaries who had been attributed to 41 AIM ACOs and for a comparable group of beneficiaries who resided in the ACO markets but were served primarily by non-ACO providers. We used a difference-in-differences study design to compare changes in outcomes from the baseline period (2013 through 2015) to the performance period (2016) among beneficiaries attributed to AIM ACOs with concurrent changes among beneficiaries in the comparison group. The primary outcome of interest was total Medicare Part A and B spending. RESULTS: Provider participation in AIM was associated with a differential reduction in total Medicare spending of $28.21 per beneficiary per month relative to the comparison group, which amounted to an aggregate decrease of $131.0 million. Over the same period, CMS made $76.2 million in prepayments and paid an additional $6.2 million in shared savings to ACOs in which shared savings exceeded the prepayments. After we accounted for this $82.4 million in CMS spending, the aggregate net reduction was $48.6 million, which corresponded to a net reduction of $10.46 per beneficiary per month. Decreases in the number of hospitalizations and use of institutional post-acute care contributed to the observed reduction in overall spending. CONCLUSIONS: With up-front investments, participation in ACO shared savings contracts by providers serving rural and underserved areas was associated with lower Medicare spending than that among non-ACO providers. (Funded by the Centers for Medicare and Medicaid Services.).

Two-Year Evaluation of Mandatory Bundled Payments for Joint Replacement.

BACKGROUND: In 2016, Medicare implemented Comprehensive Care for Joint Replacement (CJR), a national mandatory bundled-payment model for hip or knee replacement in randomly selected metropolitan statistical areas. Hospitals in such areas receive bonuses or pay penalties based on Medicare spending per hip- or knee-replacement episode (defined as the hospitalization plus 90 days after discharge). METHODS: We conducted difference-in-differences analyses using Medicare claims from 2015 through 2017, encompassing the first 2 years of bundled payments in the CJR program. We evaluated hip- or knee-replacement episodes in 75 metropolitan statistical areas randomly assigned to mandatory participation in the CJR program (bundled-payment metropolitan statistical areas, hereafter referred to as "treatment" areas) as compared with those in 121 control areas, before and after implementation of the CJR model. The primary outcomes were institutional spending per hip- or knee-replacement episode (i.e., Medicare payments to institutions, primarily to hospitals and post-acute care facilities), rates of postsurgical complications, and the percentage of "high-risk" patients (i.e., patients for whom there was an elevated risk of spending - a measure of patient selection). Analyses were adjusted for the hospital and characteristics of the patients and procedures. RESULTS: From 2015 through 2017, there were 280,161 hip- or knee-replacement procedures in 803 hospitals in treatment areas and 377,278 procedures in 962 hospitals in control areas. After the initiation of the CJR model, there were greater decreases in institutional spending per joint-replacement episode in treatment areas than in control areas (differential change [i.e., the between-group difference in the change from the period before the CJR model], -$812, or a -3.1% differential decrease relative to the treatment-group baseline; P<0.001). The differential reduction was driven largely by a 5.9% relative decrease in the percentage of episodes in which patients were discharged to post-acute care facilities. The CJR program did not have a significant differential effect on the composite rate of complications (P=0.67) or on the percentage of joint-replacement procedures performed in high-risk patients (P=0.81). CONCLUSIONS: In the first 2 years of the CJR program, there was a modest reduction in spending per hip- or knee-replacement episode, without an increase in rates of complications. (Funded by the Commonwealth Fund and the National Institute on Aging of the National Institutes of Health.).

Consequences of the 340B Drug Pricing Program.

BACKGROUND: The 340B Drug Pricing Program entitles qualifying hospitals to discounts on outpatient drugs, increasing the profitability of drug administration. By tying the program eligibility of hospitals to their Disproportionate Share Hospital (DSH) adjustment percentage, which reflects the proportion of hospitalized patients who are low-income, the program is intended to expand resources for underserved populations but provides no direct incentives for hospitals to use financial gains to enhance care for low-income patients. METHODS: We used Medicare claims and a regression-discontinuity design, taking advantage of the threshold for program eligibility among general acute care hospitals (DSH percentage, >11.75%), to isolate the effects of the program on hospital-physician consolidation (i.e., acquisition of physician practices or employment of physicians by hospitals) and on the outpatient administration of parenteral drugs by hospital-owned facilities in three specialties in which parenteral drugs are frequently used. For low-income patients, we also assessed the effects of the program on the provision of care by hospitals and on mortality. RESULTS: Hospital eligibility for the 340B Program was associated with 2.3 more hematologist-oncologists practicing in facilities owned by the hospital, or 230% more hematologist-oncologists than expected in the absence of the program (P=0.02), and with 0.9 (or 900%) more ophthalmologists per hospital (P=0.08) and 0.1 (or 33%) more rheumatologists per hospital (P=0.84). Program eligibility was associated with significantly higher numbers of parenteral drug claims billed by hospitals for Medicare patients in hematology-oncology (90% higher, P=0.001) and ophthalmology (177% higher, P=0.03) but not rheumatology (77% higher, P=0.12). Program eligibility was associated with lower proportions of low-income patients in hematology-oncology and ophthalmology and with no significant differences in hospital provision of safety-net or inpatient care for low-income groups or in mortality among low-income residents of the hospitals' local service areas. CONCLUSIONS: The 340B Program has been associated with hospital-physician consolidation in hematology-oncology and with more hospital-based administration of parenteral drugs in hematology-oncology and ophthalmology. Financial gains for hospitals have not been associated with clear evidence of expanded care or lower mortality among low-income patients. (Funded by the Agency for Healthcare Research and Quality and others.).

Medicare Spending after 3 Years of the Medicare Shared Savings Program.

BACKGROUND: Health care providers who participate as an accountable care organization (ACO) in the voluntary Medicare Shared Savings Program (MSSP) have incentives to lower spending for Medicare patients while achieving high performance on a set of quality measures. Little is known about the extent to which early savings achieved by ACOs in the program have grown and been replicated by ACOs that entered the program in later years. ACOs that are physician groups have stronger incentives to lower spending than hospital-integrated ACOs. METHODS: Using fee-for-service Medicare claims from 2009 through 2015, we performed difference-in-differences analyses to compare changes in Medicare spending for patients in ACOs before and after entry into the MSSP with concurrent changes in spending for local patients served by providers not participating in the MSSP (control group). We estimated differential changes (i.e., the between-group difference in the change from the pre-entry period) separately for hospital-integrated ACOs and physician-group ACOs that entered the MSSP in 2012, 2013, or 2014. RESULTS: MSSP participation was associated with differential spending reductions in physician-group ACOs. These reductions grew with longer participation in the program and were significantly greater than the reductions in hospital-integrated ACOs. By 2015, the mean differential change in per-patient Medicare spending was -$474 (-4.9% of the pre-entry mean, P<0.001) for physician-group ACOs that entered in 2012, -$342 (-3.5% of the pre-entry mean, P<0.001) for those that entered in 2013, and -$156 (-1.6% of the pre-entry mean, P=0.009) for those that entered in 2014. The corresponding differential changes for hospital-integrated ACOs were -$169 (P=0.005), -$18 (P=0.78), and $88 (P=0.14), which were significantly lower than for physician-group ACOs (P<0.001). Spending reductions in physician-group ACOs constituted a net savings to Medicare of $256.4 million in 2015, whereas spending reductions in hospital-integrated ACOs were offset by bonus payments. CONCLUSIONS: After 3 years of the MSSP, participation in shared-savings contracts by physician groups was associated with savings for Medicare that grew over the study period, whereas hospital-integrated ACOs did not produce savings (on average) during the same period. (Funded by the National Institute on Aging.).

Variation in Rates of Hospital Admission from the Emergency Department Among Medicare Patients at the Regional, Hospital, and Physician Levels.

STUDY OBJECTIVE: Rates of admission from the emergency department (ED) vary widely across regions of the country, hospitals within regions, and physicians within hospitals. Our objective was to determine the extent to which variation in admission decisions was described by differences in admission rates at these 3 levels. This understanding will serve to better target interventions to modify rates of admission where appropriate. METHODS: In this cross-sectional observational cohort study, we analyzed Medicare fee-for-service claims for ED visits from 2012 to 2015 in a 20% random sample of beneficiaries. We first estimated the total regional-, hospital-, and physician-level variations in rates of admission and their proportions of the total variation after adjusting for patient and each level's covariates. We then estimated the extent to which each level's characteristics accounted for variation at that respective level. RESULTS: Our study sample included 5,778,218 visits with 45,491 physicians at 3,480 EDs across 306 hospital referral regions. The mean rate of admission was 38.9% and ranged from 21.4% to 53.0% for physicians at the 10th and 90th percentile of the distribution, respectively. The residual (unexplained) variations at the regional, hospital, and physician levels were 13.3% (95% confidence interval [CI], 11.2 to 15.5%), 60.1% (57.1 to 62.9%), and 26.7% (26.4 to 26.9%), respectively. Regional, hospital, and physician characteristics accounted for 9.1% (95% CI, -5.6 to 23.8%), 51.1% (48.8 to 53.5%), and 2.7% (1.3 to 4.1%), respectively, of the explained variation at their respective levels. CONCLUSION: Within-area variation, both across hospitals within a region and across physicians within a hospital, is a more substantial component of observed variation in admission rates from the ED than regional level variation. These findings suggest that variation in admission rates is at least in part related to institutional norms and cultures as well as heterogeneity of physician decisionmaking within hospitals, both of which could be targets of interventions to modify rates of admission.

Savings or Selection? Initial Spending Reductions in the Medicare Shared Savings Program and Considerations for Reform.

Policy Points Concerns have been raised about risk selection in the Medicare Shared Savings Program (MSSP). Specifically, turnover in accountable care organization (ACO) physicians and patient panels has led to concerns that ACOs may be earning shared-savings bonuses by selecting lower-risk patients or providers with lower-risk panels. We find no evidence that changes in ACO patient populations explain savings estimates from previous evaluations through 2015. We also find no evidence that ACOs systematically manipulated provider composition or billing to earn bonuses. The modest savings and lack of risk selection in the original MSSP design suggest opportunities to build on early progress. Recent program changes provide ACOs with more opportunity to select providers with lower-risk patients. Understanding the effect of these changes will be important for guiding future payment policy. CONTEXT: The Medicare Shared Savings Program (MSSP) establishes incentives for participating accountable care organizations (ACOs) to lower spending for their attributed fee-for-service Medicare patients. Turnover in ACO physicians and patient panels has raised concerns that ACOs may be earning shared-savings bonuses by selecting lower-risk patients or providers with lower-risk panels. METHODS: We conducted three sets of analyses of Medicare claims data. First, we estimated overall MSSP savings through 2015 using a difference-in-differences approach and methods that eliminated selection bias from ACO program exit or changes in the practices or physicians included in ACO contracts. We then checked for residual risk selection at the patient level. Second, we reestimated savings with methods that address undetected risk selection but could introduce bias from other sources. These included patient fixed effects, baseline or prospective assignment, and area-level MSSP exposure to hold patient populations constant. Third, we tested for changes in provider composition or provider billing that may have contributed to bonuses, even if they were eliminated as sources of bias in the evaluation analyses. FINDINGS: MSSP participation was associated with modest and increasing annual gross savings in the 2012-2013 entry cohorts of ACOs that reached $139 to $302 per patient by 2015. Savings in the 2014 entry cohort were small and not statistically significant. Robustness checks revealed no evidence of residual risk selection. Alternative methods to address risk selection produced results that were substantively consistent with our primary analysis but varied somewhat and were more sensitive to adjustment for patient characteristics, suggesting the introduction of bias from within-patient changes in time-varying characteristics. We found no evidence of ACO manipulation of provider composition or billing to inflate savings. Finally, larger savings for physician group ACOs were robust to consideration of differential changes in organizational structure among non-ACO providers (eg, from consolidation). CONCLUSIONS: Participation in the original MSSP program was associated with modest savings and not with favorable risk selection. These findings suggest an opportunity to build on early progress. Understanding the effect of new opportunities and incentives for risk selection in the revamped MSSP will be important for guiding future program reforms.

Early Performance of Accountable Care Organizations in Medicare.

BACKGROUND: In the Medicare Shared Savings Program (MSSP), accountable care organizations (ACOs) have financial incentives to lower spending and improve quality. We used quasi-experimental methods to assess the early performance of MSSP ACOs. METHODS: Using Medicare claims from 2009 through 2013 and a difference-in-differences design, we compared changes in spending and in performance on quality measures from before the start of ACO contracts to after the start of the contracts between beneficiaries served by the 220 ACOs entering the MSSP in mid-2012 (2012 ACO cohort) or January 2013 (2013 ACO cohort) and those served by non-ACO providers (control group), with adjustment for geographic area and beneficiary characteristics. We analyzed the 2012 and 2013 ACO cohorts separately because entry time could reflect the capacity of an ACO to achieve savings. We compared ACO savings according to organizational structure, baseline spending, and concurrent ACO contracting with commercial insurers. RESULTS: Adjusted Medicare spending and spending trends were similar in the ACO cohorts and the control group during the precontract period. In 2013, the differential change (i.e., the between-group difference in the change from the precontract period) in total adjusted annual spending was -$144 per beneficiary in the 2012 ACO cohort as compared with the control group (P=0.02), consistent with a 1.4% savings, but only -$3 per beneficiary in the 2013 ACO cohort as compared with the control group (P=0.96). Estimated savings were consistently greater in independent primary care groups than in hospital-integrated groups among 2012 and 2013 MSSP entrants (P=0.005 for interaction). MSSP contracts were associated with improved performance on some quality measures and unchanged performance on others. CONCLUSIONS: The first full year of MSSP contracts was associated with early reductions in Medicare spending among 2012 entrants but not among 2013 entrants. Savings were greater in independent primary care groups than in hospital-integrated groups.

Deprotection of N-Boc Groups under Continuous-Flow High-Temperature Conditions.

The scope of thermolytic, N-Boc deprotection was studied on 26 compounds from the Pfizer compound library, representing a diverse set of structural moieties. Among these compounds, 12 substrates resulted in clean (≥95% product) deprotection, and an additional three compounds gave ≥90% product. The thermal de-Boc conditions were found to be compatible with a large number of functional groups. A combination of computational modeling, statistical analysis, and kinetic model fitting was used to support an initial, slow, and concerted proton transfer with release of isobutylene, followed by a rapid decarboxylation. A strong correlation was found to exist between the electrophilicity of the N-Boc carbonyl group and the reaction rate.

The Value-Based Payment Modifier: Program Outcomes and Implications for Disparities.

Background: When risk adjustment is inadequate and incentives are weak, pay-for-performance programs, such as the Value-Based Payment Modifier (Value Modifier [VM]) implemented by the Centers for Medicare & Medicaid Services, may contribute to health care disparities without improving performance on average. Objective: To estimate the association between VM exposure and performance on quality and spending measures and to assess the effects of adjusting for additional patient characteristics on performance differences between practices serving higher-risk and those serving lower-risk patients. Design: Exploiting the phase-in of the VM on the basis of practice size, regression discontinuity analysis and 2014 Medicare claims were used to estimate differences in practice performance associated with exposure of practices with 100 or more clinicians to full VM incentives (bonuses and penalties) and exposure of practices with 10 or more clinicians to partial incentives (bonuses only). Analyses were repeated with 2015 claims to estimate performance differences associated with a second year of exposure above the threshold of 100 or more clinicians. Performance differences were assessed between practices serving higher- and those serving lower-risk patients after standard Medicare adjustments versus adjustment for additional patient characteristics. Setting: Fee-for-service Medicare. Patients: Random 20% sample of beneficiaries. Measurements: Hospitalization for ambulatory care-sensitive conditions, all-cause 30-day readmissions, Medicare spending, and mortality. Results: No statistically significant discontinuities were found at the threshold of 10 or more or 100 or more clinicians in the relationship between practice size and performance on quality or spending measures in either year. Adjustment for additional patient characteristics narrowed performance differences by 9.2% to 67.9% between practices in the highest and those in the lowest quartile of Medicaid patients and Hierarchical Condition Category scores. Limitation: Observational design and administrative data. Conclusion: The VM was not associated with differences in performance on program measures. Performance differences between practices serving higher- and those serving lower-risk patients were affected considerably by additional adjustments, suggesting a potential for Medicare's pay-for-performance programs to exacerbate health care disparities. Primary Funding Source: The Laura and John Arnold Foundation and National Institute on Aging.

Stereoelectronic Effects in Ligand Design: Enantioselective Rhodium-Catalyzed Hydrogenation of Aliphatic Cyclic Tetrasubstituted Enamides and Concise Synthesis of (R)-Tofacitinib.

We herein report the development of a conformationally defined, electron-rich, C2 -symmetric, P-chiral bisphosphorus ligand, ArcPhos, by taking advantage of stereoelectronic effects in ligand design. With the Rh-ArcPhos catalyst, excellent enantioselectivities and unprecedentedly high turnovers (TON up to 10 000) were achieved in the asymmetric hydrogenation of aliphatic carbocyclic and heterocyclic tetrasubstituted enamides, to generate a series of chiral cis-2-alkyl-substituted carbocyclic and heterocyclic amine derivatives in excellent enantiomeric ratios. This method also enabled an efficient and practical synthesis of the Janus kinase inhibitor (R)-tofacitinib.

Performance differences in year 1 of pioneer accountable care organizations.

BACKGROUND: In 2012, a total of 32 organizations entered the Pioneer accountable care organization (ACO) program, in which providers can share savings with Medicare if spending falls below a financial benchmark. Performance differences associated with characteristics of Pioneer ACOs have not been well described. METHODS: In a difference-in-differences analysis of Medicare fee-for-service claims, we compared Medicare spending for beneficiaries attributed to Pioneer ACOs (ACO group) with other beneficiaries (control group) before (2009 through 2011) and after (2012) the start of Pioneer ACO contracts, with adjustment for geographic area and beneficiaries' sociodemographic and clinical characteristics. We estimated differential changes in spending for several subgroups of ACOs: those with and those without clear financial integration between hospitals and physician groups, those with higher and those with lower baseline spending, and the 13 ACOs that withdrew from the Pioneer program after 2012 and the 19 that did not. RESULTS: Adjusted Medicare spending and spending trends were similar in the ACO group and the control group during the precontract period. In 2012, the total adjusted per-beneficiary spending differentially changed in the ACO group as compared with the control group (-$29.2 per quarter, P=0.007), consistent with a 1.2% savings. Savings were significantly greater for ACOs with baseline spending above the local average, as compared with those with baseline spending below the local average (P=0.05 for interaction), and for those serving high-spending areas, as compared with those serving low-spending areas (P=0.04). Savings were similar in ACOs with financial integration between hospitals and physician groups and those without, as well as in ACOs that withdrew from the program and those that did not. CONCLUSIONS: Year 1 of the Pioneer ACO program was associated with modest reductions in Medicare spending. Savings were greater for ACOs with higher baseline spending than for those with lower baseline spending and were unrelated to withdrawal from the program. (Funded by the National Institute on Aging and others.).

Changes in patients' experiences in Medicare Accountable Care Organizations.

BACKGROUND: Incentives for accountable care organizations (ACOs) to limit health care use and improve quality may enhance or hurt patients' experiences with care. METHODS: Using Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey data covering 3 years before and 1 year after the start of Medicare ACO contracts in 2012 as well as linked Medicare claims, we compared patients' experiences in a group of 32,334 fee-for-service beneficiaries attributed to ACOs (ACO group) with those in a group of 251,593 beneficiaries attributed to other providers (control group), before and after the start of ACO contracts. We used linear regression and a difference-in-differences analysis to estimate changes in patients' experiences in the ACO group that differed from concurrent changes in the control group, with adjustment for the sociodemographic and clinical characteristics of the patients. RESULTS: After ACO contracts began, patients' reports of timely access to care and their primary physicians' being informed about specialty care differentially improved in the ACO group, as compared with the control group (P=0.01 and P=0.006, respectively), whereas patients' ratings of physicians, interactions with physicians, and overall care did not differentially change. Among patients with multiple chronic conditions and high predicted Medicare spending, overall ratings of care differentially improved in the ACO group as compared with the control group (P=0.02). Differential improvements in timely access to care and overall ratings were equivalent to moving from average performance among ACOs to the 86th to 98th percentile (timely access to care) and to the 82nd to 96th percentile (overall ratings) and were robust to adjustment for group differences in trends during the preintervention period. CONCLUSIONS: In the first year, ACO contracts were associated with meaningful improvements in some measures of patients' experience and with unchanged performance in others. (Funded by the National Institute on Aging and others.).