Patient-Level Savings on Generic Drugs Through the Mark Cuban Cost Plus Drug Company.

This economic evaluation estimates the out-of-pocket cost savings patients could achieve if generic drugs were purchased directly from the Mark Cuban Cost Plus Drug Company rather than using their health insurance.

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

Implementation and Outcomes of Multidisciplinary Diabetes Management Program Among Type 2 Diabetic Patients: A Comparative Study.

BACKGROUND: Current guidelines recommend shifting physician-led care (PLC) for type 2 diabetes mellitus (T2DM) to more effective multidisciplinary health care (MHC). However, few researchers have studied its real-life implementation in Saudi Arabia. Therefore, we aimed to assess the implementation and compare the outcomes of an MDC diabetes management program (DMP) among T2DM patients to a PLC at a general hospital after one year of follow-up in a real-world practice setting. METHODS: We conducted this comparative patient files review study by analyzing medical records of all T2DM patients at two private care centers. Both were compared for their effectiveness in achieving two outcomes: the glycated hemoglobin (HbA1c) <7% and low-density lipoprotein-cholesterol (LDL-c) <70 mg/dl at the end of the first year. Additionally, we assessed the implementation of the DMP. RESULTS: Eight hundred thirty-four medical records were reviewed, 537 from DMP, and 279 from the PLC center. The personal health coordination was almost complete (97.8%) in the DMP, but the implementation was incomplete regarding nutrition (65.7%), dental exam (64.8%), and foot care (58.3%). Both care groups were matched for age (p = 0.056), gender (p = 0.085), duration of diabetes (p = 0.217), and basal glycemic control (p = 0.171). The DMP showed a significant net decrease in HbA1c (-0.5 [IQR 1.47%] vs -0.2 [IQR 3.05%], p = 0.0001) and LDL-c (-10 [IQR 50] vs -5 [IQR 60.5] mg/dl, p = 0.004) compared to PLC. A higher percentage of patients achieved glycemic control in the DMP than in the PLC (49.4% vs 38.7%, p = 0.038). However, both programs demonstrated similar outcomes in lipid control (28.7% vs. 30%, p = 0.695). CONCLUSION: Despite some gaps in implementation, one year of DMP showed better glycemic control among T2DM patients compared to PLC. Both programs were comparable in terms of lipid control. Further studies identifying the gaps in care implementation could improve sustainability, future replication, and generalizability of similar programs to other healthcare systems in Saudi Arabia.

Sensing of Gunshot Residue components from real sample using Fluorescence Resonance Energy Transfer.

The present work represents a Fluorescence Resonance Energy Transfer (FRET) based sensing method for detecting Gunshot Residue (GSR) components. Two laser dyes Acf and RhB have been used as donor and acceptor respectively in the FRET pair. The real sample was collected after test firing in a forensic science laboratory. On the other hand, a standard GSR solution has been prepared in the laboratory. For the preparation of standard GSR solutions, we used the water solutions of the salts BaCl2, SbCl3, and Pb(NO3)2. The FRET efficiency was measured between Acf and RhB to sense the presence of GSR components (Pb+2, Ba+2, and Sb+3) in both real sample and standard solution by mixing the salts in aqueous solution. It has been observed that the FRET efficiency systematically decreases in the presence of GSR components. To amplify the FRET efficiency of the dye pair, inorganic clay dispersion (laponite) was used. The enhancement in FRET efficiency represents a better sensitivity of the proposed sensor. The current sensor is useful for the quantification of concentrations of the GSR components in a real sample.

Mass online training of health care workers during COVID-19: approach, impact, and outcomes for over 10,000 health care providers.

OBJECTIVES: COVID-19 revealed major shortfalls in healthcare workers (HCWs) trained in acute and critical care worldwide, especially in low-resource settings. We aimed to assess mass online courses' efficacy in preparing HCWs to manage COVID-19 patients and to determine whether rapidly deployed e-learning can enhance their knowledge and confidence during a pandemic. STUDY DESIGN: Retrospective cohort study. METHODS: This international retrospective cohort study, led by a large Academic Medical Centre (AMC), was conducted via YouTube and the AMC's online learning platform. From 2020 to 2021, multidisciplinary experts developed and deployed six online training courses based on the latest evidence-based management guidelines. Participants were selected through a voluntary sample following an electronic campaign. Training outcomes were assessed using pre-and post-test questionnaires, evaluation forms, and post-training assessment surveys. Kirkpatrick's Model guided training evaluation to measure self-reported knowledge, clinical skills, and confidence improvement. We also captured the number and type of COVID-19 patients managed by HCWs after the trainings. RESULTS: Every 22.8 reach/impression and every 1.2 engagements led to a course registration. The 10,425 registrants (56.8% female, 43.1% male) represented 584 medical facilities across 154 cities. The largest segments of participants were students/interns (20.6%) and medical officers (13.4%). Of the 2169 registered participants in courses with tests, 66.9% completed post-tests. Test scores from all courses increased from the initial baseline to subsequent improvement post-course. Participants completing post-training assessment surveys reported that the online courses improved their knowledge and clinical skills (83.5%) and confidence (89.4%). Respondents managed over 19,720 COVID-19 patients after attending the courses, with 47.7% patients being moderately/severely ill. CONCLUSIONS: Participants' confidence in handling COVID-19 patients is increased by rapidly deploying mass training to a substantial target population through digital tools. The findings present a virtual education and assessment model that can be leveraged for future global public health issues, and estimates for future electronic campaigns to target.

Nurses' attitudes, behaviours, and enablers of intravenous to oral switching (IVOS) of antibiotics: a mixed-methods survey of nursing staff in secondary care hospitals across the Midlands region of England.

BACKGROUND: Intravenous (IV) antibiotic use in secondary care in England is widespread. Timely appropriate intravenous to oral switch (IVOS) has the potential to deliver significant clinical and operational benefits. To date, antimicrobial stewardship (AMS) efforts around IVOS have not focused on the nursing staff who administer antibiotics, which represents a significant gap in AMS programmes. AIM: To determine the involvement of bedside nurses in acute trusts in the Midlands region of England in IVOS in their organizations and describe their views regarding how to improve IVOS. METHODS: An anonymous self-administered mixed-methods online survey was developed and distributed to nursing staff in acute trusts via antimicrobial stewardship networks between March and May 2023. Quantitative data was analysed to describe participant demographics and behaviours, whereas barriers and enablers to IVOS were explored through thematic content analysis of responses to open-ended questions. FINDINGS: A total of 545 nursing staff responded to the survey. The majority (65.3%) routinely suggested IVOS to clinicians, despite only 50.6% being aware of local IVOS policies. One-third (34.7%) did not suggest IVOS, relying on doctors, believing their patients needed IV treatment, or lacked knowledge and skills to request IVOS. Content analysis of suggestions for improving the rate of IVOS proposed three major themes (People, Process, System) and identified that education and training, improved confidence and interprofessional relationships, and prompts were important drivers. CONCLUSION: Nursing staff suggest IVOS to other clinicians, but more education and resources are needed to enable and empower them in this role.

Modified Tilt-integral active disturbance rejection controller with inertia emulated direct current link for frequency control of marine microgrid.

The increasing integration of intermittent renewable sources (RSs) poses a dynamic frequency stability challenge for modern marine vessel microgrids. To address this issue, this paper proposes a novel control approach, specifically targeting frequency and tie-line power stabilization in a diverse source marine microgrid (MµG) with two intertied areas featuring renewable (wind-wave) sources. The suggested approach introduces a modified tilt-integral active disturbance rejection (TI-ADRC) controller designed to ensure effective damping of power frequency oscillations. As the control scheme depends on the optimal setting of the proposed controller, a recently developed marine predator technique (MPT) has been adopted. The performance of the proposed controller is compared with other recent controllers viz. PID, tilt-integral derivative (TID), two-degree-of-freedom (2DOF)-PID, fuzzy-PI, and ADRC to validate its superiority. To further enhance the system dynamics, a precise modeling of inertia emulated direct current (IEPDC) tie link is incorporated in microgrid system. The impact assessments, considering time delays with pre/post IEPDC link, demonstrate a substantial 57.79% and 81.53% reduction in peak frequency overshoot compared to DC link (conventional model) and AC link, respectively. The analysis of the eigen plot confirms the stability of the control system. Sensitivity assessments of the controller against ± 30% parametric variations and load fluctuations are conducted, affirming its robustness. Finally, the result from OPAL-RT confirm the practicality of the proposed method. It is asserted that the suggested controller is reliable and functions well in n the presence of diverse disruptions and parametric variations.

MIF/NR3C2 Axis Regulates Glucose Metabolism Reprogramming in Pancreatic Cancer through MAPK-ERK and AP-1 Pathways.

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth and progression in PDAC. MIF positively correlates with the HK1 (hexokinase 1), HK2 (hexokinase 2), and LDHA (lactate dehydrogenase) expression and increased pyruvate and lactate production in PDAC patients. Additionally, MIF augments glucose uptake and lactate efflux by upregulating HK1, HK2 and LDHA expression in pancreatic cancer cells in vitro and in mouse models of PDAC. Conversely, a reduction in HK1, HK2, LDHA expression is observed in tumors with high NR3C2 expression in PDAC patients. NR3C2 suppresses HK1, HK2, and LDHA expression, thereby inhibiting glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves the activation of MAPK-ERK signaling pathway, whereas NR3C2 interacts with the activator protein 1 (AP-1) to regulate glycolysis. Our findings reveal an interactive role of the MIF/NR3C2 axis in regulating glucose metabolism supporting tumor growth and progression and may be a potential target for designing novel approaches for improving disease outcome.

Investigation of TiO2 Nanoparticles Influence on Tensile Properties and Thermal Stability of Dry and Wet Luffa-Epoxy Nanocomposites.

BACKGROUND: Recently, progress has been made toward understanding the efficiency of polymer composites with natural fibres. With the hope of enhancing the characteristics of polymer composites supplemented with natural fibres in a watery environment, TiO2 nanoparticles have been used to improve their performance in the field. METHOD: These nanoparticles were filled in luffa-epoxy components at 1, 3, and 5 % volume fractions. A combination of x-ray diffraction and Fourier transform infrared spectroscopy was utilized to conduct the structural examinations. The nanoparticle spread was captured by field emission scanning electron microscopy. RESULT: Results show that dry nanocomposite's tensile strength and modulus have increased by 74% and, 13%, 137%, and 50% compared with epoxy and 40 vol% luffa-epoxy [E/L] composites, respectively. In wet nanocomposites, maximum reduction in tensile strength and modulus were observed as 27.4% and 16.54%, respectively. The diminished water absorption and thickness swelling percentage of nanocomposites were recorded as 98% and 91.8%, respectively. The onset temperature of these nanocomposites was scattered in the range of 379-393°C, with a maximum char residue of 38%. CONCLUSION: The increase in the percentage of residue indicates the effectiveness of epoxy's flame retardant, improved thermal stability, diminished water absorption [approximately 2%], and 95% retention of wet composites' tensile properties. These results provided data support for improving the application of nanocomposites in the automobile field.

Changes in Use of Hepatitis C Direct-Acting Antivirals After Access Restrictions Were Eased by State Medicaid Programs.

Importance: Direct-acting antivirals (DAAs) are safe and highly effective for curing hepatitis C virus (HCV) infection, but their high cost led certain state Medicaid programs to impose coverage restrictions. Since 2015, many of these restrictions have been lifted voluntarily in response to advocacy or because of litigation. Objective: To estimate how the prescribing of DAAs to Medicaid patients changed after states eased access restrictions. Design, Setting, and Participants: This modified difference-in-differences analysis of 39 state Medicaid programs included Medicaid beneficiaries who were prescribed a DAA from January 1, 2015, to December 31, 2019. DAA coverage restrictions were measured based on a series of cross-sectional assessments performed from 2014 through 2022 by the US National Viral Hepatitis Roundtable and the Center for Health Law and Policy Innovation. Exposure: Calendar quarter when states eased or eliminated 3 types of DAA coverage restrictions: limiting treatment to patients with severe liver disease, restricting use among patients with active substance use, and requiring prescriptions to be written by or in consultation with specialists. States with none of these restrictions at baseline were excluded. Main Outcomes and Measures: Quarterly number of HCV DAA treatment courses per 100 000 Medicaid beneficiaries. Results: Of 39 states, 7 (18%) eliminated coverage restrictions, 25 (64%) eased restrictions, and 7 (18%) maintained the same restrictions from 2015 to 2019. During this period, the average quarterly use of DAAs increased from 669 to 3601 treatment courses per 100 000 Medicaid beneficiaries. After states eased or eliminated restrictions, the use of DAAs increased by 966 (95% CI, 409-1523) treatment courses per 100 000 Medicaid beneficiaries each quarter compared with states that did not ease or eliminate restrictions. Conclusions and Relevance: The results of this study suggest that there was greater use of DAAs after states relaxed coverage restrictions related to liver disease severity, sobriety, or prescriber specialty. Further reductions or elimination of these rules may improve access to a highly effective public health intervention for patients with HCV.

ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-Methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.

Availability and Cost of Expensive and Common Generic Prescription Drugs: A Cross-sectional Analysis of Direct-to-Consumer Pharmacies.

BACKGROUND: Direct-to-consumer (DTC) pharmacies sell generic prescription drugs, often at lower prices than traditional retail pharmacies; however, not all drugs are available, and prices vary. OBJECTIVE: To determine the availability and cost of generic drugs at DTC pharmacies. DESIGN: Cross-sectional study. SETTING: Five national DTC pharmacies in April and May 2023. PARTICIPANTS: Each qualifying form of 100 generic drugs with the highest cost-per-patient (expensive) and the 50 generic drugs with the highest number of patients (common) in Medicare Part D in 2020 MAIN MEASURES: Availability of these drugs and the lowest DTC pharmacy price for a standardized drug strength and supply (e.g., 30 pills), compared to GoodRx retail pharmacy prices. KEY RESULTS: Of the 118 expensive generic dosage forms, 94 (80%) were available at 1 or more DTC pharmacies; out of 52 common generic dosage forms, 51 (98%) were available (p < 0.001). Of the 88 expensive generics available in comparable quantities and strengths across pharmacies, 42 (47%) had the lowest cost at Amazon, 23 (26%) at Mark Cuban Cost Plus Drug Company, 13 (14%) at Health Warehouse, and 12 (13%) at Costco; for 51 common generic formulations, 16 (31%) had the lowest cost at Costco, 14 (27%) at Amazon, 10 (20%) at Walmart, 6 (12%) at Health Warehouse, and 5 (10%) at Mark Cuban Cost Plus Drug Company. For the 77 expensive generics with available GoodRx retail pharmacy prices, the median cost savings at DTC pharmacies were $231 (95% CI, $129-$792) or 76% (IQR, 53-91%); for 51 common generics, savings were $19 (95% CI, $10-$34) or 75% (IQR, 67-83%). CONCLUSIONS: Many of the most expensive generic drugs are unavailable at direct-to-consumer pharmacies. Meanwhile, less expensive, commonly used generics are widely available, but drug prices vary by pharmacy and savings are modest, requiring patients to shop around for the lowest cost.

LMO3 is a suppressor of the basal-like/squamous subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism.

Pancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptome and metabolome analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype and decreased survival among PDAC patients. In vitro experiments demonstrated that LMO3 transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptome and metabolome characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.

A Rare Case of Traumatic Colonic Intramural Hematoma in Saudi Arabia.

Colonic intramural hematomas are rarely encountered clinically. They are most commonly caused by blunt trauma to the abdomen. Diagnosis is usually reached by a combination of a detailed history, physical examination, and radiological investigations. A 14-year-old female patient presented to the emergency department complaining of abdominal pain with a history of a go-karting accident. Upon physical examination, the patient was tachycardic and hypertensive, with right-side abdominal tenderness and fullness. After going through routine radiological investigations, a computed tomography scan showed a large intramural hematoma of the ascending colon measuring around 7.7 x 8.4 x 2 cm. The patient was admitted for conservative management. Throughout her admission, serial examinations were performed, which showed improvement in the patient's condition and the size of the hematoma. The patient was discharged in a stable condition after showing good recovery. Following up with the patient a month later, she was in good condition with no active complaints, and an ultrasound was done that revealed complete resolution. To our understanding, this report of colonic intramural hematoma caused by the unusual etiology of the go-karting accident, which was successfully managed conservatively, adds significantly to the literature.

Dairy farmers' knowledge, awareness and practices regarding bovine lameness in Malaysian dairy farms.

Given the data paucity on dairy farmers' perspectives regarding bovine lameness and hoof diseases, particularly in South East Asian countries, this study was conducted to assess the knowledge, attitude and practices toward lameness and hoof health among dairy cattle farmers in Malaysia. An online-based and face-to-face survey was conducted among 114 dairy farmers from four states in Peninsular Malaysia. Data were analysed using descriptive statistics, principal component analysis and an independent sample t-test. Overall, farmers demonstrated satisfactory knowledge and attitude regarding lameness and its impact on dairy cattle welfare and production. Lameness was ranked the second most important health issue in dairy farms after mastitis. Notably, 90% reported the presence of at least one lame cow on their farms, and 55% stated lameness as the reason for culling their cows. While sole ulcer was the hoof lesion mostly identified by farmers, 75% of them underestimated lameness prevalence on their farms and rarely implemented management strategies such as preventive hoof trimming and footbath. Farmers' educational qualification influenced their understanding of the impact of lameness on dairy cattle production. Despite reflecting satisfactory knowledge and attitude towards lameness in dairy cows, farmers in this study need to improve their current management practices to address lameness problem in their herds. Educating farmers on the importance of early detection and prompt treatment, and preventive measures are crucial for lameness control and improving hoof health in these dairy farms.

Retraction: Epiploic Appendagitis Clinically Masquerading as an Acute Diverticulitis.

[This retracts the article DOI: 10.7759/cureus.20188.].

Association between changes in prices and out-of-pocket costs for brand-name clinician-administered drugs.

OBJECTIVE: To determine whether annual changes in prices for clinician-administered drugs are associated with changes in patient out-of-pocket costs. DATA SOURCES AND STUDY SETTING: National commercial claims database, 2009 to 2018. STUDY DESIGN: In a serial, cross-sectional study, we calculated the annual percent change in manufacturer list prices and net prices after rebates. We used two-part generalized linear models to assess the relationship between annual changes in price with (1) the percentage of individuals incurring any out-of-pocket costs and (2) the percent change in median non-zero out-of-pocket costs. DATA COLLECTION/EXTRACTION METHODS: We created annual cohorts of privately insured individuals who used one of 52 brand-name clinician-administered drugs. PRINCIPAL FINDINGS: List prices increased 4.4%/yr (interquartile range [IQR], 1.1% to 6.0%) and net prices 3.3%/yr (IQR, 0.3% to 5.5%). The median percentage of patients with any out-of-pocket costs increased from 38% in 2009 to 48% in 2018, and median non-zero annual out-of-pocket costs increased by 9.6%/yr (IQR, 4.1% to 15.4%). There was no association between changes in prices and out-of-pocket costs for individual drugs. CONCLUSIONS: From 2009 to 2018, prices and out-of-pocket costs for brand-name clinician-administered drugs increased, but these were not directly related for individual drugs. This may be due to changes to insurance benefit design and private insurer drug reimbursement rates.

Identifying therapeutic alternatives in Medicare drug price negotiation: The case of etanercept.

As the Centers for Medicare & Medicaid Services (CMS) navigates the process of negotiating drug prices, it plans to compare the cost, safety, and effectiveness of each drug with its therapeutic alternatives. How CMS selects therapeutic alternatives is a consequential decision, and there remains uncertainty about their methodology. To understand the challenges CMS will face in selecting therapeutic alternatives, we developed a methodology that leverages clinical guidelines by US medical professional associations to identify potential therapeutic alternatives for etanercept, one of the first 10 drugs selected for Medicare price negotiation. For each of etanercept's 5 US Food and Drug Administration-approved indications, we identified all drugs with the same mechanism of action as etanercept and considered drugs with different mechanisms if they were recommended in place of etanercept at the same treatment stage, or if there was no strong comparative safety or effectiveness evidence that the drug differed from etanercept. We identified 22 potential therapeutic alternatives to etanercept, including 4 drugs with the same mechanism, 10 biologics with different mechanisms, and 8 small-molecule drugs. We faced several challenges in selecting therapeutic alternatives using clinical guidelines, such as how to reconcile strong recommendations that were based on weak evidence and how to consider combination therapies. This exercise demonstrates the complex considerations that CMS will face as it negotiates drug prices based on therapies' cost, safety, and effectiveness relative to therapeutic alternatives.

Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. PATIENTS AND METHODS: Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. RESULTS: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. CONCLUSIONS: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

Trainee-Led Intervention to Motivate Resident Physician Voter Registration.

This quality improvement study describes a trainee-led intervention to improve resident physician voter registration for national elections.