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Abstract The presence of significant liver inflammation is an important indication for antiviral therapy in immune-tolerant (IT)phase with chronic hepatitis B(CHB) patients. This study aims to establish a non-invasive model to assess significant liver inflammation in the IT-phase of CHB patients. This multicenter retrospective study included a total of 535 IT-phase CHB patients who underwent liver biopsy, and were randomly divided into a training and a validation set. In the training cohort, the relevant indices were initially screened using univariate analysis. Then the least absolute shrinkage and selection operator and multivariable logistic regression were used to identify the significant independent risk factors and establish a predictive model. A diagnostic nomogram was constructed. Calibration curves, decision curve analysis, and receiver operating characteristic curves were utilized to evaluate the performance of the nomogram. In this study, 37.0% of the patients exhibited significant liver inflammation. Baseline characteristics revealed a median age of 35.0 years, with males accounting for 51.7% of the cohort. Age, Aspartate aminotransferase (AST), Prothrombin (PT), Albumin (ALB) and Hepatitis B virus DNA (HBV DNA) were identified as independent predictors of significant liver inflammation in the immune-tolerant phase, and a nomogram was constructed based on these indicators. The predictive model demonstrated good calibration and discrimination in both the training set and the validation set (aera under the curve (AUC) of 0.741 and 0.740, respectively). The nomogram can accurately identify significant liver inflammation in immune-tolerant phase CHB patients and facilitate the early initiation of antiviral therapy, thereby reducing the need for clinical liver biopsies.

DNMT3A encodes a DNA methyltransferase involved in development, cell differentiation, and gene transcription, which is mutated and aberrant-expressed in cancers. Here, we revealed that loss of DNMT3A promotes malignant phenotypes in lung cancer. Based on the epigenetic inhibitor library synthetic lethal screening, we found that small-molecule HDAC6 inhibitors selectively killed DNMT3A-defective NSCLC cells. Knockdown of HDAC6 by siRNAs reduced cell growth and induced apoptosis in DNMT3A-defective NSCLC cells. However, sensitive cells became resistant when DNMT3A was rescued. Furthermore, the selectivity to HDAC6 inhibition was recapitulated in mice, where an HDAC6 inhibitor retarded tumor growth established from DNMT3A-defective but not DNMT3A parental NSCLC cells. Mechanistically, DNMT3A loss resulted in the upregulation of HDAC6 through decreasing its promoter CpG methylation and enhancing transcription factor RUNX1 binding. Notably, our results indicated that HIF-1 pathway was activated in DNMT3A-defective cells whereas inactivated by HDAC6 inhibition. Knockout of HIF-1 contributed to the elimination of synthetic lethality between DNMT3A and HDAC6. Interestingly, HIF-1 pathway inhibitors could mimic the selective efficacy of HDAC6 inhibition in DNMT3A-defective cells. These results demonstrated HDAC6 as a HIF-1-dependent vulnerability of DNMT3A-defective cancers. Together, our findings identify HDAC6 as a potential HIF-1-dependent therapeutic target for the treatment of DNMT3A-defective cancers like NSCLC.

Abstract Background Hepatic encephalopathy (HE) represents a critical complications of end-stage liver disease, serving as an independent predictor of mortality among patients with cirrhosis. Despite effective treatment with rifaximin, some patients with HE still progress to recurrent episodes, posing a significant therapeutic challenge. Recurrent HE is defined as experiencing two or more episodes within a 6-month period. Previous research has suggested that FMT may emerge as a promising treatment for recurrent HE. However, there remains a critical need to explore the optimal dosage. This trial aims to abscess the efficacy and safety of two FMT dosages: 800 ml or 400 ml total bacterial count, including mortality and quality of life. Methods This multicenter, prospective, randomized controlled trial will enroll 100 eligible patients from 31 hospitals in China. Participants will be randomly assigned in a 1:1 ratio to either the high-dose group (800 ml total bacterial count) or the low-dose group (400 ml total bacterial count). The primary objective is to assess the efficacy and safety of both dosages on outcomes at 24 and 48 weeks, including mortality and quality of life. Discussion If either or both dosages of FMT demonstrate safe and effective treatment of recurrent HE, leading to improve quality of life and survival at 24 and 48 weeks, this trial would address a significant gap in the management of recurrent HE, carrying innovative and clinically significant implications. Trial registration NCT05669651 on ClinicalTrials.gov. Registered on 29 December 2022. CHiCTR2200067135 on China Registered Clinical Trial Registration Center. Registered on 27 December 2022.

ABSTRACT As cutting‐edge technologies in biomedicine, cell and gene therapy (CGT) products demonstrate immense potential in treating cancer, rare diseases, and genetic disorders, thereby driving the importance of clinical research in this area. This study analyzes the growth trends and key characteristics of 1033 Investigator‐Initiated Trials (IITs) conducted by mainland Chinese institutions in the CGT field. The results show that IITs have played a positive role in the early proof‐of‐concept of CGT products, helping to obtain preliminary safety and efficacy data, and exploring the combination of CGT products with other therapies. Additionally, this study discusses the regional distribution, therapeutic areas, and challenges faced by IITs in the development of CGT products in China. Based on these findings, policy suggestions are proposed to optimize the regulation of IITs in mainland China, such as improving regulatory frameworks and enhancing technical guidance. It is hoped that these measures will further improve the efficiency and quality of IITs, fully utilize the large patient base and abundant clinical resources, and support the development of high‐quality CGT products in mainland China.

Abstract This study aimed to develop a predictive tool for surgical site infections (SSI) following hysterectomy and propose strategies for their prevention and control. We conducted a retrospective analysis at a tertiary maternity and child specialist hospital in Zhejiang Province, focusing on patients who underwent hysterectomy between January 2018 and December 2023 for gynecological malignancies or benign reproductive system diseases resistant to medical treatment. Risk factors associated with surgical site infections (SSI) following hysterectomy were identified using LASSO regression analysis on data from 2018 to 2022 as the training set. Independent risk factors were then used to develop a nomogram. The model was validated using data from 2023 as the validation set. Model performance was assessed using the area under the receiver operating characteristic curve (ROC), while calibration curves were employed to gauge model accuracy. Furthermore, clinical utility was evaluated through clinical decision curve analysis (DCA) and clinical impact curve analysis (CIC), providing insights into the practical application of the nomogram. Multivariate analysis identified six independent risk factors associated with SSI development after hysterectomy: BMI ≥ 24 kg/m2 (OR: 2.58; 95% CI 1.14–6.19; P

Introduction To investigate the efficacy and safety of Cutegel® MAX (Cutegel) in the correction of moderate-to-severe nasolabial folds (NLFS) compared to Restylane® (Restylane, control).Methods This study was a 52-week, multicenter, randomized, double-blinded, active-controlled clinical trial. Qualified participants with moderate-to-severe NLFs were randomly assigned in a 1:1 ratio to receive Cutegel or Restylane. For the primary efficacy endpoint, the response rate was defined as the percentage of subjects exhibiting an improvement of at least one-point based on blinded evaluation of Wrinkle Severity Rating Scale (WSRS) at 24 weeks after injection. Other secondary efficacy endpoints and treatment-emergent adverse events (TEAEs) were assessed.Results Of 340 subjects randomized, 317 completed the week 52 visit. In the per protocol set (PPS), the blinded evaluator-assessed response rates at week 24 were 81.17% for Cutegel versus 77.56% for Restylane (p = 0.327). The between-group treatment differences in response rates were 3.60% [95% confidence interval (CI) = (−5.39%, 12.60%)], which demonstrated the noninferiority of Cutegel. Other secondary efficacy endpoints supported this. No significant differences were observed in the occurrence of adverse events between the two groups.Conclusion Similar to Restylane, Cutegel was effective and well tolerated in correcting moderate-to-severe NLFs among the Chinese population.

ObjectiveTo investigate the correlation between chronic rhinosinusitis (CRS) and bronchial asthma, focusing on the CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), as well as their impact on lung function.MethodsA total of 141 patients diagnosed with chronic nasal-sinus inflammation were included in this study. Clinical data, including medical histories, nasal endoscopy scores, CT scores, symptom scores, and quality of life assessments, were collected.ResultsAmong the patients with CRSsNP, 23.8% had concomitant bronchial asthma. The incidence of asthma was significantly associated with the severity of sinus involvement in CRSsNP patients (p = 0.049). Pulmonary function impairment was correlated with the severity of sinus inflammation in CRSsNP patients (p = 0.019). Quality of life was significantly affected in patients with concomitant asthma and CRSsNP or CRSwNP.ConclusionChronic rhinosinusitis, both with and without nasal polyps, is closely correlated with bronchial asthma. Pulmonary function impairment is associated with the extent of inflammatory lesions in CRSsNP. Although CRSwNP does not significantly affect pulmonary function, the treatment of sinus diseases can contribute to the control of asthma.

Abstract Background This study aimed to examine the reporting quality of existing economic evaluations for negotiated glucose-lowering drugs (GLDs) included in China National Reimbursement Drug List (NRDL) using the Consolidated Health Economic Evaluation Reporting Standards 2013 (CHEERS 2013). Methods We performed a systematic literature research through 7 databases to identify published economic evaluations for GLDs included in the China NRDL up to March 2021. Reporting quality of identified studies was assessed by two independent reviewers based on the CHEERS checklist. The Kruskal–Wallis test and Mann–Whitney U test were performed to examine the association between reporting quality and characteristics of the identified studies. Results We have identified 24 studies, which evaluated six GLDs types. The average score rate of the included studies was 77.41% (SD:13.23%, Range 47.62%-91.67%). Among all the required reporting items, characterizing heterogeneity (score rate = 4.17%) was the least satisfied item. Among six parts of CHEERS, results part scored least at 0.55 (score rate = 54.79%) because of the incompleteness of characterizing uncertainty. Results from the Kruskal–Wallis test and Mann–Whitney U test showed that model choice, journal type, type of economic evaluations, and study perspective were associated with the reporting quality of the studies. Conclusions There remains room to improve the reporting quality of economic evaluations for GLDs in NRDL. Checklists such as CHEERS should be widely used to improve the reporting quality of economic researches in China.

Abstract Background Autoimmune uveitis is an inflammatory disease triggered by an aberrant immune response. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) are emerging as potential therapeutic agents for this condition. CD73, an ectoenzyme present on MSC-sEVs, is involved in mitigating inflammation by converting extracellular adenosine monophosphate into adenosine. We hypothesize that the inhibitory effect of MSC-sEVs on experimental autoimmune uveitis (EAU) could be partially attributed to the surface expression of CD73. Methods To investigate novel therapeutic approaches for autoimmune uveitis, we performed lentiviral transduction to overexpress CD73 on the surface of MSC-sEVs, yielding CD73-enriched MSC-sEVs (sEVs-CD73). Mice with interphotoreceptor retinoid-binding protein (IRBP)-induced EAU were grouped randomly and treated with 50 µg MSC-sEVs, vector infected MSC-sEVs, sEVs-CD73 or PBS via single tail vein injection. We evaluated the clinical and histological features of the induced mice and analyzed the proportion and functional capabilities of T helper cells. Furthermore, T-cells were co-cultured with various MSC-sEVs in vitro, and we quantified the resulting inflammatory response to assess the potential therapeutic benefits of sEVs-CD73. Results Compared to MSC-sEVs, sEVs-CD73 significantly alleviates EAU, leading to reduced inflammation and diminished tissue damage. Treatment with sEVs-CD73 results in a decreased proportion of Th1 cells in the spleen, draining lymph nodes, and eyes, accompanied by an increased proportion of regulatory T-cells (Treg cells). In vitro assays further reveal that sEVs-CD73 inhibits T-cell proliferation, suppresses Th1 cells differentiation, and enhances Treg cells proportion. Conclusion Over-expression of CD73 on MSC-sEVs enhances their immunosuppressive effects in EAU, indicating that sEVs-CD73 has the potential as an efficient immunotherapeutic agent for autoimmune uveitis.

Abstract Understanding the local electrochemical processes is of key importance for efficient energy storage applications, including electrochemical double layer capacitors. In this work, we studied the charge storage mechanism of a model material - reduced graphene oxide (rGO) - in aqueous electrolyte using the combination of cavity micro-electrode, operando electrochemical quartz crystal microbalance (EQCM) and operando electrochemical dilatometry (ECD) tools. We evidence two regions with different charge storage mechanisms, depending on the cation-carbon interaction. Notably, under high cathodic polarization (region II), we report an important capacitance increase in Zn2+ containing electrolyte with minimum volume expansion, which is associated with Zn2+ desolvation resulting from strong electrostatic Zn2+-rGO interactions. These results highlight the significant role of ion-electrode interaction strength and cation desolvation in modulating the charging mechanisms, offering potential pathways for optimized capacitive energy storage. As a broader perspective, understanding confined electrochemical systems and the coupling between chemical, electrochemical and transport processes in confinement may open tremendous opportunities for energy, catalysis or water treatment applications in the future.

Abstract Background Prior studies suggested that antidepressant use is associated with an increased risk of dementia compared to no use, which is subject to confounding by indication. We aimed to compare the dementia risk among older adults with depression receiving first-line antidepressants (i.e., SSRI/SNRI) versus psychotherapy, which is also considered the first-line therapy for depression. Methods This retrospective cohort study was conducted using the US Medical Expenditure Panel Survey from 2010 to 2019. We included adults aged ≥ 50 years diagnosed with depression who initiated SSRI/SNRI or psychotherapy. We excluded patients with a dementia diagnosis before the first record of SSRI/SNRI use or psychotherapy. The exposure was the patient’s receipt of SSRI/SNRI (identified from self-report questionnaires) or psychotherapy (identified from the Outpatient Visits or Office-Based Medical Provider Visits files). The outcome was a new diagnosis of dementia within 2 years (i.e., survey panel period) identified using ICD-9/ICD-10 codes from the Medical Conditions file. Using a multivariable logistic regression model, we reported adjusted odds ratios (aORs) with 95% confidence intervals (CIs). We also conducted subgroup analyses by patient sex, age group, race/ethnicity, severity of depression, combined use of other non-SSRI/SNRI antidepressants, and presence of underlying cognitive impairment. Results Among 2,710 eligible patients (mean age = 61 ± 8, female = 69%, White = 84%), 89% used SSRIs/SNRIs, and 11% received psychotherapy. The SSRI/SNRI users had a higher crude incidence of dementia than the psychotherapy group (16.4% vs. 11.8%), with an aOR of 1.36 (95% CI = 1.06–1.74). Subgroup analyses yielded similar findings as the main analyses, except no significant association for patients who were aged

ObjectivesTo investigate the risk of atrial fibrillation (AF) with sodium-glucose cotransporter-2 inhibitors (SGLT2is) compared to dipeptidyl peptidase-4 inhibitor (DPP4i) use in older US adults and across diverse subgroups.MethodsWe conducted a retrospective cohort analysis using claims data from 15% random samples of Medicare fee-for-service beneficiaries. Patients were adults with type 2 diabetes (T2D), no preexisting AF, and were newly initiated on SGLT2i or DPP4i. The outcome was the first incident AF. Inverse probability treatment weighting (IPTW) was used to balance the baseline covariates between the treatment groups including sociodemographics, comorbidities, and co-medications. Cox regression models were used to assess the effect of SGLT2i compared to DPP4i on incident AF.ResultsOf the 97,436 eligible individuals (mean age 71.2 ± 9.8 years, 54.6% women), 1.01% (n = 983) had incident AF over a median follow-up of 361 days. The adjusted incidence rate was 8.39 (95% CI: 6.67–9.99) and 11.70 (95% CI: 10.9–12.55) per 1,000 person-years in the SGLT2i and DPP4i groups, respectively. SGLT2is were associated with a significantly lower risk of incident AF (HR 0.73; 95% CI, 0.57 to 0.91; p = 0.01) than DPP4is. The risk reduction of incident AF was significant in non-Hispanic White individuals and subgroups with existing atherosclerotic cardiovascular diseases and chronic kidney disease.ConclusionCompared to the use of DPP4i, that of SGLT2i was associated with a lower risk of AF in patients with T2D. Our findings contribute to the real-world evidence regarding the effectiveness of SGLT2i in preventing AF and support a tailored therapeutic approach to optimize treatment selection based on individual characteristics.

Objective The Shaxiongdong carbonatite-alkaline related Nb-REE deposit is located in the Wudang area of the south Qinling Belt, but the studies on Nb mineralization in this deposit are scarce. Methods Detailed petrographic observations were made by using polarizing microscope, optical cathodoluminescence and backscattered electron testing. The structure, composition and symbiotic relationship of the minerals were identified. The composition of two types of pyrochlore was analyzed by electron probe and the mechanism of niobium enrichment was discussed. Results The Shaxiongdong complex consists of three types of rocks that are spatially closely related: Meta-pyroxenite, syenite and carbonatite, of which the carbonatites are the major hosts of Nb mineralization characterized by main pyrochlore. This implies that Nb was concentrated to economic values in the carbonatite stage after extensive fractionation of the parental carbonated silicate magma. The pyrochlore in the deposit can be classified into two types on the basis of micro-textures: ① The primary ones (Pcl1) are euhedral to subhedral and display oscillatory zoning, implying their direct crystallization from carbonatite melts; ② The altered grains (Pcl2) exhibit patchy zonation under BSE images due to hydrothermal alteration. EPMA analytical results indicate that both types are rich in Nb and F at the B and Y sites, respectively, and at the A site, they are similarly mostly rich in Ca, thus named F-Ca-pyrochlore, with minor Na, thus named F-Na-pyrochlore. Conclusion The good positive correlations between F and Nb in both types of pyrochlore indicate that F plays a key role in the enrichment of niobium during magma differentiation. On the other hand, compared to the primary pyrochlore, the altered ones have relatively low Nb2O5, CaO, Na2O and F but high UO2, Ta2O5, SrO and SiO2, indicating that the fluids responsible for pyrochlore alteration are rich in Sr, Si and U, and the alteration tends to mobilize Nb in early pyrochlore, a process that is able to lower the Nb budgets of the deposit.

BackgroundPrior studies have shown disparities in the uptake of cardioprotective newer glucose-lowering drugs (GLDs), including sodium-glucose cotranwsporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1a). This study aimed to characterize geographic variation in the initiation of newer GLDs and the geographic variation in the disparities in initiating these medications.MethodsUsing 2017-2018 claims data from a 15% random nationwide sample of Medicare Part D beneficiaries, we identified individuals diagnosed with type 2 diabetes (T2D), who had ≥1 GLD prescriptions, and did not use SGLT2i or GLP1a in the year prior to the index date,1/1/2018. Patients were followed up for a year. The cohort was spatiotemporally linked to Dartmouth hospital-referral regions (HRRs), with each patient assigned to 1 of 306 HRRs. We performed multivariable Poisson regression to estimate adjusted initiation rates, and multivariable logistic regression to assess racial disparities in each HRR.ResultsAmong 795,469 individuals with T2D included in the analyses, the mean (SD) age was 73 (10) y, 53.3% were women, 12.2% were non-Hispanic Black, and 7.2% initiated a newer GLD in the follow-up year. In the adjusted model including clinical factors, compared to non-Hispanic White patients, non-Hispanic Black (initiation rate ratio, IRR [95% CI]: 0.66 [0.64-0.68]), American Indian/Alaska Native (0.74 [0.66-0.82]), Hispanic (0.85 [0.82-0.87]), and Asian/Pacific islander (0.94 [0.89-0.98]) patients were less likely to initiate newer GLDs. Significant geographic variation was observed across HRRs, with an initiation rate spanning 2.7%-13.6%.ConclusionsThis study uncovered substantial geographic variation and the racial disparities in initiating newer GLDs.

Introduction Traditional survey-based surveillance is costly, limited in its ability to distinguish diabetes types and time-consuming, resulting in reporting delays. The Diabetes in Children, Adolescents and Young Adults (DiCAYA) Network seeks to advance diabetes surveillance efforts in youth and young adults through the use of large-volume electronic health record (EHR) data. The network has two primary aims, namely: (1) to refine and validate EHR-based computable phenotype algorithms for accurate identification of type 1 and type 2 diabetes among youth and young adults and (2) to estimate the incidence and prevalence of type 1 and type 2 diabetes among youth and young adults and trends therein. The network aims to augment diabetes surveillance capacity in the USA and assess performance of EHR-based surveillance. This paper describes the DiCAYA Network and how these aims will be achieved.Methods and analysis The DiCAYA Network is spread across eight geographically diverse US-based centres and a coordinating centre. Three centres conduct diabetes surveillance in youth aged 0–17 years only (component A), three centres conduct surveillance in young adults aged 18–44 years only (component B) and two centres conduct surveillance in components A and B. The network will assess the validity of computable phenotype definitions to determine diabetes status and type based on sensitivity, specificity, positive predictive value and negative predictive value of the phenotypes against the gold standard of manually abstracted medical charts. Prevalence and incidence rates will be presented as unadjusted estimates and as race/ethnicity, sex and age-adjusted estimates using Poisson regression.Ethics and dissemination The DiCAYA Network is well positioned to advance diabetes surveillance methods. The network will disseminate EHR-based surveillance methodology that can be broadly adopted and will report diabetes prevalence and incidence for key demographic subgroups of youth and young adults in a large set of regions across the USA.

Abstract Background Approximately 7.4 million Americans with diabetes used insulin. This study aimed to document the 10‐year trend of insulin and other glucose‐lowering medications expenditure among insured and uninsured populations and to examine the impact of insulin out‐of‐pocket (OOP) payment and insurance status on glucose‐lowering medication OOP expenditure. Methods We extracted data from the Medical Expenditure Panel Survey (2009–2018) to document trends in the expenditure of insulin among people with diabetes. Total expenditures and OOP spending per person were documented on insulin and noninsulin glucose‐lowering medications among insured and uninsured populations. Multivariable regression was applied to assess the association of insulin OOP payment and insurance status on glucose‐lowering medication OOP expenditure. Results Although insulin usage was stable over the decades, total insulin expenditure almost doubled per person per year after the Affordable Care Act (ACA) regardless of the insurance status. The OOP cost of insulin by the uninsured population increased from $1678 per person per year in the pre‐ACA period to $2800 per person per year in the post‐ACA period. After the ACA was enacted, the uninsured population had $403.96 and $143.64 more on OOP costs than the people with public and private insurance, respectively. Conclusion For insured people, the rising financial burden of insulin was borne mainly by insurance. The uninsured population is bearing a heavy burden due to the high price of insulin. Policymakers should take action to reduce the insulin price and improve the transparency of the insulin pricing process.

Abstract Background Previous reports have indicated that disrupting the Wnt/β-catenin pathway in dendritic cells (DCs) may affect the progression of autoimmune inflammation; however, the factors and timing that regulate Wnt/β-catenin signaling have not been clearly understood. Methods Experimental autoimmune uveitis (EAU) mice and Vogt–Koyanagi–Harada disease (VKH) patient samples were used to detect the expression of Wnt/β-catenin pathway genes. Western blot, real-time PCR, flow cytometry, and ELISA were performed to examine the expression of components of the Wnt/β-catenin pathway and inflammatory factors. DC-specific β-catenin knockout mice and 6-bromoindirubin-3′-oxime (BIO) administered mice were used to observe the effect of disrupting the Wnt pathway on EAU pathogenesis. Results Wnt/β-catenin signaling was inhibited in DCs during the induction phase of EAU. The inhibition was mediated by pertussis toxin (PTX), which promoted DC maturation, in turn promoting pathogenic T cell proliferation and differentiation. In vivo experiments confirmed that deleting β-catenin in DCs enhanced EAU severity, and pre-injection of PTX advanced EAU onset. Administration of a Wnt activator (BIO) limited the effects of PTX, in turn ameliorating EAU. Conclusions Our results demonstrate that PTX plays a key role as a virulence factor in initiating autoimmune inflammation via DCs by inhibiting Wnt/β-catenin signaling in EAU, and highlight the potential mechanism by which infection can trigger apparent autoimmunity.

Global warming has been leading to frequent climate extremes, and a single variable of climate extremes is no longer sufficient to fully assess the impact of climate extremes on ecosystems, requiring a synergistic multivariate inquiry. We obtain the compound warm-dry index (CWD) and the compound cold-dry index (CCD), based on a Copula theory with a binary distribution of a standardized precipitation index (SPI) and a standardized temperature index (STI). Changes in the spatial and temporal patterns of the compound extreme climate indices (CECIs) and the direct and lag responses of ecological indicators (EIs) to the CECIs in Southwestern China (SWC) are analyzed using these two indices. We find that CECIs rise continually during 1980–2019 (p 3000 m). Spring CCD promotes the growth of vegetation at low elevation (

Introduction Medical expenditures of individuals with type 2 diabetes escalate before clinical diagnosis. How increases in medical expenditures are related to glucose levels remains unclear. We examined changes in HbA1c and medical expenditures in years prior to and shortly after type 2 diabetes diagnosis.Research design and methods Using insurance claims and laboratory test results from a commercially insured population in the USA, we built three (2014, 2015, 2016) longitudinal cohorts with type 2 diabetes up to 10 years before and 2 years after the diagnosis (index year). We identified diabetes diagnosis using International Classification of Diseases, Ninth Revision and Tenth Revision codes and antidiabetic medication use. We ran two individual fixed regression models with annual total medical expenditures and average HbA1c values as dependent variables and number of years from diagnosis as the main independent variable and examined the risk-adjusted movement of the outcomes.Results Our study included 9847 individuals (83 526 person-years). Medical expenditures and HbA1c levels increased before and peaked at the diagnosis year. Medical expenditures were $8644 lower 10 years and $5781 lower 1 year before diagnosis compared with the index year. HbA1c was 12.18 mmol/mol (1.11 percentage points) and 3.49 mmol/mol (0.32 percentage points) lower, respectively. Average annual increases in medical expenditures and HbA1c values over the prediagnosis period were $318 and 0.97 mmol/mol (0.09 percentage points), respectively.Conclusions Medical expenditures and HbA1c values followed similar trajectories before and after diabetes diagnosis. Our results can inform economic evaluations of programs and policies aimed at preventing type 2 diabetes.

This work aimed to develop organic photocatalysts (PCs) that could mediate organocatalytic atom transfer radical polymerization (O-ATRP) under visible light. Through the core-modification of known chromophoric structures and ring-locking to reach a conjugation extension, annulated N-aryl benzo[kl]acridines were identified as effective visible light-responsive photocatalysts. The corresponding selenium-doped structure showed excellent performance in the O-ATRP of methacrylates, which could afford polymer products with controlled molecular weights and low dispersities under the irradiation of visible light at a 100 ppm catalyst loading.

There is a notable correlation between mitochondrial homeostasis and metabolic disruption. In this review, we report that obesity-induced disruption of mitochondrial homeostasis adversely affects lipid metabolism, adipocyte differentiation, oxidative capacity, inflammation, insulin sensitivity, and thermogenesis in thermogenic fat. Elevating mitochondrial homeostasis in thermogenic fat emerges as a promising avenue for developing treatments for metabolic diseases, including enhanced mitochondrial function, mitophagy, mitochondrial uncoupling, and mitochondrial biogenesis. The exerkines (e.g., myokines, adipokines, batokines) released during exercise have the potential to ameliorate mitochondrial homeostasis, improve glucose and lipid metabolism, and stimulate fat browning and thermogenesis as a defense against obesity-associated metabolic diseases. This comprehensive review focuses on the manifold benefits of exercise-induced exerkines, particularly emphasizing their influence on mitochondrial homeostasis and fat thermogenesis in the context of metabolic disorders associated with obesity.

Mechanized grain harvest of maize becomes increasingly important with growing land plot size in Northeast China. Grain moisture is an important factor affecting the performance of mechanized grain harvest. However, it remains unclear what influences grain dehydration rate. In this study, maize grain dehydrating process was investigated in a two-year field experiment with five hybrids under two planting densities in 2017 and 2018. It was found that damaged-grain ratio was the main factor affecting mechanized harvest quality, and this ratio was positively correlated with grain moisture content at harvest (R2=0.6372, P

Abstract Background Autoimmune uveitis is a sight-threatening intraocular inflammation mainly caused by immune dysregulation. The development of safe and effective therapeutic approaches is urgently needed. Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) have been demonstrated to inhibit autoimmune responses; however, the immunosuppressive effect of MSC-sEVs is too weak for clinical transfer. In the current study, we investigated the therapeutic effect of IL-10-overexpressing MSC-sEVs (sEV-IL10) on experimental autoimmune uveitis (EAU) and studied the underlying mechanism. Methods Mice were randomly grouped and received a single tail vein injection of different sEVs (50 μg) or PBS on day 11 post-immunization. The clinical and histological scores were graded, and the percentage of T helper cell was measured. To investigate the effect of sEVs on the proliferation of T-cells and the differentiation of Th1, Th17 and Treg cells, T-cells were cocultured with sEVs under the corresponding culture conditions. After labeled with PKH-26, sEVs were traced both in vivo and in vitro. Results Compared with normal or vector sEV-treated groups, mice in the sEV-IL10-treated group had lower clinical and histological scores with lower percentages of Th1 and Th17 cells in the eyes and higher percentages of Treg cells in the spleen and draining lymph nodes (LN). Furthermore, sEV-IL10 enhanced the suppressive effect of MSC-sEVs on the proliferation of T-cells and differentiation of Th1 and Th17 cells, whereas upregulated the differentiation of Treg cells. Both in vivo and in vitro experiments demonstrated that MSC-sEVs were rapidly enriched in target tissues and internalized by T-cells. Conclusion These results suggested that sEV-IL10 effectively ameliorates EAU by regulating the proliferation and differentiation of T-cells, indicating sEVs as a potential novel therapy for autoimmune uveitis or other autoimmune diseases.

Wood–leaf separation aiming at classifying LiDAR points into wood and leaf components is one of the most important genres for improving leaf area index estimation and forestry survey accuracy. The wood return signals could artificially increase the apparent foliage content, which needs to be screened out for deriving vital tree attributes accurately. Previous research works tended to use intensity, waveform, and geometric information extracted from a single wavelength LiDAR for wood–leaf separation. This article employs a revised hyperspectral LiDAR (HSL) to obtain spatial and ultrawide spectral data simultaneously. We also propose a simple three steps method to separate wood and leaf components based on HSL spatial and spectral measurements under the laboratory circumstances. First, the preprocessing is conducted to acquire 3-D spatial information and the multiband laser pulse reflectance for further separation. Second, preliminary separation (band division, key feature parameter calculation, and judgment) is implemented based on reflectance. Third, we employ K-Nearest Neighbor (KNN) method to enhance separation results based on preliminary separation results and spatial features and then update the results by recorrection. Then, 3-D reconstruction is accomplished by fusing wood–leaf separation results. The experimental results demonstrate that the proposed method can separate wood and leaf components with high accuracy and indicate tree attributes straightforwardly.

The extracellular level of adenosine increases greatly during inflammation, which modulates immune responses. We have previously reported that adenosine enhances Th17 responses while it suppresses Th1 responses. This study examined whether response of DC to adenosine contributes to the biased effect of adenosine and determined whether adenosine and TLR ligands have counteractive or synergistic effects on DC function. Our results show that adenosine is actively involved in both in vitro and in vivo activation of pathogenic T cells by DCs; however, under adenosine effect DCs' capability of promoting Th1 versus Th17 responses are dissociated. Moreover, activation of A2ARs on DCs inhibits Th1 responses whereas activation of A2BRs on DC enhances Th17 responses. An intriguing observation was that TLR engagement switches the adenosine receptor from A2ARs to A2BRs usage of bone marrow-derived dendritic cells (BMDCs) and adenosine binding to BMDCs via A2BR converts adenosine's anti-to proinflammatory effect. The dual effects of adenosine and TLR ligand on BMDCs synergistically enhances the Th17 responses whereas the dual effect on Th1 responses is antagonistic. The results imply that Th17 responses will gain dominance when inflammatory environment accumulates both TLR ligands and adenosine and the underlying mechanisms include that TLR ligand exposure has a unique effect switching adenosine receptor usage of DCs from A2ARs to A2BRs, via which Th17 responses are promoted. Our observation should improve our understanding on the balance of Th1 and Th17 responses in the pathogenesis of autoimmune and other related diseases.

Commented Article: LIU, Fangfang. Research on the integrated training mode of higher art education for the deaf. Trans/Form/Ação: Unesp journal of philosophy, v. 46, Special Issue, p. 47- 72, 2023.

Abstract Layered ternary carbides and nitrides, also known as MAX phases, have attracted enormous attention for many applications, especially as precursors to produce 2D metal carbides and nitrides called MXenes. However, it is still challenging to tune and control the shape/morphology of MAX phase particles at the nanoscale, as they are typically manufactured as large grains using ceramic technology. Herein, nanostructured Ti‐Al‐C MAX phases with fine‐tuned morphology of nanofibers and nanoflakes are prepared by using 1D and 2D carbon precursors at a synthesis temperature of 900 °C. The nanostructured MAX phases are used as precursors to produce nanosized multilayered MXenes, with a considerably shorter etching time and a low reaction temperature. These nanosized MXenes exhibit good electrochemical lithium‐ion storage properties and a pseudocapacitive electrochemical signature. The obtained Ti2CTx MXene electrode can deliver delithiation capacity of 300 mAh g−1 at low rates and 100 mAh g−1 when the lithiation/delithiation cycle happens within 30 s. Availability of nanoscale MAX phases and MXene nanoflakes with small lateral size may open new opportunities for both classes of materials.

This study aimed to determine the willingness of college students to choose COVID-19 heterologous vaccination and its associated influencing factors in Taizhou, China. A population-based, self-administered online questionnaire was conducted from March 15 to 17, 2022. Of the 2,463 participants who had received the invitation, 1,821 responded to the survey (response rate = 73.9%). Only 14% (86/614) of those willing to receive a booster would chose a heterologous vaccination; the perception of better effectiveness of a COVID-19 heterologous vaccination booster was the significant factor (X2 = 22.671, p

The durability of the resin–dentin bonding interface is a key issue in clinical esthetic dentistry. Inspired by the extraordinary bioadhesive properties of marine mussels in a wet environment, we designed and synthetized N-2-(3,4-dihydroxylphenyl) acrylamide (DAA) according to the functional domain of mussel adhesive proteins. DAA’s properties of collagen cross-linking, collagenase inhibition, inducing collagen mineralization in vitro, and as a novel prime monomer for clinical dentin adhesion use, its optimal parameters, and effect on the adhesive longevity and the bonding interface’s integrity and mineralization, were evaluated in vitro and in vivo. The results showed that oxide DAA can inhibit the activity of collagenase and cross collagen fibers to improve the anti-enzymatic hydrolysis of collagen fibers and induce intrafibrillar and interfibrillar collagen mineralization. As a primer used in the etch-rinse tooth adhesive system, oxide DAA can improve the durability and integrity of the bonding interface by anti-degradation and mineralization of the exposed collagen matrix. Oxidized DAA (OX-DAA) is a promising primer for improving dentin durability; using 5% OX-DAA ethanol solution and treating the etched dentin surface for 30 s is the optimal choice when used as a primer in the etch-rinse tooth adhesive system.

Studies have shown that patients with chronic liver disease are at a higher risk of contracting novel coronavirus pneumonia than healthy individuals, and many guidelines state that patients with chronic liver disease should be prioritized for COVID-19 vaccination, but there are a few studies on its safety in CLD patients. We aimed to evaluate the safety of the inactivated COVID-19 vaccine in patients with chronic liver disease, and the effect of anxiety on adverse reactions. A questionnaire survey for self-administered post-vaccination adverse reaction monitoring was conducted from June 17, 2021, to August 11, 2021, in patients with chronic liver disease attending a tertiary care hospital in Taizhou, China. We analyzed the data from of a total of 160 participants who scanned the QR code on social media to respond to the questionnaire. The overall incidence of adverse reactions after COVID-19 vaccination in patients with chronic liver disease was 44.4% (71/160), and the most common adverse reaction was local injection site reaction, accounting for 80.3% of adverse reactions (57/71). No serious adverse reactions were reported. Approximately 53.1% of the patients had anxiety about vaccination, and 51.8% of those who felt anxious reported adverse reactions. The safety of COVID-19 vaccination in patients with chronic liver disease is good, and there is a strong association between adverse reactions and vaccine anxiety. Pre-vaccination education for patients with vaccine anxiety and psychological counseling may reduce reports of adverse reactions and improve patients’ confidence in the vaccine.

A facile and cost-effective synthesis of MXenes is not yet available. Here, the authors propose a one-pot molten salt-based method of MXenes synthesis from elemental precursors in an air atmosphere. Li-ion storage properties of the MXenes are also reported and discussed.

AIM: To observe the safety and efficacy of the 25G anterior vitrectomy surgical technique via scleral flap in phacoemulsification combined with trabeculectomy for glaucoma and cataract with extremely shallow anterior chamber.METHODS: This retrospective case review consisted of 18 eyes of 18 patients(8 males and 10 females), of those, 11 eyes had acute angle-closure glaucoma with angle-closure greater than 180 degree, and 7 eyes had lens subluxation combined with glaucoma. All 18 patients underwent phacoemulsification, intraocular lens(IOL)implantation, trabeculectomy, and anterior vitrectomy via the scleral flap in cases where conservative management techniques cannot control intraocular pressure(IOP). The main outcomes were best corrected visual acuity(BCVA), anterior chamber depth(ACD), IOP, slit-lamp microscopic examination, number of medications, fundus examination, and complications.RESULTS: The average axial length(AL)was 21.5±0.6 mm. Mean age was 62.3±7.9 years. Mean ACD increased significantly from 0.78±0.43 mm to 2.89±0.41 mm 1wk after surgery(P

Abstract MAX phases are gaining attention as precursors of two-dimensional MXenes that are intensively pursued in applications for electrochemical energy storage. Here, we report the preparation of V2SnC MAX phase by the molten salt method. V2SnC is investigated as a lithium storage anode, showing a high gravimetric capacity of 490 mAh g−1 and volumetric capacity of 570 mAh cm−3 as well as superior rate performance of 95 mAh g−1 (110 mAh cm−3) at 50 C, surpassing the ever-reported performance of MAX phase anodes. Supported by operando X-ray diffraction and density functional theory, a charge storage mechanism with dual redox reaction is proposed with a Sn–Li (de)alloying reaction that occurs at the edge sites of V2SnC particles where Sn atoms are exposed to the electrolyte followed by a redox reaction that occurs at V2C layers with Li. This study offers promise of using MAX phases with M-site and A-site elements that are redox active as high-rate lithium storage materials.

Autoimmune diseases caused by T cells can arise from either T-helper 1 (Th1) or T-helper 17 (Th17)-type pathogenic T cells. However, it is unclear whether these two T-cell subsets are influenced by distinct pathogenic factors and whether treatments that are effective for Th1 responses also work for Th17 responses. To compare these two pathogenic responses, we conducted a systematic analysis in a mouse model of experimental autoimmune uveitis (EAU) to identify the factors that promote or inhibit each response and to determine their responses to various treatments. Our study found that the two types of pathogenic responses differ significantly in their pathological progressions and susceptibility to treatments. Specifically, we observed that extracellular adenosine is a crucial pathogenic molecule involved in the pathogenicity of inflammation and T-cell reactivity and that reciprocal interaction between adenosine and gamma delta (γδ) T cells plays a significant role in amplifying Th17 responses in the development of autoimmune diseases. The potential effect of targeting adenosine or adenosine receptors is analyzed regarding whether such targeting constitutes an effective approach to modulating both γδ T-cell responses and the pathogenic Th17 responses in autoimmune diseases.

Plant N concentration (PNC) has been commonly used to guide farmers in assessing maize (Zea mays L.) N status and making in-season N fertilization decisions. However, PNC varies based on the development stage. Therefore, a relationship between biomass and N concentration is needed (i.e., critical N dilution curve; CNDC) to better understand when plants are N deficient. A few CNDCs have been developed and used for plant N status diagnoses but have not been tested in the US Midwest. The objective of this study was to evaluate under highly diverse soil and weather conditions in the US Midwest the performance of CNDCs developed in France and China for assessing maize N status. Maize N rate response trials were conducted across eight US Midwest states over three years. This analysis utilized plant and soil measurements at V9 and VT development stages and final grain yield. Results showed that the French CNDC (y = 34.0x−0.37, where y is critical PNC, and x is aboveground biomass) was better with a 91% N status classification accuracy compared to only 62% with the Chinese CNDC (y = 36.5x−0.48). The N nutrition index (NNI), which is the quotient of the measured PNC and the calculated critical N concentration (Nc) based on the French CNDC was significantly related to soil nitrate-N content (R2 = 0.38–0.56). Relative grain yield on average reached a plateau at NNI values of 1.36 at V9 and 1.21 at VT but for individual sites ranging from 0.80 to 1.41 at V9 and from 0.62 to 1.75 at VT. The NNI threshold values or ranges optimal for crop biomass production may not be optimal for grain yield production. It is concluded that the CNDC developed in France is suitable as a general diagnostic tool for assessing maize N status in US Midwest. However, the threshold values of NNI for diagnosing maize N status and guiding N applications vary significantly across the region, making it challenging to guide specific on-farm N management. More studies are needed to determine how to effectively use CNDC to make in-season N recommendations in the US Midwest.

Introduction: Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region. Methods: Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region. Results: 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (n = 123), patients with mild impairment (n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups. Conclusions: IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety data from the Chinese subpopulation are reported. Methods: IMbrave150, a global, randomized, open-label, phase 3 study in patients with systemic treatment-naive unresectable HCC, included an extension phase that enrolled additional patients from mainland China. Patients were randomized (2:1) to receive intravenous atezolizumab 1,200 mg plus bevacizumab 15 mg/kg once every 3 weeks or sorafenib 400 mg twice a day until unacceptable toxicity or loss of clinical benefit. Co-primary endpoints were OS and independent review facility-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population. Results: Of 194 Chinese patients enrolled from April 16, 2018, to April 8, 2019 (137 in the global study and 57 in the China extension phase), 133 received atezolizumab plus bevacizumab and 61 received sorafenib. At the data cutoff (August 29, 2019), the stratified hazard ratio for OS was 0.44 (95% CI, 0.25–0.76) and for PFS was 0.60 (95% CI, 0.40–0.90). The respective median OS and PFS with atezolizumab plus bevacizumab were not reached (NR; 95% CI, 13.5 months to NR) and 5.7 months (95% CI, 4.2–8.3) versus 11.4 months (95% CI, 6.7 to NR) and 3.2 months (95% CI, 2.6–4.8) with sorafenib. Grade 3–4 adverse events (AEs) occurred in 78 of 132 (59.1%) atezolizumab plus bevacizumab-treated and 27 of 58 (46.6%) sorafenib-treated patients. The most common grade 3–4 AE with atezolizumab plus bevacizumab was hypertension, occurring in 15.2% of patients; however, other high-grade AEs were infrequent. Conclusion: Clinically meaningful improvements in OS and PFS observed with atezolizumab plus bevacizumab versus sorafenib suggest that atezolizumab plus bevacizumab may become a practice-changing treatment for Chinese patients with unresectable HCC.

Abstract Background CP12 is a small chloroplast protein that is widespread in various photosynthetic organisms and is an actor of the redox signaling pathway involved in the regulation of the Calvin Benson Bassham (CBB) cycle. The gene encoding this protein is conserved in many diatoms, but the protein has been overlooked in these organisms, despite their ecological importance and their complex and still enigmatic evolutionary background. Methods A combination of biochemical, bioinformatics and biophysical methods including electrospray ionization-mass spectrometry, circular dichroism, nuclear magnetic resonance spectroscopy and small X ray scattering, was used to characterize a diatom CP12. Results Here, we demonstrate that CP12 is expressed in the marine diatom Thalassiosira pseudonana constitutively in dark-treated and in continuous light-treated cells as well as in all growth phases. This CP12 similarly to its homologues in other species has some features of intrinsically disorder protein family: it behaves abnormally under gel electrophoresis and size exclusion chromatography, has a high net charge and a bias amino acid composition. By contrast, unlike other known CP12 proteins that are monomers, this protein is a dimer as suggested by native electrospray ionization-mass spectrometry and small angle X-ray scattering. In addition, small angle X-ray scattering revealed that this CP12 is an elongated cylinder with kinks. Circular dichroism spectra indicated that CP12 has a high content of α-helices, and nuclear magnetic resonance spectroscopy suggested that these helices are unstable and dynamic within a millisecond timescale. Together with in silico predictions, these results suggest that T. pseudonana CP12 has both coiled coil and disordered regions. Conclusions These findings bring new insights into the large family of dynamic proteins containing disordered regions, thus increasing the diversity of known CP12 proteins. As it is a protein that is more abundant in many stresses, it is not devoted to one metabolism and in particular, it is not specific to carbon metabolism. This raises questions about the role of this protein in addition to the well-established regulation of the CBB cycle. Choregraphy of metabolism by CP12 proteins in Viridiplantae and Heterokonta. While the monomeric CP12 in Viridiplantae is involved in carbon assimilation, regulating phosphoribulokinase (PRK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) through the formation of a ternary complex, in Heterokonta studied so far, the dimeric CP12 is associated with Ferredoxin-NADP reductase (FNR) and GAPDH. The Viridiplantae CP12 can bind metal ions and can be a chaperone, the Heterokonta CP12 is more abundant in all stresses (C, N, Si, P limited conditions) and is not specific to a metabolism. Video Abstract

In order to improve the harmonic compensation performance of active power filter (APF) in distribution network, based on deadbeat control theory, the command current prediction algorithm and current tracking control strategy are optimized in this article. Firstly, the command current repetitive prediction in abc coordinate system is transferred to dq for improving its accuracy in lead compensation, and the equivalent for fractional delay beat is achieved by Lagrange Interpolation Polynomial to solve the problem of inaccurate prediction caused by grid frequency fluctuation. Then, considering the inherent half-sampling-period delay of sinusoidal PWM (SPWM), an improved deadbeat control strategy for current tracking is proposed by estimating the output current of next sampling period. Because the output current in next sampling period is replaced by that in current sampling period with traditional deadbeat control strategy, this estimation could make up for the defect of low control precision caused by that replacement. After that, adding error repetitive correction into the improved deadbeat control channel to reduce the periodic tracking error of output current. Finally, the stability and accuracy of the improved control system are analyzed theoretically, and its feasibility and effectiveness are verified by the simulation and hardware-in-the-loop (HIL) experiments.

Various pathological conditions are accompanied by release of adenosine triphosphate (ATP) from the intracellular to the extracellular compartment, where it degrades into adenosine and modulates immune responses. Previous studies concluded that both ATP and its degradation product adenosine are important immune-regulatory molecules; ATP acted as a danger signal that promotes immune responses, but adenosine's effect was inhibitory. We show that adenosine receptor ligation plays an important role in balancing Th1 and Th17 pathogenic T cell responses in experimental autoimmune uveitis (EAU). While its effect on Th1 responses is inhibitory, its effect on Th17 responses is enhancing, thereby impacting the balance between Th1 and Th17 responses. Mechanistic studies showed that this effect is mediated via several immune cells, among which γδ T cell activation and dendritic cell differentiation are prominent; adenosine- and γδ-mediated immunoregulation synergistically impact each other's effect. Adenosine receptor ligation augments the activation of γδ T cells, which is an important promoter for Th17 responses and has a strong effect on dendritic cell (DC) differentiation, tipping the balance from generation of DCs that stimulate Th1 responses to those that stimulate Th17 responses. The knowledge acquired in this study should improve our understanding of the immune-regulatory effect of extracellular ATP-adenosine metabolism and improve treatment for autoimmune diseases caused by both Th1- and Th17-type pathogenic T cells.

Abstract Background Clinical guidelines recommend a stepped-escalation treatment strategy for type 2 diabetes (T2DM). Across multiple treatment strategies varying in efficacy and costs, no clinical or economic studies directly compared them. This study aims to estimate and compare the cost-effectiveness of 10 commonly used pharmacologic combination strategies for T2DM. Methods Based on Chinese guideline and practice, 10 three-stepwise add-on strategies were identified, which start with metformin, then switch to metformin plus one oral drug (i.e., sulfonylurea, thiazolidinedione, α-glucosidase inhibitor, glinide, or DPP-4 inhibitor) as second line, and finally switch to metformin plus one injection (i.e., insulin or GLP-1 receptor agonist) as third line. A cohort of 10,000 Chinese patients with newly diagnosed T2DM was established. From a healthcare system perspective, the Cardiff model was used to estimate the cost-effectiveness of the strategies, with clinical data sourced from a systematic review and indirect treatment comparison of 324 trials, costs from claims data of 1164 T2DM patients, and utilities from an EQ-5D study. Outcome measures include costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). Results Over 40-year simulation, the costs accumulated for a patient ranged from $7661 with strategy 1 to $14,273 with strategy 10, while the QALY gains ranged from 13.965 with strategy 1 to 14.117 with strategy 8. Strategy 7 was dominant over seven strategies (strategies 2~6, 9~10) with higher QALYs but lower costs. Additionally, at a willingness-to-pay threshold of $30,787/QALY (i.e., 3 times GDP/capita for China), strategy 7 was cost-effective compared with strategy 1 (ICER of strategy 7 vs. 1, $3371/QALY) and strategy 8 (ICER of strategy 8 vs. 7, $132,790/QALY). Ranking the strategies by ICERs and NMBs, strategy 7 provided the best value for money when compared to all other strategies, followed by strategies 5, 9, 8, 1, 3, 6, 10, 2, and 4. Scenario analyses showed that patients insist on pharmacologic treatments increased their QALYs (0.456~0.653) at an acceptable range of cost increase (ICERs, $1450/QALY~$12,360/QALY) or even at cost saving compared with those not receive treatments. Conclusions This study provides evidence-based references for diabetes management. Our findings can be used to design the essential drug formulary, infer clinical practice, and help the decision-maker design reimbursement policy.

Abstract Background To investigate the biomechanical properties of the cornea in myopic eyes using corneal visualization Scheimpflug technology (Corvis ST). The relationships between the biomechanical properties of the cornea and the degree of myopia were also investigated. Methods 265 eyes of 265 subjects were included. Based on spherical equivalent (SE) in diopters (D), participants were divided into four groups: low myopia/control (SE: − 0.50 to − 3.00D), moderate myopia (SE: − 3.00 to − 6.00D), high myopia (SE: − 6.00 to − 10.00D) and severe myopia (SE greater than − 10.00D). Axial length (AL), anterior segment parameters, and corneal biomechanical properties were obtained with the Lenstar LS900, Pentacam HR and Corvis ST, respectively. Results Mean (±SD) SE was − 7.29 ± 4.31D (range: − 0.63 to − 25.75D). Mean AL was 26.31 ± 1.82 mm (range: 21.87 to 31.94 mm). Significant differences were detected within the four groups in terms of six corneal biomechanical parameters: deformation amplitude (DA), time from start until second applanation (A2-time), length of flattened cornea at the second applanation (A2-length), corneal velocity during the first and second applanation (A2-velocity), time from start to highest concavity (HC-time), and central curvature at highest concavity (HC radius). AL was positively associated with DA whereas negatively associated with A1-velocity and A2-length. SE was positively associated with A2-time, HC-time and A2-velocity, whereas negatively associated with DA. IOP was positively associated with four corneal biomechanical parameters and negatively associated with three parameters. Conclusions Eyes with severe myopia showed greater DA, lesser A2 time, HC time, and faster A2-velocity compared to low to high myopia. This suggests the cornea becomes weaker and more deformable with elongation of axial length with corresponding increases in myopia. DA, A2-time and A2-velocity could be useful corneal biomechanical indicators in patients with myopia.

ObjectiveTraditional metal alloy occluders for the closure of patent foramen ovale (PFO) may be associated with some potential complications, and may restrict the trans-septal access to the left atrium for future treatment of left-sided heart disease. Increasing attention has been paid to novel biodegradable occluders (NBOs) to achieve PFO closure. We aimed to evaluate the role of transesophageal echocardiography (TEE) in the diagnostic and anatomical evaluation of PFO, as well as in the Post-procedural assessment after transcatheter closure with a NBO.MethodsWe conducted a prospective, single-center clinical study of 44 patients who were diagnosed with PFO by contrast transthoracic echocardiography (c-TTE) and TEE from June 2019 to June 2020. All patients underwent PFO occlusion with NBO under TTE guidance. Follow-up was performed at 2 days and 3 months after the procedure with TTE, and at 6 months and 1 year after the procedure with c-TTE, TTE, and TEE.ResultsInterventional treatment was successfully performed in all patients. The left and right sides of the occluder device disc were significantly reduced at 3, 6, and 12 months compared to 2 days after the procedure (all P < 0.01), and decreased gradually. The thickness was significantly reduced at 12 months compared to the first three time points (all P < 0.01). Thrombus was found on the surface of the occluder device in three patients (6.4%) at 3 and 6 months after occlusion. At 6 months after procedure, there were 3 (6.8%) cases of extensive residual right-to-left shunt (RLS), 2 (4.5%) cases of moderate shunt, and 7 (15.9%) cases of small shunts. One year after procedure, 2 (4.5%) cases had a extensive residual shunt, 6 (13.6%) cases of small shunts were confirmed to originate from pulmonary veins by TEE, and the PFO-RLS occlusion rate reached 95.5%.ConclusionThis study demonstrates the feasibility, safety, and effectiveness of NBO for the closure of PFO in humans, with a high rate of complete shunt closure. Accurate TEE assessment of the PFO anatomy before closure with NBO is important to ensure that the procedure remains safe and effective. Furthermore, TEE plays a crucial role in the Post-procedure follow-up.

This work explored the mediating effects of affective commitment on transformational leadership and job performance and job insecurity on transformational leadership and affective commitment. Meanwhile, the inter-relationships between the four verified the mediating effect of affective commitment, including job insecurity. The results were as follows: (1) transformational leadership and job performance were positively related. (2) Transformational leadership was proportional to an emotional commitment. (3) The affective commitment had a positive impact on job performance. (4) Transformational leadership indirectly positively affected job performance through the intermediary effect of affective commitment. (5) Transformational leadership regulated affective commitment through job insecurity. The more job security employees have, the higher the impact of transformational leadership on affective commitment; the lower the contrary.

The electrochemical quartz crystal microbalance (EQCM) technique has been used to study the charge mechanisms in two TiC-derived nanoporous carbons (CDC), synthesized at 800 ℃ and 1100 ℃. These two carbons have a similar pore size and porous volume, but the CDC prepared at 1100 °C shows a more graphitic microstructure. The EQCM study revealed that the charge storage mechanism in the CDC-800 is mainly controlled by a counter-ion adsorption process, while an expanded ion-exchange process was observed for the CDC-1100. Combined with the potential of zero charge (PZC), these measurements suggest a strong interaction between the anions and graphitic carbon. For the first time, we provide experimental evidence that the local carbon structure affects the charge storage mechanism of the electrical double-layer capacitance in high surface area porous carbons.

Summary: The cornea is an avascular tissue for vision clarity. Alkali burn could cause severe traumatic damage on the cornea with inflammation and neovascularization (NV), leading to vision reduction and blindness. Mechanisms underlying corneal inflammation and NV are not as clear. We previously reported that Zeb1 is an important factor in corneal NV, and we sought to clarify whether it is also involved in regulation of corneal inflammation. We analyzed the alkali burn-induced corneal inflammation and wound healing in both Zeb1+/+ and Zeb1−/+ littermates through a multidisciplinary approach. We provide evidence that Zeb1 forms a positive regulatory loop with Tgfb to regulate early corneal inflammation by maintenance of immune cell viability and mobility and later wound healing by activation of both Nf-κb and Tgfb-related Stat3 signaling pathways. We believe that ZEB1 is a potential therapeutic target, and inactivation of ZEB1 could be a strategy to treat severe corneal inflammation condition.

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are approved for heart failure with reduced ejection fraction (HFrEF). However, their cost-effectiveness remains unknown. We aimed to compare the cost-effectiveness of SGLT2i versus mineralocorticoid antagonists (MRAs). Methods: Data from the RALES, EPHESUS, EMPHASIS, DAPA-HF, and EMPEROR-Reduced trials were included. We calculated the risk-ratio (RR) for a composite of cardiovascular death or heart failure hospitalization (CV death-HHF), all-cause mortality, and heart failure hospitalization (HHF) between MRAs and SGLT2i. A Markov model was developed to simulate the progression of HFrEF over 5 years. The primary outcome was incremental cost-effectiveness ratio (ICER), measured by cost per quality-adjusted life-year (QALY) gained. Results: We observed a similar benefit in CV death-HHF (RR 1.04; 95% CI 0.82–1.31), all-cause mortality (RR 0.91; 95% CI 0.78–1.06), and HHF (RR 1.05; 95% CI 0.84–1.31) between MRAs and SGLT2i. In a 5-year model, no difference in survival was observed between treatments. MRAs were associated with lower cost ($63,135.52 vs. $80,365.31) and more QALYs gained per patient (2.53 versus 2.49) than SGLT2i. The ICER for SGLT2i versus MRAs was $-172,014.25/QALY, in favor of MRAs. Conclusion: MRAs and SGLT2i provided similar benefits; however, MRAs were a more cost-effective treatment than SGLT2i.

Abstract Objectives Autologous chimeric antigen receptor (CAR) αβ T‐cell therapies have demonstrated remarkable antitumor efficacy in patients with haematological malignancies; however, not all eligible cancer patients receive clinical benefit. Emerging strategies to improve patient access and clinical responses include using premanufactured products from healthy donors and alternative cytotoxic effectors possessing intrinsic tumoricidal activity as sources of CAR cell therapies. γδ T cells, which combine innate and adaptive mechanisms to recognise and kill malignant cells, are an attractive candidate platform for allogeneic CAR T‐cell therapy. Here, we evaluated the manufacturability and functionality of allogeneic peripheral blood‐derived CAR+ Vδ1 γδ T cells expressing a second‐generation CAR targeting the B‐cell‐restricted CD20 antigen. Methods Donor‐derived Vδ1 γδ T cells from peripheral blood were ex vivo‐activated, expanded and engineered to express a novel anti‐CD20 CAR. In vitro and in vivo assays were used to evaluate CAR‐dependent and CAR‐independent antitumor activities of CD20 CAR+ Vδ1 γδ T cells against B‐cell tumors. Results Anti‐CD20 CAR+ Vδ1 γδ T cells exhibited innate and adaptive antitumor activities, such as in vitro tumor cell killing and proinflammatory cytokine production, in addition to in vivo tumor growth inhibition of B‐cell lymphoma xenografts in immunodeficient mice. Furthermore, CD20 CAR+ Vδ1 γδ T cells did not induce xenogeneic graft‐versus‐host disease in immunodeficient mice. Conclusion These preclinical data support the clinical evaluation of ADI‐001, an allogeneic CD20 CAR+ Vδ1 γδ T cell, and a phase 1 study has been initiated in patients with B‐cell malignancies (NCT04735471).

Increased protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels had been widely reported in patients with hepatocellular carcinoma (HCC) and chronic hepatitis. However, the role of PIVKA-II in hepatitis E is unclear. The aim of this study was to clarify the changes related with PIVKA-II and its clinical significance in hepatitis E. We enrolled 84 patients with hepatitis E hospitalized in two hospitals from December 2019 to June 2021. The levels of serum PIVKA-II and related serological indicators in the patients were determined to elucidate the role of PIVKA-II in hepatitis E. We observed that 59.51% (50/84) of patients showed an increase in PIVKA-II levels. Compared with the normal PIVKA-II group (32 mAU/L) had much higher serum total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), and total bile acid (TBA) levels (p < 0.05 for each). Compared with the slightly elevated PIVKA-II group (32–125 mAU/L), patients in the significantly elevated PIVKA-II group (>125 mAU/L) had much lower serum albumin, alanine aminotransferase (ALT), aspartate transaminase (AST) levels, and longer days for the hospital stay (p < 0.05 for each). The association of PIVKA-II with TBIL and DBIL was an inverted U-shaped curve with an inflection point at 199.1 mAU/L). The association of PIVKA-II with IBIL was a U-shaped curve with an inflection point at 18.6 mAU/L while the association of PIVKA-II with albumin was an inverted U-shaped curve with an inflection point at 18.6 mAU/L. With the improvement of the disease, PIVKA-II levels were gradually decreased and finally returned to normal. This trend was consistent with that of bilirubin, and a peak appeared in the third week. Therefore, findings from our study show that the increase in PIVKA-II levels can be related to the degree of hepatic insufficiency in patients with hepatitis E, wherein PIVKA-II levels are transiently increased, and the trend of change can be related to the disease course.