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Bo-Chieh Chang,1 Meng-Hsuan Kuo,1 Chi-Hui Lee,1 Ya-Lan Chu,1 Kuang-Peng Chen,2 Chun-Liong Tung,2 Ya-Hui Yang,3 Chuan-Sheng Hung,4 Jui-Hsiu Tsai,2,5 Hung-Yi Chuang6 1Department of Pharmacy, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 2Department of Psychiatry, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 3Department of Long-Term Care and Health Management, Cheng Shiu University, Kaohsiung, Taiwan; 4Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan; 5School of Medicine, Tzu Chi University, Hualien, Taiwan; 6Department of Environmental and Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence: Jui-Hsiu Tsai, Department of Psychiatry, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 2, Min-Sheng Road, Dalin Town, Chiayi, 622, Taiwan, Email faanvangogh@gmail.comIntroduction: Poor adherence to antipsychotics in patients with schizophrenia is a leading cause of relapse and functional deterioration. Long-acting injectable paliperidone may reduce relapse risks, health-care utilisation, and health-care costs in these patients.Methods: In this 24-month mirror-image study, we compared health-care utilization and costs before and after the initiation of paliperidone palmitate 3-monthly (PP3M) treatment in patients with schizophrenia spectrum disorders. Before the initiation of PP3M, the patients received paliperidone 1-monthly (PP1M) treatment. The primary study outcomes were changes in health-care utilisation and costs over the study period.Results: This study included 34 patients with schizophrenia spectrum disorders. During the 12-months period after the initiation of PP3M treatment, the mean duration of hospitalisation decreased from 57.7 to 28.5 days (p = 0.03). Moreover, significant reductions were noted in emergency room visits (PP1M vs PP3M: 0.3 vs 0.0, respectively; p = 0.05) and health-care costs (PP1M vs PP3M: 107,328.8 vs 57,848.6, respectively; p = 0.03).Conclusion: PP3M may significantly reduce hospitalisation duration, emergency room visits, and health-care costs in patients with schizophrenia.Keywords: schizophrenia, long-acting injectable antipsychotics, paliperidone palmitate, health-care cost, health-care utilisation

Jui-Hua Tsai, Ellen Janssen, John FP Bridges Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Abstract: Patient groups are increasingly engaging in research to understand patients’ preferences and incorporate their perspectives into drug development and regulation. Several models of patient engagement have emerged, but there is little guidance on how to partner with patient groups to engage the disease community. Our group has been using an approach to engage patient groups that we call research as an event. Research as an event is a method for researchers to use a community-centered event to engage patients in their own environment at modest incremental cost. It is a pragmatic solution to address the challenges of engaging patients in research to minimize patients’ frustration, decrease the time burden, and limit the overall cost. The community, the event, and the research are the three components that constitute the research as an event framework. The community represents a disease-specific community. The event is a meeting of common interest for patients and other stakeholders, such as a patient advocacy conference. The research describes activities in engaging the community for the purpose of research. Research as an event follows a six-step approach. A case study is used to demonstrate the six steps followed by recommendations for future implementation. Keywords: patients’ perspectives, decision making, drug approval, patient engagement, patient organization, patients’ preference

Yang-Pei Chang,1 Chih-Jen Yang,2 Kai-Fang Hu,3 A-Ching Chao,4 Yu-Han Chang,5 Kun-Pin Hsieh,6 Jui-Hsiu Tsai,7 Pei-Shan Ho,8,9 Shen-Yang Lim101Department of Neurology, 2Department of Internal Medicine, 3Department of Dentistry, Kaohsiung Municipal Ta-Tung Hospital, 4Department of Neurology, College of Medicine, 5Department of Management, Kaohsiung Municipal Ta-Tung Hospital, 6School of Pharmacy, College of Pharmacy, 7Department of Psychiatry, Kaohsiung Municipal Ta-Tung Hospital, 8Faculty of Dental Hygiene, College of Dental Medicine, Kaohsiung Medical University, 9Cancer Center, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan, Republic of China; 10Faculty of Medicine, University of Malaya, Kuala lumpur, MalaysiaObjective: Pneumonia is the leading cause of death in patients with Parkinson’s disease (PD). However, few studies have been performed to explore the risk factors for pneumonia development in patients with PD.Methods: We conducted a nationwide population-based cohort study of patients with PD to identify the risk factors for these patients developing pneumonia. Participants with newly diagnosed PD between 2000 and 2009 were enrolled from the 2000–2010 National Health Insurance Research Database in Taiwan. We compared patients with PD with an incidence of hospitalization with pneumonia vs those without, and Cox proportional hazard models were used to estimate the risk of pneumonia.Results: Of the 2,001 enrolled patients (mean follow-up duration 5.8 years, range: 2.7–14.7 years), 381 (19.0%) had an incidence of hospitalization with pneumonia during the study period. Multivariate Cox proportional hazards analysis identified older age group (≥80 years of age, hazard ratio [HR] =3.15 [95% confidence interval 2.32–4.28]), male sex (HR =1.59 [1.29–1.96]), certain geographic regions (northern, HR =1.36 [1.04–1.78], southern and eastern, HR =1.40 [1.05–1.88]), rural areas (HR =1.34 [1.05–1.72]), chronic heart failure (HR =1.53 [1.02–2.29]), and chronic kidney disease (HR =1.39 [1.03–1.90]) as risk factors for hospitalization with pneumonia in patients with PD. However, treatment for dental caries was a protective factor (HR =0.80 [0.64–0.99]).Conclusion: The results of this study highlight risk factors that are associated with hospitalization with pneumonia, and, for the first time, suggest a link between treated dental caries and a diminished risk of hospitalization with pneumonia in patients with PD.Keywords: pneumonia, Parkinson’s disease, dental caries, chronic heart failure, chronic kidney disease

Matrix stiffness potently regulates cellular behaviour in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased matrix stiffness and correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechanomediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing matrix stiffness. High matrix stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fibre alignment, a marker of increasing matrix stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion and metastasis.

This study investigated suspended particles (PM2.5 and PM10), formaldehyde, TVOC, ozone, carbon dioxide, and carbon monoxide in seven student-oriented indoor environments, which are inclusive of the library study room (A), computer classroom (B), teacher and student compound office (C), classroom-1 (D), classroom-2 (E), student cafeteria (F), and underground motorcycle parking lot (G) on a university campus. We monitored each indoor environment during the open hours for at least three weekdays. The averaged concentrations of CO2 in environments A, B, C, and D all exceeded the standard (1000 ppm) with values of 2,628±375, 1,908±613, 1,752±495, and 1,076±280 ppm. The corresponding minimum and maximum CO2 concentrations were 1,101 and 3,314, 836 and 3,272, 672 and 2,667, and 752 and 2,040 ppm, respectively. Sites A, B, C, D, F, and G are the environments where the concentrations of TVOC exceeded the standard (560 ppb) with the averaged values of 829±21, 920±192, 582±8, 607±15, 640±102 and 815±205 ppb, respectively. Both concentrations of PM2.5 and PM10 in site F exceeded the standards (i.e., 35 μg/m3 and 75 μg/m3) with averaged values of 39±13 μg/m3 and 103±51 μg/m3, respectively. Three target compounds, CO, O3, and HCHO, were below their respective standards.

BACKGROUND: Ischemic optic neuropathy is the most common cause of perioperative vision loss. The authors sought to determine its incidence and identify risk factors that may contribute to perioperative ischemic optic neuropathy associated with nonophthalmologic surgical procedures at their institution. METHODS: Seventeen patients who experienced perioperative ischemic optic neuropathy were included in a retrospective chart review case-control study. The authors matched each patient with two control patients who had a similar surgical procedure but did not lose vision. They analyzed multiple perioperative variables for the case and control groups. RESULTS: From among 126,666 surgical procedures performed during the study period, the authors identified 17 patients with perioperative ischemic optic neuropathy, yielding an overall incidence of 0.013%. There were no hemodynamic variables that differed significantly between the ischemic optic neuropathy patients and the matched control patients. CONCLUSION: The authors conclude that perioperative ischemic optic neuropathy can occur in the absence of atypical fluctuations in hemodynamic variables during the perioperative period. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: The goal was to determine whether the tumor vascular disrupting actions of low-intensity ultrasound were frequency dependent.Materials and Methods: The effect of the frequency (1 MHz at 2.2 W/cm2 or 3 MHz at 2.4 W/cm2) of low-intensity ultrasound as a neovascular disrupting modality was investigated in 15 murine melanomas (K1735(22)) insonated for 3 minutes after the intravenous injection of a microbubble contrast agent (Definity). In contrast-enhanced power Doppler observations of each tumor (before and after treatment), measurements were made of the size of the area of the tumor that was perfused with blood containing the ultrasound contrast agent (percentage area of flow [PAF]), and the volume of contrast agent flowing through the unit volume of the tumor (color-weighted fractional area [CWFA]). During insonation of the tumor, the temperature was measured with a fine wire thermocouple in an additional eight mice.Results: The antivascular action of low-intensity ultrasound was significantly enhanced (PAF by 64%; CWFA by 106%) when the tumor was treated with 3-MHz ultrasound rather than 1 MHz (analysis of variance: PAF, P=.02; CWFA, P=.04). The average rate of tumor temperature increase was 2.6+/-1.3 degrees C/min for 1 MHz and 5.0+/-1.7 degrees C/min for 3 MHz; these increases were significantly different (P=.04).Conclusions: Insonation of the tumor at a higher frequency amplified the heating of the neoplasm and led to greater disruption of the tumor vasculature; 3-MHz ultrasound was more efficacious than 1 MHz for antivascular cancer therapy. [ABSTRACT FROM AUTHOR]

Inconel alloy has been widely used in industry but is difficult to machine due to its rapid change in cutting force during machining. This paper investigated the cutting force for milling Inconel 718 as conventional force model is unable to handle the above situation. Theorectical force model is first reviewed and two-phase experiments of slot milling based on dry cutting are designed to measure the cutting force and the specific cutting force. Experiments in phase I are designed based on Taguchi method with spindle speed, feedrate per cutting edge and depth of cut as experimental parameters. The results showed that the first two parameters play more important roles in the cutting force. A phase II exhaust experiments is designed with spindle speed set from 400 to 800 rpm while the feedrate per cutting edge is set from 0.04 to 0.08 mm/tooth. The results are concluded as the following. (i) There exists a strong size effect in milling Inconel 718 as the cutting force changed with the chip thickness. Specific cutting force is larger at small thickness of cut and become smaller when the thickness increases. (ii) A 2nd order non-linear cutting force model, which takes spindle speed N and feedrate fz into account, for milling Inconel 718 is derived from the measured data and represented as Ft(N, fz )= (13910 -3.1N - 109900fz - 0.0028N2 +23.9Nfz+434500fz2) xapxh. The derived force model compensates the inaccuracy of conventional force model.

Background: Approximately one-third of patients with advanced colorectal cancer (CRC) and treated with bevacizumab are prescribed proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs). However, there is limited data on the effects of PPIs and H2RAs in these patients. To investigate the oncological outcomes of PPI and H2RA use in CRC patients treated with bevacizumab, we performed a retrospective cohort study using the Taiwan National Health Insurance Research Database and Taiwan Cancer Registry Database from 2005 to 2020., Methods: In CRC patients treated with bevacizumab, the PPI users and H2RA users were matched with patients without acid-reducing agents (ARAs) by 1:4 propensity score matching. PPI users and H2RA users were matched with propensity scoring in a 1:1 ratio. We divided patients into 4 cumulative PPI dosage levels to assess the dose-response relationship. The primary endpoints were 5-year overall survival and cancer-specific survival., Results: Compared with ARA non-users, both H2RA users and PPI users were associated with reduced overall survival. PPI users were associated with more significant negative effects on overall survival. Compared with H2RA users, PPI users were associated with lower 5-year overall survival (aHR: 1.19, 95% CI: 1.09-1.31) and cancer-specific survival (aHR: 1.20, 95% CI: 1.09-1.31). A similar dose-response relationship was observed for PPI users in terms of 5-year overall survival and cancer-specific overall survival., Conclusions: Compared to H2AR use, PPI use was associated with dose-dependent poorer oncological outcomes in metastatic CRC patients treated with bevacizumab.

Breast cancer remains the most prevalent cancer in women globally, posing significant challenges in treatment due to the inevitable development of resistance to targeted therapies like everolimus, an mTOR inhibitor. While several mechanisms of resistance have been proposed, the role of snoRNAs in this context remains inadequately explored. Our study unveils a novel connection between snoRNAs and everolimus resistance, focusing on the snoRNA U50A. We discovered that U50A negatively regulates mTOR signaling by transcriptionally downregulating mTOR gene expression, which consequently leads to decreased sensitivity to everolimus treatment. Through RNA sequencing, gene set enrichment analyses, and experimental validations, we established that U50A overexpression in breast cancer cells results in mTOR downregulation and subsequently, everolimus desensitization. Clinical results further supported our findings, showing a higher prevalence of everolimus resistance in tumors with elevated U50A expression. Moreover, our results suggest that U50A's effect on mTOR is mediated through the suppression of the transcription factors c-Myc, with a notable impact on cancer cell viability under everolimus treatment. This study not only highlights the complex role of snoRNAs in cancer drug resistance but also proposes U50A as a potential biomarker for predicting everolimus efficacy in breast cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: This study aimed to gain insight from patients with refractory Mycobacterium avium complex lung disease (MAC-LD) into strategies used to manage adverse events (AEs) associated with amikacin liposome inhalation suspension (ALIS)., Methods: We conducted semi-structured interviews with US patients with refractory MAC-LD prescribed ALIS in a real-world setting. Interview transcripts were analyzed and coded to identify patterns in participants' descriptions of their ALIS treatment experiences, including AEs and their disruptiveness, and AE mitigation strategies, including participants' ratings of strategies' effectiveness. Concept saturation was also assessed., Results: Twenty participants (mean age 48.7 years; 80% women; mean ALIS duration 5.45 months) were interviewed. At the time of the interview, 15 participants (75%) had received ALIS for > 1 month and 13 (65%) were currently receiving ALIS. Participants described 44 unique AE mitigation strategies, which can be categorized into three groups: prepare for treatment; prevent increased emergence of AEs; and persist on treatment by mitigating AEs. Common strategies (reported by ≥ 50% of participants) included use of educational materials from the patient support program, localized management of throat irritation, and symptom management to reduce fatigue. Evidence of concept saturation was observed: no new strategies were identified in the last five interviews, which suggests the sample was robust enough to identify all mitigation strategies likely to be used by the broader patient population., Conclusions: This real-world study identified a diverse set of potential AE mitigation strategies intended to help individual patients prepare for ALIS treatment, prevent the increased emergence of certain AEs, and mitigate the impact of AEs on treatment persistence. Developing a comprehensive accounting of the types of mitigation strategies in use among patients in real-world settings can inform future investigation of the effectiveness of such strategies, and support evidence-based recommendations for treatment management., (© 2024. The Author(s).)

As higher-valent pneumococcal conjugate vaccines (PCVs) become available for pediatric populations in the US, it is important to understand healthcare provider (HCP) preferences for and acceptability of PCVs. US HCPs (pediatricians, family medicine physicians and advanced practitioners) completed an online, cross-sectional survey between March and April 2023. HCPs were eligible if they recommended or prescribed vaccines to children age <24 months, spent ≥25% of their time in direct patient care, and had ≥2 y of experience in their profession. The survey included a discrete choice experiment (DCE) in which HCPs selected preferred options from different hypothetical vaccine profiles with systematic variation in the levels of five attributes. Relative attribute importance was quantified. Among 548 HCP respondents, the median age was 43.2 y, and the majority were male (57.9%) and practiced in urban areas (69.7%). DCE results showed that attributes with the greatest impact on HCP decision-making were 1) immune response for the shared serotypes covered by PCV13 (31.4%), 2) percent of invasive pneumococcal disease (IPD) covered by vaccine serotypes (21.3%), 3) acute otitis media (AOM) label indication (20.3%), 4) effectiveness against serotype 3 (17.6%), and 5) number of serotypes in the vaccine (9.5%). Among US HCPs, the most important attribute of PCVs was comparability of immune response for PCV13 shared serotypes, while the number of serotypes was least important. Findings suggest new PCVs eliciting high immune responses for serotypes that contribute substantially to IPD burden and maintaining immunogenicity against serotypes in existing PCVs are preferred by HCPs.

Background/purpose: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma (ICC). We aim to analyze the differences in the clinical and radiological features of LELCC and ICC., Methods: Between January 2003 and December 2019, a total of 21 patients diagnosed with LELCC were retrospectively enrolled, and 84 patients with ICC were selected through propensity score matching by sex, age, and initial cancer stage. The clinical characteristics, pathological findings, and radiological features were analyzed. The differences in overall survival (OS) between LELCC and ICC were evaluated using the Kaplan-Meier method., Results: The serum carbohydrate antigen 19-9 (CA 19-9) level was higher in the ICC group than in the LELCC group (77.9 vs 30.0 U/mL, p = 0.004). Non-rim arterial phase hyperenhancement (47.1% vs 13.7%, p = 0.005) and portovenous washout (35.3% vs 4.1%, p = 0.001) were more frequently observed in the LELCC group than in the ICC group. Intrahepatic duct dilatation was a distinct feature of the ICC group. The 5-year OS rates in the LELCC and ICC groups were 69.3% and 58.2%, respectively (p = 0.047). The 5-year OS of patients with stages I and II LELCC between ICC were not significantly different (90.0% vs 83.4%, p = 0.464). However, the 5-year OS of patients with stages III and IV LELCC was more favorable than that of patients with ICC (29.2% vs 23.0%, p = 0.017)., Conclusions: LELCC had a favorable outcome and several different clinicoradiological features compared with ICC., Competing Interests: Declaration of competing interest Nothing to report., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Objective: We describe a rare case of uterine mesothelial cysts mimicking ovarian cysts in a primipara patient with a history of Cesarean section., Case Report: A 39-year-old female patient with history of Cesarean section presented with dysmenorrhea. Sonography revealed that a hypoechoic and anechoic multicystic complex, which was located on the right side of the pelvic cavity, had infiltrated the adjacent posterior wall of the uterus, and it was preoperatively misdiagnosed as ovarian cysts with suspected endometrioma. Laparoscopic surgery revealed multiple cystic lesions filled with clear yellow fluid on the posterior uterine wall instead of the adnexa. Laparoscopic uterine cystectomy was performed, and the patient's recovery was uneventful. Pathohistological and immunohistochemical examinations confirmed the diagnosis of uterine mesothelial cysts., Conclusion: Uterine mesothelial cysts should be considered in the differential diagnosis of pelvic lesions. Increasing the awareness of this rare disease can contribute to improved evaluation, decision-making, and disease management., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: It is important to assess healthcare providers (HCPs) knowledge, attitudes, perceptions, and preferences towards new pneumococcal vaccines for adults., Methods: HCPs who met eligibility criteria completed an online survey between March - May 2024 that included a discrete choice experiment (DCE) to elicit preferences., Results: Among 340 participating HCPs, the average age was 44.9 years old, and the majority were male (55.6%), and White (85.3%). Most HCPs reported that they would support (90.3%) and implement (91.5%) a lower age-based recommendation for pneumococcal vaccines (from adults 65+ years to adults 50+ years). A majority of HCPs would offer a supplemental dose of a pneumococcal vaccine to high-risk adults 19-49 years, at-risk or high-risk adults 50-64 years, and adults 65+ years regardless of risk status to increase protection after completing the recommended series. DCE results showed that coverage of pneumococcal pneumonia and invasive pneumococcal disease (IPD) in adults 65+ years were the two most important attributes in evaluating pneumococcal vaccines., Conclusions: HCPs preferred a pneumococcal vaccine with increased coverage against pneumococcal pneumonia and IPD, and they supported lowering the age recommendation for pneumococcal vaccination as well as a supplemental vaccine dose to provide additional coverage for adults.

Background and Aims: Coronavirus disease 2019 (COVID-19) vaccines were rapidly implemented globally and vaccine-associated immune-related hepatitis was recently reported. We aim to investigate its impact in regions endemic of chronic hepatitis B (CHB)., Methods: We retrospectively collected patients who developed hepatitis within 90 days after COVID-19 vaccination in Taiwan. The mechanisms of hepatitis included vaccine induced liver injury (VILI) and immune-related hepatitis, which are direct liver injuries defined as aspartate or alanine aminotransferase (AST or ALT) increased ≥ 5-fold upper limit of normal (ULN) and/or AST or ALT ≥ 3-fold of ULN with concurrent total bilirubin ≥ 2-fold of ULN. Indirect liver injury due to HBV reactivation was defined as HBsAg reverse seroconversion or significant rise in HBV DNA level. The demographics, clinical data, and course of hepatitis were compared statistically., Results: Twenty-five patients were included with a median age of 54. The culprit vaccines were ChAdOx1 nCoV-19 (n = 9), mRNA-1273 (n = 12), and BNT162b2 (n = 4). The characteristics of hepatitis were comparable regardless of vaccine subtypes. The median onset of hepatitis was 25 days post vaccination, with a peak of 10-fold ALT-increase. The etiologies included HBV reactivation (n = 10), VILI (n = 10), and immune-related hepatitis (n = 5). HBV reactivation accounts for 90% of vaccine-induced hepatitis in patients of CHB (n = 10), and two patients died. Patients with initial AST levels >500 U/L increased 27-fold risks of liver injury greater than moderate severity compared with those without., Conclusion: COVID-19 vaccine induced hepatitis is a clinical significant complication, and HBV reactivation may account for a possible mechanism., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

To valorize livestock manure, the present study investigated the production of biochar from cow dung (CD) by microwave pyrolysis. The pore properties and chemical characteristics of CD and CD-based biochar products were found to correlate with the process parameters like microwave power (300-1000 W) and residence time (5-20 min). The findings indicated that CD is an excellent biomass based on the richness of lignocellulosic constituents from the results of proximate analysis and thermogravimetric analysis (TGA). Higher calorific values were obtained at mild microwave conditions, giving the maximal enhancement factor 139% in comparison with the calorific value of CD (18.97 MJ/kg). Also, it can be concluded that the biochar product obtained at 800 W for a holding time of 5 min had the maximal BET surface area of 127 m 2 /g and total pore volume of 0.104 cm 3 /g, which were microporous and mesoporous in the nitrogen adsorption-desorption adsorption analysis. On the other hand, the CD-based biochar contained oxygen-containing functional groups and inorganic minerals based on the spectroscopic analyses by Fourier-transform infrared spectroscopy (FTIR) and energy-dispersive X-ray spectroscopy (EDS), thus featuring to be prone to hydrophilicity in aqueous solutions.

The dose-response effect of proton pump inhibitors on colorectal cancer prognosis is still under exploration. This population-based study in Taiwan was designed to examine the effect of proton pump inhibitors on overall death, colorectal cancer-specific death, and recurrence in colorectal cancer patients with different cumulative proton pump inhibitor dose levels. This cohort study was based on the Taiwan Cancer Registry and Taiwan National Health Insurance Research Database from 2005 to 2020. After frequency matching with a 1:1 ratio, a total of 20,889 users with proton pump inhibitors and 20,889 without proton pump inhibitors were analyzed. The cumulative defined daily dose level of proton pump inhibitor was stratified to explore the dose-response relationship. A proton pump inhibitor exposure cumulative defined daily dose > 60 after colorectal cancer diagnosis had higher risk of all-cause death than non-proton pump inhibitor users with adjusted hazard ratios of 1.10 (95% CIs: 1.04-1.18). For recurrence, a proton pump inhibitor exposure cumulative defined daily dose > 60 had reduced recurrence risk with an adjusted hazard ratio of 0.84 (95% CIs: 0.76-0.93). This study demonstrated that the long-term use of proton pump inhibitors in patients with colorectal cancer was associated with an increased risk of death that related to the proton pump inhibitor exposure cumulative defined daily dose > 60 and had different dose-response effect in various dose level.

Metastasis is the leading cause of cancer-related deaths. During this process, cancer cells are likely to navigate discrete tissue-tissue interfaces, enabling them to infiltrate and spread throughout the body. Three-dimensional (3D) spheroid modeling is receiving more attention due to its strengths in studying the invasive behavior of metastatic cancer cells. While microscopy is a conventional approach for investigating 3D invasion, post-invasion image analysis, which is a time-consuming process, remains a significant challenge for researchers. In this study, we presented an image processing pipeline that utilized a deep learning (DL) solution, with an encoder-decoder architecture, to assess and characterize the invasion dynamics of tumor spheroids. The developed models, equipped with feature extraction and measurement capabilities, could be successfully utilized for the automated segmentation of the invasive protrusions as well as the core region of spheroids situated within interfacial microenvironments with distinct mechanochemical factors. Our findings suggest that a combination of the spheroid culture and DL-based image analysis enable identification of time-lapse migratory patterns for tumor spheroids above matrix-substrate interfaces, thus paving the foundation for delineating the mechanism of local invasion during cancer metastasis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Multimorbidity and polypharmacy increase the risk of hospitalization in older adults receiving potentially inappropriate medication (PIM). The current study compared the ability of PIM-Taiwan, PRISCUS, and Beers criteria to predict 90-day rehospitalization in older patients with and without PIM. Methods: The retrospective cohort study used Taiwan's Longitudinal Health Insurance Database to retrieve quarterly information about prescribed medication for adults aged ≥65 years hospitalized between 2001 and 2018. We analyzed the association of PIM with 90-day rehospitalization using logistic regression. Results: The study cohort included 206,058 older adults (mean age: 72.5 years). In the analysis, 133,201 (64.6%), 97,790 (47.5%), and 147,450 (71.6%), were identified as having PIM exposure in PIM-Taiwan, PRICUS, and Beers criteria, respectively. PIM-Taiwan criteria found exposure to PIM affecting the cardiovascular (adjusted OR [aOR] 1.37, 95% confidence interval [CI] = 1.32-1.41), gastrointestinal (aOR 1.26, 95% CI = 1.23-1.30), central nervous (aOR 1.11, 95% CI = 1.08-1.14), and respiratory (aOR 1.16, 95% CI = 1.12-1.20) systems significantly increased the risk of 90-day rehospitalization, after adjustment for covariates. In PRISCUS criteria, exposure to PIM affecting the respiratory (aOR 1.48, 95% CI = 1.41-1.56), central nervous (aOR 1.12, 95% CI = 1.09-1.15), and cardiovascular (aOR 1.20, 95% CI = 1.16-1.24) systems significantly increased the risk. In Beers criteria, exposure to PIM affecting the cardiovascular (aOR 1.37, 95% CI = 1.32-1.41), gastrointestinal (aOR 1.38, 95% CI = 1.35-1.42), central nervous (aOR 1.18, 95% CI = 1.15-1.21), endocrine (aOR 1.10, 95% CI = 1.06-1.15), and respiratory (aOR 1.09, 95% CI = 1.04-1.13) systems significantly increased the risk. Patients with 90-day rehospitalization had higher rates of the potentially harmful drug-drug interaction (DDI) pairs of serotonin syndrome (n = 19; 48.8%), QT prolongation (n = 4; 30.8%), extrapyramidal symptoms (EPS) (n = 102; 24.5%), and hypokalemia (n = 275; 20.1%). Conclusion: Beers criteria was more efficient in predicting 90-day rehospitalization among older adults experiencing PIM in Taiwan than either PIM-Taiwan or PRISCUS. The risk of 90-day rehospitalization was associated with the potentially harmful DDI classes of serotonin syndrome, QT prolongation, EPS, and hypokalemia., 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 © 2023 Hsieh, Huang, Yang, Ho, Chen, Tung, Chu and Tsai.)

Introduction: Electronic cigarette (e-cigarette) use among adolescents has become increasingly common; therefore, effectively reducing adolescent e-cigarette use is an urgent issue. We aimed to predict and identify potential factors related to adolescent e-cigarette use behaviors., Methods: This cross-sectional study was conducted using anonymous questionnaires given to Taiwanese high school students in 2020. Approximately 1,289 adolescent students completed questions on e-cigarette use, personal characteristics, family environment, and substances used. We performed multivariate logistic regression analyses to assess the model's predictive performance in terms of the area under the receiver operating characteristic curve., Results: We found that 9.3% of adolescent students used e-cigarettes. Tobacco smoking, close friends' reactions to e-cigarette use, and the use of other substances were independent risk factors for adolescent e-cigarette use. Furthermore, relative to tobacco nonuse, tobacco use and tobacco smoking dependence had odds ratios of 76.49 and 113.81, respectively. The predictive accuracy of adolescent e-cigarette use from personal characteristics, family environment, and substance use status was 73.13, 75.91, and 93.80%, respectively., Conclusion: The present study highlights the need for early prevention of e-cigarette use among adolescents, particularly those with a history of using tobacco and other substances and those who have close friends with positive attitudes towards e-cigarette use., (Copyright © 2023 Liu, Lin, Ho, Tsai, Yang, Wu and Chuang.)

Hexagonal SBA-15 mesoporous material was used as a catalytic template for impregnation, with the transition metals Fe, Co, and Ni as catalysts for chemical transformation. Nitrogen adsorption/desorption isotherms, scanning electron microscopy, and transmission electron microscopy were conducted to better understand the physicochemical properties of the metal oxide-impregnated SBA-15. The specific surface area of the original SBA-15 was approximately 680 m 2 /g, and the abundances of the catalysts impregnated ranged from 2 to 8%, corresponding to specific surface areas of 560-470 m 2 /g for Fe-SBA-15, 440-340 m 2 /g for Ni-SBA-15, and 410-340 m 2 /g for Co-SBA-15. The increase in impregnated metal loadings filled the pores and collapsed the silica walls during the metal oxides impregnation on SBA-15 and calcination procedures, resulting in a decrease in the specific surface area and pore volume of the templates. The results showed that the order of nitrogen adsorbed was SBA-15 > Fe-SBA-15 > Ni-SBA-15 > Co-SBA-15 when the metal loading was 5%. In addition, the metal oxides on SBA-15 increased the wall thickness compared with raw SBA-15. Based on the XRD spectrum analysis, Fe 2 O 3 , Co 3 O 4 , and NiO were the stable crystals on the Fe-SBA-15, Co-SBA-15, and Ni-SBA-15, respectively. The sequence of the average grain size of metal oxides on SBA-15 was Co-SBA-15 > Fe-SBA-15 > Ni-SBA-15, according to XRD spectra and Scherrer's equation. Isopropanol could be decomposed by metal oxide-impregnated SBA-15 to form carbon filament materials. Therefore, these materials have the potential to be employed for pollutant removal, catalytic reactions for organic solvent and bio-oil/biomass reforming, and recycling waste into high-value materials.

Background: Understanding how patients perceive the efficacy, safety, and administrative burden of treatments for metastatic castration-resistant prostate cancer (mCRPC) can facilitate shared-decision making for optimal management. This study sought to elicit patient preferences for mCRPC treatments in the US., Methods: We conducted a cross-sectional survey using the discrete-choice experiment method. Participants were asked to state their choices over successive sets of treatment alternatives, defined by varying levels of treatment attributes: overall survival (OS), months until patients develop a fracture or bone metastasis, likelihood of requiring radiation to control bone pain, fatigue, nausea, and administration (i.e., oral/IV injection/IV infusion). Using mixed logit models, we determined the value (i.e., preference weights) that respondents placed on each attribute. Relative attribute importance (RAI) and marginal rates of substitution (MRS) were calculated to understand patients' willingness to make tradeoffs among different attributes., Results: The final data set numbered 160 participants, with a mean age of 71.6 years old and a mean of 8.96 years since prostate cancer diagnosis. Participants' treatment preferences were as follows: OS (RAI: 31%), bone pain control (23%), nausea (16%), delaying fracture or bone metastasis (15%), fatigue (11%), and administration (3%). The MRS demonstrated that respondents were willing to trade 1.9 months of OS to eliminate moderate nausea and 3.3 months of OS for a reduction in fatigue from severe to mild., Conclusions: Improving OS is the highest priority for patients with mCRPC, but they are willing to trade some survival to reduce the risk of requiring radiation to control bone pain, delay a fracture or bone metastasis, and experience less severe nausea and fatigue., (© 2022 BAYER U.S. LLC. Cancer Medicine published by John Wiley & Sons Ltd.)

Toll-like receptor (TLR) is essential for the immune response to Mycobacterium tuberculosis (MTB) infection. However, the mechanism whereby TLR mediates the MTB-induced pleural mesothelial hyperpermeability in tuberculous pleural effusion (TBPE) remains unclear. Pleural effusion size and pleural fluid levels of vascular endothelial growth factor (VEGF) and soluble TLR2 (sTLR2) in patients with TBPE (n = 36) or transudative pleural effusion (TPE, n = 16) were measured. The effects of MTB H37Ra (MTBRa) on pleural mesothelial permeability and the expression of VEGF and zonula occludens (ZO)-1 in human pleural mesothelial cells (PMCs) were assessed. Levels of VEGF and sTLR2 were significantly elevated in TBPE compared to TPE. Moreover, effusion VEGF levels correlated positively, while sTLR2 values correlated negatively, with pleural effusion size in TBPE. In human PMCs, MTBRa substantially activated JNK/AP-1 signaling and upregulated VEGF expression, whereas knockdown of TLR2 remarkably inhibited MTBRa-induced JNK phosphorylation and VEGF overexpression. Additionally, both MTBRa and VEGF markedly reduced ZO-1 expression and induced pleural mesothelial permeability, while TLR2 silencing or pretreatment with anti-VEGF antibody significantly attenuated the MTBRa-triggered effects. Collectively, TLR2 mediates VEGF overproduction and downregulates ZO-1 expression in human PMCs, leading to mesothelial hyperpermeability in TBPE. Targeting TLR2/VEGF pathway may confer a potential treatment strategy for TBPE.

Background: Limited efficacy has been observed when using opioids to treat neuropathic pain. Lidocaine patches reduce neuropathic pain in postherpetic neuralgia, but their benefits for cancer-related neuropathic pain remain unclear. This study aimed to investigate a treatment for cancer-related neuropathic pain., Methods: We conducted a prospective, open-label, single-arm study to assess the efficacy and safety of lidocaine transdermal patches in patients experiencing localized, superficial, neuropathic cancer pain. Terminal cancer patients already receiving opioid treatment participated in the 3-day study. The primary endpoint was pain intensity evaluated by the numerical rating scale (NRS). The secondary endpoints were the pain relief score and the quality of analgesic treatment., Results: The results showed a significant difference in the median NRS over 3 days (Kruskal-Wallis test, p < 0.0001). The median NRS pain intensity from Day 1 to Day 3 was 4.0 with 95% C.I. (3.3, 5.0), 3.0 (2.5, 3.5), and 2.6 (2.0, 3.0), respectively. The difference between the median NRS pain intensities of any 2 days was significant (Wilcoxon signed-rank test, p < 0.0001). The generalized estimating equation (GEE) estimation model showed significant differences between the NRS pain intensities on any 2 days. There was no significant difference in the pain relief score or the quality of analgesic treatment., Conclusions: In this study, the 5% lidocaine transdermal patch reduced the NRS pain intensity in neuropathic cancer patients already receiving opioid treatment. Treatment of localized and superficial neuropathic pain caused by cancer was well tolerated and effective., (© 2023. The Author(s).)

Background: Prognosis of metastatic BRAF V600E mutant colorectal cancer (CRC) is poor, and the prognostic implications of immune contextures in the tumour microenvironment (TME) for CRC remain elusive., Methods: We collected the primary tumour specimens and clinicopathological characteristics of patients with de novo metastatic microsatellite-stable BRAF V600E mutant CRC from two medical centres. Gene expression analysis was performed using the nCounterⓇ PanCancer Immune Profiling Panel. The Cox proportional hazards regression model was used for analysing survival outcomes in association with immune gene expression and immune cells. Our complement score was defined on the basis of the average gene expression in the selected co-expression module., Results: High expression of classical and regulatory complement genes was significantly associated with poor prognosis (N = 54). A high complement score (defined as a score above the median value) indicated significantly shorter survival. The overall survival (OS) impact of the high score remained significant in multivariate analyses. Additionally, our complement score was strongly correlated with C4d expression in immunohistochemical staining and tumour-associated macrophage (TAM) M2 signatures., Conclusions: Complement activation in the TME was significantly associated with poor OS and was correlated with TAM M2 in patients with de novo metastatic BRAF V600E mutant CRC., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Hepatic sarcomatoid carcinoma is a rare hepatic tumor with an aggressive clinical behavior and dismal outcome. However, the molecular pathogenesis is incompletely defined. In this study, we analyzed 59 hepatic sarcomatoid carcinomas using targeted next-generation sequencing and immunohistochemistry. A panel of 14 genes commonly mutated in primary liver carcinomas was examined. PD-L1 and loss of expression for switch/sucrose nonfermenting complexes, including BAP1, ARID1A, ARID2, and PBRM1, were detected by immunohistochemistry. The 59 hepatic sarcomatoid carcinomas encompass various carcinomatous subtypes and tumors with complete sarcomatoid transformation. Mutations in TP53 and promoter of TERT (pTERT) were frequently identified in sarcomatoid hepatocellular carcinoma, sarcomatoid combined hepatocellular cholangiocarcinoma, and hepatic sarcomatoid carcinomas with complete sarcomatoid transformation but rarely in sarcomatoid cholangiocarcinoma. Alterations involving switch/sucrose nonfermenting complexes were uncommon in hepatic sarcomatoid carcinoma (n = 2). PD-L1 expressed in tumor-associated immune cells in 67% of the tumors and in tumor cells in 33% of the tumors. A multivariate survival analysis indicated that PD-L1 expression in immune cells served as an independent favorable predictive factor of patient survival (P = .036). In conclusion, hepatic sarcomatoid carcinoma displays molecular similarity with its conventional carcinomatous counterparts. This finding suggests persistent genetic characteristics during sarcomatous evolution. PD-L1 expression in immune cells is a favorable prognostic factor for patient outcomes and may be a potential biomarker for immunotherapeutic treatment., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Keloid scarring is an abnormal scar disease characterised by excessive proliferation of fibroblasts and over-deposition of collagen during wound healing. Although various treatments for keloid scars have been developed, preventive medicine is believed to be a promising strategy. The skin barrier limits the gentle topical administration of medicaments such as creams and hydrogel dressings, resulting in reduced therapeutic efficacy. In recent years, microneedles (MNs) have been regarded as an appreciable device for topical administration without inducing side effects, and they are painless and do not cause bleeding. In this study, an MN patch with controlled transdermal dual-drug release was developed to achieve combinatory treatment of keloid scars using a heterogeneous gelatin-structured composite MN. Gelatin hydrogel was used as a substrate to load gallic acid (GA) and quercetin-loaded amphiphilic gelatin nanoparticles to fabricate dual-drug heterogeneous composite MNs. The results of the insertion test and mechanical properties of the MNs showed that the heterogeneous composite MN patches could be self-pressed into the stratum corneum and control dual-drug release at different time periods. GA was released at an earlier stage to retard the proliferation of fibroblasts, and quercetin was released at a later stage as a strong antioxidant to erase the generation of reactive oxygen species. Furthermore, real-time quantitative polymerase chain reaction data indicated that the gene expression of fibroblasts (such as Col I and III) was downregulated in the dual-drug system. The above results demonstrate that using heterogeneous composite MNs with the combination of dual-drug pharmacology is beneficial for preventing keloid scar formation.

Background: Ramucirumab is indicated for salvage treatment after failure of first-line treatment for metastatic colorectal cancer (mCRC). However, the application of ramucirumab at later-line treatment in real-world practice has not received much discussion., Methods: In this retrospective study, we enrolled 70 patients with mCRC who received ramucirumab plus chemotherapy at National Taiwan University Hospital between 2018 and 2019., Results: Compared with those who received third- or later-line ramucirumab treatment, patients who received second-line ramucirumab treatment had significantly longer median time to treatment discontinuation (mTTD; 6.7 vs 3.6 months, P = .004) and median overall survival (mOS; not reached vs 7.6 months, P = .009). Multivariate analyses revealed that second-line ramucirumab and triplet chemotherapy backbone were the only independent predictive factors for long mTTD and mOS. Patients who received ramucirumab with triplet chemotherapy had a significantly longer mOS than did patients who received ramucirumab with doublet chemotherapy (not reached vs 5.6 months, P = .002). Among those receiving second-line ramucirumab treatment, combination with triplet chemotherapy led to a longer mTTD than did combination with doublet chemotherapy, but the difference was non-significant (not reached vs 4.4 months, P = .108). By contrast, in patients receiving fourth- or later-line ramucirumab, combination with triplet chemotherapy led to significantly longer mTTD than did combination with doublet chemotherapy (8.0 vs 2.9 months, P = .032)., Conclusion: Ramucirumab plus triplet chemotherapy may be an alternative regimen in patients with mCRC, particularly as a later-line treatment modality., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and is a potentially curable disease. However, it is heterogenous, and the prognosis is poor if the tumor cells harbor fusions involving MYC and BCL2 or MYC and BCL6 (double-hit [DH] lymphoma), or fusions involving all three genes (triple-hit [TH] lymphoma). Fluorescence in situ hybridization is currently the gold standard for confirming the presence of DH/TH genotypes. However, the test is laborious and not readily available in some laboratories. Germinal center B (GCB) signatures and dual expression of MYC and BCL2 are commonly used as initial screening markers (traditional model) in clinical practice. Our study proposes immunohistochemical markers for more conveniently and accessibly screening DH/TH genotypes in DLBCL. We retrospectively reviewed the clinical and pathological parameters of patients with DLBCL. We assessed the proliferative index, apoptotic index, and tumor microenvironment (TME), with regard to T cells and CD11c(+) dendritic cells, in formalin-fixed paraffin-embedded tissue. We then generated a decision tree as a screening algorithm to predict DH/TH genotypes and employed decision curve analysis to demonstrate the superiority of this new model in prediction. We also assessed the prognostic significance of related parameters. Our study revealed that GCB subtypes, a Ki67 proliferative index higher than 70%, and BCL2 expression were significantly associated with DH/TH genotypes. Decreased CD11c(+) dendritic cells in the TME indicated additional risk. Our proposed screening algorithm outperformed a traditional model in screening for the DH/TH genotypes. In addition, decreased CD11c(+) dendritic cells in the DLBCL TME were an independent unfavorable prognosticator. In conclusion, we provide a convenient, well-performing model that predicts DH/TH genotypes in DLBCL. The prognostic significance of CD11c(+) dendritic cells in the TME might influence the classification and development of immunotherapy for DLBCL in the future., (© 2022 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Background: Non-alcoholic steatohepatitis (NASH) has become an increasingly recognized problem in patients after orthotopic liver transplant. The aims of this study were to compare the clinicopathologic features of recurrent and de novo NASH., Methods: From 1995 to 2016, we performed a retrospective review of patients with a histological diagnosis of non-alcoholic steatohepatitis made more than 6 months after liver transplant at University of California, San Francisco. The cases were categorized into de novo (n = 19) or recurrent steatohepatitis (n = 37)., Results: Hepatitis C virus (HCV) infection-related cirrhosis was the most common etiology of transplantation in de novo NASH (78% of cases, n = 29). There was no difference in glycogenosis or presence of grade 3 steatosis. More recurrent NASH biopsies had small ballooned hepatocytes (62.5% of cases) compared to de novo NASH (26.7%) (p = 0.03), and were less likely to show prominent portal inflammation (5% versus 40.5%, p = 0.0049). The diagnosis of recurrent NASH was made significantly sooner after transplantation than the diagnosis of de novo NASH (2.8 years versus 4.8 years, p = 0.02)., Conclusions: Overall, our results support that recurrent NASH demonstrates distinct clinicopathologic features compared to de novo NASH arising in the post-transplant setting., (© 2022. The Author(s).)

Yohimbine (YOH) has antiproliferative effects against breast cancer and pancreatic cancer; however, its effects on vascular proliferative diseases such as atherosclerosis remain unknown. Accordingly, we investigated the inhibitory mechanisms of YOH in vascular smooth muscle cells (VSMCs) stimulated by platelet-derived growth factor (PDGF)-BB, a major mitogenic factor in vascular diseases. YOH (5-20 μM) suppressed PDGF-BB-stimulated a mouse VSMC line (MOVAS-1 cell) proliferation without inducing cytotoxicity. YOH also exhibited antimigratory effects and downregulated matrix metalloproteinase-2 and -9 expression in PDGF-BB-stimulated MOVAS-1 cells. It also promoted cell cycle arrest in the initial gap/first gap phase by upregulating p27Kip1 and p53 expression and reducing cyclin-dependent kinase 2 and proliferating cell nuclear antigen expression. We noted phospholipase C-γ1 (PLCγ1) but not ERK1/2, AKT, or p38 kinase phosphorylation attenuation in YOH-modulated PDGF-BB-propagated signaling pathways in the MOVAS-1 cells. Furthermore, YOH still inhibited PDGF-BB-induced cell proliferation and PLCγ1 phosphorylation in MOVAS-1 cells with α2B-adrenergic receptor knockdown. YOH (5 and 10 mg/kg) substantially suppressed neointimal hyperplasia in mice subjected to CCA ligation for 21 days. Overall, our results reveal that YOH attenuates PDGF-BB-stimulated VSMC proliferation and migration by downregulating a α2B-adrenergic receptor-independent PLCγ1 pathway and reduces neointimal formation in vivo. Therefore, YOH has potential for repurposing for treating atherosclerosis and other vascular proliferative diseases.

Since the power of transmitting one-bit data is higher than that of computing one thousand lines of code in IoT (Internet of Things) applications, it is very important to reduce communication costs to save battery power and prolong system lifetime. In IoT sensors, the transformation of physical phenomena to data is usually with distortion (bounded-error tolerance). It introduces bounded-error data in IoT applications according to their required QoS 2 (quality-of-sensor service) or QoD (quality-of-decision making). In our previous work, we proposed a bounded-error data compression scheme called BESDC (Bounded-Error-pruned Sensor Data Compression) to reduce the point-to-point communication cost of WSNs (wireless sensor networks). Based on BESDC, this paper proposes an online bounded-error query (OBEQ) scheme with edge computing to handle the entire online query process. We propose a query filter scheme to reduce the query commands, which will inform WSN to return unnecessary queried data. It not only satisfies the QoS 2 /QoD requirements, but also reduces the communication cost to request sensing data. Our experiments use real data of WSN to demonstrate the query performance. Results show that an OBEQ with a query filter can reduce up to 88% of the communication cost when compared with the traditional online query process.

The clinicopathological and molecular characteristics of primary hepatic undifferentiated carcinoma are poorly defined. It is speculated that primary hepatic undifferentiated carcinoma develops in the setting of preceding primary hepatic carcinoma. We investigated 14 primary hepatic undifferentiated carcinomas through targeted next-generation sequencing and immunohistochemistry. A panel of genes commonly mutated in primary liver carcinomas were examined. We found a similar clinical context as primary hepatic carcinoma, including a high prevalence of chronic viral hepatitis (86%), cirrhosis (57%), and elevated alpha-fetoprotein (29%). Tumors had sheet-like and poorly cohesive growth patterns. Rhabdoid cytomorphology was observed in four samples. Notably, the most common genetic mutations in primary hepatic undifferentiated carcinoma were in the promoter of TERT (n = 8, 57%) and TP53 (n = 8, 57%), which are common in hepatocellular carcinoma. The mutation rate of TP53 was elevated compared with hepatocellular carcinoma. No other typical genetic features of intrahepatic cholangiocarcinoma were identified, such as an IDH1/IDH2 mutation, FGFR2 fusions, or aberrant BAP1 expression. Furthermore, novel switch/sucrose nonfermenting complex inactivation was found, including SMARCA4/SMARCA2 (n = 1) and PBRM1 deficiency (n = 2). The three tumors demonstrated poorly cohesive histology, including rhabdoid features. High PD-L1 expression (57%) was observed in a majority of the tumors. Primary hepatic undifferentiated carcinoma shares clinical and genetic features with hepatocellular carcinoma but harbors progressive molecular characteristics that may initiate tumor dedifferentation. High PD-L1 expression in primary hepatic undifferentiated carcinoma may be a useful biomarker for potential immunotherapeutic strategies., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Fatal vehicle crashes (FVCs) are among the leading causes of death worldwide. Professional drivers often drive under dangerous conditions; however, knowledge of the risk factors for FVCs among professional drivers remain scant. We investigated whether professional drivers have a higher risk of FVCs than non-professional drivers and sought to clarify potential risk factors for FVCs among professional drivers. We analyzed nationwide incidence rates of FVCs as preliminary data. Furthermore, by using these data, we created a 1:4 professionals/non-professionals preliminary study to compare with the risk factors between professional and non-professional drivers. In Taiwan, the average crude incidence rate of FVCs for 2003-2016 among professional drivers was 1.09 per 1,000 person-years; professional drivers had a higher percentage of FVCs than non-professional drivers among all motor vehicle crashes. In the 14-year preliminary study with frequency-matched non-professional drivers, the risk of FVCs among professional drivers was significantly associated with a previous history of involvement in motor vehicle crashes (adjustment odds ratio [OR] = 2.157; 95% confidence interval [CI], 1.896-2.453), previous history of benzodiazepine use (adjustment OR = 1.385; 95% CI, 1.215-1.579), and speeding (adjustment OR = 1.009; 95% CI, 1.006-1.013). The findings have value to policymakers seeking to curtail FVCs., 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 Tsai, Yang, Ho, Wu, Guo, Chen and Chuang.)

Background: Acute renal infarction is a rare and under-diagnosed disease for which the optimal treatment is unknown., Objectives: This study aimed to determine the utility of catheter-directed thrombolysis (CDT) to treat acute renal infarction., Methods: From November 2010 to September 2017, 13 patients with acute renal infarction were treated with CDT. The diagnosis was confirmed by contrast-enhanced computed tomography and renal angiography., Results: The most common symptoms and signs were flank pain (53.8%) and abdominal pain (30.8%). More than two-thirds of the patients (69.2%) had atrial fibrillation. In successful reperfusion cases, the median time from symptom onset to diagnosis was 6 hours, and the average time from diagnosis to treatment was 3.5 hours. Complete resolution of thrombi in the renal artery was achieved in 10 of the 13 patients (76.9%) and partial resolution in two patients (15.4%). Only one patient (7.7%) failed to respond to treatment. Compared with admission, renal function was significantly improved at 6 months. No major complications occurred during the course of CDT therapy., Conclusions: CDT offers an alternative to surgical intervention and can achieve good angiographic results with an early diagnosis and intervention. It is relatively safe and can restore at least partial renal function.

Osteoarthritis (OA) is a globally occurring articular cartilage degeneration disease that adversely affects both the physical and mental well-being of the patient, including limited mobility. One major pathological characteristic of OA is primarily related to articular cartilage defects resulting from abrasion and catabolic and proinflammatory mediators in OA joints. Although cell therapy has hitherto been regarded as a promising treatment for OA, the therapeutic effects did not meet expectations due to the outflow of implanted cells. Here, we aimed to explore the repair effect of magnetized chondrocytes using magnetic amphiphilic-gelatin nanocarrier (MAGNC) to enhance cellular anchored efficiency and cellular magnetic guidance (MG) toward the superficial zone of damaged cartilage. The results of in vitro experiments showed that magnetized chondrocytes could be rapidly guided along the magnetic force line to form cellular amassment. Furthermore, the Arg-Gly-Asp (RGD) motif of gelatin in MAGNC could integrate the interaction among cells to form cellular stacking. In addition, MAGNCs upregulated the gene expression of collagen II (Col II), aggrecan, and downregulated that of collagen I (Col I) to reduce cell dedifferentiation. In animal models, the magnetized chondrocytes can be guided into the superficial zone with the interaction between the internal magnetic field and MAGNC to form cellular stacking. In vivo results showed that the intensity of N-sulfated-glycosaminoglycans (sGAG) and Col II in the group of magnetized cells with magnetic guiding was higher than that in the other groups. Furthermore, smooth closure of OA cartilage defects was observed in the superficial zone after 8 weeks of implantation. The study revealed the significant potential of MAGNC in promoting the high-density stacking of chondrocytes into the cartilage surface and retaining the biological functions of implanted chondrocytes for OA cartilage repair.

The number of people living with dementia globally is increasing rapidly, and there is no effective therapy. Dietary pattern is one important risk factor for the development and progression of dementia. We undertake this study to determine whether Taiwanese vegetarian diet in midlife affects dementia incidence in later years in a prospective cohort. We followed 5710 participants (average age less than 60) in the Tzu Chi Vegetarian Study (TCVS). We started recruiting in 2005 and followed until the end of 2014 when the database changed from ICD-9-CM to ICD-10-CM codes. The incidence of dementia was obtained through linkage to the National Health Insurance Research Database. We used Cox proportional hazards regression to estimate the hazard ratio of dementia between vegetarians and nonvegetarians. There were 121 cases of dementia (37 vegetarians and 84 nonvegetarians) diagnosed. Vegetarians were associated with reduced risk of clinically overt dementia compared with nonvegetarians (hazard ratio = 0.671, confidence interval: 0.452−0.996, p < 0.05) after adjusting for gender, age, smoking, drinking, education level, marriage, regular exercise, and comorbidities with stepwise regression.

Type 2 diabetes might be influenced by colonic disease; however, the association between colonic resection and type 2 diabetes has rarely been discussed. This population-based cohort study explored the association between colectomy and type 2 diabetes in patients without colorectal cancer. A total of 642 patients who underwent colectomy for noncancerous diseases at any time between 2000 and 2012 in the National Health Insurance Research Database of Taiwan were enrolled. The enrolled patients were matched with 2568 patients without colectomy at a 1:4 ratio using a propensity score that covered age, sex, and comorbidities. The risk of type 2 diabetes was assessed using a Cox proportional hazards model. The mean (standard deviation) follow-up durations in colectomy cases and non-colectomy controls were 4.9 (4.0) and 5.6 (3.6) years, respectively; 65 (10.1%) colectomy cases and 342 (15.5%) non-colectomy controls developed type 2 diabetes. After adjustment, colectomy cases still exhibited a decreased risk of type 2 diabetes (adjusted HR = 0.80, 95% CI: 0.61-1.04). A stratified analysis for colectomy type indicated that patients who underwent right or transverse colectomy had a significantly lower risk of developing type 2 diabetes (adjusted HR = 0.57, 95% CI: 0.34-0.98). In the present study, colectomy tended to be at a reduced risk of type 2 diabetes in patients without colorectal cancer, and right or transverse colectomies were especially associated with a significantly reduced risk of type 2 diabetes.

Background: A new strategy, particularly a novel combination, for immunotherapy in microsatellite stable metastatic colorectal cancer (mCRC) treatment needs to be formulated. Studies on the interferon-γ (IFN-γ)/ Janus kinase (JAK)/ signal transducer and activator of transcription (STAT)1 pathway provide new directions in this regard., Methods: Our study applies three colon cancer cell lines, including microsatellite stable (MSS) cell lines, which are SW480 and SW620, and microsatellite instability-high (MSI-H) cell line, which is DLD-1. We compared the expressions of immune surface markers on colon cancer cells in response to IFN-γ. We elucidated these mechanisms, which involved the upregulation of immune surface markers. Furthermore, we examined real-world clinical samples using the PerkinElmer Opal multiplex system and NanoString analysis., Results: We established that the baseline expression of major histocompatibility complex (MHC) class I alleles and programmed death-ligand 1 (PD-L1) were generally low in cell line models. The immune surface markers were significantly increased after IFN-γ stimulation on SW480 but were notably unresponsive on the SW620 cell line. We discovered that STAT1 and phosphorylated STAT1 (pSTAT1) were downregulated in the SW620 cell line. We verified that the STAT1/pSTAT1 could be restored through the application of proteasome inhibitors, especially bortezomib. The expression of MHC class I as downstream signals of STAT1 was also up-regulated by proteasome inhibitors. The similar results were reproduced in DLD-1 cell line, which was also initially unresponsive to IFN-γ. In real-world samples of patients with mCRC, we found that higher STAT1 expression in tumor cells was strongly indicative of a highly immunogenic microenvironment, with significantly higher expression levels of MHC class I and PD-L1, not only on tumor cells but also on non-tumor cells. Furthermore, tumor infiltrating lymphocytes (TILs) were increased in the positive-STAT1 group. Through NanoString analysis, we confirmed that the mRNA expressions of IFN-γ, human leukocyte antigen (HLA)-A, HLA-E, and HLA-G were also significantly higher in the positive-STAT1 group than those in the negative-STAT1 group., Conclusion: Our study provides a novel rationale for the addition of bortezomib, a proteasome inhibitor, into new immunotherapy combinations., (© 2021. The Author(s).)

Background. Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing quality of life impairments such as insatiable hunger (hyperphagia) and obesity. We explored caregivers' willingness to assume treatment risk in exchange for reduced hyperphagia according to a PWS-validated observer-reported outcome measure. Methods. We partnered with PWS patient organizations to develop a discrete-choice experiment exploring caregivers' benefit-risk tradeoffs for emerging PWS treatments. The treatment benefit was a reduction in hyperphagia (as measured by a 0-, 5-, or 10-point change on the Hyperphagia Questionnaire for Clinical Trials [HQ-CT]). Treatment risks included weight gain (none, 5%, 10%), added risk of skin rash (none, 10%, 20%), and risk of liver damage (none, 1 in 1000, 10 in 1000). Preference models were estimated using mixed logistic regression and maximum acceptable risk. We explored differences in preferences across familial caregivers of patients with and without hyperphagia. Results. Four hundred sixty-eight caregivers completed the online survey. The majority of caregivers reported that patients experienced hyperphagia (68%) and half of patients experienced obesity (52%). Caregivers of patients without hyperphagia were willing to accept greater weight gain (16.4% v. 8.1%, P = 0.004) and a higher risk of skin rash (11.7% v. 6.2% P = 0.008) as compared to caregivers of patients with hyperphagia. Caregivers of patients with hyperphagia would accept a higher risk of liver damage as compared to caregivers of patients without hyperphagia (11.9 out of 1000 v. 6.4 out of 1000, P = 0.04). Conclusions. This research demonstrates that caregivers are willing to accept risk in exchange for a five-point improvement on the HQ-CT, a smaller marginal improvement than had been previously classified as meaningful. Patient experience with hyperphagia is a modifier in how much risk caregivers will accept., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Methadone maintenance treatment (MMT) can alleviate opioid dependence. However, MMT possibly increases the risk of motor vehicle collisions. The current study investigated preliminary estimation of motor vehicle collision incidence rates. Furthermore, in this population-based retrospective cohort study with frequency-matched controls, opiate adults receiving MMT (cases) and those not receiving MMT (controls) were identified at a 1:2 ratio by linking data from several nationwide administrative registry databases. From 2009 to 2016, the crude incidence rate of motor vehicle collisions was the lowest in the general adult population, followed by that in opiate adults, and it was the highest in adults receiving MMT. The incidence rates of motor vehicle collisions were significantly higher in opiate users receiving MMT than in those not receiving MMT. Kaplan-Meier curves of the incidence of motor vehicle collisions differed significantly between groups, with a significant increased risk during the first 90 days of follow-up. In conclusion, drivers receiving MMT have higher motor vehicle collision risk than those not receiving MMT in opiate users, and it is worthy of noticing road safety in such drivers, particularly during the first 90 days of MMT., Competing Interests: YY, PH, TW, PW, CL, JT, YG, HC No competing interests declared, (© 2021, Yang et al.)