CST3 alleviates retinal vascular leakage by regulating the Rap1 signaling pathway.

Retinal vascular leakage is a major event in several retinal diseases, including diabetic retinopathy (DR). In a previous study, we demonstrated that the aqueous humor concentration of Cystatin C (CST3), a physiological inhibitor of cysteine protease, is negatively correlated with the severity of diabetic macular edema. However, its function in the retina has not been clearly elucidated. In this study, we found a significant decrease in the aqueous humor concentration of CST3 with DR progression. Furthermore, we found that CST3 was expressed in retinal endothelial cells and that its expression was significantly downregulated in high glucose-treated human retinal microvascular endothelial cells (HRMECs) and the retinal vessels of oxygen-induced retinopathy (OIR) mice. Silencing CST3 expression resulted in decreased HRMEC migration and tubule formation ability. Exogenous addition of the CST3 protein significantly improved HRMEC migration and tubular formation. In-vivo experiments demonstrated that CST3 silencing induced retinal vascular leakage in WT mice, while its intravitreal injection significantly reduced retinal leakage in OIR mice. Mechanistically, CST3 promoted the expression of the downstream adhesion molecules, claudin5, VE-cadherin, and ZO-1, in retinal vascular cells by regulating the Rap1 signaling pathway. Therefore, this study revealed a novel mechanism by which CST3 improves retinal vascular function and provided evidence that it is a potential therapeutic target for retinal vascular leakage.

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.

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.

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.

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.

Different types of bullae of limbs with necrotizing fasciitis predict different outcome: a prospective study.

STUDY OBJECTIVE: Necrotizing fasciitis (NF) is an uncommon life-threatening necrotizing skin and soft tissue infection. Bullae are special skin manifestations of NF. This study was conducted to analyze the differences between different types of bullae of limbs with NF for providing the information to emergency treatment. METHODS: From April 2015 to August 2018, patients were initially enrolled based on surgical confirmation of limbs with NF. According to the presence of different bullae types, patients were divided into no bullae group (Group N), serous-filled bullae group (Group S), and hemorrhagic bullae group (Group H). Data such as demographics, clinical outcomes, microbiological results, presenting symptoms/signs, and laboratory findings were compared among these groups. RESULTS: In total, 187 patients were collected, with 111 (59.4%) patients in Group N, 35 (18.7%) in Group S, and 41 (21.9%) in Group H. Group H had the highest incidence of amputation, required intensive care unit care, and most patients infected with Vibrio species. In Group N, more patients were infected with Staphylococcus spp. than Group H. In Group S, more patients were infected with ß-hemolytic Streptococcus than Group H. Patients with bacteremia, shock, skin necrosis, anemia, and longer prothrombin time constituted higher proportions in Group H and S than in Group N. CONCLUSIONS: In southern Taiwan, patients with NF accompanied by hemorrhagic bullae appear to have more bacteremia, Vibrio infection, septic shock, and risk for amputation. If the physicians at the emergency department can detect for the early signs of NF as soon as possible, and more patient's life and limbs may be saved.

Maternal insomnia during the COVID-19 pandemic: associations with depression and anxiety.

BACKGROUND: The COVID-19 outbreak has made people more prone to depression, anxiety and insomnia, and females are at a high risk of developing these conditions. As a special group, pregnant and lying-in women must pay close attention to their physical and mental health, as both have consequences for the mother and the fetus. However, knowledge regarding the status of depression, anxiety and insomnia among these women is limited. AIM: This study aimed to examine insomnia and psychological factors among pregnant and lying-in women during the COVID-19 pandemic and provide theoretical support for intervention research. METHODS: In total, 2235 pregnant and lying-in women from 12 provinces in China were surveyed; their average age was 30.25 years (SD = 3.99, range = 19-47 years). PARTICIPANTS AND SETTING: The participants completed electronic questionnaires designed to collect demographic information and assess levels of depression, anxiety and insomnia. RESULTS: The prevalence of insomnia in the sample was 18.9%. Depression and anxiety were significant predictors of insomnia. Participants in high-risk areas, those with a disease history, those with economic losses due to the outbreak, and those in the postpartum period had significantly higher insomnia scores. DISCUSSION: The incidence of insomnia among pregnant and lying-in women is not serious in the context of the epidemic, which may be related to the sociocultural background and current epidemic situation in China. CONCLUSION: Depression and anxiety are more indicative of insomnia than demographic variables.

Construction of Function-Oriented Core-Shell Nanostructures in Hydrogen-Bonded Organic Frameworks for Near-Infrared-Responsive Bacterial Inhibition.

Exploration of effective ways to integrate various functional species into hydrogen-bonded organic frameworks (HOFs) is critically important for their applications but highly challenging. In this study, according to the "bottle-around-ship" strategy, core-shell heterostructure of upconversion nanoparticles (UCNPs) and HOFs was fabricated for the first time via a ligand-grafting stepwise method. The UCNPs "core" can effectively upconvert near-infrared (NIR) irradiation (980 nm) into visible light (540 nm and 653 nm), which further excites the perylenediimide-based HOF "shell" through resonance energy transfer. In this way, the nanocomposite inherits the high porosity, excellent photothermal and photodynamic efficiency, NIR photoresponse from two parent materials, achieving intriguing NIR-responsive bacterial inhibition toward Escherichia coli. This study may shed light on the design of functional HOF-based composite materials, not only enriching the HOF library but also broadening the horizon of their potential applications.

Tumor-associated antigen-based personalized dendritic cell vaccine in solid tumor patients.

Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3-13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).

Asymmetric distribution of hypoxia-inducible factor α regulates dorsoventral axis establishment in the early sea urchin embryo.

Hypoxia signaling is an ancient pathway by which animals can respond to low oxygen. Malfunction of this pathway disturbs hypoxic acclimation and can result in various diseases, including cancers. The role of hypoxia signaling in early embryogenesis remains unclear. Here, we show that in the blastula of the sea urchin Strongylocentrotus purpuratus, hypoxia-inducible factor α (HIFα), the downstream transcription factor of the hypoxia pathway, is localized and transcriptionally active on the future dorsal side. This asymmetric distribution is attributable to its oxygen-sensing ability. Manipulations of the HIFα level entrained the dorsoventral axis, as the side with the higher level of HIFα tends to develop into the dorsal side. Gene expression analyses revealed that HIFα restricts the expression of nodal to the ventral side and activates several genes encoding transcription factors on the dorsal side. We also observed that intrinsic hypoxic signals in the early embryos formed a gradient, which was disrupted under hypoxic conditions. Our results reveal an unprecedented role of the hypoxia pathway in animal development.

Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa.

Retinitis pigmentosa (RP) is the most common manifestation of inherited retinal diseases with high degree of genetic, allelic, and phenotypic heterogeneity. CEP250 encodes the C-Nap1 protein and has been associated with various retinal phenotypes. Here, we report the identification of a mutation (c.562C>T, p.R188*) in the CEP250 in a consanguineous family with nonsyndromic RP. To gain insights into the molecular pathomechanism underlying CEP250 defects and the functional relevance of CEP250 variants in humans, we conducted a functional characterization of CEP250 variant using a novel Cep250 knockin mouse line. Remarkably, the disruption of Cep250 resulted in severe impairment of retinal function and significant retinal morphological alterations. The homozygous knockin mice showed significantly reduced retinal thickness and ERG responses. This study not only broadens the spectrum of phenotypes associated with CEP250 mutations, but also, for the first time, elucidates the function of CEP250 in photoreceptors using a newly established animal model.

Prevalence of hepatitis C infection among the general population and high-risk groups in the EU/EEA: a systematic review update.

BACKGROUND: Although significant improvement in efficacy measured by a sustained virological response, the high acquisition costs of direct-acting antivirals limit the access for patients and influence the costs of healthcare resource utilisation in hepatitis C. It is important to have the latest estimates of prevalence, especially in high-risk groups, for cost of illness, cost-effectiveness and budget impact studies. METHODS: Original studies on the estimates of the prevalence among general and high-risk groups in the European Union/European Economic Area (EU/EEA) were retrieved from Medline and Embase for the period from 2015 to 2018. All included studies were evaluated for risk of selection bias and summarised together in a narrative form. Results from previous reviews and updated searches were compared per country among different populations, respectively. RESULTS: Among the 3871 studies identified, 46 studies were included: 20 studies were used for the estimate of the general population; 3 for men who have sex with men (MSM); 6 for prisoners; and 17 for people who inject drugs (PWID). Compared with the results reported in previous systematic reviews, the updated estimates were lower than previously in most available countries. Anti-HCV general population prevalence estimates ranged from 0.54 to 1.50% by country. The highest prevalence of anti-HCV was found among PWID (range of 7.90-82.00%), followed by prisoners (7.00-41.00%), HIV-positive MSM (1.80-7.10%), HIV-negative MSM (0.20-1.80%), pregnant women (0.10-1.32%) and first-time blood donors (0.03-0.09%). CONCLUSIONS: Our study highlights the heterogeneity in anti-HCV prevalence across different population groups in EU/EEA. The prevalence also varies widely between European countries. There are many countries that are not represented in our results, highlighting the need for the development of robust epidemiological studies.

Predicted Janus SnSSe monolayer: a comprehensive first-principles study.

The Janus structure, by combining properties of different transition metal dichalcogenide (TMD) monolayers in a single polar material, has attracted increasing research interest because of its particular structure and potential application in electronics, optoelectronics and piezoelectronics. In this work, Janus SnSSe monolayer is predicted by means of first-principles calculations, and it exhibits dynamic and mechanical stability. By using the generalized gradient approximation (GGA) and spin-orbit coupling (SOC), the Janus SnSSe monolayer is found to be an indirect band-gap semiconductor, whose gap can easily be tuned by strain. High carrier mobilities are obtained for SnSSe monolayer, and the hole mobility is higher than the electron mobility. For SnSSe monolayer, a uniaxial strain in the basal plane can induce both strong in-plane and much weaker out-of-plane piezoelectric polarizations, which reveals the potential as a piezoelectric two-dimensional (2D) material. High absorption coefficients in the visible light region are observed, suggesting a potential photocatalytic application. Calculated results show that SnSSe monolayer has a very high power factor, making it a promising candidate for thermoelectric applications. Our works reveal that the Janus SnSSe structure can be fabricated with unique electronic, optical, piezoelectric and transport properties, and can motivate related experimental works.

Analysis of long non-coding RNA involved in atrazine-induced testicular degeneration of Xenopus laevis.

Long non-coding RNA (lncRNA) plays a critical role in male germline development. Atrazine (AZ) as an environmental endocrine disrupting chemical (EDCs) can induce male reproductive toxicity in amphibians. Our previous studies demonstrated that AZ can alter gene and circular RNA (circRNA) expression of damaged testes in Xenopus laevis (X. laevis). We furthered to investigate the lncRNA expression profiling in the testis of X. laevis. Over 3559 lncRNAs were detected by lncRNA sequencing. AZ induced 40 upregulated and 46 downregulated differentially expressed lncRNAs. KEGG analysis showed that AZ-affected lncRNAs mainly involve in 19 pathways among which 12 pathways are found in circRNA analysis. This study for the first time demonstrated that AZ can alter lncRNAs which may play a role in testicular degeneration through regulating expressions of functional genes in X. laevis. Our data may provide more insights on the mechanism about male reproductive toxicity of EDCs.

Effect of pseudolaric acid B on biochemical and physiologic characteristics in Colletotrichum gloeosporioides.

In our previous study on natural products with fungicidal activity, pseudolaric acid B (PAB) isolated from Pseudolarix amabilis was examined to inhibit significantly mango anthracnose (Colletotrichum gloeosporioides) in vivo and in vitro. In the current study, sensitivity of 17 plant pathogenic fungi to PAB was determined. Mycelial growth rate results showed that PAB possessed strong antifungal activities to eleven fungi with median effective concentration (EC50) values ranging from 0.087 to 1.927µg/mL. EC50 of PAB against spore germination was greater than that of mycelium growth inhibition, which suggest that PAB could execute antifungal activity through mycelial growth inhibition. Further action mechanism of PAB against C. gloeosporioides was investigated, in which PAB treatment inhibited mycelia dry weight, decreased the mycelia reducing sugar and soluble protein. Furthermore, PAB induced an increase in membrane permeability, inhibited the biosynthesis of ergosterol, caused the extreme alteration in ultrastructure as indicated by the thickened cell wall and increased vesicles. These results will increase our understanding of action mechanism of PAB against plant pathogenic fungi.

[Distribution and Community Characteristics or Epimedium myrianthum in Chongqing].

OBJECTIVE: To make clear the distribution area in Chongqing and community characteristics of Epimedium myrianthum, in order to provide evidence for sustainable utilization of resources. METHODS: Based on field investigation, recorded the GPS, and used the quadrat method to observe and analyze the abundance, frequentness and importance value of Epimedium myrianthum in the seven well-concentrated sample plots of different habitats. RESULTS: Epimedium myrianthum distributed in Changshou County, Dianjiang County, Zhongxian County and Fengdu County of Chongqing at present. The altitude of its distribution areas ranged from 351~663 m. The types of its habitats included coniferous forest, broad-leaved forest and bamboo forest. The plants in these communities were composed of 56 species belonging to 48 genera,33 families. Among associated plants, the dominant species of tree layer were Bambusa distegia, Quercus variabilis , Cupressusfunebris etc. The dominant species of shrub layer were Pittosporum illicioides, Loropetalum chinense, Myrsine africana, Ardisia japonica, Smilax china etc. The dominant species of field layer were Iris japonica, Miscanthus floridulus, Veronicastrum longispicatum, Carex lancifolia, Epimedium myrianthum etc. Species abundance index of D was between 1.1143 to 3.7781 in seven populations,the species in these communities were relatively less,and the numbers of individuals were relatively more. Compared with others, the population of the 3rd and 6th had relatively low index of H' (Shannon-wiener index) and E (Pielou index). The distribution of these species in the community was obviously uneven. The D value,H' value and E value of tree layer species richness were lower than those of shrub layer and field layer, the species diversity was worse. CONCLUSION: It is suggested to incorporate Epimedium myrianthum in the new edition of Chinese Pharmacopeia.

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.

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.

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.

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.