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The cross-classified data structure is ubiquitous in education, psychology, and health outcome sciences. In these areas, assessment instruments that are made up of multiple items are frequently used to measure latent constructs. The presence of both the cross-classified structure and multivariate categorical outcomes leads to the so-called item-level data with cross-classified structure. An example of such data structure is the routinely collected student evaluation of teaching (SET) data. Motivated by the lack of research on multilevel IRT modeling with crossed random effects and the need of an approach that can properly handle SET data, this study proposed a cross-classified IRT model, which takes into account both the cross-classified data structure and properties of multiple items in an assessment instrument. A new variant of the Metropolis-Hastings Robbins-Monro (MH-RM) algorithm was introduced to address the computational complexities in estimating the proposed model. A preliminary simulation study was conducted to evaluate the performance of the algorithm for fitting the proposed model to data. The results indicated that model parameters were well recovered. The proposed model was also applied to SET data collected at a large public university to answer empirical research questions. Limitations and future research directions were discussed.

Abstract The association between obstructive sleep apnea (OSA) and proteinuria is undetermined, with few studies on hypertension, a high-risk group for renal impairment. Therefore, we aimed to explore whether OSA is an independent risk factor for proteinuria in patients with hypertension. We investigated the cross-sectional association between OSA and proteinuria. Participants were divided into groups by apnea hypopnea index (AHI) category. Multivariable Logistic regression analysis was used to evaluate the association between OSA severity, objectively measured sleep dimensions, and proteinuria which is mainly defined by 24-h urine protein quantification > 300 mg/24 h. Sensitivity analyses were performed by excluding those with comorbidities (primary aldosteronism and homocysteine ≥ 15 μmol/L). Of the 2106 participants, the mean age was 47.57 ± 10.50 years, 67.2% were men, and 75.9% were OSA patients. In total participants, compared with those without OSA, patients with mild OSA, moderate OSA, and severe OSA showed 1.09 (95% CI 0.80–1.40), 1.24 (95% CI 0.89–1.74) and 1.47 (95% CI 1.04–2.08) fold risk for proteinuria with a trend test P trend

Abstract Immune checkpoint inhibitors (ICIs) have become an important cornerstone of many tumour treatments. However, the toxicity profile of immune-chemotherapy combination treatment approaches among older adult cancer patients is still unclear. Patients with any cancer who received camrelizumab-based immunotherapy were eligible for inclusion. The primary endpoints were adverse events (AEs) and immune-related adverse events (irAEs), which were defined based on Naranjo's algorithm. Patients were stratified by age (≥ 70 years and

Abstract High-voltage transmission lines are susceptible targets for lightning strikes. It is an interesting topic how the trip event of transmission line is related to the area, location, and intensity of thunderstorms occurring at that time and that place. Based on total lightning observation containing intra-cloud and cloud-to-ground lightning, and transmission line trip information from relaying system of power system, 8 thunderstorms associated with the lightning strike trip of local transmission lines were selected in the Pearl River Delta (PRD) region. Analysis was conducted on the total lightning activity of each thunderstorm process, including the characteristics of total lightning counts and density, followed by the variations in total lightning activity before and after lightning strike trips. Further, our investigation encompassed the spatial and temporal evolution, charge structure, and kinematic parameters of thunderstorms. It was revealed that almost all lightning trips in this area emerged in close proximity to bodies of water, accompanied by a discernible reduction in thunderstorm cloud altitude during line trip occurrences. This paper aims to enhance the understanding of total lightning and thunderstorm activity behavior, thereby providing valuable insights for lightning disaster prevention and mitigation in the meteorological bureau and power system.

Abstract Background The global BOLERO-2 trial established the efficacy and safety of combination everolimus (EVE) and exemestane (EXE) in the treatment of estrogen receptor positive (ER +), HER2-, advanced breast cancer (ABC). BOLERO-5 investigated this combination in a Chinese population (NCT03312738). Methods BOLERO-5 is a randomized, double-blind, multicenter, placebo controlled, phase II trial comparing EVE (10 mg/day) or placebo (PBO) in combination with EXE (25 mg/day). The primary endpoint was progression-free survival (PFS) per investigator assessment. Secondary endpoints included PFS per blinded independent review committee (BIRC), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), pharmacokinetics, and safety. Results A total of 159 patients were randomized to EVE + EXE (n = 80) or PBO + EXE (n = 79). By investigator assessment, treatment with EVE + EXE prolonged median PFS by 5.4 months (HR 0.52; 90% CI 0.38, 0.71), from 2.0 months (PBO + EXE; 90% CI 1.9, 3.6) to 7.4 months (EVE + EXE; 90% CI 5.5, 9.0). Similar results were observed following assessment by BIRC, with median PFS prolonged by 4.3 months. Treatment with EVE + EXE was also associated with improvements in ORR and CBR. No new safety signals were identified in BOLERO-5, with the incidence of adverse events in Chinese patients consistent with the safety profile of both drugs. Conclusion The efficacy and safety results of BOLERO-5 validate the findings from BOLERO-2, and further support the use of EVE + EXE in Chinese post-menopausal women with ER + , HER2- ABC. NCT03312738, registered 18 October 2017.

Abstract Background Lung adenocarcinoma (LUAD) patients have a dismal survival rate because of cancer metastasis and drug resistance. The study aims to identify the genes that concurrently modulate EMT, metastasis and EGFR-TKI resistance, and to investigate the underlying regulatory mechanisms. Methods Cox regression and Kaplan–Meier analyses were applied to identify prognostic oncogenes in LUAD. Gene set enrichment analysis (GSEA) was used to indicate the biological functions of the gene. Wound-healing and Transwell assays were used to detect migratory and invasive ability. EGFR-TKI sensitivity was evaluated by assessing the proliferation, clonogenic survival and metastatic capability of cancer cells with treatment with gefitinib. Methylated RNA immunoprecipitation (MeRIP) and RNA immunoprecipitation (RIP) analyses established the level of m6A modification present on the target gene and the protein’s capability to interact with RNA, respectively. Single-sample gene set enrichment (ssGSEA) algorithm used to investigate levels of immune cell infiltration. Results Our study identified dual-specificity phosphatase 5 (DUSP5) as a novel and powerful predictor of adverse outcomes for LUAD by using public datasets. Functional enrichment analysis found that DUSP5 was positively enriched in EMT and transforming growth factor-beta (TGF-β) signaling pathway, a prevailing pathway involved in the induction of EMT. As expected, DUSP5 knockdown suppressed EMT via inhibiting the canonical TGF-β/Smad signaling pathway in in vitro experiments. Consistently, knockdown of DUSP5 was first found to inhibit migratory ability and invasiveness of LUAD cells in in vitro and prevent lung metastasis in in vivo. DUSP5 knockdown re-sensitized gefitinib-resistant LUAD cells to gefitinib, accompanying reversion of EMT progress. In LUAD tissue samples, we found 14 cytosine-phosphate-guanine (CpG) sites of DUSP5 that were negatively associated with DUSP5 gene expression. Importantly, 5′Azacytidine (AZA), an FDA-approved DNA methyltransferase inhibitor, restored DUSP5 expression. Moreover, RIP experiments confirmed that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a m6A reader protein, could bind DUSP5 mRNA. YTHDF1 promoted DUSP5 expression and the malignant phenotype of LUAD cells. In addition, the DUSP5-derived genomic model revealed the two clusters with distinguishable immune features and tumor mutational burden (TMB). Conclusions Briefly, our study discovered DUSP5 which was regulated by epigenetic modification, might be a potential therapeutic target, especially in LUAD patients with acquired EGFR-TKI resistance. Graphical Abstract

Abstract Background The cumulative live birth rate (CLBR) has been regarded as a key measure of in vitro fertilization (IVF) success after a complete treatment cycle. Women undergoing IVF face great psychological pressure and financial burden. A predictive model to estimate CLBR is needed in clinical practice for patient counselling and shaping expectations. Methods This retrospective study included 32,306 complete cycles derived from 29,023 couples undergoing IVF treatment from 2014 to 2020 at a university-affiliated fertility center in China. Three predictive models of CLBR were developed based on three phases of a complete cycle: pre-treatment, post-stimulation, and post-treatment. The non-linear relationship was treated with restricted cubic splines. Subjects from 2014 to 2018 were randomly divided into a training set and a test set at a ratio of 7:3 for model derivation and internal validation, while subjects from 2019 to 2020 were used for temporal validation. Results Predictors of pre-treatment model included female age (non-linear relationship), antral follicle count (non-linear relationship), body mass index, number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, tubal factor, male factor, and scarred uterus. Predictors of post-stimulation model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. Predictors of post-treatment model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), cumulative Day-3 embryos live-birth capacity (non-linear relationship), number of previous IVF attempts, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. The C index of the three models were 0.7559, 0.7744, and 0.8270, respectively. All models were well calibrated (p = 0.687, p = 0.468, p = 0.549). In internal validation, the C index of the three models were 0.7422, 0.7722, 0.8234, respectively; and the calibration P values were all greater than 0.05. In temporal validation, the C index were 0.7430, 0.7722, 0.8234 respectively; however, the calibration P values were less than 0.05. Conclusions This study provides three IVF models to predict CLBR according to information from different treatment stage, and these models have been converted into an online calculator ( https://h5.eheren.com/hcyc/pc/index.html#/home ). Internal validation and temporal validation verified the good discrimination of the predictive models. However, temporal validation suggested low accuracy of the predictive models, which might be attributed to time-associated amelioration of IVF practice.

Abstract Background We explored the efficacy and safety of inetetamab combined with sirolimus and chemotherapy for the treatment of human epidermal factor receptor 2 (HER2)‐positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR (PAM) pathway after trastuzumab treatment. Methods For this prospective multicenter clinical study, HER2‐positive metastatic breast cancer patients with PAM pathway mutations confirmed by histology or peripheral blood genetic testing were enrolled from July 2021 to September 2022. Patients were randomly assigned to a trial or control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, while the control group patients received pyrotinib and chemotherapy. The RECIST v1.1 standard was used to evaluate efficacy. Descriptive statistics were used to summarize the clinicopathological features, and the Kaplan–Meier method was used to generate survival curves. The log‐rank test was used to compare progression‐free survival (PFS) between the two groups. Results A total of 59 HER2‐positive metastatic breast cancer patients with abnormal activation of the PAM pathway were included, of which 37 received inetetamab combined with sirolimus and chemotherapy treatment and 22 received pyrotinib and chemotherapy treatment. The median PFS was 4.64 months in the inetetamab group and 5.69 months in the pyrotinib group, with no statistically significant difference (p = 0.507). The objective response rates were 27.3% for the inetetamab group and 29.4% for the pyrotinib group. The safety assessment indicated that the adverse event (AE) incidences were 86.1% (31/36) in the inetetamab group and 78.9 (15/19) in the pyrotinib group, with 9 (25%) and four (21.1%) Grade 3/4 AEs in the inetetamab and pyrotinib groups, respectively. Conclusions For metastatic HER2‐positive breast cancer patients with abnormal PAM pathway activation and previous trastuzumab treatment, the combination of inetetamab with sirolimus and chemotherapy is equivalent to the combination of pyrotinib and chemotherapy. Therefore, this regimen could be a treatment option for PAM pathway‐activated metastatic HER2‐positive breast cancer patients.

Abstract Background The MONALEESA‐7 and ‐2 phase 3 randomized trials demonstrated a statistically significant progression‐free survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre‐ and postmenopausal patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre‐ and postmenopausal patients with HR+/HER2– ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA‐7 and ‐2 studies. Methods Patients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigator‐assessed PFS. Results As of April 25, 2022, the median follow‐up was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies. Conclusions These data demonstrate a favorable benefit–risk profile for ribociclib + ET in Chinese patients.

BackgroundObservational research has highlighted a potential relationship between rheumatoid arthritis (RA) and neurodegenerative diseases (NDs). However, the confirmation of a causal connection is impeded by the inherent limitations of such studies, including vulnerability to confounding factors and the possibility of reverse causality. This study employs a two-sample Mendelian randomization (MR) approach to assess the causal impact of RA on three NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).MethodsWe aggregated data from genome-wide association studies (GWASs) targeting RA or NDs within populations of European descent. Single nucleotide polymorphisms (SNPs) with robust associations to RA were identified as instrumental variables (IVs). To estimate the association between RA and AD, PD, and ALS, we utilized the inverse variance weighted (IVW) method in our univariable MR (UVMR) analysis. Validation of the IVW results ensued through supplementary analyses using MR-Egger and weighted median methods. The multivariable MR (MVMR) analysis was conducted, adjusting for body mass index (BMI), alcohol drinking, and type 2 diabetes mellitus (T2DM).ResultsThe UVMR analysis, based on the IVW method, revealed a significantly positive causal association between RA and late-onset (LO) AD (OR [95% CI] = 1.084 [1.020–1.153]; p = 9.980 × 10−3), while suggesting a possible inverse relationship with PD (OR [95% CI] = 0.727 [0.563–0.938]; p = 0.014). Our study did not detect any causal connections between RA and early-onset (EO) AD, atypical or mixed (AM) AD, and ALS (all p > 0.05). The MVMR analysis results indicated that after adjusting for alcohol drinking, RA remains a risk factor for LOAD (OR [95% CI] = 1.094 [1.024–1.169]; p = 0.008). However, MVMR analysis revealed no causal connections between RA and PD after adjustments for BMI, alcohol drinking, or T2DM (all p > 0.05). Sensitivity analyses showed no evidence of heterogeneity and horizontal pleiotropy.ConclusionsThis research provides genetic evidence indicating that RA potentially causes an increased risk of developing LOAD and PD. Such a revelation underscores the importance for individuals suffering from RA to be vigilant about the potential emergence of LOAD and PD. Ongoing monitoring and prompt detection are essential for successfully managing and intervening in this possible risk.

SignificanceCartilage tissue engineering is a promising strategy for effective curative therapies for treatment of osteoarthritis. However, tissue engineers depend predominantly on time-consuming, expensive, and destructive techniques as quality control to monitor the maturation of engineered cartilage. This practice can be impractical for large-scale biomanufacturing and prevents spatial and temporal monitoring of tissue growth, which is critical for the fabrication of clinically relevant-sized cartilage constructs. Nondestructive multimodal imaging techniques combining fluorescence lifetime imaging (FLIm) and optical coherence tomography (OCT) hold great potential to address this challenge.AimThe feasibility of using multimodal FLIm-OCT for nondestructive, spatial, and temporal monitoring of self-assembled cartilage tissue maturation in a preclinical mouse model is investigated.ApproachSelf-assembled cartilage constructs were developed for 4 weeks in vitro followed by 4 weeks of in vivo maturation in nude mice. Sterile and nondestructive in situ multispectral FLIm and OCT imaging were carried out at multiple time points ( t=2 , 4, and 8 weeks) during tissue development. FLIm and 3D volumetric OCT images were reconstructed and used for the analysis of tissue biochemical homogeneity, morphology, and structural integrity. A biochemical homogeneity index was computed to characterize nonhomogeneous tissue growth at different time points. OCT images were validated against histology.ResultsFLIm detects heterogenous extracellular matrix (ECM) growth of tissue-engineered cartilage. The outer edge of the tissue construct exhibited longer fluorescence lifetime in 375 to 410 and 450 to 485 nm spectral channels, indicating increase in collagen content. Significant ( p