Maryland's Global Hospital Budgets: Impacts on Medicare Cost and Utilization for the First 3 Years.

BACKGROUND: Global budgets have been proposed as a way to control health care expenditures, but experience with them in the United States is limited. Global budgets for Maryland hospitals, the All-Payer Model, began in January 2014. OBJECTIVES: To evaluate the effect of hospital global budgets on health care utilization and expenditures. RESEARCH DESIGN: Quantitative analyses used a difference-in-differences design modified for nonparallel baseline trends, comparing trend changes from a 3-year baseline period to the first 3 years after All-Payer Model implementation for Maryland and a matched comparison group. SUBJECTS: Hospitals in Maryland and matched out-of-state comparison hospitals. Fee-for-service Medicare beneficiaries residing in Maryland and comparison hospital market areas. MEASURES: Medicare claims were used to measure total Medicare expenditures; utilization and expenditures for hospital and nonhospital services; admissions for avoidable conditions; hospital readmissions; and emergency department visits. Qualitative data on implementation were collected through interviews with senior hospital staff, state officials, provider organization representatives, and payers, as well as focus groups of physicians and nurses. RESULTS: Total Medicare and hospital service expenditures declined during the first 3 years, primarily because of reduced expenditures for outpatient hospital services. Nonhospital expenditures, including professional expenditures and postacute care expenditures, also declined. Inpatient admissions, including admissions for avoidable conditions, declined, but, there was no difference in the change in 30-day readmissions. Moreover, emergency department visits increased for Maryland relative to the comparison group. CONCLUSIONS: This study provides evidence that hospital global budgets as implemented in Maryland can reduce expenditures and unnecessary utilization without shifting costs to other parts of the health care system.

Effects of Teriparatide, Denosumab, or Both on Spine Trabecular Microarchitecture in DATA-Switch: a Randomized Controlled Trial.

In postmenopausal women, 2 yr of combined teriparatide and denosumab increases bone mineral density more than either drug alone, and switching from either combination or teriparatide to denosumab for an additional 2 yr further increases bone mineral density. Conversely, switching from denosumab to teriparatide results in transient bone loss. The effects of these interventions on spine microarchitecture are unknown. In the DATA and DATA-Switch studies, 94 postmenopausal osteoporotic women were randomized to receive 24 mo of teriparatide (20 µg daily), denosumab (60 mg every 6 mo), or both. Then, women originally assigned to 24 mo of teriparatide received 24 mo of denosumab, whereas subjects originally randomized to 24 mo of denosumab received 24 mo of teriparatide. Subjects who received both drugs received an additional 24 mo of denosumab alone. Spine trabecular bone score (TBS, a gray-level textural assessment of bone microarchitecture) was measured blinded from treatment groups using images from 2-dimensional dual-energy X-ray absorptiometry spine scans at 0, 12, 24, 30, 36, and 48 mo in 65 women who had posterior-anterior spine dual-energy X-ray absorptiometry images suitable for TBS analysis. After 24 mo, TBS increased by 2.7 ± 4.7% in the teriparatide group (p = 0.009 vs baseline), by 1.8 ± 5.0% in the denosumab group (p = 0.118 vs baseline), and by 4.5 ± 6.7% in the combination group (p = 0.017 vs baseline), with no significant between-group differences. In the 6 mo after the treatments were switched (months 24-30), TBS continued to increase in the combination-to-denosumab and teriparatide-to-denosumab groups but decreased by -1.1 ± 4.0% in the denosumab-to-teriparatide group (p < 0.05 vs other groups). After 48 mo, compared to month 0, TBS increased by 5.1 ± 5.8% in the teriparatide-to-denosumab group, by 3.6 ± 4.2% in the denosumab-to-teriparatide group, and by 6.1 ± 4.7% in the combination-to-denosumab group (p < 0.001 vs baseline for all groups, p = not significant for between-group differences). Switching from teriparatide to denosumab also increased spine TBS. Conversely, switching from denosumab to teriparatide transiently degraded spine trabecular microarchitecture, the clinical consequences of which require further study.

Multilocus microsatellite genotyping array for investigation of genetic epidemiology of Pneumocystis jirovecii.

Pneumocystis jirovecii is a symbiotic respiratory fungus that causes pneumonia (PcP) in immunosuppressed patients. Because P. jirovecii cannot be reliably cultured in vitro, it has proven difficult to study and gaps in our understanding of the organism persist. The release of a draft genome for the organism opens the door for the development of new genotyping approaches for studying its molecular epidemiology and global population structure. We identified and validated 8 putatively neutral microsatellite markers and 1 microsatellite marker linked to the dihydropteroate synthase gene (dhps), the enzymatic target of sulfa drugs used for PcP prevention and treatment. Using these tools, we analyzed P. jirovecii isolates from HIV-infected patients from three geographically distant populations: Uganda, the United States, and Spain. Among the 8 neutral markers, we observed high levels of allelic heterozygosity (average He, 0.586 to 0.842). Consistent with past reports, we observed limited global population structuring, with only the Ugandan isolates showing minor differentiation from the other two populations. In Ugandan isolates that harbored mutations in dhps, the microsatellite locus linked to dhps demonstrated a depressed He, consistent with positive directional selection for sulfa resistance mutations. Using a subset of these microsatellites, analyses of individual and paired samples from infections in San Francisco, CA, showed reliable typeability within a single infection and high discriminatory power between infections. These features suggest that this novel microsatellite typing approach will be an effective tool for molecular-epidemiological investigations into P. jirovecii population structure, transmission, and drug resistance.

Working With Burmese Patients: Understanding Historical and Cultural Contexts to Improve Health Care Access and Health Status.

Introduction: Burmese patients resettled in the United States as refugees constitute one of the country's largest refugee populations. As health inequities within the wider Asian and Asian American population have garnered more attention, medical professionals have worked to better understand how to provide care to Burmese and Burmese American patients. This workshop addresses the pressing need to provide culturally responsive care to this growing population. Methods: Our interactive 60-minute workshop was developed to increase the knowledge and confidence of health care providers and trainees regarding the specific needs of Burmese communities in the United States. It was implemented once in person and twice virtually. The workshop included a PowerPoint presentation and case studies. Pre- and postworkshop evaluation forms assessed the effectiveness of the module. Results: The workshop's 70 attendees included an interdisciplinary group of medical students, academic faculty, graduate students, and health care staff. Following module completion, all learning objectives were met. Paired-samples t tests revealed significant increases in average number of correct responses for all learning objectives. Discussion: This module is part of a larger initiative to provide current and future health care providers with information to empower them to supply culturally responsive care to Burmese and Burmese American patients and their families. We offer recommendations for improving care for this patient population on individual, provider, and systemic levels. We hope that this module will inspire opportunities to advocate for change in policy and health care/research funding for Burmese and Burmese American patients.

Design of PLGA-Based Drug Delivery Systems Using a Physically-Based Sustained Release Model.

An extensive data set has been developed and used to further the progress of a model-informed design of controlled drug release. An improved drug-release model with mechanistic modeling of hydrolytic polymer degradation is used and validated by comparing model predictions to in vitro experiments. Combining parameter estimates from the literature with model fits to the data set, this study can aid in achieving a priori design of controlled drug release from a model PLGA release system. A systematic series of model release systems were formulated with FITC-labeled dextran, as a surrogate for biopharmaceuticals, in PLGA rods over a broad range of compositions. While general comparisons between the model and experiments were favorable, important discrepancies were identified for several formulations with significant first-phase drug release. Supported by cross-sectional fluorescence microscopy images of the FITC-dextran distribution within the rods, this first-phase release was attributed to a combination of two main factors: (1) percolation of the drug particles and (2) swelling of and pore formation in the rods due to water uptake. These observations indicate the importance of careful selection of the PLGA polymer grade when designing drug release systems but also reflect a need for better understanding of phenomena such as pore formation. Adapting model parameters, without modifying the physical processes included in the model, enabled accurate fitting of the experimental data for all formulations, highlighting the applicability of the model.

Repeatability of 18F-FDG PET Radiomic Features in Cervical Cancer.

Knowledge of the intrinsic variability of radiomic features is essential to the proper interpretation of changes in these features over time. The primary aim of this study was to assess the test-retest repeatability of radiomic features extracted from 18F-FDG PET images of cervical tumors. The impact of different image preprocessing methods was also explored. Methods: Patients with cervical cancer underwent baseline and repeat 18F-FDG PET/CT imaging within 7 d. PET images were reconstructed using 2 methods: ordered-subset expectation maximization (PETOSEM) or ordered-subset expectation maximization with point-spread function (PETPSF). Tumors were segmented to produce whole-tumor volumes of interest (VOIWT) and 40% isocontours (VOI40). Voxels were either left at the default size or resampled to 3-mm isotropic voxels. SUV was discretized to a fixed number of bins (32, 64, or 128). Radiomic features were extracted from both VOIs, and repeatability was then assessed using the Lin concordance correlation coefficient (CCC). Results: Eleven patients were enrolled and completed the test-retest PET/CT imaging protocol. Shape, neighborhood gray-level difference matrix, and gray-level cooccurrence matrix features were repeatable, with a mean CCC value of 0.81. Radiomic features extracted from PETOSEM images showed significantly better repeatability than features extracted from PETPSF images (P < 0.001). Radiomic features extracted from VOI40 were more repeatable than features extracted from VOIWT (P < 0.001). For most features (78.4%), a change in bin number or voxel size resulted in less than a 10% change in feature value. All gray-level emphasis and gray-level run emphasis features showed poor repeatability (CCC values < 0.52) when extracted from VOIWT but were highly repeatable (mean CCC values > 0.96) when extracted from VOI40Conclusion: Shape, gray-level cooccurrence matrix, and neighborhood gray-level difference matrix radiomic features were consistently repeatable, whereas gray-level run length matrix and gray-level zone length matrix features were highly variable. Radiomic features extracted from VOI40 were more repeatable than features extracted from VOIWT Changes in voxel size or SUV discretization parameters typically resulted in relatively small differences in feature value, though several features were highly sensitive to these changes.

Extended Characterization and Impact of Visible Fatty Acid Particles - A Case Study With a mAb Product.

In recent years, there has been increased scrutiny on the presence and formation of product-related particles in biopharmaceutical formulations. These types of particles, originating from the degradation of the active pharmaceutical ingredient or the excipients, can be challenging to identify and characterize due to their fragility. Additionally, the mechanisms of their formation as well as the impact of their presence on drug product safety can be complicated to elucidate. In this work, a case study is presented in which multiple batches of one formulated monoclonal antibody (mAb-A) were analyzed at different batch ages to better understand the formation of visible particles resulting from degradation of the surfactant polysorbate 20. The particle identity was determined by Raman spectroscopy as free fatty acid (FFA) and the particle composition over time was monitored by mass spectrometry. Further experimental work includes the counts and morphologies of subvisible particles by flow imaging microscopy. Finally, we evaluated the consequences of saline and human plasma exposure to the visible particles to better understand their fate upon dilution and/or administration which is routinely performed in the clinical setting. The experiments performed in this work can be used to support risk assessments of visible product-related particles.

Value of Packaged Testing for Sexually Transmitted Infections for Persons who Inject Drugs Hospitalized With Serious Injection-Related Infections.

BACKGROUND: Persons who inject drugs (PWID) are frequently admitted for serious injection-related infections (SIRIs). PWID are also at risk for sexually transmitted infections (STIs). METHODS: We conducted a multicenter quality improvement project at 3 hospitals in Missouri. PWID with SIRI who received an infectious diseases consultation were prospectively identified and placed into an electronic database as part of a Centers for Disease Control and Prevention-funded quality improvement project. Baseline data were collected from 8/1/2019 to 1/30/2020. During the intervention period (2/1/2020-2/28/2021), infectious diseases physicians caring for patients received 2 interventions: (1) email reminders of best practice screening for HIV, viral hepatitis, and STIs; (2) access to a customized EPIC SmartPhrase that included checkboxes of orders to include in assessment and plan of consultation notes. STI screening rates were compared before and after the intervention. We then calculated odds ratios to evaluate for risk factors for STIs in the cohort. RESULTS: Three hundred ninety-four unique patients were included in the cohort. Initial screening rates were highest for hepatitis C (88%), followed by HIV (86%). The bundled intervention improved screening rates for all conditions and substantially improved screening rates for gonorrhea, chlamydia, and syphilis (30% vs 51%, 30% vs 51%, and 39 vs 60%, respectively; P < .001). Of patients who underwent screening, 16.9% were positive for at least 1 STI. In general, demographics were not strongly associated with STIs. CONCLUSIONS: PWID admitted for SIRI frequently have unrecognized STIs. Our bundled intervention improved STI screening rates, but additional interventions are needed to optimize screening.

Use of ICD-10 Codes for Identification of Injection Drug Use-Associated Infective Endocarditis Is Nonspecific and Obscures Critical Findings on Impact of Medications for Opioid Use Disorder.

BACKGROUND: No International Classification of Diseases, 10th revision (ICD-10), diagnosis code exists for injection drug use-associated infective endocarditis (IDU-IE). Instead, public health researchers regularly use combinations of nonspecific ICD-10 codes to identify IDU-IE; however, the accuracy of these codes has not been evaluated. METHODS: We compared commonly used ICD-10 diagnosis codes for IDU-IE with a prospectively collected patient cohort diagnosed with IDU-IE at Barnes-Jewish Hospital to determine the accuracy of ICD-10 diagnosis codes used in IDU-IE research. RESULTS: ICD-10 diagnosis codes historically used to identify IDU-IE were inaccurate, missing 36.0% and misclassifying 56.4% of patients prospectively identified in this cohort. Use of these nonspecific ICD-10 diagnosis codes resulted in substantial biases against the benefit of medications for opioid use disorder (MOUD) with relation to both AMA discharge and all-cause mortality. Specifically, when data from all patients with ICD-10 code combinations suggestive of IDU-IE were used, MOUD was associated with an increased risk of AMA discharge (relative risk [RR], 1.12; 95% CI, 0.48-2.64). In contrast, when only patients confirmed by chart review as having IDU-IE were analyzed, MOUD was protective (RR, 0.49; 95% CI, 0.19-1.22). Use of MOUD was associated with a protective effect in time to all-cause mortality in Kaplan-Meier analysis only when confirmed IDU-IE cases were analyzed (P = .007). CONCLUSIONS: Studies using nonspecific ICD-10 diagnosis codes for IDU-IE should be interpreted with caution. In the setting of an ongoing overdose crisis and a syndemic of infectious complications, a specific ICD-10 diagnosis code for IDU-IE is urgently needed.

Technoeconomic Modeling of Plant-Based Griffithsin Manufacturing.

Griffithsin is a marine algal lectin that exhibits broad-spectrum antiviral activity by binding oligomannose glycans on viral envelope glycoproteins, including those found in HIV-1, HSV-2, SARS, HCV and other enveloped viruses. An efficient, scalable and cost-effective manufacturing process for Griffithsin is essential for the adoption of this drug in human antiviral prophylaxis and therapy, particularly in cost-sensitive indications such as topical microbicides for HIV-1 prevention. The production of certain classes of recombinant biologics in plants can offer scalability, cost and environmental impact advantages over traditional biomanufacturing platforms. Previously, we showed the technical viability of producing recombinant Griffithsin in plants. In this study, we conducted a technoeconomic analysis (TEA) of plant-produced Griffithsin manufactured at commercial launch volumes for use in HIV microbicides. Data derived from multiple non-sequential manufacturing batches conducted at pilot scale and existing facility designs were used to build a technoeconomic model using SuperPro Designer® modeling software. With an assumed commercial launch volume of 20 kg Griffithsin/year for 6.7 million doses of Griffithsin microbicide at 3 mg/dose, a transient vector expression yield of 0.52 g Griffithsin/kg leaf biomass, recovery efficiency of 70%, and purity of >99%, we calculated a manufacturing cost for the drug substance of $0.32/dose and estimated a bulk product cost of $0.38/dose assuming a 20% net fee for a contract manufacturing organization (CMO). This is the first report modeling the manufacturing economics of Griffithsin. The process analyzed is readily scalable and subject to efficiency improvements and could provide the needed market volumes of the lectin within an acceptable range of costs, even for cost-constrained products such as microbicides. The manufacturing process was also assessed for environmental, health and safety impact and found to have a highly favorable environmental output index with negligible risks to health and safety. The results of this study help validate the plant-based manufacturing platform and should assist in selecting preferred indications for Griffithsin as a novel drug.

Importance of prompt antiresorptive therapy in postmenopausal women discontinuing teriparatide or denosumab: The Denosumab and Teriparatide Follow-up study (DATA-Follow-up).

When teriparatide and denosumab are discontinued, bone mineral density (BMD) abruptly decreases. To compare rates of bone loss in postmenopausal women who discontinue denosumab or teriparatide and receive no additional prescription osteoporosis medications to women who discontinue these drugs followed by prompt antiresorptive therapy, we asked women concluding the Denosumab and Teriparatide Administration (DATA) study and its extension, DATA-Switch, to return for BMD measurements 1-2years after study completion. In these studies, women received 2-years of either teriparatide, denosumab or both medications followed by 2-years of the alternate therapy (women who received combination therapy initially received an additional 2-years of denosumab alone). Fifty of 69 women who completed DATA-Switch returned after a mean of 15.4±3.5months. Of the 28 women who received antiresorptive therapy (10 denosumab, 10 oral bisphosphonates, 8 intravenous zoledronic acid), the mean interval between ending DATA-Switch and beginning antiresorptive therapy was 3.8±3.1months. In the 22 women not receiving follow-up therapy, femoral neck, total hip, and spine BMD decreased by -4.2±4.3%, -4.5±3.6%, and -10.0±5.4%, respectively, while BMD was maintained in those who did receive follow-up antiresorptive drugs (femoral neck, total hip, and spine BMD changes of -0.6±2.7%, -0.8±3.1%, and -1.2±4.7%, respectively, P<0.001 for all between-group comparisons). Among untreated women, femoral neck BMD decreased more in those discontinuing denosumab (-5.8±4.0%) than in those discontinuing teriparatide (-0.8±2.6%, P=0.008). Total hip BMD, but not spine BMD, showed a similar pattern. Among treated women, denosumab increased femoral neck and total hip BMD more than bisphosphonates while BMD changes at the spine did not differ significantly. In summary, the large teriparatide and denosumab-induced gains in BMD achieved with 4years of intensive therapy in the DATA and DATA-Switch studies were maintained in patients who received prompt antiresorptive therapy but not in those left untreated. These results demonstrate the negative consequences of delaying consolidation therapy in women treated with these drugs and underscore the importance of timely medication transitions in such patients.

Improved controlled release of protein from expanded-pore mesoporous silica nanoparticles modified with co-functionalized poly(n-isopropylacrylamide) and poly(ethylene glycol) (PNIPAM-PEG).

Novel pore-expanded mesoporous silica nanoparticles (MSNs) with pore sizes of approximately 11nm were synthesized and modified with thermoresponsive, poly(n-isopropylacrylamide) (PNIPAM) gating groups on the nanoparticle exterior surface and in addition with poly(ethylene-glycol) (PEG) within the porous interior to minimize protein adsorption. PEG traditionally has been grafted to the nanoparticle exterior to minimize non-specific binding and interactions with the biological environment, but due to the templating mechanism of MSN synthesis, both the pore interior and nanoparticle surface can be separately modified. Here, an improved control release behavior of bovine hemoglobin (BHb) was observed after PEGylating the interior porous framework, compared to the release BHb from unmodified MSNs. This can be attributed to the reduced protein denaturation on PEGylated silica that was observed using circular dichroism spectroscopy.

Insights into electron leakage in the reaction cycle of cytochrome P450 BM3 revealed by kinetic modeling and mutagenesis.

As a single polypeptide, cytochrome P450 BM3 fuses oxidase and reductase domains and couples each domain's function to perform catalysis with exceptional activity upon binding of substrate for hydroxylation. Mutations introduced into the enzyme to change its substrate specificity often decrease coupling efficiency between the two domains, resulting in unproductive consumption of cofactors and formation of water and/or reactive species. This phenomenon can correlate with leakage, in which P450 BM3 uses electrons from NADPH to reduce oxygen to water and/or reactive species even without bound substrate. The physical basis for leakage is not yet well understood in this particular member of the cytochrome P450 family. To clarify the relationship between leakage and coupling, we used simulations to illustrate how different combinations of kinetic parameters related to substrate-free consumption of NADPH and substrate hydroxylation can lead to either minimal effects on coupling or a dramatic decrease in coupling as a result of leakage. We explored leakage in P450 BM3 by introducing leakage-enhancing mutations and combining these mutations to assess whether doing so increases leakage further. The variants in this study provide evidence that while a transition to high spin may be vital for coupled hydroxylation, it is not required for enhanced leakage; substrate binding and the consequent shift in spin state are not necessary as a redox switch for catalytic oxidation of NADPH. Additionally, the variants in this study suggest a tradeoff between leakage and stability and thus evolvability, as the mutations we investigated were far more deleterious than other mutations that have been used to change substrate specificity.