The Inflation Reduction Act: How Will Medicare Negotiating Drug Prices Impact Patients with Heart Disease?

PURPOSE OF REVIEW: Cardiovascular medications improve health and prevent early death. However, high drug prices reduce the use of these medications and strain the health system. The Inflation Reduction Act (IRA) of 2022 allows Medicare to negotiate drug prices with manufacturers and reduces out-of-pocket drug costs for Medicare beneficiaries. This article explores the potential impact that the IRA will have on the treatment of cardiovascular disease. RECENT FINDINGS: Cardiovascular disease medications are likely to be selected for price negotiations under the IRA, leading to savings for patients and for Medicare. Recent work suggests that the IRA's reforms to the Medicare Part D drug benefit will meaningfully reduce out-of-pocket costs for important cardiovascular medications. The IRA is expected to impact cardiovascular disease treatments via price negotiations and through the broader access to medications afforded by improvements to Part D coverage design.

Rapid Response EEG: Current State and Future Directions.

PURPOSE OF REVIEW: To critically appraise the literature on the application, methods, and advances in emergency electroencephalography (EEG). RECENT FINDINGS: The development of rapid EEG (rEEG) technologies and other reduced montage approaches, along with advances in machine learning over the past decade, has increased the rate and access to EEG acquisition. These achievements have made EEG in the emergency setting a practical diagnostic technique for detecting seizures, suspected nonconvulsive status epilepticus (NCSE), altered mental status, stroke, and in the setting of sedation. Growing evidence supports using EEG to expedite medical decision-making in the setting of suspected acute neurological injury. This review covers approaches to acquiring EEG in the emergency setting in the adult and pediatric populations. We also cover the clinical impact of this data, the time associated with emergency EEG, and the costs of acquiring EEG in these settings. Finally, we discuss the advances in artificial intelligence for rapid electrophysiological interpretation.

Cognitive Tests and Stool Frequency at Hospital Discharge Do Not Predict Outcomes in Hepatic Encephalopathy.

OBJECTIVES: Hepatic encephalopathy (HE) is associated with hospital readmissions and mortality. We sought to determine whether cognitive testing and stool frequency at discharge predicted 30-day readmission or death in cirrhotic patients admitted with overt HE. METHODS: We approached consecutive inpatients with cirrhosis and overt HE when they were within 48 hours of discharge. Patients underwent cognitive tests, including Psychometric Hepatic Encephalopathy Score (PHES), and stool frequency was documented. Chart review identified Model for End-Stage Liver Disease-sodium (MELD-Na) and the presence of non-HE extrahepatic organ failures. Cox proportional hazards models were used to evaluate predictors of time to the primary composite outcome of hospital readmission for HE or death within 30 days, censoring for liver transplantation. RESULTS: Of 51 patients consented and enrolled, 14 patients met the primary composite outcome. In unadjusted Cox models, 4 variables predicted HE readmission or death: MELD-Na (hazard ratio [HR] 1.10 [1.01-1.20], P = 0.03), respiratory failure (HR 4.26 [1.47-12.35], P = 0.008), total number of HE extrahepatic organ failures (HR 1.79 [1.12-2.88], P = 0.02), and score on a PHES subtest, Number Connection Test A (per 30 seconds; HR 1.25 [1.06-1.47], P = 0.01). PHES and 24-hour stool frequency did not predict the primary outcome. When controlling for MELD-Na, respiratory failure predicted the primary outcome (HR 3.67 [1.24-10.86], P = 0.02). CONCLUSION: Cognitive testing and stool frequency at discharge did not predict poor outcomes in patients admitted with HE, while respiratory failure appeared to be a strong predictor.

340B-Where Do We Go From Here?

This Viewpoint summarizes inefficiencies in the 340B program and provides suggestions for equitable reform that will potentially benefit patients.

Should Social Value Obligations be Local or Global?

According to prominent bioethics scholars and international guidelines, researchers and sponsors have obligations to ensure that the products of their research are reasonably available to research participants and their communities. In other words, the claim is that research is unethical unless it has local social value. In this article, we argue that the existing conception of reasonable availability should be replaced with a social value obligation that extends to the global poor (and not just research participants and host communities). To the extent the social value requirement has been understood as geographically constrained to the communities that host research and the countries that can afford the products of research, it has neglected to include the global poor as members of the relevant society. We argue that a new conception of social value obligations is needed for two reasons. First, duties of global beneficence give reason for researchers, sponsors, and institutions to take steps to make their products more widely accessible. Second, public commitments made by many institutions acknowledge and engender responsibilities to make the products of research more accessible to the global poor. Future research is needed to help researchers and sponsors discharge these obligations in ways that unlock their full potential.

Pragmatic Randomized Trials Without Standard Informed Consent?: A National Survey.

BACKGROUND: Significant debate surrounds the issue of whether written consent is necessary for pragmatic randomized, controlled trials (RCTs) with low risk. OBJECTIVE: To assess the U.S. public's views on alternatives to written consent for low-risk pragmatic RCTs. DESIGN: National experimental survey (2 × 2 factorial design) examining support for written consent versus general notification or verbal consent in 2 research scenarios. SETTING: Web-based survey conducted in December 2014. PARTICIPANTS: 2130 U.S. adults sampled from a nationally representative, probability-based online panel (response rate, 64.0%). MEASUREMENTS: Respondent's recommendation to an ethics review board and personal preference as a potential participant on how to obtain consent or notification in the 2 research scenarios. RESULTS: Most respondents in each of the 4 groups (range, 60.3% to 71.5%) recommended written informed consent, and personal preferences were generally in accord with that advice. Most (78.9%) believed that the pragmatic RCTs did not pose additional risks, but 62.5% of these respondents would still recommend written consent. In contrast, a substantial minority in all groups (28.5% to 39.7%) recommended the alternative option (general notification or verbal consent) over written consent. LIMITATION: Framing effects could have affected respondents' attitudes, and nonrespondents may have differed in levels of trust toward research or health care institutions. CONCLUSION: Most of the public favored written informed consent over the most widely advocated alternatives for low-risk pragmatic RCTs; however, a substantial minority favored general notification or verbal consent. PRIMARY FUNDING SOURCE: Time-sharing Experiments for the Social Sciences and Intramural Research Program of the National Institutes of Health Clinical Center.

HIV-1 antibodies and vaccine antigen selectively interact with lipid domains.

The rare, broadly neutralizing antibodies, 4E10 and 2F5, that target the HIV-1 membrane proximal external region also associate with HIV-1 membrane lipids as part of a required first-step in HIV-1 neutralization. HIV-1 virions have high concentration of cholesterol and sphingomyelin, which are able to organize into liquid-ordered domains (i.e., lipid rafts), and could influence the interaction of neutralizing antibodies with epitopes proximal to the membrane. The objective of this research is to understand how these lipid domains contribute to 2F5/4E10 membrane interactions and to antigen presentation in liposomal form of HIV-1 vaccines. To this end we have engineered biomimetic supported lipid bilayers and are able to use atomic force microscopy to visualize membrane domains, antigen clustering, and antibody-membrane interactions. Our results demonstrate that 2F5/4E10 do not interact with highly ordered gel and liquid-ordered domains and exclusively bind to a liquid-disordered lipid phase. This suggests that vaccine liposomes that contain key viral membrane components, such as high cholesterol content, may not be advantageous for 2F5/4E10 vaccine strategies. Rather, vaccine liposomes that primarily contain a liquid-disordered phase may be more likely to elicit production of lipid reactive, 2F5- and 4E10-like antibodies.

Reengineering Biomedical Translational Research with Engineering Ethics.

It is widely accepted that translational research practitioners need to acquire special skills and knowledge that will enable them to anticipate, analyze, and manage a range of ethical issues. While there is a small but growing literature that addresses the ethics of translational research, there is a dearth of scholarship regarding how this might apply to engineers. In this paper we examine engineers as key translators and argue that they are well positioned to ask transformative ethical questions. Asking engineers to both broaden and deepen their consideration of ethics in their work, however, requires a shift in the way ethics is often portrayed and perceived in science and engineering communities. Rather than interpreting ethics as a roadblock to the success of translational research, we suggest that engineers should be encouraged to ask questions about the socio-ethical dimensions of their work. This requires expanding the conceptual framework of engineering beyond its traditional focus on "how" and "what" questions to also include "why" and "who" questions to facilitate the gathering of normative, socially-situated information. Empowering engineers to ask "why" and "who" questions should spur the development of technologies and practices that contribute to improving health outcomes.

The high costs of anticancer therapies in the USA: challenges, opportunities and progress.

The USA spent $99 billion on orally administered and clinician-administered anticancer therapies (excluding supportive care) in 2023 and spending is projected to increase to $180 billion by 2028. This increased spending on anticancer therapies largely reflects the high launch prices of novel therapeutics and increases in the prices of existing products, even in the absence of new evidence of clinical benefit or changes in use. Consequently, high prices have impeded Americans' access to and affordability of necessary anticancer therapies and thus increased their risk of cost-related non-adherence, cancer recurrence and mortality. To address the rising prices and concerns regarding Americans' spending on anticancer therapies, state and federal governments have, over the past decade, enacted legislation that caps out-of-pocket spending, expands subsidies and requires drug price negotiations. In this Perspective, we summarize US policies aimed to lower the costs of anticancer therapies, discuss the implications of such reforms and propose additional solutions needed to reduce costs and increase value.

Risk factors contributing to morbidity associated with feeding tubes placed for esophageal cancer patients undergoing esophagectomy: a single-center retrospective study.

Background: Perioperative nutritional optimization of patients undergoing esophagectomy for cancer is important as this population is prone to malnutrition associated with poor outcomes. Nutritional supplementation has been achieved via enteral nutrition through percutaneous feeding tubes such as gastrostomy (G-tubes) and surgical jejunostomy tubes (J-tubes). While they are often routinely placed for patients undergoing esophagectomy, these are associated with adverse events including infections, dislodgement, increased healthcare visits, among others. The morbidity associated with feeding tubes has not been well characterized. We aim to determine factors associated with adverse outcomes after feeding tube placement to guide appropriate use of feeding tubes in esophageal carcinoma patients. Methods: Patients who underwent esophagectomy for carcinoma and had at least one feeding tube placed from November, 2017 to October, 2021 at a single institution were retrospectively reviewed. Subgroup analyses were performed testing for relevant characteristics. Univariate and multivariate logistic regression analyses were conducted evaluating outcomes of interest. The primary outcome was the overall rate of tube-related complications. Results: A total of 144 patients were included with 212 feeding tubes placed (75 G-tubes; 137 J-tubes). The rate of any adverse event related to feeding tubes was 39%. Of these, 11% were wound infections, 16% required procedural intervention, 11% visited the emergency department (ED), and 2.5% required admission due to feeding tube-related complications. Factors independently associated with adverse events included smoking history [odds ratio (OR), 2.80; 95% confidence interval (CI): 1.34-6.23], being female (OR, 2.98; 95% CI: 1.36-6.72), induction treatment (OR, 2.65; 95% CI: 1.14-6.55), and J-tubes (OR, 2.07; 95% CI: 1.09-4.03). Laparoscopically placed J-tubes were associated with increased unplanned admissions compared to those placed via laparotomy (9.4% vs. 0%, P=0.01). Though not statistically significant, there was a trend toward more complications in those who were high risk for malnutrition [body mass index (BMI) <18 kg/m2, weight loss >10%] and comorbid (Charlson Comorbidity Index 5-6). Conclusions: There is significant morbidity related to feeding tubes. The risk profile of these tubes for individual patients should be carefully weighed against the nutritional benefits prior to placement. Patients should be carefully counselled on the possible adverse events and care requirements.

Impact of race, ethnicity, and social determinants on outcomes following immune checkpoint therapy.

Immune checkpoint blockade (ICB) therapies are one of the greatest advances in the history of cancer care and are now commonly used in the management of many different malignancies. However, much remains unknown about the factors that affect the efficacy and side effect profile of these agents. This review delves into the published literature that evaluates the intricate interplay between race, age, gender, and social determinants in shaping outcomes following ICB across solid tumors and hematologic malignancies. We examine the pivotal phase 2 and 3 trials to evaluate the demographics of participants and outcomes based on these variables, if reported. Most, but not all, trials reported some basic demographic information like age, sex, race, ethnicity, and/or geographic area for enrollment. Clinically relevant biological markers that could affect ICB outcomes such as obesity or markers of social determinants of health were largely not reported. Trials were generally representative for men and women based on expected prevalence for a given malignancy, but often under-represented non-white participants and rarely enrolled patients from the global south. Subgroup analyses were conducted in many ICB trials for solid malignancies, but rarely conducted for hematologic malignancies. These analyses largely showed similar qualitative benefit across subgroups, but adverse events were rarely reported by subgroup. This review adds to our understanding of the populations that these clinical trials have studied and highlight the urgent need to redouble our efforts at increasing the diversity of the population in future ICB trials.

An Updated Review of Management of Resectable Stage III NSCLC in the Era of Neoadjuvant Immunotherapy.

Immune-checkpoint inhibitors (ICIs) have an established role in the treatment of locally advanced and metastatic non-small cell lung cancer (NSCLC). ICIs have now entered the paradigm of early-stage NSCLC. The recent evidence shows that the addition of ICI to neoadjuvant chemotherapy improves the pathological complete response (pCR) rate and survival rate in early-stage resectable NSCLC and is now a standard of care option in this setting. In this regard, stage III NSCLC merits special consideration, as it is heterogenous and requires a multidisciplinary approach to management. As the neoadjuvant approach is being adopted widely, new challenges have emerged and the boundaries for resectability are being re-examined. Consequently, it is ever more important to carefully individualize the treatment strategy for each patient with resectable stage III NSCLC. In this review, we discuss the recent literature in this field with particular focus on evolving definitions of resectability, T4 disease, N2 disease (single and multi-station), and nodal downstaging. We also highlight the controversy around adjuvant treatment in this setting and discuss the selection of patients for adjuvant treatment, options of salvage, and next line treatment in cases of progression on/after neoadjuvant treatment or after R2 resection. We will conclude with a brief discussion of predictive biomarkers, predictive models, ongoing studies, and directions for future research in this space.

The relationship between the collagen score at the anastomotic site of esophageal squamous cell carcinoma and anastomotic leakage.

Background: Anastomotic leakage (AL) has always been one of the most serious complications of esophagectomy with gastric conduit reconstruction. There are many strong risk factors for AL in clinical practice. Notably, the tension at the esophagogastric anastomosis and the blood supply to the gastric conduit directly affect the integrity of the anastomosis. However, there has been a lack of quantitative research on the tension and blood supply of the gastric conduit. Changes in extracellular matrix collagen reflect tension and blood supply, which affect the quality of the anastomosis. This study aimed to establish a quantitative collagen score to describe changes in the collagen structure in the extracellular matrix and to identify patients at high risk of postoperative AL. Methods: A retrospective study of 213 patients was conducted. Clinical and pathological data were collected at baseline. Optical imaging of the "donut" specimen at the anastomotic gastric end and collagen feature extraction were performed. Least absolute shrinkage and selection operator (LASSO) regression models were used to select the significant collagen features, compute collagen scores, and validate the predictive efficacy of the collagen scores for ALs. Results: LASSO regression analysis revealed three collagen-related parameters in the gastric donuts: histogram mean, histogram variance, and histogram energy. Based on this analysis, we established a formula to calculate the collagen score. The results of the univariate analysis revealed significant differences in the preoperative low albumin values (P=0.002) and collagen scores between the AL and non-AL groups (P=0.001), while the results of the multivariate analysis revealed significant differences in the collagen scores between the AL and non-AL groups (P=0.002). The areas under the curve (AUCs) of the experimental and validation cohorts were 0.978 [95% confidence interval (CI): 0.931-0.996] and 0.900 (95% CI: 0.824-0.951), respectively. Conclusions: The collagen score established herein was shown to be related to AL and can be used to predict AL in patients who underwent esophagectomy.

What is the predictive value of RECIST criteria following stereotactic lung radiation?

PURPOSE: Response EvaluationCriteriain Solid Tumors (RECIST) is commonly used to assess response to anti-cancer therapies. However, its application after lung stereotactic ablative radiotherapy (SABR) is complicated by radiation-induced lung changes. This study assesses the frequency of progressive disease (PD) by RECIST following lung SABR and correlates this with actual treatment outcomes as determined by longitudinal follow-up. METHODS AND MATERIALS: We reviewed patients treated with lung SABR for primary lung tumors or oligometastases between 2010 and 2015. Patients were treated with SABR doses of 54-60 Gy in 3-8 fractions. All follow-up scans were assessed and the treated lesion was serially measured over time, with the maximum diameter on axial CT slices used for RECIST calculations. Lesions demonstrating PD by RECIST criteria were identified and subsequently followed for long-term outcomes. The final 'gold-standard' assessment of response was based on size changes after PD and, as available, positron emission tomography scan and/or biopsy. RESULTS: Eighty-eight lesions met inclusion criteria. Seventy-five were lung primaries and thirteen were lung metastases. Median follow-up was 52 months (interquartile range: 33-68). Two-thirds (66 %, 58/88) of treated lesions met RECIST criteria for PD; however, local recurrence was only confirmed in 16 % (9/58) of cases. Most lesions that triggered PD by RECIST (47/58, 81 %) were ultimately found not to represent recurrence, while a minority (2/58, 3 %) had an uncertain response. The positive predictive value [PPV] of a RECIST defined PD event was 0.16. If PD was triggered within 12-months post-treatment, PPV was 0.08, compared to 0.21 for lesions triggering PD after 12-months. CONCLUSION: Using RECIST criteria, two-thirds of patients treated with lung SABR met criteria for PD. However, only a minority had recurrence, leading to a poor PPV of RECIST. This highlights the limitations of RECIST in this setting and provides context for physicians when interpreting post-lung SABR imaging.

Model cell membranes: Techniques to form complex biomimetic supported lipid bilayers via vesicle fusion.

Vesicle fusion has long provided an easy and reliable method to form supported lipid bilayers (SLBs) from simple, zwitterionic vesicles on siliceous substrates. However, for complex compositions, such as vesicles with high cholesterol content and multiple lipid types, the energy barrier for the vesicle-to-bilayer transition is increased or the required vesicle-vesicle and vesicle-substrate interactions are insufficient for vesicle fusion. Thus, for vesicle compositions that more accurately mimic native membranes, vesicle fusion often fails to form SLBs. In this paper, we review three approaches to overcome these barriers to form complex, biomimetic SLBs via vesicle fusion: (i) optimization of experimental conditions (e.g., temperature, buffer ionic strength, osmotic stress, cation valency, and buffer pH), (ii) α-helical (AH) peptide-induced vesicle fusion, and (iii) bilayer edge-induced vesicle fusion. AH peptide-induced vesicle fusion can form complex SLBs on multiple substrate types without the use of additional equipment. Bilayer edge-induced vesicle fusion uses microfluidics to form SLBs from vesicles with complex composition, including vesicles derived from native cell membranes. Collectively, this review introduces vesicle fusion techniques that can be generalized for many biomimetic vesicle compositions and many substrate types, and thus will aid efforts to reliably create complex SLB platforms on a range of substrates.

SOHO State of the Art Updates and Next Questions | Immunotherapeutic Options for Patients With Mantle Cell Lymphoma Who Progress on BTK Inhibitors.

Mantle cell lymphoma is a challenging subtype of B-cell non-Hodgkin lymphoma treat characterized by its aggressive nature and propensity for relapse or refractory (R/R) disease for many patients. The introduction of Bruton's tyrosine kinase inhibitors has significantly improved the outcomes for patients with R/R MCL, but a considerable proportion of patients eventually experience disease progression or develop resistance to these agents. In recent years, immunotherapeutic approaches have emerged as promising treatment options. The treatment landscape is quickly progressing with the FDA approval of CAR-T cell therapy as well as several promising bispecific antibody therapies and antibody-drug conjugates in clinical development. This review article aims to provide a comprehensive overview of the current state of immunotherapeutic options available for patients with R/R MCL.

Preoperative mediastinal staging in early-stage lung cancer: Targeted nodal sampling is not inferior to systematic nodal sampling.

OBJECTIVE: To determine whether targeted sampling (TS), which omits biopsy of triple- normal lymph nodes (LNs) on positron emission tomography, computed tomography, and endobronchial ultrasound (EBUS), is noninferior to systematic sampling (SS) of mediastinal LNs during EBUS for staging of patients with early-stage non-small cell lung cancer (NSCLC). METHODS: Patients who are clinical nodal (cN)0-N1 with suspected NSCLC eligible for EBUS based on positron emission tomography/computed tomography were enrolled in this prospective, multicenter trial. During EBUS, all patients underwent TS and then crossed over to SS, whereby at least 3 mediastinal LN stations (4R, 4L, 7) were routinely sampled. Gold standard of comparison was pathologic results. Based on the previous feasibility trial, a noninferiority margin of 6% was established for difference in missed nodal metastasis (MNM) incidence between TS and SS. The McNemar test on paired proportions was used to determine MNM incidence for each sampling method. Analysis was per-protocol using a level of significance of P < .05. RESULTS: Between November 2020 and April 2022, 91 patients were enrolled at 6 high-volume Canadian tertiary care centers. A total of 256 LNs underwent TS and SS. Incidence of MNM was 0.78% in SS and 2.34% in TS, with an absolute difference of 1.56% (95% confidence interval, -0.003% to 4.1%; P = .13). This falls within the noninferiority margin. A total of 6/256 LNs from 4 patients who were not sampled by TS were found to be malignant when sampled by SS. CONCLUSIONS: In high-volume thoracic endosonography centers, TS is not inferior to SS in nodal staging of early-stage NSCLC. This results in change of clinical management for a minority of patients.

Maintenance therapy for AML after allogeneic HCT.

Allogeneic hematopoietic cell transplant (allo-HCT) for eligible patients with acute myeloid leukemia (AML) in first complete remission is a central treatment paradigm to achieve durable remission. However, disease relapse after allo-HCT remains a significant concern and generally portends a poor prognosis. There is significant interest regarding the role for maintenance therapy after allo-HCT for patients with high risk of relapse, regardless of the presence of measurable residual disease. While there are currently no therapies approved for maintenance therapy for AML after allo-HCT, there are a number of ongoing investigations examining the role of maintenance therapies that include targeted agents against FLT3-ITD or IDH mutations, hypomethylating agents, immunomodulatory therapies and cellular therapies. In this review, we examine the current landscape and future strategies for maintenance therapy for AML after allo-HCT.