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This cross-sectional study estimates how annual US drug spending would change if prices for prescription drugs were set at the value-based price.

Recent federal drug price control proposals have included mechanisms to benchmark US prices to international prices. These international price referencing (IRP) proposals recommend that the US government develop an index based on prices paid by a group of higher-income countries and restrict US prices to a narrow range of the index. IRP is a policy tool used across the globe to control drug costs, particularly in markets in which health care resources are limited. If IRP is implemented in the United States, where the drug industry derives roughly 50% of global pharmaceutical sales, what impact might it have on innovation and access? In this brief commentary, we explore this question in the context of cell and gene therapies (CGTs) (evolving therapeutics that have high clinical potential as well as uncertainty and risk). Many CGTs are in development, and the world faces a challenge in providing access. Pressure to provide access to patients who would benefit may create greater global concerns about health equity and access. We conclude that an IRP policy in the United States might exacerbate access problems to promising CGTs and impact innovation and population health.

From the establishment of nearly universal health coverage for end stage renal disease in 1972 to 2021, the primary treatment modality has been in-center hemodialysis despite significant advances in home therapies such as peritoneal dialysis and home hemodialysis. There are many theories as to why peritoneal and home hemodialysis lack so far behind in prescriptions with profitability and or a patient’s compliance or support leading the logical explanations. But 2020 was a different year with the surge in COVID-19 cases.

We build an argument directed to agnostics who think there’s a realistic possibility some specific revelatory claim is true (for instance, the Christian, or Judaic, or Islamic claim) and who find that claim more plausible than its theistic competitors. Though such agnostics may have serious reservations about the claim, perhaps not even deeming the chance it’s true to be at least fifty-fifty, we contend that—surprisingly—it’s obligatory for them to assent to the claim if it provides a means for remediation of wrong-doing. Our focus is the Christian revelatory claim, but the argument’s template can be applied to other religions that, like Christianity, promise to fix the world’s ills in an afterlife.

The COVID-19 pandemic made creative problem-solving, a skill that nurses have long possessed, more observable and valued. This article presents a new professional practice model for nursing innovation that facilitates practice improvements and leverages skills, strengths, and values that are integral to nursing. This model integrates the nursing process with Design Thinking and Theory U change management processes. A clinical case study illustrates the model's components in a pediatric oncology ambulatory center. Using this practice model, nurse leaders can leverage "design thinking like a nurse," to enhance innovation in health-care settings.

The American Nurses Association's (ANA) recently published 4th edition of the

Aim: Stakeholder engagement is central to comparative effectiveness research yet there are gaps in definitions of success. We used a framework developed by Lavallee et al. defining effective engagement criteria to evaluate stakeholder engagement during a pragmatic cluster-randomized trial. Methods: Semi-structured interviews were developed from the framework and completed to learn about members' experiences. Interviews were analyzed in a deductive approach for themes related to the effective engagement criteria. Results: Thirteen members participated and described: respect for ideas, time to achieve consensus, access to information and continuous feedback as areas of effective engagement. The primary criticism was lack of diversity. Discussion: Feedback was positive, particularly among themes of respect, trust and competence, and led to development of a list of best practices for engagement. The framework was successful for evaluating engagement. Conclusion: Standardized frameworks allow studies to formally evaluate their stakeholder engagement approach and develop best practices for future research.

Sean D Sullivan,1 Elisabeth Sophia Hartgers-Gubbels,2 Michael Chambers3 1School of Pharmacy, University of Washington, Seattle, WA, USA; 2Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 3MC Healthcare Evaluation, London, UKCorrespondence: Elisabeth Sophia Hartgers-Gubbels, Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany, Email lisa.hartgers-gubbels@boehringer-ingelheim.comAbstract: How does budget impact and affordability in healthcare work? In this episode of the Value Insider podcast, host Mike Chambers speaks with Prof. Sean Sullivan about affordability and budget impact for the “payers” of healthcare interventions. Prof. Sullivan is Dean of the University of Washington School of Pharmacy. He is past president of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and served as chair of the health technology assessment (HTA) committee of US Health Insurer Premera Blue Cross, was part of the US Governmental Medicare coverage evidence committee and led the ISPOR Task Force on Methods for Conducting and Reporting Budget Impact Assessments. Prof. Sullivan explains how budget impact and affordability are intertwined and how this plays a role in decisions in the US, but also the rest of the world.Keywords: market access, healthcare reimbursement, health technology assessment, HTA, value demonstration, health economics and outcomes research, payer

PURPOSE Primary prophylactic colony-stimulating factors (PP-CSFs) are prescribed to reduce febrile neutropenia (FN) but their benefit for intermediate FN risk regimens is uncertain. Within a pragmatic, randomized trial of a standing order entry (SOE) PP-CSF intervention, we conducted a substudy to evaluate the effectiveness of SOE for patients receiving intermediate-risk regimens. METHODS TrACER was a cluster randomized trial where practices were randomized to usual care or a guideline-based SOE intervention. In the primary study, sites were randomized 3:1 to SOE of automated PP-CSF orders for high FN risk regimens and alerts against PP-CSF use for low-risk regimens versus usual care. A secondary 1:1 randomization assigned 24 intervention sites to either SOE to prescribe or an alert to not prescribe PP-CSF for intermediate-risk regimens. Clinicians were allowed to over-ride the SOE. Patients with breast, colorectal, or non–small-cell lung cancer were enrolled. Mixed-effect logistic regression models were used to test differences between randomized sites. RESULTS Between January 2016 and April 2020, 846 eligible patients receiving intermediate-risk regimens were registered to either SOE to prescribe (12 sites: n = 542) or an alert to not prescribe PP-CSF (12 sites: n = 304). Rates of PP-CSF use were higher among sites randomized to SOE (37.1% v 9.9%, odds ratio, 5.91; 95% CI, 1.77 to 19.70; P = .0038). Rates of FN were low and identical between arms (3.7% v 3.7%). CONCLUSION Although implementation of a SOE intervention for PP-CSF significantly increased PP-CSF use among patients receiving first-line intermediate-risk regimens, FN rates were low and did not differ between arms. Although this guideline-informed SOE influenced prescribing, the results suggest that neither SOE nor PP-CSF provides sufficient benefit to justify their use for all patients receiving first-line intermediate-risk regimens.

Atopic dermatitis is a chronic inflammatory skin disease that can negatively impact work productivity and daily activities. Ruxolitinib cream, a Janus kinase inhibitor, demonstrated efficacy and safety in patients with atopic dermatitis in two phase III studies (TRuE-AD1 and TRuE-AD2).This post hoc analysis sought to describe the effects of ruxolitinib cream on work productivity and activity impairment from pooled data from the phase III studies, to estimate indirect costs due to atopic dermatitis, and to estimate the incremental cost savings with ruxolitinib cream versus vehicle cream.Patients in both studies were ≥ 12 years old with atopic dermatitis for ≥ 2 years, an Investigator's Global Assessment score of 2 or 3, and a 3-20% affected body surface area at baseline. Patients were randomized 2:2:1 to receive ruxolitinib cream (0.75% or 1.5%) or vehicle cream for 8 weeks. Patient self-reported productivity in the efficacy-evaluable population was assessed at weeks 2, 4, and 8 using the Work Productivity and Activity Impairment Questionnaire-Specific Health Problem version 2.0. Statistical significance for the two doses versus vehicle was calculated using an analysis of covariance. Work Productivity and Activity Impairment overall work impairment scores were converted to a model of costs per employed patient due to lost productivity and incremental cost savings from ruxolitinib cream treatment using a human capital approach.Of 1249 patients enrolled (median age, 32 years; female sex, 61.7%), 1208 were included in the efficacy-evaluable population. Patients applying 0.75% or 1.5% ruxolitinib cream had significant changes in overall work impairment (- 17.9% [0.75% strength] and - 15.0% [1.5% strength] vs - 5.7% for vehicle; p0.0001 for both) and daily activity impairment (- 20.6% [0.75% strength] and - 21.5% [1.5% strength] vs - 10.6% for vehicle; p0.0001 for both). These corresponded to estimated lost productivity costs in 2021 US dollars of $1313 (0.75% strength) and $1242 (1.5% strength) versus $2008 (vehicle) over the 8-week trial period. Compared with a patient receiving vehicle, incremental annual indirect cost savings were estimated to be $5302 with 0.75% ruxolitinib cream and $4228 with 1.5% ruxolitinib cream.Ruxolitinib cream therapy is associated with improved work productivity and daily activity compared with vehicle and is estimated to reduce the indirect cost burden on the patient.ClinicalTrials.gov identifiers: NCT03745638 (registered 19 November, 2018) and NCT03745651 (registered 19 November, 2018).

Yeast vacuoles are acidified by the v-type H

Environmental contamination is widespread and can negatively impact wildlife health. Some contaminants, including heavy metals, have immunosuppressive effects, but prior studies have rarely measured contamination and disease simultaneously, which limits our understanding of how contaminants and pathogens interact to influence wildlife health. Here, we measured mercury concentrations, influenza infection, influenza antibodies and body condition in 749 individuals from 11 species of wild ducks overwintering in California. We found that the odds of prior influenza infection increased more than fivefold across the observed range of blood mercury concentrations, while accounting for species, age, sex and date. Influenza infection prevalence was also higher in species with higher average mercury concentrations. We detected no relationship between influenza infection and body fat content. This positive relationship between influenza prevalence and mercury concentrations in migratory waterfowl suggests that immunotoxic effects of mercury contamination could promote the spread of avian influenza along migratory flyways, especially if influenza has minimal effects on bird health and mobility. More generally, these results show that the effects of environmental contamination could extend beyond the geographical area of contamination itself by altering the prevalence of infectious diseases in highly mobile hosts.

Pulmonary hypertension (PH) observed during respiratory syncytial virus (RSV) bronchiolitis is associated with morbidity and mortality, especially in children with congenital heart disease. Yet, the pathophysiological mechanisms of RSV-associated PH remain unclear. Therefore, this study aimed to investigate the pathophysiological mechanism of RSV-associated PH. We used a translational mouse model of RSV-associated PH, in which wild-type (WT) and suppression of tumorigenicity 2 (ST2) knockout neonatal mice were infected with RSV at 5 days old and reinfected 4 wk later. The development of PH in WT mice following RSV reinfection was evidenced by elevated right ventricle systolic pressure, shortened pulmonary artery acceleration time (PAT), and decreased PAT/ejection time (ET) ratio. It coincided with the augmentation of periostin and IL-13 expression and increased arginase bioactivity by both arginase 1 and 2 as well as induction of nitric oxide synthase (NOS) uncoupling. Absence of ST2 signaling prevented RSV-reinfected mice from developing PH by suppressing NOS uncoupling. In summary, ST2 signaling was involved in the development of RSV-associated PH. ST2 signaling inhibition may be a novel therapeutic target for RSV-associated PH. NEW & NOTEWORTHY We report that the pathogenic role of ST2-mediated type 2 immunity and mechanisms contribute to RSV-associated pulmonary hypertension. Inhibiting ST2 signaling may be a novel therapeutic target for this condition.

Over the last several years, numerous outcrop localities have been revisited to add quantitative detail to submarine lobe facies models that previously focussed on facies relationships in a qualitative sense. This study utilises well‐exposed submarine lobe deposits of the Point Loma Formation in Cabrillo National Monument (San Diego, CA) to provide quantitative and statistical insights into the lateral variability of event‐bed (i.e. turbidite) architecture within and between lobe elements. Within a lobe element (defined as a surface‐bounded, genetically related package), event beds compensationally stack, thinning over subtle sea floor topography created by the previous event bed. Between lobe elements, larger‐scale compensation is observed, with clearly defined stratal surfaces and facies architecture distinguishing the four lobe elements. A lateral facies transition is observed for one lobe element, where sandstone beds pinch out and the element thickness halves over a distance of 100 m. However, architectural parameters of event beds (e.g. bed thickness, thinning rate, fining rate) are not appreciably different between these elements, suggesting that the observed stratal architecture does not readily translate into vertical bed thickness (i.e. stacking) patterns that could be easily recognised in common subsurface data types like borehole‐derived core. While the data derived from this outcrop study are valuable for improving the construction of realistic geological and reservoir models, caution is necessary when interpreting lobe element boundaries from borehole data. The lobe deposits measured in this study have event‐bed thicknesses and thinning rates most similar to semi‐confined proximal lobes, suggesting a more proximal position and more confined than previously interpreted. Based on the relationships between sandstone and mudstone thicknesses and thinning rates, bed and lobe‐element compensation and minimal evidence of erosion, the Point Loma Formation at Cabrillo National Monument is reinterpreted as a medial lobe environment with some degree of lateral and/or frontal confinement.

Family violence represents a major public health problem and a violation of human rights. Violent families engage in child maltreatment or intimate partner violence in response to horizontal stressors, such as the COVID-19 pandemic, and vertical stressors, including events in the family life cycle and changes in cultural contexts. Although family violence is often considered an individual problem, solutions require close examination of family structure, dynamics, and competence. The Beavers Systems Model for Family Functioning identified family groupings at risk of family violence. An emerging perspective on intergenerational transmission of violence from childhood neglect and abuse to elder abuse accounts for the accumulation of adverse childhood experiences and increasing risk of victimization or perpetration. An intergenerational systemic model identifies multiple contexts and levels for evaluating and treating family violence over the life span. Early identification and intervention facilitate prevention and rehabilitation. As families transcend adversity, they are able to realize post-traumatic growth and resilience. Recommendations for applications of the model are offered.

Objectives The Institute for Clinical and Economic Review (ICER) is an independent organization that reviews drugs and devices with a focus on emerging agents. As part of their evaluation, ICER estimates value-based prices (VBP) at $50 000 to $150 000 per quality-adjusted life-year (QALY) gained thresholds. We compared actual estimated net prices to ICER-estimated VBPs. Methods We reviewed ICER final evidence reports from November 2007 to October 2020. List prices were combined with average discounts obtained from SSR Health to estimate net prices. If a drug had been evaluated more than once for the same indication, only the more recent VBP was included. Results A total of 34 ICER reports provided unique VBPs for 102 drugs. The net price of 81% of drugs exceeded the $100 000 per QALY VBP and 71% exceeded the $150 000 per QALY VBP. The median change in net price needed to reach the $150 000 per QALY VBP was a 36% reduction. The median decrease in net price needed was highest for drugs targeting rare inherited disorders (n = 15; 62%) and lowest for cardiometabolic disorders (n = 6; 162% price increase). The reduction in net prices needed to reach ICER-estimated VBPs was higher for drugs evaluated for the first approved indication, rare diseases, less competitive markets, and if the drug approval occurred before the ICER report became available. Conclusion Net prices are often above VBPs estimated by ICER. Although gaining awareness among decision makers, the long-term impact of ICER evaluations on pricing and access to new drugs continues to evolve.

Evidence from randomized controlled trials (RCTs) has shown that second‐generation basal insulin (BI) analogues, insulin glargine 300 U/mL (Gla‐300) and insulin degludec (IDeg), provide similar glycaemic control, with a lower risk of hypoglycaemia compared with the first‐generation BI analogue insulin glargine 100 U/mL (Gla‐100) in people with type 2 diabetes (T2D). However, the highly selected participants and frequent follow‐up of RCTs may not be truly representative of real‐life clinical practice. It is important to assess the safety and effectiveness of these second‐generation BI analogues in real‐life clinical practice settings. The DELIVER programme utilized electronic healthcare records from the United States to compare clinical outcomes in people with T2D who received either Gla‐300 or other BI analogues in real‐world clinical practice. This review provides a concise overview of the results of the DELIVER studies. Overall, Gla‐300 provided similar antihyperglycaemic effectiveness and a lower risk of hypoglycaemia versus the first‐generation BI analogues Gla‐100 and insulin detemir in people with T2D who had switched BIs. In those who were insulin‐naïve, initiation with Gla‐300 versus Gla‐100 was associated with significantly better antihyperglycaemic effectiveness and similar or lower hypoglycaemic risk. Both glycaemic control and hypoglycaemia risk were also shown to be similar with Gla‐300 and IDeg, in people who had switched BIs and in those who were insulin‐naïve. In addition, the DELIVER 2 study reported that people with T2D who switched to Gla‐300 had reduced healthcare resource utilization, with an overall saving of US$1439 per person per year compared with those who switched to another BI analogue. Overall, the real‐world DELIVER programme showed that the glycaemic control with a low risk of hypoglycaemia observed with Gla‐300 in RCTs was also seen in standard clinical practice.

Particle accelerators use powerful and complex magnetic fields to turn, shape, and eventually collide beams of near-light-speed particles, yet the fundamental magnetic principles behind the accelerator magnets can be understood by undergraduate students. In this paper we use small-scale accelerator magnet analogs in a multi-faceted, low-cost exploration of the magnetic field exterior to accelerator magnets. These fields are best understood using the multipole expansion of the field. If we assume that the magnetic field is created by ideal magnetic dipoles, we can derive a theoretical model that shows that each accelerator magnet configuration is dominated by a single multipole moment and obeys $B \propto 1/r^{l+2}$, where $l$ is the multipole order (with $l = 1, 2, 3, 4$ for the dipole, quadrupole, octopole, and hexadecapole moments, respectively). Using commercially available NdFeB magnets and the magnetic field sensor inside a smartphone, we experimentally verify the power-law dependence of the accelerator magnet configurations. Finally, we use the open-source Python library Magpylib to simulate the magnetic field of the permanent magnet configurations, showing good agreement between theory, experiment, and simulation., 31 pages, 9 figures

Key Points Children with Down syndrome develop early signs of clonal evolution that resemble traditional clonal hematopoiesis. Children with trisomy 21 who exhibit clonal hematopoiesis display cytokine and gene expression profiles indicative of disrupted immunity.

The FINE-CKD model was developed to estimate the cost-effectiveness of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D).To perform internal and external validation by comparing the model estimates with trial results and outcomes from other models.Incidence rates from trials were compared with the model predictions. Statistical tests were then performed to assess whether modeled event rates aligned with trial observations. A cross-validation was also performed using the online version of the SHARP CKD-Cardiovascular Disease (SHARP CKD-CVD) model, with population characteristics from the finerenone trials analyzed. Where no finerenone data were available, the default SHARP CKD-CVD values were used. Comparison of the results considered the ranges from both models.The outcomes of the FINE-CKD model reflect the event rates observed in the trials. Based on the results of the statistical tests, the hypothesis of no difference between observed and modeled events cannot be rejected for any of the outcomes. The results of the FINE-CKD model are within the ranges from the SHARP CKD-CVD model. Disease progressions align across the models; however, incident kidney failure events in the SHARP CKD-CVD model were higher. This can be explained by simulation of more severely affected patients in the SHARP CKD-CVD model.This study demonstrates that the FINE-CKD model adequately reflects the clinical data and provides reliable extrapolation relative to the existing predictive tools while also being conservative in its approach.

Microbial strains have closely related genomes but may have different phenotypes in the same environment. Shotgun metagenomic sequencing can capture the genomes of all strains present in a community but strain-resolved analysis from shotgun sequencing alone remains difficult. We developed an approach to identify and interrogate strain-level differences in groups of metagenomes. We use this approach to perform a meta-analysis of stool microbiomes from individuals with and without inflammatory bowel disease (IBD; Crohn’s disease, ulcerative colitis; n = 605), a disease for which there are not specific microbial biomarkers but some evidence that microbial strain variation may stratify by disease state. We first developed a machine learning classifier based on compressed representations of complete metagenomes (FracMinHash sketches) and identified genomes that correlate with IBD subtype. To rescue variation that may not have been present in the genomes, we then used assembly graph genome queries to recover strain variation for correlated genomes. Lastly, we developed a novel differential abundance framework that works directly on the assembly graph to uncover all sequence variants correlated with IBD. We refer to this approach as dominating set differential abundance analysis and have implemented it in the spacegraphcats software package. Using this approach, we identified five bacterial strains that are associated with Crohn’s disease. Our method captures variation within the entire sequencing data set, allowing for discovery of previously hidden disease associations.

There have been conflicting findings on the degree to which rapidly deployed visual attention is selective for depth, and this issue has important implications for attention models. Previous findings have attempted to find depth-based cueing effects on such attention using reaction time (RT) measures for stimuli presented in stereo goggles with a display screen. Results stemming from such approaches have been mixed, depending on whether target/distractor discrimination was required. To help clarify the existence of such depth effects, we have developed a paradigm that measures accuracy rather than RT in an immersive virtual-reality environment, providing a more appropriate context of depth. Three modified Posner Cueing paradigms were run to test for depth-specific rapid attentional selectivity. Participants fixated a cross while attempting to identify a rapidly masked black letter preceded by a red cue that could be valid in depth, side, or both. In Experiment 1a, a potent cueing effect was found for lateral cueing validity, but a weak effect was found for depth despite an extreme difference in virtual depth (1 vs. 300 m). In Experiment 1b, a near-replication of 1a, the lateral effect replicated while the depth effect did not. Finally, in Experiment 2, to increase the depth cue's effectiveness, the letter matched the cue's color, and the presentation duration was increased; however, again only a minimal depth-based cueing effect - no greater than that of Experiment 1a - was observed. Thus, we conclude that rapidly deployed attention is driven largely by spatiotopic rather than depth-based information.