Search

Background: The combination of bevacizumab and atezolizumab has been established as a standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). We examined the treatment outcomes of patients in Taiwan who received the combination in 2 pivotal clinical trials., Methods: All patients who resided in Taiwan, were enrolled in the IMbrave150 and GO30140 studies, and received bevacizumab and atezolizumab as the first-line systemic therapy for unresectable HCC were included. We extracted and pooled anonymous raw data from the study records., Results: We enrolled 40 patients, with the median age of 62.5 years; 36 (90%) had Barcelona Clinic Liver Cancer stage C disease. The response rate was 37.5%, including 3 (7.5%) complete responses. The disease control rate was 85%. The median duration of response was 21.4 months (95% confidence interval [CI], 16.6-not estimable). The median progression-free survival (PFS) and overall survival (OS) were 8.6 (95% CI, 5.6-18.6) and 24.9 months (95% CI, 14.2-not estimable), respectively. The most common adverse events of all grades were proteinuria (50%) and hypertension (37.5%), the median onset of which were 157 and 127 days, respectively. Bevacizumab and atezolizumab treatment had to be interrupted in 20 (50%) and 13 (32.5%) patients, respectively. Among patients whose treatment duration was ≥6 months, 50% of them had to skip bevacizumab, but no signal of poorer PFS or OS was observed., Conclusion: In Taiwanese patients with advanced HCC, the efficacy and safety outcomes of bevacizumab and atezolizumab treatment were generally consistent with the global intent-to-treat populations., Competing Interests: Declaration of competing interest YYS had received honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Ipsen, Merck, Ono, and Roche. YHF had received honoraria from Roche, AbbVie, and Novartis. CJY declared no conflict of interest to disclose. TSY declared no conflict of interest to disclose. YCS had received honoraria from AstraZeneca, Bristol Myers Squibb/Ono, Roche and Eisai. YC declared no conflict of interest to disclose. JSC had received research founding from Ono Pharmaceutical, MSD Oncology, Lilly, TTY Biopharm, Merck KGaA, Roche, AstraZeneca, Janssen, Syncore, Astellas Pharma and Senhwa Biosciences. CYS, WJC, and HLH are employed by Roche. CHH has served as a consultant in advisory boards of Roche and AstraZeneca, has received honoraria from Bristol Myers Squibb, Ono Pharmaceutical, Merck Sharp & Dohme, and Roche, and has received research grant from AstraZeneca, Bayer, Eli Lilly, Genentech, and Roche., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Postprocedural delayed bleeding (PDB) remains the most common major complication of colorectal polypectomy. Incomplete clip closure of mucosal defect and unclosed injured blood vessels in gaps between clips may be the risk factors for PDB., Objectives: To observe whether completely no-gap closure of mucosal defect after polypectomy can reduce PDB occurrence., Design: Single-center, retrospective case-control study., Methods: In this study based on historical comparisons of patients in 2 time periods, only the patients with polyps sized between 6 and 15 mm were included. A new clip-assisted endoloop ligation (CAEL, treatment group) method was used between January 2019 and December 2020, and a traditional simple clip closure (SCC, control) was used Between January 2017 and December 2018 to prevent PDB after polypectomy. The rate of PDB of two groups and risk factors for PDB were evaluated., Results: Totally 4560 patients were included in the study; 2418 patients belong to CAEL group, and 2142 patients belong to SCC group. The overall rate of PDB was significantly lower in CAEL group compared to SCC group (0.6% versus 1.5%, p  < 0.00). On multivariate logistic analysis, CAEL was a significant independent preventive factor for PDB (odds ratio (OR), 0.092; 95% confidence interval (CI), 0.029-0.3335; p  = 0.000). Polyps located at rectum (colon versus rectum) represented a significant independent risk factor for PDB (OR, 11.888; 95% CI, 3.343-42.269; p  = 0.001)., Conclusion: Completely no-gap closure of mucosal defect after polypectomy further reduced the rate of PDB for polyps sized between 6 and 15 mm. CAEL may be a significant independent preventive factor for PDB. Polyps located at the rectum may be a significant independent risk factor for PDB., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2022.)

We introduced a novel surgery that combines ultrasound guidance, miniaturization and Galdakao-modified supine Valdivia (GMSV) position in percutaneous nephrolithotomy (PCNL) and evaluated the safety and efficacy. This retrospective, single-center study retrospectively reviewed 150 patients who underwent ultrasound-guided mini-PCNL in the GMSV position from November 2019 to March 2022. All perioperative parameters were collected. Stone-free status was defined as no residual stones or clinically insignificant residual fragments (CIRF) <0.4 cm on postoperative day one. Among the 150 patients, the mean age was 56.96 years. The mean stone size was 3.19 cm (427 mm2). The mean S.T.O.N.E. score was 7.61, including 36 patients (24%) with scores ≥9. The mean operative time was 66.22 min, and the success rate of renal access creation in the first attempt was 88.7%. One hundred and forty (93.3%) patients were stone free. The mean decrease in Hemoglobin was 1.04 g/dL, and no patient needed a blood transfusion. Complications included transient hematuria (n = 13, 8.7%), bladder blood clot retention (n = 2, 1.3%), fever (n = 15, 10%) and sepsis (n = 2, 1.3%). Totally X-ray-free ultrasound-guided mini-PCNL in the GMSV position is feasible, safe and effective for patients with upper urinary tract stones, indicating the synergistic and complementary effects of the three novel techniques.

Purpose: The aim of this study was to describe the treatment technique, outcomes, and complications of Schobinger stage IV head and neck arteriovenous malformations (HNAVMs) with associated high-output cardiac failure (HOCF) using ethanol and coils with the percutaneous suture technique., Methods: From January 2015 to December 2019, 19 patients who had HNAVMs with associated HOCF were treated first with a percutaneous suture of the remarkably dilated dominant drainage vein (RDDOV) and subsequent embolization with coils and ethanol. The percutaneous suture of RDDOV was preferred to be performed, followed by the deployment of coils and the injection of absolute ethanol via transarterial approach, direct puncture approach, or both of them. Treatment outcomes and complication rates were evaluated at follow-up., Results: A total of 19 patients who experienced HNAVMs with HOCF received 19 percutaneous suture procedures and 84 embolization procedures with ethanol and coils. Complete or >90% shunt reduction of the AVM was achieved in 16 patients. Notably, 19 patients with New York Heart Association (NYHA) stage II improved to stage I, and the symptom of dyspnea disappeared after embolization. The symptoms of five patients with bleeding disappeared. All patients presented with cosmetic concerns; Four were cured, and eight had a clearly recognizable improvement. Of note, 19 (100%) patients presented with impairment of daily life, which was resolved. The minor complications were encountered and recovered by the self. No major complications occurred., Conclusion: This study provides evidence that ethanol and coil embolotherapy is effective and safe in treating HOCF caused by HNAVMs with acceptable complications in these cases. The percutaneous suture technique for RDDOV management can act as an adjunct for embolotherapy., 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 Wen, Li, Shen, Wang, Zheng, Wang, Fan, Su and Yang.)

Background: Interferon in combination with ribavirin has been the standard of care for chronic hepatitis C virus infection (HCV) for the past few decades. However, its effect on the risk of autoimmune diseases (ADs) among patients with HCV infection remains unclear. We assessed the potential association between interferon-based therapy (IBT) and AD risk in patients with HCV infection., Methods: This retrospective cohort study identified patients diagnosed with HCV infection between January 1, 2006, and December 31, 2015, from Taiwan's National Health Insurance Research Database. In total, 16,029 patients with HCV infection who received IBT and 141,214 patients with HCV infection who did not receive IBT were included. Both cohorts were followed up to assess the development of ADs. Hazard ratios (HRs) were calculated using the Cox proportional hazards regression model, which was adjusted for potential confounders., Results: The median follow-up period for IBT and non-IBT users was 4.53 and 3.34 years, respectively. No significant difference in the risk of overall ADs (adjusted HR [aHR]: 0.96, 95% confidence interval [CI]: 0.81-1.14) or systemic ADs (aHR: 0.88, 95% CI: 0.71-1.10) was noted during the study period. However, a slight increase in the risk of organ-specific ADs was noted among IBT users (incidence rate ratio: 1.33, 95% CI: 1.02-1.72). Furthermore, analysis of AD subgroups revealed a significant increase in the risks of Graves' disease (aHR: 6.06, 95% CI: 1.27-28.8) and Hashimoto's thyroiditis (aHR 1.49, 95% CI 1.01-2.21) among IBT users., Conclusions: IBT use increases the risk of autoimmune thyroid diseases (Hashimoto's thyroiditis and Graves' disease) in patients with HCV infection to a greater extent than non-IBT use., 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 Chou, Yeh, Lin, Chang, Hsu, Shen, Kuo, Chen, Chen and Chang.)

Roselle (Hibiscus sabdariffa L.) is an increasingly attractive plant for its health and pharmaceutical, beverage, and cosmetic applications. The purpose of this study was to investigate the clinical effects of roselle drink on antioxidant activity, blood pressure, and skin condition. Roselle drink used in this study contained rich phenolics (1.96 g of gallic acid equivalent/100 ml) and anthocyanins (1.65 g of cyanidin-3-glucoside equivalent/100 ml). In a randomized, cross-over, double-blind, placebo-controlled clinical study, 39 healthy adults received drank 200 ml of roselle drink or placebo-control drink for 6 months. A significant reduction in the blood pressure was observed in the roselle drink treated group when compared with preintervention values. After 6 months of treatment with roselle drink, serum phenolics contents, the levels of Trolox equivalent antioxidant capacity (TEAC), glutathione, superoxide dismutase (SOD), glucose-6-phosphate dehydrogenase (G-6-PDH), glutathione peroxidase (GSH-Px), and glutathione reductase (GSH-Rd) were significantly increased in healthy subjects. However, a significant increment in skin redness and skin moisture was observed in the facial skin of roselle drink-treated participants. Oral administration of roselle drink for 6 months significantly lowered the blood pressure, improved antioxidation level, and positively regulated skin redness as well as moisture. Phenolics and anthocyanins in roselle could be the major potential contributors to such health effects. PRACTICAL APPLICATIONS: Roselle is a typical plant. Continuous administration of roselle drink clearly improved antioxidation levels, reduced blood pressure and positively regulated skin redness and moisture. Phenloics and anthocyanins in roselle could be the major potentila contributors of such health benefits., (© 2022 Wiley Periodicals LLC.)

The global COVID-19 pandemic remains a critical public health threat, as existing vaccines and drugs appear insufficient to halt the rapid transmission. During an outbreak from May to August 2021 in Taiwan, patients with severe COVID-19 were administered NRICM102, which was a traditional Chinese medicine (TCM) formula developed based on its predecessor NRICM101 approved for treating mild cases. This study aimed to explore the mechanism of NRICM102 in ameliorating severe COVID-19-related embolic and fibrotic pulmonary injury. NRICM102 was found to disrupt spike protein/ACE2 interaction, 3CL protease activity, reduce activation of neutrophils, monocytes and expression of cytokines (TNF-α, IL-1β, IL-6, IL-8), chemokines (MCP-1, MIP-1, RANTES) and proinflammatory receptor (TLR4). NRICM102 also inhibited the spread of virus and progression to embolic and fibrotic pulmonary injury through reducing prothrombotic (vWF, PAI-1, NET) and fibrotic (c-Kit, SCF) factors, and reducing alveolar type I (AT1) and type II (AT2) cell apoptosis. NRICM102 may exhibit its protective capability via regulation of TLRs, JAK/STAT, PI3K/AKT, and NET signaling pathways. The study demonstrates the ability of NRICM102 to ameliorate severe COVID-19-related embolic and fibrotic pulmonary injury in vitro and in vivo and elucidates the underlying mechanisms., Competing Interests: Competing interests The authors have declared that no conflict of interest exists., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Viral- and host-targeted traditional Chinese medicine (TCM) formulae NRICM101 and NRICM102 were administered to hospitalized patients with COVID-19 during the mid-2021 outbreak in Taiwan. We report the outcomes by measuring the risks of intubation or admission to intensive care unit (ICU) for patients requiring no oxygen support, and death for those requiring oxygen therapy., Methods: This multicenter retrospective study retrieved data of 840 patients admitted to 9 hospitals between May 1 and July 26, 2021. After propensity score matching, 302 patients (151 received NRICM101 and 151 did not) and 246 patients (123 received NRICM102 and 123 did not) were included in the analysis to assess relative risks., Results: During the 30-day observation period, no endpoint occurred in the patients receiving NRICM101 plus usual care while 14 (9.27%) in the group receiving only usual care were intubated or admitted to ICU. The numbers of deceased patients were 7 (5.69%) in the group receiving NRICM102 plus usual care and 27 (21.95%) in the usual care group. No patients receiving NRICM101 transitioned to a more severe status; NRICM102 users were 74.07% less likely to die than non-users (relative risk= 25.93%, 95% confidence interval 11.73%-57.29%)., Conclusion: NRICM101 and NRICM102 were significantly associated with a lower risk of intubation/ICU admission or death among patients with mild-to-severe COVID-19. This study provides real-world evidence of adopting broad-spectrum oral therapeutics and shortening the gap between outbreak and effective response. It offers a new vision in our preparation for future pandemics., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Malignant brain tumors consist of malignancies originated primarily within the brain and the metastatic lesions disseminated from other organs. In spite of intensive studies, malignant brain tumors remain to be a medical challenge. Patient-derived organoid (PDO) can recapitulate the biological features of the primary tumor it was derived from and has emerged as a promising drug-screening model for precision therapy. Here we show a proof-of-concept based on early clinical study entailing the organoids derived from the surgically resected tumors of 26 patients with advanced malignant brain tumors enrolled during December 2020 to October 2021. The tumors included nine glioma patients, one malignant meningioma, one primary lymphoma patient, and 15 brain metastases. The primary tumor sites of the metastases included five from the lungs, three from the breasts, two from the ovaries, two from the colon, one from the testis, one of melanoma origin, and one of chondrosarcoma. Out of the 26 tissues, 13 (50%) organoids were successfully generated with a culture time of about 2 weeks. Among these patients, three were further pursued to have the organoids derived from their tumor tissues tested for the sensitivity to different therapeutic drugs in parallel to their clinical care. Our results showed that the therapeutic effects observed by the organoid models were consistent to the responses of these patients to their treatments. Our study suggests that PDO can recapitulate patient responses in the clinic with high potential of implementation in personalized medicine of malignant brain tumors., (© 2022. The Author(s).)

Mesona procumbens Hemsley is a plant conventionally processed to provide popular food materials and herbal medicines in Asia. In this study, six triterpene acids, including five new ones (mesonaic acids D-H, 1 - 5 ), and one proximadiol-type sesquiterpene ( 7 ) were isolated from the methanolic extract of the air-dried M. procumbens . Chemical structures of 1 ‒ 7 were established by spectroscopic methods, especially 2D NMR techniques ( 1 H- 1 H COSY, HSQC, HMBC, and NOESY) and HRESIMS. Concerning their biological activities, compounds 1 , 2 , 6 , and 7 were examined manifesting high inhibition toward the pro-inflammatory NO production with EC 50 values ranging from 12.88 to 21.21 µM, outrunning the positive control quercetin (24.12 µM). The mesoeudesmol B ( 7 ) identified from M. procumbens is the very first example, which exhibited high anti-inflammatory activity diminishing the level of the lipopolysaccharide-induced NO in RAW264.7 macrophage cells, thereby suppressing the secretion of pro-inflammatory cytokines TNF-α and IL-6 and the level of two critical downstream inflammatory mediators iNOS and COX-2., 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 Huang, Lo, Liao, Lin, Shen, Huang, Li, Lee, Kuo and Liaw.)

Background: Periodontitis is a chronic inflammatory disease of the oral cavity characterized by inflammation of the periodontal tissue and resorption of the alveolar bone, which has a high incidence and is the main cause of tooth loss in adults. In addition to its role in promoting osteogenesis, magnesium also has a role in regulating the inflammatory response, both systemically and locally. There is growing evidence that magnesium is an important factor in maintaining the normal functioning of the body's immune system. Hypomagnesaemia can lead to a variety of chronic inflammatory diseases throughout the body, including periodontitis. Two-thirds of the US population suffers from magnesium deficiency. The connection between dietary magnesium and periodontitis is unknown. As a result, we set out to investigate the link between dietary magnesium intake and periodontitis., Methods: In this study, we collected data from the National Health and Nutrition Examination Survey (NHANES) database from 2013 to 2014. Through 24-h dietary recalls, information about food consumption was collected. We examined the association between the dietary magnesium and periodontitis using multivariable logistic regression model. Based on odds ratios (OR) and 95% confidence intervals (CIs), a strong association was detected., Results: Multivariable logistic regression analysis showed that the OR for periodontitis comparing the highest to the lowest quintile of dietary magnesium intake was 0.69 (95% CIs = 0.52~0.92). The restricted cubic spline (RCS) analysis showed that the non-linear association between dietary magnesium and periodontitis was statistically significant and that dietary magnesium supplementation reduced the prevalence of periodontitis., Conclusion: Dietary magnesium intake is associated with the prevalence of periodontitis. Dietary magnesium deficiency increases the prevalence of periodontitis., 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 Li, Wen, Liu, Shen, Su and Yang.)

Objectives: Obstructive sleep apnea (OSA) is a sleep disorder which results in daytime sleepiness and impaired memory function. The aim of this study was to investigate the effect of continuous positive airway pressure (CPAP) on daytime sleepiness and memory function in OSA patients. We also investigated whether CPAP compliance impacted the effect of this treatment., Materials and Methods: The nonrandomized, nonblinded clinical trial enrolled 66 patients with moderate-to-severe OSA subjects. All subjects completed a polysomnographic study, daytime sleepiness questionnaires (the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index), and four memory function tests (working memory; processing speed [PS]; logical memory [LM]; face memory [FM])., Results: Before CPAP treatment, no significant differences ( P < 0.05) were noted in the demographic data, daytime sleepiness, or memory function between two groups (with/without CPAP). However, OSA patients treated with CPAP for 2 months showed significant improvements in daytime sleepiness, PS, mostly of LM, and FM comparing to 2 months ago. As compared to those who did not receive CPAP treatment, CPAP can improve only parts of LM (delayed LM [DLM] and LM percentage [LMP]). In addition, compared to control group, a significant improvement of daytime sleepiness and LM (LM learning, DLM, and LMP) in good compliance with CPAP treatment group and of DLM and LMP in the low compliance with CPAP treatment group was found., Conclusion: CPAP treatment for 2 months could improve some of LM in OSA patients, especially in patients exhibiting good CPAP compliance., Competing Interests: Prof. En-Ting Chang, an editorial board member at Tzu Chi Medical Journal, had no role in the peer review process of or decision to publish this article. The other authors decalared no conflicts of interest in writing this paper., (Copyright: © 2022 Tzu Chi Medical Journal.)

Background: Periodontal disease is very common worldwide and is one of the main causes of tooth loss in adults. Periodontal disease is characterized by chronic inflammation that can destroy adjacent alveolar bone and lead to a loss of periodontal ligaments. Although previous studies have found that a daily diet can influence the development of periodontal disease (e.g., a diet low in carbohydrates and rich in vitamins C and D and fiber can have a protective effect). Periodontal disease may present as gingivitis or periodontitis. However, studies on the role of healthy eating index in periodontitis are lacking. The purpose of this study was to assess the association between healthy eating index and periodontitis., Methods: We analyzed data collected from participants in the National Health and Nutrition Examination Survey (NHANES), a nationally representative survey conducted in 2-year cycles from 2013 to 2014. As part of our analysis, we developed multivariate logistic regression models to examine the independent association between the healthy eating index and periodontitis. We evaluated the significance of association using odds ratios (OR) with 95% confidence intervals (95%CI)., Results: Individuals with a lower total healthy eating index had a higher prevalence of periodontitis. Adjusted multivariate regression models showed that a higher healthy diet index was associated with a lower prevalence of periodontitis (OR = 0.69, 95% CI: 0.55-0.86, P < 0.05)., Conclusion: The results of the study showed that dietary structure was associated with the prevalence of periodontitis. Patients with a higher healthy eating index had a lower prevalence of periodontitis. These findings will need to be confirmed by longitudinal, prospective studies in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Wen, Xu, Shen and Yang.)

Purpose: We aimed at exploring the efficacy of non-negative matrix factorization (NMF) model-based clustering for prognostic assessment of head and neck squamous carcinoma (HNSCC)., Methods: The transcriptome microarray data of HNSCC samples were downloaded from The Cancer Genome Atlas (TCGA) and the Shanghai Ninth People's Hospital. R software packages were used to establish NMF clustering, from which relevant prognostic models were developed., Results: Based on NMF, samples were allocated into 2 subgroups. Predictive models were constructed using differentially expressed genes between the two subgroups. The high-risk group was associated with poor prognostic outcomes. Moreover, multi-factor Cox regression analysis revealed that the predictive model was an independent prognostic predictor., Conclusion: The NMF-based prognostic model has the potential for prognostic assessment of HNSCC., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

The cGAS-STING axis is one of the key mechanisms guarding cells from pathogen invasion in the cytoplasmic compartment. Sensing of foreign DNA in the cytosol by the cGAS-STING axis triggers a stress cascade, culminating at stimulation of the protein kinase TBK1 and subsequently activation of inflammatory response. In cancer cells, aberrant metabolism of the genomic DNA induced by the hostile milieu of tumor microenvironment or stresses brought about by cancer therapeutics are the major causes of the presence of nuclear DNA in the cytosol, which subsequently triggers a stress response. However, how the advanced tumors perceive and tolerate the potentially detrimental effects of cytosolic DNA remains unclear. Here we show that growth limitation by serum starvation activated the cGAS-STING pathway in breast cancer cells, and inhibition of cGAS-STING resulted in cell death through an autophagy-dependent mechanism. These results suggest that, instead of being subject to growth inhibition, tumors exploit the cGAS-STING axis and turn it to a survival advantage in the stressful microenvironment, providing a new therapeutic opportunity against advanced cancer. Concomitant inhibition of the cGAS-STING axis and growth factor signaling mediated by the epidermal growth factor receptor (EGFR) synergistically suppressed the development of tumor organoids derived from primary tumor tissues of triple-negative breast cancer (TNBC). The current study unveils an unexpected function of the cGAS-STING axis in promoting cancer cell survival and the potential of developing the stress-responding pathway as a therapeutic target, meanwhile highlights the substantial concerns of enhancing the pathway's activity as a means of anti-cancer 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 Liu, Shen, Wang, Wu, Chang, Chen, Lee and Wang.)

Rapidly expanding armamentarium of systemic therapy for advanced hepatocellular carcinoma (HCC) occurred in the recent few years. Multikinase inhibitors (MKI) or targeted therapy with antiangiogenic properties have been the focus of clinical studies in advanced HCC in the past decade. The remarkable efficacy of single agent immune checkpoint inhibitors (ICI), including nivolumab and pembrolizumab, in early phase studies led to accelerated approvals as second-line treatment for advanced HCC. The excellent toxicity profile of single agent ICI also lends support to be developed as combination therapy with other targeted therapies. The success of combining atezolizumab and bevacizumab over sorafenib as the first-line treatment in advanced HCC marked the newest paradigm shift in advanced HCC. The combination exhibited unprecedented objective response rate of 30% and a median survival of 19.2 months. Many other similar ICI-based combinations are expected to be approved in the foreseeable future. In this narrative review, the development of ICI alone and in combination in advanced HCC were described and the potential impact in all stages of HCC, safety issues of ICI-based combinations, and future perspectives were discussed., Competing Interests: Declaration of competing interest Tsung-Hao Liu: none declared. Ying-Chun Shen: none declared. Ann-Lii Cheng: Travel support from Bayer Yakuhin, Ltd., Eisai, Roche/Genentech, Chugai Pharmaceutical, and IQVIA. Speakers bureau from Bayer Yakuhin, Ltd., Novartis, Eisai, Ono Pharmaceutical and Amgen Taiwan. Consulting fee from AstraZeneca, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, IPSEN Innovation, Bayer Healthcare, Merck Sharp Dohme, Roche/Genentech, BeiGene, F. Hoffmann–La Roche, and IQVIAAstraZeneca, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, IPSEN Innovation, Bayer Healthcare, Merck Sharp Dohme, Roche/Genentech, BeiGene, F. Hoffmann–La Roche, and IQVIA., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Introduction: Acne scarring, formed by the deposition of collagen following inflammatory acne, not only represents a cosmetic problem but also poses a psychological health risk to patients. As microneedling has become a common treatment for acne scarring, an increasing number of studies have compared the efficacy and safety of microneedling. In this study, we conducted a meta-analysis of randomized controlled trials (RCTs) comparing microneedling with other treatments., Method: Three databases, namely Embase, PubMED, and Cochrane library, were searched until June 20, 2021, for RCTs only. Studies using microneedling in both treatments were excluded., Results: Twelve studies, totaling 414 participants, were included in our meta-analysis. For objective scar improvement, the pooled estimate analysis of the first group, treated with microneedling without radiofrequency, yielded a mean difference of 0.42 (95% CI-0.12-0.73%) with a significant difference at the 5% significance level. The second group, treated with fractional radiofrequency microneedling, exhibited no significance at the 5% significance level. Regarding subjective satisfaction, most results exhibited no significant difference between microneedling and other treatments. Although no case of secondary scarring or infection was reported in our study, the pooled result of postinflammatory hyperpigmentation was significant at the 5% significance level and preferred microneedling treatment., Conclusion: Microneedling without radiofrequency achieved superior results in terms of scar improvement. No form of microneedling caused postinflammatory hyperpigmentation-an advantage in acne scar treatment. Thus, microneedling is a favorable choice for the treatment of acne scarring., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Purpose: The purpose of this study was to assess the accuracy, repeatability, and performance limits of in vivo Mirau ultrahigh axial resolution (UHR) line field spectral domain (LF-SD) optical coherence tomography (OCT) for the measurement of Bowman's and epithelial thickness, and to provide a reference range of these values for healthy corneas., Methods: Volunteers with no history and evidence of corneal disease were included in this study. An in vivo graph search image segmentation of the central cornea was obtained at the normal interface vector orientation. The Mirau-UHR-LF-SD-OCT system used has an axial resolution down to 2.4 µm in air (1.7 µm in tissue), with an A-scan speed of 204.8 kHz and a signal to noise ratio (sensitivity) of 69 (83) dB., Results: Nine volunteers were included, one of whom wore contact lenses. The repeatability of mean Bowman's and epithelial thicknesses were 0.3 and 1.0 µm, respectively. The measured 95% population range for healthy in vivo thickness was 13.7 to 19.6 µm for the Bowman's layer, and 41.9 to 61.8 µm for the epithelial layer., Conclusions: The measured thicknesses of Bowman's layer and the corneal epithelium using the Mirau-UHR-LF-SD-OCT were both accurate, with the range for healthy in vivo thicknesses matching prior confocal and OCT systems of varying axial resolutions, and repeatable, equaling the best value prior reported., Translational Relevance: T1. Development of a commercially viable clinical UHR OCT technology, enabling accurate measurement and interpretation of Bowman's and epithelial layer thickness in clinical practice.

Importance: Stroke centers are associated with better outcomes. There is substantial literature surrounding disparities in stroke outcomes for underserved populations. However, the existing literature has focused primarily on discrimination at the individual or institutional level, and studies of structural discrimination in stroke care are scant., Objective: To examine differences in hospitals' likelihood of adopting stroke care certification between historically underserved and general communities., Design, Setting, and Participants: This study combined a data set of hospital stroke certification from all general acute nonfederal hospitals in the continental US from January 1, 2009, to December 31, 2019, with national, hospital, and census data to define historically underserved communities by racial and ethnic composition, income distribution, and rurality. For all categories except rurality, communities were categorized by the composition and degree of segregation of each characteristic. Cox proportional hazard models were then estimated to compare the hazard of adopting stroke care certification between historically underserved and general communities, adjusting for population size and hospital bed capacity. Data were analyzed from June 2021 to April 2022., Main Outcomes and Measures: Hospitals' likelihood of adopting stroke care certification., Results: A total of 4984 hospitals were included. From 2009 to 2019, the total number of hospitals with stroke certification grew from 961 to 1763. Hospitals serving Black, racially segregated communities had the highest hazard of adopting stroke care certification (hazard ratio [HR], 1.67; 95% CI, 1.41-1.97) in models not accounting for population size, but their hazard was 26% lower than among those serving non-Black, racially segregated communities (HR, 0.74; 95% CI, 0.62-0.89) in models controlling for population and hospital size. Adoption hazard was lower in low-income communities compared with high-income communities, regardless of their level of economic segregation, and rural hospitals were much less likely to adopt any level of stroke care certification relative to urban hospitals (HR, 0.43; 95% CI, 0.35-0.51)., Conclusions and Relevance: In this analysis of stroke certification adoption across acute care hospitals in the US from 2009 to 2019, hospitals in low-income and rural communities had a lower likelihood of receiving stroke certification than hospitals in general communities. Hospitals operating in Black, racially segregated communities had the highest likelihood of adopting stroke care, but because these communities had the largest population, patients in these communities had the lowest likelihood of access to stroke-certified hospitals when the model controlled for population size. These findings provide empirical evidence that the provision of acute neurological services is structurally inequitable across historically underserved communities.

Background/aim: Triple negative breast cancer (TNBC) is one of the most challenging breast cancer types. Interleukin-8 (IL-8) is a pro-tumorigenic cytokine, promoting tumor proliferation and migration. This study aimed to examine the contribution of IL-8 rs4073 genotypes to breast cancer risk and provide a summary of related literature., Materials and Methods: IL-8 genotypic profiles were determined among 1,232 breast cancer cases and 1,232 controls via polymerase chain reaction-restriction fragment length polymorphism methodology., Results: The IL-8 rs4073 AT and AA genotypes had significantly lower prevalence in the case group compared to control group. Allelic frequency analysis showed that individuals carrying the A allele have relatively decreased risk for breast cancer. The stratification analysis showed that IL-8 rs4073 genotypes were protective markers for those with younger (≤55) age., Conclusion: IL-8 rs4073 A allele is a novel predictor for breast cancer, especially TNBC., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Study Objective: To test whether the differences across sex and race in the treatment of and outcomes for ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) have changed over a recent decade., Methods: We conducted a retrospective analysis of patients with a diagnosis of STEMI or NSTEMI in California from 2005 to 2015 using the Office of State Health Planning and Development dataset. Using multivariable linear regression with county-fixed effects, we measured the baseline and change over time in the proportions of patients with STEMI or NSTEMI who underwent appropriately-timed coronary angiography (day of admission and within 3 days of admission, respectively) and survived at 1 year according to sex and race (Asian, Black, Hispanic, and White) and adjusting for comorbidities, payor, and hospital characteristics., Results: We analyzed 159,068 STEMI and 294,068 NSTEMI presentations. In 2005, 50.0% of 12,329 men and 35.7% of 6,939 women with STEMI and 45.0% of 14,379 men and 33.1% of 10,674 women with NSTEMI underwent timely angiography. In 2015, 76.7% of 6,257 men and 66.8% of 2,808 women with STEMI underwent timely angiography and 56.3% of 13,889 men and 45.9% of 9,334 women with NSTEMI underwent timely angiography. In 2005, 1-year survival was 82.3% for men and 69.6% for women after STEMI; in 2013, 1-year survival was 88.1% for men and 79.1% for women. In the multivariable model, the baseline difference was 1.1 percentage points (95% confidence interval [CI] 0.2 to 1.9), and survival increased for women compared with men by 0.3 percentage points per year (95% CI 0.2 to 0.5). In 2005, 46.0% (5,878) of 12,789 White patients and 31.2% (330) of 1,057 Black patients with STEMI underwent timely angiography; in 2015 75.2% of 3,928 White patients and 69.2% of 522 Black patients underwent timely angiography for STEMI. In the multivariable model, this difference was 6.4 percentage points at baseline (95% CI 4.5 to 8.3), and the probability of undergoing timely angiography for Black patients increased by 0.3 percentage points per year (95% CI -0.1 to 0.6)., Conclusion: Despite overall improvements in the treatment of and outcomes for STEMI and NSTEMI, disparities persist in the treatment of and outcomes for both the conditions, particularly for women., (Copyright © 2022 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background/aim: The elevated expression of interleukin-18 (IL-18) among lung cancer patients raised our curiosity to examine the role of IL-18 genotypes in lung cancer., Materials and Methods: IL-18 -656 (rs1946519), -607 (rs1946518), and -137 (rs187238) genotypes of 358 lung cancer cases and 716 controls were determined via the PCR-RFLP methodology., Results: The distributions of genotypic and allelic frequencies of IL-18 -607, but not those of -656 or -137, were differentially distributed between cases and controls. IL-18 -607 AC and CC genotypes were both lower (45.8% and 16.2%) in lung cancer patients compared to controls (51.4% and 24.7%). In addition, IL-18 -607 AC and CC genotypes were of significantly lower percentages both among non-smokers and smokers. Otherwise, no differential distribution was found regarding IL-18 -656 or -137., Conclusion: IL-18 -607 C allele can serve as a protective predictor for lung cancer risk in Taiwanese., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Prostate cancer (PC) is one of the major diseases that affects male health and ranks as the second most frequent cancer in men worldwide. Although most newly-diagnosed PCs are well-differentiated tumors with a high cure probability, there are some patients with aggressive malignancies that show potential for recurrence and metastasis. Cytotoxic T lymphocytes are a specific immune effector cell population that mediates immune responses against cancer., Materials and Methods: In the present study, the cytotoxicity of peripheral blood mononuclear cells (PBMCs)-derived γδ T cells and cytokine-induced killer (CIK) cells in combination with chemoradiotherapy against PC cells was evaluated using Alamar blue cell viability and cell membrane permeability assays., Results: Advanced PC-3 cells, which were more resistant to docetaxel (Doc), also showed higher viability following pretreatment with radiation. The cell proliferation inhibition was significantly increased upon additional γδ T or CIK treatment. Furthermore, the proportion of apoptotic cells was significantly (p<0.05) increased in the Doc-γδ T cell co-treatment group as compared with the Doc or γδ T cell treated alone group., Conclusion: γδ T cell therapy may provide additional benefit compared to traditional chemoradiotherapy for PC treatment., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Necroptosis, a form of programmed cell death, is increasingly being investigated for its controversial role in tumorigenesis and progression. Necroptosis suppresses tumor formation and tumor development by killing tumor cells; however, the necrotic cells also promote tumor formation and tumor development via the immunosuppressive effect of necroptosis and inflammatory response caused by cytokine release. Thus, the exact mechanism of necroptosis in pan-cancer remains unknown., Methods: The data of 11,057 cancer samples were downloaded from the TCGA database, along with clinical information, tumor mutation burden, and microsatellite instability information of the corresponding patients. We used the TCGA data in a pan-cancer analysis to identify differences in mRNA level as well as single nucleotide variants, copy number variants, methylation profiles, and genomic signatures of miRNA-mRNA interactions. Two drug datasets (from GDSC, CTRP) were used to evaluate drug sensitivity and resistance against necroptosis genes., Results: Necroptosis genes were aberrantly expressed in various cancers. The frequency of necroptosis gene mutations was highest in lung squamous cell carcinoma. Furthermore, the correlation between necroptosis gene expression in the tumor microenvironment and immune cell infiltration varied for different cancers. High necroptosis gene expression was found to correlate with NK, Tfh, Th1, CD8&#95;T, and DC cells. These can therefore be used as biomarkers to predict prognosis. By matching gene targets with drugs, we identified potential candidate drugs., Conclusion: Our study showed the genomic alterations and clinical features of necroptosis genes in 33 cancers. This may help clarify the link between necroptosis and tumorigenesis. Our findings may also provide new approaches for the clinical treatment of cancer., 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 Li, Su, Chen, Liu, Zhang, Shen, You, Wang, Zhang, Wang, Wen, Wang, Shao, Chen and Yang.)

The relative benefit of ipsilateral, contralateral, and bilateral repetitive transcranial magnetic stimulation (rTMS) for tinnitus treatment remains unclear, especially for patients with lateralized tinnitus. In this study, we compared outcomes after 10 sessions of 1-Hz rTMS at 110% of resting motor threshold over a two-week period. In total, 104 right-handed patients with lateralized subjective tinnitus were randomly divided into four groups according to rTMS treatment: Left (n = 29), Right (n = 23), Bilateral (n = 30), and Sham stimulation (n = 22). Outcomes included estimates of tinnitus severity, psychological state, and psychoacoustic measures. Patients with left- or right-sided tinnitus were similarly distributed across treatment groups. There were no significant changes in outcome measures for the Right or Sham treatment groups. For the Left and Bilateral groups, tinnitus severity was significantly lower after treatment (p < 0.05). The reduction in tinnitus severity was largest for ipsilateral treatment in the Left group. The overall response rate was 56.1% for the Left group, 46.7% for the Bilateral group, 8.3% for the Right group, and 8.3% for the Sham group. For the Left and Bilateral groups, the response rate was larger for patients with left- than right-sided tinnitus. Changes in tinnitus severity were best predicted by changes in anxiety, depression, and the loudness of the tinnitus. The results suggests that rTMS on the left temporoparietal cortex is more effective for patients with left-sided than with right-sided tinnitus.

Invasion is the most prominent lethal feature of malignant cancer. However, how cell proliferation, another important feature of tumor development, is integrated with tumor invasion and the subsequent cell dissemination from primary tumors is not well understood. Proliferating cell nuclear antigen (PCNA) is essential for DNA replication in cancer cells. Loss of phosphorylation at tyrosine 211 (Y211) in PCNA (pY211-PCNA) mitigates PCNA function in proliferation, triggers replication fork arrest/collapse, which in turn sets off an anti-tumor inflammatory response, and suppresses distant metastasis. Here, we show that pY211-PCNA is important in stromal activation in tumor tissues. Loss of the phosphorylation resulted in reduced expression of mesenchymal proteins as well as tumor progenitor markers, and of the ability of invasion. Spontaneous mammary tumors that developed in mice lacking Y211 phosphorylation contained fewer tumor-initiating cells compared to tumors in wild-type mice. Our study demonstrates a novel function of PCNA as an essential factor for maintaining cancer stemness through Y211 phosphorylation.

Background: The treatment options for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases (BMs) include EGFR-tyrosine kinase inhibitors (TKIs), stereotactic radiosurgery (SRS), whole-brain radiotherapy, brain surgery, and antiangiogenesis therapy. As treatment options evolve, redefining optimal treatment strategies to improve survival are crucial., Methods: A total of 150 EGFR-mutant NSCLC patients with BMs who received first- or second-generation EGFR-TKIs as first-line treatment between January 2012 and October 2019 were included in this analysis., Results: After multivariate analysis, patients with the graded prognostic assessment for lung cancer using molecular markers (Lung-mol GPA) ≥3 (hazard ratio [HR]: 0.538, 95% confidence interval [CI]: 0.35-0.83), who received afatinib or erlotinib as first-line treatment (HR: 0.521, 95% CI: 0.33-0.82), underwent SRS therapy (HR: 0.531, 95% CI: 0.32-0.87), or were sequentially treated with osimertinib (HR: 0.400, 95% CI: 0.23-0.71) were associated with improved overall survival (OS). Furthermore, SRS plus EGFR-TKI provided more OS benefits in patients with Lung-mol GPA ≥3 compared with EGFR-TKI alone in our patient cohort (44.9 vs. 26.7 months, p = 0.005). The OS in patients who received sequential osimertinib therapy was significantly longer than those without osimertinib treatment (43.5 vs. 24.3 months, p < 0.001), regardless of T790 mutation status (positive vs. negative vs. unknown: 40.4 vs. 54.6 vs.43.4 months, p = 0.227)., Conclusions: The study demonstrated that EGFR-mutant NSCLC patients with BMs could be precisely treated with SRS according to Lung-mol GPA ≥3. Sequential osimertinib was associated with prolonged survival, regardless of T790M status., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Needle knife papillotomy (NKP) and fistulotomy (NKF) are the two most commonly used rescue techniques for patients with difficult biliary cannulation (DBC). Anatomy of the major duodenal papillae (MDP) influences the optimal precut technique for biliary access. However, comparative studies of the success and safety of NKP and NKF based on the anatomy of MDP have been scarce., Methods: Patients with intact MDPs for therapeutic endoscopic retrograde cholangio-pancreatography (ERCP) in our center were enrolled. Early needle knife precuts were uniformly applied to patients with DBC. Difficult MDPs were classified into one of five types based on their endoscopic anatomy. Each type of MDP was allocated to NKP or NKF treatment. Patients with types 1 and 2 papillae always received NKF, 3 and 4 received NKP, and 5 could receive either. The safety and efficacy were analyzed between NKP and NKF, and among different types of MDPs., Results: A total of 188 out of 1674 patients undergoing ERCP satisfied the criteria for early precutting: 75 patients were assigned to the NKP group and 113 to the NKF group. The total initial success rate of biliary cannulation (ISRBC) of the precut techniques (both NKP and NKF) for patients with DBC was 91.5%. The ISRBC of patients of the NKP group was similar to that of the NKF group (90.7% vs 92.0%, P > 0.05). The ISRBC of the patients in the swollen MDP subgroup (96.1%) was higher than that of patients in the distorted MDP subgroup (81.8%, P = 0.030). The total and specific complications of the patients of the NKP group were similar to those of the NKF group (P > 0.05)., Conclusions: NKP and NKF, as selected on the basis of MDP anatomy, are equally safe and highly efficient for patients with DBC to allow biliary cannulation. Patients with swollen MDPs had a higher ISRBC than patients with distorted MDPs. Selecting a precut method based on MDP anatomy is an effective and safe strategy for patients with DBC., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The role of miRNAs in cancer and their possible function as therapeutic agents are interesting and needed further investigation. The miR-26a-5p had been demonstrated as a tumor suppressor in various cancers. However, the importance of miR-26a-5p regulation in upper tract urothelial carcinoma (UTUC) remains unclear. Here, we aimed to explore the miR-26a-5p expression in UTUC tissues and to identify its regulatory targets and signal network involved in UTUC tumorigenesis. The miR-26a-5p expression was validated by quantitative real-time polymerase chain reaction (qPCR) using renal pelvis tissue samples from 22 patients who were diagnosed with UTUC and 64 cases of renal pelvis tissue microarray using in situ hybridization staining. BFTC-909 UTUC cells were used to examine the effects of miR-26a-5p genetic delivery on proliferation, migration and expression of epithelial-to-mesenchymal transition (EMT) markers. MiR-26a-5p was significantly down-regulated in UTUC tumors compared to adjacent normal tissue and was decreased with histological grades. Moreover, restoration of miR-26a-5p showed inhibition effects on proliferation and migration of BFTC-909 cells. In addition, miR-26a-5p delivery regulated the EMT marker expression and inhibited WNT5A/β-catenin signaling and expression of downstream molecules including NF-κB and MMP-9 in BFTC-909 cells. This study demonstrated that miR-26a-5p restoration may reverse EMT process and regulate WNT5A/β-catenin signaling in UTUC cells. Further studies warranted to explore the potential roles in biomarkers for diagnostics and prognosis, as well as novel therapeutics targets for UTUC treatment., (© 2022. The Author(s).)

Sleep and wakefulness are basic behavioral states that require coordination between several brain regions, and they involve multiple neurochemical systems, including neuropeptides. Neuropeptides are a group of peptides produced by neurons and neuroendocrine cells of the central nervous system. Like traditional neurotransmitters, neuropeptides can bind to specific surface receptors and subsequently regulate neuronal activities. For example, orexin is a crucial component for the maintenance of wakefulness and the suppression of rapid eye movement (REM) sleep. In addition to orexin, melanin-concentrating hormone, and galanin may promote REM sleep. These results suggest that neuropeptides play an important role in sleep-wake regulation. These neuropeptides can be divided into three categories according to their effects on sleep-wake behaviors in rodents and humans. (i) Galanin, melanin-concentrating hormone, and vasoactive intestinal polypeptide are sleep-promoting peptides. It is also noticeable that vasoactive intestinal polypeptide particularly increases REM sleep. (ii) Orexin and neuropeptide S have been shown to induce wakefulness. (iii) Neuropeptide Y and substance P may have a bidirectional function as they can produce both arousal and sleep-inducing effects. This review will introduce the distribution of various neuropeptides in the brain and summarize the roles of different neuropeptides in sleep-wake regulation. We aim to lay the foundation for future studies to uncover the mechanisms that underlie the initiation, maintenance, and end of sleep-wake states.

Glioma is a severe disease with a poor prognosis despite aggressive surgical resection and traditional chemotherapies. Therefore, new anti-neoplastic drugs are urgently needed. Bioactive compounds from natural products are potential sources of antiproliferative molecules, among which manzamine compounds extracted from the Formosan marine sponge Haliclona sp. have shown considerable promise as anticancer drugs. In the present study, the anti-neoplastic effect and mechanism of the manzamine derivative 1-(9'-propyl-3'-carbazole)-1, 2, 3, 4-tetrahydro-β-carboline (PCTC) were investigated using in vitro cell lines and an in vivo subcutaneous animal model. Both cytotoxic and anti-proliferative effects were shown in human and murine glioma cell lines (A172, U87MG, and GL261), together with enhanced expressions of apoptotic enzymes and intracellular reactive oxygen species, and blockage of the G1/S phase of the cell cycle. In addition, combined treatment of GL261 cells with PCTC and temozolomide had a synergic antiproliferative effect. Significant safety, efficacy, and survival benefits were also demonstrated with PCTC treatment in the murine subcutaneous GL261 model. In conclusion, PCTC could effectively promote cell death through apoptosis and cell cycle arrest in glioma cell lines, and provide survival benefits in the animal model. Therefore, PCTC may be a clinically beneficial therapy for glioblastoma., Competing Interests: None., (AJCR Copyright © 2022.)

Objectives: To investigate the influencing factors for the quality of bowel preparation before colonoscopy in children and the association of the interval from the last administration of laxative to the start of colonoscopy (shortly referred to as waiting time) with the quality of bowel preparation., Methods: A retrospective analysis was performed for the children who were admitted to the Department of Gastroenterology, Children's Hospital of Nanjing Medical University, from January to November 2020, and received bowel preparation with polyethylene glycol electrolyte powder combined with diet control before colonoscopy. According to the score of Boston bowel preparation scale, they were divided into two groups: adequate bowel preparation group ( n =337) and inadequate bowel preparation group ( n =30). Related data were collected from the children in both groups, including general information, possible influencing factors for the quality of bowel preparation, adverse reactions associated with bowel preparation, duration of colonoscopy, and postoperative diagnosis. Univariate and multivariate analyses were used to explore the influencing factors for the quality of bowel preparation., Results: The univariate analysis showed that age, body weight, and waiting time were associated with inadequate bowel preparation ( P <0.05). The multivariate analysis showed that older age ( OR =2.155, 95% CI : 1.087-4.273, P =0.028) and longer waiting time ( OR =1.559, 95% CI : 1.191-2.041, P =0.001) were independent risk factors for inadequate bowel preparation. The receiver operating characteristic (ROC) curve analysis showed that the cut-off value of waiting time was 5.5 hours in determining whether bowel preparation was adequate or not, with a sensitivity of 90.0%, a specificity of 50.7%, and an area under the ROC curve of 0.708. After grouping based on waiting time, it was found that the incidence rate of inadequate bowel preparation in the ≥5.5 hours group was significantly higher than that in the <5.5 hours group [14.0% (27/193) vs 1.7% (3/174), P <0.001]., Conclusions: For children who use polyethylene glycol electrolyte powder combined with diet control for bowel preparation, older age is an independent risk factor for inadequate bowel preparation before colonoscopy, which may be associated with an insufficient dose of polyethylene glycol in older children. Longer waiting time is also an independent risk factor for inadequate bowel preparation, and it is recommended that the waiting time should not exceed 5.5 hours.

Fallopian tube (FT) homeostasis requires dynamic regulation of heterogeneous cell populations and is disrupted in infertility and ovarian cancer. Here, we applied single-cell RNA-seq to profile 59,738 FT cells from four healthy, pre-menopausal subjects. The resulting cell atlas contains 12 major cell types representing epithelial, stromal, and immune compartments. Re-clustering of epithelial cells identified four ciliated and six non-ciliated secretory epithelial subtypes, two of which represent potential progenitor pools: one leading to mature secretory cells and the other contributing to either ciliated cells or one of the stromal cell types. To understand how FT cell numbers and states change in a disease state, we analyzed 17,798 cells from two hydrosalpinx samples and observed shifts in epithelial and stromal populations and cell-type-specific changes in extracellular matrix and TGF-β signaling; this underscores fibrosis pathophysiology. This resource is expected to facilitate future studies aimed at expanding understanding of fallopian tube homeostasis in normal development and disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Purpose: H1-antihistamines (AHs) may exert protective effects against cancer. This study investigated the association of AH use with the risk of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV), hepatitis C virus (HCV), or dual HBV-HCV virus infection., Materials and Methods: Patients with HBV, HCV, or dual HBV-HCV infection were enrolled from Taiwan's National Health Insurance Research Database and examined for the period from January 1, 2006, to December 31, 2015. We used the Kaplan-Meier method and Cox proportional hazards regression to evaluate the association between AH use and HCC risk., Results: We included patients with HBV infection (n = 521,071), HCV (n = 169,159), and dual HBV-HCV (n = 39,016). Patients with HBV, HCV, or dual virus infection who used AHs exhibited significantly lower risk of HCC relative to patients who did not use AH, with their adjusted hazard ratio being 0.489 (95% CI, 0.455 to 0.524), 0.484 (95% CI, 0.450 to 0.522), and 0.469 (95% CI, 0.416 to 0.529), respectively. Furthermore, there was a dose-response relationship between AH use and the risk of HCC in the HBV cohort. The adjusted hazard ratios were 0.597 (95% CI, 0.530 to 0.674), 0.528 (0.465 to 0.600), 0.470 (0.416 to 0.531), and 0.407 (0.362 to 0.457) for AH use of 28-42, 43-63, 64-119, and ≥ 120 cumulative defined daily doses, respectively, relative to no AH use. Additionally, there was also a dose-response relationship between AH use and the risk of HCC in the HCV and dual HBV-HCV cohorts., Conclusion: AH use may reduce the risk for HCC among patients with HBV, HCV, or dual infection in a dose-dependent manner. Further mechanistic research is needed.

Crossmodal correspondences refer to the fact that certain domains of features in different sensory modalities are associated with each other. Here, we investigated the crossmodal correspondences between speech sounds and visual shapes. Specifically, we tested whether the classification dimensions of English vowels (front-central-back) and consonants (voiced-voiceless, sonorant-obstruent, and stop-continuant) correspond to visual shapes along a bipolar rounded-angular dimension. We adapted eighteen meaningless pseudowords from a previous study that corresponded to either the round or the sharp concept. On each trial, the participants heard one of the pseudowords and saw a rounded shape and an angular shape presented side-by-side on the monitor. Participants judged which shape provided a better match to the spoken pseudoword. A logistic regression was conducted in order to elucidate the effectiveness of classification dimensions of phonemes when predicting variations in the sound-shape matchings. The results demonstrated that the sound-shape matchings were predictable using front-central-back dimensions of vowels, and voiced-voiceless and stop-continuant dimensions of consonants. Hence, we verified that sound-shape matching is underpinned by contrasting dimensions in both vowels and consonants, therefore demonstrating crossmodal correspondences at the phonetic level., Competing Interests: Declaration of Conflicting 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) 2022.)

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.)

(1) Background: This study aimed to test the feasibility of utilizing the screening tool for fall risk assessment in adult inpatient and verify its accuracy in a medical center in Taiwan. (2) Methods: This study retrospectively collected all adult fall cases among inpatients occurring in the general wards of a medical center between 1 January 2013 and 31 December 2015. This inpatient fall risk screening scale was measured by the sensitivity, specificity, and accuracy. (3) Results: There were 1331 (0.4%) falls among a total of 357,395 inpatients during this period. Factors predictive of falling risk included: age, consciousness, body shift assistance, use of fall risk medications, fall history, dizziness or weakness, toileting, and impaired mobility. Using the eight-factor assessment, two was the best cutoff point for identifying the fall risk group, with area under Receiver Operating Characteristic (ROC) curve (AUC) = 0.817, sensitivity = 80.93%, specificity = 73.0%, accuracy = 73.03%, and likelihood ratio = 11.48. (4) Conclusions: The accuracy of the eight-item fall risk assessment tool created for this study was validated. These results can serve as a reference for institutions to develop more effective fall risk assessment scale for inpatients, enabling clinical nurses to identify and more comprehensively assess the groups at highest risk for falling during their hospital stay.

Background and Objectives : The anterolateral thigh (ALT) flap is widely used in head and neck reconstruction, but the postoperative thigh sensory function lacks sufficient evaluation. The present study reports the postsurgical pain and cancer-related quality of life (QoL) in different stages of oral cancer patients receiving anterolateral thigh (ALT) flap reconstruction. Materials and Methods : Patients were subgrouped into postoperative early-, mid-, and late-recovery stages (postoperative 0.5-1 years, 1-2 years, and above 2 years) according to the time point of assessment. The QoL was examined using the EORTC C-30. Postsurgical donor and receipt site pain was evaluated through subjective reports and sensory tests. Results : Ninety-four patients were included in the final analysis. The functional and global health-related QoL significantly improved with time after surgery. However, spontaneous pain was reported in 57.7%, 72.3%, and 42% of patients in early-, mid-, and late-recovery stages, mainly in donor sites rather than in receipt sites. The highest incidence of donor site pain after ALT flap reconstruction in oral cancer surgery was in the mid-recovery stage but remained high in the late-recovery stage (56.8% and 36.7%, respectively). Conclusions : The postsurgical pain in the donor site might persist to or exhibit delayed onset one to two years postoperatively but is much improved after postoperatively two years later. A longer postsurgical follow-up for over two years for pain and sensory dysfunction is indicated.

Background/aim: Chronic inflammation is believed to play a critical role in the pathogenesis of lung cancer. Interleukin-8 (IL-8) is an inflammatory cytokine and plays an important role in cancer development. Few studies have investigated the association between interleukin-8 - 251T/A (rs4073) genotype and lung cancer risk in various populations., Materials and Methods: In the current study, genotypes of interleukin-8 rs4073 were analyzed in 358 lung cancer patients and 716 healthy controls in Taiwan, by the PCR-RFLP methodology., Results: The distribution frequencies of interleukin-8 rs4073 genotypes between control and case groups were compared, and the homozygous variant AA genotypes showed a lower percentage in the case group compared to the control group (OR=0.57, 95%CI=0.39-0.85, p=0.0059). The distributions of alleles frequencies also exhibited statistical difference (p=0.0066). There was an interaction between interleukin-8 rs4073 and smoking habits (p=0.0051)., Conclusion: Interleukin-8 rs4073 genotypes were associated with lung cancer susceptibility, especially for smokers., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To explore the effect of neoadjuvant immunotherapy on pulmonary function and the efficacy in patients with resectable non-small cell lung cancer. Methods: Data of 30 patients with non-small cell lung cancer (NSCLC) who received neoadjuvant immunotherapy before surgery in the Chest Hospital of Shanghai Jiaotong University from March 2018 to September 2021 were retrospectively collect. The efficacy and safety of neoadjuvant immunotherapy in the perioperative period and changes in pulmonary function of patients before and after neoadjuvant treatment were valuated. Results: The patients were all-male with age of (61±8)years old, The major pathological response (MPR) rate of patients receiving neoadjuvant immunotherapy was 43%(13 cases), the pathologic complete response (pCR) rate was 37% (11 cases), disease control rate (DCR) was 97% (29 cases), objective response rate (ORR) was 67% (20 cases). The forced expiratory volume in one second (FEV1) after treatment was (2.59±0.63) L, and the ratio of FEV1 to the predicted value (FEV1%pred) was 85.27%±15.86%, which were significantly higher than those before treatment [(2.48±0.59)L, 81.73%±15.94%, respectively] ( P =0.013, 0.022, respectively). Forced vital capacity (FVC) after treatment was (3.59±0.77) L, which was also significantly higher than before [(3.47±0.76) L, P =0.036]; while there were no statistical difference in FEV1/FVC and FVC accounted for the proportion of predicted values (FVC%pred) between before and after treatment ( P =0.084, 0.344, respectively). The ratio of carbon monoxide dispersion (DLCO) to the predicted value (DLCO%pred) decreased from 83.61%±13.10% to 78.69%±13.85% after treatment ( P =0.023). There was no significant difference in the incidence of postoperative complications between the DLCO%pred decreased group and the non-decreased group (3/18 vs 0/6; P =0.546). Conclusions: Neoadjuvant immunotherapy can increase the rate of MPR and PCR, significantly increase FEV1 and FEV1%pred, but also lead to a decrease in DLCO%pred; neoadjuvant immunotherapy does not increase the incidence of postoperative complications.

Objective: To investigate the effect of moxibustion on synovitis and the autophagy of synoviocytes in rheumatoid arthritis (RA)., Methods: Forty Sprague-Dawley rats were randomly divided into a normal group, model group, moxibustion group, cigarette moxibustion group, and medicine group, with eight rats included in each group. The RA model was established by subcutaneous injection of complete Freund's adjuvant into the left posterior toe. Rats in the model group were not interfered with. In the moxibustion group, rats were treated by moxibustion, where a 1-cm diameter moxa stick was applied at the left Zusanli (ST 36) point. The distance of the moxa stick to the skin was 2 cm and moxibustion was completed for 20 min daily for 15 d total. In the cigarette moxibustion group, the moxa stick was replaced by a common cigarette. In the medicine group, rats were treated with a tripterygium glycoside suspension (8 mg/kg) once a day for 15 d total. In each group, the left hind limb toe volume was measured with a toe volume meter; the synovial cells were observed by hematoxylin and eosin staining; the interleukin (IL)-4, IL-6, IL-10, IL-1β, IL-23, IL-17, and tumor necrosis factor (TNF)-α levels in serum were measured by enzyme-linked immunosorbent assay; the erythrocyte sedimentation rate (ESR) were detected by Westergren sedimentation rate testing; the C-reactive protein (CRP) and rheumatoid factor (RF) levels in serum were detected by rate nephelometry; the expression levels of ULK1, autophagy-associated protein (Atg)3, Atg5, and Atg12 messenger RNA (mRNA) in synovium were detected by real time-quantitative polymerase chain reaction (RT-qPCR); and the protein expression levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), LC3-II, beclin-1, phosphorylated-PI3K (p-PI3K), p-Akt, p-mTOR in synovium were detected by Western blotting., Results: Among the RA model rats, joint swelling, an inflammatory reaction, and the proliferation of synovial tissue were obvious and the signal of the PI3K/Akt/mTOR pathway was active, while autophagy was inhibited. Moxibustion at Zusanli (ST36) or intragastric administration of Tripterygium wilfordii glycosides could alleviate the inflammatory reaction of RA rats; relieve the swelling of the toes; downregulate the levels of ESR, CRF, RF; lower the levels of IL-6, IL-1β, TNF-α, and IL-17; and increase the IL-4 and IL-10. At the same time, the mRNA expression levels of ULK1, Atg3, Atg5, and Atg12 and those of LC3-Ⅱ and beclin-1 were increased, while the PI3K, Akt, mTOR, p-PI3K, p-Akt, p-mTOR were decreased. Cigarette moxibustion did not significantly reduce the swelling of the toe joint in RA rats, and was not as good as that of moxibustion or Tripterygium wilfordii polyglycosides in the effects of inflammation relief and the influences of the levels of ESR, CRF, RF. While cigarette moxibustion has a weak effect to affect the expression of corresponding molecules in autophages and the expression level of the autophagy biomaker in synovial tissue. Moxibustion and tripterygium glycosides can significantly reduce the joint swelling, relieve synovitis and synovial hyperplasia, and inhibit the PI3K/Akt/mTOR signaling pathway to increase autophagy in a manner superior to cigarette moxibustion., Conclusion: Moxibustion can limit the proliferation of synoviocytes in RA rats by inhibiting the PI3K/Akt/mTOR signaling pathway, promoting autophagy, effectively reducing synovitis, and alleviating joint swelling.

A multifunctional ion-sensitive floating gate Fin field-effect transistor (ISFGFinFET) for hydrogen and sodium detection is demonstrated. The ISFGFinFET comprises a FGFET and a sensing film, both of which are used to detect and improve sensitivity. The sensitivity of the ISFGFinFET can be adjusted by modulating the coupling effect of the FG. A nanoseaweed structure is fabricated via glancing angle deposition (GLAD) technology to obtain a large sensing area to enhance the sensitivity for hydrogen ion detection. A sensitivity of 266 mV per pH can be obtained using a surface area of 3.28 mm 2 . In terms of sodium ion detection, a calix[4]arene sensing film to monitor sodium ions, obtaining a Na + sensitivity of 432.7 mV per pNa, is used. In addition, the ISFGFinFET demonstrates the functionality of multiple ions detection simultaneously. The sensor arrays composed of 3 × 3 pixels are demonstrated, each of which comprise of an FGFET sensor and a transistor. Furthermore, 16 × 16 arrays with a decoder and other peripheral circuits are constructed and simulated. The performance of the proposed ISFGFinFET is competitive with that of other state-of-the-art ion sensors., (© 2021 Wiley-VCH GmbH.)

The atezolizumab (Tecentriq), a humanized antibody against human programmed death ligand 1 (PD-L1), combined with nab-paclitaxel was granted with accelerated approval to treat unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) due to the encouraging positive results of the phase 3 IMpassion130 trial using PD-L1 biomarker from immune cells to stratify patients. However, the post-market study IMpassion131 did not support the original observation, resulting in the voluntary withdrawal of atezolizumab from the indication in breast cancer by Genentech in 2021. Emerging evidence has revealed a high frequency of false negative result using the standard immunohistochemical (IHC) staining due to heavy glycosylation of PD-L1. The removal of glycosylation prevents from the false negative staining, enabling more accurate assessment of PD-L1 levels and improving prediction for response to immune checkpoint therapy. In the present study, the natural and de-glycosylated PD-L1 expression in tumor and immune cells from nine TNBC patients were analyzed by using clone 28-8 monoclonal antibody to correlate with treatment outcome. Our results demonstrate that: (1) Removal of the glycosylation indeed enhances the detection of PD-L1 by IHC staining, (2) The PD-L1 levels on tumor cell surface after removal of the glycosylation correlates well with clinical responses for atezolizumab treatment; (3) The criteria used in the IMpassion130 and IMpassion131 trials which scored the natural PD-L1 in the immune cells failed to correlate with the clinical response. Taken together, tumor cell surface staining of PD-L1 with de-glycosylation has a significant correlation with the clinical response for atezolizumab treatment, suggesting that treatment of atezolizumab may be worthy of further consideration with de-glycosylation procedure as a patient stratification strategy. A larger cohort to validate this important issue is warranted to ensure right patient population who could benefit from the existing FDA-approved drugs., Competing Interests: Mien-Chie Hung holds a patent on the methodology for de-glycosylation staining., (AJCR Copyright © 2022.)

Background: Preclinical data suggest that concurrent treatment of anti-CD38 and antiprogrammed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies substantially reduce primary tumor growth by reversing T-cell exhaustion and thus enhancing anti-PD-1/PD-L1 efficacy., Methods: This phase I/II study enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of phase I were to investigate the safety and tolerability of isatuximab (anti-CD38 monoclonal antibody)+cemiplimab (anti-PD-1 monoclonal antibody, Isa+Cemi) in patients with mCRPC (naïve to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase II used Simon's two-stage design with response rate as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) patients receiving Isa+Cemi were enrolled in phase II. Safety, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, and tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping., Results: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All patients experienced ≥1 treatment-emergent adverse event. Grade≥3 events occurred in 13 (54.2%) patients with mCRPC and 12 (60.0%) patients with NSCLC. Based on PCWG3 criteria, assessment of best overall response with Isa+Cemi in mCRPC revealed no complete responses (CRs), one (4.2%) unconfirmed partial response (PR), and five (20.8%) patients with stable disease (SD). Per RECIST V.1.1, patients with NSCLC receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. In post-therapy biopsies obtained from patients with mCRPC or NSCLC, Isa+Cemi treatment resulted in a reduction in median CD38+ tumor-infiltrating immune cells from 40% to 3%, with no consistent modulation of PD-L1 on tumor cells or T regulatory cells in the TME. The combination triggered a significant increase in peripheral activated and cytolytic T cells but, interestingly, decreased natural killer cells., Conclusions: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, such CD38 inhibition was not associated with significant antitumor activity. A lack of efficacy was observed in these small cohorts of patients with mCRPC or NSCLC., Trial Registration Numbers: NCT03367819., Competing Interests: Competing interests: PAZ: Pfizer, Novartis, Sanofi, BMS, MSD, Roche, Amgen, AstraZeneca, Astellas, Janssen, Ipsen, and Bayer. C-CL: Abbvie, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, PharmaEngine, and Roche. BCC, MT, W-CS, GD, MS, AG, SP, Y-CS, MP: nothing to disclose. TMB: AstraZeneca, Lilly, Bristol Myers Squibb, Foundation Medicine, Pfizer, Loxo, Bayer, Guardant Health, Exelixis, Blueprint Medicines, and Sanofi. AI: Epizyme, Lilly, Merck Sharp & Dohme, Novartis, Pharmamar, Roche, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Pfizer. RI: Ipsen, Pfizer, Janssen, Sanofi, Merck, Astellas, and MSD. CM: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, and Orion. MG: Bristol Myers Squibb, Merck, Eli Lilly, Esanex, Foundation Medicine, AstraZeneca, and Guardant 360. RM, GA, HL, YD, MC, RW, and LLo are employed by Sanofi and may hold stock and/or stock options in the company. LLe is employed by Excelya on behalf of Sanofi and may hold stock and/or stock options in the company. JdB: AstraZeneca, GlaxoSmithKline, Pfizer, Taiho, Daiichi Sankyo, Bayer, Orion Pharma, Roche/Genentech, Merck Serono, Sierra Oncology, MSD, Terumo, Menarini/Silicon Biosystems, Astellas, BioexcelTherapeutics, Cellcentric, Merck Sharp & Dohme, Qiagen, Sanofi Aventis, and Vertex Pharmaceuticals., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: While nocturia has been proposed to be related to various systemic diseases and even mortality, there has been little information of the impact of nocturia in other aspects of physical and mental well-being. We evaluated the impact of nocturia on quality of life (QoL), mental health, work limitation, and health-care seeking behavior., Methods: An internet-based self-administered survey was distributed among individuals aged ≥40 years with the ability to use a computer and to read the local language. Survey questions included demographic details, International Continence Society symptom definitions and the international prostate symptom score. Impact on nocturia on health-related QoL physical and mental health domain, Hospital Anxiety and Depression Scale (HADS) score and Work Limitations Questionnaire (WLQ) measures was evaluated., Results: There were 8284 participants (women, 51%) of whom 34% were aged ≥60 years. Prevalence of nocturia ≥2 was 35% in men and 37% in women. Across both genders, QoL decreased with increasing frequency of nocturia. Besides nocturia, hypertension, presence of neurological disorder, lower urinary tract symptom measures and female gender were also associated with HADS anxiety and depression scores of ≥8. Nocturia significantly impacted work ability across WLQ measures. Though the utilization of prescription medications increased with the increase in frequency of nocturia, it was also noted that up to 30% of participants who reported nocturia frequency of ≥3 did not seek any treatment for their complaints., Conclusion: Nocturia significantly affects QoL, work productivity, and mental well-being. However, healthcare utilization remains low and warrants increased awareness and education in the patients, caregivers and physicians., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Targeting protein kinase C (PKC) family was found to repress the migration and resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, none of the PKC inhibitors has been approved for anticancer therapy yet due to the limited efficacy in clinical trials, and the underlying mechanisms remain unclear. l-lactic acidosis, a common condition comprising high l-lactate concentration and acidic pH in the tumor microenvironment, has been known to induce tumor metastasis and drug resistance. In this study, l-lactic acid was found to reverse the inhibitory effects of pan-PKC inhibitors GO6983 on PKC activity, cell migration, and EGFR-TKI resistance, but these effects were not affected by the modulators of lactate receptor GPR81. Interestingly, blockade of lactate transporters, monocarboxylate transporter-1 and -4 (MCT1 and MCT4), attenuated the intracellular level of GO6983, and its inhibitory effect on PKC activity, suggesting that lactic acid promotes the resistance to PKC inhibitors by competing for the uptake through these transporters rather than by activating its receptor, GPR81. Our findings explain the underlying mechanisms of the limited response of PKC inhibitors in clinical trials., (© 2021 Wiley Periodicals LLC.)

Cinnamon ( Cinnamomum cassia ) is a well-known traditional Chinese medicine used to treat nocturia by tonifying and warming the kidney. Our recent clinical study found that overactive bladder (OAB) patients treated with cinnamon powder (CNP) patches exhibited significantly ameliorated OAB symptoms without significant side effects, but the mechanism of action is unclear. To explore the beneficial effects and action mechanisms of CNP and its major active component cinnamaldehyde (CNA) in an OAB-related murine model, cyclophosphamide- (CYP-) induced OAB injury was performed on male ICR mice in the presence or absence of CNP and CNA, as well as solifenacin, a clinical drug for OAB as a reference. Twenty-four-hour micturition patterns (frequency of urination and volume of urine per time), as well as histopathological examination, immunohistochemistry (IHC), and Western blotting of the bladder, were analyzed for mechanism elucidation. Administration of CYP (300 mg/kg, i.p.) induced typical OAB pathophysiological changes, including increased frequency of urination and reduced volume of urine. CYP-induced mice displayed strong edema of the bladder and hemorrhagic cystitis, accompanied by loss of normal corrugated folds and decreased muscarinic receptors (M2/M3) in the urothelium, and disordered/broken structures of the lamina propria and detrusor. These changes were correlated with increased leukocyte (CD11b) infiltration colocalized with inflammatory (pp65 NF κ B, macrophage migration inhibitory factor (MIF) /Toll-like receptor 4 ( TLR4)) and fibrotic (stem cell factor (SCF)/c-Kit, α - smooth muscle actin ( α -SMA)/ β -catenin) signals. Treatment with CNP (600 mg/kg, p.o.) and CNA (10-50 mg/kg, p.o.), but not solifenacin (50 mg/kg), 30 min after CYP induction significantly ameliorated CYP-induced dysfunction in micturition patterns and pathophysiological changes. CNP and CNA further suppressed MIF/TLR4-associated inflammatory and SCF/c-Kit-related fibrotic signaling pathways. Our findings indicate that suppression of inflammatory and fibrotic signals contributes to the crucial mechanism in the improvement of CYP-induced OAB by CNP and CNA., Competing Interests: The authors declare that they have no conflicts of interest regarding the publication of this paper., (Copyright © 2021 Lih-Lian Chen et al.)

Hyaluronic acid (HA) is conjugated with BHQ3 moiety with azo bonds to prepare hypoxia-responsive polymer conjugate. Because of the amphiphilic nature, the polymer conjugate self-assembles to HA-BHQ3 nanoparticles (NPs). The anticancer drug doxorubicin (DOX) is loaded into the NPs. In the physiological environment, DOX is released slowly. In contrast, under hypoxic conditions, the azo bond in BHQ3 is cleaved, thus significantly enhancing the DOX release rate. For instance, after 24 h, 25% of DOX is released under normal conditions, while 74% of DOX is released under hypoxic conditions. In vitro cytotoxicity demonstrates higher toxicity in the hypoxic conditions. DOX@HA-BHQ3 NPs exhibit greater toxicity levels against 4T1 cells in hypoxic conditions. The fluorescent microscope images confirm the oxygen-dependent intracellular DOX release from the NPs. The in vivo biodistribution results suggest the tumor targetability of HA-BHQ3 NPs in 4T1 tumor-bearing mice.