This study investigates the long-term cardiac effects of trastuzumab-based chemotherapy in early breast cancer (EBC) survivors. We extend the original MANTICORE trial which showed that angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers (BB) could mitigate the decline in left ventricular (LV) ejection fraction (EF) during the first year of trastuzumab treatment. We hypothesized that, over time, cardiac function would decline further and adverse changes in cardiac geometry would occur due to the aging of the population and prior treatment. The study enrolled 52 participants from the original MANTICORE trial cohort, with cardiac magnetic resonance (CMR) imaging conducted at a median of 6.5 years post randomization to treatment. We found that, contrary to the hypothesis, participants maintained LV EF over the follow-up period. Specifically, the placebo group exhibited a recovery in LV EF to levels comparable with the treatment groups, suggesting no long-term differential impact on cardiac function. However, a significant reduction in LV mass was observed across all groups, the clinical implications of which remain unclear. The findings suggest that in a selected population receiving trastuzumab-based chemotherapy, extended cardiac imaging surveillance beyond one-year post-treatment may be unnecessary. We posit that the presence of HER2 overexpressing breast cancer influenced hypertrophic changes to cardiac geometry observed at baseline and one year, which resolved after completing HER2-blocking treatment. The study also highlights the need for further research to understand the significance of changes in cardiac geometry during and after breast cancer treatment​.
An improved understanding of the pathophysiology of trastuzumab-mediated cardiotoxicity is required to improve outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to characterize the cardiac and cardiometabolic phenotype of trastuzumab-mediated toxicity and potential interactions with cardiac pharmacotherapy. This study was an analysis of serial magnetic resonance imaging (MRI) and circulating biomarker data acquired from patients with HER2-positive early-stage breast cancer participating in a randomized-controlled clinical trial for the pharmaco-prevention of trastuzumab-associated cardiotoxicity. Circulating biomarkers (B-type natriuretic peptide, troponin I, MMP-2 and -9, GDF-15, neuregulin-1, and IGF-1) and MRI of cardiac structure and function and abdominal fat distribution were acquired prior to trastuzumab, post-cycle 4 and post-cycle 17. Ninety-four participants (51 ± 8 years) completed the study with 30 on placebo, 33 on perindopril, and 31 on bisoprolol. Post-cycle 4, global longitudinal strain deteriorated from baseline in both placebo (+2.0 ± 2.7%, P = 0.002) and perindopril (+0.9 ± 2.5%, P = 0.04), but not with bisoprolol (-0.2 ± 2.1%, P = 0.55). In all groups combined, extracellular volume fraction and GDF-15 increased post-cycle 4 (+1.3 ± 4.4%, P = 0.004; +130 ± 150%, P ≤ 0.001, respectively). However, no significant change in troponin I was detected throughout trastuzumab. In all groups combined, visceral and intermuscular fat volume increased post-cycle 4 (+7 ± 17%, P = 0.02, +8 ± 23%, P = 0.02, respectively), while muscle volume and IGF-1 decreased from post-cycle 4 to 17 (-2 ± 10%, P = 0.008, -18 ± 28%, P < 0.001, respectively). Trastuzumab results in impaired cardiac function and early myocardial inflammation. Trastuzumab is also associated with deleterious changes to the cardiometabolic phenotype which may contribute to the increased cardiovascular risk in this population.
MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker) can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer. One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril), beta-blocker (bisoprolol), or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end-diastolic volume using cardiac MRI. Secondary objectives include 1) determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2) understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3) correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer. Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first randomized trial testing proven heart failure pharmacotherapy in the prevention of trastuzumab-mediated cardiotoxicity. We expect the findings of this trial to provide important evidence in the development of guidelines for preventive therapy. ClinicalTrials.gov: NCT01016886.
Purpose The primary toxicity of trastuzumab therapy for human epidermal growth factor receptor 2-overexpressing (HER2-positive) breast cancer is dose-independent cardiac dysfunction. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. We hypothesized that angiotensin-converting enzyme inhibitors and β-blockers could prevent trastuzumab-related cardiotoxicity. Patients and Methods In this double-blinded, placebo-controlled trial, patients with HER2-positive early breast cancer were randomly assigned to receive treatment with perindopril, bisoprolol, or placebo (1:1:1) for the duration of trastuzumab adjuvant therapy. Patients underwent cardiac magnetic resonance imaging at baseline and post-cycle 17 for the determination of left ventricular volumes and left ventricular ejection fraction (LVEF). Cardiotoxicity was evaluated as the change in indexed left ventricular end diastolic volume and LVEF. Results Thirty-three patients received perindopril, 31 received bisoprolol, and 30 received placebo. Baseline demographic, cancer, and cardiovascular profiles were similar between groups. Study drugs were well tolerated with no serious adverse events. After 17 cycles of trastuzumab, indexed left ventricular end diastolic volume increased in patients treated with perindopril (+7 ± 14 mL/m2), bisoprolol (+8 mL ± 9 mL/m2), and placebo (+4 ± 11 mL/m2; P = .36). In secondary analyses, trastuzumab-mediated decline in LVEF was attenuated in bisoprolol-treated patients (-1 ± 5%) relative to the perindopril (-3 ± 4%) and placebo (-5 ± 5%) groups ( P = .001). Perindopril and bisoprolol use were independent predictors of maintained LVEF on multivariable analysis. Conclusion Perindopril and bisoprolol were well tolerated in patients with HER2-positive early breast cancer who received trastuzumab and protected against cancer therapy-related declines in LVEF; however, trastuzumab-mediated left ventricular remodeling-the primary outcome-was not prevented by these pharmacotherapies.
Aim: Proteinuria poses a significant challenge in focal segmental glomerulosclerosis (FSGS), particularly when resistant to standard treatments. Acthar® Gel, a Food and Drug Administration (FDA)-approved treatment, may be a potential option for proteinuria in nephrotic syndrome (NS) due to FSGS, particularly given the limited alternative therapies. This study assessed the cost-per-response of Acthar Gel versus standard of care (SoC) for the treatment of refractory proteinuria in NS due to FSGS among adults from a US healthcare payer perspective over a 1- to 3-year horizon. Materials & methods: A probabilistic, cohort-based state-transition model tracked adults with nephrotic-range proteinuria due to FSGS through clinically relevant health states in 6-month cycles. All patients entered in relapse and received either Acthar Gel or SoC. At each cycle, individuals could transition to response or remain uncontrolled, progress to renal failure, or continue in relapse; death was permitted from any state. Responders were allowed to either sustain response or experience relapse in subsequent cycles. Model inputs for clinical event rates, healthcare utilization and medical costs were sourced from the published literature, and drug costs were valued using wholesale acquisition cost. Cost-per-response was defined as total healthcare costs (drug and nondrug medical costs) per patient divided by the response rate. Results: Acthar Gel showed a lower cost-per-response ($469,735) versus cyclophosphamide ($2,140,400) and rituximab ($1,272,477) over 1 year. This advantage for Acthar Gel was sustained for 2 and 3 years. Acthar Gel was potentially a dominant treatment option at 2 and 3 years, with a lower overall cost of care and higher response rates than SoC. Conclusion: From a US healthcare payer perspective, Acthar Gel appears to be a cost-effective, value-based treatment option for adults with proteinuria in NS due to FSGS over 1 to 3 years. These findings may aid providers and payers in making informed treatment decisions when conventional therapies are ineffective for these patients. What is this article about? This study looks at whether Acthar Gel provides good value compared with usual treatments for adults with focal segmental glomerulosclerosis who still have high protein in their urine despite prior care. High protein in the urine (proteinuria) is a sign that the kidneys are damaged and can lead to worse health. The study compared the costs and effectiveness of Acthar Gel with standard options used in the US, such as cyclophosphamide or rituximab, over a 1- to 3-year period, considering the perspective of healthcare payers. What were the results? Acthar Gel resulted in more patients responding to treatment and, in many cases, reduced overall medical spending. After 1 year, the cost to achieve one responder was lower with Acthar Gel than with usual treatments. This advantage persisted for 2–3 years. What do the results mean? For adults with difficult-to-treat focal segmental glomerulosclerosis, Acthar Gel appears to be a cost-effective choice. Its higher chance of response and lower use of other healthcare services can reduce total costs over time. These findings can help clinicians and health plans choose treatments when standard therapies have not worked.
It is well established tumour cells secrete signalling factors affecting distant normal tissues. What remains unresolved is whether these factors initiate a signalling cascade rendering terminally differentiated cardiomyocytes susceptible to apoptosis, a feature of chemotherapy-induced cardiotoxicity (CIC). Here we show in MANTICORE trial cancer patients, cumulative baseline plasma levels of the nucleoside inosine and its derivative hypoxanthine predict cardiotoxicity. We found the Zn2+ finger transcription factor ZNF281 increases synthesis and release of inosine and hypoxanthine, which bind the A2A receptor on cardiomyocytes, activating CAMKIIδ which phosphorylates the postnatal mRNA splicing factor RBFOX1, resulting in its caspase-dependent degradation. RBFOX1 loss reverts cardiomyocytes to a less mature state with open chromatin and susceptibility to DNA damage, apoptosis or CIC, when treated with DNA intercalating or alkylating anticancer agents. These findings suggest cumulative inosine and hypoxanthine levels may be a biomarker predicting patient susceptibility to DNA damaging anti-cancer agents.
Terlipressin is the only Food and Drug Administration-approved medication for adults with hepatorenal syndrome-acute kidney injury (HRS-AKI) with rapid reduction in kidney function. Treatment with terlipressin, particularly in patients with lower serum creatinine (SCr) at diagnosis, improves outcomes. Despite evidence suggesting that treating HRS-AKI at lower SCr thresholds may improve clinical outcomes, the impact on healthcare resource utilization (HCRU) and medical costs of an earlier intervention strategy remains unquantified. This model-based analysis was conducted from a United States hospital perspective to project the clinical and economic impact of early HRS-AKI diagnosis and treatment with terlipressin among adults. A decision-analytic model compared two SCr level-based scenarios and projected the outcomes for both scenarios. For current clinical practice, patient distribution was based on the CONFIRM trial (SCr <3 mg/dL: 45% and ≥3 to <5 mg/dL: 55%). For early diagnosis and treatment, distribution was based on the HRS medical chart review study (<3 mg/dL: 85% and ≥3 to <5 mg/dL: 15%). Terlipressin HRS reversal rate for the on-label population (SCr <5 mg/dL and acute-on-chronic liver failure grade 0-2) was 52.2% for SCr <3 mg/dL and 33.3% for SCr ≥3 to <5 mg/dL. An annual HRS incidence of 50,000 was assumed. Based on the modeled projections, early diagnosis and treatment with terlipressin versus current practice yielded an additional 3040 HRS reversals and consequently led to a reduction in hospital days and intensive care unit days. Early intervention resulted in 960 fewer patients requiring renal replacement therapy during hospitalization and 1200 more patients with 90-day transplant-free survival. Early intervention is projected to save $11,504 per patient, with total national savings of $460.2 million annually. Based on the modeled projections using data from clinical trial, earlier HRS diagnosis and treatment with terlipressin may improve clinical outcomes, reduce HCRU, and save costs versus current clinical practice.
Aim: Persistently active noninfectious keratitis can lead to permanent corneal damage and loss of vision. Given the limited treatment options, Acthar Gel, a US FDA-approved treatment for ocular inflammatory conditions, can be a potential therapy. This study evaluated the cost-per-response of Acthar® Gel compared with standard of care ([SoC]; adalimumab or infliximab) for noninfectious keratitis from a US healthcare payer perspective over 1-3 years. Materials & methods: A probabilistic, cohort-level state-transition decision-analytic model was developed to assess the economic value of Acthar Gel. The model simulated the treatment pathway over 3 years, divided into 3-month cycles. Patients started with active keratitis and received Acthar Gel or SoC. Based on treatment success, patients transitioned between relapse, response and no-response states, with no response potentially leading to complications. Clinical parameters for Acthar Gel were derived from a phase IV open-label study and for SoC from observational studies. Healthcare resource utilization and costs were derived from administrative claims data or published literature. Results: Over 1 year, Acthar Gel demonstrated a lower cost per response ($167,928) than SoC, adalimumab ($228,450) and infliximab ($195,083). This benefit for Acthar Gel over SoC was sustained for 2 and 3 years. Acthar Gel, despite having a higher acquisition cost than SoC, had lower disease management costs and incurred no treatment-related (administration, monitoring or adverse event) costs over 1 year. Acthar Gel also demonstrated a lower overall cost of care than SoC at 2 and 3 years. Further, Acthar Gel had higher response rates versus SoC over 1-3 years. Acthar Gel was a dominant treatment option versus SoC at 2 and 3 years. Conclusion: From a US healthcare payer perspective, Acthar Gel may be a cost-effective, value-based treatment option for appropriate patients with noninfectious keratitis.
Acthar® Gel Single-Dose Pre-filled SelfJect™ Injector ("Acthar Gel via SelfJect") is approved by the US Food and Drug Administration for appropriate patients with chronic and acute inflammatory and autoimmune conditions. It has fewer steps than a multi-dose vial. This survey assessed patients' perceptions of their experience with this device, including their satisfaction, confidence, convenience, and ease of use, as well as persistence and compliance. Real-World Insights on Patient Satisfaction and Experience with Acthar Gel via SelfJect (RISE™) gathered responses via a non-interventional, observational, cross-sectional online survey with a pre-specified protocol (November 2024-January 2025). Eligible participants were aged ≥18 years, had a diagnosis of an indication of Acthar Gel based on the prescribing information, and had used Acthar Gel via SelfJect for ≥6 self-injections during the survey. Fifty-four participants completed the survey (mean age 55.4 years, 76% women). Thirty-three percent (18/54) had chronic or recurring ocular inflammatory disease, and 26% (14/54) had rheumatoid arthritis. Thirty-nine percent (21/54) reported dexterity or visual problems, and 39% (21/54) had prior experience with Acthar Gel multi-dose vial. On average, administering Acthar Gel via SelfJect took 3.4 min. Overall, 91% (49/54) of participants reported that they were satisfied or very satisfied with Acthar Gel via SelfJect; 89% (48/54) felt very or extremely confident injecting with Acthar Gel via SelfJect; and 91% (49/54) found it to be convenient or very convenient. Seventy-six percent (41/54) felt that it was very or extremely easy to self-inject with this device. Eighty-seven percent (47/54) perceived that they were likely or very likely to maintain persistence and compliance with this device. Survey participants reported a favorable experience with Acthar Gel via SelfJect, with a high level of satisfaction, confidence, convenience, and ease of use. Participants reported perceptions of anticipated positive persistence and compliance with this device, which may correlate with the possibility of improved continuity of care.
Background: Proteinuria, a critical marker of glomerulosclerosis, poses a challenge in idiopathic membranous nephropathy (iMN), particularly when standard treatments fail. Acthar® Gel, a US Food and Drug Administration-approved treatment option, may offer an alternative for managing refractory proteinuria in nephrotic syndrome (NS) due to iMN where multiple treatments have failed. Objective: The cost per response of Acthar® Gel vs standard of care (SoC; cyclophosphamide or rituximab) for treatment of proteinuria in NS due to iMN was evaluated among adults who had failed multiple treatments from a US payer perspective over a 1- to 3-year horizon. Methods: A probabilistic, cohort-level state-transition model simulated patient progression through various health states using 6-month cycles. Patients began in a relapse phase and received either Acthar® Gel or SoC. Transition probabilities determined whether patients achieved a response, experienced no response, progressed to renal failure, or remained in relapse. Responders could potentially maintain their response or relapse, while nonresponders risked renal failure, with potential mortality from any state. Clinical, healthcare resource utilization, and cost data were derived from published literature. Drug prices were based on wholesale acquisition costs. Results: Over 1 year, Acthar® Gel showed a lower cost per response ( 377   185 ) t h a n c y c l o p h o s p h a m i d e ( 551 687) and rituximab ($741 373). This cost advantage of Acthar® Gel was maintained over 2 and 3 years. Acthar® Gel had higher drug acquisition costs than cyclophosphamide and rituximab but resulted in lower overall medical costs and higher response rates within 1 year, without additional treatment-related costs. Over 2 and 3 years, Acthar® Gel had a lower overall cost of care and higher response rates than SoC, establishing it as a dominant treatment option. Conclusions: Based on current model assumptions and clinical inputs, Acthar® Gel may potentially be a cost-effective and value-based treatment strategy vs unapproved SoCs for adults with refractory proteinuria in NS due to iMN, particularly for those who have not responded to conventional therapies over a 1- to 3-year period within a US payer context. These results may inform clinical and payer decision-making in cases when other standard therapies fail to achieve desired outcomes for a specific population.
Eyewash stations are an essential component of laboratory safety programs, providing first aid in case of ocular exposure to hazardous materials. However, the presence of microbial contamination in these devices poses a potential risk of ocular infection to laboratory employees. This cross-sectional study aimed to evaluate the microbial quality and performance of 40 eyewash stations fixed in 10 buildings in a laboratory setting. Water quality parameters, including temperature, pH, turbidity, and the presence of Acanthamoeba spp., were measured at various time points (first draw, after 2 min of flushing, and 15 min flushing) from samples collected from each of the 40 eyewash stations. Performance and operational data were also measured according to the American National Standards Institute (ANSI)/International Safety Equipment Association (ISEA) Z358.1-2014 standard. Our results showed variable compliance with this standard across measures of physical condition, performance, access, and maintenance. Out of the 147 water samples collected (130 eyewash samples, 17 building reference samples), 28 samples were suspected to contain Acanthamoeba spp. or other free-living amoeba based on initial testing. Further analysis using polymerase chain reaction (PCR) confirmed the presence of Acanthamoeba spp. in 5 out of 28 samples. The results of this study provide insights into the potential risk of ocular infections associated with using eyewash stations and provide the basis for the recommendations on maintenance protocols to minimize the risk of microbial contamination.
Sleep apnea is a common sleep disorder. The availability of an easy-to-use sleep apnea predictor would provide a public health benefit by promoting early diagnosis and treatment. Our goal was to develop a prediction tool that used commonly available variables and was accessible to the public through a web site. Using data from polysomnography (PSG) studies that measured the apnea-hypopnea index (AHI), we built a machine learning tool to predict the presence of moderate to severe obstructive sleep apnea (OSA) (defined as AHI ≥15). Our tool employs only seven widely available predictor variables: age, sex, weight, height, pulse oxygen saturation, heart rate and respiratory rate. As a preliminary step, we used 16,958 PSG studies to examine eight machine learning algorithms via five-fold cross validation and determined that XGBoost exhibited superior predictive performance. We then refined the XGBoost predictor by randomly partitioning the data into a training and a test set (13,566 and 3392 PSGs, respectively) and repeatedly subsampling from the training set to construct 1000 training subsets. We evaluated each of the resulting 1000 XGBoost models on the single set-aside test set. The resulting classification tool correctly identified 72.5 % of those with moderate to severe OSA as having the condition (sensitivity) and 62.8 % of those without moderate to-severe OSA as not having it (specificity); overall accuracy was 66 %. We developed a user-friendly publicly available website (https://manticore.niehs.nih.gov/OSApredictor). We hope that our easy-to-use tool will serve as a screening vehicle that enables more patients to be clinically diagnosed and treated for OSA.
Sarcoidosis is common among African Americans in the United States. Acthar® Gel is a viable option for the treatment of advanced symptomatic sarcoidosis. This study examined patient characteristics, Acthar Gel utilization, co-medication use, and treatment response based on physicians' assessments among African Americans versus non-African Americans with advanced symptomatic sarcoidosis. Data from the medical charts of patients were used. During data collection, patients had either completed ≥1 course or received treatment with Acthar Gel for ≥6 months. This study comprised 168 African Americans and 104 non-African Americans. On average, the time since the first diagnosis of sarcoidosis was slightly longer among African Americans than non-African Americans (5.2 versus 4.3 years). Skin, heart, eyes, and joints were the most common extrapulmonary sites involved among both race groups. Shortness of breath, fatigue, bone and joint pain, and wheezing/coughing were the most frequent symptoms among both race groups. A higher proportion of African Americans versus non-African Americans were first-time Acthar Gel users and had not completed treatment during data collection. Patients in both race groups with higher starting doses of Acthar Gel therapy had a shorter treatment duration and vice-versa. A significantly lower proportion of patients among both race groups were on any co-medication after Acthar Gel initiation (p<0.0001). Further, a higher proportion of African Americans versus non-African Americans had a reduction in any co-medication use after Acthar Gel initiation. The mean daily dose of prednisone decreased among African Americans (18.5 to 10.1 mg) and non-African Americans (17.6 to 10.0 mg) after Acthar Gel initiation. Improvement in patient health status and overall symptoms was similar for both race groups. Findings suggest that Acthar Gel improves health outcomes for patients with sarcoidosis, which could help to alleviate health disparities among African Americans, who are disproportionately affected by this disease.
Human sleep architecture is structured with repeated episodes of rapid-eye-movement (REM) and non-rapid-eye-movement (NREM) sleep. An overnight sleep study facilitates identification of macro and micro changes in the pattern and duration of sleep stages associated with sleep disorders and other aspects of human mental and physical health. Overnight sleep studies record, in addition to electroencephalography (EEG) and other electro-physiological signals, a sequence of sleep-stage annotations. SSAVE, introduced here, is open-source software that takes sleep-stage annotations and EEG signals as input, identifies and characterizes periods of NREM and REM sleep, and produces a hypnogram and its time-matched EEG spectrogram. SSAVE fills an important gap for the rapidly growing field of sleep medicine by providing an easy-to-use tool for sleep-period identification and visualization. SSAVE can be used as a Python package, a desktop standalone tool or through a web portal. All versions of the SSAVE tool can be found on: https://manticore.niehs.nih.gov/ssave.
Hepatorenal syndrome (HRS), a special form of acute kidney failure, is a rare, acute, life-threatening complication of cirrhosis and has a very poor prognosis. Terlipressin (TERLIVAZ®) is the first and only pharmacological treatment approved by Food and Drug Administration (September 2022) to improve kidney function for adults with HRS with rapid reduction in kidney function. We constructed a decision analytic economic model to estimate the cost per complete response/HRS reversal of terlipressin + albumin from a United States hospital perspective. A decision analytic model was developed to estimate the HRS treatment-related cost per response over an HRS hospitalization (assuming 14 days). Patients can experience either HRS reversal (complete response) or no HRS reversal (partial/no response) upon receipt of treatment. The efficacy, safety, and treatment duration data were from published head-to-head randomized international trials. Total treatment cost comprised drug acquisition and treatment-related costs (intensive care unit [ICU], dialysis [intermittent or continuous], pulse oximetry monitoring for terlipressin, and adverse events) sourced from the published literature. Cost per response, defined as the total treatment cost per HRS reversal was estimated for each treatment. The number needed to treat (NNT), defined as the number of patients treated to achieve HRS reversal in 1 additional patient, was estimated. Cost per response of terlipressin + albumin was lower than midodrine and octreotide + albumin (M&O) (US$85,315 vs. $467,794) and norepinephrine + albumin ($81,614 vs. $139,324). NNT for HRS reversal was 2 patients with terlipressin + albumin vs. M&O + albumin and 4 patients with terlipressin + albumin vs. norepinephrine + albumin, respectively. The analysis shows that terlipressin is a cost-effective treatment due to its higher efficacy and administration in the non-ICU setting. Terlipressin is a value-based treatment option for appropriate adults with HRS with rapid reduction in kidney function. Hepatorenal syndrome, a functional, progressive kidney failure, is a life-threatening complication of cirrhosis. It is important to improve kidney function in patients who are hospitalized with hepatorenal syndrome considering the cost of treatment. This study assessed the cost per complete response/ hepatorenal syndrome reversal of terlipressin + albumin from a United States hospital perspective. This study shows that terlipressin improves kidney function with lower intensive care unit and dialysis costs compared with unapproved treatments. Terlipressin is a cost-effective, value-based treatment option for appropriate adults with hepatorenal syndrome with rapid reduction in kidney function.
Strategies designed to track drug ingestion may improve medication adherence and clinical outcomes in adults with schizophrenia. This study aimed to estimate the cost-effectiveness of aripiprazole tablets with sensor (AS; Abilify MyCite®) versus generic oral atypical antipsychotics (AAPs) in schizophrenia from the United States payer and societal perspectives over 12 months. An individual-level microsimulation was developed to generate individual trajectories using data from a phase 3b multicenter, open-label, mirror-image trial in adults with schizophrenia treated prospectively for 6 months with AS. The patient's clinical characteristics and outcomes were computed as a function of the Positive and Negative Syndrome Scale (PANSS) scores. Direct and indirect medical cost estimates were sourced from the literature; EuroQol 5-Dimensions (EQ-5D) utilities were derived using risk equations based on patient and clinical characteristics. Scenario analyses were also conducted to assess outcomes under the assumption of treatment durability over 12 months. Over 12 months, AS showed a 12.2% improvement in PANSS score. AS had an incremental cost of $2168 and incremental cost savings of $22,343 from the payer and societal perspectives, respectively, with an incremental quality-adjusted life-year (QALY) gain of 0.0298 versus oral AAPs. Further, AS resulted in a 28.2% reduction in hospitalizations over 12 months. At a willingness-to-pay of $100,000 per QALY, the net monetary benefit over 12 months was $25,323 from the payer perspective. Under the assumption of the durability of the treatment effect of AS, the findings were similar to those of the base case analyses, though with greater cost savings and QALYs gained with AS. The results from the sensitivity analyses were consistent with those of the base case analysis. AS may be a cost-effective strategy, with lower costs and improved quality of life among patients with schizophrenia over 12 months, from the payer and societal perspectives.
Sarcoidosis is a multisystem, inflammatory, systemic granulomatous disease with unknown etiology. Despite the current standard of care (SoC), there is an unmet need for the treatment of advanced symptomatic sarcoidosis. This study assessed the cost-effectiveness of Acthar® Gel (repository corticotropin injection) versus SoC in patients with advanced symptomatic sarcoidosis from the United States (US) payer and societal perspectives over 2 and 3 years. A probabilistic cohort-level state-transition approach was used for this cost-effectiveness analysis. Patients were monitored at the end of a 3-month cycle for the attainment of partial or complete response. Patients in the partial, complete, or no-response state were allowed to transition in each of these states at each 3-month cycle. Following the attainment of response, patients could have a durable response or relapse to a no-response state. Patients in a no-response state received treatment and could transition into a response or no-response state based on the probability of treatment success with the respective treatment. Clinical parameters and health utility data were sourced from the Acthar Gel in Participants with Pulmonary Sarcoidosis (PULSAR) trial (NCT03320070) and healthcare utilization, costs, and disutilities were sourced from the published literature. Base case analysis considered a payer perspective over 2 years. From a payer perspective, Acthar Gel versus SoC results in an incremental cost-effectiveness ratio (ICER) of $134,796 per quality-adjusted life-year (QALY) and $39,179 per QALY over 2 and 3 years, respectively. From a societal perspective, Acthar Gel versus SoC results in an ICER of $117,622 per QALY and $21,967 per QALY over 2 and 3 years, respectively. Sensitivity analysis findings were consistent with the base case. The results from this cost-effectiveness analysis indicate that Acthar Gel is a cost-effective, value-based treatment option for advanced symptomatic sarcoidosis compared to the SoC from the US payer and societal perspectives.
This study aims to analyze the correlation between financial stability, oil price shocks, and business cycle uncertainty in the economies of the Association of Southeast Asian Nations (ASEAN) amidst the COVID-19 pandemic. This study examines the interplay and effects of various factors on the economic resilience of the ASEAN region, utilizing data from ten-member countries spanning the years 2002 to 2022. The results underscore the notable impact of oil price shocks on financial systems' stability, suggesting that oil price variations have the potential to disrupt financial markets, particularly in the context of the ongoing pandemic. Moreover, the research illustrates that the presence of business cycle uncertainty amplifies the negative consequences of oil price shocks, thereby heightening their influence on the financial system's stability. The study also uncovers a robust correlation between the COVID-19 pandemic and heightened levels of business cycle uncertainty within the ASEAN economies. The ongoing global pandemic has increased market volatility, a deceleration in economic growth, and disruptions in supply chains, generating a heightened sense of uncertainty within the business landscape. As a result, the heightened level of uncertainty has impeded the efficacy of monetary and fiscal policies in preserving financial stability.
Polyploidization is a well-known speciation and adaptation mechanism. Traces of former polyploidization events were discovered within many genomes, and especially in plants. Allopolyploidization by interspecific hybridization between two species is common. Among hybrid plants, many are domesticated species of agricultural interest and many of their genomes and of their presumptive parents have been sequenced. Hybrid genomes remain challenging to analyse because of the presence of multiple subgenomes. The genomes of hybrids often undergo rearrangement and degradation over time. Based on 10 hybrid plant genomes from six different genera, with hybridization dating from 10,000 to 5 million years ago, we assessed subgenome degradation, subgenomic intermixing and biased subgenome fractionation. The restructuring of hybrid genomes does not proceed proportionally with the age of the hybrid. The oldest hybrids in our data set display completely different fates: whereas the subgenomes of the tobacco plant Nicotiana benthamiana are in an advanced stage of degradation, the subgenomes of quinoa (Chenopodium quinoa) are exceptionally well conserved by structure and sequence. We observed statistically significant biased subgenome fractionation in seven out of 10 hybrids, which had different ages and subgenomic intermixing levels. Hence, we conclude that no correlation exists between biased fractionation and subgenome intermixing. Lastly, domestication may encourage or hinder subgenome intermixing, depending on the evolutionary context. In summary, comparative analysis of hybrid genomes and their presumptive parents allowed us to determine commonalities and differences between their evolutionary fates. In order to facilitate the future analysis of further hybrid genomes, we automated the analysis steps within manticore, which is publicly available at https://github.com/MatteoSchiavinato/manticore.git.