Incidence and Costs of Clinically Significant Events with Systemic Therapy in Patients with Unresectable Hepatocellular Carcinoma: A Retrospective Cohort Study.

INTRODUCTION: Systemic therapies have been associated with clinically significant events (CSEs) in patients with unresectable hepatocellular carcinoma (uHCC). We evaluated the incidence of CSEs (bleeding, clotting, encephalopathy, and portal hypertension), and their impact on healthcare resource utilization (HCRU) and costs, in patients with uHCC treated with first-line (1L) atezolizumab plus bevacizumab (A + B), lenvatinib (LEN), or sorafenib (SOR) in the USA. METHODS: A retrospective cohort study was performed using medical/pharmacy claims from Optum® Clinformatics® Data Mart. Patients diagnosed with HCC who initiated 1L A + B between June 01, 2020 and December 31, 2020 or LEN/SOR between January 01, 2016 and May 31, 2020 were included. Outcomes included incidence rates of CSEs, HCRU, and costs. Subgroup analysis was performed in patients with no CSEs or ≥ 1 CSE. RESULTS: In total, 1379 patients were selected (A + B, n = 271; LEN, n = 217; SOR, n = 891). Clotting (incidence rate per 100 patient-years [PY] 94.9) and bleeding (88.1 per 100 PY) were the most common CSEs in the A + B cohort. The most common CSEs in the LEN cohort were clotting (78.6 per 100 PY) and encephalopathy (66.3 per 100 PY). Encephalopathy (73.0 per 100 PY) and portal hypertension (72.3 per 100 PY) were the most common CSEs in the SOR cohort. Mean total all-cause healthcare costs per patient per month (PPPM) were $32,742, $35,623, and $29,173 in the A + B, LEN, and SOR cohorts, respectively. Mean total all-cause healthcare costs PPPM were higher in patients who had ≥ 1 CSE versus those who did not (A + B $34,304 versus $30,889; LEN $39,591 versus $30,621; SOR $31,022 versus $27,003). CONCLUSION: Despite improved efficacy of 1L systemic therapies, CSEs remain a concern for patients with uHCC, as well as an economic burden to the healthcare system. Newer treatments that reduce the risk of CSEs, while improving long-term survival in patients with uHCC, are warranted.

Certain treatments for liver cancer can cause serious side effects, including bleeding, blood clots, brain injury (encephalopathy), or increased blood flow to the liver (portal hypertension). We used an insurance database to find out how often these events, known as clinically significant events, occurred in people with liver cancer who were given treatments that target the immune system (immunotherapy) or specific proteins involved in cancer growth and survival (targeted therapy). The study included 1379 patients treated with atezolizumab (immunotherapy) plus bevacizumab (targeted therapy), or lenvatinib or sorafenib alone (both targeted therapies), as their first treatment. Clotting and bleeding were the most common clinically significant events in patients treated with atezolizumab plus bevacizumab, whereas clotting and encephalopathy were the most common clinically significant events with lenvatinib, and encephalopathy and portal hypertension were the most common clinically significant events with sorafenib. On average, for every 100 patients treated for 1 year, there were more than 50 of each of these events. Average healthcare costs per patient per month ranged from around $29,000 to around $36,000 in the three different treatment groups, and were higher in people who had at least one clinically significant event. These results suggest that clinically significant events are common in people with liver cancer who are given various types of treatment. As well as raising concerns for patient safety, these events result in higher costs to healthcare systems. Therefore, newer treatments that are less likely to cause clinically significant events, while improving survival in patients with liver cancer, are needed.

Engineered tissue geometry and Plakophilin-2 regulate electrophysiology of human iPSC-derived cardiomyocytes.

Engineered heart tissues have been created to study cardiac biology and disease in a setting that more closely mimics in vivo heart muscle than 2D monolayer culture. Previously published studies suggest that geometrically anisotropic micro-environments are crucial for inducing "in vivo like" physiology from immature cardiomyocytes. We hypothesized that the degree of cardiomyocyte alignment and prestress within engineered tissues is regulated by tissue geometry and, subsequently, drives electrophysiological development. Thus, we studied the effects of tissue geometry on electrophysiology of micro-heart muscle arrays (µHM) engineered from human induced pluripotent stem cells (iPSCs). Elongated tissue geometries elicited cardiomyocyte shape and electrophysiology changes led to adaptations that yielded increased calcium intake during each contraction cycle. Strikingly, pharmacologic studies revealed that a threshold of prestress and/or cellular alignment is required for sodium channel function, whereas L-type calcium and rapidly rectifying potassium channels were largely insensitive to these changes. Concurrently, tissue elongation upregulated sodium channel (NaV1.5) and gap junction (Connexin 43, Cx43) protein expression. Based on these observations, we leveraged elongated µHM to study the impact of loss-of-function mutation in Plakophilin 2 (PKP2), a desmosome protein implicated in arrhythmogenic disease. Within µHM, PKP2 knockout cardiomyocytes had cellular morphology similar to what was observed in isogenic controls. However, PKP2-/- tissues exhibited lower conduction velocity and no functional sodium current. PKP2 knockout µHM exhibited geometrically linked upregulation of sodium channel but not Cx43, suggesting that post-translational mechanisms, including a lack of ion channel-gap junction communication, may underlie the lower conduction velocity observed in tissues harboring this genetic defect. Altogether, these observations demonstrate that simple, scalable micro-tissue systems can provide the physiologic stresses necessary to induce electrical remodeling of iPS-CM to enable studies on the electrophysiologic consequences of disease-associated genomic variants.

Durvalumab Treatment Patterns for Patients with Unresectable Stage III Non-Small Cell Lung Cancer in the Veterans Health Administration (VHA): A Nationwide, Real-World Study.

BACKGROUND: Durvalumab is approved for the treatment of adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This real-world study describes patient characteristics and durvalumab treatment patterns (number of doses and therapy duration; treatment initiation delays, interruptions, discontinuations, and associated reasons) among VHA-treated patients. METHODS: This was a retrospective cohort study of adults with unresectable stage III NSCLC receiving durvalumab at the VHA between 1 January 2017 and 30 June 2020. Patient characteristics and treatment patterns were presented descriptively. RESULTS: A total of 935 patients were included (median age: 69 years; 95% males; 21% Blacks; 46% current smokers; 16% ECOG performance scores ≥ 2; 50% squamous histology). Durvalumab initiation was delayed in 39% of patients (n = 367). Among the 200 patients with recorded reasons, delays were mainly due to physician preference (20%) and CRT toxicity (11%). Overall, patients received a median (interquartile range) of 16 (7-24) doses of durvalumab over 9.0 (2.9-11.8) months. Treatment interruptions were experienced by 19% of patients (n = 180), with toxicity (7.8%) and social reasons (2.6%) being the most cited reasons. Early discontinuation occurred in 59% of patients (n = 551), largely due to disease progression (24.2%) and toxicity (18.2%). CONCLUSIONS: These real-world analyses corroborate PACIFIC study results in terms of the main reasons for treatment discontinuation in a VHA population with worse prognostic factors, including older age, predominantly male sex, and poorer performance score. One of the main reasons for durvalumab initiation delays, treatment interruptions, or discontinuations was due to toxicities. Patients could benefit from improved strategies to prevent, identify, and manage CRT and durvalumab toxicities timely and effectively.

Hydrogel-Assisted Double Molding Enables Rapid Replication of Stereolithographic 3D Prints for Engineered Tissue Design.

Tissue-engineered in vitro models are an essential tool in biomedical research. Tissue geometry is a key determinant of function, but controlling the geometry of microscale tissues remains challenging. Additive manufacturing approaches have emerged as a promising means for rapid and iterative changes in the geometry of microdevices. However, it has been shown that poly(dimethylsiloxane) (PDMS) cross-linking is often inhibited at the interface of materials printed with stereolithography. While approaches to replica mold stereolithographic three-dimensional (3D) prints have been described, these methods are inconsistent and often lead to print destruction when unsuccessful. Additionally, 3D-printed materials often leach toxic chemicals into directly molded PDMS. Here, we developed a double molding approach that allows precise replication of high-resolution stereolithographic prints into poly(dimethylsiloxane) (PDMS) elastomer, facilitating rapid design iterations and highly parallelized sample production. Inspired by lost wax casting, we used hydrogels as intermediary molds to transfer high-resolution features from high-resolution 3D prints into PDMS, while previously published work focused on enabling direct molding of PDMS onto 3D prints through the use of coatings and post-cross-linking treatments of the 3D print itself. Hydrogel mechanical properties, including cross-link density, predict replication fidelity. We demonstrate the ability of this approach to replicate a variety of shapes that would be impossible to create using photolithography techniques traditionally used to create engineered tissue designs. This method also enabled the replication of 3D-printed features into PDMS that would not be possible with direct molding as the stiffness of these materials leads to material fracture when unmolding, while the increased toughness in the hydrogels can elastically deform around complex features and maintain replication fidelity. Finally, we highlight the ability of this method to minimize the potential for toxic materials to transfer from the original 3D print into the PDMS replica, enhancing its use for biological applications. This minimization of the transfer of toxic materials has not been reported in other previously reported methods describing replication of 3D prints into PDMS, and we demonstrate its use through the creation of stem cell-derived microheart muscles. This method can also be used in future studies to understand the effects of geometry on engineered tissues and their constitutive cells.

Incentivizing COVID-19 Vaccination in a Polarized and Partisan United States.

CONTEXT: As COVID-19 vaccines were rolled out in early 2021, governments at all levels in the United States experienced significant difficulty in consistently and efficiently administering injections in the face of vaccination resistance among a public increasingly politically polarized on vaccination preferences before the beginning of mass vaccinations. METHODS: Using an original conjoint experiment fielded to a nationally representative sample before the mass proliferation of COVID-19 vaccines, the authors examined how different incentives (e.g., employer mandates, state-organized or health care provider-organized vaccination clinics, and financial incentives) affect the public's preference to get vaccinated. They also tested how financial incentive preferences correlated with self-reported vaccination intention using observational data from the June 2021 Kaiser Family Foundation Health Tracking Poll. FINDINGS: The authors found financial incentives positively influenced vaccine preferences among the mass public and all partisan groups, including Republicans who were initially "unlikely" to be vaccinated. The authors used the observational data to replicate their experimental findings, showing positive financial incentive attitudes positively correlated with self-reported vaccination disclosures. CONCLUSIONS: These results provide support for direct financial incentives, rather than other incentives, as being a valuable tool for policy makers tasked with alleviating vaccination resistance among a US mass public increasingly polarized along partisan lines.

Assessing the effectiveness of COVID-19 vaccine lotteries: A cross-state synthetic control methods approach.

Vaccines are the most effective means at combating sickness and death caused by COVID-19. Yet, there are significant populations within the United States who are vaccine-hesitant, some due to ideological or pseudo-scientific motivations, others due to significant perceived and real costs from vaccination. Given this vaccine hesitancy, twenty state governors from May 12th to July 21st 2021 implemented some form of vaccination lottery aiming to increase low vaccination rates. In the aftermath of these programs, however, the critical question of whether these lotteries had a direct effect on vaccination remains. Previous literature on financial incentives for public health behaviors is consistent: Financial incentives significantly increase incentivized behaviors. Yet, work done specifically on state vaccine lotteries is both limited in scope and mixed in its conclusions. To help fill this gap in the literature, we use synthetic control methods to analyze all 20 states and causally identify, for eighteen states, the effects of their lotteries on both first-dose and complete vaccination rates. Within those eighteen states, we find strong evidence that all but three states' lotteries had positive effects on first-dose vaccination. We find for complete vaccinations, however, over half the states analyzed had negative or null effects. We explore possibilities related to these mixed results including the states' overall partisanship, vaccine hesitancy, and the size of their lotteries finding null effects for each of these explanations. Therefore, we conclude that the design of these programs is likely to blame: Every state lottery only incentivized first-doses with no additional or contingent incentive based on a second dose. Our findings suggest that the design of financial incentives is critical to their success, or failure, but generally, these programs can induce an uptake in vaccination across diverse demographic, ideological, and geographic contexts in the United States.

Cost-Effectiveness Analysis of Olaparib in Combination with Bevacizumab Compared with Bevacizumab Monotherapy for the First-Line Maintenance Treatment of Homologous Recombination Deficiency-Positive Advanced Ovarian Cancer.

BACKGROUND: In the PAOLA-1 trial, olaparib plus bevacizumab demonstrated significant clinical benefit following partial or complete response to platinum-based chemotherapy in homologous recombination deficiency (HRD)-positive ovarian cancer. Our study evaluated the cost effectiveness of olaparib plus bevacizumab compared with bevacizumab alone as a maintenance treatment for women in this population. METHODS: Our model was a cohort-level partitioned survival model with a lifetime horizon from a US healthcare system perspective. Its four health states were progression-free, post first progression, post second progression, and death, modeled using time to first progression (PFS1), second progression (PFS2), and overall survival (OS) from PAOLA-1. We modeled PFS1 through mixture survival modeling, and PFS2 and OS by fitting standard parametric models. Time-on-treatment was sourced directly from PAOLA-1, with treatment capped at 24 months for olaparib and 15 months for bevacizumab. Costs included drug acquisition and administration, adverse events, disease management, biomarker testing, and subsequent treatments. Deterministic and probabilistic sensitivity analyses tested the results. RESULTS: Compared with bevacizumab alone, olaparib plus bevacizumab increased quality-adjusted life-years (QALYs; +2.89) and life-years (LYs; +3.43) at an incremental cost of $164,209, leading to an incremental cost-effectiveness ratio of $56,863 per QALY. Olaparib plus bevacizumab had a 97.0% probability of being cost effective compared with bevacizumab alone at a willingness-to-pay threshold of $100,000 per QALY. CONCLUSION: The addition of olaparib to bevacizumab led to clinically significant increases in progression-free survival, resulting in substantial predicted LYs and QALYs gained, while being cost effective in the maintenance treatment of advanced ovarian cancer with HRD in the US.

Robust, Automated Analysis of Electrophysiology in Induced Pluripotent Stem Cell-Derived Micro-Heart Muscle for Drug Toxicity.

Drugs are often removed from clinical trials or market progression owing to their unforeseen effects on cardiac action potential and calcium handling. Induced pluripotent stem cell-derived cardiomyocytes and tissues fabricated from these cells are promising as screening tools for early identification of these potential cardiac liabilities. In this study, we describe an automated, open-source MATLAB-based analysis software for calculating cardiac action potentials and calcium transients from fluorescent reporters. We first identified the most robust manner in which to automatically identify the initiation point for action potentials and calcium transients in a user-independent manner, and used this approach to quantify the duration and morphology of these signals. We then demonstrate the software by assessing changes to action potentials and calcium transients in our micro-heart muscles after exposure to hydroxychloroquine, an antimalarial drug with known cardiac liability. Consistent with clinical observations, our system predicted mild action potential prolongation. However, we also observed marked calcium transient suppression, highlighting the advantage of testing multiple physiologic readouts in cardiomyocytes rather than relying on heterologous overexpression of single channels such as the human ether-a-go-go-related gene channel. This open-source software can serve as a useful, high-throughput tool for analyzing cardiomyocyte physiology from fluorescence imaging.

iPSC-Derived Micro-Heart Muscle for Medium-Throughput Pharmacology and Pharmacogenomic Studies.

Micro-heart muscle arrays enable medium-throughput experiments to model the cardiac response to a variety of environmental and pharmaceutical effects. Here, we describe stem cell culture maintenance, methods for successful cardiac differentiation, and formation of micro-heart muscle arrays for electrophysiology and molecular biology assays.

Health Care Resource Utilization and Costs Associated with Disease Progression in Ovarian Cancer.

INTRODUCTION: Ovarian cancer (OC) is one of the leading causes of cancer mortality among women in the United States. With the approval of first-line maintenance therapies, patients with OC experienced prolonged first-line progression-free survival. While the literature addresses some costs associated with OC, further research is needed on the costs of progression that are potentially deferred or prevented by early maintenance. The objective of this study was to capture the health care resource utilization and costs of patients with advanced OC who never received poly(ADP ribose) polymerase (PARP) inhibitor maintenance. METHODS: We conducted a descriptive retrospective analysis of treatment patterns and the consequences of progression through several lines of therapy (LOTs) in patients with OC, using claims from commercial and Medicare Advantage health plan members in the United States from the Optum Research Database between January 1, 2010, and April 30, 2019. Patients were required to have an index OC diagnosis (≥ 2 non-diagnostic claims). We examined up to 4 LOTs and the time between treatments. RESULTS: A total of 5498 women met the eligibility criteria. As the number of LOTs increased, the median duration of each line decreased from 137 days in LOT1 to 94 days in LOT4, and the time between lines also decreased from 245 to 0 days. Ambulatory care visits were a major driver of health care resource utilization, with a median of about 6 monthly visits during active treatment. The mean total monthly health care costs for patients with at least 2 LOTs were US$8588 (SD: $8533) before LOT2 and increased to $15,358 (SD: $21,460) during or after LOT2. CONCLUSIONS: Prolonging progression-free survival after first-line treatment in patients with OC may provide the opportunity to delay or prevent later treatment, the financial toxicity felt by patients, and the economic burden to the health care system associated with progression.

Ovarian cancer is a complex disease in which > 70% of patients are diagnosed with advanced disease, and one of the leading causes of cancer mortality among women in the United States. A variety of maintenance therapy options, including bevacizumab, PARP inhibitors, and PARP plus bevacizumab combination therapies, have demonstrated improvements in progression-free survival. By delaying disease progression after completion of first-line therapy, a simultaneous decrease in post-progression health care costs may be seen. The objective of this study was to capture the health care resource utilization and costs of patients with advanced ovarian cancer who did not receive a PARP inhibitor at any time in their treatmentIn patients never receiving a PARP inhibitor, this study documented substantial health care resource usage and costs associated with progression beyond the first line of treatment (surgery and/or chemotherapy) in ovarian cancer. These were largely driven by the number of ambulatory care visits. When these visits are combined with emergency department visits and inpatient stays, high costs are incurred by both patients and third-party payersProlonging progression-free survival after first-line treatment in patients with ovarian cancer may delay or prevent the need for later treatment, the financial burden felt by patients, and the economic burden to the health care system associated with subsequent disease progressions.

Pharmacists improve diabetes outcomes: a randomized controlled trial.

BACKGROUND: There is a growing shortage of primary care physicians. Pharmacists can fill the gap, and interdisciplinary teams are being evaluated as part of health care reform. OBJECTIVE: This study aimed to determine whether adding a pharmacist to an interprofessional health team will improve diabetes outcomes. METHODS: In this 2-phase pilot study, Medicaid-eligible patients with diabetes were randomized to receive standard of care (control arm) or standard of care plus the care of a pharmacist (intervention arm) for 12 months (phase 1). The primary outcome was change in glycated hemoglobin (A1C) from baseline. Secondary outcomes included identifying and correcting medication therapy problems (MTPs) for comorbid conditions, adherence to preventive care visits, health care utilization, self-rated health, and satisfaction surveys. After phase 1, patients in the control arm who did not achieve an A1C of < 8% were eligible to enroll into phase 2 where they received treatment with a pharmacist for 6 months. RESULTS: Of the 239 patients enrolled, 122 completed phase 1. At 12 months, intervention patients' mean A1C was 1.85 percentage point (pp) below baseline versus 0.94 pp for control (between-group difference 0.91 pp; P = 0.0218). Most control patients (79%) who completed phase 1 and enrolled into phase 2 improved their A1C by more than 1 pp (P < 0.01). The pharmacists completed 806 patient visits and identified 2638 MTPs. Intervention patients were more adherent to preventive care visits with nutrition (P = 0.043), ophthalmology (P = 0.002), and dentistry (P = 0.007). For intervention patients, 78% rated their experience with the pharmacist as excellent whereas, for control patients, 37% rated their experience with their provider as excellent. CONCLUSION: Pharmacist comanagement of patients with diabetes can significantly improve glucose control and patient satisfaction. Creative payment models were used to include pharmacists in the interprofessional patient care team.

Bulk calibration method of micro-electromechanical system (MEMS) microphones.

In recent years, there has been rapid growth in demand for precision grade micro-electromechanical system microphones (MEMSMs). While new applications are increasingly demanding in terms of MEMSM performance, research and development of the technology is thus far keeping pace. To calibrate all these new MEMSMs, a reliable and cost-efficient method for bulk calibration of MEMSMs is urgently required. This paper describes a pilot version of such a method, carried out at the United Kingdom's National Physical Laboratory. The method was intended for use by MEMSM manufacturers themselves for bulk calibration. It may also be usable by manufacturers of devices that incorporate multiple MEMSMs for bulk calibration of these MEMSMs, provided that they are detachable from the devices' circuit-boards. The uncertainty of the method has been compared to that of the coupler comparison calibration which is a technique for acoustic pressure calibration of precision microphones. It is concluded that the pilot method is promising as the basis of a method for the bulk calibration of precision MEMSMs.

BioID reveals an ATG9A interaction with ATG13-ATG101 in the degradation of p62/SQSTM1-ubiquitin clusters.

ATG9A, the only multi-pass transmembrane protein among core ATG proteins, is an essential regulator of autophagy, yet its regulatory mechanisms and network of interactions are poorly understood. Through quantitative BioID proteomics, we identify a network of ATG9A interactions that includes members of the ULK1 complex and regulators of membrane fusion and vesicle trafficking, including the TRAPP, EARP, GARP, exocyst, AP-1, and AP-4 complexes. These interactions mark pathways of ATG9A trafficking through ER, Golgi, and endosomal systems. In exploring these data, we find that ATG9A interacts with components of the ULK1 complex, particularly ATG13 and ATG101. Using knockout/reconstitution and split-mVenus approaches to capture the ATG13-ATG101 dimer, we find that ATG9A interacts with ATG13-ATG101 independently of ULK1. Deletion of ATG13 or ATG101 causes a shift in ATG9A distribution, resulting in an aberrant accumulation of ATG9A at stalled clusters of p62/SQSTM1 and ubiquitin, which can be rescued by an ULK1 binding-deficient mutant of ATG13. Together, these data reveal ATG9A interactions in vesicle-trafficking and autophagy pathways, including a role for an ULK1-independent ATG13 complex in regulating ATG9A.

Elastomer-Grafted iPSC-Derived Micro Heart Muscles to Investigate Effects of Mechanical Loading on Physiology.

Mechanical loading plays a critical role in cardiac pathophysiology. Engineered heart tissues derived from human induced pluripotent stem cells (iPSCs) allow rigorous investigations of the molecular and pathophysiological consequences of mechanical cues. However, many engineered heart muscle models have complex fabrication processes and require large cell numbers, making it difficult to use them together with iPSC-derived cardiomyocytes to study the influence of mechanical loading on pharmacology and genotype-phenotype relationships. To address this challenge, simple and scalable iPSC-derived micro-heart-muscle arrays (µHM) have been developed. "Dog-bone-shaped" molds define the boundary conditions for tissue formation. Here, we extend the µHM model by forming these tissues on elastomeric substrates with stiffnesses spanning from 5 to 30 kPa. Tissue assembly was achieved by covalently grafting fibronectin to the substrate. Compared to µHM formed on plastic, elastomer-grafted µHM exhibited a similar gross morphology, sarcomere assembly, and tissue alignment. When these tissues were formed on substrates with different elasticity, we observed marked shifts in contractility. Increased contractility was correlated with increases in calcium flux and a slight increase in cell size. This afterload-enhanced µHM system enables mechanical control of µHM and real-time tissue traction force microscopy for cardiac physiology measurements, providing a dynamic tool for studying pathophysiology and pharmacology.

Bilateral Sciatic Neuropathies as a Complication of Positioning During Neuraxial Anesthesia for Cesarean Delivery: A Case Report.

Neurologic complications following neuraxial anesthesia for cesarean delivery are rare. We present a 33-year-old parturient who developed prolonged lower extremity weakness following a single-shot subarachnoid block for cesarean delivery. After neurologic evaluation, she was diagnosed with bilateral sciatic neuropathies due to prolonged positioning for the anesthetic. We review the incidence of nerve injury associated with neuraxial anesthesia and risk factors for developing peripheral nerve injury in this context. We offer a solution to prevent this complication from occurring.

Lambert-Eaton myasthenic syndrome and merkel cell carcinoma.

Lambert-Eaton myasthenic syndrome (LEMS) is an antibody-mediated disorder of the neuromuscular junction that is most commonly diagnosed in association with small cell lung carcinoma (SCLC). Small cell lung carcinoma is histologically similar to the aggressive cutaneous neuroendocrine malignancy Merkel cell carcinoma (MCC). We provide a full report and longitudinal clinical follow-up of a case of LEMS occurring with MCC. We also review the literature on paraneoplastic syndromes associated with MCC and other nonpulmonary small cell carcinomas.