Chung Shan Medical University Hospital

MicroRNAs (miRNAs) are small non-coding RNAs of ∼ 22 nucleotides that are involved in negative regulation of mRNA at the post-transcriptional level. Previously, we developed miRTarBase which provides information about experimentally validated miRNA-target interactions (MTIs). Here, we describe an updated database containing 422 517 curated MTIs from 4076 miRNAs and 23 054 target genes collected from over 8500 articles. The number of MTIs curated by strong evidence has increased ∼1.4-fold since the last update in 2016. In this updated version, target sites validated by reporter assay that are available in the literature can be downloaded. The target site sequence can extract new features for analysis via a machine learning approach which can help to evaluate the performance of miRNA-target prediction tools. Furthermore, different ways of browsing enhance user browsing specific MTIs. With these improvements, miRTarBase serves as more comprehensively annotated, experimentally validated miRNA-target interactions databases in the field of miRNA related research. miRTarBase is available at http://miRTarBase.mbc.nctu.edu.tw/.

MicroRNAs (miRNAs) are small non-coding RNAs (typically consisting of 18-25 nucleotides) that negatively control expression of target genes at the post-transcriptional level. Owing to the biological significance of miRNAs, miRTarBase was developed to provide comprehensive information on experimentally validated miRNA-target interactions (MTIs). To date, the database has accumulated >13,404 validated MTIs from 11,021 articles from manual curations. In this update, a text-mining system was incorporated to enhance the recognition of MTI-related articles by adopting a scoring system. In addition, a variety of biological databases were integrated to provide information on the regulatory network of miRNAs and its expression in blood. Not only targets of miRNAs but also regulators of miRNAs are provided to users for investigating the up- and downstream regulations of miRNAs. Moreover, the number of MTIs with high-throughput experimental evidence increased remarkably (validated by CLIP-seq technology). In conclusion, these improvements promote the miRTarBase as one of the most comprehensively annotated and experimentally validated miRNA-target interaction databases. The updated version of miRTarBase is now available at http://miRTarBase.cuhk.edu.cn/.

BACKGROUND: Dementia is an irreversible illness. The caregiver is expected to assume increased responsibility as the condition of the person with dementia declines. It is important to explore the factors constituting caregiver burden on the informal caregivers of people with dementia. AIMS: The purpose of this article is to identify the factors constituting caregiver burden on the informal caregivers of people with dementia living in the community. METHODS: A systematic review of the four databases, including PubMed, PsycINFO, CINAHL and the Cochrane Library, was carried out to access relevant articles published between 2003 and 2012. Twenty-one articles met the inclusion criteria of this study. RESULTS: Behavioural problems or psychological symptoms were the primary factor of the person with dementia that is associated with caregiver burden. Caregiver socio-demographical factors and psychological factors were the two primary factors of the caregiver burden. LIMITATIONS: Several results of this study were based on studies that had their own limitations. Furthermore, the concept of caregiver 'burden' was not clearly defined in some of the studies; instead, the term was broadly defined. CONCLUSION: Factors of caregiver burden in regard to people with dementia living in the community were clarified in this review study. By identifying all of the factors, healthcare professionals can deliver appropriate assistance to relieve caregiver burden and improve the quality of caregiving for people with dementia. IMPLICATIONS FOR NURSING AND HEALTH POLICY: It is important to identify the factors of the burden on the caregivers of people with dementia living in the community to prevent early nursing home placement, deterioration of caregiver's health and reduce the adverse health outcomes for care recipients. A health-related policy should be formulated to help informal caregivers receive more professional assistance. Training opportunities should be provided for family caregivers to reduce the impact of caregiving on the delivery of effective care.

Abstract Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

BACKGROUND: Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA). OBJECTIVE: To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy. METHODS: Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail. RESULTS: Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient's status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9-10 (10: maximum agreement) for all recommendations. A research agenda was formulated. CONCLUSIONS: The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA.

BACKGROUND: The minimal detectable change (MDC) is the smallest amount of difference in individual scores that represents true change (beyond random measurement error). The MDCs of the Timed "Up & Go" Test (TUG) and the Dynamic Gait Index (DGI) in people with Parkinson disease (PD) are largely unknown, limiting the interpretability of the change scores of both measures. OBJECTIVE: The purpose of this study was to estimate the MDCs of the TUG and the DGI in people with PD. DESIGN: This investigation was a prospective cohort study. METHODS: Seventy-two participants were recruited from special clinics for movement disorders at a university hospital. Their mean age was 67.5 years, and 61% were men. All participants completed the TUG and the DGI assessments twice, about 14 days apart. The MDC was calculated from the standard error of measurement. The percentage MDC (MDC%) was calculated as the MDC divided by the mean of all scores for the sample. Furthermore, the intraclass correlation coefficient was used to examine the reproducibility between testing sessions (test-retest reliability). RESULTS: The respective MDC and MDC% of the TUG were 3.5 seconds and 29.8, and those of the DGI were 2.9 points and 13.3. The test-retest reliability values for the TUG and the DGI were high; the intraclass correlation coefficients were .80 and .84, respectively. LIMITATIONS: The study sample was a convenience sample, and the participants had mild to moderately severe PD. CONCLUSIONS: The results showed that the TUG and the DGI have generally acceptable random measurement error and test-retest reliability. These findings should help clinicians and researchers determine whether a change in an individual patient with PD is a true change.

OBJECTIVES: To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS). METHODS: A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug. RESULTS: At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was -2.5% (95% CI -21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups. CONCLUSIONS: Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS. TRIAL REGISTRATION NUMBER: NCT02047110; Pre-results.

Background: The long-term cardiovascular outcomes in COVID-19 survivors remain largely unclear. The aim of this study was to investigate the long-term cardiovascular outcomes in COVID-19 survivors. Methods: This study used the data from the US Collaborative Network in TriNetX. From a cohort of more than 42 million records between 1 January 2019 and 31 March 2022, a total of 4,131,717 participants who underwent SARS-CoV-2 testing were recruited. Study population then divided into two groups based on COVID-19 test results. To avoid reverse causality, the follow-up initiated 30 days after the test, and continued until 12 months. Hazard ratios (HRs) and 95% Confidence intervals (CIs) of the incidental cardiovascular outcomes were calculated between propensity score-matched patients with versus without SARS-CoV-2 infection. Subgroup analyses on sex, and age group were also conducted. Sensitivity analyses were performed using different network, or stratified by hospitalization to explore the difference of geography and severity of COVID-19 infection. Findings: The COVID-19 survivors were associated with increased risks of cerebrovascular diseases, such as stroke (HR [95% CI] = 1.618 [1.545-1.694]), arrhythmia related disorders, such as atrial fibrillation (HR [95% CI] = 2.407 [2.296-2.523]), inflammatory heart disease, such as myocarditis (HR [95% CI] =4.406 [2.890-6.716]), ischemic heart disease(IHD), like ischemic cardiomyopathy (HR [95% CI] = 2.811 [2.477-3.190]), other cardiac disorders, such as heart failure (HR [95% CI] =2.296 [2.200-2.396]) and thromboembolic disorders (e.g. pulmonary embolism: HR [95% CI] =2.648 [2.443-2.870]). The risks of two composite endpoints, major adverse cardiovascular event (HR [95% CI] = 1.871 [1.816-1.927]) and any cardiovascular outcome (HR [95% CI] = 1.552 [1.526-1.578]), were also higher in the COVID-19 survivors than in the controls. Moreover, the survival probability of the COVID-19 survivors dramatically decreased in all the cardiovascular outcomes. The risks of cardiovascular outcomes were evident in both male and female COVID-19 survivors. Furthermore, the risk of mortality was higher in the elderly COVID-19 survivors (age ≥ 65 years) than in the young ones. Sensitivity analyses presented roughly similar results globally. Furthermore, the impact of COVID-19 on cardio-related outcomes appeared to be more pronounced in inpatients than in outpatients. Interpretation: The 12-month risk of incidental cardiovascular diseases is substantially higher in the COVID-19 survivors than the non-COVID-19 controls. Clinicians and patients with a history of COVID-19 should pay attention to their cardiovascular health in long term. Funding: The Fundamental Research Funds for the Central public welfare research institutes and Young Elite Scientists Sponsorship Program by CACM.

BACKGROUND: Although recent short-term cross-sectional studies have revealed that chronic periodontitis (CP) may be a risk factor for increased cognitive impairment in patients with Alzheimer's disease (AD), systematic reviews and long-term longitudinal studies have provided less clear evidence regarding the relationship between CP and AD. Therefore, we conducted a retrospective cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan to determine whether patients with CP are at increased risk of developing AD. METHODS: We conducted a retrospective matched-cohort study using the NHIRD of Taiwan. We identified 9291 patients newly diagnosed with CP between 1997 and 2004. A total of 18,672 patients without CP were matched to the patient cohort according to sex, age, index year, co-morbidity and urbanisation level. Cox proportional hazards regression analyses were performed to evaluate the subsequent risk of AD. RESULTS: Patients with CP had a higher prevalence of hyperlipidaemia, depression, traumatic brain injury and co-morbidities, as well as higher urbanisation levels, than those in the unexposed cohort (all p < 0.01). At the final follow-up, totals of 115 (1.24%) and 208 (1.11%) individuals in the CP exposed and unexposed groups, respectively, had developed AD. Patients with 10 years of CP exposure exhibited a higher risk of developing AD than unexposed groups (adjusted HR 1.707, 95% CI 1.152-2.528, p = 0.0077). CONCLUSIONS: Our findings demonstrate that 10-year CP exposure was associated with a 1.707-fold increase in the risk of developing AD. These findings highlight the need to prevent progression of periodontal disease and promote healthcare service at the national level.

Abstract Purpose: The new classification announced by the World Health Organization in 2016 recognized five molecular subtypes of diffuse gliomas based on isocitrate dehydrogenase (IDH) and 1p/19q genotypes in addition to histologic phenotypes. We aim to determine whether clinical MRI can stratify these molecular subtypes to benefit the diagnosis and monitoring of gliomas. Experimental Design: The data from 456 subjects with gliomas were obtained from The Cancer Imaging Archive. Overall, 214 subjects, including 106 cases of glioblastomas and 108 cases of lower grade gliomas with preoperative MRI, survival data, histology, IDH, and 1p/19q status were included. We proposed a three-level machine-learning model based on multimodal MR radiomics to classify glioma subtypes. An independent dataset with 70 glioma subjects was further collected to verify the model performance. Results: The IDH and 1p/19q status of gliomas can be classified by radiomics and machine-learning approaches, with areas under ROC curves between 0.922 and 0.975 and accuracies between 87.7% and 96.1% estimated on the training dataset. The test on the validation dataset showed a comparable model performance with that on the training dataset, suggesting the efficacy of the trained classifiers. The classification of 5 molecular subtypes solely based on the MR phenotypes achieved an 81.8% accuracy, and a higher accuracy of 89.2% could be achieved if the histology diagnosis is available. Conclusions: The MR radiomics-based method provides a reliable alternative to determine the histology and molecular subtypes of gliomas. Clin Cancer Res; 24(18); 4429–36. ©2018 AACR.

Background: There are a growing number of case reports of various autoimmune diseases occurring after COVID-19, yet there is no large-scale population-based evidence to support this potential association. This study provides a closer insight into the association between COVID-19 and autoimmune diseases and reveals discrepancies across sex, age, and race of participants. Methods: This is a retrospective cohort study based on the TriNetX U.S. Collaborative Network. In the test-negative design, cases were participants with positive polymerase chain reaction (PCR) test results for SARS-CoV-2, while controls were participants who tested negative and were not diagnosed with COVID-19 throughout the follow-up period. Patients with COVID-19 and controls were propensity score-matched (1: 1) for age, sex, race, adverse socioeconomic status, lifestyle-related variables, and comorbidities. The primary endpoint is the incidence of newly recorded autoimmune diseases. Adjusted hazard ratios (aHRs) and 95% confident intervals (CIs) of autoimmune diseases were calculated between propensity score-matched groups with the use of Cox proportional-hazards regression models. Findings: Between January 1st, 2020 and December 31st, 2021, 3,814,479 participants were included in the study (888,463 cases and 2,926,016 controls). After matching, the COVID-19 cohort exhibited significantly higher risks of rheumatoid arthritis (aHR:2.98, 95% CI:2.78-3.20), ankylosing spondylitis (aHR:3.21, 95% CI:2.50-4.13), systemic lupus erythematosus (aHR:2.99, 95% CI:2.68-3.34), dermatopolymyositis (aHR:1.96, 95% CI:1.47-2.61), systemic sclerosis (aHR:2.58, 95% CI:2.02-3.28), Sjögren's syndrome (aHR:2.62, 95% CI:2.29-3.00), mixed connective tissue disease (aHR:3.14, 95% CI:2.26-4.36), Behçet's disease (aHR:2.32, 95% CI:1.38-3.89), polymyalgia rheumatica (aHR:2.90, 95% CI:2.36-3.57), vasculitis (aHR:1.96, 95% CI:1.74-2.20), psoriasis (aHR:2.91, 95% CI:2.67-3.17), inflammatory bowel disease (aHR:1.78, 95%CI:1.72-1.84), celiac disease (aHR:2.68, 95% CI:2.51-2.85), type 1 diabetes mellitus (aHR:2.68, 95%CI:2.51-2.85) and mortality (aHR:1.20, 95% CI:1.16-1.24). Interpretation: COVID-19 is associated with a different degree of risk for various autoimmune diseases. Given the large sample size and relatively modest effects these findings should be replicated in an independent dataset. Further research is needed to better understand the underlying mechanisms. Funding: Kaohsiung Veterans General Hospital (KSVGH111-113).

BACKGROUND: The severe acute respiratory syndrome (SARS) outbreak in 2003 affected 29 countries. The SARS outbreak was unique in its rapid transmission and it resulted in heavy stress in first-line healthcare workers, particularly in the emergency department. AIM: : To determine the influence of SARS on the psychological status, including post-traumatic stress disorder (PTSD) symptoms, of the staff in the emergency department. METHODS: To investigate whether different working conditions in the hospital led to different psychological effects on healthcare workers, the psychological effect on emergency department staff in the high-risk ward was compared with that on psychiatric ward staff in the medium-risk ward. Davidson Trauma Scale-Chinese version (DTS-C) and Chinese Health Questionnaire-12 (CHQ-12) items were designed to check the psychological status of the staff in the month after the end of the SARS outbreak. RESULTS: 86 of 92 (93.5%) medical staff considered the SARS outbreak to be a traumatic experience. The DTS-C scores of staff in the emergency department and in the psychiatric ward were significantly different (p = 0.04). No significant difference in CHQ score was observed between the two groups. Emergency department staff had more severe PTSD symptoms than staff in the psychiatric ward. CONCLUSION: SARS was a traumatic experience for healthcare providers in Taiwan. Most staff in the emergency department and in the psychiatric ward had PTSD. Emergency department staff had more severe PTSD symptoms than staff in the psychiatric ward.

AIMS: This study aimed to assess whether enalapril could improve cardioversion outcome and facilitate sinus rhythm maintenance after conversion of chronic atrial fibrillation (AF). METHODS AND RESULTS: Patients with chronic AF for more than 3 months were assigned to receive either amiodarone (200mg orally 3 times a day; group I: n=75) or the same dosage of amiodarone plus enalapril (10mg twice a day; group II: n=70) 4 weeks before scheduled external cardioversion. The end-point was the time to first recurrence of AF. In 125 patients (86.2%), AF was converted to sinus rhythm. Group II had a trend to a trend to a lower rate of immediate recurrence of AF than group I did (4.3% vs 14.7%, P=0.067). Kaplan-Meier analysis demonstrated a higher probability of group II remaining in sinus rhythm at 4 weeks (84.3% vs 61.3%, P=0.002) and at the median follow-up period of 270 days (74.3% vs 57.3%, P=0.021) than in group II. CONCLUSIONS: The addition of enalapril to amiodarone decreased the rate of immediate and subacute arrhythmia recurrences and facilitated subsequent long-term maintenance of sinus rhythm after cardioversion of persistent AF.

OBJECTIVE: The aim of this study was to evaluate the efficacy of transabdominal color Doppler ultrasound in diagnosing placenta previa accreta. DESIGN: Eighty patients with persistent placenta previa underwent transabdominal B-mode and color Doppler ultrasound evaluation in the second and third trimesters because they had a high risk of placenta accreta. Color Doppler imaging criteria used included diffuse intraparenchymal placental lacunar flow; focal intraparenchymal placental lacunar flow; bladder-uterine serosa interphase hypervascularity; prominent subplacental venous complex; and loss of subplacental Doppler vascular signals. The color Doppler images were interpreted prospectively for signs of placenta previa accreta according to the exhibited color Doppler sonographic features. RESULTS: Sixteen of the 80 patients exhibited characteristic color Doppler imaging patterns highly specific for placenta accreta according to the preceding criteria, and 14 of these had histopathological proof of placenta accreta. Two patients had false-positive color Doppler imaging evidence mistaken for interphase hypervascularity caused by bladder varices. Thirteen patients underwent hysterectomy in the group suspicious for accreta. Of the 64 patients with negative color Doppler imaging results, three had placenta accreta, while two required cesarean hysterectomy; the remaining patient underwent uterine artery ligation for bleeding from the lower uterine segment. The sensitivity of color Doppler imaging in the diagnosis of placenta previa accreta was 82.4% (14/17) and the specificity was 96.8% (61/63). The positive and negative predictive values were 87.5% (14/16) and 95.3% (61/64), respectively. CONCLUSIONS: Variable vascular morphological patterns of placenta previa accreta were exhibited and categorized by transabdominal color Doppler sonography in the antenatal period. The identification of these specific vascular patterns had a positive impact on the peripartum clinical management of the affected patients.

BACKGROUND: Anti-Müllerian hormone (AMH) is reported to be a reliable marker of the ovarian response to controlled ovarian stimulation (COS). The objective of this study is to determine whether the serum AMH level can predict ovarian hyperstimulation syndrome (OHSS) prior to selection of COS protocols. METHODS: A cohort of 262 IVF cycles was investigated prospectively, in order to evaluate the predictive value for OHSS by means of certain risk factors, including age, body mass index (BMI), serum estradiol (E2) level, number of retrieved oocytes and basal serum AMH level. RESULTS: The basal serum AMH level predicted OHSS better than age and BMI with a sensitivity of 90.5% and specificity of 81.3%. Both the basal serum AMH level (odds ratio: 1.7856, P = 0.0003) and serum E2 level on the day of HCG administration (odds ratio: 1.0005, P = 0.0455) proved to be significant predictors of OHSS by logistic regression analysis. However, age (odds ratio: 0.9346, P = 0.049) was the only significant factor for prediction of clinical pregnancy. CONCLUSIONS: The basal serum AMH level could be utilized effectively to predict OHSS and thus to direct the selection of mild COS protocols.

Abstract Melatonin is a naturally occurring molecule secreted by the pineal gland and known as a gatekeeper of circadian clocks. Mounting evidence indicates that melatonin, employing multiple and interrelated mechanisms, exhibits a variety of oncostatic properties in a myriad of tumors during different stages of their progression. Tumor metastasis, which commonly occurs at the late stage, is responsible for the majority of cancer deaths; metastases lead to the development of secondary tumors distant from a primary site. In reference to melatonin, the vast majority of investigations have focused on tumor development and progression at the primary site. Recently, however, interest has shifted toward the role of melatonin on tumor metastases. In this review, we highlight current advances in understanding the molecular mechanisms by which melatonin counteracts tumor metastases, including experimental and clinical observations; emphasis is placed on the impact of both cancer and non‐neoplastic cells within the tumor microenvironment. Due to the broad range of melatonin's actions, the mechanisms underlying its ability to interfere with metastases are numerous. These include modulation of cell–cell and cell–matrix interaction, extracellular matrix remodeling by matrix metalloproteinases, cytoskeleton reorganization, epithelial–mesenchymal transition, and angiogenesis. The evidence discussed herein will serve as a solid foundation for urging basic and clinical studies on the use of melatonin to understand and control metastatic diseases.

An 8-channel closed-loop neural-prosthetic SoC is presented for real-time intracranial EEG (iEEG) acquisition, seizure detection, and electrical stimulation in order to suppress epileptic seizures. The SoC is composed of eight energy-efficient analog front-end amplifiers (AFEAs), a 10-b delta-modulated SAR ADC (DMSAR ADC), a configurable bio-signal processor (BSP), and an adaptive high-voltage-tolerant stimulator. A wireless power-and-data transmission system is also embedded. By leveraging T-connected pseudo-resistors, the high-pass (low-pass) cutoff frequency of the AFEAs can be adjusted from 0.1 to 10 Hz (0.8 to 7 kHz). The noise-efficiency factor (NEF) of the AFEA is 1.77, and the DMSAR ADC achieves an ENOB of 9.57 bits. The BSP extracts the epileptic features from time-domain entropy and frequency spectrum for seizure detection. A constant 30- μA stimulus current is delivered by closed-loop control. The acquired signals are transmitted with on-off keying (OOK) modulation at 4 Mbps over the MedRadio band for monitoring. A multi-LDO topology is adopted to mitigate the interferences across different power domains. The proposed SoC is fabricated in 0.18- μm CMOS and occupies 13.47 mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> . Verified on Long Evans rats, the proposed SoC dissipates 2.8 mW and achieves high detection accuracy (> 92%) within 0.8 s.

A series of new amino (NH)-type hydrogen-bonding (H-bonding) compounds comprising 2-(2'-aminophenyl)benzothiazole and its extensive derivatives were designed and synthesized. Unlike in the hydroxyl (OH)-type H-bonding systems, one of the amino hydrogens can be replaced with electron-donating/withdrawing groups. This, together with a versatile capability for modifying the parent moiety, makes feasible the comprehensive spectroscopy and dynamics studies of amino-type excited-state intramolecular proton transfer (ESIPT), which was previously inaccessible in the hydroxyl-type ESIPT systems. Empirical correlations were observed among the hydrogen-bonding strength (the N-H bond distances and proton acidity), ESIPT kinetics, and thermodynamics, demonstrating a trend that the stronger N-H···N hydrogen bond leads to a faster ESIPT, as experimentally observed, and a more exergonic reaction thermodynamics. Accordingly, ESIPT reaction can be harnessed for the first time from a highly endergonic type (i.e., prohibition) toward equilibrium with a measurable ESIPT rate and then to the highly exergonic, ultrafast ESIPT reaction within the same series of amino-type intramolecular H-bond system.

PD-L1 has been widely demonstrated to contribute to failed antitumor immunity. Blockade of PD-L1 with monoclonal antibody could modulate the tumor immune environment to augment immunotherapy. PD-L1 expression is also detected in several types of cancer and is associated with poor prognosis. However, the prognostic role of PD-L1 in oral squamous cell carcinoma (OSCC) is still controversial. Our aim was to determine the role of PD-L1 in the prognosis of OSCC patients to identify its potential therapeutic relevance. PD-L1 immunoreactivity was analyzed by immunohistochemistry in 305 cancer specimens from primary OSCC patients. The medium follow-up time after surgery was 3.8 years (range from 0.1 to 11.1 years). The prognostic value of PD-L1 on overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. Higher PD-L1 expression is more likely in tumor tissues of female than male OSCC patients (P = 0.0062). Patients with distant metastasis also had high PD-L1 expression (P = 0.0103). Multivariate analysis identified high PD-L1 expression as an independent risk factor in males and smokers (males: hazard ratio = 1.556, P = 0.0077; smokers: hazard ratio = 2.058, P = 0.0004). We suggest that PD-L1 expression, determined by IHC staining, could be an independent prognostic marker for OSCC patients who are male or who have a smoking habit.

Hibiscus sabdariffa L., a local soft drink material and medicinal herb, is usually used effectively in native medicines against hypertension, pyrexia, and liver disorders. Here, we report an extract, HSE (H. sabdariffa extract), which is designed to exhibit hypolipidemia and antiatherosclerotic effects in rabbits with experimental atherosclerosis. New Zealand White rabbits were fed with a normal diet, high cholesterol (1.3%), lard oil (3%) diet (HCD) with or without 0.5 or 1% HSE for 10 weeks. The levels of triglyceride, cholesterol, and low-density lipoprotein cholesterol (LDL-C) were lower in the serum of rabbits fed HCD plus HSE than in the serum of rabbits fed HCD. Feeding HSE (0.5 and 1% in the diet) to rabbits significantly reduced severe atherosclerosis in the aorta. Histopathological examination showed that HSE reduced foam cell formation and inhibited smooth muscle cell migration and calcification in the blood vessel of rabbits. These results suggest that HSE inhibits serum lipids and shows an antiatherosclerotic activity.