High Molar Mass Polycarbonates as Closed-Loop Recyclable Thermoplastics.

Using carbon dioxide (CO2) to make recyclable thermoplastics could reduce greenhouse gas emissions associated with polymer manufacturing. CO2/cyclic epoxide ring-opening copolymerization (ROCOP) allows for >30 wt % of the polycarbonate to derive from CO2; so far, the field has largely focused on oligocarbonates. In contrast, efficient catalysts for high molar mass polycarbonates are underinvestigated, and the resulting thermoplastic structure-property relationships, processing, and recycling need to be elucidated. This work describes a new organometallic Mg(II)Co(II) catalyst that combines high productivity, low loading tolerance, and the highest polymerization control to yield polycarbonates with number average molecular weight (Mn) values from 4 to 130 kg mol-1, with narrow, monomodal distributions. It is used in the ROCOP of CO2 with bicyclic epoxides to produce a series of samples, each with Mn > 100 kg mol-1, of poly(cyclohexene carbonate) (PCHC), poly(vinyl-cyclohexene carbonate) (PvCHC), poly(ethyl-cyclohexene carbonate) (PeCHC, by hydrogenation of PvCHC), and poly(cyclopentene carbonate) (PCPC). All these materials are amorphous thermoplastics, with high glass transition temperatures (85 < Tg < 126 °C, by differential scanning calorimetry) and high thermal stability (Td > 260 °C). The cyclic ring substituents mediate the materials' chain entanglements, viscosity, and glass transition temperatures. Specifically, PCPC was found to have 10× lower entanglement molecular weight (Me)n and 100× lower zero-shear viscosity compared to those of PCHC, showing potential as a future thermoplastic. All these high molecular weight polymers are fully recyclable, either by reprocessing or by using the Mg(II)Co(II) catalyst for highly selective depolymerizations to epoxides and CO2. PCPC shows the fastest depolymerization rates, achieving an activity of 2500 h-1 and >99% selectivity for cyclopentene oxide and CO2.

Alternatives to fluorinated binders: recyclable copolyester/carbonate electrolytes for high-capacity solid composite cathodes.

Optimising the composite cathode for next-generation, safe solid-state batteries with inorganic solid electrolytes remains a key challenge towards commercialisation and cell performance. Tackling this issue requires the design of suitable polymer binders for electrode processability and long-term solid-solid interfacial stability. Here, block-polyester/carbonates are systematically designed as Li-ion conducting, high-voltage stable binders for cathode composites comprising of single-crystal LiNi0.8Mn0.1Co0.1O2 cathodes, Li6PS5Cl solid electrolyte and carbon nanofibres. Compared to traditional fluorinated polymer binders, improved discharge capacities (186 mA h g-1) and capacity retention (96.7% over 200 cycles) are achieved. The nature of the new binder electrolytes also enables its separation and complete recycling after use. ABA- and AB-polymeric architectures are compared where the A-blocks are mechanical modifiers, and the B-block facilitates Li-ion transport. This reveals that the conductivity and mechanical properties of the ABA-type are more suited for binder application. Further, catalysed switching between CO2/epoxide A-polycarbonate (PC) synthesis and B-poly(carbonate-r-ester) formation employing caprolactone (CL) and trimethylene carbonate (TMC) identifies an optimal molar mass (50 kg mol-1) and composition (wPC 0.35). This polymer electrolyte binder shows impressive oxidative stability (5.2 V), suitable ionic conductivity (2.2 × 10-4 S cm-1 at 60 °C), and compliant viscoelastic properties for fabrication into high-performance solid composite cathodes. This work presents an attractive route to optimising polymer binder properties using controlled polymerisation strategies combining cyclic monomer (CL, TMC) ring-opening polymerisation and epoxide/CO2 ring-opening copolymerisation. It should also prompt further examination of polycarbonate/ester-based materials with today's most relevant yet demanding high-voltage cathodes and sensitive sulfide-based solid electrolytes.

Scope and Incentives for Risk Selection in Health Insurance Markets With Regulated Competition: A Conceptual Framework and International Comparison.

In health insurance markets with regulated competition, regulators face the challenge of preventing risk selection. This paper provides a framework for analyzing the scope (i.e., potential actions by insurers and consumers) and incentives for risk selection in such markets. Our approach consists of three steps. First, we describe four types of risk selection: (a) selection by consumers in and out of the market, (b) selection by consumers between high- and low-value plans, (c) selection by insurers via plan design, and (d) selection by insurers via other channels such as marketing, customer service, and supplementary insurance. In a second step, we develop a conceptual framework of how regulation and features of health insurance markets affect the scope and incentives for risk selection along these four dimensions. In a third step, we use this framework to compare nine health insurance markets with regulated competition in Australia, Europe, Israel, and the United States.

Evaluating Heterodinuclear Mg(II)M(II) (M = Mn, Fe, Ni, Cu, and Zn) Catalysts for the Chemical Recycling of Poly(cyclohexene carbonate).

Polymer chemical recycling to monomers (CRM) is important to help achieve a circular plastic economy, but the "rules" governing catalyst design for such processes remain unclear. Here, carbon dioxide-derived polycarbonates undergo CRM to produce epoxides and carbon dioxide. A series of dinuclear catalysts, Mg(II)M(II) where M(II) = Mg, Mn, Fe, Co, Ni, Cu, and Zn, are compared for poly(cyclohexene carbonate) depolymerizations. The recycling is conducted in the solid state, at 140 °C monitored using thermal gravimetric analyses, or performed at larger-scale using laboratory glassware. The most active catalysts are, in order of decreasing rate, Mg(II)Co(II), Mg(II)Ni(II), and Mg(II)Zn(II), with the highest activity reaching 8100 h-1 and with >99% selectivity for cyclohexene oxide. Both the activity and selectivity values are the highest yet reported in this field, and the catalysts operate at low loadings and moderate temperatures (from 1:300 to 1:5000, 140 °C). For the best heterodinuclear catalysts, the depolymerization kinetics and activation barriers are determined. The rates in both reverse depolymerization and forward CHO/CO2 polymerization catalysis show broadly similar trends, but the processes feature different intermediates; forward polymerization depends upon a metal-carbonate intermediate, while reverse depolymerization depends upon a metal-alkoxide intermediate. These dinuclear catalysts are attractive for the chemical recycling of carbon dioxide-derived plastics and should be prioritized for recycling of other oxygenated polymers and copolymers, including polyesters and polyethers. This work provides insights into the factors controlling depolymerization catalysis and steers future recycling catalyst design toward exploitation of lightweight and abundant s-block metals, such as Mg(II).

Chemical Recycling of Commercial Poly(l-lactic acid) to l-Lactide Using a High-Performance Sn(II)/Alcohol Catalyst System.

Poly(l-lactic acid) (PLLA) is a leading commercial polymer produced from biomass, showing useful properties for plastics and fiber applications; after use, it is compostable. One area for improvement is postconsumer waste PLLA chemical recycling to monomer (CRM), i.e., the formation of l-lactide (l-LA) from waste plastic. This process is currently feasible at high reaction temperatures and shows low catalytic activity accompanied, in some cases, by side reactions, including epimerization. Here, a commercial Sn(II) catalyst, applied with nonvolatile commercial alcohol, enables highly efficient CRM of PLLA to yield l-LA in excellent yield and purity (92% yield, >99% l-LA from theoretical max.). The depolymerization is performed using neat polymer films at low temperatures (160 °C) under a nitrogen flow or vacuum. The chemical recycling operates with outstanding activity, achieving turnover frequencies which are up to 3000× higher than previously excellent catalysts and applied at loadings up to 6000× lower than previously leading catalysts. The catalyst system achieves a TOF = 3000 h-1 at 0.01 mol % or 1:10,000 catalyst:PLLA loading. The depolymerization of waste PLLA plastic packaging (coffee cup lids) produces pure l-LA in excellent yield and selectivity. The new catalyst system (Sn + alcohol) can itself be recycled four times in different PLLA "batch degradations" and maintains its high catalytic productivity, activity, and selectivity.

A Chemoselective Polarity-Mismatched Photocatalytic C(sp3 )-C(sp2 ) Cross-Coupling Enabled by Synergistic Boron Activation.

We report the development of a C(sp3 )-C(sp2 ) coupling reaction using styrene boronic acids and redox-active esters under photoredox catalysis. The reaction proceeds through an unusual polarity-mismatched radical addition mechanism that is orthogonal to established processes. Synergistic activation of the radical precursor and organoboron are critical mechanistic events. Activation of an N-hydroxyphthalimide (NHPI) ester by coordination to boron enables electron transfer, with decomposition leading to a nucleofuge rebound, activating the organoboron to radical addition. The unique mechanism enables chemoselective coupling of styrene boronic acids in the presence of other alkene radical acceptors. The scope and limitations of the reaction, and a detailed mechanistic investigation are presented.

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.

Discovery of Clinical Candidate AZD0095, a Selective Inhibitor of Monocarboxylate Transporter 4 (MCT4) for Oncology.

Due to increased reliance on glycolysis, which produces lactate, monocarboxylate transporters (MCTs) are often upregulated in cancer. MCT4 is associated with the export of lactic acid from cancer cells under hypoxia, so inhibition of MCT4 may lead to cytotoxic levels of intracellular lactate. In addition, tumor-derived lactate is known to be immunosuppressive, so MCT4 inhibition may be of interest for immuno-oncology. At the outset, no potent and selective MCT4 inhibitors had been reported, but a screen identified a triazolopyrimidine hit, with no close structural analogues. Minor modifications to the triazolopyrimidine were made, alongside design of a constrained linker and broad SAR exploration of the biaryl tail to improve potency, physical properties, PK, and hERG. The resulting clinical candidate 15 (AZD0095) has excellent potency (1.3 nM), MCT1 selectivity (>1000×), secondary pharmacology, clean mechanism of action, suitable properties for oral administration in the clinic, and good preclinical efficacy in combination with cediranib.

Solid-State Chemical Recycling of Polycarbonates to Epoxides and Carbon Dioxide Using a Heterodinuclear Mg(II)Co(II) Catalyst.

Polymer chemical recycling to monomers (CRM) could help improve polymer sustainability, but its implementation requires much better understanding of depolymerization catalysis, ensuring high rates and selectivity. Here, a heterodinuclear [Mg(II)Co(II)] catalyst is applied for CRM of aliphatic polycarbonates, including poly(cyclohexene carbonate) (PCHC), to epoxides and carbon dioxide using solid-state conditions, in contrast with many other CRM strategies that rely on high dilution. The depolymerizations are performed in the solid state giving very high activity and selectivity (PCHC, TOF = 25700 h-1, CHO selectivity >99 %, 0.02 mol %, 140 °C). Reactions may also be performed in air without impacting on the rate or selectivity of epoxide formation. The depolymerization can be performed on a 2 g scale to isolate the epoxides in up to 95 % yield with >99 % selectivity. In addition, the catalyst can be re-used four times without compromising its productivity or selectivity.

Performance Metrics of Substance Use Disorder Care Among Medicaid Enrollees in New York, New York.

Importance: There is limited evaluation of the performance of Medicaid managed care (MMC) private plans in covering substance use disorder (SUD) treatment. Objective: To compare the performance of MMC plans across 19 indicators of access, quality, and outcomes of SUD treatment. Design Setting and Participants: This cross-sectional study used administrative claims and mandatory assignment to plans of up to 159 016 adult Medicaid recipients residing in 1 of the 5 counties (boroughs) of New York, New York, from January 2009 to December 2017 to identify differences in SUD treatment access, patterns, and outcomes among different types of MMC plans. Data from the latest years were received from the New York State Department of Health in October 2019, and analysis began soon thereafter. Approximately 17% did not make an active choice of plan, and a subset of these (approximately 4%) can be regarded as randomly assigned. Exposures: Plan assignment. Main Outcomes and Measures: Percentage of the enrollees achieving performance measures across 19 indicators of access, process, and outcomes of SUD treatment. Results: Medicaid claims data from 159 016 adults (mean [SD] age, 35.9 [12.7] years; 74 261 women [46.7%]; 8746 [5.5%] Asian, 73 783 [46.4%] Black, and 40 549 [25.5%] White individuals) who were auto assigned to an MMC plan were analyzed. Consistent with national patterns, all plans achieved less than 50% (range, 0%-62.1%) on most performance measures. Across all plans, there were low levels of treatment engagement for alcohol (range, 0%-0.4%) and tobacco treatment (range, 0.8%-7.2%), except for engagement for opioid disorder treatment (range, 41.5%-61.4%). For access measures, 4 of the 9 plans performed significantly higher than the mean on recognition of an SUD diagnosis, any service use for the first time, and tobacco use screening. Of the process measures, total monthly expenditures on SUD treatment was the only measure for which plans differed significantly from the mean. Outcome measures differed little across plans. Conclusions and Relevance: The results of this cross-sectional study suggest the need for progress in engaging patients in SUD treatment and improvement in the low performance of SUD care and limited variation in MMC plans in New York, New York. Improvement in the overall performance of SUD treatment in Medicaid potentially depends on general program improvements, not moving recipients among plans.

An Enantioselective Suzuki-Miyaura Coupling To Form Axially Chiral Biphenols.

Axial chirality features prominently in molecules of biological interest as well as chiral catalyst designs, and atropisomeric 2,2'-biphenols are particularly prevalent. Atroposelective metal-catalyzed cross-coupling is an attractive and modular approach to access enantioenriched biphenols, and yet existing protocols cannot achieve this directly. We address this challenge through the use of enantiopure, sulfonated SPhos (sSPhos), an existing ligand that has until now been used only in racemic form and that derives its chirality from an atropisomeric axis that is introduced through sulfonation. We believe that attractive noncovalent interactions involving the ligand sulfonate group are responsible for the high levels of asymmetric induction that we obtain in the 2,2'-biphenol products of Suzuki-Miyaura coupling, and we have developed a highly practical resolution of sSPhos via diastereomeric salt recrystallization.

Racial/Ethnic Disparities in Substance Use Treatment in Medicaid Managed Care in New York City: The Role of Plan and Geography.

OBJECTIVE: The aim was to assess the magnitude of health care disparities in treatment for substance use disorder (SUD) and the role of health plan membership and place of residence in observed disparities in Medicaid Managed Care (MMC) plans in New York City (NYC). DATA SOURCE: Medicaid claims and managed care plan enrollment files for 2015-2017 in NYC. RESEARCH DESIGN: We studied Medicaid enrollees with a SUD diagnosis during their first 6 months of enrollment in a managed care plan in 2015-2017. A series of linear regression models quantified service disparities across race/ethnicity for 5 outcome indicators: treatment engagement, receipt of psychosocial treatment, follow-up after withdrawal, rapid readmission, and treatment continuation. We assessed the degree to which plan membership and place of residence contributed to observed disparities. RESULTS: We found disparities in access to treatment but the magnitude of the disparities in most cases was small. Plan membership and geography of residence explained little of the observed disparities. One exception is geography of residence among Asian Americans, which appears to mediate disparities for 2 of our 5 outcome measures. CONCLUSIONS: Reallocating enrollees among MMC plans in NYC or evolving trends in group place of residence are unlikely to reduce disparities in treatment for SUD. System-wide reforms are needed to mitigate disparities.

Chemical Recycling of Poly(Cyclohexene Carbonate) Using a Di-MgII Catalyst.

Chemical recycling of polymers to true monomers is pivotal for a circular plastics economy. Here, the first catalyzed chemical recycling of the widely investigated carbon dioxide derived polymer, poly(cyclohexene carbonate), to cyclohexene oxide and carbon dioxide is reported. The reaction requires dinuclear catalysis, with the di-MgII catalyst showing both high monomer selectivity (>98 %) and activity (TOF=150 h-1 , 0.33 mol %, 120 °C). The depolymerization occurs via a chain-end catalyzed depolymerization mechanism and DFT calculations indicate the high selectivity arises from Mg-alkoxide catalyzed epoxide extrusion being kinetically favorable compared to cyclic carbonate formation.

Improving the Performance of Risk Adjustment Systems: Constrained Regressions, Reinsurance, and Variable Selection.

Modifications of risk-adjustment systems used to pay health plans in individual health insurance markets typically seek to reduce selection incentives at the individual and group levels by adding variables to the payment formula. Adding variables can be costly and lead to unintended incentives for upcoding or service utilization. While these drawbacks are recognized, they are hard to quantify and difficult to balance against the concrete, measurable improvements in fit that may be achieved by adding variables to the formula. This paper takes a different approach to improving the performance of health plan payment systems. Using the HHS-HHC V0519 model from the Marketplaces as a starting point, we constrain fit at the individual and group level to be as good or better than the current payment model while reducing the number of variables in the model. We introduce three elements in the design of plan payment: reinsurance, constrained regressions, and machine learning methods for variable selection. The fit performance of our alternative formulas with many fewer variables is as good or better than the current HHS-HHC V0519 formula.

Coding-Driven Changes In Measured Risk In Accountable Care Organizations.

Claims data, which form the foundation of risk adjustment in payment for health care services, may reflect efforts to capture more-or more severe-clinical conditions rather than true changes in health status. This can distort payments. We quantify this in the context of Medicare's accountable care organization (ACO) program by comparing risk scores derived from two different measurement approaches. One approach uses diagnoses coded on claims based on Centers for Medicare and Medicaid Services Hierarchical Condition Categories (HCC), and the other uses self-reported, survey-based health data from the Consumer Assessment of Healthcare Providers and Systems (CAHPS). During 2013-16 HCC-based risk scores grew faster than CAHPS-based risk scores (2.1 percent versus 0.3 percent annually), and the gap in HCC- and CAHPS-based risk score growth varied widely across ACOs. The average gap in risk score growth appears to be the result primarily of HCC coding practices rather than poor performance of the CAHPS model, suggesting that coding practices (not necessarily driven by ACO contracts) may account for most of the observed risk score growth for ACO beneficiaries.

Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement.

Optimization of a series of azabenzimidazoles identified from screening hit 2 and the information gained from a co-crystal structure of the azabenzimidazole-based lead 6 bound to CDK9 led to the discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles 38 and 39. These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 in vivo.

The Evolution of Supply and Demand in Markets for Generic Drugs.

Policy Points Much concern about generic drug markets has emerged in recent policy debates. Important changes in regulations, the structure of purchasing, and the length of the drug supply chain have affected generic drug markets. Effective price competition remains the rule in generic markets for large-selling drugs. Smaller markets and those for injectable products often have less price competition and are more susceptible to supply disruptions. CONTEXT: The image of generic drugs as a commodity sold in competitive markets is an oversimplification, as evidenced by increasing accounts of price spikes, sustained high price-cost margins, and market disruptions. The mismatch between the canonical economic model of generic drug markets and reality motivated our empirical project. METHODS: To explore recent changes in those factors impacting the supply and demand for generic drugs, we studied, from a variety of sources, the data on price, competition, supply disruptions and recalls, changes to the supply chain, and buy-side concentration. We examined quarterly data through 2018 for a cohort of 77 molecules that lost patent protection during the so-called patent cliff between 2010 and 2013. FINDINGS: On the supply side, we found that for large-market oral solids, generic entry and price declines were consistent with past studies showing a significant number of market entrants and substantial reductions in the average price of a molecule. In smaller markets for oral solids and injectable products, we observed fewer entrants, higher rates of exit, smaller price reductions, and, in some cases, considerable price instability. The number of reported shortages increased across all generic market types over time, with the rate of shortage increases especially pronounced in markets for injectable products. The number of product recalls also rose over our study period. Although we did not estimate causal effects, we did find several changes in the market environment for generic drugs that may contribute to these phenomena. The demand side for generics has become more concentrated. Supply chains rely more on producers outside the United States (particularly from China and India). Contracting practices have undergone changes that may inhibit competition in product supply. FDA regulatory scruitiny has increased. CONCLUSIONS: Competition in generic drug markets varies widely by market size and product form. Recent changes in demand-side market structure imply more downward pressure on prices stemming from buy-side concentration. The FDA's greater regulatory oversight puts upward pressure on costs, and the lengthening of the supply chain increases production uncertainty for producers. Demand and supply-side changes point to further market instabilities across all generic markets due to producers' changing economic position.

Cu(OTf)2 -Mediated Cross-Coupling of Nitriles and N-Heterocycles with Arylboronic Acids to Generate Nitrilium and Pyridinium Products*.

Metal-catalyzed C-N cross-coupling generally forms C-N bonds by reductive elimination from metal complexes bearing covalent C- and N-ligands. We have identified a Cu-mediated C-N cross-coupling that uses a dative N-ligand in the bond-forming event, which, in contrast to conventional methods, generates reactive cationic products. Mechanistic studies suggest the process operates via transmetalation of an aryl organoboron to a CuII complex bearing neutral N-ligands, such as nitriles or N-heterocycles. Subsequent generation of a putative CuIII complex enables the oxidative C-N coupling to take place, delivering nitrilium intermediates and pyridinium products. The reaction is general for a range of N(sp) and N(sp2 ) precursors and can be applied to drug synthesis and late-stage N-arylation, and the limitations in the methodology are mechanistically evidenced.

Very high and low residual spenders in private health insurance markets: Germany, The Netherlands and the U.S. Marketplaces.

We study the extremely high and low residual spenders in individual health insurance markets in three countries. A high (low) residual spender is someone for whom the residual-spending less payment (from premiums and risk adjustment)-is high (low), indicating that the person is highly underpaid (overpaid). We begin with descriptive analysis of the top and bottom 1% and 0.1% of residuals building to address the question of the degree of persistence in membership at the extremes. Common findings emerge among the countries. First, the diseases found among those with the highest residual spending are also disproportionately found among those with the lowest residual spending. Second, those at the top of the residual spending distribution (where spending exceeds payments the most) account for a massively high share of the unexplained variance in the predictions from the risk adjustment model. Third, in terms of persistence, we find that membership in the extremes of the residual spending distribution is highly persistent, raising concerns about selection-related incentives targeting these individuals. As our results show, the one-in-a-thousand people (on both sides of the residual distribution) play an outsized role in creating adverse incentives associated with health plan payment systems. In response to the observed importance of the extremes of the residual spending distribution, we propose an innovative combination of risk-pooling and reinsurance targeting the predictively undercompensated group. In all three countries, this form of risk sharing substantially improves the overall fit of payments to spending. Perhaps surprisingly, by reducing the burden on diagnostic indicators to predict high payments, our proposed risk sharing policy reduces the gap between payments and spending not only for the most undercompensated individuals but also for the most overcompensated people.

Control of Crystallinity and Stereocomplexation of Synthetic Carbohydrate Polymers from d- and l-Xylose.

Manipulating the stereochemistry of polymers is a powerful method to alter their physical properties. Despite the chirality of monosaccharides, reports on the impact of stereochemistry in natural polysaccharides and synthetic carbohydrate polymers remain absent. Herein, we report the cocrystallisation of regio- and stereoregular polyethers derived from d- and l-xylose, leading to enhanced thermal properties compared to the enantiopure polymers. To the best of our knowledge, this is the first example of a stereocomplex between carbohydrate polymers of opposite chirality. In contrast, atactic polymers obtained from a racemic mixture of monomers are amorphous. We also show that the polymer hydroxyl groups are amenable to post-polymerisation functionalization. These strategies afford a family of carbohydrate polyethers, the physical and chemical properties of which can both be controlled, and which opens new possibilities for polysaccharide mimics in biomedical applications or as advanced materials.