Clinical Outcomes in Patients With Refractory Anemia With Excess Blasts (RAEB) Who Receive Hypomethylating Agents (HMAs).

BACKGROUND: We sought to understand the clinical effectiveness associated with use of hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) for patients with refractory anemia with excess blasts (RAEB; an established proxy for higher-risk myelodysplastic syndromes/neoplasms) in contemporary and representative real-world settings. PATIENTS AND METHODS: We used the Surveillance, Epidemiology and End Results (SEER)-Medicare database, a linkage of cancer registry and Medicare claims data, to identify patients aged ≥ 66 years diagnosed with RAEB, between 2009 and 2017 in the United States, and who received AZA or DEC as first-line therapy. Outcomes measured were overall survival (OS), event-free survival (EFS), and incidence of progression-related acute myeloid leukemia (AML). RESULTS: Of 973 eligible patients, 738 (75.8%) received AZA and 235 (24.2%) received DEC; 6.4% received hematopoietic cell transplantation during follow-up. In the overall population, median OS was 13.9 months (95% confidence interval [CI]: 12.9-15.0), median EFS was 5.2 months (95% CI: 4.9-5.7), and 38.0% of patients progressed to AML. Incidences of AML progression and death were 25.6% and 29.9%, respectively, at Year 1, and 34.3% and 44.8%, respectively, at Year 2. There were no significant differences in clinical benefits between AZA and DEC. CONCLUSION: Median OS with both HMAs remained significantly shorter than in the AZA-001 clinical trial, highlighting how patient outcomes vary between clinical and real-world settings. Further research is required to understand why these disparities exist.

Post-remission cytopenia management in patients with AML treated with venetoclax in combination with hypomethylating agents: Pre- versus post-VIALE-A real-world experience from a predominantly US community setting.

BACKGROUND: This retrospective cohort study used an electronic health record-derived, de-identified, US patient-level database to better understand the real-world treatment experience, in a predominantly community setting (80.3% of patients), of venetoclax+hypomethylating agents (HMAs) in routine clinical care, pre- and post-VIALE-A, to determine whether the post-remission cytopenia management insight from VIALE-A was reflected in real-world clinical practice. METHODS: Patients with newly diagnosed acute myeloid leukemia (AML; N = 498), who initiated venetoclax+HMA ≤30 days from AML diagnosis from June 1, 2018, to March 31, 2021, were stratified into pre-(n = 330) and post-(n = 168) VIALE-A cohorts. RESULTS: More patients in the post-(61%) versus pre-(45%) VIALE-A cohort had their first biopsy by 28 ± 14 days post-treatment initiation. Patients underwent bone marrow (BM) assessment earlier in the post- versus pre-VIALE-A cohort, and first identification of response was also earlier (2.5 vs 5.1 months, respectively). More venetoclax schedule modifications post-remission occurred among post-(82.1%) versus pre-(73.8%) VIALE-A responders; the most common reason for modification was treatment toxicities, specifically cytopenia. Treatment survival outcomes were comparable with or without venetoclax schedule modifications. CONCLUSIONS: Findings suggest that venetoclax schedule modifications can be used to manage cytopenia events without adversely affecting outcomes. Opportunities remain to improve earlier BM assessment to determine venetoclax schedule modifications, providing the best chance for optimal treatment outcomes.

Real-World Effectiveness of 8-Week Glecaprevir/Pibrentasvir in Treatment-Naïve, Compensated Cirrhotic HCV Patients.

INTRODUCTION: The EXPEDITION-8 clinical trial has demonstrated that treatment-naïve patients with compensated cirrhosis (TN/CC) of HCV genotypes 1-6 can achieve a 98% intent-to-treat sustained virologic response rate 12 weeks post-treatment with an 8-week glecaprevir/pibrentasvir (G/P) regimen. Further real-world evidence is needed to support the effectiveness of 8-week G/P in a clinical practice setting and to consolidate these treatment recommendations. The aim of this study is to contribute real-world evidence for the effectiveness of an 8-week G/P treatment in TN/CC patients with HCV genotypes 1-6. METHODS: Retrospective real-world data from 494 TN/CC patients with HCV genotypes 1-6 were collected between August 2017 to December 2020 from the Symphony Health Solutions administrative claims database. Demographic and clinical characteristics were collected at baseline. Patients were required to have a follow-up HCV ribonucleic acid level at least 8 weeks or more after the end of treatment. The percentage of patients achieving a sustained virologic response (SVR) is reported. RESULTS: The majority of patients were male (58%) and Caucasian (40%), with a mean age of 58 years; 74%, 12%, 12%, and 1% of patients were HCV genotype 1, 2, 3, and 4-6 infected, respectively. SVR was achieved in 95.5% of all patients. Across patient subgroups, SVR was achieved in 95.6% of patients with HCV genotype 3 and in 93% of HCV patients with a recent diagnosis of illicit drug use or abuse (within 6 months prior to G/P initiation). CONCLUSION: Early real-world evidence indicates high effectiveness of the 8-week G/P regimen in TN/CC patients of HCV genotypes 1-6 from a large US claims database.

Shorter Duration Hepatitis C Virus Treatment is Associated with Better Persistence to Prescription Refills in People Who Inject Drugs: A Real-World Study.

INTRODUCTION: Direct-acting antiviral (DAA) therapy is highly effective in curing hepatitis C virus (HCV) infection in people who inject drugs (PWID). Previous studies showed declining persistence to DAA therapy over the course of treatment. This study compares real-world medication persistence to prescription refills for 8- versus 12-week DAA in treatment-naïve PWID with chronic HCV with compensated cirrhosis or without cirrhosis. METHODS: Symphony Health's claims database was used to collect data from patients with chronic HCV aged ≥ 12 years who were prescribed 8- or 12-week DAA therapy between August 2017 and November 2020 and had a diagnosis of addicted drug use within 6 months prior to index date. Eligible patients had medical/pharmacy claims in the 6 months before and 3 months after the first index medication fill date (i.e., index date). Patients completing all refills (8-week = 1 refill, 12-week = 2 refills) were deemed persistent. The percentage of persistent patients in each group, and at each refill step, was determined; outcomes were also assessed in a subgroup of Medicaid-insured patients. RESULTS: This study assessed 7203 PWID with chronic HCV (8-week, 4002; 12-week, 3201). Patients prescribed 8-week DAA treatment were younger (42.9 ± 12.4 vs 47.5 ± 13.2, P < 0.001) and had fewer comorbidities (P < 0.001). Patients receiving 8- versus 12-week DAA had greater refill persistence (87.9% vs 64.4%, P < 0.001). Similar percentages of patients missed their first refill (8-week, 12.1% vs 12-week, 10.8%); nearly 25% of patients receiving 12-week DAA missed their second refill. After baseline characteristics were controlled, patients prescribed 8- versus 12-week DAA were more likely to be persistent (odds ratio [95% confidence interval] 4.3 [3.8, 5.0]). Findings in the Medicaid-insured subgroup were consistent. CONCLUSION: Patients prescribed 8- vs 12-week DAA therapy had significantly greater prescription refill persistence. Most nonpersistence was due to missed second refills, highlighting the potential benefit of shorter treatment durations in this population.

Electrospun Polyvinylidene Fluoride Piezoelectric Fiber Glass/Carbon Hybrid Self-Sensing Composites for Structural Health Monitoring.

In this study, a polyvinylidene fluoride (PVDF)/graphene nanoplatelet (GNP) micro-nanocomposite membrane was fabricated through electrospinning technology and was employed in the fabrication of a fiber-reinforced polymer composite laminate. Some glass fibers were replaced with carbon fibers to serve as electrodes in the sensing layer, and the PVDF/GNP micro-nanocomposite membrane was embedded in the laminate to confer multifunctional piezoelectric self-sensing ability. The self-sensing composite laminate has both favorable mechanical properties and sensing ability. The effects of different concentrations of modified multiwalled carbon nanotubes (CNTs) and GNPs on the morphology of PVDF fibers and the ß-phase content of the membrane were investigated. PVDF fibers containing 0.05% GNPs were the most stable and had the highest relative ß-phase content; these fibers were embedded in glass fiber fabric to prepare the piezoelectric self-sensing composite laminate. To test the laminate's practical application, four-point bending and low-velocity impact tests were performed. The results revealed that when damage occurred during bending, the piezoelectric response changed, confirming that the piezoelectric self-sensing composite laminate has preliminary sensing performance. The low-velocity impact experiment revealed the effect of impact energy on sensing performance.

A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes.

Patients with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open-label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28-day cycle. Azacitidine was administered on Days 1-7 every cycle at 75 mg/m2 /day intravenously/subcutaneously. Responses were assessed per modified 2006 International Working Group (IWG) criteria. Forty-four patients (male 86%, median age 74 years) received venetoclax + azacitidine treatment. Median follow-up was 21.2 months. Hematological adverse events of Grade ≥ 3 included febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common Grade ≥ 3 infection. Marrow responses were seen including complete remission (CR, n = 3, 7%) and marrow CR (mCR, n = 14, 32%); 36% (16/44) achieved transfusion independence (TI) for RBCs and/or platelets, and 43% (6/14) with mCR achieved hematological improvement (HI). The median time to CR/mCR was 1.2 months, and the median duration of response for CR + mCR was 8.6 months. Median OS was 12.6 months. Venetoclax + azacitidine shows activity in patients with R/R MDS following prior HMA therapy failure and provides clinically meaningful benefits, including HI and TI, and encouraging OS.

Plasma-Modified PI Substrate for Highly Reliable Laser-Sintered Copper Films Using Cu2O Nanoparticles.

Plasma modification of polyimide (PI) substrates upon which electrical circuits are fabricated by the laser sintering of cuprous oxide nanoparticle pastes was investigated systematically in this study. Surface properties of the PI substrate were investigated by carrying out atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS), and contact angle measurements. Experimental results show that surface characteristics of PI substrates, including surface energy, surface roughness, and surface binding significantly affected the mechanical reliability of the sintered copper structure. Among the plasma gases tested (air, O2, Ar-5%H2, and N2-30%H2), O2 plasma caused the roughest PI surface as well as the most C=O and C-OH surface binding resulting in an increased polar component of the surface energy. The combination of all those factors caused superior bending fatigue resistance.

Awareness and Epidemiology of Chronic Hepatitis C Virus Infections in Florida.

INTRODUCTION: Progress towards achieving hepatitis C virus (HCV) elimination in Florida has been hampered by barriers to screening, linkage to care, and treatment. This study aims to describe the HCV care cascade and patient characteristics in Florida. METHODS: This analysis combined HCV-related laboratory data and patient characteristics from two, large US laboratory datasets that included individuals tested for HCV antibody (Ab) and HCV ribonucleic acid (RNA) viral load between January 2015 and December 2019. A decline in sequential HCV RNA viral loads was used to impute HCV treatment. Machine-learning algorithms were used to identify cured patients. The actual number of individuals with HCV Ab screening, and the number and percentage of persons who were HCV RNA-positive and treated, were calculated. RESULTS: The number of persons in Florida diagnosed as HCV RNA-positive was 31,659 in 2019. The number of individuals HCV Ab screened in 2019 was 1,024,379, an increase of 82.5% from 2015. The percentage of HCV Ab-positive individuals was 4.1%, demonstrating a 16.2% decrease from 2015. The percentage of HCV RNA-positive patients who were treated was 27.0%, a 10.5% decrease from 2015 to 2019. CONCLUSION: An Ab positivity rate > 4-times higher than national estimates with increased screening among baby boomers, but decreased screening among younger individuals, suggests risk-based screening is still common practice in Florida, despite universal screening recommendations. Public health efforts to decrease barriers to screening, linkage to care, and treatment are needed to reduce the burden of HCV in Florida and to ensure progress toward virus elimination.

The Netherlands Is on Track to Meet the World Health Organization Hepatitis C Elimination Targets by 2030.

BACKGROUND: The Netherlands strives for hepatitis C virus (HCV) elimination, in accordance with the World Health Organization targets. An accurate estimate when HCV elimination will be reached is elusive. We have embarked on a nationwide HCV elimination project (CELINE) that allowed us to harvest detailed data on the Dutch HCV epidemic. This study aims to provide a well-supported timeline towards HCV elimination in The Netherlands. METHODS: A previously published Markov model was used, adopting published data and unpublished CELINE project data. Two main scenarios were devised. In the Status Quo scenario, 2020 diagnosis and treatment levels remained constant in subsequent years. In the Gradual Decline scenario, an annual decrease of 10% in both diagnoses and treatments was implemented, starting in 2020. WHO incidence target was disregarded, due to low HCV incidence in The Netherlands (≤5 per 100,000). RESULTS: Following the Status Quo and Gradual Decline scenarios, The Netherlands would meet WHO's elimination targets by 2027 and 2032, respectively. From 2015 to 2030, liver-related mortality would be reduced by 97% in the Status Quo and 93% in the Gradual Decline scenario. Compared to the Status Quo scenario, the Gradual Decline scenario would result in 12 excess cases of decompensated cirrhosis, 18 excess cases of hepatocellular carcinoma, and 20 excess cases of liver-related death from 2020-2030. CONCLUSIONS: The Netherlands is on track to reach HCV elimination by 2030. However, it is vital that HCV elimination remains high on the agenda to ensure adequate numbers of patients are being diagnosed and treated.

Epidemiology and Clinical Characteristics of Individuals with Hepatitis C Virus Infection in the United States, 2017-2019.

INTRODUCTION: Hepatitis C virus (HCV) is the most common bloodborne chronic infection in the US. Following approval of highly effective, direct-acting antivirals in 2014, the diagnostic and treatment rates for HCV infection in the US have evolved. This study assessed the number of individuals with HCV screening or diagnostic testing and the clinical characteristics and treatment of HCV-infected individuals between 2017 and 2019. METHODS: Individuals screened for HCV antibody and/or tested for HCV ribonucleic acid (RNA) from 2017 to 2019 by two large US laboratory companies were included in this analysis. Clinical characteristics, such as HCV genotype, fibrosis stage, HIV coinfection and demographics, were assessed in HCV RNA-positive individuals. HCV treatment and subsequent achievement of sustained virologic response were imputed using data-driven algorithms based on successive viral load decline and negativity. RESULTS: From 2017 to 2019, the number of individuals tested for HCV antibody increased by 5.7%, from 7,580,303 in 2017 to 8,009,081 in 2019. The percentage of individuals tested who were HCV antibody positive was stable, ranging from 5.0% in 2017 to 4.9% in 2018 and 2019. The number of HCV RNA-positive individuals decreased by 5.0% from 382,500 in 2017 to 363,532 in 2019. Of HCV RNA-positive individuals, the proportions with genotype (GT) 3 and minimal fibrosis increased over time; proportions of individuals aged < 40 years increased, while the proportion aged 50 to 59 years decreased. Treatment rates increased from 23.4% in 2017 to 26.8% in 2019. CONCLUSIONS: The percentage of HCV antibody-positive individuals remained stable from 2017 to 2019. The number of individuals tested HCV RNA positive decreased over the years. Demographics shifted toward a younger population with less fibrosis and higher rates of GT3. More than 70% of diagnosed individuals were not treated during this interval, highlighting a need for unfettered access to treatment.

Low-Thermal-Budget Photonic Sintering of Hybrid Pastes Containing Submicron/Nano CuO/Cu2O Particles.

Copper oxide particles of various sizes and constituent phases were used to form conductive circuits by means of photonic sintering. With the assistance of extremely low-energy-density xenon flash pulses (1.34 J/cm2), a mixture of nano/submicron copper oxide particles can be reduced in several seconds to form electrical conductive copper films or circuits exhibiting an average thickness of 6 µm without damaging the underlying polymeric substrate, which is quite unique compared to commercial nano-CuO inks whose sintered structure is usually 1 µm or less. A mixture of submicron/nano copper oxide particles with a weight ratio of 3:1 and increasing the fraction of Cu2O in the copper oxide both decrease the electrical resistivity of the reduced copper. Adding copper formate further improved the continuity of interconnects and, thereby, the electrical conductance. Exposure to three-pulse low-energy-density flashes yields an electrical resistivity of 64.6 µΩ·cm. This study not only shed the possibility to use heat-vulnerate polymers as substrate materials benefiting from extremely low-energy light sources, but also achieved photonic-sintered thick copper films through the adoption of submicron copper oxide particles.

Estimating the Year Each State in the United States Will Achieve the World Health Organization's Elimination Targets for Hepatitis C.

INTRODUCTION: Although hepatitis C virus (HCV) infection remains a major clinical, economic, and societal burden, the development of curative antiviral therapy may accelerate the path toward elimination. This analysis assessed the progress of United States (US) states towards achieving the World Health Organization's (WHO) 2030 HCV elimination targets for incidence, mortality, diagnosis, and treatment. METHODS: A previously published Markov model was used to simulate HCV progression over time to estimate the path to HCV elimination in each state based on prevalence, annual treatment, and diagnosis inputs from two large US laboratory datasets from January 2013 to December 2017. State-specific fibrosis stage restrictions on treatment in 2017 were included. The model estimated the year individual states would meet the WHO targets for diagnosing 90% of the HCV-infected population, treating 80% of the eligible population, reducing new HCV infections by 80%, and reducing HCV-related deaths by 65%. The minimum number of annual treatments needed between 2020 and 2030 to achieve the WHO treatment target was also calculated. RESULTS: Overall, the USA is projected to achieve HCV elimination by 2037, with individual targets related to mortality, diagnosis, treatment, and incidence being achieved by 2020, 2027, 2033, and 2037, respectively. Three states (Connecticut, South Carolina, and Washington) are on track to meet all four elimination targets by 2030, and 18 states are not expected to meet these targets before 2040. The estimated annual number of treatments required during 2020-2030 nationally to reach the WHO treatment target is 173,514. CONCLUSION: With the exception of three states, the USA is not on target to meet the WHO 2030 elimination targets and 35% are off track by 10 years or more. Strategies must be implemented to reduce overall prevalence by preventing new infections, increasing rates of screening, improving linkage to care, and implementing unfettered access to curative therapy.

PCSK9 Inhibitors Show Value for Patients and the US Health Care System.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved by the US Food and Drug Administration (FDA) as cholesterol-lowering therapies for patients with familial hypercholesterolemia or atherosclerotic cardiovascular disease. OBJECTIVES: To estimate the long-term health and economic value of PCSK9 inhibitors for Americans (51 years and older). METHODS: We conducted simulations using the Future Elderly Model, an established dynamic microsimulation model to project the lifetime outcomes for the US population aged 51 years and older. Health effects estimates and confidence intervals from published meta-analysis studies were used to project changes in life expectancy, quality-adjusted life-years, and lifetime medical spending resulting from the use of PCSK9 inhibitors. We considered two treatment scenarios: 1) current FDA eligibility and 2) an extended eligibility scenario that includes patients with no pre-existing cardiovascular disease but at high risk. We assumed that the price of PCSK9 inhibitors was discounted by 35% in the first 12 years and by 57% thereafter, with gradual uptake of the drug in eligible populations. RESULTS: Use of PCSK9 inhibitors by individuals covered by current FDA approval would extend life expectancy at the age of 51 years by an estimated 1.1 years and would yield a lifetime net value of $5800 per person. If use was extended to those at high risk for cardiovascular disease, PCSK9 inhibitors would generate a lifetime net benefit of $14,100 per person. CONCLUSIONS: Expanded access to PCSK9 inhibitors would offer positive long-term net value for patients and the US health care system at the current discounted prices.

Quality of Pharmacist-Managed Anticoagulation Therapy in Long-Term Ambulatory Settings: A Systematic Review.

OBJECTIVE: To perform a systematic review to evaluate the quality of warfarin anticoagulation control in outpatient pharmacist-managed anticoagulation services (PMAS) compared with routine medical care (RMC). DATA SOURCES: MEDLINE, SCOPUS, EMBASE, IPA, CINAHL, and Cochrane CENTRAL, from inception to May 2017. Search terms employed: ("pharmacist-managed" OR "pharmacist-provided" OR "pharmacist-led" OR "pharmacist-directed") AND ("anticoagulation services" OR "anticoagulation clinic" OR "anticoagulation management" OR "anticoagulant care") AND ("quality of care" OR "outcomes" OR "bleeding" OR "thromboembolism" OR "mortality" OR "hospitalization" OR "length of stay" OR "emergency department visit" OR "cost" OR "patient satisfaction"). STUDY SELECTION AND DATA EXTRACTION: Criteria used to identify selected articles: English language; original studies (comments, letters, reviews, systematic reviews, meta-analyses, editorials were excluded); warfarin use; outpatient setting; comparison group present; time in therapeutic range (TTR) included as a measure of quality of anticoagulant control; study design was not a case report. DATA SYNTHESIS: Of 177 articles identified, 25 met inclusion criteria. Quality of anticoagulation control was better in the PMAS group compared with RMC in majority of the studies (N = 23 of 25, 92.0%). Clinical outcomes were also favorable in the PMAS group as evidenced by lower or equal risk of major bleeding (N = 10 of 12, 83.3%) or thromboembolic events (N = 9 of 10, 90.0%), and lower rates of hospitalization or emergency department visits (N = 9 of 9, 100%). When reported, PMAS have also resulted in cost-savings in all (N=6 of 6, 100%) of studies. CONCLUSIONS: Compared with routine care, pharmacist-managed outpatient-based anticoagulation services attained better quality of anticoagulation control, lower bleeding and thromboembolic events, and resulted in lower health care utilization.

Positive Outcomes of Varicose Vein Surgery: The Patient Perspective.

BACKGROUND: Patient-reported outcomes are increasingly recognized as important to understanding outcomes of medical interventions such as varicose vein surgery (VVS). Our aim was to compare positive outcomes of VVS as defined by several patient-reported measures, and to identify baseline characteristics associated with positive outcomes of VVS. METHODS: A secondary analysis of the UK Patient-Reported Outcome Measures database was conducted on patients undergoing VVS, in the period 2009-2011 who completed the generic EQ-5D (index and visual analog scale [VAS] summary scores) and disease-specific Aberdeen varicose vein questionnaire (AVVQ). Surgical outcome was defined as positive if pre/post change scores exceeded half a standard deviation of mean baseline scores. Logistic regression models were used to identify significant predictors of positive outcomes, including age, gender, and baseline health. RESULTS: Of 9,113 patients analyzed (71% females, 57% aged >50 years), positive outcomes were identified in 62% using the AVVQ, 43% based on EQ-5D index scores, and 24% according to EQ-VAS; 10% improved on all three measures. Patients with poorer baseline functioning (AVVQ scores ≥ 11) were more likely to have a positive outcome based on the EQ-5D index (odds ratio [OR] 1.23, 95% confidence interval [CI] 1.11-1.36) and EQ-VAS (OR 1.30, 95% CI 1.14-1.47). CONCLUSIONS: Defining surgery as successful will clearly depend on how health-related quality of life (HRQL) is operationalized and the criteria used to identify meaningful change. Across a range of criteria, a consistently greater proportion of patients had positive outcomes in terms of VV-related functioning (via AVVQ) compared with those who improved in terms of generic health (via EQ-index), or self-rated health (EQ-VAS).