Outcomes of the 340B Drug Pricing Program: A Scoping Review.

Importance: The 340B Drug Pricing Program requires manufacturers to offer discounted drug prices to support safety net hospitals and clinics (covered entities) providing care to low-income populations. Amid expansion, the program has received criticism and calls for reform. Objective: To assess the literature on the foundations of and outcomes associated with the 340B program. Evidence Review: The databases searched in this scoping review included PubMed, Embase, EconLit, National Bureau of Economic Research (NBER), Westlaw, the Department of Health and Human Services Office of the Inspector General (HHS-OIG) website, the Government Accountability Office (GAO) website, and Google in February 2023 for peer-reviewed literature, legal publications, opinion pieces, and government agency and committee reports related to the 340B program. Findings: Among a collected 900 documents, 289 met inclusion criteria: 83 articles from PubMed, 12 articles from Embase, 2 articles from EconLit, 1 article from NBER, 28 articles from Westlaw, 23 legislative history documents, 103 documents from Google, 11 GAO reports, and 26 HHS-OIG reports. Included literature pertained to 4 stakeholders in the 340B program: covered entities, pharmacies, pharmaceutical manufacturers, and patients. This literature showed that hospitals, clinics, and pharmacies generated revenue and manufacturers have forgone revenue from 340B discounted drugs. Audits of covered entities found low rates of compliance with 340B program requirements, whereas mixed evidence was uncovered on how covered entities used their 340B revenue, with some studies suggesting use to expand health care services for low-income populations and others to acquire physician practices and open sites in higher-income neighborhoods. These studies were hampered by a lack of transparency and reporting on the use of 340B revenue. Studies revealed patient benefits from access to expanded health care services, but there was mixed evidence on patient cost savings. Although the review identified considerable research on 340B hospitals, pharmacies, and patients, less research was found evaluating the 340B program's effect on nonhospital covered entities, drug pricing, and racial and ethnic minority groups. Conclusions and Relevance: In this scoping review of the 340B program, we found that the 340B program was associated with financial benefits for hospitals, clinics, and pharmacies; improved access to health care services for patients; and substantial costs to manufacturers. Increased transparency regarding the use of 340B program revenue and strengthened rulemaking and enforcement authority for the Health Resources and Services Administration would support compliance and help ensure the 340B program achieves its intended purposes.

Patents and regulatory exclusivities on FDA-approved insulin products: A longitudinal database study, 1986-2019.

BACKGROUND: Insulin is the primary treatment for type 1 and some type 2 diabetes but remains costly in the United States, even though it was discovered more than a century ago. High prices can lead to nonadherence and are often sustained by patents and regulatory exclusivities that limit competition on brand-name products. We sought to examine how manufacturers have used patents and regulatory exclusivities on insulin products approved from 1986 to 2019 to extend periods of market exclusivity. METHODS AND FINDINGS: We used the publicly available Food and Drug Administration (FDA) Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) to identify all approved biosynthetic insulin products. Individual products approved under the same New Drug Application (NDA)-e.g., a vial and pen-were considered as separate products for the purposes of analysis. We recorded all patents and regulatory exclusivities listed in the Orange Book on each product and used Google Patents to extract the timing of patent application and whether patents were obtained on delivery devices or others aspects of the product. The primary outcome was the duration of expected protection, which was determined by subtracting the FDA approval date for each product from its last-to-expire patent or regulatory exclusivity (whichever occurred later). We performed a secondary analysis that considered overall protection on insulin lines-defined as groups of products approved under the same NDA with the same active ingredients manufactured by the same company. We also examined competition from follow-on insulin products-defined as products approved with the same active ingredients as originators but manufactured by different companies (approved via a specific drug approval pathway under section 505(b)(2) of the Food, Drug, and Cosmetic Act). During the study period, the FDA approved 56 individual products across 25 different insulin lines and 5 follow-ons across 3 different insulin lines. Thirty-three (59%) of the 56 products were drug-device combinations. Manufacturers of 9 products approved during the study period obtained patents filed after FDA approval that extended their duration of expected protection (by a median of 6 years). Approximately 63% of all patents on drug-device combinations approved during the study period were related to delivery devices. The median duration of expected protection on insulin products was 16.0 years, and the median protection on insulin lines was 17.6 years. An important limitation of our analysis is that manufacturers may continue to add patents on existing insulin products while competitors may challenge patents; therefore, periods of protection may change over time. CONCLUSIONS: Among several strategies that insulin manufacturers have employed to extend periods of market exclusivity on brand-name insulin products are filing patents after FDA approval and obtaining a large number of patents on delivery devices. Policy reforms are needed to promote timely competition in the pharmaceutical market and ensure that patients have access to low-cost drugs.

Tree crown damage and its effects on forest carbon cycling in a tropical forest.

Crown damage can account for over 23% of canopy biomass turnover in tropical forests and is a strong predictor of tree mortality; yet, it is not typically represented in vegetation models. We incorporate crown damage into the Functionally Assembled Terrestrial Ecosystem Simulator (FATES), to evaluate how lags between damage and tree recovery or death alter demographic rates and patterns of carbon turnover. We represent crown damage as a reduction in a tree's crown area and leaf and branch biomass, and allow associated variation in the ratio of aboveground to belowground plant tissue. We compare simulations with crown damage to simulations with equivalent instant increases in mortality and benchmark results against data from Barro Colorado Island (BCI), Panama. In FATES, crown damage causes decreases in growth rates that match observations from BCI. Crown damage leads to increases in carbon starvation mortality in FATES, but only in configurations with high root respiration and decreases in carbon storage following damage. Crown damage also alters competitive dynamics, as plant functional types that can recover from crown damage outcompete those that cannot. This is a first exploration of the trade-off between the additional complexity of the novel crown damage module and improved predictive capabilities. At BCI, a tropical forest that does not experience high levels of disturbance, both the crown damage simulations and simulations with equivalent increases in mortality does a reasonable job of capturing observations. The crown damage module provides functionality for exploring dynamics in forests with more extreme disturbances such as cyclones and for capturing the synergistic effects of disturbances that overlap in space and time.

Hydraulically-vulnerable trees survive on deep-water access during droughts in a tropical forest.

Deep-water access is arguably the most effective, but under-studied, mechanism that plants employ to survive during drought. Vulnerability to embolism and hydraulic safety margins can predict mortality risk at given levels of dehydration, but deep-water access may delay plant dehydration. Here, we tested the role of deep-water access in enabling survival within a diverse tropical forest community in Panama using a novel data-model approach. We inversely estimated the effective rooting depth (ERD, as the average depth of water extraction), for 29 canopy species by linking diameter growth dynamics (1990-2015) to vapor pressure deficit, water potentials in the whole-soil column, and leaf hydraulic vulnerability curves. We validated ERD estimates against existing isotopic data of potential water-access depths. Across species, deeper ERD was associated with higher maximum stem hydraulic conductivity, greater vulnerability to xylem embolism, narrower safety margins, and lower mortality rates during extreme droughts over 35 years (1981-2015) among evergreen species. Species exposure to water stress declined with deeper ERD indicating that trees compensate for water stress-related mortality risk through deep-water access. The role of deep-water access in mitigating mortality of hydraulically-vulnerable trees has important implications for our predictive understanding of forest dynamics under current and future climates.

Early prediction of pediatric acute kidney injury from the emergency department: A pilot study.

BACKGROUND: Identifying acute kidney injury (AKI) early can inform medical decisions key to mitigation of injury. An AKI risk stratification tool, the renal angina index (RAI), has proven better than creatinine changes alone at predicting AKI in critically ill children. OBJECTIVE: To derive and test performance of an "acute" RAI (aRAI) in the Emergency Department (ED) for prediction of inpatient AKI and to evaluate the added yield of urinary AKI biomarkers. METHODS: Study of pediatric ED patients with sepsis admitted and followed for 72 h. The primary outcome was inpatient AKI defined by a creatinine >1.5× baseline, 24-72 h after admission. Patients were denoted renal angina positive (RA+) for an aRAI score above a population derived cut-off. Test characteristics evaluated predictive performance of the aRAI compared to changes in creatinine and incorporation of 4 urinary biomarkers in the context of renal angina were assessed. RESULTS: 118 eligible subjects were enrolled. Mean age was 7.8 ± 6.4 years, 16% required intensive care admission. In the ED, 27% had a +RAI (22% had a >50% creatinine increase). The aRAI had an AUC of 0.92 (0.86-0.98) for prediction of inpatient AKI. For AKI prediction, RA+ demonstrated a sensitivity of 94% (69-99) and a negative predictive value of 99% (92-100) (versus sensitivity 59% (33-82) and NPV 93% (89-96) for creatinine ≥2× baseline). Biomarker analysis revealed a higher AUC for aRAI alone than any individual biomarker. CONCLUSIONS: This pilot study finds the aRAI to be a sensitive ED-based tool for ruling out the development of in-hospital AKI.

Forest responses to simulated elevated CO2 under alternate hypotheses of size- and age-dependent mortality.

Elevated atmospheric carbon dioxide (eCO2 ) is predicted to increase growth rates of forest trees. The extent to which increased growth translates to changes in biomass is dependent on the turnover time of the carbon, and thus tree mortality rates. Size- or age-dependent mortality combined with increased growth rates could result in either decreased carbon turnover from a speeding up of tree life cycles, or increased biomass from trees reaching larger sizes, respectively. However, most vegetation models currently lack any representation of size- or age-dependent mortality and the effect of eCO2 on changes in biomass and carbon turnover times is thus a major source of uncertainty in predictions of future vegetation dynamics. Using a reduced-complexity form of the vegetation demographic model the Functionally Assembled Terrestrial Ecosystem Simulator to simulate an idealised tropical forest, we find increases in biomass despite reductions in carbon turnover time in both size- and age-dependent mortality scenarios in response to a hypothetical eCO2 -driven 25% increase in woody net primary productivity (wNPP). Carbon turnover times decreased by 9.6% in size-dependent mortality scenarios due to a speeding up of tree life cycles, but also by 2.0% when mortality was age-dependent, as larger crowns led to increased light competition. Increases in aboveground biomass (AGB) were much larger when mortality was age-dependent (24.3%) compared with size-dependent (13.4%) as trees reached larger sizes before death. In simulations with a constant background mortality rate, carbon turnover time decreased by 2.1% and AGB increased by 24.0%, however, absolute values of AGB and carbon turnover were higher than in either size- or age-dependent mortality scenario. The extent to which AGB increases and carbon turnover decreases will thus depend on the mechanisms of large tree mortality: if increased size itself results in elevated mortality rates, then this could reduce by about half the increase in AGB relative to the increase in wNPP.

Insulin insulated: barriers to competition and affordability in the United States insulin market.

Insulin prices in the United States are skyrocketing. In addition to several challenges common to high-priced prescription drugs, insulin faces several unique legal, regulatory, and practical challenges to increasing access and affordability. Despite the fact that insulin was developed almost 100 years ago, the insulin market is dominated by only three companies and there continue to be no biosimilar competitors in the United States. Unlike many high-priced prescription drugs, insulin has been insulated from competition for years. This article examines the barriers to competition in the insulin market, considering the challenges surrounding regulatory approval, interchangeability, trade secrets, and anticompetitive behavior. Further, this article discusses the potential and limitations of various legislative proposals to address access to insulin. In doing so, this article attempts to explain why there is such limited competition in the insulin market and identifies issues specific to the insulin market for lawmakers to consider in developing proposals to address access to affordable insulin in the United States.

Fourth Amendment Protections of Prescription Drug Monitoring Programs: Patient Privacy in the Opioid Crisis.

The opioid crisis is one of the largest public health problems in the history of the United States. Prescription drug monitoring programs ("PDMPs")-state databases containing the records of all prescriptions for controlled substances written in the state-have emerged as a means to track opioid prescribing and use. While PDMPs are typically used as a tool for physicians to inform their prescribing practices, many states also permit law enforcement to access PDMPs when investigating controlled substance distribution, often without prior judicial approval. Such law enforcement use of PDMPs raises serious questions of patient privacy. The Fourth Amendment protects individuals from unreasonable searches and seizures where they have a reasonable expectation of privacy and has been interpreted to require law enforcement have probable cause and a search warrant before infringing upon an individual's reasonable expectation of privacy. Several courts have held that patients have no reasonable expectation of privacy, or a severely diminished expectation of privacy, in their prescription drug records held in PDMPs. As support, courts rely on the third-party doctrine because the information is disclosed to physicians and then held by the state; the highly regulated nature of the prescription drug industry; and the statutory framework of the Controlled Substances Act. Such analysis disregards patients' expectation of privacy in their personal health information, the confidentiality in the physician-patient relationship, and the resulting patient incentives not to seek care. Therefore, this Article argues that law enforcement must have probable cause and a search warrant to access PDMPs because the exceptions to the Fourth Amendment's probable cause and warrant requirements do not apply.

Fourth Amendment Protections of Health Information After Carpenter v. United States: The Devil's In The Database.

Every day, companies collect health information from customers and analyze it for commercial purposes. This poses a significant threat to privacy, particularly as the Fourth Amendment protection of this deeply personal information is limited. Generally, law enforcement officers do not need probable cause and a warrant to access these private health information databases; only a subpoena is required, and sometimes nothing at all. The Fourth Amendment protections for health information may, however, have changed after the Supreme Court's 2018 decision in Carpenter v. United States, which held that the Fourth Amendment protects people from warrantless searches of historical cell-site location information possessed by their cell phone providers. The Court explained that, because of the nature of historical cell-site location information, individuals retain a reasonable expectation of privacy despite the information being in the possession of a third party. In reaching its holding, the Supreme Court considered the type of data, the uniqueness of cell-site location information, the impact of technological advancement on privacy, the voluntariness of the disclosure, and the property rights associated with the records. Many of these factors could support heightened Fourth Amendment protection for health information. This Article argues that Carpenter v. United States provides additional protections for future searches of health information in private databases.

Variation in hydroclimate sustains tropical forest biomass and promotes functional diversity.

The fate of tropical forests under climate change is unclear as a result, in part, of the uncertainty in projected changes in precipitation and in the ability of vegetation models to capture the effects of drought-induced mortality on aboveground biomass (AGB). We evaluated the ability of a terrestrial biosphere model with demography and hydrodynamics (Ecosystem Demography, ED2-hydro) to simulate AGB and mortality of four tropical tree plant functional types (PFTs) that operate along light- and water-use axes. Model predictions were compared with observations of canopy trees at Barro Colorado Island (BCI), Panama. We then assessed the implications of eight hypothetical precipitation scenarios, including increased annual precipitation, reduced inter-annual variation, El Niño-related droughts and drier wet or dry seasons, on AGB and functional diversity of the model forest. When forced with observed meteorology, ED2-hydro predictions capture multiple BCI benchmarks. ED2-hydro predicts that AGB will be sustained under lower rainfall via shifts in the functional composition of the forest, except under the drier dry-season scenario. These results support the hypothesis that inter-annual variation in mean and seasonal precipitation promotes the coexistence of functionally diverse PFTs because of the relative differences in mortality rates. If the hydroclimate becomes chronically drier or wetter, functional evenness related to drought tolerance may decline.

Ecosystem heterogeneity and diversity mitigate Amazon forest resilience to frequent extreme droughts.

The impact of increases in drought frequency on the Amazon forest's composition, structure and functioning remain uncertain. We used a process- and individual-based ecosystem model (ED2) to quantify the forest's vulnerability to increased drought recurrence. We generated meteorologically realistic, drier-than-observed rainfall scenarios for two Amazon forest sites, Paracou (wetter) and Tapajós (drier), to evaluate the impacts of more frequent droughts on forest biomass, structure and composition. The wet site was insensitive to the tested scenarios, whereas at the dry site biomass declined when average rainfall reduction exceeded 15%, due to high mortality of large-sized evergreen trees. Biomass losses persisted when year-long drought recurrence was shorter than 2-7 yr, depending upon soil texture and leaf phenology. From the site-level scenario results, we developed regionally applicable metrics to quantify the Amazon forest's climatological proximity to rainfall regimes likely to cause biomass loss > 20% in 50 yr according to ED2 predictions. Nearly 25% (1.8 million km2 ) of the Amazon forests could experience frequent droughts and biomass loss if mean annual rainfall or interannual variability changed by 2σ. At least 10% of the high-emission climate projections (CMIP5/RCP8.5 models) predict critically dry regimes over 25% of the Amazon forest area by 2100.

Vegetation demographics in Earth System Models: A review of progress and priorities.

Numerous current efforts seek to improve the representation of ecosystem ecology and vegetation demographic processes within Earth System Models (ESMs). These developments are widely viewed as an important step in developing greater realism in predictions of future ecosystem states and fluxes. Increased realism, however, leads to increased model complexity, with new features raising a suite of ecological questions that require empirical constraints. Here, we review the developments that permit the representation of plant demographics in ESMs, and identify issues raised by these developments that highlight important gaps in ecological understanding. These issues inevitably translate into uncertainty in model projections but also allow models to be applied to new processes and questions concerning the dynamics of real-world ecosystems. We argue that stronger and more innovative connections to data, across the range of scales considered, are required to address these gaps in understanding. The development of first-generation land surface models as a unifying framework for ecophysiological understanding stimulated much research into plant physiological traits and gas exchange. Constraining predictions at ecologically relevant spatial and temporal scales will require a similar investment of effort and intensified inter-disciplinary communication.

The fate of Amazonian ecosystems over the coming century arising from changes in climate, atmospheric CO2, and land use.

There is considerable interest in understanding the fate of the Amazon over the coming century in the face of climate change, rising atmospheric CO2 levels, ongoing land transformation, and changing fire regimes within the region. In this analysis, we explore the fate of Amazonian ecosystems under the combined impact of these four environmental forcings using three terrestrial biosphere models (ED2, IBIS, and JULES) forced by three bias-corrected IPCC AR4 climate projections (PCM1, CCSM3, and HadCM3) under two land-use change scenarios. We assess the relative roles of climate change, CO2 fertilization, land-use change, and fire in driving the projected changes in Amazonian biomass and forest extent. Our results indicate that the impacts of climate change are primarily determined by the direction and severity of projected changes in regional precipitation: under the driest climate projection, climate change alone is predicted to reduce Amazonian forest cover by an average of 14%. However, the models predict that CO2 fertilization will enhance vegetation productivity and alleviate climate-induced increases in plant water stress, and, as a result, sustain high biomass forests, even under the driest climate scenario. Land-use change and climate-driven changes in fire frequency are predicted to cause additional aboveground biomass loss and reductions in forest extent. The relative impact of land use and fire dynamics compared to climate and CO2 impacts varies considerably, depending on both the climate and land-use scenario, and on the terrestrial biosphere model used, highlighting the importance of improved quantitative understanding of all four factors - climate change, CO2 fertilization effects, fire, and land use - to the fate of the Amazon over the coming century.

Impact of deforestation in the Amazon basin on cloud climatology.

Shallow clouds are prone to appear over deforested surfaces whereas deep clouds, much less frequent than shallow clouds, favor forested surfaces. Simultaneous atmospheric soundings at forest and pasture sites during the Rondonian Boundary Layer Experiment (RBLE-3) elucidate the physical mechanisms responsible for the observed correlation between clouds and land cover. We demonstrate that the atmospheric boundary layer over the forested areas is more unstable and characterized by larger values of the convective available potential energy (CAPE) due to greater humidity than that which is found over the deforested area. The shallow convection over the deforested areas is relatively more active than the deep convection over the forested areas. This greater activity results from a stronger lifting mechanism caused by mesoscale circulations driven by deforestation-induced heterogeneities in land cover.