Multi-therapeutic-activity selenium nanodot toward preventing brain injury and restoring neurobehavioral functions following hemorrhagic stroke.

Intracerebral hemorrhage is a lethal cerebrovascular disease, and the inevitable secondary brain injury (SBI) is responsible for serious disability and death. Perfect therapeutic goal is to minimize SBI and restore neurobehavioral functions. Recently, neuroprotection is highlighted to reduce SBI, but it still faces "Neuronal survival but impaired functions" dilemma. Herein, this work further proposes a novel combinational therapeutic strategy of neuroprotection and neurogenesis toward this goal. However, appropriate therapeutic agents are rarely reported, and their discovery and development are urgently needed. Selenium participates in various physiological/pathological processes, which is hypothesized as a potential targeting molecule. To explore this effect, this work formulates an ultra-small selenium nanodot with a seleno-amino acid derived carbon dot domain and a hydrophilic PEG layer, surprisingly finding that it increases various selenoproteins levels at perihematomal region, to not only exert multiple neuroprotective roles at acute phase but promote neurogenesis and inhibit glial scar formation at recovery phase. At a safe dose, this combinational strategy effectively prevents SBI and recovers neurobehavioral functions to a normal level. Furthermore, its molecular mechanisms are revealed to broaden application scopes in other complex diseases.

Is Bevacizumab a Cost-Effective Regimen for Treating Cerebral Radiation Necrosis in the United States?

BACKGROUND: Bevacizumab has been demonstrated to have superior efficacy in the treatment of cerebral radiation necrosis (CRN), but its high cost may exacerbate the disease burden. This study aimed to assess the cost-effectiveness of bevacizumab in comparison to corticosteroids for treating CRN from the US payers' perspective. METHODS: Decision tree models were constructed to simulate the process of bevacizumab and corticosteroids in CRN short-term and long-term therapy. Critical clinical data were derived from the NCT01621880 trial. Costs and utility values were obtained from the US official websites and published literature. The main outcomes were total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analyses were performed to assess the robustness of the models. RESULTS: In the short-term and long-term models, bevacizumab added 0.11 (0.46 vs 0.35) and 0.16 (0.54 vs 0.38) QALYs compared with corticosteroids therapy, with corresponding incremental costs of $12,351 and $23,253, respectively. The resultant ICERs were $112,987/QALY and $150,245/QALY for short-term and long-term treatment, respectively. The one-way sensitivity analysis indicated that utility value of nonrecurrence status, body weight, and bevacizumab price per cycle were the most influential factors for ICER of both models. At the willingness-to-pay threshold of $150,000/QALY in the United States, the probabilities of bevacizumab being cost-effective for CRN short and long-term treatment were 63.9% and 49%, respectively. CONCLUSIONS: Compared with corticosteroids, bevacizumab is an economical alternative for CRN short-term treatment from the US payers' perspective, whereas long-term therapy draws an opposite conclusion.

Inhalation of SP-101 Followed by Inhaled Doxorubicin Results in Robust and Durable hCFTRΔR Transgene Expression in the Airways of Wild-Type and Cystic Fibrosis Ferrets.

Cystic fibrosis (CF) is a serious genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approved small molecule therapies benefit the majority of people with CF (pwCF), but unfortunately not all. Gene addition offers a mutation agnostic treatment option for all pwCF. SP-101 is an adeno-associated virus gene therapy vector (AAV2.5T) that has been optimized for efficient human airway cell transduction, and that contains a functional and regulated shortened human CFTR minigene (hCFTRΔR) with a small synthetic promoter/enhancer. To understand SP-101 airway distribution, activity, and the associated immune response, in vivo studies were performed in wild-type and CF ferrets. After single dose inhaled delivery of SP-101, followed by single dose inhaled doxorubicin (an AAV transduction augmenter) or saline, SP-101 vector genomes were detected throughout the respiratory tract. hCFTRΔR mRNA expression was highest in ferrets also receiving doxorubicin and persisted for the duration of the study (13 weeks). Pre-existing mucus in the CF ferrets did not present a barrier to effective transduction. Binding and neutralizing antibodies to the AAV2.5T capsid were observed regardless of doxorubicin exposure. Only a portion of ferrets exhibited a weak T-cell response to AAV2.5T and no T-cell response was seen against hCFTRΔR. These data strongly support the continued development of inhaled SP-101, followed by inhaled doxorubicin, for the treatment of CF.

SP-101, A Novel Adeno-Associated Virus Gene Therapy for the Treatment of Cystic Fibrosis, Mediates Functional Correction of Primary Human Airway Epithelia From Donors with Cystic Fibrosis.

Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Although CF affects multiple organs, lung disease is the main cause of morbidity and mortality, and gene therapy is expected to provide a mutation-agnostic option for treatment. SP-101 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a human CFTR minigene, hCFTRΔR, and is being investigated as an inhalation treatment for people with CF. To further understand SP-101 activity, in vitro studies were performed in human airway epithelia (HAE) derived from multiple CF and non-CF donors. SP-101 restored CFTR-mediated chloride conductance, measured via Ussing chamber assay, at a multiplicity of infection (MOI) as low as 5E2 in the presence of doxorubicin, a small molecule known to augment AAV transduction. Functional correction of CF HAE increased with increasing MOI and doxorubicin concentration and correlated with increasing cell-associated vector genomes and hCFTRΔR mRNA expression. Tropism studies using a fluorescent reporter vector and single-cell mRNA sequencing of SP-101-mediated hCFTRΔR mRNA demonstrated broad expression in all cell types after apical transduction, including secretory, ciliated, and basal cells. In summary, SP-101, particularly in combination with doxorubicin, shows promise for a novel CF treatment strategy and strongly supports continued development.

Myocardial ischemia-reperfusion injury: The balance mechanism between mitophagy and NLRP3 inflammasome.

Myocardial ischemia-reperfusion injury (MIRI) is an injury to cardiomyocytes due to restoration of blood flow after myocardial infarction (MI). It has recently gained much attention in clinical research with special emphasis on the roles of mitochondrial autophagy and inflammation. A mild inflammatory response promotes recovery of post-ischemic cardiomyocyte function and vascular regeneration, but a severe inflammatory response can cause irreversible and substantial cellular damage. Similarly, moderate mitochondrial autophagy can help inhibit excessive inflammation and protect cardiomyocytes. However, MIRI is aggravated when mitochondrial function is disrupted, such as inadequate clearance of damaged mitochondria or excessive activation of mitophagy. How to moderately control mitochondrial autophagy while promoting its balance with nucleotide-binding oligomerization structural domain receptor protein 3 (NLRP3) inflammasome activation is critical. In this paper, we reviewed the molecular mechanisms of mitochondrial autophagy and NLRP3 inflammasome, described the interaction between NLRP3 inflammasome and mitochondrial autophagy, and the effects of different signaling pathways and molecular proteins on MIRI, to provide a reference for future research.

Analysis of risk factors for persistent PSA after radical prostatectomy: results from a high-volume center in Southeast China.

BACKGROUND: For localized prostate cancer, a comprehensive treatment approach centered around radical prostatectomy (RP) is often their optimal choice. Successful RP can typically reduce prostate-specific antigen (PSA) levels to below 0.1 ng/mL within 6 to 8 weeks postoperatively. However, in clinical practice, 5 to 24% of patients may have a PSA ≥ 0.1 ng/mL at 6 to 8 weeks after surgery, a phenomenon known as PSA persistence. Many studies based on data from Europe and United States have shown an association between PSA persistence and poor postoperative outcomes, further analyzing the risk factors for PSA persistence. However, relevant research based on data from China remains scarce. METHODS: Retrospective study of 1,347 prostate cancer patients who underwent RP at the First Affiliated Hospital of Zhejiang University School of Medicine from July 15, 2016, to August 31, 2022. Based on inclusion criteria, univariate and multivariate logistic regression analyses were conducted to explore the independent risk factors for persistent PSA. RESULTS: Among the 826 prostate cancer patients after RP, 124 patients experienced persistent PSA. In univariate logistic regression analysis, robot-assisted laparoscopic radical prostatectomy (RARP), preoperative PSA, high-risk group, preoperative International Society of Urological Pathology (ISUP) grades 2-5, postoperative ISUP grades 3-5, percentage of positive cores, cT3, ≥pT3b, extracapsular extension (EPE), seminal vesicle invasion (SVI), positive surgical margins (PSM) and Prostate Specific Antigen Density (PSAD) were all significantly associated with PSA persistence after RP (P < 0.05). In terms of surgical approach, RARP was considered a protective factor against postoperative PSA persistence (OR:0.53, p < 0.05). In multivariate logistic regression analysis, preoperative ISUP grade 4, percentage of positive cores and PSM were independent risk factors of PSA persistence after RP (P < 0.05). CONCLUSION: Preoperative PSA, high-risk group, preoperative ISUP grades 2-5, postoperative ISUP grades 3-5, percentage of positive cores, cT3, ≥pT3b, EPE, SVI, PSM and PSAD were independent risk factors for PSA persistence in prostate cancer patients after RP. This provides assistance for early monitoring and treatment of patients at high risk of persistent PSA in clinical practice.

Immigrant and Racialized Populations' Cumulative Exposure to Discrimination and Associations with Long-Term Conditions During COVID-19: A Nationwide Large-Scale Study in Canada.

BACKGROUND: This cross-sectional study examines associations between the race-migration nexus, cumulative exposure to intersectional discrimination (2 years before and during the COVID-19 pandemic), and long-term conditions. METHODS: A nationwide self-selected sample (n = 32,605) was obtained from a Statistics Canada's Crowdsourcing online survey from August 4 to 24, 2020. Binary and multinomial logistic regression models were used to examine disparities by the race-migration nexus in accumulative experiences of multiple situations- and identity-based discrimination and their relations with long-term conditions, after controlling for sociodemographic covariates. RESULTS: During the pandemic, discrimination stemming from racialization - such as race/skin color (24.4% vs 20.1%) and ethnicity/culture (18.5% vs 16.5%) - and cyberspace (34.1% vs 29.8%) exaggerated relative to pre-pandemic period; compared to Canadian-born (CB) whites, the likelihood of experiencing multiple discrimination increased alongside the domains of discrimination being additively intersected (e.g., identity-based, all p's < 0.001) among CB racialized minorities (ORs 2.08 to 11.78), foreign-born (FB) racialized minorities (ORs 1.99 to 12.72), and Indigenous populations (ORs 1.62 to 8.17), except for FB whites (p > 0.01); dose-response relationships were found between cumulative exposure to multiple discrimination and odds of reporting long-term conditions (p's < 0.001), including seeing (ORs 1.63 to 2.99), hearing (ORs 1.83 to 4.45), physical (ORs 1.66 to 3.87), cognitive (ORs 1.81 to 3.79), and mental health-related impairments (ORs 1.82 to 3.41). CONCLUSIONS: Despite a universal health system, Canadians who are CB/FB racialized and Indigenous populations, have a higher prevalence of cumulative exposure to different aspects of discrimination that are associated with multiple long-term conditions during the COVID-19 pandemic. Equity-driven solutions are needed to tackle upstream determinants of health inequalities through uprooting intersectional discrimination faced by racialized and immigrant communities.

YTHDF2 Regulates Advanced Glycation End Products-Induced Melanogenesis through Inhibiting A20 Expression in Human Dermal Fibroblasts.

Fibroblast A20 suppresses advanced glycation end products (AGEs)-induced melanogenesis by inhibiting NLRP3 inflammasome activation. AGEs repress A20 expression and significantly m6A-methylate A20 mRNA in fibroblasts. YTHDF2 is the most studied m6A reader protein and can accelerate degradation of m6A-modified mRNA. Whether YTHDF2 regulates AGEs-induced A20 expression and pigmentation is unknown. In this study, we confirmed that YTHDF2 inversely regulated AGEs-BSA-inhibited A20 expression but facilitated AGEs-BSA-activated NF-κB signaling and NLRP3 inflammasome in fibroblasts via YTHDF2 knockdown and overexpression experiments. Mechanistically, YTHDF2 bound to m6A-modified A20 mRNA induced by AGEs-BSA and increased its degradation. Moreover, fibroblast YTHDF2 robustly promoted AGEs-BSA-induced IL-18 level in coculture supernatants and melanin content, tyrosinase activity, and expression of microphthalmia-associated transcription factor and tyrosinase in melanocytes, which were significantly blocked by IL-18 binding protein. Further, fibroblast YTHDF2 markedly increased AGEs-BSA-induced epidermal melanin level in cocultured ex vivo skin and MAPKs activation in melanocytes. Importantly, upregulated dermal YTHDF2 expression was negatively correlated with dermal A20 level and positively associated with both epidermal melanin and dermal AGEs content in sun-exposed skin and lesions of melasma and solar lentigo. These findings suggest that fibroblast YTHDF2 positively regulates AGEs-induced melanogenesis mainly via A20/ NF-κB /NLRP3 inflammasome/ IL-18 /MAPKs axis in an m6A-dependent manner and functions in photoaging-induced hyperpigmentation skin disorders.

Reducing Left Ventricular Wall Stress through Aortic Valve Enlargement via Transcatheter Aortic Valve Implantation in Severe Aortic Stenosis.

Background: In aortic stenosis, the left ventricle exerts additional force to pump blood through the narrowed aortic valve into the downstream arterial vasculature. Adaptive hypertrophy helps to maintain wall stress homeostasis but at the expense of impaired compliance. Advanced ventricular deformation impacts the extent of functional recovery benefits achieved through transcatheter aortic valve implantation. Methods and Results: Subgroups were stratified based on output, with low-flow severe aortic stenosis defined as stroke volume index <35 mL· m-2. Before intervention, the low-flow subgroup exhibited worse effective orifice area index and arterial and global impedance, along with thinner wall thickness and larger chamber volume marginally. LV performance, including stroke volume index, ventricular elastance, and ventricular-arterial coupling, were notably inferior, consistent with worse adverse remodeling. Although the effective orifice area index was similarly augmented after TAVI, inferior recovery benefits were noted. Persistently higher wall stress and energy consumption were observed, along with poorer ventricular-arterial coupling. These changes in wall stress showed an inverse relationship with alterations in wall thickness and were proportional to changes in dimension and volume. Additionally, they were proportional to changes in left ventricular end-systolic pressure, pressure-volume area, and ventricular-arterial coupling but inversely related to ventricular end-systolic elastance. Conclusions: The study revealed that aortic valve enlargement through transcatheter aortic valve implantation reduces left ventricular wall stress in severe aortic stenosis. The reduced recovery benefits in the low-flow subgroup were evident. Wall stress could serve as a marker of mechanical benefit after the intervention.

Association between gait video information and general cardiovascular diseases: a prospective cross-sectional study.

Aims: Cardiovascular disease (CVD) may not be detected in time with conventional clinical approaches. Abnormal gait patterns have been associated with pathological conditions and can be monitored continuously by gait video. We aim to test the association between non-contact, video-based gait information and general CVD status. Methods and results: Individuals undergoing confirmatory CVD evaluation were included in a prospective, cross-sectional study. Gait videos were recorded with a Kinect camera. Gait features were extracted from gait videos to correlate with the composite and individual components of CVD, including coronary artery disease, peripheral artery disease, heart failure, and cerebrovascular events. The incremental value of incorporating gait information with traditional CVD clinical variables was also evaluated. Three hundred fifty-two participants were included in the final analysis [mean (standard deviation) age, 59.4 (9.8) years; 25.3% were female]. Compared with the baseline clinical variable model [area under the receiver operating curve (AUC) 0.717, (0.690-0.743)], the gait feature model demonstrated statistically better performance [AUC 0.753, (0.726-0.780)] in predicting the composite CVD, with further incremental value when incorporated with the clinical variables [AUC 0.764, (0.741-0.786)]. Notably, gait features exhibited varied association with different CVD component conditions, especially for peripheral artery disease [AUC 0.752, (0.728-0.775)] and heart failure [0.733, (0.707-0.758)]. Additional analyses also revealed association of gait information with CVD risk factors and the established CVD risk score. Conclusion: We demonstrated the association and predictive value of non-contact, video-based gait information for general CVD status. Further studies for gait video-based daily living CVD monitoring are promising.

Cost-effectiveness analysis of bevacizumab for cerebral radiation necrosis treatment based on real-world utility value in China.

BACKGROUND: Bevacizumab shows superior efficacy in cerebral radiation necrosis (CRN) therapy, but its economic burden remains heavy due to the high drug price. This study aims to evaluate the cost-effectiveness of bevacizumab for CRN treatment from the Chinese payers' perspective. METHODS: A decision tree model was developed to compare the costs and health outcomes of bevacizumab and corticosteroids for CRN therapy. Efficacy and safety data were derived from the NCT01621880 trial, which compared the effectiveness and safety of bevacizumab monotherapy with corticosteroids for CRN in nasopharyngeal cancer patients, and demonstrated that bevacizumab invoked a significantly higher response than corticosteroids (65.5% vs. 31.5%, P < 0.001) with no significant differences in adverse events between two groups. The utility value of the "non-recurrence" status was derived from real-world data. Costs and other utility values were collected from an authoritative Chinese network database and published literature. The primary outcomes were total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). The uncertainty of the model was evaluated via one-way and probabilistic sensitivity analyses. RESULTS: Bevacizumab treatment added 0.12 (0.48 vs. 0.36) QALYs compared to corticosteroid therapy, along with incremental costs of $ 2010 ($ 4260 vs. $ 2160). The resultant ICER was $ 16,866/QALY, which was lower than the willingness-to-pay threshold of $ 38,223/QALY in China. The price of bevacizumab, body weight, and the utility value of recurrence status were the key influential parameters for ICER. Probabilistic sensitivity analysis revealed that the probability of bevacizumab being cost-effectiveness was 84.9%. CONCLUSION: Compared with corticosteroids, bevacizumab is an economical option for CRN treatment in China.

The cost-effectiveness of zolbetuximab in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma.

Aim: To estimate the cost-effectiveness of zolbetuximab plus capecitabine/oxaliplatin (CAPOX) in CLDN18.2-positive, HER2-negative, mG/GEJ adenocarcinoma from the perspective of Chinese payers.Materials & methods: A partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICER) of zolbetuximab plus CAPOX versus placebo plus CAPOX. Sensitivity analyses were performed to test the robustness of model.Results: Zolbetuximab plus CAPOX gained an additional cost of $91,551 and an extra health benefit of 0.24 QALY over placebo plus CAPOX, producing an ICER of $388,186/QALY, which exceeded the willingness-to-pay threshold of $38,223/QALY. Sensitivity analysis shows that the model was generally robust.Conclusion: Zolbetuximab plus CAPOX would not be a cost-effective first-line treatment regimen in CLDN18.2-positive, HER2-negative, mG/GEJ adenocarcinoma in China.

[Box: see text].

Prediction of coronary artery disease based on facial temperature information captured by non-contact infrared thermography.

BACKGROUND: Current approaches for initial coronary artery disease (CAD) assessment rely on pretest probability (PTP) based on risk factors and presentations, with limited performance. Infrared thermography (IRT), a non-contact technology that detects surface temperature, has shown potential in assessing atherosclerosis-related conditions, particularly when measured from body regions such as faces. We aim to assess the feasibility of using facial IRT temperature information with machine learning for the prediction of CAD. METHODS: Individuals referred for invasive coronary angiography or coronary CT angiography (CCTA) were enrolled. Facial IRT images captured before confirmatory CAD examinations were used to develop and validate a deep-learning IRT image model for detecting CAD. We compared the performance of the IRT image model with the guideline-recommended PTP model on the area under the curve (AUC). In addition, interpretable IRT tabular features were extracted from IRT images to further validate the predictive value of IRT information. RESULTS: A total of 460 eligible participants (mean (SD) age, 58.4 (10.4) years; 126 (27.4%) female) were included. The IRT image model demonstrated outstanding performance (AUC 0.804, 95% CI 0.785 to 0.823) compared with the PTP models (AUC 0.713, 95% CI 0.691 to 0.734). A consistent level of superior performance (AUC 0.796, 95% CI 0.782 to 0.811), achieved with comprehensive interpretable IRT features, further validated the predictive value of IRT information. Notably, even with only traditional temperature features, a satisfactory performance (AUC 0.786, 95% CI 0.769 to 0.803) was still upheld. CONCLUSION: In this prospective study, we demonstrated the feasibility of using non-contact facial IRT information for CAD prediction.

Risk factor analysis and optimal cutoff value selection of PSAD for diagnosing clinically significant prostate cancer in patients with negative mpMRI: results from a high-volume center in Southeast China.

BACKGROUND: Multi-parametric magnetic resonance imaging (mpMRI) is a diagnostic tool used for screening, localizing, and staging prostate cancer. Patients with Prostate Imaging Reporting and Data System (PI-RADS) score of 1 and 2 are considered negative mpMRI, with a lower likelihood of detecting clinically significant prostate cancer (csPCa). However, relying solely on mpMRI is insufficient to completely exclude csPCa, necessitating further stratification of csPCa patients using biomarkers. METHODS: A retrospective study was conducted on mpMRI-negative patients who underwent prostate biopsy at the First Affiliated Hospital of Zhejiang University from January 2022 to June 2023. A total of 607 patients were included based on inclusion and exclusion criteria. Univariate and multivariate logistic regression analysis were performed to identify risk factors for diagnosing csPCa in patients with negative mpMRI. Receiver Operating Characteristic (ROC) curves were plotted to compare the discriminatory ability of different Prostate-Specific Antigen Density (PSAD) cutoff values for csPCa. RESULTS: Among the 607 patients with negative mpMRI, 73 patients were diagnosed with csPCa. In univariate logistic regression analysis, age, PSA, f/tPSA, prostate volume, and PSAD were all associated with diagnosing csPCa in patients with negative mpMRI (P < 0.05), with PSAD being the most accurate predictor. In multivariate logistic regression analysis, f/tPSA, age, and PSAD were independent predictors of csPCa (P < 0.05). PSAD cutoff value of 0.20 ng/ml/ml has better discriminatory ability for predicting csPCa and is a significant risk factor for csPCa in multivariate analysis. CONCLUSION: Age, f/tPSA, and PSAD are independent predictors of diagnosing csPCa in patients with negative mpMRI. It is suggested that patients with negative mpMRI and PSAD less than 0.20 ng/ml/ml could avoid prostate biopsy, as a PSAD cutoff value of 0.20 ng/ml/ml has better diagnostic performance than the traditional cutoff value of 0.15 ng/ml/ml.

Alterations in peripheral T- and B-cell subsets in patients with systemic sclerosis.

OBJECTIVES: To determine the alteration of peripheral T and B cell subsets in patients with systemic sclerosis (SSc) and to evaluate their correlation with the progression of SSc. METHODS: We recruited 47 SSc patients and 45 healthy controls (HCs) in this study. Demographic and clinical data were then collected. Flow cytometry was used to detect the proportions of 44 different T and B cell subsets in circulating blood. RESULTS: The proportion of total B cells (p = .043) decreased in SSc patients, together with similar frequencies of total T cells, CD4+ T cells, and CD8+ T cells in both groups. Several subsets of T and B cells differed significantly between these two groups. Follicular helper T cells-1 (Tfh1) (p < .001), helper T cells-1 (Th1) (p = .001), regulatory T cells (Treg) (p = .004), effector memory CD8+ T cells (p = .041), and cytotoxic T cells-17 (Tc17) (p = .01) were decreased in SSc patients. Follicular helper T cells-2 (Tfh2) (p = .001) and, helper T cells-2 (Th2) (p = .001) levels increased in the SSc group. Regulatory B cells (Breg) (p = .015) were lower in the SSc group, together with marginal zone (MZ) B cells (p < .001), memory B cells (p = .001), and non-switched B cells (p = .005). The modified Rodnan skin score (mRSS) correlated with helper T cells-17 (Th17) (r = -.410, p = .004), Tfh1 (r = -.321, p = .028), peripheral helper T cells (Tph) (r = -.364, p = .012) and plasma cells (r = -.312, p = .033). CONCLUSIONS: The alterations in T and B cells implied immune dysfunction, which may play an essential role in systemic sclerosis.

Frontostriatal circuit dysfunction leads to cognitive inflexibility in neuroligin-3 R451C knockin mice.

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.

Lenvatinib plus pembrolizumab in the patients with advanced previously treated endometrial cancer: A cost-effectiveness analysis in the United States and in China.

PURPOSE: To investigate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) compared to chemotherapy as a second-line treatment for advanced endometrial cancer (EC) from the United States and Chinese payers' perspective. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of the United States and Chinese payers. The survival data were derived from the clinical trial (309-KEYNOTE-775), while costs and utility values were sourced from databases and published literature. Total costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were estimated. The robustness of the model was evaluated through sensitivity analyses, and price adjustment scenario analyses was also performed. RESULTS: Base-case analysis indicated that LP wouldn't be cost-effective in the United States at the WTP threshold of $200 000, with improved effectiveness of 0.75 QALYs and an additional cost of $398596.81 (ICER $531392.20). While LP was cost-effective in China, with improved effectiveness of 0.75 QALYs and an increased overall cost of $62270.44 (ICER $83016.29). Sensitivity analyses revealed that the above results were stable. The scenario analyses results indicated that LP was cost-effective in the United States when the prices of lenvatinib and pembrolizumab were simultaneously reduced by 61.95% ($26.5361/mg for lenvatinib and $19.1532/mg for pembrolizumab). CONCLUSION: LP isn't cost-effective in the patients with advanced previously treated endometrial cancer in the United States, whereas it is cost-effective in China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about budget impact and affordability for patients is needed.

Acute Effect in Mechanical Efficiency by Pressure-Volume Loop Analysis after Transcatheter Aortic Valve Implantation.

Background: This study aimed to evaluate the immediate effect of transcatheter aortic valve implantation (TAVI) on mechanical efficiency. Methods: A total of 46 patients (25 females) with an average age of 83 ± 6.4 years underwent TAVI using the CoreValve system. During the same hospitalization, we conducted a comprehensive comparison of the patients before and after TAVI without inotropic support using echocardiography. The parameters encompassed left ventricular (LV) geometry, valvular load, global LV afterload and ventricular hemodynamics. The analysis using pressure-volume loops enabled the determination of load-independent contractility (Ees) and afterload, in addition to assessing potential energy, stroke work, and mechanical efficiency. Results: The immediate effect was an augmented aortic valve area accompanied by a reduction in the transvalvular pressure gradient. We observed reductions in left ventricular end-systolic volume and end-diastolic volume, and also reductions in global afterload and end-systolic meridional wall stress. The Ea index decreased, while the Ees index remained relatively stable. We noted increases in stroke volume and systemic arterial compliance, indicating more efficient blood transfer from the ventricle to aorta. These changes contributed to the normalization of ventricular-arterial coupling. In terms of mechanical work of the chamber, we observed significant decreases in potential energy, stroke work, and pressure-volume area. There was an increase in the mechanical efficiency of the chamber. Conclusions: The TAVI procedure immediately reduced global afterload and improved diastolic compliance of the chamber, resulting in enhanced ventricular function and mechanical efficiency.