Aldehyde Dehydrogenase 2 (ALDH2) Deficiency, Obesity, and Atrial Fibrillation Susceptibility: Unraveling the Connection.

Atrial fibrillation (AF), characterized by structural remodeling involving atrial myocardial degradation and fibrosis, is linked with obesity and transforming growth factor beta 1 (TGF-ß1). Aldehyde dehydrogenase 2 (ALDH2) deficiency, highly prevalent in East Asian people, is paradoxically associated with a lower AF risk. This study investigated the impact of ALDH2 deficiency on diet-induced obesity and AF vulnerability in mice, exploring potential compensatory upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme-oxygenase 1 (HO-1). Wild-type (WT) and ALDH2*2 knock-in (KI) mice were administered a high-fat diet (HFD) for 16 weeks. Despite heightened levels of reactive oxygen species (ROS) post HFD, the ALDH2*2 KI mice did not exhibit a greater propensity for AF compared to the WT controls. The ALDH2*2 KI mice showed equivalent myofibril degradation in cardiomyocytes compared to WT after chronic HFD consumption, indicating suppressed ALDH2 production in the WT mice. Atrial fibrosis did not proportionally increase with TGF-ß1 expression in ALDH2*2 KI mice, suggesting compensatory upregulation of the Nrf2 and HO-1 pathway, attenuating fibrosis. In summary, ALDH2 deficiency did not heighten AF susceptibility in obesity, highlighting Nrf2/HO-1 pathway activation as an adaptive mechanism. Despite limitations, these findings reveal a complex molecular interplay, providing insights into the paradoxical AF-ALDH2 relationship in the setting of obesity.

Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.

Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor's phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment.

Isoliquiritigenin inhibits apoptosis and ameliorates oxidative stress in rheumatoid arthritis chondrocytes through the Nrf2/HO-1-mediated pathway.

Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its irreversible destructive impact on the joints. Chondrocytes play a pivotal role in the production and maintenance of the cartilage matrix. However, the presence of inflammatory cytokines can hinder chondrocyte proliferation and promote apoptosis. Isoliquiritigenin (ISL), a flavonoid, potentially exerts protective effects against various inflammatory diseases. However, its specific role in regulating the nuclear factor E2-associated factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in chondrocytes in RA remains unclear. To investigate this, this study used human chondrocytes and Sprague-Dawley rats to construct in vitro and in vivo RA models, respectively. The study findings reveal that cytokines markedly induced oxidative stress, the activation of matrix metalloproteinases, and apoptosis both in vitro and in vivo. Notably, ISL treatment significantly mitigated these effects. Moreover, Nrf2 or HO-1 inhibitors reversed the protective effects of ISL, attenuated the expression of Nrf2/HO-1 and peroxisome proliferator-activated receptor gamma-coactivator-1α, and promoted chondrocyte apoptosis. This finding indicates that ISL primarily targets the Nrf2/HO-1 pathway in RA chondrocytes. Moreover, ISL treatment led to improved behavior scores, reduced paw thickness, and mitigated joint damage as well as ameliorated oxidative stress in skeletal muscles in an RA rat model. In conclusion, this study highlights the pivotal role of the Nrf2/HO-1 pathway in the protective effects of ISL and demonstrates the potential of ISL as a treatment option for RA.

A Novel KCNH2 S981fs Mutation Identified by Whole-Exome Sequencing Is Associated with Type 2 Long QT Syndrome.

KCNH2 loss-of-function mutations cause long QT syndrome type 2 (LQT2), an inherited cardiac disorder associated with life-threatening ventricular arrhythmia. Through whole-exome sequencing, we discovered a novel AGCGACAC deletion (S981fs) in the hERG gene of an LQT2 patient. Using a heterologous expression system and patch clamping, we found that the mutant K channel had reduced cell surface expression and lower current amplitude compared to the wild type. However, functional expression was restored by lowering temperature and using potassium channel inhibitors or openers (E4031, cisapride, nicorandil). Co-immunoprecipitation experiments confirmed the assembly of mutant proteins with wild-type hERG. Confocal imaging showed decreased hERG distribution on the cell membrane in cells expressing S981fs. Notably, treatment with G418 significantly increased hERG current in wild-type/S981fs heterozygotes. In conclusion, our study identifies a novel hERG mutation leading to impaired Kv11.1 function due to trafficking and nonsense-mediated RNA decay defects. These findings shed light on the mechanisms underlying LQT2 and offer potential therapeutic avenues.

Nasal Patency in Sitting, Supine, and Prone Positions in Individuals with and without Allergic Rhinitis.

(1) Background: Physiological changes in nasal patency in response to posture contribute to sleep-related problems. Previously, we reported that the supine and prone positions cause a significant decrease in nasal patency in subjective and objective assessments of healthy individuals. Therefore, we conducted a study to evaluate the effect of posture on nasal patency in patients with allergic rhinitis (AR); (2) Methods: The present study comprised 30 patients diagnosed with AR and 30 healthy subjects without nasal disease (non-AR). Changes in nasal patency were evaluated in the sitting, supine, and prone positions. We used the visual analog scale to evaluate subjective nasal blockage. Acoustic rhinometry and endoscopy were used to objectively measure changes in nasal patency; (3) Results: In the non-AR group, the prone position had a significant effect on subjective nasal blockage compared with the sitting position, with significant decreases in the minimal cross-sectional area (mCSA) measured by acoustic rhinometry. Furthermore, endoscopy demonstrated a significantly increased inferior turbinate hypertrophy in the non-AR group. In the AR group, there was no statistical difference in subjective nasal blockage symptoms between the different positions. However, in objective examinations (acoustic rhinometry and endoscopy), the prone position showed significantly decreased nasal patency; (4) Conclusions: In patients with AR, subjective nasal blockage did not significantly increase in the supine or prone position. Endoscopy demonstrated increased inferior turbinate hypertrophy in supine and prone positions resulting in a significant reduction in nasal cavity mCSA, indicating an objective reduction in nasal patency.

Reduction of Viral and Bacterial Activity by Using a Self-Powered Variable-Frequency Electrical Stimulation Device.

Viruses and bacteria, which can rapidly spread through droplets and saliva, can have serious effects on people's health. Viral activity is traditionally inhibited using chemical substances, such as alcohol or bleach, or physical methods, such as thermal energy or ultraviolet-light irradiation. However, such methods cannot be used in many applications because they have certain disadvantages, such as causing eye or skin injuries. Therefore, in the present study, the electrical stimulation method is used to stimulate a virus, namely, coronavirus 229E, and two types of bacteria, namely, Escherichia coli and Staphylococcus aureus, to efficiently reduce their infectivity of healthy cells (such as the Vero E6 cell in a viral activity-inhibition experiment). The infectivity effects of the aforementioned virus and bacteria were examined under varying values of different electrical stimulation parameters, such as the stimulation current, frequency, and total stimulation time. The experimental results indicate that the activity of coronavirus 229E is considerably inhibited through direct-current pulse stimulation with a current of 25 mA and a frequency of 2 or 20 Hz. In addition, E. coli activity was reduced by nearly 80% in 10 s through alternating-current pulse stimulation with a current of 50 mA and a frequency of 25 Hz. Moreover, a self-powered electrical stimulation device was constructed in this study. This device consists of a solar panel and battery to generate small currents with variable frequencies, which has advantages of self-powered and variable frequencies, and the device can be utilized on desks, chairs, or elevator buttons for the inhibition of viral and bacterial activities.

Betulinic Acid Inhibits the Stemness of Gastric Cancer Cells by Regulating the GRP78-TGF-ß1 Signaling Pathway and Macrophage Polarization.

Cancer stemness is the process by which cancer cells acquire chemoresistance and self-renewal in the tumor microenvironment. Glucose-regulated protein 78 (GRP78) is a biomarker for gastric cancer and is involved in cancer stemness. By inducing cancer stemness in various types of cancer, the polarization of macrophages into tumor-associated macrophages (TAMs) controls tumor progression. Betulinic acid (BA) is a bioactive natural compound with anticancer properties. However, whether GRP78 regulates TAM-mediated cancer stemness in the tumor microenvironment and whether BA inhibits GRP78-mediated cancer stemness in gastric cancer remain unknown. In this study, we investigated the role of GRP78 in gastric cancer stemness in a tumor microenvironment regulated by BA. The results indicated that BA inhibited not only GRP78-mediated stemness-related protein expression and GRP78-TGF-ß-mediated macrophage polarization into TAMs, but also TAM-mediated cancer stemness. Therefore, BA is a promising candidate for clinical application in combination-chemotherapy targeting cancer stemness.

Four Sessions of Combining Wearable Devices and Heart Rate Variability (HRV) Biofeedback are Needed to Increase HRV Indices and Decrease Breathing Rates.

Heart rate variability biofeedback (HRVB) is a behavioral intervention that uses resonance frequency breathing to synchronize the heart rate and breathing patterns. This study aimed to explore how many sessions of wearable HRVB devices are needed to increase the HRV index and decrease breathing rates and to compare the HRVB protocol with other psychological intervention programs in HRV indices and breathing rates. Sixty-four participants were randomly assigned to either the HRVB or relaxation training (RT) group. Both groups received interbeat intervals (IBIs) and breathing rates measurement at the pre-training baseline, during training, and post-training baseline from weeks 1 to 4. IBIs were transformed into HRV indices as the index of the autonomic nervous system. The Group × Week interaction effects significantly in HRV indices and breathing rates. The between-group comparison found a significant increase in HRV indices and decreased breathing rates in the HRVB group than in the RT group at week 4. The within-session comparison in the HRVB group revealed significantly increased HRV indices and decreased breathing rates at weeks 3 and 4 than at weeks 1 and 2. There was a significant increase in HRV indices and a decrease in breathing rates at mid- and post-training than pre-training in the HRVB group. Therefore, 4 weeks of HRVB combined with a wearable device are needed in increasing HRV indices and decrease breathing rates compared to the relaxation training. Three weeks of HRVB training are the minimum requirement for increasing HRV indices and reducing breathing rates compared to the first week of HRVB.

Effects of Supine and Prone Positions on Nasal Patency in Healthy Individuals.

OBJECTIVES: Supine position reduces nasal patency compared with that in the sitting position; however, data on the effects of prone position on nasal patency is lacking. METHODS: We assessed the nasal patency of 30 healthy individuals without upper respiratory tract disorders by using visual analog scale (VAS) score and acoustic rhinometry in 7 positions: sitting; frontal, right, and left supine; and frontal, right, and left prone. RESULTS: According to the VAS scores, compared with that in the sitting position, both the supine and prone positions significantly increased subjective nasal obstruction (P < .001). The prone position had a more significant effect than did the supine position (P = .017). The results of minimal cross-sectional area measured through acoustic rhinometry demonstrated that both the supine and prone positions reduced the nasal patency significantly, but without significant differences between the effects of prone and supine positions (P = .794). CONCLUSION: This is the first study to elucidate that the prone position can significantly reduce the nasal patency in healthy individuals through subjective and objective assessments. LEVEL OF EVIDENCE: IV.

Gastric Cancer Cell-Derived Exosomal GRP78 Enhances Angiogenesis upon Stimulation of Vascular Endothelial Cells.

Exosomes containing glucose-regulated protein 78 (GRP78) are involved in cancer malignancy. GRP78 is thought to promote the tumor microenvironment, leading to angiogenesis. No direct evidence for this role has been reported, however, mainly because of difficulties in accurately measuring the GRP78 concentration in the exosomes. Recently, exosomal GRP78 concentrations were successfully measured using an ultrasensitive ELISA. In the present study, GRP78 concentrations in exosomes collected from gastric cancer AGS cells with overexpression of GRP78 (OE), knockdown of GRP78 (KD), or mock GRP78 (mock) were quantified. These three types of exosomes were then incubated with vascular endothelial cells to examine their effects on endothelial cell angiogenesis. Based on the results of a tube formation assay, GRP78-OE exosomes accelerated angiogenesis compared with GRP78-KD or GRP78-mock exosomes. To investigate the mechanisms underlying this effect, we examined the Ser473 phosphorylation state ratio of AKT, which is involved in the angiogenesis process, and found that AKT phosphorylation was increased by GRP78-OE exosome application to the endothelial cells. An MTT assay showed that GRP78-OE exosome treatment increased the proliferation rate of endothelial cells, and a wound healing assay showed that this treatment increased the migration capacity of the endothelial cells. These findings demonstrated that GRP78-containing exosomes promote the tumor microenvironment and induce angiogenesis.

Ultrasensitive ELISA detection of proteins in separated lumen and membrane fractions of cancer cell exosomes.

Exosomes transfer molecules horizontally to surrounding cells and therefore have a key role in cancer progression. To clarify the role of exosomes in cancer progression, trace amounts of proteins in their lumen and membrane fractions should be analyzed separately. For this purpose, an adequate and easy-to-use method of separating the lumen and membrane fractions of exosomes must be developed. Further, because exosomes contain only trace amounts of proteins, an ultrasensitive protein detection method is necessary. To develop an adequate and easy-to-use lumen and membrane fraction separation method, we applied a commercially available kit originally developed for cells to exosomes and examined the validity of the results compared with those obtained using a conventional, complicated Na2CO3 method. To develop an ultrasensitive protein detection method, we designated GRP78, which is upregulated in cancer cells and contributes to cancer progression, as the target protein and detected it at the subattomolar level using an ultrasensitive ELISA combined with thio-NAD cycling. By applying these methods together, GRP78 was successfully quantified in both the lumen and membrane fractions of exosomes obtained from cultured cancer cells. The present results will facilitate studies to broaden our understanding of the tumor microenvironment.

Ultrasensitive Detection of GRP78 in Exosomes and Observation of Migration and Proliferation of Cancer Cells by Application of GRP78-Containing Exosomes.

Cancer cells communicate with each other via exosomes in the tumor microenvironment. However, measuring trace amounts of proteins in exosomes is difficult, and thus the cancer stemness-promoting mechanisms of exosomal proteins have not been elucidated. In the present study, we attempted to quantify trace amounts of 78-kDa glucose-regulated protein (GRP78), which is involved in cancer progression, in exosomes released from cultured gastric cancer cells using an ultrasensitive ELISA combined with thio-NAD cycling. We also evaluated the cancer stemness-promoting effects by the application of high-GRP78-containing exosomes to cultured gastric cancer cells. The ultrasensitive ELISA enabled the detection of GRP78 at a limit of detection of 0.16 pg/mL. The stemness of cancer cultured cells incubated with high-GRP78-containing exosomes obtained from GRP78-overexpressed cells was increased on the basis of both an MTT assay and a wound healing assay. Our results demonstrated that the ultrasensitive ELISA has strong potential to measure trace amounts of proteins in exosomes. Further, exosomes with a high concentration of GRP78 promote the cancer stemness of surrounding cells. The technique for quantifying proteins in exosomes described here will advance our understanding of cancer stemness progression via exosomes.

Isoliquiritigenin Inhibits Gastric Cancer Stemness, Modulates Tumor Microenvironment, and Suppresses Tumor Growth through Glucose-Regulated Protein 78 Downregulation.

Chemotherapy is the treatment of choice for gastric cancer; however, the currently available therapeutic drugs for treatment have limited efficacy. Cancer stemness and the tumor microenvironment may play crucial roles in tumor growth and chemoresistance. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum chaperone facilitating protein folding and cell homeostasis during stress and may participate in chemoresistance. Isoliquiritigenin (ISL) is a bioactive flavonoid found in licorice. In this study, we demonstrated the role of GRP78 in gastric cancer stemness and evaluated GRP78-mediated stemness inhibition, tumor microenvironment regulation, and chemosensitivity promotion by ISL. ISL not only suppressed GRP78-mediated gastric cancer stem cell-like characteristics, stemness-related protein expression, and cancer-associated fibroblast activation but also gastric tumor growth in xenograft animal studies. The findings indicated that ISL is a promising candidate for clinical use in combination chemotherapy.

The reimbursement coverage decisions and pricing rules for medical devices in Taiwan.

Medical technology is undergoing rapid transformations, and the classifications of medical devices have also expanded greatly; therefore, it is necessary to develop appropriate reimbursement policies and pricing mechanisms in a timely manner. This paper aims to introduce the reimbursement coverage and pricing rules for medical devices in Taiwan. In addition, this paper identifies and evaluates available health technology assessments (HTA) and literature on published websites concerning medical device decision-making processes and pricing systems in South Korea and Japan, which are near Taiwan and have similar reimbursement coverage processes. Reimbursement policy and pricing mechanisms are constantly being revised in Taiwan, Japan, and South Korea. Recently, all three countries attempted to establish new reimbursement coverage decision-making and pricing rules, adopting a differentiated approach based on the level of evidence required for the appropriated reimbursement in terms of a feasible evaluation mechanism for providing patients with more effective medical devices. This article is expected to contribute to providing references to new reimbursement coverage decision-making and pricing rules.

Real-world cost-effectiveness analysis of the fracture liaison services model of care for hip fracture in Taiwan.

BACKGROUND: This study was to perform an economic evaluation to understand clinical outcomes and health resource use between hip fracture patients receiving hospital-based postfracture fracture liaison service (FLS) care and those receiving usual care (UC) in Taiwan. METHODS: This cohort study included hospital-based data of 174 hip fracture patients who received FLS care (FLS group) from National Taiwan University Hospital, and 1697 propensity score-matched patients who received UC (UC group) of National Health Insurance claim-based data. Two groups had similar baseline characteristics but differed in hip fracture care after propensity score matching. Clinical outcomes included refracture-free survival (RFS), hip-refracture-free survival (HRFS), and overall survival (OS). Health resource use included inpatient, outpatient, and pharmacy costs within 2 years follow-up after the index of hip fracture. The economic evaluation of the FLS model was analyzed using the net monetary benefit regression framework based on the National Health Insurance perspective. RESULTS: The FLS group had longer RFS than the UC group, with an adjusted difference of 44.3 days (95% confidence interval: 7.2-81.4 days). Two groups did not differ in inpatient and outpatient costs during follow-up, but the FLS group had a higher expenditure than the UC group on osteoporosis-related medication. The probability of FLS being cost-effective was >80% and of increasing RFS, HRFS, and OS was 95%, 81%, and 80%, respectively, when the willingness-to-pay threshold was >USD 65/gross domestic product per day. CONCLUSION: FLS care was cost-effective in reducing refracture occurrence days for patients initially diagnosed with hip fractures.

Luteolin Inhibits Breast Cancer Stemness and Enhances Chemosensitivity through the Nrf2-Mediated Pathway.

Cancer stem cells (CSCs) are subpopulations of tumor masses with unique abilities in self-renewal, stemness maintenance, drug resistance, and the promotion of cancer recurrence. Recent studies have suggested that breast CSCs play essential roles in chemoresistance. Therefore, new agents that selectively target such cells are urgently required. Reactive oxygen species (ROS)-producing enzymes are the reason for an elevated tumor oxidant status. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor, which upon detecting cellular oxidative stress, binds to the promoter region of antioxidant genes. By triggering a cytoprotective response, Nrf2 maintains cellular redox status. Cripto-1 participates in the self-renewal of CSCs. Herein, luteolin, a flavonoid found in Taraxacum officinale extract, was determined to inhibit the expressions of stemness-related transcriptional factors, the ATP-binding cassette transporter G2 (ABCG2), CD44, aldehyde dehydrogenase 1 activity as well as the sphere formation properties of breast CSCs. Furthermore, luteolin suppressed the protein expressions of Nrf2, heme oxygenase 1 (HO-1), and Cripto-1 which have been determined to contribute critically to CSC features. The combination of luteolin and the chemotherapeutic drug, Taxol, resulted in enhanced cytotoxicity to breast cancer cells. These findings suggest that luteolin treatment significantly attenuated the hallmarks of breast cancer stemness by downregulating Nrf2-mediated expressions. Luteolin constitutes a potential agent for use in cancer stemness-targeted breast cancer treatments.

Surface Wettability and Electrical Resistance Analysis of Droplets on Indium-Tin-Oxide Glass Fabricated Using an Ultraviolet Laser System.

Indium tin oxide (ITO) is widely used as a substrate for fabricating chips because of its optical transparency, favorable chemical stability, and high electrical conductivity. However, the wettability of ITO surface is neutral (the contact angle was approximately 90°) or hydrophilic. For reagent transporting and manipulation in biochip application, the surface wettability of ITO-based chips was modified to the hydrophobic or nearly hydrophobic surface to enable their use with droplets. Due to the above demand, this study used a 355-nm ultraviolet laser to fabricate a comb microstructure on ITO glass to modify the surface wettability characteristics. All of the fabrication patterns with various line width and pitch, depth, and surface roughness were employed. Subsequently, the contact angle (CA) of droplets on the ITO glass was analyzed to examine wettability and electrical performance by using the different voltages applied to the electrode. The proposed approach can succeed in the fabrication of a biochip with suitable comb-microstructure by using the optimal operating voltage and time functions for the catch droplets on ITO glass for precision medicine application. The experiment results indicated that the CA of droplets under a volume of 20 µL on flat ITO substrate was approximately 92° ± 2°; furthermore, due to its lowest surface roughness, the pattern line width and pitch of 110 µm exhibited a smaller CA variation and more favorable spherical droplet morphology, with a side and front view CA of 83° ± 1° and 78.5° ± 2.5°, respectively, while a laser scanning speed of 750 mm/s was employed. Other line width and pitch, as well as scanning speed parameters, increased the surface roughness and resulted in the surface becoming hydrophilic. In addition, to prevent droplet morphology collapse, the droplet's electric operation voltage and driving time did not exceed 5 V and 20 s, respectively. With this method, the surface modification process can be employed to control the droplet's CA by adjusting the line width and pitch and the laser scanning speed, especially in the neutral or nearly hydrophobic surface for droplet transporting. This enables the production of a microfluidic chip with a surface that is both light transmittance and has favorable electrical conductivity. In addition, the shape of the microfluidic chip can be directly designed and fabricated using a laser direct writing system on ITO glass, obviating the use of a mask and complicated production processes in biosensing and biomanipulation applications.

Resveratrol Analog 4-Bromo-Resveratrol Inhibits Gastric Cancer Stemness through the SIRT3-c-Jun N-Terminal Kinase Signaling Pathway.

Chemotherapy is the treatment of choice for gastric cancer, but the currently available therapeutic drugs have limited efficacy. Studies have suggested that gastric cancer stem cells may play a key role in drug resistance in chemotherapy. Therefore, new agents that selectively target gastric cancer stem cells in gastric tumors are urgently required. Sirtuin-3 (SIRT3) is a deacetylase that regulates mitochondrial metabolic homeostasis to maintain stemness in glioma stem cells. Targeting the mitochondrial protein SIRT3 may provide a novel therapeutic option for gastric cancer treatment. However, the mechanism by which stemness is regulated through SIRT3 inhibition in gastric cancer remains unknown. We evaluated the stemness inhibition ability of the SIRT3 inhibitor 4'-bromo-resveratrol (4-BR), an analog of resveratrol in human gastric cancer cells. Our results suggested that 4-BR inhibited gastric cancer cell stemness through the SIRT3-c-Jun N-terminal kinase pathway and may aid in gastric cancer stem-cell-targeted therapy.

Abiraterone and enzalutamide had different adverse effects on the cardiovascular system: a systematic review with pairwise and network meta-analyses.

BACKGROUND: Abiraterone and enzalutamide may increase the risk of cardiovascular events in patients with castration-resistant prostate cancer (CRPC). METHODS: A comprehensive literature search was performed using a combination of keywords related to "abiraterone," "enzalutamide," "prostate cancer," and "adverse events." Phase II-IV randomized controlled trials (RCTs) on abiraterone or enzalutamide for patients with nonmetastatic or metastatic CRPC were included. Outcome measures included (1) any grade cardiac disorder, (2) severe grade cardiac disorder, (3) any grade hypertension, and (4) severe grade hypertension, as defined by the Common Terminology Criteria for Adverse Events. Pairwise meta-analysis and Bayesian network meta-analyses were performed to investigate the risk ratios (RRs) of abiraterone and enzalutamide. Surface under cumulative ranking curves (SUCRAs) and cumulative ranking probability plots based on the probability of developing cardiac disorders or hypertension were presented. RESULTS: A total of 7103 patients from seven RCTs were included. Upon pairwise meta-analysis, abiraterone was associated with increased risks of any grade (RR = 1.34, 95% confidence interval (CI) = 1.05-1.73) and severe grade cardiac disorders (RR = 1.71, 95% CI = 1.16-2.53); enzalutamide was associated with increased risks of any grade (RR = 2.66, 95% CI = 1.93-3.66) and severe grade hypertension (RR = 2.79, 95% CI = 1.86-4.18). Based on the SUCRA rankings, abiraterone had a higher probability of cardiac disorders (84.84% for any grade and 85.12% for severe grade) than enzalutamide (62.83% for any grade and 50.76% for severe grade); whereas enzalutamide had a higher probability of hypertension (99.43% for any grade and 89.71% for severe grade) than abiraterone (49.08% for any grade and 49.37% for severe grade). CONCLUSIONS: Abiraterone and enzalutamide had different adverse effects on the cardiovascular system. We should take this into consideration when we are deciding on the choice of novel hormonal agents for patients with CRPC.

Impact of changing reimbursement criteria on statin treatment patterns among patients with atherosclerotic cardiovascular disease or cardiovascular risk factors.

WHAT IS KNOWN AND OBJECTIVE: Starting 1 August 2013, the eligible cholesterol level for statin reimbursement in patients with atherosclerotic cardiovascular disease (ASCVD) or cardiovascular disease (CVD)-related risk factors changed from LDL-C ≥ 130 mg/dl (or TC ≥ 200 mg/dl) to LDL-C ≥ 100 mg/dl (or TC ≥ 160 mg/dl) in Taiwan, which may modify clinician prescribing behaviours. We aimed to evaluate the impact of changing reimbursement criteria on statin treatment patterns. METHODS: A before-after cohort design was conducted using Taiwan's National Health Insurance Research Database. Differences in statin treatment patterns between the pre- and postregulation periods were compared. Two prespecified study cohorts were identified to examine the impacts of this change on those who need statins for "secondary prevention" (patients newly diagnosed with ASCVD) and those who need statins for "primary prevention" (patients newly diagnosed with CVD-related risk factors, such as diabetes mellitus [DM]). Treatment patterns measured in this study included initiation, discontinuation, switching, dose increase, dose decrease and dose maximization. RESULTS: The proportion of patients who initiated statins during the postregulation period was higher than that of patients who initiated statins during the preregulation period (eg coronary heart disease (CHD) patients, pre- vs. postregulation: 41.23% vs. 48.25%). Notably, only 30%-40% of patients initiated statin use in the postregulation period across different conditions. In addition, the proportion of patients who discontinued statins remained very high. Even in the postregulation period, more than half of CHD patients discontinued statins during the 1-year follow-up period (eg CHD patients, pre- vs. postregulation: 59.07% vs. 52.75%). WHAT IS NEW AND CONCLUSION: The new reimbursement criteria started on 1 August 2013 seemed to lower the barriers of access to the first statin prescription among patients with CHD, cerebrovascular disease (CBVD) and DM. Nevertheless, the proportion of patients who initiated statin use was suboptimal, and the proportion of patients who discontinued statins was very high in the postregulation period.