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ABSTRACTPaeonia lactiflora (P. lactiflora) has been recently reported to increase the production of proinflammatory mediators and activates phagocytosis in macrophages. Thus, in this study, we tried to verify the macrophage activation of Paeoniae Radix Rubra (PRR, also known as red peony root) and elucidate its mechanism of action. PRR upregulated the production of proinflammatory mediators and activated phagocytosis in RAW264.7 cells. However, these effects were reversed by inhibition of TLR2/4. In addition, the inhibition of p38, JNK, and ERK1/2 reduced the PRR-mediated production of proinflammatory mediators, and the SPL-mediated activation of p38, JNK, and ERK1/2 was blocked by the TLR4 inhibition. These findings indicate that PRR may activate macrophages through TLR4-dependent activation of p38, JNK, and ERK1/2. These indicate that PRR has immunostimulatory activity. Thus, it is believed that PRR can be used as a functional food agent that enhances the immune system.

In this study, we investigated the effect of Solanum nigrum aerial parts (SNAP) on macrophage activation and macrophage autophagy in RAW264.7 cells. SNAP increased the production of immunostimulatory factors and phagocytosis in RAW264.7 cells. TLR4 inhibition blocked SNAP-mediated production of immunostimulatory factors. In addition, the JNK inhibition reduced the SNAP-mediated production of immunostimulatory factors, and the SNAP-mediated JNK activation was blocked by the TLR4 inhibition. SNAP activated macrophage autophagy. TLR4 inhibition blocked SNAP-mediated macrophage autophagy and inhibition of p38 and JNK attenuated SNAP-mediated macrophage autophagy. These findings indicate that SNAP may induce TLR4/JNK-mediated macrophage activation and TLR4/p38 and JNK-mediated macrophage autophagy.

The objective of this study was to investigate the effect of low-molecular-weight fish collagen (valine-glycine-proline-hydroxyproline-glycine-proline-alanine-glycine; LMWCP) on H2O2- or LPS-treated primary chondrocytes and monoiodoacetate (MIA)-induced osteoarthritis rat models. Our findings indicated that LMWCP treatment exhibited protective effects by preventing chondrocyte death and reducing matrix degradation in both H2O2-treated primary chondrocytes and cartilage tissue from MIA-induced osteoarthritis rats. This was achieved by increasing the levels of aggrecan, collagen type I, collagen type II, TIMP-1, and TIMP-3, while simultaneously decreasing catabolic factors such as phosphorylation of Smad, MMP-3, and MMP-13. Additionally, LMWCP treatment effectively suppressed the activation of inflammation and apoptosis pathways in both LPS-treated primary chondrocytes and cartilage tissue from MIA-induced osteoarthritis rats. These results suggest that LMWCP supplementation ameliorates the progression of osteoarthritis through its direct impact on inflammation and apoptosis in chondrocytes.

OBJECTIVES This study aimed to evaluate changes in the cancer treatment rate among patients newly diagnosed with stage IV cancer using socio-demographic and clinical subgroups in a nationwide cohort of Korean patients. METHODS This retrospective, national-level study used the Korea Central Cancer Registry (KCCR), which is linked to the National Health Insurance Service (NHIS) database, from January 1, 2012 to December 31, 2017. The records of patients newly diagnosed with stage IV of the 5 cancers with the highest cancer-related mortality rate were identified to analyze changes in the treatment rate. The main outcome examined in this study was the change in the cancer treatment rate between 2012 and 2017, as measured using the annual percent change (APC). RESULTS A total of 106,082 patients with newly diagnosed gastric, colorectal, liver, pancreatic, and lung cancers at the end of life (EoL) were identified from the KCCR-NHIS database. Of these patients, 76,533 (72.1%) received cancer treatment. Over the study period (2012-2017), the proportion of patients who received cancer treatment at EoL decreased by 8.3%, with an APC of -2.1% (95% confidence interval, -2.6 to -1.6). This declining trend of cancer treatment among patients with advanced cancer stage at EoL was consistent among socio-demographic and clinical subgroups. CONCLUSIONS The proportion of untreated patients with stage IV cancer is increasing in the Korea. For patients who are not undergoing standard cancer treatment near EoL, an alternative care plan, such as early palliative care, should be considered.

Autophagy regulates multiple pathways including YAP/TAZ of the Hippo pathway, but precise mechanisms are unclear as autophagy may either activate or inhibit YAP/TAZ. Here, the authors show that autophagy can either activate or regulate YAP/TAZ via dynamic negative feedback loops involving alpha-catenin.

Rhizopus rot is a serious postharvest disease of various crops caused by Rhizopus spp. and controlled mainly by synthetic fungicides. We detected the antifungal activity of a culture extract of Setosphaeria rostrata F3736 against Rhizopus oryzae. The active ingredient was identified as moriniafungin, a known sordarin derivative, which showed minimum inhibitory concentrations of 1-8 μg/ml against Colletotrichum spp. and 0.03-0.13 μg/ml against Rhizopus spp. in vitro. Moriniafungin showed protective control efficacies against Rhizopus rot on apple and peach fruits. Treatment with 25 μg/ ml moriniafungin delimited the lesion diameter significantly by 100% on R. oryzae-inoculated apple fruits compared with the non-treated control. Treatment with 0.04 μg/ml of moriniafungin reduced the lesion diameter significantly by 56.45%, and treatment with higher concentrations of 0.2-25 μg/ml reduced the lesion diameter by 70-90% on Rhizopus stolonifer var. stolonifer-inoculated peach fruit. These results suggest moriniafungin has potential as a control agent of postharvest diseases caused by Rhizopus spp.

Leucine is a critical amino acid that inhibits autophagy. Here, the authors show that the leucine inhibits autophagy in most cell types, predominantly via its catabolite acetyl CoA, which drives acetylation of raptor, which activates mTORC1, a negative regulator of this catabolic process.

Abstract As a dynamic organelle, mitochondria continuously fuse and divide with adjacent mitochondria. Imbalance in mitochondria dynamics leads to their dysfunction, which implicated in neurodegenerative diseases. However, how mitochondria alteration and glucose defect contribute to pathogenesis of Alzheimer’s disease (AD) is still largely unknown. Dynamin‐related protein 1 (Drp1) is an essential regulator for mitochondria fission. Among various posttranslational modifications, O-GlcNAcylation plays a role as a sensor for nutrient and oxidative stress. In this study, we identified that Drp1 is regulated by O-GlcNAcylation in AD models. Treatment of Aβ as well as PugNAc resulted in mitochondrial fragmentation in neuronal cells. Moreover, we found that AD mice brain exhibits an upregulated Drp1 O-GlcNAcylation. However, depletion of OGT inhibited Drp1 O-GlcNAcylation in Aβ-treated cells. In addition, overexpression of O-GlcNAc defective Drp1 mutant (T585A and T586A) decreased Drp1 O-GlcNAcylation and Aβ-induced mitochondria fragmentation. Taken together, these finding suggest that Aβ regulates mitochondrial fission by increasing O-GlcNAcylation of Drp1.

Abstract Background The goal of this study is to obtain basic information to improve the bone adhesion of silica components, which are used as the main ingredient in glass ionomer cement (GIC). To achieve this, nanorod hydroxyapatite (nHA) was grafted to the surface of silica cover glass. Surface analysis confirmed nHA was joined to the glass surface and biocompatibility with osteoblasts was investigated. Results The grafting of nHA on the surface of slide cover glass (Glass) was confirmed by X-ray photoelectron spectroscopy (XPS) and contact angle (θ) measurement. MC3T3-E1 cells were more stretched out on the nHA-grafted cover glass (Glass-nHA) in comparison to the Glass. In addition, the Glass-nHA was more bioactive in supporting the proliferation of MC3T3-E1 cells in comparison to cells seeded on the Glass. Conclusion The Glass-nHA was to be highly bioactive and this might be useful information for property modification of GIC.

Abstract Background Degenerative knee osteoarthritis is a leading cause of disability in the elderly. If patients do not respond to pharmacological or nonpharmacological intervention, total knee replacement surgery is recommended. However, owing to the contraindications and adverse effects of surgery, the need for a new treatment strategy is emerging. Traditional herbal medicine is a widely used intervention in east Asia to treat knee osteoarthritis. Gyejigachulbutang is one of the frequently prescribed herbal formulae. The aim of our study is to evaluate the efficacy and safety of gyejigachulbutang for knee osteoarthritis. Methods This study is a randomized, placebo-controlled, patient and assessor blinded, superiority clinical trial. A total of 80 patients with knee osteoarthritis will be enrolled. The participants will be randomly assigned to the gyejigachulbutang or placebo group in a 1:1 ratio in two Korean medical hospitals. Every participant will take gyejigachulbutang or placebo at a dose of 2.5 g three times a day for 4 weeks. Additional follow-up will be conducted 4 weeks after treatment completion. Any concomitant treatment to relive knee pain will not be allowed except for rescue medicine (acetaminophen). The primary outcome will be a comparison of the change in the visual analogue scale score for knee pain from baseline to visit 3 (week 4) for both the treatment and placebo groups. Secondary outcomes include clinical relevance, minimal clinically important difference, disability, quality of life, and safety. Discussion This protocol presents a research methodology for clinical trials of gyejigachulbutang for knee osteoarthritis. Various secondary outcomes make this trial more informative. Our trial will provide fundamental evidence for knee osteoarthritis management via herbal medicine treatment. Trial registration Clinical Research Information Service (CRIS), KCT0003024. Registered on 25 July 2018.

BackgroundThoracotomy is an invasive surgical procedure that produces intense postoperative pain. Electroacupuncture has been used to induce analgesia in various situations, including after surgery. The aim of the following systematic review and meta-analysis was to evaluate the effect of electroacupuncture on post-thoracotomy pain.MethodsThe studies for the systematic review were searched using the following 9 databases: PubMed, Cochrane Library, EMBASE, MEDLINE Complete, Google Scholar, China National Knowledge Infrastructure (CNKI), Korean Medical Database (KMBASE), Koreanstudies Information Service System (KISS), and OASIS, without language restriction. Randomized controlled trials (RCTs) that met the inclusion criteria were selected. The quality assessment was performed using the Cochrane risk-of-bias tool, and RevMan 5.3 was used for meta-analysis. The review protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42019142157.ResultsEleven randomized controlled trials were included in the systematic review. The meta-analysis was performed for two outcome measures: pain score 24 hours after surgery and total dose of opioid analgesics. A subgroup analysis was performed according to the control group: sham acupuncture and conventional analgesia group. Pain score 24 hours after surgery of electroacupuncture group showed a standard mean difference of -0.98 (95% CI: -1.62 to -0.35) compared to sham acupuncture. The standard mean difference was -0.94 (95% CI: -1.33 to -0.55) compared to conventional analgesia. The total dose of opioid analgesics of electroacupuncture group showed a standard mean difference values of -0.95 (95% CI: -1.42 to -0.47) compared to sham acupuncture. The standard mean difference was -1.96 (95% CI: -2.82 to -1.10) compared to conventional analgesia.ConclusionCurrent evidence suggests that electroacupuncture might provide useful pain relieving effect on post-thoracotomy patients. However, due to low quality and high heterogeneity of existing data, further rigorously designed studies should be performed to confirm the safety and efficacy.

At high cell density or when plated on soft matrix, YAP/TAZ are redistributed from the nucleus to the cytosol, becoming transcriptionally inactive. Here the authors show that at high cell density, autophagosome formation is impaired due to reduced YAP/TAZ-dependent transcription of actomyosin genes

Given the growing number of Latino English learners and the lack of evidence-based educational opportunities they are provided, we investigated the impact of one potentially effective literacy intervention that targets struggling first-grade Spanish-speaking students: Descubriendo La Lectura (DLL). DLL provides first-grade Spanish-speaking students one-on-one literacy instruction in their native language and is implemented at an individualized pace for approximately 12 to 20 weeks by trained bilingual teachers. Using a multisite, multicohort, student-level randomized controlled trial, we examined the impact of DLL on both Spanish and English literacy skills. In this article, we report findings from the first of three cohorts of students to participate in the study. Analyses of outcomes indicate that treated students outperformed control students on all 11 Spanish literacy assessments with statistically significant effect sizes ranging from 0.34 to 1.06. Analyses of outcomes on four English literacy assessments yielded positive effect sizes, though none were statistically significant.

Galgeuntang (GGT), a traditional herbal medicine, is widely co-administered with acetaminophen (AAP) for treatment of the common cold, but this combination has not been the subject of investigation. Therefore, we investigated the herb–drug interaction between GGT and AAP by population pharmacokinetics (PKs) modeling and simulation studies. To quantify PK parameters and identify drug interactions, an open label, three-treatment, three-period, one-sequence (AAP alone, GGT alone, and AAP and GGT in combination) clinical trial involving 12 male healthy volunteers was conducted. Ephedrine (EPD), the only GGT component detected, was identified using a one-compartment model. The PKs of AAP were described well by a one-compartment model and exhibited two-phase absorption (rapid followed by slow) and first-order elimination. The model showed that EPD significantly influenced the PKs of AAP. The simulation results showed that at an AAP dose of 1000 mg × 4 times daily, the area under the concentration versus time curve of AAP increased by 16.4% in the presence of GGT compared to AAP only. In conclusion, the PKs of AAP were affected by co-administration of GGT. Therefore, when AAP is combined with GGT, adverse effects related to overdose of AAP could be induced possibly.

Drawing on state reading achievement data provided by a California school district, we analyze the achievement impacts of Achieve3000, an intervention designed to offer K-12 students expanded opportunities to acquire literacy skills. Achieve3000 is a personalized, technology-adaptive program to supplement regular instruction in English language arts, science, and social studies. We apply propensity score matching methods to match 1,761 participating Achieve3000 students to 945 similar students to estimate the effects of the Achieve3000 intervention. Applying a doubly-robust regression model, our results suggest that Achieve3000 students outperformed comparison students by a mean effect size of 0.06. Further, two-stage least squares regression models reveal that treatment students' scores increased statistically significantly by 0.001 standard deviations for both each activity completed and for each additional hour of Achieve3000 participation. Despite some problems of implementation, our quasi-experimental evidence of the positive impacts of Achieve3000 suggests a possibly promising way to overcome COVID-19 learning losses through computer-based, one-on-one tutoring at scale.

We present findings across three randomized trials of "Descubriendo la Lectura" (DLL), an intervention designed to improve literacy skills of Spanish-speaking first graders struggling with reading. DLL is a one-to-one Spanish-language literacy program lasting 12-20 weeks offered to a school's lowest performing emerging bilingual first graders. Directly replicating procedures across three cohorts, we examined Spanish and English literacy outcomes for approximately 400 students across 30 schools, 10 districts, and five states. Analyses revealed statistically significant effects of student-level assignment to DLL on all 11 Spanish-language outcomes, with an average impact of d = 0.57. Impacts across the four English-language outcomes were positive but not statistically significant. Descriptive results suggest that the Spanish-language impacts are reliably replicated, most likely due to the intervention's strong implementation supports.

Purpose: This study analyzes the advantages and disadvantages of the electoral mechanism of local education superintendents in South Korea, draws conclusions and makes suggestions for future reforms. Design/methodology/approach: The research method of this study included document analysis and interviews. Document analysis was used to collect and analyze the relevant official documents of education superintendents across countries. Semi-structured interviews were conducted with four professors and two superintendents. Findings: The results of the interviews indicate the following: 1) Korean stakeholders are getting more familiar with the direct election of superintendents, as the interviews indicate a more mature direct election system due to previous experience and public officials taking direct election into account; 2) The direct election of superintendents has advantages and disadvantages. The advantages include increasing the participation of the general public in education, and the disadvantages include conflict between the central government and local superintendents belonging to different political parties. However, the current system is likely to be retained; 3) The superintendent systems in various countries differ due to their respective traditions and social contexts. However, the authors can always learn lessons and implications from foreign countries if the authors compare their education systems with their foreign counterparts. Research limitations/implications: As far research limitations, although this was a small study, it shows the importance of collecting multiple stakeholders' views on the direct election of education superintendents as a basis for future reform of education management. Practical implications: The Korean system for electing superintendents provides a good model for other countries reflecting on the educational autonomy and accountabilities of their own systems. Social implications: The direct election of superintendents provides an example of professionalism, independence and political neutrality in education that other countries can learn from. The separation of general and educational administration in Korea through direct elections protects educational activities from political influence. Originality/value: In terms of originality/value, this study adds a new perspective to the debate about whether the general public should directly elect education superintendents, as well as to the literature on local education management.

The primary cilium is an organelle protruding from the cell body that senses external stimuli including chemical, mechanical, light, osmotic, fluid flow, and gravitational signals. Skin is always exposed to the external environment and responds to external stimuli. Therefore, it is possible that primary cilia have an important role in skin. Ciliogenesis was reported to be involved in developmental processes in skin, such as keratinocyte differentiation and hair formation. However, the relation between skin pigmentation and primary cilia is largely unknown. Here, we observed that increased melanogenesis in melanocytes treated with a melanogenic inducer was inhibited by a ciliogenesis inducer, cytochalasin D, and serum-free culture. However, these inhibitory effects disappeared in GLI2 knockdown cells. In addition, activation of sonic hedgehog (SHH)-smoothened (Smo) signaling pathway by a Smo agonist, SAG inhibited melanin synthesis in melanocytes and pigmentation in a human skin model. On the contrary, an inhibitor of primary cilium formation, ciliobrevin A1, activated melanogenesis in melanocytes. These results suggest that skin pigmentation may be regulated partly by the induction of ciliogenesis through Smo-GLI2 signaling.

Primary cilia are conserved cellular organelles that regulate diverse signaling pathways. Autophagy is a complex process of cellular degradation and recycling of cytoplasmic proteins and organelles, and plays an important role in cellular homeostasis. Despite its potential importance, the role of autophagy in ciliogenesis is largely unknown. In this study, we identified sertraline as a regulator of autophagy and ciliogenesis. Sertraline, a known antidepressant, induced the growth of cilia and blocked the disassembly of cilia in htRPE cells. Following treatment of sertraline, there was an increase in the number of cells with autophagic puncta and LC3 protein conversion. In addition, both a decrease of ATG5 expression and the treatment of an autophagy inhibitor resulted in the suppression of the sertraline-induced activation of autophagy in htRPE cells. Interestingly, we found that genetic and chemical inhibition of autophagy attenuated the growth of primary cilia in htRPE cells. Taken together, our results suggest that the inhibition of autophagy suppresses sertraline-induced ciliogenesis.

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) secrete various beneficial molecules, which have anti-apoptotic activity and cell proliferation. However, the effect of hUCB-MSCs in melanogenesis is largely unclear. In this study, we show that conditioned media (CM) derived from hUCB-MSCs inhibit melanogenesis by regulating microphthalmia-associated transcription factor (MITF) expression via the ERK signalling pathway. Treatment of hUCB-MSC-CM strongly inhibited the alpha-melanocyte stimulating hormone-induced hyperpigmentation in melanoma cells as well as melanocytes. Treatment of hUCB-MSC-CM induced ERK1/2 activation in melanocytes. In addition, inhibition of ERK1/2 suppressed the anti-pigmentation activity of the hUCB-MSC-CM in melanocytes and in vitro artificial skin models. We also found that the expression of MITF was appreciably diminished while expression of phosphorylated MITF, which leads to its proteasomal degradation, was increased in cells treated with hUCB-MSC-CM. These results suggested that hUCB-MSC-CM significantly suppresses melanin synthesis via MITF degradation by the ERK pathway activation.

To date, several regulatory proteins involved in mitochondrial dynamics have been identified. However, the precise mechanism coordinating these complex processes remains unclear. Mitochondrial chaperones regulate mitochondrial function and structure. Chaperonin 10 (Cpn10) interacts with heat shock protein 60 (HSP60) and functions as a co-chaperone. In this study, we found that down-regulation of Cpn10 highly promoted mitochondrial fragmentation in SK-N-MC and SH-SY5Y neuroblastoma cells. Both genetic and chemical inhibition of Drp1 suppressed the mitochondrial fragmentation induced by Cpn10 reduction. Reactive oxygen species (ROS) generation in 3-NP-treated cells was markedly enhanced by Cpn10 knock down. Depletion of Cpn10 synergistically increased cell death in response to 3-NP treatment. Furthermore, inhibition of Drp1 recovered Cpn10-mediated mitochondrial dysfunction in 3-NP-treated cells. Moreover, an ROS scavenger suppressed cell death mediated by Cpn10 knockdown in 3-NP-treated cells. Taken together, these results showed that down-regulation of Cpn10 increased mitochondrial fragmentation and potentiated 3-NP-mediated mitochondrial dysfunction in neuroblastoma cells.

BACKGROUND:Autophagy has paradoxical and complex functions in cancer development, and autophagy-related genes (ATG) are key regulators in autophagy. Until now, more than 30 different ATG proteins have been identified in yeast, and their mammalian counterparts also have been reported. Although the roles of a few ATG proteins in cancer have been characterized, the role of ATG10 is almost completely unknown. METHODOLOGY/PRINCIPAL FINDINGS:To investigate the clinicopathological role of ATG10 in colorectal cancer, we analyzed ATG10 expression in colorectal cancer tissues and cell lines. Protein expression analysis showed that ATG10 is highly increased in colorectal cancer (tissue - 18/37 cases, 48%; cell line -8/12 cell lines, 66%). Immunohistochemical analysis with clinicopathological features indicated a strong association of the up-regulation of ATG10 with tumor lymph node metastasis (p = 0.005) and invasion (p

Clonal hematopoiesis of indeterminate potential (CHIP) allows estimation of clonal dynamics and documentation of somatic mutations in the hematopoietic system. Recent studies utilizing large cohorts of the general population and patients have revealed significant associations of CHIP burden with age and disease status, including in cancer and chronic diseases. An increasing number of cancer patients are treated with immune checkpoint inhibitors (ICIs), but the association of ICI response in non-small cell lung cancer (NSCLC) patients with CHIP burden remains to be determined. We collected blood samples from 100 metastatic NSCLC patients before and after ICI for high-depth sequencing of the CHIP panel and 63 samples for blood single-cell RNA sequencing. Whole exome sequencing was performed in an independent replication cohort of 180 patients. The impact of CHIP status on the immunotherapy response was not significant. However, metastatic lung cancer patients showed higher CHIP prevalence (44/100 for patients vs. 5/42 for controls; p = 0.01). In addition, lung squamous cell carcinoma (LUSC) patients showed increased burden of larger clones compared to lung adenocarcinoma (LUAD) patients (8/43 for LUSC vs. 2/50 for LUAD; p = 0.04). Furthermore, single-cell RNA-seq analysis of the matched patients showed significant enrichment of inflammatory pathways mediated by NF-κB in myeloid clusters of the severe CHIP group. Our findings suggest minimal involvement of CHIP mutation and clonal dynamics during immunotherapy but a possible role of CHIP as an indicator of immunologic response in NSCLC patients. [ABSTRACT FROM AUTHOR]

Aims Pharmacological therapy remains a cornerstone in heart failure (HF) treatment despite the implantation of a cardiac resynchronization therapy (CRT) device. The aim of this study was to investigate the association between (i) drug discontinuation and (ii) long-term adherence to HF pharmacotherapy after CRT implantation and socioeconomic position and multimorbidity. Methods and results We conducted a registry-based cohort study including all patients who underwent a first-time CRT implantation at Aarhus University Hospital from 2000 to 2017. Heart failure pharmacotherapy included beta-blockers (BBs), renin–angiotensin system inhibitors [angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker (ARB)], and mineralocorticoid receptor antagonists (MRAs). Patients were identified using the Danish Pacemaker and International Classification for Disease Registry, and information about medication and comorbidities was obtained through linkage to the Danish health registries. We identified 2007 patients, of whom 1880 (94%) were eligible for inclusion. The cumulative incidence of drug discontinuation at 10 years was 6% [95% confidence interval (CI) 5–8%] for BB, 10% (95% CI 9–12%) for ACEI/ARB, and 24% (95% CI 20–27%) for MRAs. Living alone was associated with higher BB discontinuation rates [hazard ratio (HR) 1.83, 95% CI 1.20–2.79], whereas patients with multimorbidity were more likely to discontinue ACEI/ARB (HR 1.92, 95% CI 1.33–2.80) and MRA therapy (HR 1.51, 95% CI 1.10–2.09). Income and educational level did not influence drug discontinuation rates, and similar adherence patterns were observed across all strata of socioeconomic position and multimorbidity. Conclusion In patients with CRTs, drug discontinuation rates were low, and adherence to HF pharmacotherapy was comparable regardless of socioeconomic position. Living alone and multimorbidity were associated with the discontinuation of specific HF drugs. [ABSTRACT FROM AUTHOR]