The national financial burden of guideline directed medical therapy for heart failure patients from 2013 to 2021.

BACKGROUND: Guideline Directed Medical Therapy (GDMT) has been revolutionary in improving outcomes of heart failure patients. However, with the addition of more medication classes, the annual cost of these medications on the US healthcare system needs further evaluation. OBJECTIVES: We aim to evaluate the trend of annual cost of GDMT from 2013 to 2021 using the Medicare-part D Database. METHODS: Using Medicare Part D database (2013-2021), we determined the number of beneficiaries receiving these drugs, the total number of 30-day fills for each medication, and the total annual spending on these medications. Linear regression was used to analyze data using Python Programming Language. P value of less than 0.05 was considered to be statistically significant. RESULTS: The estimated annual Medicare- part D spending on empagliflozin had a 50 % increase in cost between 2020 and 2021, which could be attributed to its FDA approval for heart failure with reduced ejection fraction. Empagliflozin cost Medicare 3.73 billion USD in 2021 alone. In addition, sacubitril-valsartan had a strong trajectory since its introduction to the market in 2015. Since its approval in July 2015, it cost Medicare 4.51 billion USD. The Mineralocorticoid Receptor Antagonist class was the least costly class of GDMT. CONCLUSION: The rise in the cost of GDMT is not proportionate amongst the different classes of GDMT. Newer classes of medications cast a significant cost on Medicare in recent years.

Risk assessment and molecular mechanism of Sclerotium rolfsii resistance to boscalid.

Boscalid, a widely used SDHI fungicide, has been employed in plant disease control for over two decades. However, there is currently no available information regarding its antifungal activity against Sclerotium rolfsii and the potential risk of resistance development in this pathogen. In this study, we evaluated the sensitivity of 100 S. rolfsii strains collected from five different regions in China during 2018-2019 to boscalid using mycelial growth inhibition method and assessed the risk of resistance development. The EC50 values for boscalid ranged from 0.2994 µg/mL to 1.0766 µg/mL against the tested strains, with an average EC50 value of 0.7052 ± 0.1473 µg/mL. Notably, a single peak sensitivity baseline was curved, indicating the absence of any detected resistant strains. Furtherly, 10 randomly selected strains of S. rolfsii were subjected to chemical taming to evaluate its resistance risk to boscalid, resulting in the successful generation of six stable and inheritable resistant mutants. These mutants exhibited significantly reduced mycelial growth, sclerotia production, and virulence compared to their respective parental strains. Cross-resistance tests revealed a correlation between boscalid and flutolanil, benzovindiflupyr, pydiflumetofen, fluindapyr, and thifluzamide; however, no cross-resistance was observed between boscalid and azoxystrobin. Thus, we conclude that the development risk of resistance in S. rolfsii to boscalid is low. Boscalid can be used as an alternative fungicide for controlling peanut sclerotium blight when combined with other fungicides that have different mechanisms of action. Finally, the target genes SDHB, SDHC, and SDHD in S. rolfsii were initially identified, cloned and sequenced to elucidate the mechanism of S. rolfsii resistance to boscalid. Two mutation genotypes were found in the mutants: SDHD-D111H and SDHD-H121Y. The mutants carrying SDHD-H121Y exhibited moderate resistance, while the mutants with SDHD-D111H showed low resistance. These findings contribute to our comprehensive understanding of molecular mechanisms underlying plant pathogens resistance to SDHI fungicides.

Description of Solvent-Extractable Chemicals in Thermal Receipts and Toxicological Assessment of Bisphenol S and Diphenyl Sulfone.

Research on thermal receipts has previously focused on the toxic effects of dermal exposure from the most publicized developers (e.g., bisphenol A (BPA) and bisphenol S (BPS)), while no studies have reported on the other solvent-extractable compounds therein. Diphenyl sulfone (DPS) is a sensitizer added to thermal receipts, but little is known about DPS concentrations in receipts or potential toxicity. Here, we quantified BPA, BPS, and DPS concentrations and tentatively identified the solvent-extractable compounds of thermal receipts collected from three South Dakota (USA) cities during 2016-2017. An immortalized chicken hepatic cell line, cultured as 3D spheroids, was used to screen effects of DPS, BPS, and 17ß estradiol (E2; 0.1-1000 µM) on cell viability and gene expression changes. These chemicals elicited limited cytotoxicity with LC50 values ranging from 113 to 143 µM, and induced dysregulation in genes associated with lipid and bile acid homeostasis. Taken together, this study generated novel information on solvent-extractable chemicals from thermal receipts and toxicity data for DPS.

Assessment of Mitochondrial Function in the AmE-711 Honey Bee Cell Line: Boscalid and Pyraclostrobin Effects.

There is a growing concern that chronic exposure to fungicides contributes to negative effects on honey bee development, life span, and behavior. Field and caged-bee studies have helped to characterize the adverse outcomes (AOs) of environmentally relevant exposures, but linking AOs to molecular/cellular mechanisms of toxicity would benefit from the use of readily controllable, simplified host platforms like cell lines. Our objective was to develop and optimize an in vitro-based mitochondrial toxicity assay suite using the honey bee as a model pollinator, and the electron transport chain (ETC) modulators boscalid and pyraclostrobin as model fungicides. We measured the effects of short (~30 min) and extended exposures (16-24 h) to boscalid and pyraclostrobin on AmE-711 honey bee cell viability and mitochondrial function. Short exposure to pyraclostrobin did not affect cell viability, but extended exposure reduced viability in a concentration-dependent manner (median lethal concentration = 4175 µg/L; ppb). Mitochondrial membrane potential (MMP) was affected by pyraclostrobin in both short (median effect concentration [EC50] = 515 µg/L) and extended exposure (EC50 = 982 µg/L) scenarios. Short exposure to 10 and 1000 µg/L pyraclostrobin resulted in a rapid decrease in the oxygen consumption rate (OCR), approximately 24% reduction by 10 µg/L relative to the baseline OCR, and 64% by 1000 µg/L. Extended exposure to 1000 µg/L pyraclostrobin reduced all respiratory parameters (e.g., spare capacity, coupling efficiency), whereas 1- and 10-µg/L treatments had no significant effects. The viability of AmE-711 cells, as well as the MMP and cellular respiration were unaffected by short and extended exposures to boscalid. The present study demonstrates that the AmE-711-based assessment of viability, MMP, and ETC functionality can provide a time- and cost-effective platform for mitochondrial toxicity screening relevant to bees. Environ Toxicol Chem 2024;43:976-987. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Budget Impact Analysis of Utilization of Sacubitril/Valsartan for the Treatment of Heart Failure With Reduced Ejection Fraction in the Philippines.

OBJECTIVES: This study aimed to estimate the financial and economic impact of sacubitril/valsartan compared with enalapril for the treatment and prevention of hospitalization/rehospitalization because of heart failure with reduced ejection fraction (HFrEF). METHODS: The budget impact analysis was guided by the Philippine Reference Case and ISPOR's Principles of Good Practice for Budget Impact Analysis. A government-funded healthcare payer perspective and a societal perspective were considered. Data collection was guided by the pathways of disease progression and care. Collection of costing data followed a bottom-up approach. The model was based on a Markov model used in a study in Thailand. RESULTS: Over the next 5 years, there will be 17 625 less hospitalizations (∼5.1% less than enalapril arm) and 7968 less cardiovascular-related deaths (∼7.0% less than enalapril arm). In 5 years, the total cost of treating patients with HFrEF with sacubitril/valsartan at current market coverage and annual growth conditions is ₱15.430 billion, which is ₱11.077 billion higher than fully treating with enalapril only. The total required additional investment with treatment of sacubitril/valsartan compared with the full enalapril arm are ₱407 million (at 30-day coverage), ₱800 million (at 60-day coverage), and ₱1.181 billion (at 90-day coverage). If hospitalizations costs alone are considered, only the 30-day coverage is cost-saving. If a societal perspective is considered, all options are cost-saving where at least ₱4.003 billion is saved by the economy. CONCLUSION: The initial investment required to treat patients with HFrEF with sacubitril/valsartan is high; nevertheless, the year-on-year cost deficit shrinks in favor of investing in sacubitril/valsartan treatment.

Sacubitril/Valsartan for Heart Failure with Preserved Ejection Fraction: A Cost-Effectiveness Analysis from the Perspective of the Chinese Healthcare System.

BACKGROUND AND OBJECTIVES: Sacubitril/valsartan has shown effectiveness in reducing hospitalization compared with valsartan in HFpEF patients with heart failure with preserved ejection fraction (HFpEF). We aimed to investigate the cost effectiveness of sacubitril/valsartan as an alternative to valsartan in Chinese patients with heart failure with HFpEF. METHODS: A Markov model was built to investigate the cost effectiveness of sacubitril/valsartan as an alternative to valsartan in Chinese patients with HFpEF, from the healthcare system perspective. The time horizon was a lifetime, with a cycle length of 1 month. Costs were obtained from local information or published papers, discounted at a rate of 0.05 for future costs. The transition probability and utility were based on other studies. The primary outcome of the study was the incremental cost-effectiveness ratio (ICER). Sacubitril/valsartan was considered cost effective if the ICER obtained was lower than the willingness-to-pay threshold of US dollars (US$) 12,551.5 per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses, as well as scenario analysis, were performed to test robustness. RESULTS: Over a lifetime simulation, a 73-year-old Chinese patient with HFpEF could gain 6.44 QALYs (9.15 life-years) if sacubitril/valsartan plus standard treatment was administered, and 6.37 QALYs (9.07 life-years) if valsartan plus standard treatment was prescribed. The corresponding costs in both groups were US$12,471 and US$8663, respectively. The ICER was US$49,019/QALY (US$46,610/life-year), higher than the willingness-to-pay threshold. Sensitivity analyses and scenario analysis showed that our results were robust. CONCLUSION: Adding sacubitril/valsartan to standard treatment as an alternative to valsartan for the treatment of HFpEF resulted in more effectiveness but higher costs. Sacubitril/valsartan was likely to not be cost effective in Chinese patients with HFpEF. The cost of sacubitril/valsartan needs to reduce to 34% of its current price to be cost effective in this population. Studies based on real-world data are needed to confirm our conclusions.

Deciding Whether to Take Sacubitril/Valsartan: How Cardiologists and Patients Discuss Out-of-Pocket Costs.

Background Out-of-pocket costs have significant implications for patients with heart failure and should ideally be incorporated into shared decision-making for clinical care. High out-of-pocket cost is one potential reason for the slow uptake of newer guideline-directed medical therapies for heart failure with reduced ejection fraction. This study aims to characterize patient-cardiologist discussions involving out-of-pocket costs associated with sacubitril/valsartan during the early postapproval period. Methods and Results We conducted content analysis on 222 deidentified transcripts of audio-recorded outpatient encounters taking place between 2015 and 2018 in which cardiologists (n=16) and their patients discussed whether to initiate, continue, or discontinue sacubitril/valsartan. In the 222 included encounters, 100 (45%) contained discussions about cost. Cost was discussed in a variety of contexts: when sacubitril/valsartan was initiated, not initiated, continued, and discontinued. Of the 97 cost conversations analyzed, the majority involved isolated discussions about insurance coverage (64/97 encounters; 66%) and few addressed specific out-of-pocket costs or affordability (28/97 encounters; 29%). Discussion of free samples of sacubitril/valsartan was common (52/97 encounters; 54%), often with no discussion of a longer-term plan for addressing cost. Conclusions Although cost conversations were somewhat common in patient-cardiologist encounters in which sacubitril/valsartan was discussed, these conversations were generally superficial, rarely addressing affordability or cost-value judgments. Cardiologists frequently provided patients with a course of free sacubitril/valsartan samples without a plan to address the cost after the samples ran out.

Spatial distribution, sources identification, and health risk assessment polycyclic aromatic hydrocarbon compounds and polychlorinated biphenyl compounds in total suspended particulates (TSP) in the air of South Pars Industrial region-Iran.

South Pars Industrial Energy Zone, located in the southwest of Iran along the Persian Gulf coast, encompasses many industrial units in the vicinity of urban areas. This research study investigated the effects of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) on human health and the environment. Suspended particulate matters (SPM) in the air sampled, in summer and winter 2019, from ten stations next to industrial units and residential areas. The samples were analyzed by gas chromatography-mass spectrometry (GC-MS). Spatial distribution maps of pollutants in the region were prepared using GIS software. The highest carcinogenic risk due to PAHs and PCBs measured as ([Formula: see text]) and ([Formula: see text], respectively. According to the US Environmental Protection Agency limit ([Formula: see text]), the cancer risks from PAH compounds were significant and need further investigation. The PCB cancer risks were within acceptable ranges. The highest adsorption ratios for PAHs were obtained through skin and PCBs by ingestion. The maximum measured non-carcinogenic hazard indexes (HI) turned out to be 0.037 and 0.023 for PAH and PCB, respectively, and were reported as acceptable risks. The predominant source of PAH in industrial areas was liquid fossil combustion, and in urban areas replaced by coal-wood-sugarcane combustion. Petrochemical complexes, flares, power plants (69%), electric waste disposal sites, and commercial pigments (31%) were reported as PCB sources. Industries activities were the most effective factors in producing the highest level of carcinogenic compounds in the region, and it is necessary to include essential measures in the reform programs.

Risk of Acute Kidney Injury Among Older Adults With Heart Failure and With Reduced Ejection Fraction Treated With Angiotensin-Neprilysin Inhibitor vs Renin-Angiotensin System Inhibitor in Routine Clinical Care.

BACKGROUND: The acute hemodynamic effects of sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), may result in early changes in kidney function, raising concerns about acute kidney injury (AKI), particularly in those who are naïve to renin-angiotensin system inhibitors (RASis). METHODS: We conducted a cohort study using U.S. Medicare fee-for-service claims data (2014-2017). Patients with HFrEF ≥ 65 years newly initiating ARNI or RASi, with no prior use of either drug class, were included. The primary outcome was hospitalization due to AKI as the primary discharge diagnosis, and the secondary outcome included AKI as a primary or secondary discharge diagnosis. AKI risks were described under an as-treated follow-up approach, with censoring on treatment discontinuation, switch, insurance disenrollment, death, or administrative censoring as well as an intent-to-treat approach. Propensity-score-based fine-stratification weighting was used to account for potential confounding by 81 pre-exposure characteristics. Cumulative incidence functions were used to report absolute risks, and Cox proportional hazards models were used to provide hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We included 27,166 patients with a mean (SD) age of 73 (7.3) years, and 4155 (15.3%) were initiating ARNI. After propensity score weighting, the 180-day cumulative incidence was 2.7% (2.4%-3.1%) among RASi initiators and 2.7% (2.2%-3.5%) among ARNI initiators for the primary outcome, and it was 6.5% (6.0%-7.1%) and 6.1% (5.2%-7.1%), respectively, for the secondary outcome under as-treated follow-up. HR (95% CI) comparing ARNI with RASi were 0.91 (95% CI: 0.72-1.16) for the primary outcome and 0.92 (95% CI: 0.79-1.08) for the secondary outcome. Similar results were observed in the intent-to-treat analysis. CONCLUSIONS: Among a large cohort of U.S. Medicare beneficiaries with HFrEF, ARNI treatment was not associated with higher rates of AKI than RASi treatment. These results provide reassurance for providers considering ARNI initiation in older patients who are RASi-naïve.

Monitoring antioxidants by coulometry: Quantitative assessment of the strikingly high antioxidant capacity of bergamot (Citrus bergamia R.) by-products.

A recently optimized rapid, cheap, and accurate coulometric method has been exploited to determine the antioxidant capacity of bergamot (Citrus bergamia Risso) by-products, including first (FPJ) and second press juices (SPJ), in comparison to analogous products from several citrus species. Extracts from the entire edible part (i.e., juice and pulp) and de-oiled peel of bergamot were also assayed. The Coulometrically Determined Antioxidant Capacity (CDAC) data, expressed as moles of electrons per mass of sample, were evaluated with other parameters such as total phenolic compounds, ascorbic acid, total carotenoids, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical inhibition. The CDAC of bergamot FPJ (39 mmol e- kg-1) was comparable with other citrus juices (20-65 mmol e- kg-1 range), whereas the CDAC of bergamot SPJ (816 mmol e- kg-1) was strikingly higher than the counterparts from other citrus fruits. This value approached that of bergamot peel extracts (822 mmol e- kg-1). Bergamot peel and SPJ also exhibited the highest DPPH inhibition. The CDAC values were associated with the HPLC-determined content of flavonoids, namely neoeriocitrin, naringin, and neohesperidin, which were 4-10-fold more concentrated in bergamot SPJ and peel than in SPJ from other citrus species. These findings contribute to point at bergamot by-products as rich sources of antioxidant compounds on a quantitative basis, highlighting their enormous potential for pharmaceutical, nutraceutical and food applications.

Sacubitril-valsartan for the treatment of hypertension in China: A cost-utility analysis based on meta-analysis of randomized controlled trials.

Background: Sacubitril-valsartan was recommended for heart failure (HF) and proven cost-effective in HF. Recently, sacubitril-valsartan has been recommended to treat hypertension by the Chinese expert consensus. The cost utility of sacubitril-valsartan for hypertension remains uninvestigated. Methods: A meta-analysis of randomized controlled trials (RCTs) was performed to investigate the real efficacy of sacubitril-valsartan on blood pressure, compared with angiotensin receptor blockers or placebo. A lifetime Markov model was developed to compare the cost utility of sacubitril-valsartan vs. valsartan. The primary outcome was the incremental cost-utility ratio (ICUR), representing the ratio of incremental costs to the incremental utility. The willingness-to-pay (WTP) threshold was three times of per capita gross domestic product (GDP) in China in 2021. Sacubitril-valsartan was considered cost-effective if the ICUR obtained was lower than the WTP threshold, otherwise, sacubitril-valsartanis was not cost-effective. Results: A total of 10 RCTs of 5,781 patients were included in the meta-analysis. For comparison of sacubitril-valsartan 400 mg/day vs. valsartan 320 mg/day, a reduction in blood pressure (BP) of -5.97 (-6.38, -5.56) (p < 0.01) was observed. Cost-utility analysis showed that for a 60-year-old patient with hypertension, if sacubitril-valsartan was prescribed as the antihypertensive agent, he had a life expectancy of 11.91 quality-adjusted life-years (QALYs) with costs of 65,066 CNY, and if valsartan was prescribed as the antihypertensive agent, the life expectancy would be 11.82 QALY with costs of 54,769 CNY; thus, an ICUR of 108,622 CNY/QALY was obtained, lower than the WTP threshold. Conclusion: Compared with valsartan, sacubitril-valsartan is more effective in reducing blood pressure and may result in more quality-adjusted life-year, although with higher costs. Sacubitril-valsartan is cost-effective for hypertension in the current China setting under the willingness-to-pay threshold of 3 times of per capita GDP.

Exposure assessment of aryl-organophosphate esters based on specific urinary biomarkers and their associations with reproductive hormone homeostasis disruption in women of childbearing age.

The effects of aryl-organophosphate esters (aryl-OPEs) on female reproduction health are still unclear owing to the lack of specific exposure biomarkers. Here, we analyzed the hydroxylated metabolites of three aryl-OPEs (phenyl diphenyl phosphate [TPhP], 2-ethylhexyl diphenyl phosphate [EHDPP], and tricresyl phosphate [TCrP]) and diphenyl phosphate (DPhP) in urine samples from 913 women of childbearing age, and explored the association between exposure to the aryl-OPEs and reproductive hormone levels. The detection frequencies of 2-ethyl-5-hydroxyhexyl diphenyl phosphate (5-OH-EHDPP), phenyl di-p-tolyl phosphate (4-OH-MDTP), and 4-hydroxyphenyl diphenyl phosphate (4-OH-TPhP) were 94.6 %, 93.3 %, and 84.2 %, respectively. Multivariate linear regression analyses revealed that the quartiles of 4-OH-TPhP were positively associated with the progesterone (P4) level (p-trend = 0.008), and the P level in the highest quartile of 5-OH-EHDPP was 7.2 % (95 % CI, 5.7 % to 8.7 %) higher than that in the lowest quartile. The 17ß-estradiol levels in the highest quartiles of 4-OH-TPhP and 5-OH-EHDPP were 15.0 % (95 % CI, 13.7 % to16.1 %) and 5.9 % (95 % CI, 15.7 % to 16.1 %) lower than those in the lowest quartiles, respectively. The anti-Müllerian hormone level linearly increased across the quartiles of 4-OH-MDTP (p-trend = 0.036), and the follicle-stimulating hormone exhibited the opposite trend (p-trend = 0.0047). These results indicate that aryl-OPEs may disrupt hormone homeostasis using their specific biomarkers and may negatively affect female reproduction.

Use and Out-of-Pocket Cost of Sacubitril-Valsartan in Patients With Heart Failure.

Background Current guidelines recommend use of sacubitril-valsartan in patients with heart failure with reduced ejection fraction (HFrEF). Early data suggested low uptake of sacubitril-valsartan, but contemporary data on real-world use and their associated cost are limited. Methods and Results This was a retrospective study of individuals enrolled in Optum Clinformatics, a national insurance claims data set from 2016 to 2018. We included all adult patients with HFrEF with 2 outpatient encounters or 1 inpatient encounter with an International Classification of Diseases, Tenth Revision (ICD-10), diagnosis of HFrEF and 6 months of continuous enrollment, also receiving ß-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers within 6 months of HFrEF diagnosis. We included 70 245 patients with HFrEF, and 5217 patients (7.4%) received sacubitril-valsartan prescriptions. Patients receiving care through a cardiologist compared with a primary care physician alone were more likely to receive sacubitril-valsartan (odds ratio, 1.61 [95% CI, 1.52-1.71]). Monthly out-of-pocket (OOP) cost for sacubitril-valsartan, compared with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, was higher for both commercially insured patients (mean, $69 versus $6.74) and Medicare Advantage (mean, $62 versus $2.52). For patients with commercial insurance, OOP cost was lower in 2016 than in 2018. For patients with Medicare Advantage, there was a significant geographic variation in the OOP costs across the country, ranging from $31 to $68 per month across different regions, holding all other patient-related factors constant. Conclusions Sacubitril-valsartan use was infrequent among patients with HFrEF. Patients receiving care with a cardiologist were more likely to receive sacubitril-valsartan. OOP costs remain high, potentially limiting use. Significant geographic variation in OOP costs, unexplained by patient factors, was noted.

In vitro cytocompatibility assessment and antibacterial effects of quercetin encapsulated alginate/chitosan nanoparticle.

The present work aims at evaluating the in vitro biocompatibility, antibacterial activity and antioxidant capacity of the fabricated and optimized Alginate/Chitosan nanoparticles (ALG/CSNPs) and quercetin loaded Alginate/Chitosan nanoparticles (Q-ALG/CSNPs) with an improved biological efficacy on the hydrophobic flavonoid.The physicochemical properties were determined by TEM and FTIR analysis. The nanoparticles evaluated for the encapsulation of quercetin exerted % encapsulation efficiency (EE) that varied between 76 and 82.4 % and loading capacity (LC) from 31 to 46.5 %. Potential cytotoxicity of the ALG/CSNPs and Q-ALG/CSNPs upon L929 fibroblast cell line was evaluated by MTT reduction Assay and expressed as % cell viability. The in vitro antibacterial property was studied by well diffusion method against gram-positive bacteria Staphylococcus aureus (ATCC 25925) and gram-negative bacteria Escherichia coli (ATCC 25923). The inhibitory efficacy by scavenging free radical intermediates was evaluated by 1,1, diphenyl 2-picrylhydrazyl (DPPH) assay. The results of in vitro cytotoxicity showed biocompatibility towards L929 cells. Quercetin loaded Alginate/Chitosan nanoparticles inhibited the growth of microorganisms than pure quercetin. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging results have shown a high level of antioxidant property for encapsulated Quercetin in Alginate/Chitosan nanoparticles compared to free Quercetin. The findings of our study suggest that the developed ALG/CSNPs and Q-ALG/CSNPs possess the prerequisites and be proposed as a suitable system for delivering quercetin with enhanced therapeutic effectuality.

Dissipation Residue Behaviors and Dietary Risk Assessment of Boscalid and Pyraclostrobin in Watermelon by HPLC-MS/MS.

Fungicides containing active ingredients of boscalid and pyraclostrobin have been widely applied in watermelon disease control. To provide data for avoiding health hazards caused by fungicides, we investigated its terminal residues and evaluated the dietary risk. In this work, watermelon samples were collected from field sites in six provinces and analyzed with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The average recoveries of boscalid and pyraclostrobin in the watermelon matrix were 97-108% and 93-103%, respectively, with the relative standard deviations (RSDs) ≤ 9.1%. The limits of quantifications (LOQs) were 0.01 and 0.005 mg/kg for boscalid and pyraclostrobin. Twenty-one days after applying the test pesticide with 270 g a.i./ha, the terminal residues of boscalid and pyraclostrobin were all below 0.05 mg/kg and below the maximum residue limits (MRLs) recommended by European Food Safety Authority (EFSA). According to the national estimated daily intake (NEDI), the risk quotients (RQs) of boscalid and pyraclostrobin were 48.4% and 62.6%, respectively. That indicated the pesticide evaluated in watermelon exhibited a low dietary risk to consumers. All data provide a reference for the MRL establishment of boscalid in watermelon for China.

Cost-benefit analysis of sacubitril/valsartan in a Medicaid population.

OBJECTIVE: To evaluate the cost-benefit of sacubitril/valsartan in adults with heart failure (HF) enrolled in a state Medicaid plan to prevent HF-related hospitalizations and emergency department (ED) visits. STUDY DESIGN: Retrospective, claims-based, cost-benefit study. METHODS: This exploratory cost-benefit study evaluated Massachusetts Medicaid (MassHealth) members with HF who had an initial pharmacy claim for sacubitril/valsartan between July 7, 2015, and August 31, 2018 (index date). Efficacy outcomes, HF-related hospitalizations and ED visits, and cost outcomes for HF-related medical and pharmacy claims were compared 1 year pre- and post index date. Benefit-cost ratio and net benefit were calculated for all members. A subgroup analysis evaluated the outcomes for members who were adherent to sacubitril/valsartan. RESULTS: A total of 22 members were identified for the study. There were fewer hospitalizations and ED visits post sacubitril/valsartan initiation in the overall population (post vs pre-: 23 vs 26) and among 12 members adherent to sacubitril/valsartan (10 vs 12). The median (IQR) cost for hospitalizations and ED visits was lower during the postindex period ($576 [$19,439] vs $132 [$11,692]) whereas the median (IQR) cost for HF pharmacotherapies was greater during the postindex period ($4578 [$3033] vs $270 [$255]). The benefit-cost ratio and net benefit were 0.91 and -$336, respectively, for all members and 1.43 and $2337, respectively, for members adherent to sacubitril/valsartan. CONCLUSIONS: The benefit as demonstrated by the cost avoidance of HF-related hospitalizations and ED visits did not outweigh the additional costs of sacubitril/valsartan, but cost-benefit was observed in members who were adherent to sacubitril/valsartan.

Sacubitril/valsartan use patterns among older adults with heart failure in clinical practice: a population-based cohort study of >25 000 Medicare beneficiaries.

AIMS: Sacubitril/valsartan is strongly supported in guidelines for the management of heart failure, but suboptimal adherence and treatment non-persistence may limit the population-level benefit that this therapy might otherwise offer. METHODS AND RESULTS: We identified a cohort of Medicare beneficiaries (2014-2017) initiating sacubitril/valsartan after ≥6 months of continuous enrolment. We assessed adherence as the proportion of days covered (PDC) and proportion of patients non-persistent (having no prescription available) at 180 days after initiation. We fit a multivariable negative binomial model with a count of adherent days to evaluate independent factors associated with of sacubitril/valsartan adherence. Among 27 063 new sacubitril/valsartan users, most (n = 17 663, 65%) were prescribed low-dose at 24 mg/26 mg and most (n = 19 984, 74%) were switched from prior angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) rather than being RASi treatment naïve. Median 180-day PDC was 86% (25th-75th percentiles 58-98%). Black patients, those with high comorbid disease burden (≥8 comorbidities), and patients with recent hospitalization within 30 days had fewer adherent days, while those treated with preceding ACEi/ARB had more adherent days. Thirty-four percent of patients did not have an active sacubitril/valsartan prescription at day 180. Among these, few had preceding dose down-titrations (6% among patients on 49 mg/51 mg and 9% among patients on 97 mg/103 mg) and 68% did not have a subsequent ACEi/ARB prescription. Among patients who remained persistent, dose up-titrations occurred in 29% of patients who started on 24 mg/26 mg and 27% of patients on 49 mg/51 mg. CONCLUSIONS: Overall adherence to sacubitril/valsartan among Medicare beneficiaries is acceptable, but is lower in Black patients, those with higher comorbidities or those who started therapy after recent hospitalization. While broad implementation of guideline-directed medical therapy is a key priority, additional focused efforts to improve adherence early after hospitalization and among at-risk patients are needed in parallel.

Sacubitril/valsartan vs ACEi/ARB at hospital discharge and 5-year survival in older patients with heart failure with reduced ejection fraction: A decision analysis approach.

BACKGROUND: In clinical trials, sacubitril/valsartan has demonstrated significant survival benefits compared to angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB). Whether older patients with heart failure with reduced ejection fraction (HFrEF) benefit as much, due to higher rates of comorbidities, frailty and drug discontinuation, is unknown. METHODS AND RESULTS: Using a cohort of Medicare beneficiaries hospitalized with HFrEF between 2016 and 2018, we determined all-cause mortality and HF-readmission rates among patients not given ACEi/ARB or sacubitril/valsartan at hospital discharge, by age. We then used risk reductions from the SOLVD, PARADIGM-HF and PIONEER-HF trials to estimate the benefits of ACEi/ARB and sacubitril/valsartan. We then incorporated age-specific estimates of drug discontinuation from Medicare. A Markov decision process model was used to simulate 5-year survival and estimate number needed to treat, comparing discharge on ACEi/ARB vs sacubitril/valsartan by age. After accounting for drug discontinuation rates, which were surprisingly slightly higher among those discharged on ACEi/ARB (2.3%/month vs 1.9%/month), there was a small but significant survival advantage to discharge on sacubitril/valsartan over 5 years (+0.81 months [95% CI 0.80, 0.81]). The benefit of sacubitril/valsartan over ACEi/ARB did not decrease with increasing age - the number needed to treat among 66 to 74-year-old patients was 84 and among 85+ year-old patients was 67. CONCLUSIONS: Even after accounting for "real world" rates of drug discontinuation, discharge on sacubitril/valsartan after conferred a small, but significant, survival advantage which does not appear to wane with increasing age.