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Abstract Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48–0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Abstract Re-irradiation with intensity-modulated radiotherapy (IMRT) remains the primary treatment modality for inoperable locally recurrent nasopharyngeal carcinoma (NPC). However, the rate of radiation-related late adverse effects is often substantially high. Therefore, we aimed to explore failure patterns and individualized treatment plans of re-irradiation for inoperable locally recurrent NPC. Ninety-seven patients who underwent IMRT were retrospectively analyzed. Sixty-two patients had clinical target volume of recurrence (rCTV) delineated, and thirty-five patients had only gross tumor volume of recurrence (rGTV) delineated. Twenty-nine patients developed second local failures after re-irradiation with IMRT (28 cases available). Among those patients, 64.3% (18/28) of patients and 35.7% (10/28) developed in-field or out-field, respectively. No statistical correlation was observed between target volume (rGTV or rCTV) and the local recurrence rate, local failure patterns, grade ≥ 3 toxicity, and survival. Multivariate analysis showed that recurrent T (rT) stage (HR 2.62, P = 0.019) and rGTV volume (HR 1.73, P = 0.037) were independent prognostic factors for overall survival (OS). Risk stratification based on rT stage and rGTV volume revealed that low risk group had a longer 3-year OS rate (66.7% vs. 23.4%), lower total grade ≥ 3 toxicity (P = 0.004), and lower re-radiation associated mortality rates (HR 0.45, P = 0.03) than high risk group. This study demonstrates that the delineation of rCTV may not be beneficial for re-irradiation using IMRT in locally recurrent NPC. Patients with low risk were most suitable for re-irradiation, with maximizing local salvage and minimizing radiation-related toxicities. More precise and individualized plans of re-irradiation are warranted.

Abstract Cephalosporin antibiotics are widely used in clinical settings, but they can cause hypersensitivity reactions, which may be influenced by genetic factors such as the expression of Human leukocyte antigen (HLA) molecules. This study aimed to investigate whether specific HLA alleles were associated with an increased risk of adverse reactions to cephalosporins among individuals in the Taiwanese population. This retrospective case–control study analyzed data from the Taiwan Precision Medicine Initiative (TPMI) on 27,933 individuals who received cephalosporin exposure and had HLA allele genotyping information available. Using logistic regression analyses, we examined the associations between HLA genotypes, comorbidities, allergy risk, and severity. Among the study population, 278 individuals had cephalosporin allergy and 2780 were in the control group. Our results indicated that certain HLA alleles, including HLA-B*55:02 (OR = 1.76, 95% CI 1.18–2.61, p = 0.005), HLA-C*01:02 (OR = 1.36, 95% CI 1.05–1.77, p = 0.018), and HLA-DQB1*06:09 (OR = 2.58, 95% CI 1.62–4.12, p

Abstract Dihydroorotase (DHOase) is the third enzyme in the six enzymatic reaction steps of the endogenous pyrimidine nucleotide de novo biosynthesis pathway, which is a metabolic pathway conserved in both bacteria and eukaryotes. However, research on the biological function of DHOase in plant pathogenic fungi is very limited. In this study, we identified and named MoPyr4, a homologous protein of Saccharomyces cerevisiae DHOase Ura4, in the rice blast fungus Magnaporthe oryzae and investigated its ability to regulate fungal growth, pathogenicity, and autophagy. Deletion of MoPYR4 led to defects in growth, conidiation, appressorium formation, the transfer and degradation of glycogen and lipid droplets, appressorium turgor accumulation, and invasive hypha expansion in M. oryzae, which eventually resulted in weakened fungal pathogenicity. Long-term replenishment of exogenous uridine-5’-phosphate (UMP) can effectively restore the phenotype and virulence of the ΔMopyr4 mutant. Further study revealed that MoPyr4 also participated in the regulation of the Pmk1-MAPK signaling pathway, co-localized with peroxisomes for the oxidative stress response, and was involved in the regulation of the Osm1-MAPK signaling pathway in response to hyperosmotic stress. In addition, MoPyr4 interacted with MoAtg5, the core protein involved in autophagy, and positively regulated autophagic degradation. Taken together, our results suggested that MoPyr4 for UMP biosynthesis was crucial for the development and pathogenicity of M. oryzae. We also revealed that MoPyr4 played an essential role in the external stress response and pathogenic mechanism through participation in the Pmk1-MAPK signaling pathway, peroxisome-related oxidative stress response mechanism, the Osm1-MAPK signaling pathway and the autophagy pathway.

Abstract Background Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. Methods A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. Results Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274–1.783, p

Objective To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/- mice. Methods The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/- mice. Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers. Results Proteomic analysis showed that there were 43 significantly up-regulated and 58 significantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group. Among them, GBP2, TAOK3, TFR1 and UCP1 were biomarkers with great diagnostic potential. KEGG pathway enrichment analysis indicated that ferroptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model. The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model. Conclusion Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferroptosis. Four potential biomarkers are selected for myocardial injury diagnosis, providing a new direction for sudden cardiac death （SCD） caused by hyperlipidemia combined with the restraint stress.

Abstract This study demonstrates a novel use of the U-Net convolutional neural network (CNN) for modeling pixel-based electrostatic potential distributions in GaN metal–insulator-semiconductor high-electron mobility transistors (MIS-HEMTs) with various gate and source field plate designs and drain voltages. The pixel-based images of the potential distribution are successfully modeled from the developed U-Net CNN with an error of less than 1% error relative to a TCAD simulated reference of a 500-V electrostatic potential distribution in the AlGaN/GaN interface. Furthermore, the modeling time of potential distributions by U-Net takes about 80 ms. Therefore, the U-Net CNN is a promising approach to efficiently model the pixel-based distributions characteristics in GaN power devices.

Abstract Csn5 is subunit 5 of the COP9 signalosome (CSN), but the mechanism by which it strictly controls the pathogenicity of pathogenic fungi through autophagy remains unclear. Here, we found that Csn5 deficiency attenuated pathogenicity and enhanced autophagy in Magnaporthe oryzae. MoCSN5 knockout led to overubiquitination and overdegradation of MoTor (the core protein of the TORC1 complex [target of rapamycin]) thereby promoted autophagy. In addition, we identified MoCsn5 as a new interactor of MoAtg6. Atg6 was found to be ubiquitinated through linkage with lysine 48 (K48) in cells, which is necessary for infection-associated autophagy in pathogenic fungi. K48-ubiquitination of Atg6 enhanced its degradation and thereby inhibited autophagic activity. Our experimental results indicated that MoCsn5 promoted K48-ubiquitination of MoAtg6, which reduced the MoAtg6 protein content and thus inhibited autophagy. Aberrant ubiquitination and autophagy in ΔMocsn5 led to pleiotropic defects in the growth, development, stress resistance, and pathogenicity of M. oryzae. In summary, our study revealed a novel mechanism by which Csn5 regulates autophagy and pathogenicity in rice blast fungus through ubiquitination.

Abstract Epstein-Barr virus (EBV) encoded microRNA BART8-3p (miR-BART8-3p) was significantly associated with the metastasis in nasopharyngeal carcinoma (NPC). To explore the clinical values of plasma miR-BART8-3p in patients with early NPC. We retrospectively analyzed 126 patients with stage I and II NPC. A receiver operating characteristic curve was used to examine the diagnostic performance. Kaplan‒Meier analysis was applied to determine survival differences. Cox regression was used for univariate and multivariate analyses. Compared to healthy subjects, plasma EBV miR-BART8-3p was highly expressed in early NPC patients. The sensitivity, specificity, and area under the curve value of plasma miR-BART8-3p combined with plasma EBV DNA was up to 88.9%, 94.4%, and 0.931. Compared to patients with low expression of miR-BART8-3p, patients with high expression of miR-BART8-3p had poorer 5-year overall survival (OS) (98.9% vs. 91.1%, P = 0.025), locoregional recurrence-free survival (LRRFS) (100% vs. 83.9%, P

Abstract A Go endgame database consists of optimal game values and moves for every legal arrangement of no more than S pieces on an N by N board. This paper describes methods for constructing such databases when $$1 < N \le 5$$ 1 < N ≤ 5 and $$S = N^2$$ S = N 2 . When cycles of plies with lengths greater than 4 are encountered, two rules, one allowing cycles and the other disallowing them, are implemented. Observations and knowledge are obtained for these endgames, which may elucidate the fundamental properties of the popular game Go. First, the optimal game values are different when N is even and odd, regardless of whether the repetition of positions is allowed. When N is odd, the first player can occupy the whole board, while this is not the case when N is even. Second, allowing cycles makes the first and second players equal in strength when N is even, whereas the first player always dominates when N is odd. Using the state-of-the-art open-source deep learning Go engine KataGo to correctly solve a given position as an indicator, factors affecting level of difficulty are found, including the distributions of the optimal game values among all legal plies and the cardinality and values of the true optimal plies. A simple formula is designed that works on more than 10% of the positions so that positions with a given level of difficulty can be found with a high probability.

Key Clinical Message One Kirsten Ras (KRAS) G12C mutated non‐small cell lung cancer (NSCLC) patient had improved poor performance status and obtained mixed response with the first‐line KRAS‐targeted treatment of sotorasib. After disease progression, partial response was achieved with chemotherapy plus immunotherapy. KRAS G12C mutated immunoenvironment in NSCLC may favor the immunotherapy. Abstract KRAS is one of the most commonly mutated genes, which used to be untargetable. The phase II CodeBreak 100 trial revealed 6.8‐month median progress‐free survival (PFS) and 12.5‐month overall survival (OS) in previously treated KRAS G12C‐mutant NSCLC patients treated with KRAS inhibitor, sotorasib. The specimens of the brain, lymph node (LN), and blood from the patient were analyzed by next‐generation sequencing. Hematoxylin and eosin staining and immunohistochemistry were performed for pathological characterization. Computed tomography (CT) and magnetic resonance imaging (MRI) scan were used for treatment response evaluation. The patient was diagnosed in a bad Eastern Cooperative Oncology Group performance status (ECOG‐PS) with metastatic KRAS G12C‐mutated lung adenocarcinoma who had achieved mixed response to sotorasib as the first‐line treatment. Although 5‐month PFS of the treatment with sotorasib was not surprising, the patient achieved significantly improved ECOG‐PS score from 4 to 1. Subsequently, partial response (PR) was achieved with the treatment of pemetrexed plus pembrolizumab. This case highlights superior efficacy of first‐line treatment with sotorasib for the advance untreated KRAS G12C‐mutant patients. The high efficacy of the treatment with chemotherapy plus immunotherapy revealed that immunoenvironment of KRAS G12C‐mutated patient may favor the immunotherapy.

Abstract To develop a prognostic nomogram for individualized strategies on locoregional radiation therapy (LRRT) in patients with de novo metastatic nasopharyngeal carcinoma (dmNPC) treated with chemoimmunotherapy. Ninety patients with dmNPC treated with chemoimmunotherapy and diagnosed between 2019 and 2022 were included in our study. Cox regression analysis was performed to identify independent prognostic factors for overall survival (OS) and progression-free survival (PFS) to establish a nomogram. With a median follow-up of 17.5 months, the median PFS and OS were 24.9 months and 29.4 months, respectively. Sixty-nine patients and twenty-one patients were included in the LRRT group and without LRRT group, respectively. Multivariate analysis revealed that younger age, lower EBV DNA copy number before treatment, a single metastatic site, more cycles of chemotherapy and immunotherapy were significantly associated with better OS. A prognostic nomogram was constructed incorporating the above 5 independent factors, with a C-index of 0.894. Patients were divided into low- and high-risk cohorts based on nomogram scores. A significant improvement in OS was revealed in the LRRT group compared with the without-LRRT group for patients in the high-risk cohort (HR = 2.46, 95% CI 1.01–6.00, P = 0.049), while the OS was comparable between the two groups in the low-risk cohort. Our study indicates that LRRT may be associated with better prognosis in high-risk patients with dmNPC in the era of immunotherapy.

Abstract The cell cycle is pivotal to cellular differentiation in plant pathogenic fungi. Cell wall integrity (CWI) signaling plays an essential role in coping with cell wall stress. Autophagy is a degradation process in which cells decompose their components to recover macromolecules and provide energy under stress conditions. However, the specific association between cell cycle, autophagy and CWI pathway remains unclear in model pathogenic fungi Magnaporthe oryzae. Here, we have identified MoSwe1 as the conserved component of the cell cycle in the rice blast fungus. We have found that MoSwe1 targets MoMps1, a conserved critical MAP kinase of the CWI pathway, through protein phosphorylation that positively regulates CWI signaling. The CWI pathway is abnormal in the ΔMoswe1 mutant with cell cycle arrest. In addition, we provided evidence that MoSwe1 positively regulates autophagy by interacting with MoAtg17 and MoAtg18, the core autophagy proteins. Moreover, the S phase initiation was earlier, the morphology of conidia and appressoria was abnormal, and septum formation and glycogen degradation were impaired in the ΔMoswe1 mutant. Our research defines that MoSWE1 regulation of G1/S transition, CWI pathway, and autophagy supports its specific requirement for appressorium development and virulence in plant pathogenic fungi. Video Abstract

Abstract To explore the influence of wind speed on the quality of tobacco in this study, we employed a heat pump-powered intensive curing barn and a three-stage curing process. By evaluating the influence of fan parameters on the quality of tobacco leaves at different curing stages, the optimal wind speed was determined. After adopting the optimized wind speed process, the degradation of macromolecular substances was faster, the accumulation of aroma substances was delayed to 55 °C, and the accumulation was more complete. Among them, the contents of reducing sugar and total sugar in flue-cured tobacco leaves were 22.25% and 29.2%, respectively, which were lower than those in the control group. The sugar was converted into more aroma substances, and the total amount of neutral aroma substances was 48.82% higher than that of the control group. The content of related aroma substances increased significantly. The content of petroleum ether extract related to aroma substances increased by 0.93% compared with the control group. The macromolecular substances were degraded more fully than the control group, such as the starch content decreased to 1.56%. The results of metabolomics showed that the contents of aldehydes, heterocyclic compounds, alcohols, ketones and esters increased significantly in different degrees after this process. These results show that the optimization of wind speed parameters can significantly improve the baking quality of tobacco leaves. This study provides a reference for the optimization of the flue-cured tobacco baking process.

Abstract Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

Objectives This study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese population.Methods Patients with SLE (n=2782) and matched non-SLE controls (n=11 128) were genotyped using Genome-Wide TWB 2.0 single-nucleotide polymorphism (SNP) array. PRS models (C+T, LDpred2, Lassosum, PRSice-2, PRS-continuous shrinkage (CS)) were constructed for predicting SLE susceptibility. Logistic regression was assessed for C+T-based PRS association with renal involvement in patients with SLE.Results In the training set, C+T-based SLE-PRS, only incorporating 27 SNPs, outperformed other models with area under the curve (AUC) values of 0.629, surpassing Lassosum (AUC=0.621), PRSice-2 (AUC=0.615), LDpred2 (AUC=0.609) and PRS-CS (AUC=0.602). Additionally, C+T-based SLE-PRS demonstrated consistent predictive capacity in the testing set (AUC=0.620). Individuals in the highest quartile exhibited earlier SLE onset (39.06 vs 44.22 years, p150 mg/day (OR 2.07, 95% CI 1.49 to 2.89, p

Background Breast cancer is a common clinical malignant tumor, which seriously affects the health of women. Although the current targeted therapy system for breast cancer is well established, the difference in clinical efficacy between double-target therapy and single-target therapy remains unclear.Objective To explore the effects of different neoadjuvant chemotherapy regimens on the immune indicators and tumor microenvironment in HER2-positive breast cancer patients.Methods A total of 92 patients with HER-2-positive breast cancer admitted to Changzhou No.2 People's Hospital Affiliated to Nanjing Medical University from September 2017 to September 2021 were collected and randomly divided into the study group (trastuzumab+patuzumab+docetaxel therapy, n=46) and the control group (trastuzumab+docetaxel therapy, n=46) . The clinical efficiency rate and control rate, the changes of inflammatory factors levels and immunological indicators were compared between the two groups.Results The clinical efficiency rate and control rate after treatment of the study group were higher than those of the control group (P

Background/Objectives: Benign paroxysmal positional vertigo (BPPV) is the most common cause of recurrent vertigo and the most common peripheral vestibular disorder. It is characterized by intense vertigo triggered by head and position changes. This study investigates the risk of subsequent injury in BPPV patients and the effects of treatment. Methods: A population-based retrospective cohort study was conducted using data from the Longitudinal Health Insurance Database 2005 in Taiwan. Patients with and without BPPV were identified between 2000 and 2017. The study outcomes were diagnoses of all-cause injuries. The Kaplan–Meier method determined the cumulative incidence rates of injury in both cohorts, and a log-rank test analyzed the differences. Cox proportional hazard models calculated each cohort’s 18-year hazard ratios (HRs). Results: We enrolled 50,675 patients with newly diagnosed BPPV and 202,700 matched individuals without BPPV. During follow-up, 47,636 patients were diagnosed with injuries (13,215 from the BPPV cohort and 34,421 from the non-BPPV cohort). The adjusted HR for injury in BPPV patients was 2.63 (95% CI, 2.49–2.88). Subgroup analysis showed an increased incidence of unintentional and intentional injuries in BPPV patients (aHR 2.86; 95% CI, 2.70–3.13 and 1.10; 95% CI, 1.04–1.21, respectively). A positive dose–response relationship was observed with increasing BPPV diagnoses. Treatment with canalith repositioning therapy (CRT) or medications reduced the risk of injury slightly but not significantly (aHR, 0.78; 95% CI, 0.37–1.29, 0.88; 95% CI, 0.40–1.40, respectively). Conclusions: BPPV is independently associated with an increased risk of injuries. CRT or medications have limited effects on mitigating this risk. Physicians should advise BPPV patients to take precautions to prevent injuries even after treatment.

The heterogeneity of etiology may serve as a crucial factor in the challenges of treatment, including the low response rate and the delay in establishing therapeutic effect. In the present study, we examined whether social experience since early life is one of the etiologies, with the involvement of the 5-HT1A receptors, and explored the potentially therapeutic action of the subchronic administration of buspirone, a partial 5-HT1A agonist. Rats were isolation reared (IR) since their weaning, and the depressive profile indexed by the forced-swim test (FST) was examined in adulthood. Nonspecific locomotor activity was used for the IR validation. Buspirone administration (1 mg/kg/day) was introduced for 14 days (week 9–11). The immobility score of the FST was examined before and after the buspirone administration. Tissue levels of serotonin (5-HT) and its metabolite 5-HIAA were measured in the hippocampus, the amygdala, and the prefrontal cortex. Efflux levels of 5-HT, dopamine (DA), and norepinephrine (NE) were detected in the hippocampus by brain dialysis. Finally, the full 5-HT1A agonist 8-OH-DPAT (0.5 mg/kg) was acutely administered in both behavioral testing and the dialysis experiment. Our results showed (i) increased immobility time in the FST for the IR rats as compared to the social controls, which could not be reversed by the buspirone administration; (ii) IR-induced FST immobility in rats receiving buspirone was corrected by the 8-OH-DPAT; and (iii) IR-induced reduction in hippocampal 5-HT levels can be reversed by the buspirone administration. Our data indicated the 5-HT1A receptor-linked early life social experience as one of the mechanisms of later life depressive mood.

The current study aimed to determine the safety profile of intra-articular-injected allogeneic adipose-derived mesenchymal stem cells (ADSCs) GXCPC1 in subjects with knee osteoarthritis (OA) and its preliminary efficacy outcome. The 3 + 3 phase I study was designed with two dose-escalation cohorts: low dose (6.7 × 10 6 GXCPC1, N = 5) and high dose (4 × 10 7 GXCPC1, N = 6). The primary endpoint was safety, which was evaluated by recording adverse events throughout the trial; the secondary endpoints included total, pain, stiffness, and function subscales of the Western Ontario and McMaster Universities Arthritis Index (WOMAC), Visual Analogue Scale (VAS) for pain, and 12-Item Short Form (SF-12) health survey questionnaire. The GXCPC1 treatment was found to be safe after 1 year of follow-up with no treatment-related severe adverse events observed. When compared to baseline, subjects in both the low- and high-dose cohorts demonstrated improving trends in pain and knee function after receiving GXCPC1 treatment. Generally, the net change in pain (95% confidence interval (CI) = −7.773 to −2.561t at 12 weeks compared to baseline) and knee function (95% CI = −24.297 to −10.036t at 12 weeks compared to baseline) was better in subjects receiving high-dose GXCPC1. Although this study included a limited number of subjects without a placebo arm, it showed that the intra-articular injection of ADSCs was safe and well-tolerated in subjects with therapeutic alternatives to treat knee OA. However, a larger scale study with an appropriate control would be necessary for clinical efficacy in the following study.

AbstractBackground Liver transplant recipients have an increased risk of osteoporosis and fractures. The aim of this study was to identify risk factors for fractures after liver transplant in a Taiwanese population.Methods We identified newly diagnosed liver transplant recipients from the National Health Insurance Research Database in Taiwan between 2003 and 2015. Risk factors of post-transplant fractures were analyzed using a Cox proportional hazards model.Results A total of 4821 patients underwent liver transplantation, of whom 419 (8.7%) had post-transplant fractures. Independent predictors of post-transplant fractures were age ≥65 years at transplantation (hazard ratio (HR): 1.566; 95% confidence interval (CI) 1.122–2.186), female sex (HR: 1.648; 95% CI 1.319–2.057), fractures within 1 year prior to transplant (HR: 3.664; 95% CI 2.503–5.364), hepatitis C carriers (HR: 1.594; 95% CI 1.289–1.970), alcoholism (HR: 1.557; 95% CI 1.087–2.230) and daily prednisolone dose >1.61–3.78 mg/day (HR: 1.354; 95% CI 1.005–1.824), >3.78–9.18 mg (HR: 4.182; 95% CI 3.155–5.544) and >9.18 mg (HR: 13.334; 95% CI 9.506–18.703). Post-transplant fractures were inversely correlated with tacrolimus (HR: 0.617; 95% CI 0.417–0.913) and sirolimus/everolimus (HR: 0.504; 95% CI 0.391–0.650) treatment.Conclusions The liver transplant recipients, and especially those who were aged ≥65 years, female, hepatitis C carriers, had a history of fractures within 1 year prior to transplant, alcoholism, and higher daily prednisolone dose were associated with an increased risk of post-transplant fractures. Conversely, the use of tacrolimus and sirolimus/everolimus was associated with a decreased risk of fractures.

Few cases of patients with Cheng’s type III portal vein tumor thrombus (PVTT) have been reported to achieve radical cure without recurrence over time. In this study, we reported on a 55-year-old male patient with a diagnosis of stage IIIa China liver cancer staging (CNLC), PVTT Cheng’s type III, mild cirrhosis, and chronic viral hepatitis B. TACE combined with radioactive iodine-125 ( 125 I) particle implantation was applied to achieve radical treatment with sequential oral anlotinib hydrochloride capsules. This case might serve as a reference for the treatment of this disease.

Abstract The alteration in circadian typology and insomnia were prevalent among both Individuals with IGD and those with attention deficit hyperactivity disorder (ADHD), the most comorbid psychiatric disorder of IGD. This study aimed to evaluate the relationships between circadian typologies, insomnia, and internet gaming disorder (IGD) and how ADHD affects this relationship. We recruited three groups of 69 young adults: an IGD group, a control group comprising age- and sex-matched nongamers, and a group of gamers without IGD through diagnostic interviews. The participants with IGD exhibited lower composite scale of morningness (CSM) scores and thus a higher eveningness preference In addition, the score of Pittsburgh insomnia rating scale—20-item version (PIRS_20) was significantly higher among those with IGD. The participants with IGD and ADHD exhibited lower CSM scores but higher PRIS_20 scores than the participants with IGD but without ADHD. The present findings indicate that participants with IGD exhibited a tendency of eveningness preference and experienced more severe insomnia. ADHD exacerbated the eveningness preference and insomnia of individuals with IGD. Close attention should be paid to sleep problems in individuals with IGD, particularly to those with ADHD.

Objective To analyze the levels of serum procalcitonin (PCT) , heart-type fatty acid binding protein (H-FABP) and mean platelet volume to platelet count ratio (MPV/PLT) in patients with urosepsis and their prognostic value. Methods A total of 140 patients with urosepsis admitted to Zhangjiakou First Hospital from March 2020 to March 2022 were selected. The patients were divided into survival group (105 patients) and death group (35 patients) according to whether they were survived 28 d after hospitalization. A total of 30 healthy subjects matched with gender and age of patients with urosepsis were selected as the control group. Levels of PCT, H-FABP and MPV/PLT were compared among the three groups, and the value of each index alone and in combination for predicting the outcome of urosepsis was evaluated. Results The levels of PCT, H-FABP and MPV/PLT decreased in the order of death group, survival group, and control group (P＜0.05) . Logistic regression analysis showed that low SBP and PaO2/FiO2, high PCT, H-FABP and MPV/PLT levels were independent risk factors for poor outcome in urosepsis (P＜0.05) . The areas under the ROC curve of PCT, H-FABP and MPV/PLT alone in predicting the poor outcome of urosepsis were 0.692, 0.860 and 0.674, respectively, and the area under the ROC curre for combined prediction were 0.862. Conclusion Compared with healthy subjects, the levels of PCT, H-FABP and MPV/PLT are abnormally increased in patients with urosepsis, which may be valuable for prognostic evaluation.

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith–Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

Introduction Organ preservation is now considered an acceptable alternative option in distal rectal cancer patients with clinical complete response (cCR) after neoadjuvant chemoradiation (CRT). But the cCR rate is low and about one-third of tumour will regrow, which requires more effective local treatment. CRT combined with intra-arterial chemotherapy (IAC) might be a promising approach. Additionally, total neoadjuvant therapy using FOLFIRINOX induction chemotherapy improved survival while consolidation chemotherapy improved organ preservation. We assess whether IAC plus CRT and FOLFIRINOX consolidation chemotherapy can improve the chance of organ preservation and survival in distal rectal cancer.Methods and analysis This prospective, monocentric, open-label, single-arm phase II study will include 32 patients with cT3-4NanyM0 distal rectal adenocarcinoma. All patients will receive one cycle of IAC (irinotecan, raltitrexed and oxaliplatin), followed by CRT (50 Gy/25 fractions with concomitant capecitabine) and then with six cycles of FOLFIRINOX (leucovorin, 5-fluorouracil, oxaliplatin and irinotecan). After final evaluation, patients with cCR will receive non-operative management or surgery at their own discretion and others are mandatorily referred to surgery. Adjuvant chemotherapy with six cycles of mFOLFOX6 (leucovorin, 5-fluorouracil and oxaliplatin) will be used for patients with adverse pathological features. The primary endpoint is the rate of complete response (CR; pathological CR or sustained cCR≥2 years). The main secondary endpoints are toxicity, compliance, short-term and long-term oncological outcomes, surgical morbidity and quality of life. This protocol has been designed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials 2013 guidelines.Ethics and dissemination This study was approved by the Academic and Ethics Committee of The Affiliated Hospital of Youjiang Medical University for Nationalities in March 2023. Trial results will be published in peer-reviewed international journals and on the ChiCTR website.Protocol version Registered on 18 April 2023; version #1.Trial registration number ChiCTR2300070620.

Intrauterine devices (IUDs) are one of the most popular reversible contraception methods. However, if an event related to them is unanticipated, or if they are not located when missing, it can be dangerous. We present a case of chronic lower abdomen pain and recurrent urinary tract infection ongoing for 1.5 years. Despite the patient undergoing laparoscopic uterine myomectomy, her symptoms had not improved. The patient visited a genitourinary clinic for lower urinary tract symptoms and accepted cystoscopy and electrohydraulic lithotomy. Incidentally, a part of an IUD was found in the calculus. This case highlights the need for careful diagnosis and for locating missing IUDs to avoid serious complications.

Abstract Background In endothelial cells, phospholipase C (PLC) β1-activated Ca2+ is a crucial second messenger for the signaling pathways governing angiogenesis. PLCβ1 is inactivated by complexing with an intracellular protein called translin-associated factor X (TRAX). This study demonstrates specific interactions between Globo H ceramide (GHCer) and TRAX, which highlight a new angiogenic control through PLCβ1 activation. Methods Globo-series glycosphingolipids (GSLs), including GHCer and stage-specific embryonic antigen-3 ceramide (SSEA3Cer), were analyzed using enzyme-linked immunosorbent assay (ELISA) and Biacore for their binding with TRAX. Angiogenic activities of GSLs in human umbilical vein endothelial cells (HUVECs) were evaluated. Molecular dynamics (MD) simulation was used to study conformations of GSLs and their molecular interactions with TRAX. Fluorescence resonance energy transfer (FRET) analysis of HUVECs by confocal microscopy was used to validate the release of PLCβ1 from TRAX. Furthermore, the in vivo angiogenic activity of extracellular vesicles (EVs) containing GHCer was confirmed using subcutaneous Matrigel plug assay in mice. Results The results of ELISA and Biacore analysis showed a stable complex between recombinant TRAX and synthetic GHCer with Kd of 40.9 nM. In contrast, SSEA3Cer lacking a fucose residue of GHCer at the terminal showed ~ 1000-fold decrease in the binding affinity. These results were consistent with their angiogenic activities in HUVECs. The MD simulation indicated that TRAX interacted with the glycan moiety of GHCer at amino acid Q223, Q219, L142, S141, and E216. At equilibrium the stable complex maintained 4.6 ± 1.3 H-bonds. TRAX containing double mutations with Q223A and Q219A lost its ability to interact with GHCer in both MD simulation and Biacore assays. Removal of the terminal fucose from GHCer to become SSEA3Cer resulted in decreased H-bonding to 1.2 ± 1.0 by the MD simulation. Such specific H-bonding was due to the conformational alteration in the whole glycan which was affected by the presence or absence of the fucose moiety. In addition, ELISA, Biacore, and in-cell FRET assays confirmed the competition between GHCer and PLCβ1 for binding to TRAX. Furthermore, the Matrigel plug assay showed robust vessel formation in the plug containing tumor-secreted EVs or synthetic GHCer, but not in the plug with SSEA3Cer. The FRET analysis also indicated the disruption of colocalization of TRAX and PLCβ1 in cells by GHCer derived from EVs. Conclusions Overall, the fucose residue in GHCer dictated the glycan conformation for its complexing with TRAX to release TRAX-sequestered PLCβ1, leading to Ca2+ mobilization in endothelial cells and enhancing angiogenesis in tumor microenvironments.

Learning about one’s implicit bias is crucial for improving one’s cultural competency and thereby reducing health inequity. To evaluate bias among medical students following a previously developed cultural training program targeting New Zealand Māori, we developed a text-based, self-evaluation tool called the Similarity Rating Test (SRT). The development process of the SRT was resource-intensive, limiting its generalizability and applicability. Here, we explored the potential of ChatGPT, an automated chatbot, to assist in the development process of the SRT by comparing ChatGPT’s and students’ evaluations of the SRT. Despite results showing non-significant equivalence and difference between ChatGPT’s and students’ ratings, ChatGPT’s ratings were more consistent than students’ ratings. The consistency rate was higher for non-stereotypical than for stereotypical statements, regardless of rater type. Further studies are warranted to validate ChatGPT’s potential for assisting in SRT development for implementation in medical education and evaluation of ethnic stereotypes and related topics.

Abstract Bone morphogenetic protein 2 (BMP2) is highly overexpressed in human non-small cell lung cancer (NSCLC) and correlates with tumor stage and metastatic burden. Although several lines of evidence suggest that BMP2 promotes cell migration and invasiveness in vitro, the in vivo role of BMP2 in the metastasis of lung adenocarcinoma cells remains less well understood. Here, we revealed that BMP2 is highly overexpressed in lung adenocarcinoma patients with lymph node metastasis compared with patients without lymph node metastasis. Using an in vivo orthotopic mouse model, we clearly demonstrated that BMP2 promotes lung adenocarcinoma metastasis. The depletion of BMP2 or its receptor BMPR2 significantly reduced cell migration and invasiveness. We further identified that BMP2/BMPR2-mediated cell migration involves the activation of the SMAD1/5/8 signaling pathway, independent of the KRAS signaling pathway. Significantly, the depletion of SMAD1/5/8 or the inhibition of SMAD1/5/8 by LDN193189 inhibitor significantly reduced cell migration. These findings show that BMP2 promotes NSCLC metastasis, indicating that targeting the BMP2 signaling pathway may represent a potential therapeutic strategy for treating patients with metastatic NSCLC.

ObjectiveTo assess the risk factors of puerperal genital hematomas in women after vaginal delivery. Methods Clinical data of 34 945 cases of vaginal delivery were reviewed retrospectively. According to the incidence of puerperal genital hematomas, 112 women presenting with puerperal genital hematomas were divided into the genital hematomas group, and 260 randomly selected from 34 833 normal women were assigned into the control group. Clinical data of 372 cases were collected and compared between two groups. The risk factors of puerperal genital hematomas were assessed by logistic regression analysis. Results The total incidence of puerperal genital hematomas was 0.32% （112/34 945） in this study. No statistical significance was observed in the gravidity, first stage of labor time, second stage of labor time, the number of precipitate labor, neonatal birth weight and the number of macrosomia between two groups （all P > 0.05）. However, the proportion of nulliparity, episiotomy, perineal laceration, vaginal laceration, and instrumental delivery in the genital hematomas group was significantly higher compared with that in the control group （all P < 0.05）. Multivariate logistic regression analysis showed that nulliparity （OR=1.663, 95%CI 1.003-2.757） and vaginal laceration （OR=3.698, 95%CI 1.962-6.970） were risk factors of puerperal genital hematomas （both P < 0.05）. Conclusions Nulliparity, episiotomy, perineal laceration, vaginal laceration, and instrumental delivery are associated with a higher rate of puerperal genital hematomas. Clinicians should pay extensive attention to nulliparity and vaginal laceration, deliver effective interventions and improve clinical prognosis of pregnant women after vaginal delivery.

Abstract This study aims to investigate whether an augmented wire in the treatment of patella distal pole fracture could improve knee range of motion (ROM) and radiographic features. Thirty-five consecutive patients with patellar distal pole fracture were analyzed from January 2014 to July 2019. The treatment is divided into two groups according to the presence or absence of augmented wire. Knee ROM, bone union, extension lag, and patellar height were compared between these two groups as the clinical and radiological outcomes. There was no significant difference in mean knee ROM (110° vs. 108°, p = 0.79), proportion of patella baja or bone union. More extension lag was noted in the augmentation group (5/20, 25%) than in the tendon reattachment group (1/15, 6.7%) with no statistically significant difference. In the augmentation group, four cases (20%) would need to remove the fixator due to irritation or broken hardware. Maintaining the patella length by preserving the distal pole and repairing the torn retinaculum allowed early motion to avoid knee stiffness safely without augmentation wire, which doesn’t improve knee ROM. The patellar tendon reattachment alone could achieve a great recovery and prevent the need for a second surgery due to broken wire or irritation.

Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of depression patients have implicated glucose metabolic dysfunction in the pathophysiology of depression. However, the molecular mechanisms by which glucose and related metabolic pathways modulate depressive-like behaviors are largely uncharacterized. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a donor molecule for O-GlcNAcylation. O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, catalyzes protein posttranslational modification by O-GlcNAc and acts as a stress sensor. Here, we show that Ogt mRNA was increased in depression patients and that astroglial OGT expression was specifically upregulated in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social-defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like effects, and moreover, astrocytic OGT in the mPFC bidirectionally regulated vulnerability to social stress. Furthermore, OGT modulated glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1) in astrocytes. OGT astrocyte–specific knockout preserved the neuronal morphology atrophy and Ca2+ activity deficits caused by chronic stress and resulted in antidepressant effects. Our study reveals that astrocytic OGT in the mPFC regulates depressive-like behaviors through the O-GlcNAcylation of GLT-1 and could be a potential target for antidepressants.

Abstract Early recognition and prevention comprise the first ring of the Chain of Survival for in-hospital cardiac arrest (IHCA). We previously developed and internally validated an emergency department (ED) triage tool, Emergency Department In-hospital Cardiac Arrest Score (EDICAS), for predicting ED-based IHCA. We aimed to externally validate this novel tool in another ED population. This retrospective cohort study used electronic clinical warehouse data from a tertiary medical center with approximately 130,000 ED visits per year. We retrieved data from 268,208 ED visits over a 2-year period. We selected one ED visit per person and excluded out-of-hospital cardiac arrest or children. Patient demographics and computerized triage information were retrieved, and the EDICAS was calculated to predict the ED-based IHCA. A total of 145,557 adult ED patients were included. Of them, 240 (0.16%) developed IHCA. The EDICAS showed excellent discrimination with an area under the receiver operating characteristic (AUROC) of 0.88. The AUROC of the EDICAS outperformed those of other early warning scores (0.80 for Modified Early Warning Score [MEWS] and 0.83 for Rapid Emergency Medicine Score [REMS]) in the same ED population. An EDICAS of 6 or above (i.e., high-risk patients) corresponded to a sensitivity of 33%, a specificity of 97%, and a positive likelihood ratio of 12.2. In conclusion, we externally validated a tool for predicting imminent IHCA in the ED and demonstrated its superior performance over other early warning scores. The real-world impact of the EDICAS warning system with appropriate interventions would require a future prospective study.

Abstract Tomato (Solanum lycopersicum) is one of the most economically important vegetable crops worldwide. Bacterial wilt (BW), caused by the Ralstonia solanacearum species complex, has been reported as the second most important plant pathogenic bacteria worldwide, and likely the most destructive. Extensive research has identified two major loci, Bwr-6 and Bwr-12, that contribute to resistance to BW in tomato; however, these loci do not completely explain resistance. Segregation of resistance in two populations that were homozygous dominant or heterozygous for all Bwr-6 and Bwr-12 associated molecular markers suggested the action of one or two resistance loci in addition to these two major QTLs. We utilized whole genome sequence data analysis and pairwise comparison of six BW resistant and nine BW susceptible tomato lines to identify candidate genes that, in addition to Bwr-6 and Bwr-12, contributed to resistance. Through this approach we found 27,046 SNPs and 5975 indels specific to the six resistant lines, affecting 385 genes. One sequence variant on chromosome 3 captured by marker Bwr3.2dCAPS located in the Asc (Solyc03g114600.4.1) gene had significant association with resistance, but it did not completely explain the resistance phenotype. The SNP associated with Bwr3.2dCAPS was located within the resistance gene Asc which was inside the previously identified Bwr-3 locus. This study provides a foundation for further investigations into new loci distributed throughout the tomato genome that could contribute to BW resistance and into the role of resistance genes that may act against multiple pathogens.

Abstract Hypertension and pain are both prevalent conditions in the older adult population. We aimed to report the prevalence of pain discomforts and investigated the association between hypertension and pain discomforts among older adults in the United States. Data from the 2011 National Health and Aging Trends Study were analyzed. In-person interviews were conducted in 7601 adults ages ≥ 65 years. Prevalence of bothersome pain, activity-limiting pain, locations of pain and usage of pain medicine were evaluated. Demographics, comorbidities, and other covariates were compared between older adults with hypertension and those without. Multivariate regression was further performed to yield adjusted odd ratios. Among 6825 older adults, 4533 of them had a history of hypertension while 2272 of them had not. Prevalence of bothersome pain (57.12% versus 44.81%, p

BackgroundAngiotensin receptor blockers (ARBs) are considered an alternative to angiotensin-converting enzyme inhibitors (ACEIs) in patients with acute myocardial infarction (AMI), but in the era of extensive use of preventive therapies and percutaneous coronary intervention, this has not been adequately evaluated in Asians.MethodsThis retrospective cohort study used data from the Taiwan National Health Insurance Research Database. In total, 52,620 patients initially hospitalized due to AMI between 2002 and 2015 were assessed.ResultsAfter propensity score matching, 14,993 patients each were assigned to ACEI and ARB groups. Patients who received ARBs had significantly lower all-cause mortality (adjusted hazard ratio [aHR]: 0.82; 95% confidence interval [CI]: 0.75-0.90) and hospitalization for heart failure (aHR: 0.92; 95% CI: 0.85-0.99) compared with those who received ACEIs at 18 month follow-up. No significant difference was observed between the two groups in terms of major adverse cardiovascular events (aHR: 098; 95% CI: 0.90-1.07), cardiovascular death (aHR: 0.82; 95% CI: 0.68-1.00), ischemia stroke (aHR: 0.93; 95% CI: 0.77-1.11), and nonfatal myocardial infarction (aHR: 1.04; 95% CI: 0.93-1.17). ARBs showed benefits in many subgroups in terms of all-cause mortality and cardiovascular death.ConclusionsReal-world data demonstrate that ARBs might be associated with lower all-cause mortality and hospitalization for heart failure compared with ACEIs among patients with AMI.

Obesity-related diseases have been on the rise, making it important to promote physical activity. Smart sports watches are popular among young people and can play a role in this regard. This study aims to evaluate the impact of different watch head design types on the visual image of smart sports watches. Based on sales data, seven sports smartwatches with sales of over 2000 units were selected from a sample of 50 as representative samples. A factor analysis and questionnaire survey were used to identify four groups of adjectives that describe watch heads: Sporty and Smart, precious and exquisite, distinctive and avant-garde, and trendy and technological. College students evaluated the seven watches using these adjectives, and using triangular fuzzy mathematics theory, the watches were divided into three categories. The results show that the seven watches had significant differences in appearing "Sporty and Smart" and "precious and exquisite", while the visual imagery of "distinctive and avant-garde" and "trendy and technological" had no significant difference. Based on the grouping analysis of the seven samples, it is concluded that: the slim and compact shape without excessive decoration has a sense of sportiness and simplicity; the square shape combined with left and right buttons has a sense of sportiness and fashion; the unique connection between the round shape, the watch strap, and the watch head, as well as the strong mechanical feeling, have a sense of value. To substantiate the validity of our research findings, we devised three novel specimens based on the morphological elements of sports watches and conducted surveys accordingly. Statistical analysis revealed a fundamental coherence between the performance of these specimens in four stylistic domains and the expression of style-forming elements, confirming the reference value of these findings in the stylistic design of sports smartwatches. This study provides designers with references for improving the design and development efficiency of smart sports watches, promoting their sustainable development.

Patient safety is a paramount concern in the medical field, and advancements in deep learning and Artificial Intelligence (AI) have opened up new possibilities for improving healthcare practices. While AI has shown promise in assisting doctors with early symptom detection from medical images, there is a critical need to prioritize patient safety by enhancing existing processes. To enhance patient safety, this study focuses on improving the medical operation process during X-ray examinations. In this study, we utilize EfficientNet for classifying the 49 categories of pre-X-ray images. To enhance the accuracy even further, we introduce two novel Neural Network architectures. The classification results are then compared with the doctor’s order to ensure consistency and minimize discrepancies. To evaluate the effectiveness of the proposed models, a comprehensive dataset comprising 49 different categories and over 12,000 training and testing sheets was collected from Taichung Veterans General Hospital. The research demonstrates a significant improvement in accuracy, surpassing a 4% enhancement compared to previous studies.

The global population of individuals afflicted with diabetes mellitus has been increasing year by year, and this disease poses a serious threat to human health as well as the economies worldwide. Pancreatic or islet transplantations provide one of the most effective and long-term therapies available to treat diabetes, but the scarcity and quality of pancreatic islets limit their use in treatments. Here, we report the development of a one-step, monolayer culture, and chemical-based protocol that efficiently mediates the differentiation of human adipose-derived stem cells (hADSCs) into insulin-producing cells (IPCs). Our data indicate that hADSCs in monolayer culture that are allowed to differentiate into IPCs are superior to those in suspension cultures with respect to insulin secretion capacity (213-fold increase), cell viability (93.5 ± 3.27% vs. 41.67 ± 13.17%), and response to glucose stimulation. Moreover, the expression of genes associated with pancreatic lineage specification, such as PDX1 , ISL1 , and INS (encoding insulin), were expressed at significantly higher levels during our differentiation protocol (6-fold for PDX1 and ISL1 , 11.5-fold for INS ). Importantly, in vivo studies demonstrated that transplantation with IPCs significantly mitigated hyperglycemia in streptozotocin-induced diabetic rats. Our results indicate that this one-step, rapid protocol increases the efficiency of IPC generation and that the chemical-based approach for IPC induction may reduce safety concerns associated with the use of IPCs for clinical applications, thereby providing a safe and effective cell-based treatment for diabetes.

Image recognition and neuroimaging are increasingly being used to understand the progression of Alzheimer’s disease (AD). However, image data from single-photon emission computed tomography (SPECT) are limited. Medical image analysis requires large, labeled training datasets. Therefore, studies have focused on overcoming this problem. In this study, the detection performance of five convolutional neural network (CNN) models (MobileNet V2 and NASNetMobile (lightweight models); VGG16, Inception V3, and ResNet (heavier weight models)) on medical images was compared to establish a classification model for epidemiological research. Brain scan image data were collected from 99 subjects, and 4711 images were used. Demographic data were compared using the chi-squared test and one-way analysis of variance with Bonferroni’s post hoc test. Accuracy and loss functions were used to evaluate the performance of CNN models. The cognitive abilities screening instrument and mini mental state exam scores of subjects with a clinical dementia rating (CDR) of 2 were considerably lower than those of subjects with a CDR of 1 or 0.5. This study analyzed the classification performance of various CNN models for medical images and proved the effectiveness of transfer learning in identifying the mild cognitive impairment, mild AD, and moderate AD scoring based on SPECT images.

Emotion detection is a fundamental component in the field of Affective Computing. Proper recognition of emotions can be useful in improving the interaction between humans and machines, for instance, with regard to designing effective user interfaces. This study aims to understand the relationship between emotion and pupil dilation. The Tobii Pro X3-120 eye tracker was used to collect pupillary responses from 30 participants exposed to content designed to evoke specific emotions. Six different video scenarios were selected and presented to participants, whose pupillary responses were measured while watching the material. In total, 16 data features (8 features per eye) were extracted from the pupillary response distribution during content exposure. Through logistical regression, a maximum of 76% classification accuracy was obtained through the measurement of pupillary response in predicting emotions classified as fear, anger, or surprise. Further research is required to precisely calculate pupil size variations in relation to emotionally evocative input in affective computing applications.

Abstract Background Columbianadin (CBN) is one of the main coumarin constituents isolated from Angelica pubescens. The pharmacological value of CBN is well demonstrated, especially in the prevention of several cancers and analgesic activity. A striking therapeutic target for arterial thrombosis is inhibition of platelet activation because platelet activation significantly contributes to these diseases. The current study examined the influence of CBN on human platelet activation in vitro and vascular thrombotic formation in vivo. Methods Aggregometry, immunoblotting, immunoprecipitation, confocal microscopic analysis, fibrin clot retraction, and thrombogenic animals were used in this study. Results CBN markedly inhibited platelet aggregation in washed human platelets stimulated only by collagen, but was not effective in platelets stimulated by other agonists such as thrombin, arachidonic acid, and U46619. CBN evidently inhibited ATP release, intracellular ([Ca2+]i) mobilization, and P-selectin expression. It also inhibited the phosphorylation of phospholipase C (PLC)γ2, protein kinase C (PKC), Akt (protein kinase B), and mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase [ERK] 1/2 and c-Jun N-terminal kinase [JNK] 1/2, but not p38 MAPK) in collagen-activated platelets. Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, reversed the CBN-mediated inhibition of platelet aggregation. CBN had no significant effect in triggering vasodilator-stimulated phosphoprotein phosphorylation. Moreover, it markedly hindered integrin αIIbβ3 activation by interfering with the binding of PAC-1; nevertheless, it had no influences on integrin αIIbβ3-mediated outside-in signaling such as adhesion number and spreading area of platelets on immobilized fibrinogen as well as thrombin-stimulated fibrin clot retraction. Additionally, CBN did not attenuate FITC-triflavin binding or phosphorylation of proteins, such as integrin β3, Src, and focal adhesion kinase, in platelets spreading on immobilized fibrinogen. In experimental mice, CBN increased the occlusion time of thrombotic platelet plug formation. Conclusion This study demonstrated that CBN exhibits an exceptional activity against platelet activation through inhibition of the PLCγ2-PKC cascade, subsequently suppressing the activation of Akt and ERKs/JNKs and influencing platelet aggregation. Consequently, this work provides solid evidence and considers that CBN has the potential to serve as a therapeutic agent for the treatment of thromboembolic disorders.

Shotgun metagenomic sequencing is a powerful approach to study microbiomes in an unbiased manner and of increasing relevance for identifying novel enzymatic functions. However, the potential of metagenomics to relate from microbiome composition to function has thus far been underutilized. Here, we introduce the Metagenomics Genome-Phenome Association (MetaGPA) study framework, which allows linking genetic information in metagenomes with a dedicated functional phenotype. We applied MetaGPA to identify enzymes associated with cytosine modifications in environmental samples. From the 2365 genes that met our significance criteria, we confirm known pathways for cytosine modifications and proposed novel cytosine-modifying mechanisms. Specifically, we characterized and identified a novel nucleic acid-modifying enzyme, 5-hydroxymethylcytosine carbamoyltransferase, that catalyzes the formation of a previously unknown cytosine modification, 5-carbamoyloxymethylcytosine, in DNA and RNA. Our work introduces MetaGPA as a novel and versatile tool for advancing functional metagenomics.

Post-traumatic stress disorder (PTSD) is a unique clinical mental abnormality presenting a cluster of symptoms in which patients primarily experience flashbacks, nightmares and uncontrollable thoughts about the event that triggered their PTSD. Patients with PTSD may also have comorbid depression and anxiety in an intractable and long-term course, which makes establishing a comprehensive treatment plan difficult and complicated. The present article reviews current pharmacological manipulations for adjusting abnormal fear memory. The roles of the central monoaminergic systems (including serotonin, norepinephrine and dopamine) within the fear circuit areas and the involvement of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor (GR) are explored based on attempts to integrate current clinical and preclinical basic studies. In this review, we explain how these therapeutic paradigms function based on their connections to stages of the abnormal fear memory process from condition to extinction. This may provide useful translational interpretations for clinicians to manage PTSD.

Abstract Background Traumatic experience may lead to various psychological sequelae including the unforgettable trauma-associated memory as seen in posttraumatic stress disorder (PTSD), with a mechanism of impaired fear extinction due to biological imbalance among hypothalamic-pituitary-adrenal (HPA) axis and fear circuit areas such as medial prefrontal cortex (mPFC), hippocampus, and amygdala. Recently the impaired sociability seen in PTSD patients received great attention and the involvement of oxytocin (OXT) mediation is worth being investigated. This study examined whether the trauma-altered prosocial behavior can be modulated by OXT manipulation and its relationship with corticotropin-releasing hormone (CRH) signaling. Methods Male rats previously exposed to a single prolonged stress (SPS) were evaluated for their performance in social choice test (SCT) and novel object recognition test (NORT) following the introduction of intranasal oxytocin (OXT) and OXT receptor antagonist atosiban (ASB). OXT receptors (OXTR) and CRH receptors (CRHR1, CRHR2) were quantified in both protein and mRNA levels in medial prefrontal cortex (mPFC), hippocampus, and amygdala. Results SPS reduced inclination of rats staying at the sociable place with performing less prosocial contacts. OXT can amend the deficit but this effect was blocked by ASB. Expression of OXTR became reduced following SPS in mPFC and amygdala, the latter exhibited higher therapeutic specificity to OXT. Expression of CRHR1 appeared more sensitive than CRHR2 to SPS, higher CRHR1 protein levels were found in mPFC and amygdala. Conclusion Psychological trauma-impaired sociability is highly associated with OXT signaling pathway. Intranasal OXT restored both the SPS-impaired prosocial contacts and the SPS-reduced OXTR expressions in mPFC and amygdala. OXT may have therapeutic potential to treat PTSD patients with impaired social behaviors.

Objective: Cognitive and somatic symptoms were vital factors in developing personalized treatment of depressive disorder. The study aimed to evaluate the following: (1) the cognitive and somatic symptoms of premenstrual dysphoric disorder (PMDD) in the early luteal (EL) and later luteal (LL) phase; and (2) their association with depression and functional impairment of PMDD. Methods: We prospectively evaluated executive function, emotion regulation, cognitive and somatic symptoms, and depression in the EL and LL phases in women with PMDD. Sixty-three women with PMDD and 53 healthy controls completed Simon’s task and questionnaire to assess emotion regulation, inattention, fatigue, insomnia, and depression. Results: Women with PMDD had a poor performance in Simon’s task during the LL phase. They were less likely to exercise cognitive reappraisal during EL and LL phases. Their cognitive reappraisal positively correlated with executive function and negatively associated with depression. In the LL phase, they also experience higher inattention, insomnia, and fatigue, which correlate with the depression and functional impairment of PMDD. Inattention is the most associated factor of PMDD and functional impairment in controlling depression. Conclusion: Executive function was impaired in women with PMDD during the LL phase. Its performance correlated positively with emotion regulation and negatively with depression. The association between inattention and PMDD functional impairment indicates that evaluation and intervention for cognitive impairment were essential in treating women with PMDD. Further studies were required to elucidate the possible etiology underlying these associations.

Objectives To evaluate the association between night-shift work exposure and visual health, this cross-sectional study utilized visual acuity, a surrogate measure for visual function, as a parameter, and performed an analysis comparing visual acuity between daytime and nighttime employees in an electronics manufacturing company. Material and Methods Data of personal histories, occupational records, physical examinations and blood tests was obtained from the electronic health records of workers. The total of 8280 workers including 3098 women and 5182 men, wearing their own daily used eyeglasses, were included in the final analysis. The mean age of the sample population was 34.7 years old (standard deviation = 5.4 years). All workers were divided into 3 work categories – consistent daytime worker (CDW), day-shift worker (DSW) and night-shift worker (NSW). The check-up results of glasses-corrected visual acuity (c-VA) were utilized to classify individuals as good (≥ 1.2, both eyes) and inadequate (< 0.8, the better eye) c-VA. Results Consistent daytime workers had the highest rate of good c-VA (42.5% vs. 25.1% DSW and 21.1% NSW, p = 0.047). Night-shift workers had the highest rate of inadequate c-VA (CDW, DSW and NSW: 2.6%, 6.2%, and 7.6%, p = 0.03) among all employees. After controlling for covariates, NSW were found at an increased risk for inadequate c-VA (adjusted odds ratio (ORa) = 2.7, 95% confidence interval (CI): 2.0–3.6, vs. CDW), and less likely to have good c-VA (ORa = 0.4, 95% CI: 0.4–0.5, vs. CDW). Conclusions Night-shift work is moderately associated with compromised visual acuity of employees in this electronics manufacturing company. Int J Occup Med Environ Health 2018;31(1):71–79

Patients who undergo splenectomy are at a high risk of infection. We aimed to investigate the rate of pneumonia in patients who underwent splenectomy, specifically comparing those who had splenectomy due to spleen injury and those who had it for other reasons. A population-based cohort study was conducted. Overall, 17,498 patients who underwent splenectomy between 2000 and 2015 were enrolled, including 11,817 patients with a history of spleen injury and 5681 controls without spleen injury. The incidence of pneumonia was calculated at the end of 2016. A multivariable Cox proportional hazards regression model was used to compare the hazard ratio with 95% CI for pneumonia associated with the spleen injury-caused splenectomy and splenectomy due to other causes. The crude HR for patients with splenectomy due to spleen injury to develop pneumonia was 1.649. After adjusting for covariates, the adjusted hazard ratio was 1.567. There were statistically significant differences in all subgroups, except for the group with a tracking duration >10 years. We found an increase in pneumonia risk in the ‘spleen injury’ group when comparing it to that of the ‘other causes’ group, regardless of age, sex, and area of residence.