Does Ownership Matter for Medical System Performance? Evidence From a Natural Experiment in Suqian, China.

There has long been a major policy debate on the role of hospital ownership (private vs public) in medical system performance. China's health care delivery system is mainly a public system. In 2000, a full privatization reform was implemented in the city of Suqian, offering a unique opportunity to assess possible effects of private delivery based on a major external shock to the existing system. Compared with all other cities in Jiangsu province since 2003, Suqian did not experience any greater increase either in total outpatient or inpatient expenditures. In the meantime, Suqian performed equally well as other cities in terms of changes in number of inpatient admissions and average inpatient days, and even better for mortality rate in emergency rooms. This study concludes that under appropriate public financing, private delivery can serve the public demand at least equally well as public providers in terms of cost inflations and utilizations.

Trends in Hospitalization Expenditures for Acute Exacerbations of COPD in Beijing from 2009 to 2017.

Background: Chronic obstructive pulmonary disease (COPD) is the cause of substantial economic and social burden. We investigated trends in hospitalizations for acute exacerbation of COPD in Beijing, China, from 2009 to 2017. Patients and Methods: Investigations were conducted using data from the discharge records of inpatients that were given a primary diagnosis of acute exacerbation of COPD. The dataset was a retrospective review of information collected from electronic medical records and included 315,116 admissions (159,368 patients). Descriptive analyses and multivariate regressions were used to investigate trends in per admission and per capita expenditures, as well as other potential contributing factors. Results: The mean per admission expenditures increased from 19,760 CNY ($2893, based on USD/CNY=6.8310) in 2009 to 20,118 CNY ($2980) in 2017 (a growth rate of 0.11%). However, the per capita expenditures increased from 23,716 CNY ($3472) in 2009 to 31,000 CNY ($4538) in 2017 (a growth rate of 1.7%). In terms of per admission expenditures, drug costs accounted for 52.9% of the total expenditures in 2009 and dropped to 39.4% in 2017 (P trend < 0.001). The mean length of stay (LOS) decreased from 16.0 days to 13.5 days (P trend < 0·001). Age, gender, COPD type, LOS, and hospital level were all associated with per admission and per capita expenditures. Interpretation: Relatively stable per admission expenditures along with the decline in drug costs and LOS reflect the effectiveness of cost containment on some indicators in China's health care reform. However, the increase in hospitalization expenditures per capita calls for better policies for controlling hospitalizations, especially multiple admissions.

Potential Effects Of Eliminating The Individual Mandate Penalty In California.

The tax penalty for noncompliance with the Affordable Care Act's individual mandate is to be eliminated starting in 2019. We investigated the potential impact of this change on enrollees' decisions to purchase insurance and on individual-market premiums. In a survey of enrollees in the individual market in California in 2017, 19 percent reported that they would not have purchased insurance had there been no penalty. We estimated that premiums would increase by 4-7 percent if these enrollees were not in the risk pool. The percentages of enrollees who would forgo insurance were higher among those with lower income and education, Hispanics, and those who had been uninsured in the prior year, relative to the comparison groups. Compared to older enrollees and those with two or more chronic conditions, respectively, younger enrollees and those with no chronic conditions were also more likely to say that they would not have purchased insurance. Eliminating the mandate penalty alone is unlikely to destabilize the California individual market but could erode coverage gains, especially among groups whose members have historically been less likely to be insured.

Modeling individual health care expenditures in China: Evidence to assist payment reform in public insurance.

Reforming the payment system of public health insurance from fee-for-service to more efficient alternative schemes has become an urgent policy issue in developing countries. Using a large sample of administrative data drawn from China, we examine a variety of econometric models for predicting the medical expenditures of individuals. We show that the standard ordinary least squares model performs relatively well compared with other models. We then propose two alternative payment schemes on risk-adjusted capitation. The first is a prospective capitation model and the second incorporates both prospective and retrospective features. We simulate the corresponding payments based on model predictions and evaluate the payment/cost ratios for health care providers. The results show that the prospective capitation method generates smaller financial fluctuation, suggesting that policymakers may prefer this method to achieve a smooth transition.

Adverse Selection into and within the Individual Health Insurance Market in California in 2014.

OBJECTIVE: The Affordable Care Act (ACA) introduced reforms to mitigate adverse selection into and within the individual insurance market. We examined the traits and predicted medical spending of enrollees in California post-ACA. DATA SOURCES: Survey of 2,103 enrollees in individual market plans, on- and off-exchange, in 2014. STUDY DESIGN: We compared actual versus potential participants using data from the 2014 California Health Interview Survey on respondents who were individually insured or uninsured. We predicted annual medical spending for each group using age, sex, self-rated health, body mass index, smoking status, and income. PRINCIPAL FINDINGS: Average predicted spending was similar for actual ($3,377, 95 percent CI [$3,280-$3,474]) and potential participants ($3,257 [$3,060-$3,454]); however, some vulnerable subgroups were underrepresented. On- versus off-exchange enrollees differed in sociodemographic and health traits with modest differences in spending ($3,448 [$3,330-$3,565] vs. $3,175 [$3,012-$3,338]). CONCLUSIONS: We did not find evidence of selection into the overall insurance pool in 2014; however, differences by exchange status reflect the importance of including off-exchange enrollees in analyses and the pool for risk adjustment. California's post-ACA individual market has been a relative success, highlighting the importance of state policies and outreach efforts to encourage participation in the market.

Matching and Imputation Methods for Risk Adjustment in the Health Insurance Marketplaces.

New state-level health insurance markets, denoted Marketplaces, created under the Affordable Care Act, use risk-adjusted plan payment formulas derived from a population ineligible to participate in the Marketplaces. We develop methodology to derive a sample from the target population and to assemble information to generate improved risk-adjusted payment formulas using data from the Medical Expenditure Panel Survey and Truven MarketScan databases. Our approach requires multi-stage data selection and imputation procedures because both data sources have systemic missing data on crucial variables and arise from different populations. We present matching and imputation methods adapted to this setting. The long-term goal is to improve risk-adjustment estimation utilizing information found in Truven MarketScan data supplemented with imputed Medical Expenditure Panel Survey values.

Multivalent display of pendant pro-apoptotic peptides increases cytotoxic activity.

Several cationic antimicrobial peptides have been investigated as potential anti-cancer drugs due to their demonstrated selective toxicity towards cancer cells relative to normal cells. For example, intracellular delivery of KLA, a pro-apoptotic peptide, results in toxicity against a variety of cancer cell lines; however, the relatively low activity and small size lead to rapid renal excretion when applied in vivo, limiting its therapeutic potential. In this work, apoptotic peptide-polymer hybrid materials were developed to increase apoptotic peptide activity via multivalent display. Multivalent peptide materials were prepared with comb-like structure by RAFT copolymerization of peptide macromonomers with N-(2-hydroxypropyl) methacrylamide (HPMA). Polymers displayed a GKRK peptide sequence for targeting p32, a protein often overexpressed on the surface of cancer cells, either fused with or as a comonomer to a KLA macromonomer. In three tested cancer cell lines, apoptotic polymers were significantly more cytotoxic than free peptides as evidenced by an order of magnitude decrease in IC50 values for the polymers compared to free peptide. The uptake efficiency and intracellular trafficking of one polymer construct was determined by radiolabeling and subcellular fractionation. Despite their more potent cytotoxic profile, polymeric KLA constructs have poor cellular uptake efficiency (<1%). A significant fraction (20%) of internalized constructs localize with intact mitochondrial fractions. In an effort to increase cellular uptake, polymer amines were converted to guanidines by reaction with O-methylisourea. Guanidinylated polymers disrupted function of isolated mitochondria more than their lysine-based analogs, but overall toxicity was decreased, likely due to inefficient mitochondrial trafficking. Thus, while multivalent KLA polymers are more potent than KLA peptides, these materials can be substantially improved by designing next generation materials with improved cellular internalization and mitochondrial targeting efficiency.

Peptide Targeting of an Antibiotic Prodrug toward Phagosome-Entrapped Mycobacteria.

Mycobacterial infections are difficult to treat due to the bacterium's slow growth, ability to reside in intracellular compartments within macrophages, and resistance mechanisms that limit the effectiveness of conventional antibiotics. Developing antibiotics that overcome these challenges is therefore critical to providing a pipeline of effective antimicrobial agents. Here, we describe the synthesis and testing of a unique peptide-drug conjugate that exhibits high levels of antimicrobial activity against M. smegmatis and M. tuberculosis as well as clearance of intracellular mycobacteria from cultured macrophages. Using an engineered peptide sequence, we deliver a potent DHFR inhibitor and target the intracellular phagosomes where mycobacteria reside and also incorporate a ß-lactamase-cleavable cephalosporin linker to enhance the targeting of quiescent intracellular ß-lactam-resistant mycobacteria. By using this type of prodrug approach to target intracellular mycobacterial infections, the emergence of antibacterial resistance mechanisms could be minimized.

Assessing incentives for service-level selection in private health insurance exchanges.

Even with open enrollment and mandated purchase, incentives created by adverse selection may undermine the efficiency of service offerings by plans in the new health insurance Exchanges created by the Affordable Care Act. Using data on persons likely to participate in Exchanges drawn from five waves of the Medical Expenditure Panel Survey, we measure plan incentives in two ways. First, we construct predictive ratios, improving on current methods by taking into account the role of premiums in financing plans. Second, relying on an explicit model of plan profit maximization, we measure incentives based on the predictability and predictiveness of various medical diagnoses. Among the chronic diseases studied, plans have the greatest incentive to skimp on care for cancer, and mental health and substance abuse.

Integrating risk adjustment and enrollee premiums in health plan payment.

In two important health policy contexts - private plans in Medicare and the new state-run "Exchanges" created as part of the Affordable Care Act (ACA) - plan payments come from two sources: risk-adjusted payments from a Regulator and premiums charged to individual enrollees. This paper derives principles for integrating risk-adjusted payments and premium policy in individual health insurance markets based on fitting total plan payments to health plan costs per person as closely as possible. A least squares regression including both health status and variables used in premiums reveals the weights a Regulator should put on risk adjusters when markets determine premiums. We apply the methods to an Exchange-eligible population drawn from the Medical Expenditure Panel Survey (MEPS).

Effect of polyplex morphology on cellular uptake, intracellular trafficking, and transgene expression.

Nanoparticle morphology has been shown to affect cellular uptake, but there are few studies investigating the impact of particle shape on biologic drug delivery. Recently, our group synthesized a series of N-(2-hydroxypropyl) methacrylamide (HPMA)-oligolysine brush polymers for nucleic acid delivery that varied in oligolysine peptide length and polymer molecular weight. Interestingly, a 50% longer peptide (K15) transfected very poorly compared to the optimized polymer comprised of K10 peptide despite similar chemical composition and molecular weight. We hypothesized that differences in particle morphology contributed to the differences in plasmid DNA delivery. We found that particles formed with plasmid DNA and a polymer with the longer oligolysine peptide (pHK15) had larger aspect ratios than particles formed with optimized polymer (pHK10). Even though both formulations showed similar percentages of cellular association, particles of a higher aspect ratio were internalized to a lesser extent. Furthermore, the rod-like particles accumulated more in endosomal/lysosomal compartments, leading to delayed nuclear delivery. Other parameters, such as particle surface charge, unpackaging ability, uptake mechanism, intracellular trafficking, and the presence of heparan sulfate proteoglycans did not significantly differ between the two polymer formulations. These results indicate that, for this system, polyplex morphology primarily impacts nucleic acid delivery efficiency through differences in cellular internalization rates.

Engineering biodegradable and multifunctional peptide-based polymers for gene delivery.

The complex nature of in vivo gene transfer establishes the need for multifunctional delivery vectors capable of meeting these challenges. An additional consideration for clinical translation of synthetic delivery formulations is reproducibility and scale-up of materials. In this review, we summarize our work over the last five years in developing a modular approach for synthesizing peptide-based polymers. In these materials, bioactive peptides that address various barriers to gene delivery are copolymerized with a hydrophilic backbone of N-(2-hydroxypropyl)methacrylamide (HPMA) using reversible-addition fragmentation chain-transfer (RAFT) polymerization. We demonstrate that this synthetic approach results in well-defined, narrowly-disperse polymers with controllable composition and molecular weight. To date, we have investigated the effectiveness of various bioactive peptides for DNA condensation, endosomal escape, cell targeting, and degradability on gene transfer, as well as the impact of multivalency and polymer architecture on peptide bioactivity.

Block copolymers containing a hydrophobic domain of membrane-lytic peptides form micellar structures and are effective gene delivery agents.

Endosomal release peptides have been incorporated in synthetic gene delivery formulations to increase transfection efficiencies. In this work, cationic copolymers containing sHGP, a membrane-lytic peptide derived from HIV gp41, were synthesized and evaluated. Diblock, with sHGP displayed on one block, and statistical, with sHGP randomly displayed, copolymers were prepared via RAFT polymerization. While the statistical copolymer existed as unimers in solution, amphiphilic diblock copolymers self-assembled into cationic micelles in aqueous solution as evidenced by TEM and dynamic light scattering analyses. This self-assembly sequestered the lytic domain and significantly reduced the cytotoxicity of the materials. However, when complexed with plasmid DNA, both the diblock and statistical copolymers of sHGP showed higher gene delivery efficacy compared to the copolymers without the membrane lytic motif. The ability of amphiphilic, diblock copolymers containing endosomal release motifs to self-assemble and sequester lytic domains is a promising feature for the nucleic acid delivery.

Influence of histidine incorporation on buffer capacity and gene transfection efficiency of HPMA-co-oligolysine brush polymers.

One of the major intracellular barriers to nonviral gene delivery is efficient endosomal escape. The incorporation of histidine residues into polymeric constructs has been found to increase endosomal escape via the proton sponge effect. Statistical and diblock copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA), oligolysine, and oligohistidine were synthesized via reversible-addition fragmentation chain transfer (RAFT) polymerization and tested for in vitro transfection efficiency, buffering ability, and polyplex uptake mechanism via the use of chemical endocytic inhibitors. Interestingly, histidine-containing statistical and diblock polymers exhibited increased buffer capacity in different endosomal pH ranges. Statistical copolymers transfected better than block copolymers that contained similar amounts of histidine. In addition, only the polymer containing the highest incorporation of oligohistidine residues led to increases in transfection efficiency over the HPMA-oligolysine base polymer. Thus, for these polymer architectures, high histidine incorporation may be required for efficient endosomal escape. Furthermore, inhibitor studies indicate that nonacidified caveolae-mediated endocytosis may be the primary route of transfection for these copolymers, suggesting that alternative approaches for increasing endosomal escape may be beneficial for enhancing transfection efficiency with these HPMA-oligolysine copolymers.

Investigation of Polyethylenimine/DNA Polyplex Transfection to Cultured Cells Using Radiolabeling and Subcellular Fractionation Methods.

Quantitative analysis of the intracellular trafficking of nonviral vectors provides critical information that can guide the rational design of improved cationic systems for gene delivery. Subcellular fractionation methods, combined with radiolabeling, produce quantitative measurements of the intracellular trafficking of nonviral vectors and the therapeutic payload. In this work, differential and density-gradient centrifugation techniques were used to determine the intracellular distribution of radiolabeled 25 kDa branched polyethylenimine (bPEI)/plasmid DNA complexes ("polyplexes") in HeLa cells over time. By differential centrifugation, [(14)C]bPEI was found mostly in the lighter fractions whereas [(3)H]DNA was found mostly in the heavier fractions. A majority of the intracellular polymer (∼60%) and DNA (∼90%) were found in the nuclear fraction. Polymer and DNA also differed in their distribution to heavier and denser organelles (lysosomes, mitochondria) in density-gradient centrifugation studies. An unexpected finding from this study was that between 18 and 50% of the DNA applied to the cells became cell-associated (either with the cell membrane and/or internalized), while only 1-6% of the polymer did so, resulting in an effective N/P ratio of less than 1. These results suggest that a significant amount of cationic polymer is dissociated from the DNA cargo early on in the transfection process.

Intracellular delivery and trafficking dynamics of a lymphoma-targeting antibody-polymer conjugate.

Ratiometric fluorescence and cellular fractionation studies were employed to characterize the intracellular trafficking dynamics of antibody-poly(propylacrylic acid) (PPAA) conjugates in CD22+ RAMOS-AW cells. The HD39 monoclonal antibody (mAb) directs CD22-dependent, receptor-mediated uptake in human B-cell lymphoma cells, where it is rapidly trafficked to the lysosomal compartment. To characterize the intracellular-release dynamics of the polymer-mAb conjugates, HD39-streptavidin (HD39/SA) was dual-labeled with pH-insensitive Alexa Fluor 488 and pH-sensitive pHrodo fluorophores. The subcellular pH distribution of the HD39/SA-polymer conjugates was quantified as a function of time by live-cell fluorescence microscopy, and the average intracellular pH value experienced by the conjugates was also characterized as a function of time by flow cytometry. PPAA was shown to alter the intracellular trafficking kinetics strongly relative to HD39/SA alone or HD39/SA conjugates with a control polymer, poly(methacryclic acid) (PMAA). Subcellular trafficking studies revealed that after 6 h, only 11% of the HD39/SA-PPAA conjugates had been trafficked to acidic lysosomal compartments with values at or below pH 5.6. In contrast, the average intracellular pH of HD39/SA alone dropped from 6.7 ± 0.2 at 1 h to 5.6 ± 0.5 after 3 h and 4.7 ± 0.6 after 6 h. Conjugation of the control polymer PMAA to HD39/SA showed an average pH drop similar to that of HD39/SA. Subcellular fractionation studies with tritium-labeled HD39/SA demonstrated that after 6 h, 89% of HD39/SA was associated with endosomes (Rab5+) and lysosomes (Lamp2+), while 45% of HD39/SA-PPAA was translocated to the cytosol (lactate dehydrogenase+). These results demonstrate the endosomal-releasing properties of PPAA with antibody-polymer conjugates and detail their intracellular trafficking dynamics and subcellular compartmental distributions over time.

Application of living free radical polymerization for nucleic acid delivery.

Therapeutic gene delivery can alter protein function either through the replacement of nonfunctional genes to restore cellular health or through RNA interference (RNAi) to mask mutated and harmful genes. Researchers have investigated a range of nucleic acid-based therapeutics as potential treatments for hereditary, acquired, and infectious diseases. Candidate drugs include plasmids that induce gene expression and small, interfering RNAs (siRNAs) that silence target genes. Because of their self-assembly with nucleic acids into virus-sized nanoparticles and high transfection efficiency in vitro, cationic polymers have been extensively studied for nucleic acid delivery applications, but toxicity and particle stability have limited the clinical applications of these systems. The advent of living free radical polymerization has improved the quality, control, and reproducibility of these synthesized materials. This process yields well-defined, narrowly disperse materials with designed architectures and molecular weights. As a result, researchers can study the effects of polymer architecture and molecular weight on transfection efficiency and cytotoxicity, which will improve the design of next-generation vectors. In this Account, we review findings from structure-function studies that have elucidated key design motifs necessary for the development of effective nucleic acid vectors. Researchers have used robust methods such as atom transfer radical polymerization (ATRP), reverse addition-fragmentation chain transfer polymerization (RAFT), and ring-opening metastasis polymerization (ROMP) to engineer materials that enhance extracellular stability and cellular specificity and decrease toxicity. In addition, we discuss polymers that are biodegradable, form supramolecular structures, target specific cells, or facilitate endosomal release. Finally, we describe promising materials with a range of in vivo applications from pulmonary gene delivery to DNA vaccines.

Reducible HPMA-co-oligolysine copolymers for nucleic acid delivery.

Biodegradability can be incorporated into cationic polymers via use of disulfide linkages that are degraded in the reducing environment of the cell cytosol. In this work, N-(2-hydroxypropyl)methacrylamide (HPMA) and methacrylamido-functionalized oligo-l-lysine peptide monomers with either a non-reducible 6-aminohexanoic acid (AHX) linker or a reducible 3-[(2-aminoethyl)dithiol] propionic acid (AEDP) linker were copolymerized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Both of the copolymers and a 1:1 (w/w) mixture of copolymers with reducible and non-reducible peptides were complexed with DNA to form polyplexes. The polyplexes were tested for salt stability, transfection efficiency, and cytotoxicity. The HPMA-oligolysine copolymer containing the reducible AEDP linkers was less efficient at transfection than the non-reducible polymer and was prone to flocculation in saline and serum-containing conditions, but was also not cytotoxic at charge ratios tested. Optimal transfection efficiency and toxicity were attained with mixed formulation of copolymers. Flow cytometry uptake studies indicated that blocking extracellular thiols did not restore transfection efficiency and that the decreased transfection of the reducible polyplex is therefore not primarily caused by extracellular polymer reduction by free thiols. The decrease in transfection efficiency of the reducible polymers could be partially mitigated by the addition of low concentrations of EDTA to prevent metal-catalyzed oxidation of reduced polymers.

The transduction of Coxsackie and Adenovirus Receptor-negative cells and protection against neutralizing antibodies by HPMA-co-oligolysine copolymer-coated adenovirus.

Adenoviral (AdV) gene vectors offer efficient nucleic acid transfer into both dividing and non-dividing cells. However issues such as vector immunogenicity, toxicity and restricted transduction to receptor-expressing cells have prevented broad clinical translation of these constructs. To address this issue, engineered AdV have been prepared by both genetic and chemical manipulation. In this work, a polymer-coated Ad5 formulation is optimized by evaluating a series of N-(2-hydroxypropyl) methacrylamide (HPMA)-co-oligolysine copolymers synthesized by living polymerization techniques. This synthesis approach was used to generate highly controlled and well-defined polymers with varying peptide length (K(5), K(10) and K(15)), polymer molecular weight, and degradability to coat the viral capsid. The optimal formulation was not affected by the presence of serum during transduction and significantly increased Ad5 transduction of several cell types that lack the Coxsackie and Adenovirus Receptor (CAR) by up to 6-fold compared to unmodified AdV. Polymer-coated Ad5 also retained high transduction capability in the presence of Ad5 neutralizing antibodies. The critical role of heparan sulfate proteoglycans (HSPGs) in mediating cell binding and internalization of polymer-coated AdV was also demonstrated by evaluating transduction in HSPG-defective recombinant CHO cells. The formulations developed here are attractive vectors for ex vivo gene transfer in applications such as cell therapy. In addition, this platform for adenoviral modification allows for facile introduction of alternative targeting ligands.

HPMA-oligolysine copolymers for gene delivery: optimization of peptide length and polymer molecular weight.

Polycations are one of the most frequently used classes of materials for non-viral gene transfer in vivo. Several studies have demonstrated a sensitive relationship between polymer structure and delivery activity. In this work, we used reverse addition-fragmentation chain transfer (RAFT) polymerization to build a panel of N-(2-hydroxypropyl)methacrylamide (HPMA)-oligolysine copolymers with varying peptide length and polymer molecular weight. The panel was screened for optimal DNA-binding, colloidal stability in salt, high transfection efficiency, and low cytotoxicity. Increasing polyplex stability in PBS correlated with increasing polymer molecular weight and decreasing peptide length. Copolymers containing K(5) and K(10) oligocations transfected cultured cells with significantly higher efficiencies than copolymers of K(15). Four HPMA-oligolysine copolymers were identified that met the desired criteria. Polyplexes formed with these copolymers demonstrated both salt stability and transfection efficiencies on-par with poly(ethylenimine) PEI in cultured cells.