Binding of interleukin-1 receptor antagonist to cholinergic receptor muscarinic 4 promotes immunosuppression and neuroendocrine differentiation in prostate cancer.

The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.

MCTP1 increases the malignancy of androgen-deprived prostate cancer cells by inducing neuroendocrine differentiation and EMT.

Neuroendocrine prostate cancer (PCa) (NEPC), an aggressive subtype that is associated with poor prognosis, may arise after androgen deprivation therapy (ADT). We investigated the molecular mechanisms by which ADT induces neuroendocrine differentiation in advanced PCa. We found that transmembrane protein 1 (MCTP1), which has putative Ca2+ sensing function and multiple Ca2+-binding C2 domains, was abundant in samples from patients with advanced PCa. MCTP1 was associated with the expression of the EMT-associated transcription factors ZBTB46, FOXA2, and HIF1A. The increased abundance of MCTP1 promoted PC3 prostate cancer cell migration and neuroendocrine differentiation and was associated with SNAI1-dependent EMT in C4-2 PCa cells after ADT. ZBTB46 interacted with FOXA2 and HIF1A and increased the abundance of MCTP1 in a hypoxia-dependent manner. MCTP1 stimulated Ca2+ signaling and AKT activation to promote EMT and neuroendocrine differentiation by increasing the SNAI1-dependent expression of EMT and neuroendocrine markers, effects that were blocked by knockdown of MCTP1. These data suggest an oncogenic role for MCTP1 in the maintenance of a rare and aggressive prostate cancer subtype through its response to Ca2+ and suggest its potential as a therapeutic target.

Analysis of Prognostic Factors in Non-Traumatic and Non-Diabetic Retinopathy Patients Undergoing Vitrectomy.

AIM: Vitrectomy is one of the crucial therapeutic interventions for non-traumatic and non-diabetic retinal diseases. However, the prognosis of patients undergoing this procedure and the factors affecting prognosis remain to be clarified. The aim of this study was to analyze the prognostic factors of non-traumatic and non-diabetic retinopathy complicated by vitreous hemorrhage. METHODS: A retrospective study was conducted on 352 patients, including 152 (43.18%) females, who underwent vitrectomy in our hospital from March 2018 to December 2022, divided into Group A (postoperative complications) and Group B (no complications) according to whether complications occurred during postoperative follow-up. General and clinical data of the two groups were collected and compared. Binary logistic regression was used to analyze the main factors affecting prognosis. RESULTS: All patients were followed up for 12 months. A total of 87 patients had postoperative complications, accounting for 24.72% (87/352), and were classified as Group A. A total of 265 patients who had no postoperative complications, accounting for 75.28% (265/352), were classified as Group B. There were significant differences in preoperative visual acuity, time of surgical intervention, preoperative fundus condition, stage of retinopathy, preoperative intraocular pressure and age between the two groups (p < 0.05), and these indices were identified as independent risk factors affecting the prognosis of patients (odds ratio >1). CONCLUSIONS: Preoperative visual acuity, time of surgical intervention, preoperative fundus condition, stage of retinopathy, preoperative intraocular pressure and age are all factors affecting the prognosis of patients with non-traumatic and non-diabetic retinopathy while undergoing vitrectomy. Personalized care is required to improve the surgical outcome for these patients.

Modelling the Public Health Burden of Herpes Zoster and the Impact of Adjuvanted Recombinant Zoster Vaccine in Five Selected Countries in Southeast Asia.

INTRODUCTION: Herpes zoster (HZ) can cause substantial patient morbidity and lead to large healthcare costs. However, the disease burden of HZ in Southeast Asia may be underestimated. This study aimed to estimate the public health burden of HZ and the impact of vaccinating adults aged ≥ 50 years old in five Southeast Asian countries (Indonesia, Malaysia, Philippines, Thailand, and Vietnam), with adjuvanted recombinant zoster vaccine (RZV) compared with no vaccination. METHODS: For each country, we adapted a static multicohort Markov model developed with a 1-year cycle length and lifetime horizon. Demographics were obtained from the World Health Organization, HZ incidence from a worldwide meta-regression reporting Asian-specific values, proportions of postherpetic neuralgia (PHN) and non-PHN complications from local/regional studies, and vaccine efficacy from a long-term follow-up trial. First-dose coverage and second-dose compliance were assumed to be 30% and 70%, respectively. A one-way deterministic sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA) were performed to assess the robustness and uncertainty of inputs for each country. RESULTS: Without RZV, it was estimated that there would be a total of approximately 10 million HZ cases, 2.1 million PHN cases, and 1.4 million non-PHN complications in individuals aged ≥ 50 years included in the model. Introducing RZV under 30% coverage could avoid approximately 2.2 million (22%) HZ cases, almost 500,000 (21%) PHN cases, and around 300,000 (22%) non-PHN complications. OWSA showed that first-dose coverage and initial HZ incidence had the largest impact on the estimated number of HZ cases avoided. The number needed to vaccinate ranged from 15 to 21 to prevent one case of HZ and from 68 to 104 to prevent one case of PHN across each country. CONCLUSIONS: This study demonstrated that there is substantial HZ disease burden in older adults for the five selected countries in Southeast Asia, negatively impacting national healthcare systems. Introducing RZV could potentially reduce this burden. A graphical abstract is available with this article.

Immunosuppressive role of BDNF in therapy-induced neuroendocrine prostate cancer.

Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT-driven LIF/LIFR signaling induces brain-derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration-resistant PCa (CRPC) and a positive correlation with programmed death-ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.

Anti-Toxoplasma gondii effect of tylosin in vitro and in vivo.

BACKGROUND: Toxoplasma gondii is an important protozoan pathogen with medical and veterinary importance worldwide. Drugs currently used for treatment of toxoplasmosis are less effective and sometimes cause serious side effects. There is an urgent need for the development of more effective drugs with relatively low toxicity. METHODS: The effect of tylosin on the viability of host cells was measured using CCK8 assays. To assess the inhibition of tylosin on T. gondii proliferation, a real-time PCR targeting the B1 gene was developed for T. gondii detection and quantification. Total RNA was extracted from parasites treated with tylosin and then subjected to transcriptome analysis by RNA sequencing (RNA-seq). Finally, murine infection models of toxoplasmosis were used to evaluate the protective efficacy of tylosin against T. gondii virulent RH strain or avirulent ME49 strain. RESULTS: We found that tylosin displayed low host toxicity, and its 50% inhibitory concentration was 175.3 µM. Tylsoin also inhibited intracellular T. gondii tachyzoite proliferation, with a 50% effective concentration of 9.759 µM. Transcriptome analysis showed that tylosin remarkably perturbed the gene expression of T. gondii, and genes involved in "ribosome biogenesis (GO:0042254)" and "ribosome (GO:0005840)" were significantly dys-regulated. In a murine model, tylosin treatment alone (100 mg/kg, i.p.) or in combination with sulfadiazine sodium (200 mg/kg, i.g.) significantly prolonged the survival time and raised the survival rate of animals infected with T. gondii virulent RH or avirulent ME49 strain. Meanwhile, treatment with tylosin significantly decreased the parasite burdens in multiple organs and decreased the spleen index of mice with acute toxoplasmosis. CONCLUSIONS: Our findings suggest that tylosin exhibited potency against T. gondii both in vitro and in vivo, which offers promise for treatment of human toxoplasmosis.

A Latent Transition Analysis of Aggression Victimization Patterns During the Transition from Primary to Middle School.

School transitions provide contexts for adolescents to reconstruct peer relationships and re-establish social positions. Scarce research has captured the transition of aggressor and victim roles during this period and examined associated factors. To investigate the stability and shifts of aggressor and victim roles following the transition to middle school, this study conducted latent transition analysis with 1261 Chinese adolescents (32.6% female, Mage in Grade 6 = 12.1 years, SD = 0.7). Three subgroups were identified across Grades 5 to 8: aggressive-victims, victims and uninvolved. Adolescents were more likely to transition from aggressive-victim and victim roles to the uninvolved group during the transition to middle school compared to the transitions within the same educational phase. Males and those with insecure parental attachment were at higher risk of being and remaining in the involved groups. The findings underscore the dynamic nature of adolescent aggression and victimization and highlight the transition to middle school as a critical window for interventions aimed at helping adolescents disengage from aggression and victimization.

Bifidobacteria in disease: from head to toe.

Bifidobacteria as a strictly anaerobic gram-positive bacteria, is widely distributed in the intestine, vagina and oral cavity, and is one of the first gut flora to colonize the early stages of life. Intestinal flora is closely related to health, and dysbiosis of intestinal flora, especially Bifidobacteria, has been found in a variety of diseases. Numerous studies have shown that in addition to maintaining intestinal homeostasis, Bifidobacteria may be involved in diseases covering all parts of the body, including the nervous system, respiratory system, genitourinary system and so on. This review collects evidence for the variation of Bifidobacteria in typical diseases among various systems, provides mild and effective therapeutic options for those diseases that are difficult to cure, and moves Bifidobacteria from basic research to further clinical applications.

CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer.

Current treatment options for prostate cancer focus on targeting androgen receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of muscarinic acetylcholine receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate cancer. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/AKT/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.

Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer.

Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa.

Favorable Mortality-to-Incidence Ratio Trends of Lung Cancer in Countries with High Computed Tomography Density.

Background and Objectives: The prognoses of lung cancer deteriorate dramatically as the cancer progresses through its stages. Therefore, early screening using techniques such as low-dose computed tomography (LDCT) is critical. However, the epidemiology of the association between the popularization of CT and the prognosis for lung cancer is not known. Materials and Methods: Data were obtained from GLOBOCAN and the health data and statistics of the World Health Organization. Mortality-to-incidence ratios (MIRs) and the changes in MIR over time (δMIR; calculated as the difference between MIRs in 2018 and 2012) were used to evaluate the correlation with CT density disparities via Spearman's rank correlation coefficient. Results: Countries with zero CT density presented a relatively low incidence crude rate and a relatively high MIR in 2018 and a negative δMIR. Conversely, countries with a CT density over 30 had a positive δMIR. The CT density was significantly associated with the HDI score and MIR in 2018, whereas it demonstrated no association with MIR in 2012. The CT density and δMIR also showed a significant linear correlation. Conclusions: CT density was significantly associated with lung cancer MIR in 2018 and with δMIR, indicating favorable clinical outcomes in countries in which CT has become popularized.

How large could the public health impact of introducing recombinant zoster vaccination for people aged ≥50 years in five Latin American countries be?

This study aimed to: (1) estimate the disease burden of herpes zoster (HZ) and (2) assess the potential public health impact of introducing adjuvanted recombinant zoster vaccine (RZV) compared with no vaccination in adults aged ≥50 years in Argentina, Brazil, Mexico, Chile, and Colombia using the ZOster ecoNomic Analysis (ZONA) static multicohort Markov model. The model followed individuals aged ≥50 years from administration of RZV over their remaining lifetime. Inputs were based, most often, on local data. First dose coverage was assumed to be 35%, with 75% second dose compliance. It was predicted that without RZV, there would be 23,558,675 HZ cases, 6,115,981 post-herpetic neuralgia (PHN) cases, and 7,058,779 non-PHN complications in the five countries, but introducing RZV under assumed coverage could avoid 4,583,787 (19%) HZ cases, 1,130,751 (18%) PHN cases, and 1,373,419 (19%) non-PHN complications. Also, 10427,504 (20%) doctor's office visits and 1,630,201 (19%) days of hospitalization could be averted in the three countries (Argentina, Brazil, and Mexico) with available input data. The numbers needed to be vaccinated to avoid one case of HZ were 9-10 across countries, and to avoid one case of PHN, 35-40. One-way sensitivity analyses showed that the input parameters with the largest impact on the estimated number of HZ cases avoided were first dose coverage, initial HZ incidence, and vaccine efficacy waning. In conclusion, the introduction of RZV for older adults in Latin America could greatly reduce the public health burden of HZ and reduce the related doctor visits and hospitalization days.

Why was the study done?Herpes zoster (HZ), commonly known as shingles or "culebrilla," typically causes a painful, itchy rash on the trunk in older adults, and can result in long-term complications. It is difficult to study the lifetime burden of HZ due to follow-up time constraints. We therefore wanted to predict how many people could develop HZ as they age and how many cases of HZ could be avoided by introducing adjuvanted recombinant zoster vaccine (RZV) in people aged 50 years and older in five Latin American countries (Argentina, Brazil, Mexico, Chile, and Colombia).What did the researchers do and find?Using a mathematical model, we predicted that nearly 5 million of an estimated 24 million cases of HZ could be avoided by vaccinating 35% of older adults with RZV in the five countries. This vaccination approach would also avert various complications of HZ, including post-herpetic neuralgia (long-lasting pain at the rash site) and save doctor's office visits and hospitalizations for HZ.What do the results mean?Introducing RZV for older adults in Latin America ­ as is already the case in various other countries ­ could prevent a substantial proportion of HZ cases, leading to improved public health and less health care resource utilization.What is the objective influence on the wider field?In the absence of real-world data on the potential impact of RZV on HZ in Latin America, these predictions could help policymakers to assess the potential value of introducing RZV for older adults in Latin America.

[Retracted] Astragaloside IV inhibits oxidized low­density lipoprotein­induced endothelial damage via upregulation of miR­140­3p.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the ß­actin control western blotting data featured in Fig. 3E were strikingly similar to data appearing in different form in another article by different authors. Upon asking the authors to explain this phenomenon, they were unable to provide the raw data for this experiment. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 847­856, 2019; DOI: 10.3892/ijmm.2019.4257].

Co-administration of tacrolimus and low molecular weight heparin in patients with a history of implantation failure and elevated peripheral blood natural killer cell proportion.

AIM: To investigate the therapeutic effect of co-administration of tacrolimus (TAC) and low-molecular-weight heparin (LMWH) or LMWH only on pregnancy outcomes in the female with a history of implantation failure and elevated peripheral blood natural killer (pNK) cell proportion in frozen-thawed embryo transfer cycles. METHODS: To evaluate the pregnancy parameters for 249 patients with ≥2 implantation failures and pNK cell proportion ≥12% by analyzing a retrospective observational cohort study. Sixty patients had received the co-administration TAC and LMWH (TAC & LMWH group), 85 others had only taken LMWH (LWMH group), and the rest did not take any particular drugs (control group). RESULTS: The experimental finding indicated that the TAC & LMWH group and the LMWH group showed higher clinical pregnancy rates than the control group (p < 0.05), and TAC & LMWH group had a much higher live birth rate. According to the binary logistic regression analysis, the combination of TAC and LMWH was conducive to clinical pregnancy and live birth rate and reduced the possibility of miscarriage. It would not affect the result of spontaneous abortion and live birth, although the LMWH was only beneficial to clinical pregnancy. In addition, these findings were similar for these three groups' obstetrical and neonatal outcomes. CONCLUSIONS: The combination of TAC and LMWH can improve clinical pregnancy and live birth rates and reduce the risk of spontaneous miscarriage in patients with a history of implantation failure and elevated pNK ratio. LMWH is also beneficial to clinical pregnancy.

A high genetic diversity of Enterocytozoon bieneusi in diarrheic pigs in southern China.

Enterocytozoon bieneusi is an important pathogen that is responsible for over 90% of documented cases of human microsporidiosis worldwide, causing a threat to public health and husbandry development. In immunocompromised patients, it can cause persistent diarrhoea, wasting diathesis and malabsorption and developing life-threatening chronic diarrhoea. However, there was little information on the prevalence and multilocus genotypes of E. bieneusi in diarrheic pigs in three provinces of southern China. In this study, 1254 faecal samples of diarrheic pigs were collected from 37 pig farms in Hunan, Jiangxi, and Fujian provinces in southern China, and were investigated the prevalence and genotypes of E. bieneusi by nested polymerase chain reaction (PCR) based on the internal transcribed spacer (ITS) region of the nuclear ribosomal DNA gene. The overall prevalence of E. bieneusi was 5.7% (72/1254) in three provinces. Furthermore, the difference was statistically significant (p < 0.001) in the prevalence of E. bieneusi in age groups. ITS sequence analysis revealed that 13 E. bieneusi genotypes were identified, including 8 known genotypes (EbpC, n = 30; Henan-IV, n = 21; CH5, n = 6; EbpA, n = 3; KIN-1, n = 2; O, n = 1; GX3, n = 1; CHS5, n = 1) and 5 novel genotypes (JX1, n = 2; JX2, n = 1; JX3, n = 2; FJ1, n = 1; FJ2, n = 1), and the genotype EbpC was the preponderant genotype. Phylogenetic analysis indicated that all genotypes of E. bieneusi were clustered as the zoonotic group 1. Moreover, a high genetic diversity of E. bieneusi were identified in this study, which the 64, 57, 52 and 64 samples were identified by multilocus sequence typing (MLST) at MS1, MS3, MS4 and MS7 loci, respectively. Then, 45 samples were successfully amplified and sequenced at four loci, forming 41 distinct multilocus genotypes (MLGs). These findings suggest that diarrheic pigs may potentially threaten to transmit E. bieneusi to humans, revealing E. bieneusi genetic variability in diarrheic pigs in three provinces of southern China.

The incidence and risk of cardiovascular events associated with immune checkpoint inhibitors in Asian populations.

OBJECTIVES: Immune checkpoint inhibitors are associated with adverse cardiovascular events. However, there are no data characterizing cardiovascular events among Asians on immune checkpoint inhibitors. We aim to determine the incidence and risk of cardiac events associated with immune checkpoint inhibitors in an Asian population. METHODS: We performed a retrospective, propensity score-matched cohort study at two tertiary referral centers in Taiwan. Immune checkpoint inhibitor users were matched with non-immune checkpoint inhibitor users based on predetermined clinical variables. The primary outcome was major adverse cardiovascular events, defined as a composite of myocardial infarction, ischemic stroke, acute peripheral occlusive disease, pulmonary embolism, deep venous thrombosis, heart failure, pericardial disease, myocarditis, cardiac arrhythmias and conduction block. RESULTS: Between January 2010 and November 2021, 868 immune checkpoint inhibitor users were matched 1:1 with non-immune checkpoint inhibitor users. Among immune checkpoint inhibitor users, 67 (7.7%) patients developed major adverse cardiovascular events. During a median follow-up period of 188 days, the incidence rate of major adverse cardiovascular events for immune checkpoint inhibitor and non-immune checkpoint inhibitor users was 94.8 and 46.2 per 1000 patient-years, respectively, resulting in an incidence rate ratio of 2.1 [95% confidence interval: 1.5-2.9]. In multivariate Cox proportional hazard models, immune checkpoint inhibitor users had a 60% increased risk for major adverse cardiovascular events [hazard ratio, 1.6 (95% confidence interval: 1.1-2.3)]. Immune checkpoint inhibitors use was independently associated with increased risk of ischemic stroke [hazard ratio, 3.0 (95% confidence interval: 1.0-9.0)] and pulmonary embolism [hazard ratio, 5.5 (95% confidence interval: 1.4-21.3)]. In multivariate logistic regression analysis, age > 65, metastatic disease, hypertension and baseline platelet-to-lymphocyte ratio < 180 were risk factors for major adverse cardiovascular events. CONCLUSIONS: Among Asians, immune checkpoint inhibitors were associated with an increased risk of major adverse cardiovascular events, particularly ischemic stroke and pulmonary embolism.

Mortality-to-Incidence Ratio for Nasopharyngeal Carcinoma Is Associated with Health Expenditure.

Geographic and gender-specific disparity can be observed in nasopharyngeal carcinoma (NPC). While screening and more effective therapies, such as induction chemotherapy, could improve survival rates, they are costly. This study aims to explore the correlation between healthcare expenditure and the mortality-to-incidence ratio (MIR) in NPC. Data were obtained from the World Health Organization and the Global Cancer Observatory. The correlation was evaluated by Spearman's rank correlation coefficient. Most new cases and deaths occur in Asia, and more males are affected than females. Our study shows that countries with higher MIRs have lower levels of health expenditure regardless of the NPC's gender-specific incidence. Correspondingly, MIRs are all significantly negatively associated with current health expenditure (CHE) per capita and CHE as a percentage of gross domestic product (CHE/GDP) in both genders. CHE per capita and CHE/GDP have a significant impact on NPC outcomes. Moreover, economic status is a potential major factor in MIR differences between countries.

iStent inject® and cataract surgery for mild-to-moderate primary open angle glaucoma in Japan: a cost-utility analysis.

AIM: To evaluate the cost-utility of iStent inject® with cataract surgery vs cataract surgery alone in patients with mild-to-moderate primary open angle glaucoma (POAG) in the Japanese setting from a public payer's perspective. METHODS: A Markov model was adapted to estimate the cost-utility of iStent inject® plus cataract surgery vs cataract surgery alone in one eye in patients with mild-to-moderate POAG over lifetime horizon from the perspective of Japanese public payer. Japanese sources were used for patients' characteristics, clinical data, utility, and costs whenever available. Non-Japanese data were validated by Japanese clinical experts. RESULTS: In the probabilistic base case analysis, iStent inject® with cataract surgery was found to be cost-effective compared with cataract surgery alone over a lifetime horizon when using the ¥5 000 000/quality-adjusted life year (QALY) willingness-to-pay threshold. The incremental cost-utility ratio (ICUR) was estimated to be ¥1 430 647/QALY gained and the incremental cost-utility ratio (ICER) was estimated to be ¥12 845 154/blind eye avoided. iStent inject® with cataract surgery vs cataract surgery alone was found to increase costs (¥1 025 785 vs ¥933 759, respectively) but was more effective in increasing QALYs (12.80 vs 12.74) and avoiding blinded eyes (0.133 vs 0.141). The differences in costs were mainly driven by costs of primary surgery (¥279 903 vs ¥121 349). In the scenario analysis from a societal perspective, which included caregiver burden, iStent inject® with cataract surgery was found to dominate cataract surgery alone. CONCLUSION: The iStent inject® with cataract surgery is a cost-effective strategy over cataract surgery alone from the public payer's perspective and cost-saving from the societal perspective in patients with mild-to-moderate POAG in Japan.