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Colorectal cancer (CRC) ranks third in the United States for incidence or mortality. Surgical resection is the primary treatment for patients at an early stage, while patients with advanced and metastatic CRC receive combined treatment with chemotherapy, radiotherapy, or targeted therapy. C-RAF plays a key role in maintaining clonogenic and tumorigenic capacity in CRC cells and it might be a potential therapeutic target for CRC. Sorafenib is a popular oral multi-kinase inhibitor, including a B-RAF inhibitor that targets the RAF-MEK-ERK pathway. Sorafenib, as a single agent, has tumor-suppressing efficacy, but its clinical application is limited due to many complex drug resistance mechanisms and side effects. GW5074 is one of the C-RAF inhibitors and has the potential to enhance the efficacy of existing cancer chemotherapies. In this study, we investigated whether the combination of sorafenib with GW5074 could reduce the dosage of sorafenib and enhance its tumor-suppressive effect in two CRC cell lines, HCT116 and LoVo cells. Our findings demonstrate that GW5074 can potentiate the cytotoxicity of sorafenib and dramatically reduce the half-maximal inhibitory concentration (IC50) dose of sorafenib from 17 and 31 µM to 0.14 and 0.01 µM in HCT116 and LoVo cells, respectively. GW5074, similar to sorafenib, suppressed the cellular proliferation and induced cellular apoptosis and cytosolic ROS, but had no further enhancement on the above-mentioned effects when combined with sorafenib. The synergistic effects of GW5074 and sorafenib were mainly found in mitochondrial functions, including ROS generation, membrane potential disruption, and fission-fusion dynamics, which were examined by using the flow cytometry analysis. In summary, the C-RAF inhibitor GW5074 might potentiate the cytotoxicity of the B-RAF inhibitor sorafenib mediated through mitochondrial dysfunctions, suggesting that GW5074 potentially serves as a sensitizer for sorafenib application to reduce the risk of drug resistance of CRC treatment. Our findings also provide novel insights on using C-RAF inhibitors combined with sorafenib, the current CRC therapeutic drug choice, in CRC treatment., 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 Hu, Chang, Hsieh and Huang.)

Thermosynechococcus sp. CL-1 (TCL-1) has a high potency to utilize CO 2 under extreme conditions including high temperature, alkaline condition, and the occurrence of 17β-estradiol (E2). In this study, TCL-1 cultivation with E2 addition in the range of 0-20 mg/L was combined with various growth arrangements (light intensity and dissolved inorganic nitrogen/DIN level). After 120 h cultivation, the 1.0 mg/L E2, 200 µmol photons/m 2 /s light intensity, and 5.8 mM available nitrogen performed the best growth with 4.58 ± 0.18 mg/L/h biomass productivity, 94.9 ± 3.3% total estrogen removal, and 11.41 ± 0.11 mg/L/h CO 2 fixation rate. Estrogen degradation was mainly carried out by biodegradation route which started from E2 conversion into estrone/E1 and with only 4-6% influence from the abiotic factors. Compared with the accumulated zeaxanthin, β-carotene was dominantly generated with a productivity of 0.043 ± 0.019 mg/L/h. Therefore, TCL-1 cultivation is an efficient strategy for simultaneous CO 2 fixation, estrogen removal, and carotenoid accumulation as valuable byproducts., (Copyright © 2022. Published by Elsevier Ltd.)

Aims: To evaluate the association between respiratory distress syndrome (RDS) and intrauterine fetal growth restriction (IUGR) by using a dichorionic twin model., Methods: We retrospectively analyzed twins delivered between September 2012 and December 2018. A dichorionic (DC) twin pregnancy with selective IUGR (sIUGR) was defined as the presence of (i) a birthweight discordance of ≥25% and (ii) a smaller twin with birth weight below the 10th percentile. Pregnancies with major fetal anomalies, delivery at gestational age below 23 weeks, and intrauterine fetal demise were excluded., Results: We included 53 DC twins with sIUGR. The sIUGR twin had a higher risk of RDS than did his appropriate for gestational age (AGA) cotwin (32.1% vs. 11.3%, p = 0.001); however, the risk of severe RDS did not significantly differ between the twins (17.0% vs 9.4%, p = 0.125). The findings of logistic regression analysis indicated that younger gestational age (weeks) at delivery (odds ratio = 0.48, p < 0.001) and IUGR (odds ratio = 13.87, p = 0.009) were significant risk factors for RDS in newborns in DC twin pregnancies with selective sIUGR., Conclusions: IUGR was identified as a risk factor for newborn RDS. However, the association between IUGR and severe newborn RDS was not significant possibly due to the small sample size of this study., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: The clinical guidelines suggest that the dosing of cyclosporine (CsA), during combination therapy with paritaprevir/ritonavir-ombitasvir and dasabuvir (PrOD), would be only one-fifth of the pre-PrOD total daily dose to be administered once daily. However, this dosing may not be applicable to all patients depending on their clinical condition. This study focuses on the pharmacokinetic dynamics of PrOD with CsA in Asian organ transplant recipients with severe liver fibrosis or cirrhosis who undergo concurrent treatment with PrOD treatment and CsA. The efficacy and safety of PrOD treatment was also evaluated., Methods: Data from 7 patients obtained between January 2017 and September 2017 were retrospectively analyzed. Determinations of the blood concentrations of CsA were made, whether used as a single treatment or in combination therapy with PrOD., Results: The combination regimen compared with CsA administered alone resulted in a 4.53-fold and 5.52-fold increase in the area under the concentration-time curve from time 0-12 hours (AUC0-12 h) of CsA on days 1 and 15, respectively. In addition, the maximal concentration, time to maximum concentration, and terminal phase elimination half-life (t1/2) of CsA were increased during the combined treatment of PrOD and CsA. The authors proposed reducing the CsA dosage during PrOD treatment to one-seventh of that of the pre-PrOD treatment of the total daily dose to maintain target CsA levels. All patients achieved sustained virologic responses at week 12. There were no episodes of serious adverse events or graft rejections observed., Conclusions: Although the combination with PrOD significantly affects the pharmacokinetics of CsA, it is effective and safe with regular monitoring of the CsA blood concentrations and appropriate CsA dose adjustment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is the primary histological subtype of liver cancer, and its incidence rates increase with age. Recently, systemic therapies, such as immune checkpoint inhibitors, monoclonal antibodies, and tyrosine kinase inhibitors (TKIs), have been more beneficial than conventional therapies for treating HCC. Nonetheless, the prognosis of late-stage HCC remains dismal because of its high recurrence rates, even with substantial advances in current therapeutic strategies. A new treatment, such as a combination of current systemic therapies, is urgently required. Therefore, we adopted a repurposing strategy and tried to combine ascorbate with TKIs, including lenvatinib and regorafenib, in HepG2 and Hep3B cells. We investigated the potential functional impact of pharmacological concentrations of ascorbate on the cell-cycle profiles, mitochondrial membrane potential, oxidative response, synergistic effects of lenvatinib or regorafenib, and differential responsiveness between HepG2 and Hep3B cells. Our data suggest that the relative level of cell density is an important determinant for ascorbate cytotoxicity in HCC. Furthermore, the data also revealed that the cytotoxic effect of pharmacological concentrations of ascorbate might not be mediated via our proposed elevation of ROS generation. Ascorbate might be involved in redox homeostasis to enhance the efficacy of TKIs in HepG2 and Hep3B cells. The synergistic effects of ascorbate with TKIs (lenvatinib and regorafenib) support their potential as an adjuvant for HCC targeted TKI therapy. This research provides a cheap and new combinatory therapy for HCC treatment., 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 Fan, Liu, Chang, Chiu, Huang and Chen.)

Pemphigus is an autoantibody-mediated blistering disease. In addition to conventional pemphigus vulgaris and pemphigus foliaceus, several other types have been reported. Among them, IgG/IgA pemphigus is less well defined and seldom reported. To characterize the clinical, histopathologic, and immunohistochemical presentation of IgG/IgA pemphigus, we retrospectively identified 22 patients with the disease at a referral center in Taiwan. These patients showed two types of skin lesion: annular or arciform erythemas with blisters or erosions (45.5%) and discrete erosions or blisters such as those in conventional pemphigus (54.5%). Mucosal involvement was found in 40.9%. Histopathologic analysis identified acantholysis (77.3%) and intra-epidermal aggregates of neutrophils (40.9%) and eosinophils (31.8%). Direct immunofluorescence studies showed IgG/IgA (100%) and C3 (81.8%) depositions in the intercellular space of the epidermis. In immunohistochemical staining, patients with IgG/IgA pemphigus demonstrated significantly higher levels of epidermal expression of interleukin-8 and matrix metalloproteinase-9 than those with conventional pemphigus (p < 0.05). In conclusion, although IgG/IgA pemphigus is heterogeneous in presentation, it shows characteristic features that are different from other forms of pemphigus and should be considered a distinct type of pemphigus.

Catalytic nitrite reductions by Cu II complexes containing anionic Me2 Tp, neutral Me2 Tpm, or neutral i Pr TIC ligands in the presence of L-ascorbic acid, which served as an electron donor and proton source, were investigated. The results showed that auxiliary ligands are important for copper-mediated catalytic nitrite reduction. Furthermore, the electronic effects of the ligand govern the nitrite reduction efficiency, which should be considered at two control points: one is the susceptibility of the LCu I -nitrite species to protonation and the other is the susceptibility of LCu II to reduction giving LCu I . In addition, an external strong acid leads to the production of nitrous acid, which may suggest that the reactivity of nitrous acid toward the LCu I species is a third control point.

Purpose: To identify factors associated with posttraumatic growth (PTG) of head-and-neck cancer squamous cancer (HNC) patients with oncologic emergencies (OE) within the first six months post-treatment., Methods: We conducted a cross-sectional study of HNC patients in Taiwan from May 2019 to April 2021 using patient-reported outcomes. Patients were assessed for symptom distress, anxiety, fear of recurrence (FCR), and PTG. Multiple regression analysis was conducted to identify factors associated with PTG. The independent-samples t-test was used to compare PTG and its five specific domains in patients with low FCR, high FCR, low anxiety, and high anxiety., Results: Of the 114 patients surveyed, 46.5% reported little-to-no PTG, and 53.5% had moderate-to-high PTG. Greater PTG was associated with greater FCR, longer time since OE, less anxiety, having a cancer recurrence, and greater educational attainment. These factors explained 38.6% of the variance in PTG., Conclusion: A notable proportion of HNC patients with OE-reported PTG but almost half-reported little-to-no PTG. PTG occurred most in the domain of appreciation of life. The study results also suggest that training patients in coping skills and inviting them to group growth experiences can help them increase PTG and cope with cancer-related psychological threats related to OE., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Current clinical guidelines are unclear regarding the association of cardiovascular medication with the risk of acute exacerbation (AE) in patients with asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO)., Methods: We conducted a retrospective cohort study by interrogating the claims database of Taipei Veterans General Hospital. Patients with coexistent fixed airflow limitation and asthma were enrolled as an ACO cohort between 2009 and 2017. Exposure to cardiovascular medications, including angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), non-selective beta-blockers, cardioselective beta-blockers, dihydropyridine (DHP) calcium channel blockers (CCBs), and non-DHP CCBs, in 3-month period each served as time-dependent covariates. Patients receiving a cardiovascular medication ≥ 28 cumulative daily doses were defined as respective cardiovascular medication users. Patients were followed up until December 31, 2018. The primary endpoint was severe AE, defined as hospitalization or emergency department visit for either asthma, COPD, or respiratory failure. The secondary outcome was moderate AE., Results: The final study cohort consisted of 582 ACO subjects, with a mean follow-up period of 2.98 years. After adjustment, ARB (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.44-0.93, P = 0.019), cardioselective beta-blocker (HR, 0.29, 95% CI, 0.11-0.72, P = 0.008) and DHP CCB (HR, 0.66, 95% CI, 0.45-0.97, P = 0.035) therapies were associated with lower risks of severe AE. ARB (HR, 0.42, 95% CI, 0.30-0.62, P < 0.001) and DHP CCB (HR, 0.55, 95% CI, 0.38-0.80, P = 0.002) therapies were associated with lower risks of moderate AE. Cardioselective beta-blockers, ARBs, and DHP CCBs were associated with lower risks of severe AE in frequent exacerbators. ACEI, non-selective beta-blocker, or non-DHP CCB use did not change the risk of severe AE., Conclusions: ARB, cardioselective beta-blocker, and DHP CCB therapies may lower the risk of AE in patients with ACO., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2022 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Purpose: Inappropriate dosing of glucose-lowering drugs in patients with renal insufficiency can cause severe harm. This study evaluated the short- and long-term effects of clinical decision support systems (CDSS) on inappropriate prescriptions of glucose-lowering agents for patients with renal insufficiency in an ambulatory care setting., Methods: This retrospective longitudinal observational study was conducted by using an electronic medical record database and the CDSS log data at Taipei Veterans General Hospital between January 1, 2015, and December 31, 2018. Outpatients who received 7 target glucose-lowering medications and had an estimated glomerular filtration rate <50 mL/min/1.73 m 2 were included. Inappropriate prescriptions were defined as a dose, frequency, or daily dose of target drugs that exceeded the dosing recommendations based on renal function. Inappropriate monthly rates were calculated, and the interrupted time series analysis method was used to explore the 1- and 3-year post-implementation effects of CDSS. The major outcome measurements were the level changes and the inappropriate prescription rate trend changes after renal CDSS implementation. The acceptance rates of alerts were also analyzed., Findings: A total of 141,037 drug prescriptions were obtained during the study period. In the short-term analysis, the baseline inappropriate rate for overall medications was estimated to range from 30.54% in the first month to 27.06% in month 12. The predicted inappropriate rate 12 months after implementation was 19.35%, corresponding to an estimated 28.49% [(27.06 - 19.35)/27.06] decrease in inappropriate rate. However, after long-term analysis, the predicted inappropriate rate at the end of the study (36 months after implementation) was 18.02%. A total of 27,189 alerts were generated and 628 were accepted during the study period. Thus, after short- and long-term analysis, the overall acceptance rate was 3.06% and 2.31%, respectively., Implications: Implementing a CDSS for renal dosing adjustment could significantly decrease the inappropriate prescription rate of glucose-lowing agents among patients with renal insufficiency in an ambulatory setting in the short term, while the long-term effect of a CDSS is limited., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background. Studies have demonstrated that patients with diabetes mellitus who receive metformin have a lower risk of developing Parkinson’s disease (PD). However, studies have also suggested that metformin may increase the risk of PD. In this study, we investigated whether metformin use was associated with the risk of PD in type 2 diabetes mellitus (T2DM). Methods. In this population-based cross-sectional study, patients with T2DM diagnosed between 2001 and 2018 were enrolled. We categorized these patients as metformin users or nonusers. Participants below 50 years old were excluded. Two models were employed to evaluate the associations of metformin exposure and use intensity with PD after 3 and 5 years of follow-up. Results. Patients with T2DM who received <300 cumulative defined daily doses (cDDD) of metformin and those with metformin use intensity of <10 DDD/month had respective odds ratios (ORs) for PD of 0.88 (95% confidence interval [CI] = 0.83−0.94) and 0.87 (95% CI = 0.81−0.93) in a 3-year follow-up. In a 5-year follow-up, such patients had respective ORs for PD of 0.94 (95% CI = 0.90−0.98) and 0.93 (95% CI = 0.89−0.98). Patients with T2DM who received ≥300 cDDD of metformin or used metformin with intensity of ≥10 DDD/month experienced no neuroprotective effects after 3 or 5 years. Conclusions. Metformin was associated with PD odds in T2DM in a dose−response association manner. Patients who received low dosage and intensity of metformin use were associated with lower odds of PD, while higher dosage and intensity of metformin use had no neuroprotective effect.

(1) Background: Glucose is transferred from maternal blood to the fetus by glucose transporters. What is the effect of hypoxia on the gene expression of placenta glucose transporter 1 ( GLUT1 ) and glucose transporter 3 ( GLUT3 ) in growth-restricted fetus is interesting. (2) Methods: The gene expression of GLUT1 and GLUT3 and the protein expression of HIF-1α were evaluated under nonhypoxic conditions and after 4 and 8 h under hypoxic conditions in placental mesenchymal stem cells derived from monochorionic twin pregnancies with selective intrauterine growth restriction. (3) Results: The gene expressions of GLUT1 and GLUT3 under hypoxia conditions were higher in placental mesenchymal stem cells derived from appropriate-for-gestational-age fetuses than in those from selective intrauterine growth-restricted fetuses. However, the protein expression of hypoxia induced factor-1 α (HIF-1α) at hypoxia condition was not lower in placenta mesenchymal stem cells from selective intrauterine growth-restricted fetuses than in placental mesenchymal stem cells from appropriate-for-gestational-age fetuses. (4) Conclusions: Hypoxia-induced upregulation of GLUT 1 and GLUT3 expression was decreased in placental mesenchymal stem cells from selective intrauterine growth-restricted fetuses but not due to decreased HIF-1α expression. Selective growth-restricted fetuses have less capacity for hypoxia-induced upregulation of placental glucose transport.

Background: Right ventricular outflow tract obstruction (RVOTO) is the most frequently encountered congenital heart disease in patients with twin -twin transfusion syndrome (TTTS) and is especially prevalent in the recipient twin. In this retrospective study, we evaluated the incidence, prognosis, postnatal management, and perinatal outcomes of and risk factors for RVOTO in the recipient twin in severe TTTS cases which diagnosed before 26 weeks after fetoscopic laser photocoagulation (FLP) at a single center in Taiwan., Methods: RVOTO was diagnosed using fetal or postnatal echocardiography. The fetal outcomes evaluated were perinatal survival rate, neonatal brain image anomalies rate, gestational age at delivery, and birth weight., Results: Total 187 severe TTTS cases were included; 14 (7.49%) had a recipient twin with RVOTO (12 cases of pulmonary stenosis and 2 of pulmonary atresia). Of these 14 cases, 3 (21.4%) demonstrated improvements in outflow obstruction after FLP, and 11 (78.6%) resulted in perinatal survival. Of the 11 survivors, 5 (45.5%) received transcatheter balloon valvuloplasty to alleviate the RVOTO. The perinatal survival rate, gestational age at delivery, neonatal brain image anomaly rate, and birth weights did not significantly differ between the groups in which the recipient twin had versus did not have RVOTO. Generally, the recipient twin had RVOTO received FLP at a younger gestational age (in weeks; 19.3 ± 2.4 vs. 20.7 ± 2.6, p = 0.048) and had a higher percentage of cases at Quintero stage IV (50.0% vs. 12.1%, p < 0.001) than those in which the recipient twin did not have with RVOTO. Using logistic regression, we discovered that FLP at a younger gestational age (p = 0.046, odds ratio = 0.779) and TTTS at Quintero stage IV (p = 0.001, odds ratio = 7.206) were risk factors for the recipient twin developing RVOTO after FLP in severe TTTS cases., Conclusions: The post-FLP perinatal outcomes of cases of severe TTTS in which the recipient twin had versus did not have RVOTO were comparable in this study, which may have been due to the similar gestational ages at delivery and strong influence of high Quintero stages (stages III and IV)., (© 2022. The Author(s).)

Background: Microbial dysbiosis has been implicated in the development of atopic dermatitis (AD). The risk of development of AD following early-life infections remains unclear., Objective: To investigate the impact of early-life infections on AD development., Methods: This population-based nested case-control study was conducted using the Taiwan's National Health Insurance Research Database. A total of 5454 AD patients and 16 362 control subjects without AD were identified, for the period 1997 to 2013. Demographic characteristics, comorbidities and maternal factors were compared. Adjusted odds ratio (aOR) was calculated to examine the associations between early-life infections and subsequent AD by conditional stepwise logistic regression analysis., Results: Mean age was 2.6 ± 2.9 years in both groups. Overall infections (41.8% vs. 28.9%) before the diagnosis of AD were more common in AD patients than in control subjects (P < 0.001). Infectious diseases [aOR, 1.40; 95% confidence interval (CI), 1.29-1.51], skin infections (aOR, 1.55; 95% CI, 1.40-1.71) and systemic antibiotic exposure (aOR 1.67, 95% CI 1.55-1.79) before AD diagnosis were independently associated with AD development on multivariate analyses. These results were consistent across observation periods (0-1, 1-2 and >2 years after birth) and sensitivity analyses after redefining the index date as 3 or 6 months before the date of AD diagnosis. Other independent risk factors included asthma, allergic rhinitis, intussusception and neonatal hyperbilirubinemia. No association with subsequent AD was found for maternal age at delivery, Caesarean delivery or prenatal antibiotic exposure., Conclusion: Infections in early life are associated with AD development in infancy and early childhood., (© 2022 European Academy of Dermatology and Venereology.)

Background: Antibiotic-driven dysbiosis may impair immune function and reduce vaccine-induced antibody titers., Objectives: This study aims to investigate the impacts of early-life antibiotic exposure on subsequent varicella and breakthrough infections., Methods: This is a nationwide matched cohort study. From Taiwan's National Health Insurance Research Database, we initially enrolled 187,921 children born from 1997 to 2010. Since 2003, the Taiwan government has implemented a one-dose universal varicella vaccination program for children aged 1 year. We identified 82,716 children born during the period 1997 to 2003 (pre-vaccination era) and 48,254 children born from July 1, 2004, to 2009 (vaccination era). In the pre-vaccination era, 4,246 children exposed to antibiotics for at least 7 days within the first 2 years of life (Unvaccinated A-cohort) were compared with reference children not exposed to antibiotics (Unvaccinated R-cohort), with 1:1 matching for gender, propensity score, and non-antibiotic microbiota-altering medications. Using the same process, 9,531 children in the Vaccinated A-cohort and Vaccinated R-cohort were enrolled from the vaccination era and compared. The primary outcome was varicella. In each era, demographic characteristics were compared, and cumulative incidences of varicella were calculated. Cox proportional hazards model was used to examine associations., Results: In the pre-vaccination era, the 5-year cumulative incidence of varicella in the Unvaccinated A-cohort (23.45%, 95% CI 22.20% to 24.70%) was significantly higher than in the Unvaccinated R-cohort (16.72%, 95% CI 15.62% to 17.82%) (p<.001). In the vaccination era, a significantly higher 5-year cumulative incidence of varicella was observed in the Vaccinated A-cohort (1.63%, 95% 1.32% to 1.93%) than in the Vaccinated R-cohort (1.19%, 95% CI 0.90% to 0.45%) (p=0.006). On multivariate analyses, early-life antibiotic exposure was an independent risk factor for varicella occurrence in the pre-vaccination (adjusted hazard ratio [aHR] 1.92, 95% CI 1.74 to 2.12) and vaccination eras (aHR 1.66, 95% CI 1.24 to 2.23). The use of penicillins, cephalosporins, macrolides, or sulfonamides in infancy was all positively associated with childhood varicella regardless of vaccine administration., Conclusions: Antibiotic exposure in early life is associated with varicella occurrence and breakthrough infections., 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 Lin, Fan, Chang, Ho, Liang, Chen and Wu.)

The Internet of Things (IoT) technology has revolutionized the healthcare industry by enabling a new paradigm for healthcare delivery. This paradigm is known as the Internet of Medical Things (IoMT). IoMT devices are typically connected via a wide range of wireless communication technologies, such as Bluetooth, radio-frequency identification (RFID), ZigBee, Wi-Fi, and cellular networks. The ZigBee protocol is considered to be an ideal protocol for IoMT communication due to its low cost, low power usage, easy implementation, and appropriate level of security. However, maintaining ZigBee's high reliability is a major challenge due to multi-path fading and interference from coexisting wireless networks. This has increased the demand for more efficient channel coding schemes that can achieve a more reliable transmission of vital patient data for ZigBee-based IoMT communications. To meet this demand, a novel coding scheme called inter-multilevel super-orthogonal space-time coding (IM-SOSTC) can be implemented by combining the multilevel coding and set partitioning of super-orthogonal space-time block codes based on the coding gain distance (CGD) criterion. The proposed IM-SOSTC utilizes a technique that provides inter-level dependency between adjacent multilevel coded blocks to facilitate high spectral efficiency, which has been compromised previously by the high coding gain due to the multilevel outer code. In this paper, the performance of IM-SOSTC is compared to other related schemes via a computer simulation that utilizes the quasi-static Rayleigh fading channel. The simulation results show that IM-SOSTC outperforms other related coding schemes and is capable of providing the optimal trade-off between coding gain and spectral efficiency whilst guaranteeing full diversity and low complexity.

Background: Physical activity (PA) is important for health. However, there is little evidence on how weight stigma, time spent on sedentary activities (including smartphone, social media, online learning), time spent on outdoor activity, and nomophobia associate with PA among Chinese individuals with consideration of gender. The present study examined the aforementioned associations in the COVID-19 pandemic era., Methods: University students ( N = 3,135; 1,798 females, 1,337 males) with a mean age of 19.65 years ( SD = 2.38) years completed an online survey from November to December, 2021. The online survey assessed weight stigma (using the Perceived Weight Stigma Scale and Weight Bias Internalization Scale), PA (using the International Physical Activity Questionnaire Short Form), time spent on different activities (using self-designed items for time on smartphone, outdoor activity, social media, and online learning), and nomophobia (using the Nomophobia Questionnaire). Parallel mediation models were constructed (dependent variable: PA; mediators: perceived weight stigma, weight-related self-stigma, time spent on smartphone, time spent on outdoor activity, time spent on social media, and time spent online learning; independent variable: nomophobia) and evaluated using Hayes' Process Macro Model 4 (IBM SPSS 20.0)., Results: Weight-related self-stigma (β = -0.06; p = 0.03), time spent on outdoor activity (β = 0.21; p < 0.001), time spent on social media (β = 0.07; p = 0.02), time spent on online learning (β = 0.06; p = 0.03), and nomophobia (β = -0.07; p = 0.01) were all significant factors explaining the PA among female participants. Perceived weight stigma (β = -0.07; p = 0.01), time spent on outdoor activity (β = 0.27; p < 0.001), and time spent on online learning (β = 0.10; p = 0.002) were all significant factors explaining PA among male participants., Conclusion: Chinese healthcare providers should design programs on weight stigma reduction and outdoor activity improvement to enhance PA among university students., Competing Interests: CY-L was employed by Biostatistics Consulting Center. The remaining 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 Xu, Chen, Chang, Wang, Jiang, Griffiths, Pakpour and Lin.)

Backgrounds : Leber's hereditary optic neuropathy (LHON) is known as an inherited retinal disorder characterized by the bilateral central vision loss and degeneration of retinal ganglion cells (RGCs). Unaffected LHON carriers are generally asymptomatic, suggesting that certain factors may contribute to the disease manifestations between carriers and patients who carry the same mutated genotypes. Methods: We first aimed to establish the iPSC-differentiated RGCs from the normal healthy subject, the carrier, and the LHON patient and then compared the differential expression profile of circular RNAs (CircRNAs) among RGCs from these donors in vitro. We further overexpressed or knocked down the most upregulated circRNA to examine whether this circRNA contributes to the distinct phenotypic manifestations between the carrier- and patient-derived RGCs. Results : iPSCs were generated from the peripheral blood cells from the healthy subject, the carrier, and the LHON patient and successfully differentiated into RGCs. These RGCs carried equivalent intracellular reactive oxygen species, but only LHON-patient iPSC-derived RGCs exhibited remarkable apoptosis. Next-generation sequencing and quantitative real-time PCR revealed the circRNA hsa&#95;circ&#95;0087207 as the most upregulated circRNA in LHON-patient iPSC-derived RGCs. Overexpression of hsa&#95;circ&#95;0087207 increased the apoptosis in carrier iPSC-derived RGCs, while knockdown of hsa&#95;circ&#95;0087207 attenuated the apoptosis in LHON-patient iPSC-derived RGCs. Predicted by bioinformatics approaches, hsa&#95;circ&#95;0087207 acts as the sponge of miR-665 to induce the expression of a variety of apoptosis-related genes in LHON patient iPSC-derived RGCs. Conclusions : Our data indicated that hsa&#95;circ&#95;0087207 upregulation distinguishes the disease phenotype manifestations between iPSC-derived RGCs generated from the LHON patient and carrier. Targeting the hsa&#95;circ&#95;0087207/miR-665 axis might hold therapeutic promises for the treatment of LHON.

Background: The incidence of human papillomavirus (HPV) positive oropharyngeal cancer (OPC) is rising but HPV negative OPC is decreasing in Western countries. In Taiwan, the incidence of HPV negative OPC is common but the incidence of HPV positive OPC remains unknown. The objective of this study is to estimate the incidence trend and the survival of HPV positive OPC in Taiwan., Methods: Between 1999 and 2014, primary tumor tissues from 425 incident OPCs were obtained from 5 medical centers in Taiwan. 408 OPCs were evaluated by the EasyChip HPV genotyping (King-Car, I-Lan, Taiwan) and 369 OPCs by p16 staining. The clinical data were retrospectively obtained from the medical records., Results: In our study, 29% of OPCs were HPV positive. The percentage of HPV positive OPC was stable from 1999 to 2014 (25% (1999-2002), 30% (2003-2006), 30% (2007-2010), 29% (2011-2014)). The estimated crude incidence rate of HPV positive OPC increased significantly from 0.62 (1999-2002), 1.06 (2003-2006), 1.52 (2007-2010) to 1.74 (2011-2014) per 100,000 person-year. The sensitivity and specificity of p16 staining for positive HPV infection were 92% and 91%, respectively. The 5-year overall survival rates for patients with HPV positive OPC and with HPV negative OPC were 67.8% and 49.0%, respectively (HR = 0.52 (0.35-0.76), p = 0.0005). Patients with HPV positive OPC but no betel nut/cigarette exposure had the best overall survival (5-year: 88.2%, p < 0.0001). Patients with HPV negative OPC and betel nut/cigarette exposure had the worst overall survival (5-year: 46.6%, p < 0.0001). Patients with HPV positive OPC but also with betel nut/cigarette exposure had poorer 5-year overall survival (48.3%, p < 0.01)., Conclusion: The incidence of HPV positive OPC is increasing along with HPV negative OPC, which leads to stably low percentage of HPV positive OPC in Taiwan. HPV positive OPC may become an important head and neck cancer when the incidence of HPV negative OPC declines in the near future. P16 is a useful surrogate marker for HPV infection in OPC and a good prognostic indicator for treatment outcome of OPC. Patients with HPV positive OPC but no betel nut/cigarette exposure has an excellent prognosis. Betel nut/cigarette exposure significantly worsens the prognosis of HPV positive OPC., (© 2022. The Author(s).)

Large-area surface-enhanced Raman spectroscopy (SERS) sensing platforms displaying ultrahigh sensitivity and signal uniformity have potentially enormous sensing applicability, but they are still challenging to prepare in a scalable manner. In this study, silver nanopaste (AgNPA) was employed to prepare a wafer-scale, ultrasensitive SERS substrate. The self-generated, high-density Ag nanocracks (NCKs) with small gaps could be created on Si wafers via a spin-coating process, and provided extremely abundant hotspots for SERS analyses with ultrahigh sensitivity-down to the level of single molecules (enhancement factor: ca. 10 10 ; detection limit: ca. 10 -18  M)-and great signal reproducibility (variation: ca. 3.6%). Moreover, the Ag NCK arrays demonstrated broad applicability and practicability for on-site detection when combined with a portable 785 Raman spectrometer. This method allowed the highly sensitive detection of a diverse range of analytes (benzo[a]pyrene, di-2-ethylhexyl phthalate, aflatoxins B1, zearalenone, ractopamine, salbutamol, sildenafil, thiram, dimethoate, and methamidophos). In particular, pesticides are used extensively in agricultural production. Unfortunately, they can affect the environment and human health as a result of acute toxicity. Therefore, the simultaneous label-free detection of three different pesticides was demonstrated. Finally, the SERS substrates are fabricated through a simple, efficient, and scalable process that offers new opportunities for mass production., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: We aimed to evaluate the impact of tumor location on cancer outcomes in patients with pT3N0M0 upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU) with bladder cuff excision., Materials and Methods: We retrospectively reviewed 302 patients with pT3N0M0 UTUC who underwent RNU with bladder cuff excision at our institution between 2005 and 2019, including 191 renal pelvis tumors and 111 ureteral tumors. Clinicopathologic characteristics were compared between renal pelvis and ureter urothelial carcinomas. Multivariate Cox proportional hazard regression was used to assess the association between outcomes and clinical factors. Outcomes of interest included intravesical recurrence-free survival (IVRFS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and cancer-specific survival (CSS), which were measured using the Kaplan-Meier curve with a log-rank test., Results: A total of 302 patients underwent RNU with bladder cuff excision. During the median follow-up of 42.7 months, 70 (23.2%), 95 (31.5%), and 99 (32.8%) patients experienced intravesical recurrence, local recurrence, and distant metastasis, respectively. Seventy (23.2%) patients died from UTUC. Multivariate Cox regression analysis showed that tumor location was an independent predictor of local recurrence (HR = 2.05, p = 0.001), with borderline independent significance in intravesical recurrence (HR = 1.54, p = 0.074) and distant metastasis (HR = 1.45, p = 0.08). Kaplan-Meier analysis showed that ureter tumors had a worse 5-year local recurrence (log-rank p < 0.001) and borderline worse 5-year intravesical recurrence (log-rank p = 0.055) and 5-year distant metastasis (log-rank p = 0.073)., Conclusion: Ureter tumors seem to be associated with worse oncological outcomes, especially with local recurrence in UTUC. Further large and long-term studies are warranted for investigating biological differences based on tumor location., 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 Chen, Chen, Wang, Chiang, Yang, Lee, Chuang, Cheng, Kang, Lee, Chen, Shen, Liu, Liu, Chang, Su, Huang and Luo.)

Conductive and porous nitrogen-rich materials have great potential as supercapacitor electrode materials. The exceptional efficiency of such compounds, however, is dependent on their larger surface area and the level of nitrogen doping. To address these issues, we synthesized a porous covalent triazine framework (An-CTFs) based on 9,10-dicyanoanthracene (An-CN) units through an ionothermal reaction in the presence of different molar ratios of molten zinc chloride (ZnCl 2 ) at 400 and 500 °C, yielding An-CTF-10-400, An-CTF-20-400, An-CTF-10-500, and An-CTF-20-500 microporous materials. According to N 2 adsorption-desorption analyses (BET), these An-CTFs produced exceptionally high specific surface areas ranging from 406-751 m 2 ·g -1 . Furthermore, An-CTF-10-500 had a capacitance of 589 F·g -1 , remarkable cycle stability up to 5000 cycles, up to 95% capacity retention, and strong CO 2 adsorption capacity up to 5.65 mmol·g -1 at 273 K. As a result, our An-CTFs are a good alternative for both electrochemical energy storage and CO 2 uptake.

A series of partially fused N-doped nanographenes (2-4) are synthesized via the oxidative cyclodehydrogenation of oligoaryl-substituted dibenzo[e,l]pyrene (1), and five, six, and seven new C-C bonds are formed, respectively, implying stepwise C-C bond fusion and extended π-conjugation. Single-crystal X-ray diffraction analysis of compound 4 a revealed that the presence of sterically demanding groups hindered the formation of planar and fully fused nanographene in the oxidative cyclodehydrogenation reaction step. Optical study of compounds 2 to 4 showed that extended π-conjugation leads to a regular stepwise bathochromic shift in the absorption and emission spectra. Furthermore, the HOMO-LUMO gaps of these compounds exhibit a decrease as C-C bond formation proceeds. Thus, the optoelectronic properties of nanographenes are highly dependent on the formation of new C-C bonds in the molecular skeleton., (© 2022 Wiley-VCH GmbH.)

Background: Prior research has shown preliminary evidence that calligraphy activity improves various body functions and decreases severity of psychotic symptoms in individuals with schizophrenia. However, major limitations of earlier studies include small and heterogeneous samples. The current large-scale randomized controlled trial examined effects of calligraphy activity on cognition (including attention), emotions, psychotic symptoms, quality of life, and mood in people with schizophrenia., Methods: One-hundred-and-fifty patients with schizophrenia were randomly allocated to the treatment group (receiving calligraphy activity) or the control group (receiving general activity), both of which lasted for 24 weeks (70 minutes per session; one session per week). Assessments were conducted at pretest, posttest, and three-month follow-up. The Montreal Cognitive Assessment, Chu's Attention Test, Depression, Anxiety, and Stress Scale, Positive and Negative Syndrome Scale, World Health Questionnaire on the Quality of Life-Brief Form, and Visual Analogue Scale were used., Results: Improved cognition and attention were found in both groups, although no group effects were shown. The treatment group appeared to show lower severity of positive symptoms at follow-up than posttest, whereas the control group appeared to show the opposite pattern. Improved mood was found in the treatment group., Conclusion: This study provides evidence regarding effects of calligraphy activity on increasing cognition and potentially decreasing severity of positive symptoms in patients with schizophrenia. Calligraphy activity can be incorporated in clinical occupational therapy and may be provided to supplement medication treatment., Trial Registration: ClinicalTrials.gov NCT03882619; https://clinicaltrials.gov/ct2/show/NCT03882619., Competing Interests: Conflict of interest statement: All the authors declare that there is no conflict of interest. Dr. Potenza has consulted for Opiant Therapeutics, Game Day Data, the Addiction Policy Forum, Opiant, AXA and Idorsia Pharmaceuticals; has received research support from Mohegan Sun Casino, the Connecticut Council on Problem Gambling and the National Center for Responsible Gaming; has participated in surveys, mailings or telephone consultations related to drug addiction, impulse-control disorders or other health topics; has consulted for and/or advised gambling and legal entities on issues related to impulse-control/addictive disorders; has provided clinical care in a problem gambling services program; has performed grant reviews for research-funding agencies; has edited journals and journal sections; has given academic lectures in grand rounds, CME events and other clinical or scientific venues; and has generated books or book chapters for publishers of mental health texts. The other authors report no disclosures., (© The Author(s), 2022.)

Extracorporeal membrane oxygenation (ECMO) is one of the common invasive treatments for the care of critically ill patients with heart failure, respiratory failure, or both. There are two modes of ECMO, namely, veno-venous (VV) and veno-arterial (VA), which have different indications, survival rates, and incidences of complications. This study's aim was to examine whether depression status differed between patients who had received VV-ECMO or VA-ECMO and had been discharged from the hospital. This was a descriptive, cross-sectional, and correlational study of patients who had been discharged from the hospital at least one month after receiving ECMO at a medical center in northern Taiwan from June 2006 to June 2020 ( N = 142). Participants were recruited via convenience and quota sampling. Data were collected in the cardiovascular outpatient department between October 2015-October 2016 ( n = 52) and September 2019-August 2020 ( n = 90). Participants completed the Hospital Anxiety and Depression Scale-Depression (HADS-D) as a measure of depression status. Post-discharge depression scores for patients who received VV-ECMO ( n = 67) was significantly higher ( p = 0.018) compared with participants who received VA-ECMO ( n = 75). In addition, the mode of ECMO was a predictor of post-discharge depression ( p = 0.008) for participants who received VV-ECMO. This study concluded that patients who received VV-ECMO may require greater mental health support. Healthcare professionals should establish a psychological clinical care pathway evaluated by multiple healthcare professionals.

Background: Alzheimer disease (AD) and other types of dementia are now considered one of the world's most pressing health problems for aging people worldwide. It was the seventh-leading cause of death, globally, in 2019. With a growing number of patients with dementia and increasing costs for treatment and care, early detection of the disease at the stage of mild cognitive impairment (MCI) will prevent the rapid progression of dementia. In addition to reducing the physical and psychological stress of patients' caregivers in the long term, it will also improve the everyday quality of life of patients., Objective: The aim of this study was to design a digital screening system to discriminate between patients with MCI and AD and healthy controls (HCs), based on the Rey-Osterrieth Complex Figure (ROCF) neuropsychological test., Methods: The study took place at National Taiwan University between 2018 and 2019. In order to develop the system, pretraining was performed using, and features were extracted from, an open sketch data set using a data-driven deep learning approach through a convolutional neural network. Later, the learned features were transferred to our collected data set to further train the classifier. The first data set was collected using pen and paper for the traditional method. The second data set used a tablet and smart pen for data collection. The system's performance was then evaluated using the data sets., Results: The performance of the designed system when using the data set that was collected using the traditional pen and paper method resulted in a mean area under the receiver operating characteristic curve (AUROC) of 0.913 (SD 0.004) when distinguishing between patients with MCI and HCs. On the other hand, when discriminating between patients with AD and HCs, the mean AUROC was 0.950 (SD 0.003) when using the data set that was collected using the digitalized method., Conclusions: The automatic ROCF test scoring system that we designed showed satisfying results for differentiating between patients with AD and MCI and HCs. Comparatively, our proposed network architecture provided better performance than our previous work, which did not include data augmentation and dropout techniques. In addition, it also performed better than other existing network architectures, such as AlexNet and Sketch-a-Net, with transfer learning techniques. The proposed system can be incorporated with other tests to assist clinicians in the early diagnosis of AD and to reduce the physical and mental burden on patients' family and friends., (©Wen-Ting Cheah, Jwu-Jia Hwang, Sheng-Yi Hong, Li-Chen Fu, Yu-Ling Chang, Ta-Fu Chen, I-An Chen, Chun-Chen Chou. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 09.03.2022.)

In this study, aluminum complexes bearing ferrocene-based and arylthiomethylphenolate ligands were synthesized, and their catalytic activity for ε-caprolactone (CL) polymerization was investigated. The catalytic activity of the reduced form of Al complexes was higher than that of the oxidized form. The CL polymerization rate of the reduced form fcO 2 AlMe (75 min, conversion = 100%) was higher than that of the oxidized form fc ox O 2 AlMe (4320 min, conversion = 45%), and the CL polymerization rate of fc(OAlMe 2 ) 2 (40 min, conversion = 100%) was higher than that of fc ox (OAlMe 2 ) 2 (60 min, conversion = 97%). Electron deficiency substituents on phenolate decreased the catalytic activity of Al complexes bearing arylthiomethylphenolate ligands. Density functional theory calculations revealed that thioether coordination stabilized the transition state ( TS1 ) and that the oxidized form fc ox (OAlMe 2 ) 2 exhibited weaker thioether coordination and higher activation energy in TS1 compared with those of the reduced form fcO 2 AlMe . In addition, our study determined that the thioether group is a suitable chelating group for Al catalysts in CL polymerization due to its labile nature.

Background: The early life microbiome can shape human immunity. Recent studies have revealed gut dysbiosis after laxative administration., Objective: To investigate the impact of infantile laxative exposure on subsequent allergic diseases., Methods: This nationwide matched cohort study was conducted using Taiwan's National Health Insurance Research Database for the period 1997 to 2013. A total of 32,986 patients who had complete information of maternal history and delivery modes were identified. We included 291 children having laxatives for at least 7 days within the first 6 months of life and 1164 reference children not receiving laxatives, matching by sex, propensity score, number of hospital visits, and maternal age at delivery. Demographic characteristics and maternal factors were compared, and cumulative incidences of allergic diseases were calculated. Cox proportional hazard model was used to evaluate associations., Results: The 5-year cumulative incidence of allergic diseases in the laxative cohort was significantly higher than that in the reference cohort (49.81% vs 41.68%; P = .01). Early life laxative exposure (adjusted hazard ratio, 1.61; 95% confidence interval, 1.32-1.97) was independently associated with allergic disease development. Other independent risk factors included preterm, male sex, maternal allergic diseases, and prenatal laxative use. Multivariable stratified analyses verified the association between early life laxative exposure and subsequent allergic disease development in all subgroups of children, including those born to mothers without allergic diseases or prenatal laxative use., Conclusion: Early life laxative exposure is associated with allergic disease development., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Primary caregivers (PC) of patients with advanced head and neck cancer (HNC) report stress during caregiving time post-treatment. We sought to identify the trajectories of resilience from initial completion of treatment to 1-year post-treatment in PC of patients with advanced HNC and to determine the factors associated with trajectories of resilience., Design: In this prospective cohort study with convenience sampling, patient-PC dyads were recruited from a medical center in northern Taiwan between August 2015 and July 2020., Methods: We recruited 120 patient-PC dyads and followed up at treatment completion and 1, 6, and 12 months post-treatment. Generalized estimating equation analysis was performed to identified factors related to resilience., Findings: PCs' overall resilience increased from initial completion of treatment to peak at 1-year post-treatment. Patient factors associated with greater overall resilience included older age, higher performance status, and shorter time since cancer diagnosis; PC factors included reporting more social support, better physical health, and better mental health., Conclusions: PC mental health was the most important factor in the resilience trajectory of patients with advanced HNC cancer., Clinical Relevance: Quantifying the relevant factors of trajectories of resilience will help to identify vulnerable PCs and guide survivorship care in the early stages of the post-treatment period., (© 2021 Sigma Theta Tau International.)

Purpose: After suddenly stopping smoking after an initial oral cancer (OC) diagnosis, patients may restart smoking and nicotine dependence. This study sought to identify factors associated with high nicotine dependence in OC patients who restarted smoking post-treatment., Design: A cross-sectional study., Methods: A group of 220 OC patients who restarted smoking post-treatment were recruited from the outpatient radiation department of a single cancer center in northern Taiwan. Demographic and clinical characteristics were recorded, and patients were assessed for nicotine and smoking dependence, physical activity and function, socio-emotional function, social support, and depression., Results: Among patients who restarted smoking after treatment for OC, 75.9% reported low-to-moderate dependence on smoking, while 24.1% reported high nicotine dependence. Factors associated with high nicotine dependence included higher incidence of smoking per day, greater dependence on smoking, less physical activity per week, and poorer social-emotional function. Those highly dependent on nicotine were younger, unmarried, had less education, and had begun smoking earlier than those with low-to-moderate nicotine dependence., Conclusions: The amount of smoking per day, greater smoking behavioral dependence, less physical activity per week, and worse social-emotional function affected high nicotine dependence., Clinical Relevance: Smoking cessation training and counseling for OC patients may help them better control their use of tobacco after treatment., (© 2021 Sigma Theta Tau International.)

Background: Diabetes mellitus (DM) can worsen the prognosis or survival in prostate cancer (PC) patients. We investigated whether glycemic control impacts mortality in PC patients with existing diabetes., Methods: All PC patients with or without preexisting DM were enrolled from 2006 to 2017. Mean hemoglobin A1c (HbA1c) values (<7%, 7%-9%, ≥9%) were used to represent glycemic control. Major outcomes included all-cause, PC-specific, and non-PC mortalities. Statistical analyses were performed using Cox regression models with adjusted mean HbA1c and other related confounders., Results: A total of 831 PC patients were enrolled (non-DM group, n = 690; DM group with a record of mean HbA1c values, n = 141). Results showed that the DM group with mean HbA1c level ≥ 9% (n = 14) had significantly increased risk for all-cause and non-PC mortality (hazard ratio [HR], 3.09; 95% CIs, 1.15-8.32; p=0.025 and HR, 5.49; 95% CIs, 1.66-18.16; p = 0.005, respectively), but not for PC-specific mortality (HR, 1.03; 95% CIs, 0.13-8.44; p = 0.975), compared with the non-DM group., Conclusion: Our findings indicate that PC patients with DM who had a mean HbA1c level ≥ 9% had higher risks of all-cause and non-PC mortality compared with non-DM subjects. Further large and long-term studies are needed to verify the effect of glycemic control in PC patients with DM., Competing Interests: Conflicts of interest: Dr. Wayne Huey-Herng Sheu, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Physical inactivity is a common health problem in female college students, and factors such as weight self-stigma and smartphone addiction may negatively impact physical activity in this population. The aim of the current study was to investigate the associations between these variables and identify the moderating effects of smartphone addiction between weight stigma and physical activity. Using a cross-sectional study, information on the level of physical activity in the past week, weight-related self-stigma, and smartphone addiction, as well as demographics, were collected via an online survey from 391 female college students in Taiwan. Participants in two groups of moderate to high and low physical activity were compared using a zero-order bivariate correlation in terms of independent variables. A moderated mediation model using Model 14 in the Hayes’ PROCESS macro with 1000 bootstrapping resamples was applied to assess moderation effects. There were significant differences in terms of weight status, smartphone addiction, and weight stigma between active and inactive groups (p < 0.001). All independent variables except for age were positively correlated (0.14 < r < 0.45). Multivariate regression models indicated that weight status was associated with weight stigma (odds ratio [OR] = 9.13, p < 0.001; 95% CI = 6.90, 11.35). Weight status (OR = 0.47, p = 0.03; 95% CI = 0.23, 0.93), weight stigma (OR = 0.96, p = 0.03; 95% CI = 0.922, 0.997), and smartphone addiction (OR = 0.11, p = 0.003; 95% CI = 0.03, 0.47) were associated with physical activity. The moderating role of smartphone addiction on the association between weight stigma and physical activity was also identified (OR = 1.05, p = 0.049; 95% CI = 1.0001, 1.1004). The moderating effect of smartphone addiction on the association between weight stigma and physical activity suggests that designing interventions to address the negative impacts of both weight stigma and smartphone addiction may help to improve physical activity in female college students.

Background: The study aimed to examine the association between perceived weight stigma (PWS), weight status, and eating disturbances. We hypothesized that PWS would partially mediate the association between weight status and eating disturbances among university students., Methods: The study involved 705 undergraduate students (379 females and 326 males) recruited from Hong Kong and Taiwan Universities (399 Hong Kong; 306 Taiwan participants). Our sample was from one Hong Kong university (located in Kowloon) and five Taiwan universities (three located in Southern Taiwan, one located in Central Taiwan, and one located in North Taiwan). Participants' mean age was 20.27 years (SD = 1.79). All participants completed a demographic information sheet, the Three-Factor Eating Questionnaire-18 (TFEQ-R18), and the PWS questionnaire. PROCESS macro models were used to analyze potential mediations., Results: We found a significantly higher PWS scores in a high weight group for females and males. There was a significant difference between weight status and eating disturbances. Moreover, PWS partially mediated the association between weight status and eating disturbances for both genders., Conclusions: PWS is associated with weight status and eating disturbances, making it an important target for health improvement among young adults. Further studies are needed to corroborate such associations in participants from other societies and cultures., (© 2022. The Author(s).)

Urothelial carcinoma includes upper urinary tract cancer (UTUC) and bladder cancer. Although nephroureterectomy is the standard treatment for UTUC, the recurrence rate is approximately half and the tumor is associated with poor prognoses. Metastases are the most devastating and lethal clinical situation in urothelial carcinoma. Despite its clinical importance, few potential diagnostic biomarkers are suitable for early UC detection. We compared high-stage/high-grade urothelial carcinoma tissues to adjacent normal urothelial tissues using methyl-CpG binding domain protein capture for genome-wide DNA methylation analysis. Based on our findings, inhibin βA (INHBA) might be associated with carcinogenesis and metastasis. Further, clinical UC specimens had significant INHBA hypomethylation based on pyrosequencing. INHBA was detected by real-time PCR and immunohistochemistry staining, and was found to be highly expressed in clinical tissues and cell lines of urothelial carcinoma. Further, INHBA depletion was found to significantly reduce BFTC-909 cell growth and migration by INHBA-specific small interfering RNA. Interestingly, a positive correlation was found between SMAD binding and extracellular structure organization with INHBA using gene set enrichment analysis and gene ontology analysis. Together, these results are the first evidence of INHBA promoter hypomethylation and INHBA overexpression in UTUC. INHBA may affect urothelial carcinoma migration by reorganizing the extracellular matrix through the SMAD pathway.

Rationale: Sleep disturbance is commonly noted after Guillain-Barré syndrome (GBS) and is often caused by persistent discomfort after disease survival. Intravascular laser irradiation of blood (ILIB) has been shown to be effective in pain modulation owing to the influence of nociceptive signals in the peripheral nervous system. We investigated the application of ILIB on post-Oxford -AstraZeneca vaccination GBS and evaluated its effect on sleep quality., Patient Concerns: A 48-year-old woman was subsequently diagnosed with GBS after Oxford-AstraZeneca vaccination. The patient was discharged after a 5-day course of intravenous immunoglobulin administration. However, 1 week after discharge, the previously relieved symptoms flared with accompanying sleep disturbance., Diagnosis and Interventions: The patient was diagnosed with post-vaccination GBS, and persistent pain and sleep disturbances persisted after disease survival. ILIB was performed., Outcomes: We used the Pittsburgh Sleep Quality Index before and after intravascular laser irradiation. There was a marked improvement in the sleep duration, efficiency, and overall sleep quality. The initial score was 12 out of 21 and the final score was 7 out of 21., Lessons: We found that ILIB was effective in pain modulation in post-vaccination GBS and significantly improved sleep quality., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

It is known that children and adolescents with Kawasaki disease (KD) can maintain normal cardiopulmonary fitness (CPF) after the disease's acute stage has subsided. This study aimed to investigate whether gender differences affect CPF in children and adolescents with KD. We retrospectively reviewed a cohort of 204 participants (120 boys and 84 girls) with KD. All participants were instructed to complete a symptom-limited cardiopulmonary exercise test (CPET) adapted to assess their CPF. Based on body mass index (BMI), boys and girls were categorized into groups of underweight (19 boys and 12 girls), normal (62 boys and 59 girls), and overweight (39 boys and 13 girls). Although a similarity in body composition was found among both genders for KD subjects and normal Taiwanese peers, the percentage of overweight subjects was higher in KD boys than the normal Taiwanese boys. When comparing CPF for different BMI groups, the whole KD group showed no discrepancy, but a significantly lower peak VO2 for the overweight KD boys group was observed, representing poorer CPF. In conclusion, girls with KD had better CPF than boys, and gender stereotypes affect sports participation as well as self-efficacy, and may be contributing to poorer CPF in KD boys.

Here, we report a metal-free approach for the construction of methylene-bridged bis-1,3-dicarbonyl compounds via cross-dehydrogenative coupling of 1,3-dicarbonyl compounds with 2-methoxyethanol. In addition, we have extended this methodology to synthesize tetra-substituted pyridine derivatives using 1,3-dicarbonyl, 2-methoxyethanol and NH 4 OAc in one step. The key advantages include accepting a wide range of substrates, utilizing O 2 as the sole oxidant, and synthesizing biologically active compounds such as 1,4-dihydropyridine and pyrazole.

To compare the frequency and clinical significance of familial and de novo chromosomal inversions during prenatal diagnosis. This was a retrospective study of inversions diagnosed prenatally in an Asian population by applying conventional GTG-banding to amniocyte cultures. Data from 2005 to 2019 were extracted from a single-center laboratory database. The types, frequencies, and inheritance patterns of multiple inversions were analyzed. Pericentric variant inversions of chromosome 9 or Y were excluded. In total, 56 (0.27%) fetuses with inversions were identified in the 15-year database of 21,120 confirmative diagnostic procedures. Pericentric and paracentric inversions accounted for 62.5% (35/56) and 37.5% of the inversions, respectively. Familial inversions accounted for nearly 90% of cases, and de novo mutation was identified in two pericentric and two paracentric cases. Inversions were most frequently identified on chromosomes 1 and 2 (16.1% of all inversions), followed by chromosomes 6, 7, and 10 (8.9% of all cases). The indications for invasive testing were as follows: advanced maternal age (67.3%), abnormal ultrasound findings (2.1%), abnormal serum aneuploidy screening (20.4%), and other indications (10.2%). The mode of inheritance was available for 67.9% of cases (38/56), with 89.5% of inversions being inherited (34/38). A slight preponderance of inheritance in female fetuses was observed. Three patients with inherited inversions opted for termination (two had severe central nervous system lesions and one had thalassemia major). Gestation continued for 53 fetuses, who exhibited no structural defects at birth or significant developmental problems a year after birth. Our study indicates that approximately 90% of prenatally diagnosed inversions involve familial inheritance, are spreading, and behave like founder effect mutations in this isolated population on an island. This finding can help to alleviate anxiety during prenatal counseling, which further underscores the importance of parental chromosomal analysis, further genetic studies, and appropriate counseling in cases where a nonfamilial inversion is diagnosed., (© 2022. The Author(s).)

This study investigated the diagnostic accuracy and affecting factors of ultrasound (US)-guided core-needle biopsy (CNB) in patients with treated head and neck squamous cell carcinoma (HNSCC). We retrospectively reviewed patients with treated HNSCC who received US-guided CNB from January 2011 to December 2018 with corresponding imaging. Pathological necrosis and fibrosis of targeted lymph nodes (LNs) were evaluated. We analyzed the correlation between CNB accuracy and clinical and pathological characteristics. In total, 260 patients were included. The overall sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of CNB for nodal recurrence were 84.47%, 100%, 100%, 54.67%, and 86.92%, respectively. CNB of fibrotic LNs had significantly worse sensitivity, NPV, and accuracy than that of non-fibrotic LNs. Similarly, CNB of necrotic LNs had significantly worse sensitivity, NPV, and accuracy than non-necrotic LNs. Multivariate regression revealed that fibrotic LN was the only independent factor for a true positive rate, whereas both necrotic LN and fibrotic LN were independent factors for a false negative rate. The diagnostic accuracy of CNB in treated HNSCC patients is affected by LN necrosis and fibrosis. Therefore, CNB results, particularly for necrotic or fibrotic LNs, should be interpreted carefully., (© 2022. The Author(s).)

Background: Extranodal extension (ENE) is a crucial prognostic factor of oral squamous cell carcinoma (OSCC). However, the role of ENE in regional recurrence (rENE) remains unclear. The purpose of our study is to assess the salvage outcome according to the presence of rENE in oral cancer patients with isolated nodal recurrence., Methods: Oral cancer patients diagnosed with isolated nodal recurrence at the National Taiwan University Hospital between January 2010 and December 2015 were reviewed. All patients were classified into two groups: with and without rENE. The treatment included salvage neck dissection (ND) ± metronomic chemotherapy, salvage ND and radiation (RT)/concurrent chemoradiation (CCRT), Salvage RT/CCRT alone, metronomic chemotherapy, or supportive care., Results: We analyzed 198 patients, 156 with rENE and 42 without rENE. rENE presented more frequently in patients with initial ENE+ (OR = 3.17, p = 0.04), prior RT+ (OR = 2.96, p = 0.02), initial N2/N3 (OR = 2.76, p = 0.01), and recurrent LN size >1.5 cm (OR = 2.33, p = 0.03). The extent of rENE were also significantly different in these patients. The 2-year disease-free survival for patients with and without rENE were 15.7% and 31.7%, respectively (p = 0.002). The 2-year overall survival for patients with and without rENE were 19.6% and 43.9%, respectively (p = 0.004). For patients without rENE, those received salvage ND had better survival outcome (p < 0.001). By contrast, for patients with rENE, those received salvage RT/CCRT had better survival outcome (p < 0.001)., Conclusion: The rENE is frequently present (78.79%) in OSCC patients with isolated nodal recurrence. Individualized treatment modalities based on the presence of rENE should be recommended to achieve better salvage outcomes., Competing Interests: Conflicts of 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 © 2021 Elsevier B.V. All rights reserved.)

Targeted therapies against human epidermal growth factor receptor 2 (HER2) are associated with increased interstitial lung disease (ILD). Trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine have markedly extended HER2 breast cancer survival but current knowledge on how these HER2-targeted agents induce interstitial lung disease is still poorly defined due to limited cases in the literature. Physicians mostly managed this complication by dose interruption, dose de-escalation, or discontinuation with success. In 2019, the FDA had granted accelerated approval on trastuzumab deruxtecan (T-Dxd) in HER2 breast cancer in the late line setting. Severe ILD incidence rate was over ten percent and led to fatal outcomes in 2.2% of patients in the T-Dxd trial. Searching for biomarkers to detect ILD incidence before it becomes clinically fulminant or for treatment response monitoring is of high clinical value. A Case of life-threatening trastuzumab-induced ILD was encountered in our facility. The ILD was confirmed to be antineutrophil cytoplasmic antibody (ANCA) pulmonary capillaritis. The biomarker of neutrophil extracellular traps (NETs), serum MPO-DNA complex, showed a good correlation with the clinical severity. Soon after B cell depleting agent rituximab usage, the serum MPO-DNA outperformed ANCA autoantibody and maintained its correlation with clinical severity. In addition to the trastuzumab-induced ILD case, a prospective cohort in our facility also confirmed the usefulness of MPO-DNA in monitoring vasculitis activity. We postulated that upfront testing with biomarkers of vasculitis during HER2 targeted treatment with high ILD incidence may be beneficial in the future., Competing Interests: Declaration of competing interest The author(s) had declared that no conflicts of interest exist., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While hyaluronic acid encapsulating superparamagnetic iron oxide nanoparticles have been reported to exhibit selective cytotoxicity toward cancer cells, it is unclear whether low-molecular-weight hyaluronic acid-conjugated superparamagnetic iron oxide nanoparticles also display such cytotoxicity. In this study, high-molecular-weight hyaluronic acid was irradiated with γ-ray, while Fe 3 O 4 nanoparticles were fabricated using chemical co-precipitation. The low-molecular-weight hyaluronic acid and Fe 3 O 4 nanoparticles were then combined according to a previous study. Size distribution, zeta potential, and the binding between hyaluronic acid and iron oxide nanoparticles were examined using dynamic light scattering and a nuclear magnetic resonance spectroscopy. The ability of the fabricated low-molecular-weight hyaluronic acid conjugated superparamagnetic iron oxide nanoparticles to target cancer cells was examined using time-of-flight secondary ion mass spectrometry and T2* weighted magnetic resonance images to compare iron signals in U87MG human glioblastoma and NIH3T3 normal fibroblast cell lines. Comparison showed that the present material could target U87MG cells at a higher rate than NIH3T3 control cells, with a viability inhibition rate of 34% observed at day two and no cytotoxicity observed in NIH3T3 normal fibroblasts during the three-day experimental period. Supported by mass spectrometry images confirming that the nanoparticles accumulated on the surface of cancer cells, the fabricated materials can reasonably be suggested as a candidate for both magnetic resonance imaging applications and as an injectable anticancer agent.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with an increased risk of developing non-Hodgkin lymphoma (NHL); however, adequate data corroborating these associations are lacking. Therefore, a study based on the national database was performed to investigate the correlation between HBV and HCV with NHL in Taiwan. This research was a retrospective cohort study using a nationally representative database established by the Health and Welfare Data Science Center of the Ministry of Health and Welfare, Taiwan. The participants were patients with HBV and HCV, analyzed using the propensity score matching method. The study results indicated that the incidence rate of NHL (0.13%) was significantly higher than that in patients from the general population. After controlling related variables, the hazard ratio (HR) of the incidence of NHL in patients with hepatitis was 2.37 (95% CI, 1.93-2.91). Furthermore, the incidence of NHL in patients with HBV was significantly higher than in patients from the general population (HR, 2.49; 95% CI, 1.94-3.19). The incidence of NHL in patients with HCV was significantly higher than in patients from the general population (HR, 2.36; 95% CI, 1.73-3.22). This study indicated that HBV and HCV significantly increase the risk of NHL.

Chloroplasts are the sites for photosynthesis, and two Golden2-like factors act as transcriptional activators of chloroplast development in rice (Oryza sativa L.) and maize (Zea mays L.). Rice OsGLK1 and OsGLK2 are orthologous to maize ZmGLK1 (ZmG1) and ZmGLK2 (ZmG2), respectively. However, while rice OsGLK1 and OsGLK2 act redundantly to regulate chloroplast development in mesophyll cells, maize ZmG1 and ZmG2 are functionally specialized and expressed in different cell-specific manners. To boost rice chloroplast development and photosynthesis, we generated transgenic rice plants overexpressing ZmG1 and ZmG2, individually or simultaneously, with constitutive promoters (pZmUbi::ZmG1 and p35S::ZmG2) or maize promoters (pZmG1::ZmG1, pZmG2::ZmG2, and pZmG1::ZmG1/pZmG2::ZmG2). Both ZmG1 and ZmG2 genes were highly expressed in transgenic rice leaves. Moreover, ZmG1 and ZmG2 showed coordinated expression in pZmG1::ZmG1/pZmG2::ZmG2 plants. All Golden2-like (GLK) transgenic plants had higher chlorophyll and protein contents, Rubisco activities and photosynthetic rates per unit leaf area in flag leaves. However, the highest grain yields occurred when maize promoters were used; pZmG1::ZmG1, pZmG2::ZmG2, and pZmG1::ZmG1/pZmG2::ZmG2 transgenic plants showed increases in grain yield by 51%, 47%, and 70%, respectively. In contrast, the pZmUbi::ZmG1 plant produced smaller seeds without yield increases. Transcriptome analysis indicated that maize GLKs act as master regulators promoting the expression of both photosynthesis-related and stress-responsive regulatory genes in both rice shoot and root. Thus, by promoting these important functions under the control of their own promoters, maize GLK1 and GLK2 genes together dramatically improved rice photosynthetic performance and productivity. A similar approach can potentially improve the productivity of many other crops., (© The Author(s) 2021. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Objective: To explore the help seeking efficacy and social assistance willingness of medical staff during major public health events, so as to provide basis for improving the psychological resources and service quality of medical staff and further optimizing the prevention and treatment policies. Methods: In February 2020, a convenient sampling method was used to conduct an online questionnaire survey on medical staff in Henan Province, and a total of 2136 questionnaires were collected. Among them, there were 1940 valid questionnaires, and the effective recovery rate was 90.82%. The questionnaire of help seeking efficacy and willingness to social assistance under epidemic situation was used to investigate the help seeking efficacy and willingness of medical staff. The frequency and rate (%) were used to analyze the overall situation of medical staff's help seeking efficacy and social assistance willingness. The differences among different demographic variables were tested by χ(2) test. Results: Among the 1940 medical and nursing staff, 18.81% (365/1940) did not know how to obtain appropriate psychological assistance. Compared with the low age group, the medical staff in the high age group had the ability of information query, the ability to occupy knowledge resources, the ability to distinguish rumors and facts and the sense of efficacy of obtaining appropriate medical help, and the difference was statistically significant ( P <0.05) . The willingness of medical and nursing staff to actively cooperate with the government, maintain social stability and volunteer work were 99.43% (1929/1940) , 98.81% (1917/1940) and 97.11% (1884/1940) . Conclusion: The medical staff had a higher sense of help seeking efficacy and willingness to social assistance. It is necessary to further strengthen the resource support of psychological, social and humanistic care for medical staff.

Introduction: The default mode network (DMN) is selectively vulnerable in brain aging. Little is known about the effect of multimorbidity as a whole onto the brain structural integrity., Objective: We aimed to investigate the association between multimorbidity and the structural integrity of DMN., Methods: We enrolled senior volunteers aged between 60 and 80 years in Hualien County during 2014-2018 and conducted in-person interview to collect information on chronic diseases. Fasting blood glucose and glycated hemoglobin (HbA1c) were tested. We assessed multimorbidity burden by the cumulative illness rating scale-geriatric (CIRS-G). MRI brain scans were standardized to measure the regional volume within the DMN. In a cross-sectional design, we employed stepwise regression models to evaluate the effects of age, sex, hyperglycemia, and multimorbidity on the DMN., Results: A total of 170 volunteers were enrolled with a mean age of 66.9 years, female preponderance (71%), an average mini-mental state examination score of 27.6, a mean HbA1c of 6.0, and a mean CIRS-G total score (TS) of 7.2. We found that older age was associated with reduced volumes in the hippocampus, left rostral anterior cingulate cortex, right posterior cingulate, right isthmus, precuneus, and right supramarginal. Higher levels of HbA1c and fasting glucose were associated with a reduced volume in the hippocampus only. A higher CIRS-G-TS was associated with reduced volumes in the left posterior cingulate cortex and right supramarginal gyrus; while a higher CIRS-G severity index was associated with a smaller right precuneus and right supramarginal., Conclusions: In the DMN, hippocampal volume shows vulnerability to aging and hyperglycemia, whereas the posterior cingulate, supramarginal, and precuneus cortices may be the key sites to reflect the total effects of multimorbidity., (© 2021 S. Karger AG, Basel.)

Background: Mild cognitive impairment (MCI), which is common in older adults, is a risk factor for dementia. Rapidly growing health care demand associated with global population aging has spurred the development of new digital tools for the assessment of cognitive performance in older adults., Objective: To overcome methodological drawbacks of previous studies (e.g., use of potentially imprecise screening tools that fail to include patients with MCI), this study investigated the feasibility of assessing multiple cognitive functions in older adults with and without MCI by using a social robot., Methods: This study included 33 older adults with or without MCI and 33 healthy young adults. We examined the utility of five robotic cognitive tests focused on language, episodic memory, prospective memory, and aspects of executive function to classify age-associated cognitive changes versus MCI. Standardized neuropsychological tests were collected to validate robotic test performance., Results: The assessment was well received by all participants. Robotic tests assessing delayed episodic memory, prospective memory, and aspects of executive function were optimal for differentiating between older adults with and without MCI, whereas the global cognitive test (i.e., Mini-Mental State Examination) failed to capture such subtle cognitive differences among older adults. Furthermore, robot-administered tests demonstrated sound ability to predict the results of standardized cognitive tests, even after adjustment for demographic variables and global cognitive status., Conclusion: Overall, our results suggest the human-robot interaction approach is feasible for MCI identification. Incorporating additional cognitive test measures might improve the stability and reliability of such robot-assisted MCI diagnoses.