Real-World Effectiveness of All-Oral Direct-Acting Antivirals in Patients With Hepatitis C Virus-Related HCC.

The association between direct-acting antiviral (DAA) treatment and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is currently unclear. Hence, we aim to assess the association between DAA treatment and mortality rate among Medicare beneficiaries with HCV-related HCC. This retrospective cohort study screened 19,813 adults in 2013-2019 Surveillance, Epidemiology, and End Results data linked with Medicare data. Patients with HCV-related HCC initiating DAA therapy after their first HCC diagnosis were compared with patients with HCV-related HCC who received no HCV treatment. After inverse probability treatment weighting, multivariable Cox proportional hazards models compared mortality rates between the groups. Subgroup and sensitivity analyses were based on HCC stage (early vs. advanced), type of HCC treatment (curative, palliative, none), and DAA treatment duration. In total 3,777 patients with HCV-related HCC were identified (mean age: 68.2 years, 75.2% male, 61.8% White), of whom 19% initiated DAA therapy. Crude incidence mortality rates were 17.9 and 90.7 deaths per 100 person-years in the DAA and HCV-untreated groups, respectively. Cox regression models indicated that DAA therapy was associated with decreased risk of all-cause mortality (adjusted hazard ratio, 0.33; 95% CI 0.31-0.36). Median survival time was 45.7 (95% CI 40.9-57.9) months in the DAA group and 7.7 (95% CI 7.3-8.2) months in the HCV-untreated group (P < 0.001). All subgroup and sensitivity analyses were consistent with the main analyses. DAA therapy was associated with survival benefits for patients with HCV-related HCC regardless of the stage or type of HCC treatment and should not be withheld from this population of Medicare beneficiaries.

Lumican/Lumikine Promotes Healing of Corneal Epithelium Debridement by Upregulation of EGFR Ligand Expression via Noncanonical Smad-Independent TGFß/TBRs Signaling.

The synthetic peptide of lumican C-terminal 13 amino acids with the cysteine replaced by an alanine, hereafter referred to as lumikine (LumC13C-A: YEALRVANEVTLN), binds to TGFß type I receptor/activin-like kinase5 (TBR1/ALK5) in the activated TGFß receptor complex to promote corneal epithelial wound healing. The present study aimed to identify the minimum essential amino acid epitope necessary to exert the effects of lumikine via ALK5 and to determine the role of the Y (tyrosine) residue for promoting corneal epithelium wound healing. This study also aimed to determine the signaling pathway(s) triggered by lumican-ALK5 binding. For such, adult Lum knockout (Lum-/-) mice (~8-12 weeks old) were subjected to corneal epithelium debridement using an Agerbrush®. The injured eyes were treated with 10 µL eye drops containing 0.3 µM synthetic peptides designed based on the C-terminal region of lumican for 5-6 h. To unveil the downstream signaling pathways involved, inhibitors of the Alk5 and EGFR signaling pathways were co-administered or not. Corneas isolated from the experimental mice were subjected to whole-mount staining and imaged under a ZEISS Observer to determine the distance of epithelium migration. The expression of EGFR ligands was determined following a scratch assay with HTCE (human telomerase-immortalized cornea epithelial cells) in the presence or not of lumikine. Results indicated that shorter LumC-terminal peptides containing EVTLN and substitution of Y with F in lumikine abolishes its capability to promote epithelium migration indicating that Y and EVTLN are essential but insufficient for Lum activity. Lumikine activity is blocked by inhibitors of Alk5, EGFR, and MAPK signaling pathways, while EGF activity is only suppressed by EGFR and MAPK inhibitors. qRT-PCR of scratched HTCE cells cultures treated with lumikine showed upregulated expression of several EGFR ligands including epiregulin (EREG). Treatment with anti-EREG antibodies abolished the effects of lumikine in corneal epithelium debridement healing. The observations suggest that Lum/lumikine binds Alk5 and promotes the noncanonical Smad-independent TGFß/TBRs signaling pathways during the healing of corneal epithelium debridement.

Cost-effectiveness of early vs delayed use of abemaciclib combination therapy for patients with high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative early breast cancer.

BACKGROUND: Abemaciclib was newly approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high-risk early breast cancer (EBC). Clinical guidelines recommended abemaciclib as the first-line treatment for HR+/ HER2- EBC (early use) or HR+/ HER2- metastatic breast cancer (MBC) (delayed use). OBJECTIVE: To compare the cost-effectiveness of early vs delayed use of abemaciclib for treatment of HR+/HER2- high-risk EBC. Early use was defined as combined abemaciclib and endocrine therapy as first-line therapy for EBC, followed by treatment with fulvestrant for MBC. Delayed use was defined as endocrine therapy for EBC, followed by combined abemaciclib and fulvestrant therapy for MBC. METHODS: A 5-state model was developed to estimate lifetime costs, life-years (LYs), and quality-adjusted life-years (QALYs) of hypothetical patients with HR+/ HER2- EBC from a third-party US payer's perspective. Key clinical and safety data were derived from the monarchE and MONARCH 2 clinical trials. Costs, utilities, and disutility values of adverse events were obtained from the literature. We calculated the incremental cost-effectiveness ratio (ICER) of early vs delayed abemaciclib use and compared it with a willingness-to-pay (WTP) threshold of $100,000 per LY or QALY. Deterministic and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case model. RESULTS: Base-case analysis showed early use yielded 21.08 LYs and 17.93 QALYs for $586,213 and delayed use yielded 11.14 LYs and 9.38 QALYs for $157,576. The ICER of early vs delayed use was $43,136/LY and $50,104/QALY, which was cost-effective at the WTP threshold of $100,000. The PSA result indicated that a 94.6% likelihood of early use (vs delayed use) was cost-effective at the WTP threshold of $100,000 per QALY. CONCLUSIONS: This study suggests that giving abemaciclib in the early stage rather than waiting until patients develop metastatic disease (current standard of care in MBC) is a cost-effective strategy.

Nanoscaled biphasic calcium phosphate modulates osteogenesis and attenuates LPS-induced inflammation.

Micron-scale structure biphasic calcium phosphate (BCP) materials have demonstrated promising clinical outcomes in the field of bone tissue repair. However, research on biphasic calcium phosphate materials at the nanoscale level remains limited. In this study, we synthesize granular-shaped biphasic calcium phosphate nanomaterials with multiple desirable characteristics, including negatively charged surfaces, non-cytotoxicity, and the capability to penetrate cells, using a nanogrinding dispersion process with a polymeric carboxylic acid as the dispersant. Our results reveal that treating human osteoblasts with 0.5 µg/mL biphasic calcium phosphate nanomaterials results in a marked increase in alkaline phosphatase (ALP) activity and the upregulation of osteogenesis-related genes. Furthermore, these biphasic calcium phosphate nanomaterials exhibit immunomodulatory properties. Treatment of THP-1-derived macrophages with BCP nanomaterials decreases the expression of various inflammatory genes. Biphasic calcium phosphate nanomaterials also mitigate the elevated inflammatory gene expression and protein production triggered by lipopolysaccharide (LPS) exposure in THP-1-derived macrophages. Notably, we observe that biphasic calcium phosphate nanomaterials have the capacity to reverse the detrimental effects of LPS-stimulated macrophage-conditioned medium on osteoblastic activity and mineralization. These findings underscore the potential utility of biphasic calcium phosphate nanomaterials in clinical settings for the repair and regeneration of bone tissue. In conclusion, this study highlights the material properties and positive effects of biphasic calcium phosphate nanomaterials on osteogenesis and immune regulation, opening a promising avenue for further research on inflammatory osteolysis in patients undergoing clinical surgery.

Improving the Efficiency of Medication Reconciliation in Two Taiwanese Hospitals by Using the Taiwan National Health Insurance PharmaCloud Medication System.

Purpose: Medication reconciliation (MedRec) is a process to ensure complete and accurate communication of patient medication information throughout care transitions to prevent medication errors. Hospitals in Taiwan have stride to implement a universal protocol for MedRec. To establish a feasible protocol indigenously, the World Health Organization (WHO) protocol was incorporated with the Taiwan National Health Insurance (NHI) PharmaCloud patient medication profile. The efficiency and error detection capability of this modified protocol was evaluated in two hospitals. Methods: A prospective, non-randomized, unblinded, multicenter cohort study was conducted. Subjects were recruited among patients admitted for colorectal or orthopedic surgery with at least 4 or more chronic drugs. To obtain the best possible medication history (BPMH), the control group was conducted according to the WHO protocol, and the experimental group used the modified WHO protocol with the medication data from the PharmaCloud system. The time spent on the two protocols was recorded. Admission and discharge orders were reconciled against the BPMH to identify any discrepancies. Discrepancies were evaluated by appropriateness, prescribing intentions, and types of inappropriateness. The levels of potential harm were classified for inappropriate discrepancies. Results: The mean time to obtain BPMH in the control group was 34.3±10.8 minutes and in the experimental group 27.5±11.5 minutes (P = 0.01). The experimental group had more subjects with discrepancies (87.9%) than the control (58.3%) (p < 0.001). The discrepancies in both admission and discharge orders for the experimental group (84.5 and 67.2%) were higher than those of the control (47.9 and 37.5%). Many inappropriate discrepancies were classified as the potential harm of level 2 (77.8%). Conclusion: Through the establishment of BPMH with the medication data from the Taiwan NHI PharmaCloud, MedRec could be achieved with greater efficiency and error detection capability in both the admission and discharge order validation processes.

Experimental evaluation of stiffening effect induced by UVA/Riboflavin corneal cross-linking using intact porcine eye globes.

UVA/riboflavin corneal cross-linking (CXL) is a common used approach to treat progressive keratoconus. This study aims to investigate the alteration of corneal stiffness following CXL by mimicking the inflation of the eye under the in vivo loading conditions. Seven paired porcine eye globes were involved in the inflation test to examine the corneal behaviour. Cornea-only model was constructed using the finite element method, without considering the deformation contribution from sclera and limbus. Inverse analysis was conducted to calibrate the non-linear material behaviours in order to reproduce the inflation test. The corneal stress and strain values were then extracted from the finite element models and tangent modulus was calculated under stress level at 0.03 MPa. UVA/riboflavin cross-linked corneas displayed a significant increase in the material stiffness. At the IOP of 27.25 mmHg, the average displacements of corneal apex were 307 ± 65 µm and 437 ± 63 µm (p = 0.02) in CXL and PBS corneas, respectively. Comparisons performed on tangent modulus ratios at a stress of 0.03 MPa, the tangent modulus measured in the corneas treated with the CXL was 2.48 ± 0.69, with a 43±24% increase comparing to its PBS control. The data supported that corneal material properties can be well-described using this inflation methods following CXL. The inflation test is valuable for investigating the mechanical response of the intact human cornea within physiological IOP ranges, providing benchmarks against which the numerical developments can be translated to clinic.

The Relationship Between Mechanical Properties, Ultrastructural Changes, and Intrafibrillar Bond Formation in Corneal UVA/Riboflavin Cross-linking Treatment for Keratoconus.

PURPOSE: To determine the relationship between mechanical behavior in cross-linked corneas and changes in the corneal ultrastructure after corneal cross-linking (CXL). METHODS: Porcine corneas were treated following the "Dresden" protocol, the current gold standard for clinical treatment, consisting of dropwise application of 0.1% riboflavin in 20% dextran followed by 30 minutes of ultraviolet-A (UVA) irradiation. The effect of CXL was assessed using uniaxial tensile testing, transmission electron microscopy, and Fourier transform infrared spectroscopy, with results compared against corneas treated with each of the treatment solution components individually. RESULTS: UVA/riboflavin cross-linked corneas displayed 28% ± 17% increase in the material tangent modulus compared with dextran treatment alone, and altered collagen architecture within the first 300 µm of stromal depth consisting of 5% increase in the thickness of collagen fibrils, no significant changes to interfibrillar spacing, and an 8% to 12% decrease in number of fibrils per unit area. Fourier transform infrared spectroscopy confirmed formation of interfibrillar bonds (P = .012) induced by UVA-mediated CXL. CONCLUSIONS: The data support a model wherein collagen fibril diameter and structural density are fundamental parameters in defining tissue stiffening following UVA/riboflavin CXL and provide benchmarks against which modifications to the Dresden CXL protocol can be evaluated. [J Refract Surg. 2018;34(4):264-272.].

Serum-free culture of rat proximal tubule cells with enhanced function on chitosan.

The proximal tubule performs a variety of important renal functions and is the major site for nutrient reabsorption. The purpose of this study is to culture rat renal proximal tubule cells (PTCs) on chitosan without serum to maintain a transcellular pathway to transport water and ions effectively without loss of highly differentiated cell function. The effect of chitosan, which is structurally similar to glycosaminoglycans, in the absence of serum on the primary cultured PTCs was compared that of collagen with or without serum. Two days after seeding, more tubule fragments and higher PTC viability were observed on chitosan than on collagen with or without serum. Proliferation marker Ki-67 immunostaining and phosphorylated extracellular-regulated kinase (ERK) expression results displayed similar proliferation capability of PTCs established on chitosan without serum and collagen with 2% fetal bovine serum after 4 days of incubation. When grown to confluence, PTCs formed a monolayer with well-organized tight junctions and formation of domes on chitosan without serum. Moreover, evaluation of the transepithelial electrical resistance showed that both chitosan and serum were involved in the modification of water and ion transport in confluent cells. By showing the direct suppression of PTC growth and dome formation treated with heparinase, we demonstrated that the interaction between cell surface heparin sulfate proteoglycan and chitosan played an important role in PTC proliferation and differentiation. A successful primary culture of PTCs has now been produced on chitosan in serum-free culture condition, which offers potential applications for chitosan in renal tissue engineering.