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Jiun-Ling Wang,1,* Chih-Feng Kuo,2,* Che-Ming Yeh,3 Jung-Ren Chen,4 Ming-Fang Cheng,5–7 Chih-Hsin Hung3 1Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC; 2Department of Nursing, I-Shou University, Kaohsiung, Taiwan, ROC; 3Department of Chemical Engineering and Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, Taiwan, ROC; 4Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan, ROC; 5Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC; 6School of Medicine, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; 7Department of Nursing, Fooyin University, Kaohsiung, Taiwan, ROC *These authors contributed equally to this work Purpose: Few effective antibiotics are available for treating extensively drug-resistant Acinetobacter baumannii (XDRAB) sepsis. Phage therapy may show potential in treating XDRAB infections. Materials and methods: We studied ϕkm18p phage therapy in BALB/c and C57BL/6 mice models of XDRAB bacteremia. Results: We observed survival rates of nearly 100% in groups given phage therapy concurrent with XDRAB at different multiplicities of infection. In mice that received phage therapy after a 1-hour delay, the survival rate decreased to about 50%. The bacterial load in the blood decreased from 108 to 102 and 103 colony-forming units (CFU)/mL in the concurrent treatment group. In the phage therapy group, the levels of the cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), were low at 3 hours after infection. Although some phage-resistant mutants were isolated after phage therapy, a cytotoxicity study showed that they had reduced fitness. Conclusion: Phage therapy in XDRAB bacteremia increased the animal survival rates, decreased the bacteremia loads, and decreased the levels of inflammatory markers TNF-α and IL-6. However, the reduced therapeutic effect with delayed administrations may be a concern in developing a successful phage therapy for treating acute infections of multidrug-resistant pathogens. Keywords: Acinetobacter baumannii, survival rates, bacteria, multiple antimicrobial drug resistance, phage therapy

Hematopoietic stem cell transplantation (HSCT) is pivotal in treating hematologic disorders, yet it poses the risk of post-transplantation pancytopenia. Prophylactic platelet transfusions are often administered to mitigate this risk. Utilizing practical markers, such as immature platelet fraction (IPF), to predict hematopoietic recovery in advance could reduce unnecessary prophylactic transfusions. Our prospective study, involving 53 HSCT patients at Taipei Veterans General Hospital between September 2022 and May 2023, utilized the Sysmex XN analyzer to assess peripheral blood cell parameters. We investigated whether IPF could predict platelet recovery early, determined the optimal cut-off value, and compared platelet usage. Neutrophil and platelet engraftment occurred 10 (median; range: 10-12) and 15 (median; range: 15-18) days post-HSCT. Notably, 71.7% of patients exhibited an IPF increase exceeding 2% before platelet recovery. The optimal cut-off IPF on day 10 for predicting platelet recovery within five days was 2.15% (specificity 0.89, sensitivity 0.65). On average, patients received 3.89 units of post-transplantation platelet transfusion. Our results indicate that IPF serves as a predictive marker for platelet engraftment, peaking before the increase in platelet count. This insight aids clinicians in assessing the need for prophylactic platelet transfusions. Integrating reference IPF values alongside platelet counts enhances the accuracy of evaluating a patient's hematopoietic recovery status. Anticipating the timing of platelet recovery optimizes blood product usage and mitigates transfusion reaction risks., (© 2024. The Author(s).)

Bendamustine is used to treat lymphoma with excellent efficacy but is known for its immunosuppressive effect. Cytomegalovirus (CMV) reactivation after bendamustine use has been reported. We aim to address the impact of CMV infection in lymphoma patients treated with bendamustine-containing regimens. We retrospectively analyzed lymphoma patients at Taipei Veterans General Hospital in Taiwan between September 1, 2010, and April 30, 2022. Clinically significant CMV infection (CS-CMVi) was defined as the first CMV reactivation after bendamustine use necessitating CMV therapy. Patients' baseline characteristics and laboratory data were recorded. The primary endpoint of the study was CS-CMVi. A time-dependent covariate Cox regression model was used to estimate the risk factors of CS-CMVi and mortality. A total of 211 lymphoma patients treated with bendamustine were enrolled. Twenty-seven (12.8%) had CS-CMVi. The cumulative incidence was 10.1 per 100 person-years during the three-year follow-up period. In the multivariate analysis, lines of therapy before bendamustine ≥ 1 (95% CI 1.10-24.76), serum albumin < 3.5 g/dL (95% CI 2.63-52.93), and liver disease (95% CI 1.51-28.61) were risk factors for CS-CMVi. In conclusion, CS-CMVi (95% confidence interval [CI] 1.23-10.73) was one of the major independent risk factors of mortality. Lines of therapy before bendamustine ≥ 1, hypoalbuminemia, and liver disease were risk factors for CS-CMVi in lymphoma patients treated with bendamustine., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance., Methods: MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro., Results: Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner., Conclusion: Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation., (© 2024. The Author(s).)

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34 + cells collected ≥ 4 × 10 6 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m 2 ; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials., (© 2024. The Author(s).)

Recent advancements in pre-trained language-image models have ushered in a new era of visual comprehension. Leveraging the power of these models, this article tackles two issues within the realm of visual analytics: (1) the efficient exploration of large-scale image datasets and identification of data biases within them; (2) the evaluation of image captions and steering of their generation process. On the one hand, by visually examining the captions generated from language-image models for an image dataset, we gain deeper insights into the visual contents, unearthing data biases that may be entrenched within the dataset. On the other hand, by depicting the association between visual features and textual captions, we expose the weaknesses of pre-trained language-image models in their captioning capability and propose an interactive interface to steer caption generation. The two parts have been coalesced into a coordinated visual analytics system, fostering the mutual enrichment of visual and textual contents. We validate the effectiveness of the system with domain practitioners through concrete case studies with large-scale image datasets.

Bladder cancer stands as a prevailing neoplasm among men globally, distinguished for its pronounced malignancy attributed to invasiveness and metastatic proclivity. Tannic acid (TA), an organic compound in many plants, has garnered recent attention for its discernible anti-mutagenic attributes. This investigation endeavored to scrutinize the repercussions of TA on grade II bladder cancer, with a concerted focus on unraveling its anti-cancer mechanisms. The cytotoxic effects of TA on grade II bladder cancer cells were investigated using multiple techniques, including MTT assay, flow cytometry, TUNEL assay, and western blot. Our findings revealed that elevated concentrations of TA induced cytotoxic effects in grade II bladder cancer cells. Both flow cytometry and the TUNEL assay substantiated the dose-dependent capacity of TA to prompt apoptosis. Western blot analysis corroborated that TA treatment in bladder cancer cells resulted in the upregulation of cleaved caspase-3 expression and PARP. Furthermore, heightened TA dosage elicited an augmentation in the expression of pro-apoptotic proteins, namely Bax and Bak, alongside a reduction in the expression of the anti-apoptotic protein Bcl-2 within bladder cancer cells. This study confirms TA as a potential anticancer agent, demonstrably diminishing the viability of bladder cancer cells. TA exerts cytotoxicity through the activation of mitochondrial apoptotic pathways. Specifically, TA initiates the cleavage of PARP and caspase-3, concurrently augmenting the expression of pro-apoptotic proteins to facilitate apoptosis. Collectively, the present study indicates that TA effectively impedes the proliferation of bladder cancer cells by instigating apoptosis through the intrinsic mitochondrial pathway., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The literature on the association between diabetes severity and cancer risk is limited and inconclusive. The study aimed to evaluate the association between the adapted Diabetes Complications Severity Index (aDCSI) and the duration of type 2 diabetes and cancer risk., Methods: Patients ages 20 years or older with newly diagnosed type 2 diabetes between January 1, 2007, and December 31, 2011, were identified from Taiwan National Health Insurance claims data. Standardized incidence ratios (SIR) were calculated to compare cancer incidence in people with diabetes with that in the general population. Poisson regression was used to examine whether SIRs differed by age, sex, aDSCI, and duration of diabetes., Results: A total of 756,547 patients were included, with a median follow-up of 8.8 years. Excluding the first year after diagnosis, the SIR for overall cancer was 1.18 [95% confidence interval (CI) 1.17-1.19]. Higher aDCSI was associated with increased SIRs for overall [SIR ratio 1.03 (1.02-1.03) per point increase], head and neck (1.03; 1.01-1.04), liver (1.04; 1.03-1.05), pancreas (1.03; 1.00-1.05), kidney (1.13; 1.10-1.15), and leukemia (1.09; 1.06-1.13). There was no association between aDCSI and colorectal, extrahepatic biliary tract, uterus and thyroid cancer, and a negative association with breast cancer (0.97; 0.95-0.98). Type 2 diabetes duration was associated with increased SIRs for overall [1.01 (1.00-1.02) per year increase], head and neck (1.03; 1.01-1.05), and liver cancer (1.04; 1.02-1.05)., Conclusions: The heterogeneity in the association between diabetes severity and diabetes-related cancers suggests diverse underlying connections., Impact: Adopting distinct approaches in further research and prevention strategies for different kinds of diabetes-related cancers is important., (©2024 American Association for Cancer Research.)

Background: Paclitaxel (PTX), which is a first-line chemotherapy drug used to treat various types of cancers, exhibits peripheral neuropathy as a common side effect that is difficult to treat. Protein arginine methyltransferase 5 (PRMT 5) is a key regulator of the chemotherapy response, as chemotherapy drugs induce PRMT5 expression. However, little is known about the PRMT5-mediated epigenetic mechanisms involved in PTX-induced neuropathic allodynia., Methods: Sprague-Dawley rats were intraperitoneally given PTX to induce neuropathic pain. Biochemical analyses were conducted to measure the protein expression levels in the dorsal root ganglion (DRG) of the animals. The von Frey test and hot plate test were used to evaluate nociceptive behaviors., Results: PTX increased the PRMT5 (mean difference [MD]: 0.68, 95% confidence interval [CI], 0.88-0.48; P < .001 for vehicle)-mediated deposition of histone H3R2 dimethyl symmetric (H3R2me2s) at the transient receptor potential vanilloid 1 ( Trpv1 ) promoter in the DRG. PRMT5-induced H3R2me2s recruited WD repeat domain 5 (WDR5) to increase trimethylation of lysine 4 on histone H3 (H3K4me3) at Trpv1 promoters, thus resulting in TRPV1 transcriptional activation (MD: 0.65, 95% CI, 0.82-0.49; P < .001 for vehicle) in DRG in PTX-induced neuropathic pain. Moreover, PTX increased the activity of NADPH oxidase 4 (NOX4) (MD: 0.66, 95% CI, 0.81-0.51; P < .001 for vehicle), PRMT5-induced H3R2me2s, and WDR5-mediated H3K4me3 in the DRG in PTX-induced neuropathic pain. Pharmacological antagonism and the selective knockdown of PRMT5 in DRG neurons completely blocked PRMT5-mediated H3R2me2s, WDR5-mediated H3K4me3, or TRPV1 expression and neuropathic pain development after PTX injection. Remarkably, NOX4 inhibition not only attenuated allodynia behavior and reversed the above-mentioned signaling but also reversed NOX4 upregulation via PTX., Conclusions: Thus, the NOX4/PRMT5-associated epigenetic mechanism in DRG has a dominant function in the transcriptional activation of TRPV1 in PTX-induced neuropathic pain., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Acute promyelocytic leukemia (APL) is a highly curable hematologic malignancy in the era of all-trans retinoic acid (ATRA) combination treatment. However, only a modest change in early mortality rate has been observed despite the wide availability of ATRA. In addition to the clinical characteristics of APL patients, studies on the hospital volume-outcome relationship and the physician volume-outcome relationship remained limited. We aim to evaluate the association between hospital and physician volume and the early mortality rate among APL patients. The patients were collected from Taiwan's National Health Insurance Research Database (NHIRD). Early mortality is defined as death within 30 days of diagnosis. Patients were categorized into four groups according to individual cumulative hospital and physician volume. The risk of all-cause mortality in APL patients with different cumulative volume groups was compared using a Cox proportional hazard model. The probability of overall survival was estimated using the Kaplan-Meier method. All 741 patients were divided into four quartile volume groups. In the multivariate analysis, only physician volume was significantly associated with early mortality rate. The physician volume of the highest quartile was a protective factor for early mortality compared with the physician volume of the lowest quartile (HR 0.10, 95% CI 0.02-0.65). Hospital characteristics were not associated with early mortality. In the sensitivity analyses, the results remained consistent using two other different definitions of early mortality. Higher physician volume was independently associated with lower early mortality, while hospital volume was not. Enhancing the clinical expertise of low-volume physicians may ensure better outcomes., (© 2024. The Author(s).)

Colorectal cancer (CRC) patients who receive cancer surgeries from higher-volume providers may have better outcomes. However, the definitions of surgical volume may affect the results. We aim to analyze the effects of different definitions of surgical volume on patient outcomes. We conducted a nationwide population-based study in Taiwan that enrolled all patients who underwent definitive surgery for newly diagnosed CRC. We used three common definitions of surgical volume: total volume means the total surgical number conducted by the same provider during the study period; cumulative volume was calculated as the number of operations the surgeon performed before the index procedure; annual volume was calculated as the number of times the surgeon had been responsible for surgery during the index year. In this study, we included 100,009 newly diagnosed CRC patients, including 55.8% males, of median age 66 years at diagnosis (range 20-105 years). After adjustment for the patient and provider characteristics, we found that CRC patients receiving definitive surgery by higher-volume providers had better outcomes, especially where surgeon volume may play a more important role than hospital volume. The cumulative volume could predict the 5-year mortality of the study cohort better than the total and annual volume., (© 2024. The Author(s).)

The neurohormone melatonin (MLT) demonstrates promising potential in ameliorating neuropathic pain induced by paclitaxel (PTX) chemotherapy. However, little is known about its protective effect on dorsal root ganglion (DRG) neurons in neuropathic pain resulting from the chemotherapeutic drug PTX. Here, PTX-treated rats revealed that intrathecal administration of MLT dose-dependently elevated hind paw withdrawal thresholds and latency, indicating that MLT significantly reversed PTX-induced neuropathic pain. Mechanistically, the analgesic effects of MLT were found to be mediated via melatonin receptor 2 (MT2), as pretreatment with an MT2 receptor antagonist inhibited these effects. Moreover, intrathecal MLT injection reversed the pNEK2-dependent epigenetic program induced by PTX. All of the effects caused by MLT were blocked by pretreatment with an MT2 receptor-selective antagonist, 4P-PDOT. Remarkably, multiple MLT administered during PTX treatment (PTX+MLTs) exhibited not only rapid but also lasting reversal of allodynia/hyperalgesia compared to single-bolus MLT administered after PTX treatment (PTX+MLT). In addition, PTX+MLTs exhibited greater efficacy in reversing PTX-induced alterations in pRSK2, pNEK2, JMJD3, H3K27me3, and TRPV1 expression and interaction in DRG neurons than PTX+MLT. These results indicated that MLT administered during PTX treatment reduced the incidence and/or severity of neuropathy and had a better inhibitory effect on the pNEK2-dependent epigenetic program compared to MLT administered after PTX treatment. In conclusion, MLT/MT2 is a promising therapy for the treatment of pNEK2-dependent painful neuropathy resulting from PTX treatment. MLT administered during PTX chemotherapy may be more effective in the prevention or reduction of PTX-induced neuropathy and maintaining quality.

Background: The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of patients. The mechanistic role for NIMA-related kinase 2 (NEK2) in the progression of PTX-induced neuropathic pain has not been established., Methods: Adult male Sprague-Dawley rats intraperitoneally received PTX to induce neuropathic pain. The protein expression levels in the dorsal root ganglion (DRG) of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by von Frey tests and hot plate tests., Results: PTX increased phosphorylation of the important microtubule dynamics regulator NEK2 in DRG neurons and induced profound neuropathic allodynia. PTX-activated phosphorylated NEK2 (pNEK2) increased jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, to specifically catalyze the demethylation of the repressive histone mark H3 lysine 27 trimethylation (H3K27me3) at the Trpv1 gene, thereby enhancing transient receptor potential vanilloid subtype-1 (TRPV1) expression in DRG neurons. Moreover, the pNEK2-dependent PTX response program is regulated by enhancing p90 ribosomal S6 kinase 2 (RSK2) phosphorylation. Conversely, intrathecal injections of kaempferol (a selective RSK2 activation antagonist), NCL 00017509 (a selective NEK2 inhibitor), NEK2-targeted siRNA, GSK-J4 (a selective JMJD3 inhibitor), or capsazepine (an antagonist of TRPV1 receptor) into PTX-treated rats reversed neuropathic allodynia and restored silencing of the Trpv1 gene, suggesting the hierarchy and interaction among phosphorylated RSK2 (pRSK2), pNEK2, JMJD3, H3K27me3, and TRPV1 in the DRG neurons in PTX-induced neuropathic pain., Conclusions: pRSK2/JMJD3/H3K27me3/TRPV1 signaling in the DRG neurons plays as a key regulator for PTX therapeutic approaches., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

With the fast-growing number of classification models being produced every day, numerous model interpretation and comparison solutions have also been introduced. For example, LIME [1] and SHAP [2] can interpret what input features contribute more to a classifier's output predictions. Different numerical metrics (e.g., accuracy) can be used to easily compare two classifiers. However, few works can interpret the contribution of a data feature to a classifier in comparison with its contribution to another classifier. This comparative interpretation can help to disclose the fundamental difference between two classifiers, select classifiers in different feature conditions, and better ensemble two classifiers. To accomplish it, we propose a learning-from-disagreement (LFD) framework to visually compare two classification models. Specifically, LFD identifies data instances with disagreed predictions from two compared classifiers and trains a discriminator to learn from the disagreed instances. As the two classifiers' training features may not be available, we train the discriminator through a set of meta-features proposed based on certain hypotheses of the classifiers to probe their behaviors. Interpreting the trained discriminator with the SHAP values of different meta-features, we provide actionable insights into the compared classifiers. Also, we introduce multiple metrics to profile the importance of meta-features from different perspectives. With these metrics, one can easily identify meta-features with the most complementary behaviors in two classifiers, and use them to better ensemble the classifiers. We focus on binary classification models in the financial services and advertising industry to demonstrate the efficacy of our proposed framework and visualizations.

Aberrant expression of UNC13C (Unc-13 Homolog C) has been observed during the progression of oral squamous cell carcinoma. However, the expression pattern and clinical relevance of UNC13C in Hepatocellular carcinoma (HCC) remain to be elucidated. The purpose of this study is to examine UNC13C expression in HCC and explore its role in clinicopathological factor or prognosis in HCC. Two hundred and sixty-five patients diagnosed with HCC were included in the present study. The expression of UNC13C in HCC tissues was analyzed by immunohistochemistry analysis. The relationship between UNC13C protein and clinicopathological characteristics in HCC was investigated. Moreover, the high expression of UNC13C was significantly correlated with T stage, AJCC stage and overall survival rates. Cox regression analysis identified UNC13C as an independent prognostic indicator for HCC patients. UNC13C might be a prognostic biomarker and therapeutic target in HCC. Further studies with larger sample sets are needed to understand the clinical implications of UNC13C in hepatocellular carcinoma., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Postacute care (PAC) heavily relies on effective connection between acute and postacute providers. However, little is known about whether and to what extent providers' patient-sharing relationships influence patient outcomes. This study aimed to examine whether patients with stroke who were discharged to PAC hospitals with which the originating hospital had a strong patient-sharing relationship have a lower rate of rehospitalization and lower mortality risk., Study Design: This population-based retrospective cohort study used the Taiwan National Health Insurance Research Database. A total of 1988 patients initially hospitalized for stroke between July 1, 2017, and June 30, 2018, who were newly discharged to 193 PAC hospitals from 175 originating hospitals were included., Methods: We described the partnership between originating acute hospitals and PAC hospitals using tie strength and referral concentration. The main outcome included unplanned readmission and mortality. Hierarchical logistic regression analysis and Cox proportional hazards models were applied., Results: A dose-response relationship was clearly observed between tie strength and patient outcomes. Patients with stroke who were discharged to a PAC hospital that had the strongest tie strength with the originating hospital were least likely to be readmitted and had the lowest mortality risk. Moreover, patients who received care from hospital pairs with highly or moderately concentrated referrals also had lower readmission and mortality risk., Conclusions: A greater number of shared patients and a more concentrated referral linkage between acute and PAC providers may reduce potential adverse outcomes in PAC patients. Instead of attaining more partners, PAC policies should encourage providers to strengthen their patient-sharing relationship with their existing PAC partners.

Introduction: Mucoepidermoid carcinoma (MEC) is a rare malignancy of primary endobronchial lesions in children. Early diagnosis is crucial for the disease, but it is often misdiagnosed as asthma or lung infection. Chest computed tomography and bronchoscopy are the most important diagnostic tools. Surgical resection is the current treatment of choice for low-grade MEC. In the past, lobectomy, sleeve lobectomy, or segmental resections were the most standard surgeries. Endoscopic treatment was used for lung preservation and effectual removal of the lesions., Methods: A retrospective study of pediatric patients with primary endobronchial lesions who underwent rigid bronchoscopic laser ablation since 2010 was conducted. Pre-operative images, endoscopic pictures, post-operative images, histological analyses, and patients' clinical conditions were recorded and illustrated., Results: Four patients were enrolled. Three patients presented initially with cough or hemoptysis. The lesion sites were the bronchus of the left upper lobe, left lower lobe, left main bronchus, and trachea. All patients underwent bronchoscopic laser ablation for tumor excision without anatomical resection. No major surgical complications were encountered. All patients survived without recurrence after a mean postoperative follow-up of 4.5 years (3-6 years)., Conclusion: Video-assisted rigid endoscopic laser ablation for pediatric low-grade endobronchial MEC is a feasible, effective, and safe method. Close follow-up is essential for lung preservation management., Evidence Level: Level IV., Type of Study: Case series with no comparison group., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Nonsense-mediated messenger RNA (mRNA) decay increases targeted mRNA degradation and has been implicated in the regulation of gene expression in neurons. The authors hypothesized that nonsense-mediated μ-opioid receptor mRNA decay in the spinal cord is involved in the development of neuropathic allodynia-like behavior in rats., Methods: Adult Sprague-Dawley rats of both sexes received spinal nerve ligation to induce neuropathic allodynia-like behavior. The mRNA and protein expression contents in the dorsal horn of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by the von Frey test and the burrow test., Results: On Day 7, spinal nerve ligation significantly increased phosphorylated upstream frameshift 1 (UPF1) expression in the dorsal horn (mean ± SD; 0.34 ± 0.19 in the sham ipsilateral group vs. 0.88 ± 0.15 in the nerve ligation ipsilateral group; P < 0.001; data in arbitrary units) and drove allodynia-like behaviors in rats (10.58 ± 1.72 g in the sham ipsilateral group vs. 1.19 ± 0.31 g in the nerve ligation ipsilateral group, P < 0.001). No sex-based differences were found in either Western blotting or behavior tests in rats. Eukaryotic translation initiation factor 4A3 (eIF4A3) triggered SMG1 kinase (0.06 ± 0.02 in the sham group vs. 0.20 ± 0.08 in the nerve ligation group, P = 0.005, data in arbitrary units)-mediated UPF1 phosphorylation, leading to increased nonsense-mediated mRNA decay factor SMG7 binding and µ-opioid receptor mRNA degradation (0.87 ± 0.11-fold in the sham group vs. 0.50 ± 0.11-fold in the nerve ligation group, P = 0.002) in the dorsal horn of the spinal cord after spinal nerve ligation. Pharmacologic or genetic inhibition of this signaling pathway in vivo ameliorated allodynia-like behaviors after spinal nerve ligation., Conclusions: This study suggests that phosphorylated UPF1-dependent nonsense-mediated μ-opioid receptor mRNA decay is involved in the pathogenesis of neuropathic pain., (Copyright © 2023, the American Society of Anesthesiologists. All Rights Reserved.)

Vision transformer (ViT) expands the success of transformer models from sequential data to images. The model decomposes an image into many smaller patches and arranges them into a sequence. Multi-head self-attentions are then applied to the sequence to learn the attention between patches. Despite many successful interpretations of transformers on sequential data, little effort has been devoted to the interpretation of ViTs, and many questions remain unanswered. For example, among the numerous attention heads, which one is more important? How strong are individual patches attending to their spatial neighbors in different heads? What attention patterns have individual heads learned? In this work, we answer these questions through a visual analytics approach. Specifically, we first identify what heads are more important in ViTs by introducing multiple pruning-based metrics. Then, we profile the spatial distribution of attention strengths between patches inside individual heads, as well as the trend of attention strengths across attention layers. Third, using an autoencoder-based learning solution, we summarize all possible attention patterns that individual heads could learn. Examining the attention strengths and patterns of the important heads, we answer why they are important. Through concrete case studies with experienced deep learning experts on multiple ViTs, we validate the effectiveness of our solution that deepens the understanding of ViTs from head importance, head attention strength, and head attention pattern.

Oral squamous cell carcinoma (OSCC) has a high recurrence rate and poor prognosis. Hispolon, a polyphenolic compound with antiviral, antioxidant, and anticancer activities, is a potential chemotherapy agent. However, few studies have investigated the anti-cancer mechanism of hispolon in oral cancer. This present study used the cell viability assay, clonogenic assay, fluorescent nuclear staining, and flow cytometry assay to analyse the apoptosis-inducing effects of hispolon in OSCC cells. After hispolon treatment, the apoptotic initiators, cleaved caspase-3, -8, and - 9, were upregulated, whereas the cellular inhibitor of apoptosis protein-1 (cIAP1) was downregulated. Furthermore, a proteome profile analysis using a human apoptosis array revealed the overexpression of heme oxygenase-1 (HO-1) by hispolon, which was determined to be involved in caspase-dependent apoptosis. Moreover, cotreatment with hispolon and mitogen-activated protein kinase (MAPK) inhibitors revealed that hispolon induces apoptosis in OSCC cells through activation of the c-Jun N-terminal kinase (JNK) pathway and not the extracellular signal-regulated kinase (ERK) or p38 pathway. These findings indicate that hispolon may exert an anticancer effect on oral cancer cells by upregulating HO-1 and inducing caspase-dependent apoptosis by activating the JNK pathway., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Ceramides, structural components of the cell, are known to play a range of roles in glucose metabolism and apoptosis. C 16 -ceramide, an abundant molecular species of endogenous ceramide, has not had its influence on learning and memory explored. We administered C 16 -ceramide to mice immediately after weaning and examined the learning and memory behavior of these mice during adulthood. Mice given C 16 -ceramide early in life showed improved adult learning/short-term memory behavior without affecting their glucose metabolism. Looking for a plausible mechanism for this, we found that calcium influx, CaMKII/CREB, and the Erk-relevant signaling transduction are increased after C 16 -ceramide stimulation in primary neurons in vitro . Possible downstream epigenetic molecular events, such as H3K4 methylation and Egr-1 abundance, were also found to be upregulated. Utilizing J20 mice, an Alzheimer disease mice model in which mice were injected after weaning with C 16 -ceramide, we found that these mice also show improved learning and short-term memory behavior when assessed by the Morris water maze test. Taken together, giving C 16 -ceramide early in life would seem to benefit learning and short-term memory behavior during adulthood.

Introduction: Adapted Diabetes Complications Severity Index (aDCSI) is a commonly used severity measure based on the number and severity of diabetes complications using diagnosis codes. The validity of aDCSI in predicting cause-specific mortality has yet to be verified. Additionally, the performance of aDCSI in predicting patient outcomes compared with Charlson Comorbidity Index (CCI) remains unknown., Research Design and Methods: Patients aged 20 years or older with type 2 diabetes prior to January 1, 2008 were identified from the Taiwan National Health Insurance claims data and were followed up until December 15, 2018. Complications for aDCSI including cardiovascular, cerebrovascular and peripheral vascular disease, metabolic disease, nephropathy, retinopathy and neuropathy, along with comorbidities for CCI, were collected. HRs of death were estimated using Cox regression. Model performance was evaluated by concordance index and Akaike information criterion., Results: 1,002,589 patients with type 2 diabetes were enrolled, with a median follow-up of 11.0 years. After adjusting for age and sex, aDCSI (HR 1.21, 95% CI 1.20 to 1.21) and CCI (HR 1.18, 1.17 to 1.18) were associated with all-cause mortality. The HRs of aDCSI for cancer, cardiovascular disease (CVD) and diabetes mortality were 1.04 (1.04 to 1.05), 1.27 (1.27 to 1.28) and 1.28 (1.28 to 1.29), respectively, and the HRs of CCI were 1.10 (1.09 to 1.10), 1.16 (1.16 to 1.17) and 1.17 (1.16 to 1.17), respectively. The model with aDCSI had a better fit for all-cause, CVD and diabetes mortality with C-index of 0.760, 0.794 and 0.781, respectively. Models incorporating both scores had even better performance, but the HR of aDCSI for cancer (0.98, 0.97 to 0.98) and the HRs of CCI for CVD (1.03, 1.02 to 1.03) and diabetes mortality (1.02, 1.02 to 1.03) became neutral. When aDCSI and CCI were considered time-varying scores, the association with mortality was stronger. aDCSI had a strong correlation with mortality even after 8 years (HR 1.18, 1.17 to 1.18)., Conclusions: The aDCSI predicts all-cause, CVD and diabetes deaths but not cancer deaths better than the CCI. aDCSI is also a good predictor for long-term mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of hyperinflammatory statuses that are difficult to diagnose and can be life-threatening. Bone marrow (BM) hemophagocytosis is one of the diagnostic criteria according to HLH 2004 diagnostic criteria and HS score. Limited studies have focused on the prognostic factors of BM hemophagocytosis and its association with hematologic malignancies. We aimed to analyze the clinical significance of BM hemophagocytosis. Patients with BM hemophagocytosis, either by cytology or pathology, were enrolled at Taipei Veterans General Hospital from January 2002 to July 2021. Relevant clinical and laboratory data were extracted from medical records. Of 119 patients with BM hemophagocytosis, 57 were diagnosed with hematologic malignancies. The median age of the patients was 58, ranging from 21 to 90. Splenomegaly (adjusted odds ratio [aOR] 2.96; 95% confidence interval [CI] 1.13-7.79) was a risk factor for hematologic malignancies, while autoimmune disease (aOR 0.07; 95% CI 0.01-0.39) and increased D-dimer (aOR 0.25; 95% CI 0.07-0.92) were protective factors. Risk factors for mortality in patients with BM hemophagocytosis were hematologic malignancies (adjusted hazard ratio [aHR] 2.34; 95% CI 1.24-4.44), Eastern Cooperative Oncology Group score ≥3 (aHR 2.42; 95% CI 1.20-4.89) and thrombocytopenia (aHR 3.09; 95% CI 1.04-9.16). In conclusion, among patients with BM hemophagocytosis, splenomegaly was a predictor of hematologic malignancies. Patients with hematologic malignancies, poor performance status, or thrombocytopenia had a higher mortality risk. Further validation studies are warranted., (© 2022 John Wiley & Sons Ltd.)

Background: Multiple myeloma (MM) is known for its immune disturbance and patients suffering from MM are thus vulnerable to opportunistic infections, including herpes zoster (HZ). As HZ infection remarkably affects patients' quality of life and poses huge economic burdens on the health system, we aim to identify the risk factors of HZ infection and evaluate the effects of different dosages, types, and durations of anti-HZ prophylaxis drugs to prevent HZ infection., Methods: 551 MM patients at Taipei Veterans General Hospital in Taiwan between January 1, 2009 and August 31, 2021 were restrospectively analyzed. The patients' baseline characteristics were recorded. The primary endpoint of the study was the incidence of HZ infection among the studied patient population. Due to the lack of cost coverage from Taiwanese public health insurance on HZ prophylaxis drugs, the use of anti-HZ drugs mainly depends on physicians' preferences and patients' choices., Results: In our study, prophylaxis was given to 283 of the patients. In the multivariate analysis, we included non-prophylaxis, age ≥ 60, corrected serum calcium ≥12 mg/dl, serum creatinine ≥2 mg/dl, serum β2-microglobulin ≥5500 mg/L, autologous stem cell transplant (SCT), and allogeneic SCT for analysis. Our results demonstrated that the non-prophylaxis group (HR: 2.37, 95% CI 1.57-3.57) and patients receiving autologous SCT (HR: 2.22, 95% CI 1.28-3.86) and allogeneic SCT (HR: 5.12, 95% CI 1.13-23.22) had higher risk of HZ infection. The difference in dosage and types of anti-HZ drugs showed similar protective effects. In patients who stopped anti-HZ prophylaxis before active cancer-related treatment, a higher risk of getting HZ infection compared to the corresponding group was also observed (adjusted HR 3.09, 95% CI 1.35-7.07, p = 0.008)., Conclusions: We concluded that MM patients should receive HZ prophylaxis drugs while receiving active cancer-related treatment. Patients receiving SCT are also at high risk of getting HZ infection, even under prophylaxis., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Deep reinforcement learning (DRL) targets to train an autonomous agent to interact with a pre-defined environment and strives to achieve specific goals through deep neural networks (DNN). Recurrent neural network (RNN) based DRL has demonstrated superior performance, as RNNs can effectively capture the temporal evolution of the environment and respond with proper agent actions. However, apart from the outstanding performance, little is known about how RNNs understand the environment internally and what has been memorized over time. Revealing these details is extremely important for deep learning experts to understand and improve DRLs, which in contrast, is also challenging due to the complicated data transformations inside these models. In this article, we propose Deep Reinforcement Learning Interactive Visual Explorer (DRLIVE), a visual analytics system to effectively explore, interpret, and diagnose RNN-based DRLs. Having focused on DRL agents trained for different Atari games, DRLIVE accomplishes three tasks: game episode exploration, RNN hidden/cell state examination, and interactive model perturbation. Using the system, one can flexibly explore a DRL agent through interactive visualizations, discover interpretable RNN cells by prioritizing RNN hidden/cell states with a set of metrics, and further diagnose the DRL model by interactively perturbing its inputs. Through concrete studies with multiple deep learning experts, we validated the efficacy of DRLIVE.

Tumour necrosis family superfamily (TNFSF) member 15 (TNFSF15), encoded by TNFSF15, regulates immune responses and inflammation. However, the roles of TNFSF15 single-nucleotide variants (SNVs; formerly SNPs) in oral cavity squamous cell carcinoma (OCSCC) remain unclear. This case-control study included 2523 participants (1324 patients with OCSCC [52.5%] and 1199 healthy controls [47.5%]). The effects of TNFSF15 rs3810936, rs6478108 and rs6478109 on cancer development and prognosis were analysed by real-time PCR genotype assay. The Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases were used to validate our findings. The results demonstrated that the patients with altered TNFSF15 SNVs had poorer histological differentiation than did those with wild-type alleles. TNFSF15 SNVs were significantly associated with moderate-to-poor histological differentiation in univariate logistic regression. In the GTEx database, the expression of altered TNFSF15 SNVs in whole blood was lower than that of wild-type alleles. However, the expression of altered SNVs in the upper aerodigestive mucosa was higher than that of wild-type alleles. In the TCGA database, the patients with higher TNFSF15 expression had shorter overall survival than did those with lower TNFSF15 expression, especially for human papillomavirus-negative and advanced staging groups. In conclusion, although TNFSF15 SNVs did not affect OCSCC development, the patients with altered TNFSF15 SNVs exhibited poorer histological differentiation. The patients with higher TNFSF15 expression had poorer prognosis than did those with lower TNFSF15 expression., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Introduction: Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment for patients with multiple myeloma (MM), and adequate stem cell collection must be assured before ASCT. However, prediction of poor mobilizers (PMs) is still difficult despite several risk factors for mobilization failure having been identified., Methods: We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan who underwent stem cell collection between October 2006 and August 2020. A CD34 + cell collection of <1 × 10 6 cells/kg was defined as a mobilization failure. The primary endpoint was mobilization failure. The secondary endpoint was overall survival (OS). Odds ratios (ORs) and 95% confidence intervals (CIs) for mobilization failure were calculated using a logistic regression model. The cumulative incidence of mortality was estimated using the Kaplan-Meier method., Results: In the multivariate analysis, absolute monocyte count <500/µL (adjusted OR 10.75, 95% CI: 1.82-63.57, p = 0.009), platelet count <150,000/µL (adjusted OR 12.49, 95% CI: 2.65-58.89, p = 0.001) before mobilization, and time interval from diagnosis to stem cell harvest ≥180 days (adjusted OR 7.69, 95% CI: 1.61-36.87, p = 0.011) were risk factors for PMs. PM patients had poorer OS compared to patients with successful stem cell collection in the univariate analysis (log-rank test p = 0.027). The predicted probability of PMs was estimated by the multiple logistic regression model with a sensitivity of 84.6% and a specificity of 84.0%., Conclusion: Absolute monocyte count <500/µL, platelet count <150,000/µL, and treatment duration more than 180 days before stem cell mobilization are risk factors for unsuccessful stem cell collection. Our prediction models have high sensitivity and specificity for mobilization failure prediction and allow for early interventions for possible PMs., Competing Interests: All authors declare no conflict of interest., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Although prostate cancer (PC) is the most common cancer among men in the Western world, there are no good biomarkers that can reliably differentiate between potentially aggressive and indolent PC. This leads to overtreatment, even for patients who can be managed conservatively. Previous studies have suggested that nuclear lamin proteins-especially lamin B1 (LMNB1)-play important roles in PC progression. However, the results of these studies are inconsistent. Here, we transfected the LMNB1 gene into the telomerase reverse transcriptase-immortalized benign prostatic epithelial cell line, EP156T to generate a LMNB1-overexpressing EP156T (LMN-EP156T) cell line with increased cellular proliferation. However, LMN-EP156T cells could neither form colonies in soft agar, nor establish subcutaneous growth or metastasis in the xenograft NOD/SCID mouse model. In addition, immunohistochemical staining of LMNB1 in PC specimens from 143 patients showed a statistically significant trend of stronger LMNB1 staining with higher Gleason scores. A univariate analysis of the clinicopathological parameters of 85 patients with PC who underwent radical prostatectomy revealed that pathological stage, resection margin, and extracapsular extension were significant predictors for biochemical recurrence (BCR). However, LMNB1 staining showed only a non-significant trend of association with BCR (high vs. low staining: hazard ratio (HR), 1.83; 95% confidence interval (CI), 0.98-3.41; P = 0.059). In multivariate analysis, only pathological stage was a significant independent predictor of BCR (pT3 vs. pT2: HR, 2.29; 95% CI, 1.18-4.43; P = 0.014). In summary, LMNB1 may play a role in the early steps of PC progression, and additional molecular alterations may be needed to confer full malignancy potential to initiated cells., Competing Interests: None., (AJCR Copyright © 2022.)

Plant argonautes (AGOs) play important roles in the defense responses against viruses. The expression of Nicotiana benthamiana AGO5 gene ( NbAGO5 ) is highly induced by Bamboo mosaic virus (BaMV) infection; however, the underlying mechanisms remain elusive. In this study, we have analyzed the potential promoter activities of NbAGO5 and its interactions with viral proteins by using a 2,000 bp fragment, designated as PN1, upstream to the translation initiation of NbAGO5. PN1 and seven serial 5'-deletion mutants (PN2-PN8) were fused with a β-glucuronidase (GUS) reporter and introduced into the N. benthamiana genome by Agrobacterium -mediated transformation for further characterization. It was found that PN4-GUS transgenic plants were able to drive strong GUS expression in the whole plant. In the virus infection tests, the GUS activity was strongly induced in PN4-GUS transgenic plants after being challenged with potexviruses. Infiltration of the transgenic plants individually with BaMV coat protein (CP) or triple gene block protein 1 (TGBp1) revealed that only TGBp1 was crucial for inducing the NbAGO5 promoter. To identify the factors responsible for controlling the activity of the NbAGO5 promoter, we employed yeast one-hybrid screening on a transcription factor cDNA library. The result showed that NbNAC42 and NbZFP3 could directly bind the 704 bp promoter regions of NbAGO5 . By using overexpressing and virus-induced gene silencing techniques, we found that NbNAC42 and NbZFP3 regulated and downregulated, respectively, the expression of the NbAGO5 gene. Upon virus infection, NbNAC42 played an important role in regulating the expression of NbAGO5. Together, these results provide new insights into the modulation of the defense mechanism of N. benthamiana against viruses. This virus inducible promoter could be an ideal candidate to drive the target gene expression that could improve the anti-virus abilities of crops in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ke, Huang, Viswanath, Hu, Yeh, Mitsuda, Lin and Hsu.)