RESUMEN
Researchers have found that machine learning methods are typically better at prediction than econometric models when the choice environment is stable. We study hospital demand models, and evaluate the relative performance of machine learning algorithms when the choice environment changes substantially due to natural disasters that closed previously available hospitals. While machine learning algorithms outperform traditional econometric models in prediction, the gain they provide shrinks when patients' choice sets are more profoundly affected. We show that traditional econometric methods provide important additional information when there are major changes in the choice environment.
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Algoritmos , Aprendizaje Automático , Hospitales , HumanosRESUMEN
Despite the boom in biologics over the past decade, the intrinsic instability of these large molecules poses significant challenges to formulation development. Almost half of all pharmaceutical protein products are formulated in the solid form to preserve protein native structure and extend product shelf-life. In this review, both traditional and emerging drying techniques for producing protein solids will be discussed. During the drying process, various stresses can impact the stability of protein solids. However, understanding the impact of stress on protein product quality can be challenging due to the lack of reliable characterization techniques for biological solids. Both conventional and advanced characterization techniques are discussed including differential scanning calorimetry (DSC), solid-state Fourier transform infrared spectrometry (ssFTIR), solid-state fluorescence spectrometry, solid-state hydrogen deuterium exchange (ssHDX), solid-state nuclear magnetic resonance (ssNMR) and solid-state photolytic labeling (ssPL). Advanced characterization tools may offer mechanistic investigations into local structural changes and interactions at higher resolutions. The continuous exploration of new drying techniques, as well as a better understanding of the effects caused by different drying techniques in solid state, would advance the formulation development of biological products with superior quality.
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Productos Biológicos/administración & dosificación , Proteínas/administración & dosificación , Tecnología Farmacéutica/métodos , Productos Biológicos/química , Técnicas de Química Analítica/métodos , Química Farmacéutica/métodos , Desarrollo de Medicamentos , Humanos , Estabilidad Proteica , Proteínas/químicaRESUMEN
This study aims to determine the impacts of drying method and excipient on changes in protein structure and physical stability of model protein solids. Protein solids containing one of two model proteins (lysozyme or myoglobin) were produced with or without excipients (sucrose or mannitol) using freeze drying or spray freeze drying (SFD). The protein powders were then characterized using solid-state Fourier transform infrared spectroscopy (ssFTIR), differential scanning calorimetry (DSC), circular dichroism spectrometry (CD), size exclusion chromatography (SEC), BET surface area measurements and solid-state hydrogen deuterium exchange with mass spectrometry (ssHDX-MS). ssFTIR and CD could identify little to no difference in structure of the proteins in the formulation. ssHDX-MS was able to identify the population heterogeneity, which was undetectable by conventional characterization techniques of ssFTIR and CD. ssHDX-MS metrics such as Dmax and peak area showed a good correlation with the protein physical instability (loss of the monomeric peak area by size exclusion chromatography) in 90-day stability studies conducted at 40 °C for lysozyme. Higher specific surface area was associated with greater loss in monomer content for myoglobin-mannitol formulations as compared to myoglobin-only formulations. Spray freeze drying seems a viable manufacturing technique for protein solids with appropriate optimization of formulations. The differences observed within the formulations and between the processes using ssHDX-MS, BET surface area measurements and SEC in this study provide an insight into the influence of drying methods and excipients on protein physical stability.
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Química Farmacéutica , Excipientes , Composición de Medicamentos , Estabilidad de Medicamentos , Liofilización , Espectrometría de MasasRESUMEN
Using commercial claims for 2012-2013 from the Colorado All Payer Claims Database, we examine how medical service prices vary for five hospital-based procedures and the complexity-adjusted inpatient price. We find that prices vary substantially in multiple dimensions. Our analysis indicates that there is significant price variation across payers for the same service in the same hospital. If prices converged to the lowest rate each hospital receives, commercial expenditures would fall by 10% to 20%. Differences across hospitals account for an even more substantial amount of the overall variation. For five out of six prices, we find that differences associated just with hospitals' metropolitan areas account for over 35% of the total variation. We observe substantial residual variation (18%-32%) after accounting for factors specific to a given payer or provider.
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Gastos en Salud , Hospitales , Humanos , Estados UnidosRESUMEN
PURPOSE: The aim of this study is to determine the effects of saccharide-containing excipients on the surface composition of spray-dried protein formulations and their matrix heterogeneity. METHODS: Spray-dried formulations of myoglobin or bovine serum albumin (BSA) were prepared without excipient or with sucrose, trehalose, or dextrans. Samples were characterized by solid-state Fourier-transform infrared spectroscopy (ssFTIR), differential scanning calorimetry (DSC), size exclusion chromatography (SEC) and scanning electron microscopy (SEM). Protein surface coverage was determined by X-ray photoelectron spectroscopy (XPS), while conformational differences were determined by solid-state hydrogen/deuterium exchange with mass spectrometry (ssHDX-MS). RESULTS: Structural differences were exhibited with the inclusion of different excipients, with dextran formulations indicating perturbation of secondary structure. XPS indicated sucrose and trehalose reduced protein surface concentration better than dextran-containing formulations. Using ssHDX-MS, the amount of deuterium incorporation and populations present were the largest in the samples processed with dextrans. Linear correlation was found between protein surface coverage and ssHDX-MS peak area (R2 = 0.853) for all formulations with saccharide-containing excipients. CONCLUSIONS: Lower molecular weight species of saccharides tend to enrich the particle surface and reduce protein concentration at the air-liquid interface, resulting in reduced population heterogeneity and improved physical stability, as identified by ssHDX-MS.
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Excipientes/química , Mioglobina/química , Albúmina Sérica Bovina/química , Química Farmacéutica/métodos , Desecación/métodos , Deuterio/química , Dextranos/química , Espectrometría de Masas/métodos , Sacarosa/química , Propiedades de Superficie , Trehalosa/químicaRESUMEN
Powders containing one of four model proteins (myoglobin, bovine serum albumin, lysozyme, ß-lactoglobulin) were formulated with either sucrose, trehalose, or mannitol and dried using lyophilization or spray-drying. The powders were characterized using solid-state Fourier transform infrared spectroscopy (ssFTIR), solid-state fluorescence spectroscopy, differential scanning calorimetry (DSC) and solid-state hydrogen/deuterium exchange mass spectrometry (ssHDX-MS). ssFTIR and fluorescence spectroscopy identified minor structural differences among powders with different excipients and drying methods for some proteins. Using ssHDX-MS, differences in protein structure were observed among protein formulations containing sucrose or trehalose and mannitol, and/or with varying processing conditions, including proteins like ß-lactoglobulin, for which standard characterization techniques showed no differences. Proteins processed by spray-drying typically showed greater heterogeneity by ssHDX-MS than those lyophilized; these differences were not detected by ssFTIR or solid-state fluorescence spectroscopy. The ssHDX-MS metrics were better correlated with protein physical instability measured by size-exclusion chromatography in 90-day stability studies (40⯰C, 33% RH) than with the results of DSC, ssFTIR, or fluorescence spectroscopy. Thus, ssHDX-MS detected subtle changes in conformation and/or matrix interactions for these proteins that were correlated with storage stability, suggesting that the method can be used to design robust solid-state pharmaceutical protein products more rapidly.
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Desecación/métodos , Lactoglobulinas/química , Muramidasa/química , Mioglobina/química , Albúmina Sérica Bovina/química , Excipientes/química , Liofilización , Espectrometría de Masas de Intercambio de Hidrógeno-Deuterio , Conformación Proteica , Estabilidad ProteicaRESUMEN
The abuse of heroin (diamorphine) and heroin-related deaths are increasing around the world. The interpretation of the toxicological results from suspected heroin-related deaths is notoriously difficult, especially in cases where there may be limited samples. To help forensic practitioners with heroin interpretation, we determined the concentration of morphine (M), morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) in blood (femoral and cardiac), brain (thalamus), liver (deep right lobe), bone marrow (sternum), skeletal muscle (psoas), and vitreous humor in 44 heroin-related deaths. The presence of 6-monoacetylmorphine (6-MAM) in any of the postmortem samples was used as confirmation of heroin use. Quantitation was carried out using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with solid-phase extraction. We also determined the presence of papaverine, noscapine and codeine in the samples, substances often found in illicit heroin and that may help determine illicit heroin use. The results of this study show that vitreous is the best sample to detect 6-MAM (100% of cases), and thus heroin use. The results of the M, M3G, and M6G quantitation in this study allow a degree of interpretation when samples are limited. However in some cases it may not be possible to determine heroin/morphine use as in four cases in muscle (three cases in bone marrow) no morphine, M3G, or M6G were detected, even though they were detected in other case samples. As always, postmortem cases of suspected morphine/heroin intoxication should be interpreted with care and with as much case knowledge as possible.
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Heroína/toxicidad , Derivados de la Morfina/farmacocinética , Morfina/farmacocinética , Adulto , Anciano , Médula Ósea/metabolismo , Encéfalo/metabolismo , Codeína/farmacocinética , Femenino , Toxicología Forense , Humanos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Morfina/sangre , Derivados de la Morfina/sangre , Músculo Esquelético/metabolismo , Noscapina/farmacocinética , Papaverina/farmacocinética , Cuerpo Vítreo/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To understand the impact of changes in physician market structure on clinical outcomes and health care utilization. DATA SOURCES: 2005-2012 Medicare fee-for-service claims and enrollment data. STUDY DESIGN: We consider the effect of cardiology market structure on utilization and health outcomes for four patient populations. We estimate the risk-adjusted impact of competition using multivariate regression models. PRINCIPAL FINDINGS: The study finds that an increase in consolidation leads to statistically and economically significant increases in negative health outcomes. For example, we find that moving from a zip code at the 25th percentile of cardiology market concentration to one at the 75th percentile would be associated with 5 to 7 percent increases in risk-adjusted mortality for three of the sample populations. We also found higher expenditures in more concentrated markets. For example, moving from a zip code at the 25th percentile of cardiology market concentration to one at the 75th would be associated with 7 to 11 percent increases in expenditures, depending on sample population. CONCLUSIONS: Our estimates indicate that increases in cardiology market concentration are associated with worse health outcomes and higher health care expenditures. Some effects may be attributed to vertical as well as horizontal changes.
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Cardiología/economía , Competencia Económica/economía , Planes de Aranceles por Servicios/economía , Gastos en Salud/estadística & datos numéricos , Medicare/economía , Evaluación de Resultado en la Atención de Salud , Características de la Residencia , Anciano , Femenino , Humanos , Masculino , Estados UnidosRESUMEN
PURPOSE: Lyophilization and spray drying are widely used to manufacture solid forms of therapeutic proteins. Lyophilization is used to stabilize proteins vulnerable to degradation in solution, whereas spray drying is mainly used to prepare inhalation powders or as an alternative to freezing for storing bulk drug substance. Both processes impose stresses that may adversely affect protein structure, stability and bioactivity. Here, we compared lyophilization with and without controlled ice nucleation, and spray drying for their effects on the solid-state conformation and matrix interactions of a model IgG1 monoclonal antibody (mAb). METHODS: Solid-state conformation and matrix interactions of the mAb were probed using solid-state hydrogen-deuterium exchange with mass spectrometric analysis (ssHDX-MS), and solid-state Fourier transform infrared (ssFTIR) and solid-state fluorescence spectroscopies. RESULTS: mAb conformation and/or matrix interactions were most perturbed in mannitol-containing samples and the distribution of states was more heterogeneous in sucrose and trehalose samples that were spray dried. CONCLUSIONS: The findings demonstrate the sensitivity of ssHDX-MS to changes weakly indicated by spectroscopic methods, and support the broader use of ssHDX-MS to probe formulation and process effects on proteins in solid samples.
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Medición de Intercambio de Deuterio/métodos , Deuterio/química , Hidrógeno/química , Inmunoglobulina G/química , Espectrometría de Masas/métodos , Química Farmacéutica/métodos , Cristalización , Liofilización/métodos , Humanos , Manitol/química , Microscopía Electrónica de Rastreo/métodos , Polvos/química , Unión Proteica , Conformación Proteica , Espectrometría de Fluorescencia/métodos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Sacarosa/química , Trehalosa/química , Difracción de Rayos X/métodosRESUMEN
Health systems are employing physicians in growing numbers. The implications of this trend are poorly understood and controversial. We use rich data from the Centers for Medicare and Medicaid Services to examine the effects of a set of physician acquisitions by hospital systems on outpatient utilization and spending. We find that financial integration systematically produces economically large changes in the acquired physicians' behavior, but has less consistent effects at the acquiring system level.
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Prestación Integrada de Atención de Salud/economía , Costos de la Atención en Salud/estadística & datos numéricos , Medicare/organización & administración , Atención a la Salud/economía , Atención a la Salud/organización & administración , Atención a la Salud/estadística & datos numéricos , Prestación Integrada de Atención de Salud/organización & administración , Prestación Integrada de Atención de Salud/estadística & datos numéricos , Hospitales/estadística & datos numéricos , Humanos , Medicare/economía , Medicare/estadística & datos numéricos , Modelos Econométricos , Médicos/economía , Médicos/organización & administración , Pautas de la Práctica en Medicina/economía , Pautas de la Práctica en Medicina/estadística & datos numéricos , Estados Unidos , Recursos HumanosRESUMEN
This paper examines why for-profit dialysis providers have displaced non-profit providers over the last 25 years. Using detailed data on individual markets' evolutions, I find that for-profit facilities were quicker to enter growing markets and slower to exit declining ones than non-profit facilities. Moreover, for-profit providers' presence in a market had a larger impact on the exit and entry behavior of competitors. These results suggest that for-profit dialysis providers have an advantage in static competition relative to non-profit providers, and that this-rather than lower entry costs-explains their increasing prominence. Additional empirical analyses indicate that for-profits' advantage cannot solely be attributed to efficiencies related to membership in a large, multi-facility chain. This further suggests that managerial incentives have had an economically significant impact on long-run market structure in this industry.
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Instituciones de Atención Ambulatoria/economía , Sector de Atención de Salud , Instituciones Privadas de Salud/economía , Diálisis Renal/economía , Diálisis , Competencia Económica , Medicare , Organizaciones sin Fines de Lucro , Propiedad , Estados UnidosRESUMEN
The interpretation of postmortem drug levels is complicated by changes in drug blood levels in the postmortem period, a phenomena known as postmortem drug redistribution. We investigated the postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in a rabbit model. Heroin (1 mg/kg) was injected into anesthetised rabbit; after 1 h, an auricular vein blood sample was taken and the rabbit was euthanised. Following death rabbits were placed in a supine position at room temperature and divided into three groups namely (1) immediate autopsy, (2) autopsy after 30 minutes and (3) autopsy 24 h after death. Various samples which included femoral blood, cardiac blood, lung, liver, kidney, vitreous humour, subcutaneous and abdominal fat, liver, bone marrow and skeletal muscle were taken. The samples were analysed with a validated LC-MS/MS method. It was observed that within minutes there was a significant increase in free morphine postmortem femoral blood concentration compared to the antemortem sample (0.01 ± 0.01 to 0.05 ± 0.02 mg/L).Various other changes in free morphine and metabolite concentrations were observed during the course of the experiment in various tissues. Principal component analysis was used to investigate possible correlations between free morphine in the various samples. Some correlations were observed but gave poor predictions (>20 % error) when back calculating. The results suggest that rabbits are a good model for further studies of postmortem redistribution but that further study and understanding of the phenomena is required before accurate predictions of the blood concentration at the time of death are possible.