A long section of serpentinized depleted mantle peridotite.

The upper mantle is critical for our understanding of terrestrial magmatism, crust formation, and element cycling between Earth's solid interior, hydrosphere, atmosphere, and biosphere. Mantle composition and evolution have been primarily inferred by surface sampling and indirect methods. We recovered a long (1268-meter) section of serpentinized abyssal mantle peridotite interleaved with thin gabbroic intrusions. We find depleted compositions with notable variations in mantle mineralogy controlled by melt flow. Dunite zones have predominantly intermediate dips, in contrast to the originally steep mantle fabrics, indicative of oblique melt transport. Extensive hydrothermal fluid-rock interaction is recorded across the full depth of the core and is overprinted by oxidation in the upper 200 meters. Alteration patterns are consistent with vent fluid composition in the nearby Lost City hydrothermal field.

CC chemokine receptor 2 is allosterically modulated by sodium ions and amiloride derivatives through a distinct sodium ion binding site.

CC chemokine receptor 2 and CCL2 are highly involved in cancer growth and metastasis, and immune escape. Raised sodium ion concentrations in solid tumours have also been correlated to metastasis and immune modulation. Sodium ions can modulate class A G protein-coupled receptors through the sodium ion binding site characterized by a highly conserved aspartic acid residue (D2.50), also present in CCR2. Hence, we further explored this binding site in CCR2 by radioligand binding studies and mutagenesis. Modulation of three distinctly binding radioligands by sodium ions and amiloride derivates was investigated. Sodium ions were observed to be relatively weak modulators of antagonist binding, but substantially increased 125I-CCL2 dissociation from CCR2. 6-Substituted Hexamethylene Amiloride (HMA) modulated all tested radioligands. Induced-fit docking of HMA in the presumed sodium ion binding site of CCR2 confirmed its binding site. Finally, investigation of (cancer-associated) mutations in the sodium ion binding site showed a markedly decreased expression compared to wild type. Only two mutants, G123A3.35 and G127K3.39, were able to be bound by [3H]INCB3344 and [3H]CCR2-RA-[R]. Thus, mutagenesis showed that the sodium ion binding site residues, which are distinct from other class A GPCRs and related to chemokine receptor evolution, are crucial for receptor integrity. Moreover, the tested mutations appeared to have no effect on modulation observed by HMA or a minor effect on sodium chloride modulation on the tested radioligands. All in all, these results invite further exploration of the CCR2 sodium ion binding site in (cancer) biology, and potentially as a third druggable binding site.

Visual and Quantitative Analysis of the Trapping Volume in Dielectrophoresis of Nanoparticles.

Nanoparticle manipulation requires careful analysis of the forces at play. Unfortunately, traditional force measurement techniques based on the particle velocity do not provide sufficient resolution, while balancing approaches involving counteracting forces are often cumbersome. Here, we demonstrate that a nanoparticle dielectrophoretic response can be quantitatively studied by a straightforward visual delineation of the dielectrophoretic trapping volume. We reveal this volume by detecting the width of the region depleted of gold nanoparticles by the dielectrophoretic force. Comparison of the measured widths for various nanoparticle sizes with numerical simulations obtained by solving the particle-conservation equation shows excellent agreement, thus providing access to the particle physical properties, such as polarizability and size. These findings can be further extended to investigate various types of nano-objects, including bio- and molecular aggregates, and offer a robust characterization tool that can enhance the control of matter at the nanoscale.

Long-Term Survival in Patients With Advanced Melanoma.

IMPORTANCE: Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival. OBJECTIVE: To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials. DESIGN, SETTING, AND PARTICIPANTS: Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023. EXPOSURES: Patients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti-PD-1), or ipilimumab. MAIN OUTCOMES AND MEASURES: Progression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR). RESULTS: A total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69). CONCLUSIONS AND RELEVANCE: This cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

Inbreeding depression affects the growth of seedlings of an African timber species with a mixed mating reproductive system, Pericopsis elata (Harms) Meeuwen.

Selfing or mating between related individuals can lead to inbreeding depression (ID), which can influence the survival, growth and evolution of populations of tree species. As selective logging involves a decrease in the density of congeneric partners, it could lead to increasing biparental inbreeding or self-fertilization, exposing the population to higher ID. We assessed the influence of inbreeding on the growth of a commercial timber species, Pericopsis elata (Fabaceae), which produced about 54% of self-fertilized seedlings in a natural population of the Congo basin. We followed the survival and growth of 540 plants raised in a plantation along a gradient of plant density (0.07-15.9 plants per m2). Parentage analysis allowed us distinguishing selfed and outcrossed seedlings. The annual growth was higher for outcrossed than selfed plants, on average by 10.8% for diameter and 12.9% for height growth. Based on the difference in above ground biomass between selfed and outcrossed seedlings after 41 months, we estimated the level of ID at δ = 0.33, while a lifetime estimate of ID based on the proportions of selfed plants at seedling and adult stages led to δ = 0.7. The level of ID on growth rate did not change significantly with age but tended to vanish under high competition. Pericopsis elata is a particularly interesting model because inbreeding depression is partial, with about 26% of reproducing adults resulting from selfing, contrary to most tropical tree species where selfed individuals usually die before reaching adulthood. Hence, the risks of ID must be considered in the management and conservation of the species.

Eco-Friendly Fungal Chitosan-Silica Dual-Shell Microcapsules with Tailored Mechanical and Barrier Properties for Potential Consumer Product Applications.

Commercial perfume microcapsules are becoming popular across the globe to fulfill consumers' demands. However, most of microcapsules rely on synthetic polymers and/or animal-sourced ingredients to form the shells. Therefore, replacement of the shell materials is imperative to minimize environmental microplastic pollution, as well as to meeting peoples' needs, religious beliefs, and lifestyles. Herein, we report a methodology to fabricate environmentally benign dual-shell (fungal chitosan-SiO2) microcapsules laden with fragrance oil (hexyl salicylate). Anionically stabilized oil droplets were coated with fungal chitosan via interfacial electrostatic interactions at pH 2, which were then covered by an inorganic coating of SiO2 produced via external alkaline mineralization of sodium silicate. Core-shell microcapsules with a spherical morphology were achieved. Under compression, dual-shell chitosan-SiO2 microcapsules yielded a mean nominal rupture stress of 3.0 ± 0.2 MPa, which was significantly higher than that of single-shell microcapsules (1.7 ± 0.2 MPa). After 20 days in neutral pH water, only ∼2.5% of the oil was released from dual-shell microcapsules, while single-shell microcapsules cumulatively released more than 10%. These findings showed that the additional SiO2 coating significantly enhanced both mechanical and barrier properties of microcapsules, which may be appealing for multiple commercial applications, including cosmetics and detergents.

Gestational CBD shapes insular cortex in adulthood.

Many expectant mothers use CBD to alleviate symptoms like nausea, insomnia, anxiety, and pain, despite limited research on its long-term effects. However, CBD passes through the placenta, affecting fetal development and impacting offspring behavior. We investigated how prenatal CBD exposure affects the insular cortex (IC), a brain region involved in emotional processing and linked to psychiatric disorders. The IC is divided into two territories: the anterior IC (aIC), processing socioemotional signals, and the posterior IC (pIC), specializing in interoception and pain perception. Pyramidal neurons in the aIC and pIC exhibit sex-specific electrophysiological properties, including variations in excitability and the excitatory/inhibitory balance. We investigated IC's cellular properties and synaptic strength in the offspring of both sexes from mice exposed to low-dose CBD during gestation (E5-E18; 3mg/kg, s.c.). Prenatal CBD exposure induced sex-specific and territory-specific changes in the active and passive membrane properties, as well as intrinsic excitability and the excitatory/inhibitory balance, in the IC of adult offspring. The data indicate that in-utero CBD exposure disrupts IC neuronal development, leading to a loss of functional distinction between IC territories. These findings may have significant implications for understanding the effects of CBD on emotional behaviors in offspring.

Sales Revenues for New Therapeutic Agents Approved by the United States Food and Drug Administration From 1995 to 2014.

OBJECTIVES: This study aimed to analyze worldwide sales of new therapeutic agents and to estimate the time it takes for product sales to exceed industry-wide average drug development costs. METHODS: Data obtained from company reports were analyzed to track worldwide sales of new medicines approved by the US Food and Drug Administration from 1995 to 2014. All sales figures were reported in 2019 US dollars. Kaplan-Meier curves were used to evaluate the time it took for discounted product sales to exceed the average costs associated with developing 1 new drug (accounting for the costs of failed trials), using published estimates of these costs. RESULTS: Based on data for 361 of 558 new therapeutic agents approved over the study period (median follow-up 13.2 years), mean sales revenue per product was $15.2 billion through the end of 2019; the median was $6.7 billion. These products jointly generated global sales of $5.5 trillion since approval. Revenues were highly skewed, with the 25 best selling products (7%, 25 of 361) accounting for 38% of this amount ($2.1 trillion of $5.5 trillion). Approximately 47% of products had discounted sales that exceeded the estimated industry-wide average costs of development within 5 years of approval, and 75% within 10 years. After attributing potential production, marketing, and other costs, these numbers dropped to 21% of products within 5 years of approval, and 46% within 10 years. CONCLUSIONS: Sales of new medicines approved from 1995 to 2014 were highly skewed, but many products had net discounted sales that exceeded the industry-wide average costs of development within 10 years of approval. An understanding of how sales revenues accrue in the years after initial approval, alongside data on business costs, can inform discussions about how to incentivize private investment in innovation while ensuring affordable prices for patients and the healthcare system.

Current Challenges in Microcapsule Designs and Microencapsulation Processes: A Review.

Microencapsulation is an advanced methodology for the protection, preservation, and/or delivery of active materials in a wide range of industrial sectors, such as pharmaceuticals, cosmetics, fragrances, paints, coatings, detergents, food products, and agrochemicals. Polymeric materials have been extensively used as microcapsule shells to provide appropriate barrier properties to achieve controlled release of the encapsulated active ingredient. However, significant limitations are associated with such capsules, including undesired leaching and the nonbiodegradable nature of the typically used polymers. In addition, the energy cost of manufacturing microcapsules is an important factor to be considered when designing microcapsule systems and the corresponding production processes. Recent factors linked to UN sustainability goals are modifying how such microencapsulation systems should be designed in pursuit of "ideal" microcapsules that are efficient, safe, cost-effective and environmentally friendly. This review provides an overview of advances in microencapsulation, with emphasis on sustainable microcapsule designs. The key evaluation techniques to assess the biodegradability of microcapsules, in compliance with recently evolving European Union requirements, are also described. Moreover, the most common methodologies for the fabrication of microcapsules are presented within the framework of their energy demand. Recent promising microcapsule designs are also highlighted for their suitability toward meeting current design requirements and stringent regulations, tackling the ongoing challenges, limitations, and opportunities.

Adaptive group behavior of Fragile X mice in unfamiliar environments.

Fragile X Syndrome (FXS) stands out as a prominent cause of inherited intellectual disability and a prevalent disorder closely linked to autism. FXS is characterized by substantial alterations in social behavior, encompassing social withdrawal, avoidance of eye contact, heightened social anxiety, increased arousal levels, language deficits, and challenges in regulating emotions. Conventional behavioral assessments primarily focus on short-term interactions within controlled settings. In this study, we conducted a comprehensive examination of the adaptive group behavior of Fmr1 KO male mice over a three-day period, without introducing experimental interventions or task-based evaluations. The data unveiled intricate behavioral anomalies, with the most significant changes manifesting during the initial adaptation to unfamiliar environments. Notably, certain behaviors exhibited a gradual return to typical patterns over time. This dynamic Fmr1 KO phenotype exhibited heightened activity, featuring increased exploration, amplified social interest, and an unconventional approach to social interactions characterized by a higher frequency of shorter engagements. These findings contribute to the growing understanding of social behavior in individuals with FXS and underscore the significance of comprehending their adaptive responses in various environmental contexts.

Layerwise complexity-matched learning yields an improved model of cortical area V2.

Human ability to recognize complex visual patterns arises through transformations performed by successive areas in the ventral visual cortex. Deep neural networks trained end-to-end for object recognition approach human capabilities, and offer the best descriptions to date of neural responses in the late stages of the hierarchy. But these networks provide a poor account of the early stages, compared to traditional hand-engineered models, or models optimized for coding efficiency or prediction. Moreover, the gradient backpropagation used in end-to-end learning is generally considered to be biologically implausible. Here, we overcome both of these limitations by developing a bottom-up self-supervised training methodology that operates independently on successive layers. Specifically, we maximize feature similarity between pairs of locally-deformed natural image patches, while decorrelating features across patches sampled from other images. Crucially, the deformation amplitudes are adjusted proportionally to receptive field sizes in each layer, thus matching the task complexity to the capacity at each stage of processing. In comparison with architecture-matched versions of previous models, we demonstrate that our layerwise complexity-matched learning (LCL) formulation produces a two-stage model (LCL-V2) that is better aligned with selectivity properties and neural activity in primate area V2. We demonstrate that the complexity-matched learning paradigm is responsible for much of the emergence of the improved biological alignment. Finally, when the two-stage model is used as a fixed front-end for a deep network trained to perform object recognition, the resultant model (LCL-V2Net) is significantly better than standard end-to-end self-supervised, supervised, and adversarially-trained models in terms of generalization to out-of-distribution tasks and alignment with human behavior. Our code and pre-trained checkpoints are available at https://github.com/nikparth/LCL-V2.git.

How does V1 population activity inform perceptual certainty?

Neural population activity in sensory cortex informs our perceptual interpretation of the environment. Oftentimes, this population activity will support multiple alternative interpretations. The larger the spread of probability over different alternatives, the more uncertain the selected perceptual interpretation. We test the hypothesis that the reliability of perceptual interpretations can be revealed through simple transformations of sensory population activity. We recorded V1 population activity in fixating macaques while presenting oriented stimuli under different levels of nuisance variability and signal strength. We developed a decoding procedure to infer from V1 activity the most likely stimulus orientation as well as the certainty of this estimate. Our analysis shows that response magnitude, response dispersion, and variability in response gain all offer useful proxies for orientation certainty. Of these three metrics, the last one has the strongest association with the decoder's uncertainty estimates. These results clarify that the nature of neural population activity in sensory cortex provides downstream circuits with multiple options to assess the reliability of perceptual interpretations.

Adjuvant treatment with anti-PD-1 in acral melanoma: A nationwide study.

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HRadj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM.

Phylogenomics of Brachystegia: Insights into the origin of African miombo woodlands.

PREMISE: Phylogenetic approaches can provide valuable insights on how and when a biome emerged and developed using its structuring species. In this context, Brachystegia Benth, a dominant genus of trees in miombo woodlands, appears as a key witness of the history of the largest woodland and savanna biome of Africa. METHODS: We reconstructed the evolutionary history of the genus using targeted-enrichment sequencing on 60 Brachystegia specimens for a nearly complete species sampling. Phylogenomic inferences used supermatrix (RAxML-NG) and summary-method (ASTRAL-III) approaches. Conflicts between species and gene trees were assessed, and the phylogeny was time-calibrated in BEAST. Introgression between species was explored using Phylonet. RESULTS: The phylogenies were globally congruent regardless of the method used. Most of the species were recovered as monophyletic, unlike previous plastid phylogenetic reconstructions where lineages were shared among geographically close individuals independently of species identity. Still, most of the individual gene trees had low levels of phylogenetic information and, when informative, were mostly in conflict with the reconstructed species trees. These results suggest incomplete lineage sorting and/or reticulate evolution, which was supported by network analyses. The BEAST analysis supported a Pliocene origin for current Brachystegia lineages, with most of the diversification events dated to the Pliocene-Pleistocene. CONCLUSIONS: These results suggest a recent origin of species of the miombo, congruently with their spatial expansion documented from plastid data. Brachystegia species appear to behave potentially as a syngameon, a group of interfertile but still relatively well-delineated species, an aspect that deserves further investigations.

Audit of an in-patient palliative care quality improvement process for patients with pancreatic ductal adenocarcinoma in a South African teaching hospital.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor survival rates. Timeously introduced palliative care (PC) improves the quality of life (QoL) for patients with terminal diseases. In 2020, an in-patient PC-quality improvement (QI) programme was implemented for PDAC patients. This study compared PC outcomes before and after the introduction of the PC-QI programme. METHODS: A focus group identified five critical intervention areas that could improve care. These were in-patient PC referral, pain and symptom control, shared decision-making, interdisciplinary collaborative care, and continuity of care. A hospital record audit of PDAC patients was conducted in pre- and post-implementation cohorts, and the results were compared. RESULTS: A total of 68 (2017 pre-PC-QI) and 39 (2022 post-PC-QI) patient records were audited. Demography, symptom duration, referral delay, and clinical findings were similar in both cohorts. In-patient PC referrals improved significantly from 54.4% in 2017 to 82.1% in 2022 (p = 0.0059). Significant improvements were also recorded in shared decisionmaking, collaboration, and continuity of care, while the reassessment of pain and symptoms after treatment improved. Fewer invasive procedures were done in the 2022 cohort (p = 0.0056). The delay from admission to an invasive diagnostic procedure decreased from a mean of 8.7 to 1.5 days (p = 0.0001). The duration of hospital admission, overall survival (OS), and readmissions during the final 30 days of life were similar. CONCLUSION: The QI programme resulted in improved use of the in-hospital PC service and made better use of scarce resources. Increasing patient and family participation and feedback will further inform the development of the quality of PC services.

Cell- and Pathway-Specific Disruptions in the Accumbens of Fragile X Mouse.

Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism spectrum disorder. The mesocorticolimbic system, which includes the prefrontal cortex (PFC), basolateral amygdala (BLA), and nucleus accumbens core (NAcC), is essential for regulating socioemotional behaviors. We employed optogenetics to compare the functional properties of the BLA→NAcC, PFC→NAcC, and reciprocal PFC↔BLA pathways in Fmr1-/y::Drd1a-tdTomato male mice. In FXS mice, the PFC↔BLA reciprocal pathway was unaffected, while significant synaptic modifications occurred in the BLA/PFC→NAcC pathways. We observed distinct changes in D1 striatal projection neurons (SPNs) and separate modifications in D2 SPNs. In FXS mice, the BLA/PFC→NAcC-D2 SPN pathways demonstrated heightened synaptic strength. Focusing on the BLA→NAcC pathway, linked to autistic symptoms, we found increased AMPAR and NMDAR currents and elevated spine density in D2 SPNs. Conversely, the amplified firing probability of BLA→NAcC-D1 SPNs was not accompanied by increased synaptic strength, AMPAR and NMDAR currents, or spine density. These pathway-specific alterations resulted in an overall enhancement of excitatory-to-spike coupling, a physiologically relevant index of how efficiently excitatory inputs drive neuronal firing, in both BLA→NAcC-D1 and BLA→NAcC-D2 pathways. Finally, the absence of fragile X messenger ribonucleoprotein 1 (FMRP) led to impaired long-term depression specifically in BLA→D1 SPNs. These distinct alterations in synaptic transmission and plasticity within circuits targeting the NAcC highlight the potential role of postsynaptic mechanisms in selected SPNs in the observed circuit-level changes. This research underscores the heightened vulnerability of the NAcC in the context of FMRP deficiency, emphasizing its pivotal role in the pathophysiology of FXS.

Not seeing the forest for the trees: combination of path integration and landmark cues in human virtual navigation.

Introduction: In order to successfully move from place to place, our brain often combines sensory inputs from various sources by dynamically weighting spatial cues according to their reliability and relevance for a given task. Two of the most important cues in navigation are the spatial arrangement of landmarks in the environment, and the continuous path integration of travelled distances and changes in direction. Several studies have shown that Bayesian integration of cues provides a good explanation for navigation in environments dominated by small numbers of easily identifiable landmarks. However, it remains largely unclear how cues are combined in more complex environments. Methods: To investigate how humans process and combine landmarks and path integration in complex environments, we conducted a series of triangle completion experiments in virtual reality, in which we varied the number of landmarks from an open steppe to a dense forest, thus going beyond the spatially simple environments that have been studied in the past. We analysed spatial behaviour at both the population and individual level with linear regression models and developed a computational model, based on maximum likelihood estimation (MLE), to infer the underlying combination of cues. Results: Overall homing performance was optimal in an environment containing three landmarks arranged around the goal location. With more than three landmarks, individual differences between participants in the use of cues are striking. For some, the addition of landmarks does not worsen their performance, whereas for others it seems to impair their use of landmark information. Discussion: It appears that navigation success in complex environments depends on the ability to identify the correct clearing around the goal location, suggesting that some participants may not be able to see the forest for the trees.

Price benchmarks of drugs selected for Medicare price negotiation and their therapeutic alternatives.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) are currently negotiating prices with pharmaceutical manufacturers for the first 10 Part D drugs selected for Medicare drug price negotiation. Non-publicly available data, including the net prices of selected drugs and their therapeutic alternatives, will play a central role in the determination of the maximum fair prices (MFPs). OBJECTIVE: To estimate price benchmarks involved in the derivation of the starting point of the CMS initial price offer for the 10 drugs selected for Medicare price negotiation. METHODS: For the 10 drugs selected for negotiation, we reported (1) the list price, (2) the net price after manufacturer discounts, (3) the maximum negotiated price based on the minimum statutory discount, and (4) the ceiling of the MFP, estimated as the lowest of the latter 2. We also estimated net prices for therapeutic alternatives to the selected drugs. Net prices were estimated using peer-reviewed methodology that isolates commercial discounts negotiated between payers and manufacturers from mandatory discounts under government programs. All price benchmarks were estimated at the product level, for 30-day equivalent dosing, using 2021 data. RESULTS: 6 products (apixaban, rivaroxaban, empagliflozin, sacubitril/valsartan, etanercept, and insulin aspart) had therapeutic alternatives with lower net prices, which will be integrated with clinical benefit data in the derivation of initial price offers. The other 4 products (ustekinumab, ibrutinib, sitagliptin, and dapagliflozin) had therapeutic alternatives with higher net prices than the drugs selected for negotiation. For ibrutinib and ustekinumab, prices based on the minimum discounts were considerably lower than the estimated net prices and will likely set the starting point of the initial price offer. For dapagliflozin and sitagliptin, the starting point of the initial price offer will likely resemble their existing net prices. CONCLUSIONS: Our analyses identify different negotiation scenarios for the first 10 drugs selected for Medicare price negotiation, based on key elements involved in the derivation of the initial price offer. Our analyses can help improve transparency in the negotiation process, because the CMS is not required to reveal the information used in the derivation of price offers.