AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial.

BACKGROUND: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. METHODS: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. FINDINGS: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. INTERPRETATION: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.

Cold Snare Polypectomy With or Without Submucosal Injection for Endoscopic Resection of Colorectal Polyps: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: The impact of submucosal injection during cold snare polypectomy (CSP) remains uncertain. We conducted an evidence-based comparison of conventional CSP (C-CSP) and CSP with submucosal injection (SI-CSP) for colorectal polyp resection. METHODS: PubMed, Embase, and the Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing C-CSP with SI-CSP. Major outcomes included the rates of complete resection, en bloc resection, polyp retrieval, and adverse events, as well as the duration of polypectomy. Data were analyzed by using a random-effects model. RESULTS: A total of seven RCTs were included. Complete resection rates for all polyps (RR 0.98; 95% CI 0.93-1.03), polyps ≤ 10 mm (RR 0.99; 95% CI 0.96-1.02) and polyps > 10 mm (RR 0.92; 95% CI 0.69-1.12) were not substantially different between C-CSP and SI-CSP groups. En bloc resection rate (RR 0.93; 95% CI 0.79-1.09) and polyp retrieval rate (RR 1.00; 95% CI 0.99-1.01) were also not significantly different between the two groups. The SI-CSP group required a prolonged polypectomy time than the C-CSP group (SMD - 0.89; 95% CI -1.29 to -0.49). Adverse events were rare in both groups. CONCLUSIONS: SI-CSP is not an optimal substitute for CSP in the resection of colorectal polyps, particularly diminutive and small polyps.

Multiomics Approaches Identify Biomarkers for BAT Thermogenesis.

Brown adipose tissue (BAT) thermogenesis confers beneficial effects on metabolic diseases such as obesity and type-2 diabetes. Nevertheless, the mechanism and lipid driving the process that evokes this response have not been investigated yet. Here, a multiomics approach of integrative transcriptomics and lipidomics is used to explore the mechanism of regulating thermogenesis in BAT and providing promising lipid biomarkers and biomarker genes for thermogenic activators as antiobesity drugs. Lipidomics analysis demonstrated that a high abundance of glycerophospholipids and sphingolipids was more significant in BAT than in WAT. Enrichment analysis of upregulated DEGs between WAT and BAT screened suggested that the differences were mainly involved in lipid metabolism. Besides, ß3-adrenergic agonist stimulation reduced the levels of TAG and DAG and increased the content of PC, PE, CL, and LPC and expression of genes involved in thermogenesis, fatty acid elongation, and glycerophospholipid metabolism in BAT. In this study, based on interpreting the inherent characterization of BAT as thermogenic tissue through comparison with WAT as fat storage tissue, adrenergic stimulation-induced BAT thermogenesis further identified specific lipid biomarkers (7 TAG species, 10 PC species, 1 LPC species, and 1 CL species) and Elovl3 and Crat gene biomarkers, which may provide targets for combating obesity by boosting BAT thermogenesis.

Ethylene-responsive SbWRKY50 suppresses leaf senescence by inhibition of chlorophyll degradation in sorghum.

The onset of leaf de-greening and senescence is governed by a complex regulatory network including environmental cues and internal factors such as transcription factors (TFs) and phytohormones, in which ethylene (ET) is one key inducer. However, the detailed mechanism of ET signalling for senescence regulation is still largely unknown. Here, we found that the WRKY TF SbWRKY50 from Sorghum bicolor L., a direct target of the key component ETHYLENE INSENSITIVE 3 in ET signalling, functioned for leaf senescence repression. The clustered regularly interspaced short palindromic repeats/CRISPR-associated protein9-edited SbWRKY50 mutant (SbWRKY5O-KO) of sorghum displayed precocious senescent phenotypes, while SbWRKY50 overexpression delayed age-dependent and dark-induced senescence in sorghum. SbWRKY50 negatively regulated chlorophyll degradation through direct binding to the promoters of several chlorophyll catabolic genes. In addition, SbWRKY50 recruited the Polycomb repressive complex 1 through direct interaction with SbBMI1A, to induce histone 2A mono-ubiquitination accumulation on the chlorophyll catabolic genes for epigenetic silencing and thus delayed leaf senescence. Especially, SbWRKY50 can suppress early steps of chlorophyll catabolic pathway via directly repressing SbNYC1 (NON-YELLOW COLORING 1). Other senescence-related hormones could also influence leaf senescence through repression of SbWRKY50. Hence, our work shows that SbWRKY50 is an essential regulator downstream of ET and SbWRKY50 also responds to other phytohormones for senescence regulation in sorghum.

Expression and purification of snustorr snarlik protein from Plutella xylostella.

Snustorr snarlik (Snsl) is a type of extracellular protein essential for insect cuticle formation and insect survival, but is absent in mammals, making it a potential selective target for pest control. Here, we successfully expressed and purified the Snsl protein of Plutella xylostella in Escherichia coli. Two truncated forms of Snsl protein, Snsl 16-119 and Snsl 16-159, were expressed as a maltose-binding protein (MBP) fusion protein and purified to a purity above 90% after a five-step purification protocol. Snsl 16-119, forming stable monomer in solution, was crystallized, and the crystal was diffracted to a resolution of ∼10 Å. Snsl 16-159, forming an equilibrium between monomer and octamer in solution, was shown to form rod-shaped particles on negative staining electron-microscopy images. Our results lay a foundation for the determination of the structure of Snsl, which would improve our understanding of the molecular mechanism of cuticle formation and related pesticide resistance and provide a template for structure-based insecticide design.

Application value of EV/EV71/CA16-SAT detection in children with hand-foot-mouth disease.

The objective of this work was to explore the application value of a new type of fluorescent nucleic acid isothermal amplification (SAT) to detect EV/EV71/CA16-SAT in children with hand-foot-mouth disease (HFMD). For this purpose, from March 2017 to September 2019, Chengdu Children's Specialized Hospital collected throat swabs from children with clinical manifestations of hand, foot and mouth disease, and used SAT technology to screen and detect universal enterovirus (EV) nucleic acid (There were 1860 children with EV-RNA) positive. Patients who are EV-RNA positive at any time: first use the same throat swab specimen to detect EV71/CA16-RNA; secondly, collect venous blood and use the colloidal gold method to detect IgM antibodies in EV71/CA16 serum. The patients with positive EV71/CA16-RNA or EV71/CA16-IgM (or both) were repeated the above two methods 2 weeks and 4 weeks after standard treatment for review and comprehensive analysis. Results showed that 763 cases were enrolled for the first time: 59.76% were male and 40.24% were female; the age ranged from 1 month to 13 years, of which 69.06% were from 1 to 4 years old; CA16-RNA positive 56.23%, EV71-RNA positive 21.89%, CA16/EV71 -RNA were all positive in 1.57%; CA16-IgM was positive in 64.48%, EV71-IgM was positive in 54.26%, and CA16/EV71-IgM were both positive in 18.74%. After 2 weeks, 722 cases were reexamined: 26.73% were positive for CA16-RNA, 7.89% were positive for EV71-RNA, 0.28% were both positive for CA16/EV71-RNA; 66.21% were positive for CA16-IgM, 51.52% were positive for EV71-IgM, and IgM were all positive in 17.73%. Four weeks later, 489 cases were reexamined: among them, CA16-RNA positive 5.73% of which were positive for EV71 color RNA (0.005%), and 12.68% of them were all positive for EV71lym. The strategy of combining SAT technology and colloidal gold method to detect EV/EV71/CA16 nucleic acid (RNA) and serum IgM antibody in children HFMD can improve the early detection rate and accuracy of HFMD; According to the comprehensive analysis of the detection results of children with HFMD at the early stage, 2 weeks and 4 weeks of the present study, it is suggested that EV/EV71/CA16-SAT nucleic acid detection can be used to judge the prognosis, follow-up treatment, set isolation time, return students to school, and community management in children with HFMD. and prevention and control have more clinical application value.

Development and validation of a model to determine the risk of esophageal strictures after endoscopic submucosal dissection for esophageal neoplasms.

BACKGROUND: Currently, endoscopic submucosal dissection (ESD) is widely used as therapeutic methods for superficial esophageal neoplasms (SENs). However, patients are likely to develop esophageal strictures after ESD. Our study aims to explore the possible risk factors for esophageal strictures after ESD and develop and validate a risk model for predicting the progression of postoperative esophageal strictures. METHODS: Clinical data of patients who underwent ESD in our hospital for suspected early esophageal squamous cell carcinoma were collected from January 2014 to March 2020. The possible risk factors for postoperative esophageal strictures were analyzed by univariate and multivariate logistic regression analysis. Eventually, a risk-scoring model was built, in which 70% of patients were used to develop the model and the remaining 30% were used for validation. RESULTS: A total of 553 patients who received ESD were involved, and the incidence of esophageal strictures after ESD was 16.6% (92/553). In our study, the operating time, circumferential range, lesion location, depth of infiltration, and R0 resection were independent risk factors for esophageal strictures after ESD. According to the risk of postoperative esophageal stenosis, a risk-scoring model for esophageal strictures prediction was developed. The risk score ranged from 0 to 11 points, and the risk scores were divided into low risk (0-3 points), intermediate risk (4-7 points), and high risk (8-11 points). The proportions of esophageal stenosis progression in the corresponding risk categories were 6.33%, 29.14%, and 100%. CONCLUSIONS: We developed a risk-scoring model based on factors including circumferential range, lesion location, depth of infiltration, and R0 resection. It stratified patients into low-, intermediate-, and high-risk groups for postoperative esophageal strictures development. This scoring model may have the potential to guide the management of patients after ESD in the future.

Speckle tracking tissue motion mitral annulus displacement to assess early changes in the left ventricle and its association with lung function in patients with chronic obstructive pulmonary disease.

OBJECTIVE: To evaluate the early changes in left ventricular (LV) in patients with chronic obstructive pulmonary disease (COPD) by measuring tissue motion mitral annulus displacement (TMAD) and three-dimensional (3D) parameters using speckle tracking imaging (STI), and to explore its correlation with lung function. METHODS: Forty two COPD patients (GOLD I, GOLD II, GOLD III) and 30 healthy individuals (control group) were included. STI was used to assess the changes in LV structure and systolic function. Receiver operating characteristic (ROC) curves were drawn, and correlations among TMAD parameters, LV systolic function, structural, pulmonary artery systolic pressure (PASP), and lung function were analyzed. RESULTS: Compared to the control group, COPD patients were able to undergo LV remodeling, with a decrease in the absolute value of global longitudinal strain (GLS) and TMAD, but no significant modification of LVEF. Correlation analysis showed that TMAD was positively related to the absolute value of GLS (r > 0.51, P < 0.01) and predicted forced expiratory volume in the first second (FEV1%) (r > 0.56, P < 0.01), and negatively to PASP (r < -0.52, P < 0.01). The LV posterior wall thickness (LVPWd), relative wall thickness (RWT), end-diastolic volume (LVEDV) and PASP negatively correlated with FEV1%. CONCLUSION: The LV geometric changes and systolic function impairment in COPD patients were found to correlate with airflow restriction (FEV1%). TMAD aided in detection of early changes in LV systolic function in COPD patients. It negatively correlated with PASP and positively with FEV1%. Moreover, it was more convenient than GLS.

Degradation of levofloxacin in wastewater by photoelectric and ultrasonic synergy with TiO2/g-C3N4@AC combined electrode.

A novel particle combined electrode named TiO2/g-C3N4@AC (TGCN-AC) was prepared by loading TiO2 and g-C3N4 on activated carbon through gel method, which was used to degrade levofloxacin (LEF) in pharmaceutical wastewater by photoelectric process. The remarkable physicochemical features of particle electrodes were verified by using diverse characterization techniques including SEM-EDS, XRD, FT-IR, BET and pHZPC. EIS-CV and photocurrent showed excellent electrocatalysis and photoelectrocatalysis performance of particle electrodes. The photocatalytic characteristics and fluorescence properties of the particle electrode were proved by UV-vis DRS and PL spectra measurements. Combined with Tauc's plot and Mott-Schottky plots curves, the ECB and EVB of particle electrodes were determined. The experiments on different influence factors such as pH, ultrasonic, aeration, current density and the concentration of LEF were carried out in the photoelectric reactor. Under the conditions of pH values 3.0, 200 W ultrasonic, 8 L/min aeration, the mass ratio of g-C3N4 and TiO2 is 8%, after 4.0 h of photoelectric process, about 94.76% of LEF (20 mg/L) in water was degraded. TGCN-AC also has excellent reusability. The degradation rate of LEF can still reach 71.17% after repeated use for 6 times. Scavenger studies showed that h+ and O2- were the main active species. By observing the colony size of E. coli, it was proved that the LEF in the effluent had no antibacterial activity. The degradation pathways of LEF was analyzed and drawn by HPLC-MS spectra.

Risk assessment of Artemia egg shell-Mg-P composites as a slow-release phosphorus fertilizer during its formation and application in typical heavy metals contaminated environment.

Artemia egg shell loaded with nano-magnesium (shell-Mg) can be used to recover phosphorus from wastewater. The exhausted Artemia egg shell-Mg (denoted as shell-Mg-P) can be used as a slow-release fertilizer for phosphorus reuse. However, due to the coexistence of heavy metal ions in the environment, the application of slow-release fertilizer for phosphorus removal and reuse may have potential risks. In this paper, the potential risks of Pb2+, Cd2+, Zn2+ and Cu2+ in phosphorus wastewater and soil were studied from the formation and application process of shell-Mg-P. The result showed that shell-Mg adsorbed Pb2+, Cd2+, Zn2+ and Cu2+ in phosphate wastewater during the formation of shell-Mg-P and became shell-Mg-P-metal hybrid biomaterial. Although the experiment proved that the existence of heavy metal ions did not affect the phosphorus slow-release behavior of slow-release fertilizer, but the heavy metal ions in the shell-Mg-P-metal were also slow released. The pot experiment results confirmed that the slow-release phosphorus fertilizers (shell-Mg-P and shell-Mg-P-metal) in the soil polluted in low concentration of heavy metals can reduce the amount of heavy metals in whole wheat seedlings and promote wheat seedling growth. However, the application of slow-release fertilizers increased the translocation efficiency (TFR to SL) of metal from root (R) to aboveground part (stem and leaves, SL), promoted the transportation of heavy metals from roots to the stems and leaves, and increased the safety risk of the wheat seedling edible. Therefore, besides the positive role of slow-release fertilizers in retaining heavy metals and reducing the amount of heavy metals in whole seedlings, the risk that it may aggravate the translocation of heavy metals to stems and leaves should be paid more attention, so as to ensure the safe and reliable application of slow-release fertilizers.

The association between sleep and empathy in young preschoolers: A population study.

Sleep is vital for children's early socio-emotional development, particularly empathy. This study aimed to explore the associations between sleep and empathy in young preschoolers. A sample of 23,259 preschoolers (4.3 ± 0.3 years) at the entry year of preschool was recruited as part of the Shanghai Children's Health, Education and Lifestyle Evaluation-Preschool (SCHEDULE-P) study. Caregivers reported on child sleep, affective empathy, and cognitive empathy through the Children's Sleep Habits Questionnaire and the Griffith Empathy Measure. Ordinary least-square regression and quantile regression were performed for the associations between sleep and empathy. Sex differences were also investigated. Night sleep duration was negatively associated with affective empathy (ß = -0.35, p < 0.001), and positively associated with cognitive empathy (ß = 0.41, p < 0.001). Longer nap duration was associated with higher affective empathy (ß = 0.28, p < 0.001). Sleep disturbances were positively associated with affective empathy (ß = 0.04, p < 0.001) and negatively associated with cognitive empathy (ß = -0.09, p < 0.001). These associations were generally stronger in children at higher empathy quantiles and also those at the 10th cognitive empathy quantile. The associations between sleep and affective empathy were mainly contributed by girls, and were more common in boys in terms of cognitive empathy, particularly at the 10th and the 30th quantiles. In conclusion, longer night sleep duration and fewer sleep disturbances are associated with a more mature empathy pattern in young preschoolers. The associations are more prominent in children at the higher end of the empathy spectrum, and vary by sex. These findings highlight the importance to promote sleep health in young children for optimal socio-emotional development.

Long-term outcomes of refractory esophageal strictures after endoscopic submucosal dissection of superficial esophageal neoplasms.

BACKGROUND: Many studies have focused on prophylactic therapy for post-endoscopic submucosal dissection (ESD) of esophageal strictures. However, various strategies cannot prevent the occurrence of postoperative strictures after extensive ESD. Postoperative strictures often inevitably occur, and endoscopic dilation is still a temporarily effective therapy. METHODS: This study included patients with post-ESD refractory esophageal strictures (RESs) from January 2014 to November 2019. Clinical effectiveness was assessed using univariate analysis and multivariate logistic regression. Hierarchical linear models were used to identify factors that predicted the dysphagia-free period. RESULTS: A total of 50 patients fulfilled the inclusion criteria and entered the study. Twenty-seven (54%) patients had a history of prophylactic oral steroid therapy. Forty-six patients (92%) underwent ≥ 75% circumferential resection, including 32 (64%) cases involving entire circumferential ESD. The mean dysphagia-free period of 50 patients was 2.9 months (95% CI 2.3-3.5). The dysphagia-free period had a linear growth trend over time, increasing by 6.9 days per endoscopic therapy, and the estimated last dysphagia-free period was 85.9 days. Old and female patients had shorter dysphagia-free periods compared with young and male patients. Endoscopic therapy success was achieved in 30 (60%) patients. Multivariate analysis revealed that circumferential lesions (OR 6.106, 95% CI 1.013-36.785, P = 0.048) were significant predictive factors for poor clinical outcome. CONCLUSION: Endoscopic dilation seemed effective in patients with post-ESD RESs by increasing the dysphagia-free period. After approximately 10 continuous dilations, 60% of patients achieved endoscopic success, and the remission rate of obstruction was increased. Prophylactic oral steroid therapy could reduce the occurrence of RESs. However, once a RES had occurred, prophylactic steroid therapy could not reduce the frequency of dilations or change the long-term outcomes. TRIAL REGISTRATION: This study was prospectively registered and approved by the Ethics Committee of West China Hospital of Sichuan University (IRB number: ChiCTR-ONN-17012382) on 2015.

Adverse Event Profile for Nanoparticle Albumin-Bound Paclitaxel Compared With Solvent-Based Taxanes in Solid-Organ Tumors: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an innovative form of taxane that has superior antitumor effects; however, the safety profile between nab-paclitaxel and traditional taxanes remains controversial. OBJECTIVE: To determine the burden of adverse events (AEs) in patients with multiple malignancies receiving nab-paclitaxel compared with that in patients receiving traditional taxanes. METHODS: Randomized clinical trials comparing nab-paclitaxel with traditional taxanes (solvent-based paclitaxel [sb-paclitaxel] or docetaxel) in the treatment of primary solid-organ malignancies were included if AEs were reported as an outcome. Statistical analyses were conducted to calculate the summary odds ratio (OR) of the relevant adverse outcomes related to nab-paclitaxel and traditional taxanes. Prespecified subgroup analyses based on intervention and doses, primary tumor sites, and different ethnic groups were also performed. RESULTS: Twelve clinical trials were included in the meta-analysis. Grade 3/4 anemia, thrombocytopenia, and neurotoxicity were more frequent with nab-paclitaxel than with traditional taxanes. Nab-paclitaxel at 100 or 125 mg/m2/w dosage was associated with fewer or similar grade 3/4 specific AEs. Allergy was less common with nab-paclitaxel. The median recovery times of neurotoxicity were 25, 64, and 37 days in patients receiving nab-paclitaxel, sb-paclitaxel, and docetaxel, respectively. Elevated incidences of specific AEs were more common in breast cancer and non-Asian patients than in other malignancies and ethnic groups, respectively. CONCLUSION AND RELEVANCE: Nab-paclitaxel increased the risk of hematologic and non-hematologic AEs in general, but anaphylaxis was less common, and the recovery duration of neurotoxicity was shorter. Weekly administration of nab-paclitaxel at a lower dosage provided better tolerance.

Trends in Hospital Admissions for Chronic Obstructive Pulmonary Diseases After Comprehensive Tobacco Control Policies in Beijing, China.

INTRODUCTION: Only a few studies have examined the effectiveness of tobacco control policies on respiratory conditions, and the results were less consistent. The 2015 Beijing tobacco control policy package incorporating all six components of MPOWER has been implemented since Jun 2015. The present study aimed to evaluate the impact of a comprehensive tobacco control policy package on hospital admissions for chronic obstructive pulmonary disease (COPD) in Beijing, China. AIMS AND METHODS: An interrupted time-series study was conducted based on the hospital admission information for about 18 million residents, who were covered by the Beijing Medical Claim Data for Employees from January 2013 to June 2017. The average percentage change of COPD hospital admission rates and reductions in hospital admission numbers were estimated by segmented Poisson regression models. RESULTS: There were 54 040 COPD hospital admissions with a crude rate of 67.2 per 100 000 residents during the observational period. After the implementation of the policy package, the hospital admission rates of COPD were reduced by -14.7% (95%CI: -17.8%, -11.5%) immediately. The secular trend was slowed down by -3.0% (95% CI: -5.6%, -0.4%) annually. A total of 5 581 reductions in COPD hospital admissions were estimated during the 25 months post-law period, accounting for 17.5% (95% CI: 12.5%, 22.5%) of overall COPD hospital admissions. More reductions were shown in males and those aged over 65 years old. CONCLUSIONS: The results indicated significant protections against hospitalization of COPD after the 2015 Beijing comprehensive tobacco control policy package. The results provide support for public health benefits for respiratory conditions from WHO-recommended tobacco control measures. IMPLICATIONS: Only a few studies have examined the effectiveness of tobacco control policies on respiratory conditions, and the results were less consistent. Based on medical records for about 18 million residents, this study showed an association between comprehensive tobacco control policies and significant reductions of hospital admissions for chronic obstructive pulmonary disease. The results provide support for public health benefits for respiratory conditions from WHO-recommended tobacco control measures.

Cost-effectiveness analysis of sintilimab plus bevacizumab biosimilar compared with lenvatinib as the first-line treatment of unresectable or metastatic hepatocellular carcinoma.

BACKGROUND: In recent years, programmed cell death protein-1 inhibitors, including sintilimab, have significantly prolonged the overall survival time of patients with unresectable or metastatic hepatocellular carcinoma (HCC); however, the cost-effectiveness of sintilimab is unclear. The aim of this study was to assess the cost-effectiveness of sintilimab plus bevacizumab biosimilar compared with lenvatinib as first-line treatment in patients with unresectable or metastatic HCC. METHODS: A lifetime partitioned survival model was developed to conduct a cost-effectiveness analysis of sintilimab plus bevacizumab biosimilar vs. lenvatinib for advanced HCC from a Chinese healthcare system perspective. The clinical and safety data were derived from two recent randomized clinical trials, the ORIENT-32 and REFLECT studies. Utility data were obtained from previous studies. Long-term direct medical costs and quality-adjusted life-years (QALYs) were predicted. Deterministic and probabilistic sensitivity analyses were performed to verify the robustness of the model. RESULTS: Compared with lenvatinib, combination therapy with sintilimab and bevacizumab biosimilar yielded an additional 0.493 QALYs at a higher cost ($33,102 vs. $21,037) (2021 US dollars). This resulted in a deterministic incremental cost-effectiveness ratio (ICER) of $24,462 per QALY in the base-case analysis. The ICERs were sensitive to the utility of post-progression and the cost of bevacizumab biosimilar. A lower ICER was estimated when the dose of bevacizumab biosimilar decreased from 15 mg to 7.5 mg per kilogram in the scenario analysis. In the probabilistic sensitivity analysis, the probability of being cost-effective for sintilimab treatment at willingness-to-pay (WTP) thresholds of one ($12,516) and three times the gross domestic product per capita in China ($37,547) were 11.6% and 88.6%, respectively. CONCLUSION: Sintilimab plus bevacizumab biosimilar is likely to be a cost-effective treatment option as a first-line treatment for unresectable or metastatic HCC in China when WTP threshold is over $23,650.

Corylin from Psoralea fructus (Psoralea corylifolia L.) protects against UV-induced skin aging by activating Nrf2 defense mechanisms.

Oxidative stress damage can lead to premature skin aging or age-related skin disorders. Therefore, strategies to improve oxidative stress-induced aging are needed to protect the skin and to treat skin diseases. This study aimed to determine whether the flavonoid corylin derived from Psoralea corylifolia can prevent UV-induced skin aging and if so, to explore the potential molecular mechanisms. We found that corylin potently blocked UV-induced skin photoaging in mice by reducing oxidative stress and increasing the nuclear expression of nuclear factor-erythroid factor 2-related factor 2 Nrf2. We also found that corylin stimulated Nrf2 translocation into the nucleus and increased the delivery of its target antioxidant genes together with Kelch-like ECH-associated protein 1 (Keap1) to dissociate Nrf2. These findings indicate that corylin could prevent skin aging by inhibiting oxidative stress via Keap1-Nrf2 in mouse cells. Thus, Nrf2 activation might be a therapeutic target for preventing skin aging or skin diseases caused by aging. Our findings also provided evidence that warrants the further investigation of plant ingredients to facilitate the discovery of novel therapies targeting skin aging.

The value of contrast-enhanced ultrasound for the diagnosis of metastatic cervical lymph nodes of papillary thyroid carcinoma: A systematic review and meta-analysis.

To investigate the diagnostic efficiency of contrast-enhanced ultrasound (CEUS) for the diagnosis of cervical lymph nodes metastasis (CLNM) of papillary thyroid carcinoma (PTC), eight available datasets of seven qualified articles before March 31, 2021 were included after a comprehensive search. Meta-analysis results showed that CEUS demonstrated acceptable diagnostic performance in the diagnosis of CLNM of PTC. Furthermore, meta-regression analysis was conducted to identify the reasons for heterogeneity and the results indicated that the criteria of CEUS for the diagnosis of CLNM in PTC need to be unified.

Exploring the relationship between depression and different multimorbidity patterns among older people covered by long-term care insurance in Shanghai, China.

BACKGROUND: Depression is common in patients with multimorbidity, but little is known about the relationship between depression and multimorbidity. The purpose of our research was to investigate multimorbidity patterns and their association with depression in a sample of older people covered by long-term care insurance in Shanghai, China. METHOD: This was a population-based cross-sectional study, with 1871 participants aged ≥60 years old who are covered by Shanghai long-term care insurance. Multimorbidity was defined as the presence of two or more chronic diseases at the same time. We collected information on chronic conditions using a self-reported medical history, and we used the 30-item Geriatric Depression Scale (GDS-30) to evaluate depressive symptoms. Patterns of multimorbidity were identified with exploratory factor analysis, using oblimin rotation. Logistic regression was used to estimate the relationship between multimorbidity patterns and depressive symptoms. RESULTS: Among the participants, the prevalence of multimorbidity was 64.7%, and the prevalence of depression was 64.6%. Hypertension, cardiovascular disease, cerebrovascular disease (CVD), and cataracts showed strong associations with depression when co-occurring with other conditions. Three patterns of multimorbidity were identified: a musculoskeletal pattern, cardiometabolic pattern, and degenerative disease pattern. Among these, the cardiometabolic (adjusted odds ratio (AOR) 1.223; 95% confidence interval (CI) 1.102, 1.357) and degenerative disease (AOR 1.185; 95% CI 1.071, 1.311) patterns were associated with a higher risk of depressive symptoms. CONCLUSION: Two of three multimorbidity patterns were found to be associated with depression. Physical and psychological dimensions require greater attention in the care of older adults who are covered by long-term care insurance.

Integration of Metabolomics and Transcriptomics Reveals Ketone Body and Lipid Metabolism Disturbance Related to ER Stress in the Liver.

Once protein synthesis is excessive or misfolded protein becomes aggregated, which eventually overwhelms the capacity of the endoplasmic reticulum (ER), a state named ER stress would be reached. ER stress could affect many tissues, especially the liver, in which nonalcoholic fatty liver disease, liver steatosis, etc. have been reported relative. However, there is still a lack of systematic insight into ER stress in the liver, which can be obtained by integrating metabolomics and transcriptomics of the tissue. Here, tunicamycin was utilized to induce ER stress in C57BL/6N mice. Microarray and untargeted metabolomics were performed to identify the genes and metabolites significantly altered in liver tissues. Surprisingly, apart from the predictable unfolded protein response, liver lipid, arginine, and proline metabolisms were affirmed to be related to ER stress. Also, the ketone body metabolism changed most prominently in response to ER stress, with few studies backing. What is more, succinate receptor 1 (Sucnr1) may be a novel marker and therapeutical target of liver ER stress. In this study, the combination of the metabolome and transcriptome provided reliable information about liver pathological processes, including key relative pathways, potential markers, and targets involved in ER stress of the liver.

Safety and efficacy study of oral metronomic vinorelbine combined with trastuzumab (mNH) in HER2-positive metastatic breast cancer: a phase II trial.

PURPOSE: We conducted a single-arm prospective phase II trial to evaluate the efficacy and safety of oral metronomic vinorelbine combined with trastuzumab (mNH) in human epidermal growth factor receptor 2-positive (HER2-positive) metastatic breast cancer (MBC) patients. METHODS: HER2-positive MBC patients received oral vinorelbine 40 mg thrice a week and trastuzumab (loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoints were objective response rate (ORR), clinical benefit rate (CBR; CR + PR + SD for ≥ 24 weeks). The secondary endpoints were progression-free survival (PFS), tolerability, and overall survival (OS). RESULTS: Twenty patients with HER2-positive MBC were enrolled, with a median of 1 prior chemotherapy regimens for MBC. Median age was 61.5 years (95% Confidence Interval (CI) 48.6-63.1). Visceral involvements presented in 14 patients (70.0%). ORR was 20.0%, and CBR was 75% with 4 PR (20.0%) and 11 SD (55.0%). The median PFS (mPFS) and median OS (mOS) were 7.4 months (95% CI 3.2-11.5) and 45.8 months (95%CI: not reached), respectively. The mPFS was 17.7 months (95%CI not reached) and 5.8 months (95%CI 5.6-5.9) in mNH as first-line and ≥ second-line therapy (log rank p = 0.03), respectively. The most common grade 1 adverse events (AEs) included nausea (15%), leukopenia (15%), ALT/AST elevation (15%), diarrhea (10%), and peripheral neuropathy (10%). Grade 2 adverse events included leukopenia (5%) and neutropenia (10%). No grade 3/4 AEs were observed. CONCLUSIONS: Oral metronomic vinorelbine combined with trastuzumab is a well-tolerated and effective anti-tumor regimen for HER2-positive MBC.