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AbstractIntroduction Chronic kidney disease is related to neurodegeneration and structural changes in the brain which might lead to cognitive decline. The Fazekas scale used for assessing white matter hyperintensities (WMHs) was associated with poor cognitive performance. Therefore, this study investigated the associations between the mini-mental status examination (MMSE), Montreal cognitive assessment (MoCA), cognitive abilities screening instrument (CASI), and Fazekas scale in patients under hemodialysis (HD).Methods The periventricular (PV) WMHs and deep WMHs (DWMHs) in brain magnetic resonance images of 59 patients under dialysis were graded using the Fazekas scale. Three cognition function tests were also performed, then multivariable ordinal regression and logistic regression were used to identify the associations between cognitive performance and the Fazekas scale.Results There were inverse associations between the three cognitive function tests across the Fazekas scale of PVWMHs (p = .037, .006, and .008 for MMSE, MoCA, and CASI, respectively), but the associations were attenuated in the DWMHs group. In CASI, significant differences were identified in short-term memory, mental manipulation, abstract thinking, language, spatial construction, and name fluency in the PVWMHs group. However, DWMHs were only significantly correlated with abstract thinking and short-term memory.Conclusion An inverse correlation existed between the Fazekas scale, predominantly in PVWMHs, and cognition in patients undergoing HD. The PVWMHs were associated with cognitive performance assessed by MMSE, MoCA, and CASI, as well as with subdomains of CASI such as memory, language and name fluency in patients undergoing HD.

In the net-zero era, the burgeoning demands within engineering applications require materials that are not only lighter and stronger but also ductile. A robust strain hardening, crucial for achieving high strength and ductility, is challenging due to limited dislocation density evolution. This study discovers a cooperative strain-hardening strategy in a newly designed high-entropy steel (HES) with a density of 6.82 g/cm3. In this lightweight HES, the duplex microstructure of compositionally complex austenite and D03 intermetallic compounds facilitates the interplay between geometrically necessary dislocations (GNDs) and deformation twins (DTs) during plastic deformation. It generates a strain-hardening resilience during deformation and yields a very high dislocation density of 6.62 × 1015 m-2, contributing to strain hardening of over 900 MPa and a large elongation of 47 %. The resilient strain hardening achieved by the GND-DT cooperative strategy can be applied to various heterostructured alloys, offering a pathway for strong and ductile lightweight materials.

Abstract Background Examining patients with first-episode psychosis (FEP) provides opportunities to better understand the mechanism underlying these illnesses. By incorporating quantitative measures in FEP patients, we aimed to (1) determine the baseline distribution of clinical features; (2) examine the impairment magnitude of the quantitative measures by comparing with external controls and then the counterparts of schizophrenia patients of different familial loadings; and (3) evaluate whether these quantitative measures were associated with the baseline clinical features. Methods Patients with FEP were recruited from one medical center, two regional psychiatric centers, and two private clinics in northern Taiwan with clinical features rated using the Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale. Quantitative measurements included the Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), niacin response abnormality (NRA), and minor physical anomalies and craniofacial features (MPAs). To evaluate the relative performance of the quantitative measures in our FEP patients, four external comparison groups from previous studies were used, including three independent healthy controls for the CPT, WCST, and NRA, respectively, and one group of treatment-resistant schizophrenia patients for the MPAs. Additionally, patients from simplex families and patients from multiplex families were used to assess the magnitude of FEP patients’ impairment on the CPT, WCST, and NRA. Results Among the 80 patients with FEP recruited in this study (58% female, mean age = 25.6 years, mean duration of untreated psychosis = 132 days), the clinical severity was mild to moderate (mean PANSS score = 67.3; mean PSP score = 61.8). Patients exhibited both neurocognitive and niacin response impairments (mean Z-scores: −1.24 for NRA, − 1.06 for undegraded d', − 0.70 for degraded d', − 0.32 for categories achieved, and 0.44 for perseverative errors) but did not show MPAs indicative of treatment resistance. Among these quantitative measures, three of the four neurocognitive indices were correlated with the baseline clinical features, whereas NRA did not show such correlation. Conclusions This FEP study of Taiwanese patients revealed the presence of neurocognitive performance and niacin response and their different relationships with clinical features, rendering this sample useful for future follow-up and incorporation of multiomics investigation.

Abstract Background Helicobacter pylori (HP) infection is associated with various diseases. Early detection can prevent the onset of illness. We constructed a nomogram to predict groups at high risk of HP infection. Methods Patients who underwent regular medical check-ups at hospital in Chaoshan, China from March to September 2022 were randomly allocated to the training and validation cohorts. Risk factors including basic characteristics and lifestyle habits associated with HP infection were analyzed by logistic regression analyses. The independent varieties were calculated and plotted into a nomogram. The nomogram was internally validated by receiver operating characteristic curve, calibration, and decision curve analyses (DCAs). Results Of the 945 patients, 680 were included in the training cohort and 265 in the validation cohort. 356 patients in training cohort with positive 13 C-UBT results served as the infected group, and 324 without infection were the control group. The multivariate regression analyses showed that the risk factors for HP infection included alcohol consumption (OR = 1.29, 95%CI = 0.78–2.13, P = 0.03), family history of gastric disease (OR = 4.35, 95%CI = 1.47–12.84, P = 0.01), living with an HP-positive individual (OR = 18.09, 95%CI = 10.29–31.82, P 3 times per day (OR = 0.56, 95%CI = 0.33–0.95, P = 0.03), using serving chopsticks (OR = 0.30, 95%CI = 0.12–0.49, P

Pneumonia stands as the leading infectious cause of childhood mortality annually, underscoring its significant impact on pediatric health. Although dexamethasone (DXMS) is effective for treating pulmonary inflammation, its therapeutic potential is compromised by systemic side effects and suboptimal carrier systems. To address this issue, the current study introduces solid lipid nanoparticles encapsulating hydrophobic dexamethasone palmitate (DXMS-Pal-SLNs) as an anti-inflammatory nanoplatform to treat pneumonia. The specialized nanoparticle formulation is characterized by high drug loading efficiency, low drug leakage and excellent colloidal stability in particular during nebulization and is proficiently designed to target alveolar macrophages in deep lung regions via local delivery with the nebulization administration. In vitro analyses revealed substantial reductions in the secretions of tumor necrosis factor-α and interleukin-6 from alveolar macrophages, highlighting the potential efficacy of DXMS-Pal-SLNs in alleviating pneumonia-related inflammation. Similarly, in vivo experiments showed a significant reduction in the levels of these cytokines in the lungs of mice experiencing lipopolysaccharide-induced pulmonary inflammation after the administration of DXMS-Pal-SLNs via nebulization. Furthermore, the study demonstrated that DXMS-Pal-SLNs effectively control acute infections without causing pulmonary infiltration or excessive recruitment of immunocytes in lung tissues. These findings highlight the potential of nebulized DXMS-Pal-SLNs as a promising therapeutic strategy for mitigating pneumonia-related inflammations.

Abstract Background Residing in a nursing home (NH) may increase emergency department (ED) utilization in patients with dementia; however, evidence regarding the status of and predictors for ED utilization of NH residents with dementia remains unclear, especially in Asia. This study aimed to assess the incidence density of ED visits and associated factors for the risk of ED utilization among NH residents with dementia. Methods This one-year cohort study followed 6595 NH residents with dementia aged ≧ 40 years from Taiwan’s National Health Insurance Research Database between 2012 and 2014. The Andersen-Gill extension of Cox regression analysis with death as a competing risk was applied to investigate the association of the risk of all causes and the most common causes of ED utilization with the predisposing, enabling, and need factors as defined by the Andersen model. Results All participants encountered 9254 emergency visits in the 5371.49 person-years observed, representing incidence densities of ED visits of 1722.80 per 1000 person-years. Among them, respiratory disease was the most common cause of ED visits. The significant predictors for the risk of all-cause and respiratory-cause ED visits included: (1) predisposing factors (i.e., age and gender); (2) enabling factors (i.e., regional variables); and (3) need factors (i.e., prolonged ventilator dependence and comorbidity status). Conclusions Predisposing, enabling, and need factors could influence ED visits among studies patients. NH providers should consider these factors to develop strategies for reducing ED utilization.

Introduction: Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA) are rare neurodegenerative diseases associated with rapid decline and require complex symptom management. Caregiving responsibilities significantly increase with progression of these atypical Parkinsonian syndromes, yet care burden in these syndromes has not been researched extensively to date. Methods: The Zarit Burden Interview (ZBI) was used to assess burden in care partners of patients clinically diagnosed with PSP, CBS, or MSA seen in specialty interdisciplinary clinics at two academic movement disorders centers. Univariable and multivariable regression analyses were performed to evaluate cross-sectional demographic and clinical determinants of care partner burden. Results: A total of 139 care partners completed the ZBI (59.0% PSP, 28.1% MSA, 12.9% CBS). Cohorts at both medical centers were similar across all variables. Female gender of both patients and care partners was independently associated with higher ZBI scores. Additionally, MSA-Parkinsonian type was significantly associated with lower total care partner burden compared to PSP and CBS. Conclusion: Several determinants of higher care partner burden in atypical Parkinsonian syndromes were identified, particularly female gender and diagnosis. Healthcare professionals can consider this information when assessing individualized needs of patients and care partners and referring to disease-specific resources. Additionally, this study’s methods and results highlight the potential to further explore interdisciplinary care as a means of comprehensive evaluation and support for those with atypical Parkinsonism.

Microbiota tryptophan metabolism and the biosynthesis of indole derivatives play an important role in homeostasis and pathogenesis in the human body and can be affected by the gut microbiota. However, studies on the interplay between gut microbiota and tryptophan metabolites in patients undergoing dialysis are lacking. This study aimed to identify the gut microbiota, the indole pathway in tryptophan metabolism, and significant functional differences in ESRD patients with regular hemodialysis. We performed the shotgun metagenome sequencing of stool samples from 85 hemodialysis patients. Using the linear discriminant analysis effect size (LEfSe), we examined the composition of the gut microbiota and metabolic features across varying concentrations of tryptophan and indole metabolites. Higher tryptophan levels promoted tyrosine degradation I and pectin degradation I metabolic modules; lower tryptophan levels were associated with glutamate degradation I, fructose degradation, and valine degradation modules. Higher 3-indoxyl sulfate concentrations were characterized by alanine degradation I, anaerobic fatty acid beta-oxidation, sulfate reduction, and acetyl-CoA to crotonyl-CoA. Contrarily, lower 3-indoxyl sulfate levels were related to propionate production III, arabinoxylan degradation, the Entner–Doudoroff pathway, and glutamate degradation II. The present study provides a better understanding of the interaction between tryptophan, indole metabolites, and the gut microbiota as well as their gut metabolic modules in ESRD patients with regular hemodialysis.

Abstract Background Patients with glycogen storage disease type Ia (GSDIa) are prone to hypoglycemia. Uncooked cornstarch (CS) is the treatment, but maintaining nighttime blood glucose levels is still difficult. Methods The study enrolled patients with GSDIa to investigate the benefits of bedtime extended release CS (ER‐CS, Glycosade®) versus regular CS. The daytime CS schedule was not altered. A 7‐day continuous glucose monitoring (CGM) was performed at the baseline and 12 weeks after using ER‐CS. Biochemical profile, sleep quality (Pittsburgh Sleep Quality Index, PSQI), and quality of life (SF‐36 questionnaire) were measured at the baseline and 24 weeks after using ER‐CS. Results Nine patients (9 to 33 years of age) were enrolled. Compared with the baseline (80.0 ± 6.33 mg/dL), the 12‐week evaluations revealed higher mean morning glucose levels (86.5 ± 8.26 mg/dL, p = 0.015). Twenty‐four weeks after the use of bedtime ER‐CS, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels both decreased (from 69.3 ± 77.8 to 41.1 ± 40.4 U/L and from 78.8 ± 99.6 to 37.8 ± 28.81 U/L, respectively, p = 0.013 for both analyses), and sleep and fasting time both elongated (from 7.8 ± 0.87 to 8.6 ± 1.02 h and from 6.5 ± 1.22 to 7.6 ± 1.02 h, respectively, p = 0.011 for both analyses). The mean PSQI score in the five adult patients decreased significantly (from 5.8 ± 1.29 to 3.0 ± 1.71, p = 0.042). Conclusion This study provides evidence of clinically meaningful improvements by shifting only bedtime regular CS to ER‐CS in patients with GSDIa. As ER‐CS is considerably more expensive than regular CS, this approach presents a cost‐effective alternative.

Background: Heart rate recovery (HRR) and N terminal-pro B type natriuretic peptide (NT-proBNP) are markers for survival and cardiac function; however, Little is known about their association. Method: We examined 2540 healthy subjects aged 12–49 years with data from National Health and Nutrition Examination Survey(NHANES) 1999–2002. HRR parameters 1–3 min after exercise were calculated from exercise test results. Baseline characteristics, anthropometric and NT-proBNP, and other risk covariates were obtained. Result: The results showed that NT-proBNP was positively correlated with HRR2(correlation coefficient (cc) = 0.042 [0.029–0.054], P

This paper presents an 8-element phased array system and proposes a novel beam control method—namely, matrix-sum method—that can achieve beam steering and beam-width control. The system architecture comprises an $8\times 8$ phase matrix network and a 1-to-8 real number weighting network. The 1-to-8 real number weighting network simultaneously supplies the required weighting value to all input ports of the phase matrix network, enabling the adjustment of the phase difference and power ratio between adjacent output signals and thereby generating the desired beam. According to the equations used to calculate the weighting values, the matrix-sum method requires only real number weighting to achieve beam synthesis with steering and tapering functions if used with a suitable phase matrix. Comparison results revealed that for the same number of control bits, the proposed method system exhibited higher beam-steering accuracy and system gain in different beam pattern cases than phased array systems that use conventional and vector-sum phase shifters. The proposed phased array system was fabricated and experimentally investigated at 3.5 GHz. The results indicated that it achieved fully controllable beam steering with a fine beam resolution of 1° steps. Additionally, the system’s sum, difference, and tapering beam patterns were accurate compared with ideal beam patterns.

Assessing the condition of every schizophrenia patient correctly normally requires lengthy and frequent interviews with professionally trained doctors. To alleviate the time and manual burden on those mental health professionals, this paper proposes a multimodal assessment model that predicts the severity level of each symptom defined in Scale for the Assessment of Thought, Language, and Communication (TLC) and Positive and Negative Syndrome Scale (PANSS) based on the patient’s linguistic, acoustic, and visual behavior. The proposed deep-learning model consists of a multimodal fusion framework and four unimodal transformer-based backbone networks. The second-stage pre-training is introduced to make each off-the-shelf pre-trained model learn the pattern of schizophrenia data more effectively. It learns to extract the desired features from the view of its modality. Next, the pre-trained parameters are frozen, and the light-weight trainable unimodal modules are inserted and fine-tuned to keep the number of parameters low while maintaining the superb performance simultaneously. Finally, the four adapted unimodal modules are fused into a final multimodal assessment model through the proposed multimodal fusion framework. For the purpose of validation, we train and evaluate the proposed model on schizophrenia patients recruited from National Taiwan University Hospital, whose performance achieves 0.534/0.685 in MAE/MSE, outperforming the related works in the literature. Through the experimental results and ablation studies, as well as the comparison with other related multimodal assessment works, our approach not only demonstrates the superiority of our performance but also the effectiveness of our approach to extract and integrate information from multiple modalities.

Background: We conducted a longitudinal survey for methicillin-resistant Staphylococcus aureus (MRSA) carriage in nursing homes and long-term care facilities (LTCFs) in northern Taiwan. Methods: From July 2016 to February 2017, healthcare workers and residents in four institutions were enrolled. One swab sample from nares and another swab sample from umbilicus were obtained from each participant for detection of MRSA at enrolment and then follow-up samples were collected every two months for additional three times if feasible. Results: We enrolled a total of 194 participants, including 127 residents and 67 healthcare workers. MRSA colonization rates were 23.2%, 22.8%, 20.7% and 18.6% at enrolment, the 2-, 4-, and 6-month follow-up survey, respectively, and the cumulative colonization rate was 40.2%. The MRSA detection rate was significantly higher at Institution 2 (70.7%) than that at other three institutions (25.7% ∼ 35%) (p

Abstract Human gut microbiota produce a variety of molecules, some of which enter the bloodstream and impact health. Conversely, dietary or pharmacological compounds may affect the microbiota before entering the circulation. Characterization of these interactions is an important step towards understanding the effects of the gut microbiota on health. In this cross-sectional study, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for a detailed characterization of the gut microbiota and plasma metabolome, respectively, of 8583 participants invited at age 50 to 64 from the population-based Swedish CArdioPulmonary bioImage Study. Here, we find that the gut microbiota explain up to 46% of the variance of individual plasma metabolites and we present 997 associations between alpha diversity and plasma metabolites and 546,819 associations between specific gut metagenomic species and plasma metabolites in an online atlas ( https://gutsyatlas.serve.scilifelab.se/ ). We exemplify the potential of this resource by presenting novel associations between dietary factors and oral medication with the gut microbiome, and microbial species strongly associated with the uremic toxin p-cresol sulfate. This resource can be used as the basis for targeted studies of perturbation of specific metabolites and for identification of candidate plasma biomarkers of gut microbiota composition.

Indole-3-acetic acid (IAA), a protein-bound uremic toxin resulting from gut microbiota-driven tryptophan metabolism, increases in hemodialysis (HD) patients. IAA may induce endothelial dysfunction, inflammation, and oxidative stress, elevating cardiovascular and cognitive risk in HD patients. However, research on the microbiome–IAA association is limited. This study aimed to explore the gut microbiome’s relationship with plasma IAA levels in 72 chronic HD patients aged over 18 (August 2016–January 2017). IAA levels were measured using tandem mass spectrometry, and gut microbiome analysis utilized 16s rRNA next-generation sequencing. Linear discriminative analysis effect size and random forest analysis distinguished microbial species linked to IAA levels. Patients with higher IAA levels had reduced microbial diversity. Six microbial species significantly associated with IAA levels were identified; Bacteroides clarus, Bacteroides coprocola, Bacteroides massiliensi, and Alisteps shahii were enriched in low-IAA individuals, while Bacteroides thetaiotaomicron and Fusobacterium varium were enriched in high-IAA individuals. This study sheds light on specific gut microbiota species influencing IAA levels, enhancing our understanding of the intricate interactions between the gut microbiota and IAA metabolism.

Background: Follow-up of subjects with putative pre-psychotic states is essential to clarify the transition process to psychosis, while “non-converters” also deserve clinical attention as many may evolve into other psychiatric disorders with diverse outcomes. This study aimed to examine help-seeking individuals who have been labelled at clinical high-risk state but not converting to full-blown psychosis during first two years of follow-up. Methods: A retrospective observational cohort study of help-seeking subjects was conducted by reviewing medical records of participants in a previous early psychosis study at the study hospital between 2006 and 2020. We portrayed those who developed first episode psychosis after first 2-year follow-up in detail, and provided sketches of clinical macrophenotypes other than psychosis emerging from subjects among different risk groups. Results: Among 132 eligible subjects, data of 98 (74.2%) were available for detailed evaluation. Of these, 15 transitioned to first-episode psychosis (11.4%) with time to psychosis from 2 to 11 years, 11 had anxiety spectrum (8.3%), 11 had depressive spectrum (8.3%), 10 had obsessive compulsive (7.6%), 5 had bipolar spectrum disorders (3.8%), 13 had predominantly schizotypal (9.8%) and 4 had other personality traits (3%), and 13 had problems attributable to adjustment or developmental issues (9.8%). Conclusion: Various diagnoses, either full- or sub-threshold, appropriately describe the diverse clinical phenomenology of a cohort presenting with non-specific and/or subthreshold psychotic symptoms. The clinical high-at-risk mental state (CHARMS) paradigm provides a reasonable transdiagnostic approach for orienting clinicians’ attention toward young subjects seeking mental health help at an early stage of illness to potentially pluripotent trajectories.

Abstract Tracking kinematic details of motor behaviors is a foundation to study the neuronal mechanism and biology of motor control. However, most of the physiological motor behaviors and movement disorders, such as gait, balance, tremor, dystonia, and myoclonus, are highly dependent on the overall momentum of the whole‐body movements. Therefore, tracking the targeted movement and overall momentum simultaneously is critical for motor control research, but it remains an unmet need. Here, we introduce the intrinsic oscillatory property (IOP), a fundamental mechanical principle of physics, as a method for motion tracking in a force plate. The overall kinetic energy of animal motions can be transformed into the oscillatory amplitudes at the designed IOP frequency of the force plate, while the target movement has its own frequency features and can be tracked simultaneously. Using action tremor as an example, we reported that force plate‐based IOP approach has superior performance and reliability in detecting both tremor severity and tremor frequency, showing a lower level of coefficient of variation (CV) compared with video‐ and accelerometer‐based motion tracking methods and their combination. Under the locomotor suppression effect of medications, therapeutic effects on tremor severity can still be quantified by dynamically adjusting the overall locomotor activity detected by IOP. We further validated IOP method in optogenetic‐induced movements and natural movements, confirming that IOP can represent the intensity of general rhythmic and nonrhythmic movements, thus it can be generalized as a common approach to study kinematics.

Abstract Despite the consistent finding of an attenuated niacin-induced flush response in schizophrenia, its long-term stability and relationship to the membrane polyunsaturated fatty acid (PUFA) levels remain unknown. We conducted niacin skin tests and measured the membrane PUFAs using gas chromatography among 46 schizophrenia inpatients and 37 healthy controls at the baseline and the 2-month follow-up. Attenuated flush responses were persistently observed in schizophrenia patients in both acute and partial remission states, whereas an increased flush response was found in the controls. A persistent decrease in both dihomo-gamma-linolenic acid and docosahexaenoic acid and an increased turnover of arachidonic acid (ARA) via endogenous biosynthesis were found in schizophrenia patients. A composite niacin flush score by combining those with a control-to-case ratio of >1.4 (i.e., scores at 5 min of 0.1 M, 0.01 M, and 0.001 M + 10 min of 0.01 M and 0.001 M + 15 min of 0.001 M) at the baseline was correlated positively with ARA levels among controls but not among schizophrenia patients, whereas the flush score at the 2-month follow-up was correlated positively with ARA levels among patients. The 2-month persistence of attenuated niacin-induced flush response in schizophrenia patients implies that the niacin skin test might tap a long-term vulnerability to schizophrenia beyond acute exacerbation.

Thought, language, and communication disorders are among the salient characteristics of schizophrenia. Such impairments are often exhibited in patients’ conversations. Researches have shown that assessments of thought disorder are crucial for tracking the clinical patients’ conditions and early detection of clinical high-risks. Detecting such symptoms require a trained clinician’s expertise, which is prohibitive due to cost and the high patient-to-clinician ratio. In this paper, we propose a machine learning method using Transformer-based model to help automate the assessment of the severity of the thought disorder of schizophrenia. The proposed model uses both textual and acoustic speech between occupational therapists or psychiatric nurses and schizophrenia patients to predict the level of their thought disorder. Experimental results show that the proposed model has the ability to closely predict the results of assessments for Schizophrenia patients base on the extracted semantic, syntactic and acoustic features. Thus, we believe our model can be a helpful tool to doctors when they are assessing schizophrenia patients.

Abstract Background Patients with remitted psychosis wish to reduce antipsychotic doses yet facing increased risks of relapse. Examining dose-tapering processes may provide insights to re-evaluate the risk-to-benefit balance. We aimed to depict and subgroup tapering trajectories, and explore factors associated with different dose-reduction patterns. Methods A 2-year open-label randomized prospective comparative trial from August 2017 to September 2022 in Taiwan. Patients with a history of schizophrenia-related psychotic disorders under stable medications and symptoms were eligible, randomizing a proportion to conduct guided dose reduction. We depicted the trajectories of individual patients and named subgroups based on dose-tapering patterns. Predictors of baseline characteristics for designated subgroups were examined by logistic regression analysis; changes in outcomes were compared by paired t-test. Results Fifty-one patients undergoing guided dose reduction, 18 (35.3%) reduced 4 steps consecutively (sequential reducers, SR), 14 (27.5%) reduced 1 to 3 steps (modest reducers, MR), 3 (5.9%) re-escalated to previous level (alert reducers, AR), 7 (13.7%) returned to baseline level (baseline returners, BR), 6 (11.7%) relapsed (failed reducers, FR) and 3 (5.9%) withdrew without relapse (early exits, EE). Patients with a history of relapse assumed a conservative dose-tapering pace; only the SR subgroup exhibited significant improvements in functioning and quality of life while failing to identify variables for predicting who would become SR or FR. Conclusions Guided dose reduction comprises dynamic processes with differences between individual trajectories. The proposed naming of dose-tapering patterns/subgroups provides a framework depicting patients undergoing dose-tapering. Longer-term observation and more flexible tapering approaches are anticipated to reveal favorable outcomes.

Background Ambulatory blood pressure monitoring (ABPM) is increasingly recommended for clinical use, but more knowledge about the prevalence and variability in ABPM-derived phenotypes in the general population is needed. We describe these parameters in the community-based Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort. Methods We examined 5881 men and women aged 50–64 with 24-hour ABPM recordings using validated monitors. ABPM phenotypes were defined according to European guidelines. White coat hypertension was defined as elevated office BP (≥140/90 mmHg) with normal mean ambulatory BP (

Abstract Little is known about the relationship between gut dysbiosis, inflammation, and adverse outcomes in patients with chronic kidney disease. We examined the association of microbial diversity with all-cause mortality in hemodialysis patients. The gut microbiota was assessed by 16S ribosomal RNA gene sequencing. During a median follow-up of 2.1 years, the adjusted risk of death among patients with higher diversity (above median) was 74% lower than that among patients with lower diversity (below median). We then compared the microbial composition between nonsurvivors and survivors in a matched case-control study. We observed significantly lower microbial diversity and higher proinflammatory cytokines among nonsurvivors than survivors. Specifically, the relative abundance of Succinivibrio and Anaerostipes, two short-chain fatty acid-producing bacteria, was markedly reduced in nonsurvivors. Thus, a unique gut microbial composition is associated with an increased risk of mortality among hemodialysis patients and may be used to identify subjects with a poor prognosis.

Abstract Protein-bound uremic toxins (Indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) are both associated with cardiovascular (CV) and all-cause mortality in subjects with chronic kidney disease (CKD). Possible mechanisms have not been elucidated. In hemodialysis patients, we investigated the relationship between the free form of IS and PCS and 181 CV-related proteins. First, IS or PCS concentrations were checked, and high levels were associated with an increased risk of acute coronary syndrome (ACS) in 333 stable HD patients. CV proteins were further quantified by a proximity extension assay. We examined associations between the free form protein-bound uremic toxins and the quantified proteins with correction for multiple testing in the discovery process. In the second step, the independent association was evaluated by multivariable-adjusted models. We rank the CV proteins related to protein-bound uremic toxins by bootstrapped confidence intervals and ascending p-value. Six proteins (signaling lymphocytic activation molecule family member 5, complement component C1q receptor, C–C motif chemokine 15 [CCL15], bleomycin hydrolase, perlecan, and cluster of differentiation 166 antigen) were negatively associated with IS. Fibroblast growth factor 23 [FGF23] was the only CV protein positively associated with IS. Three proteins (complement component C1q receptor, CCL15, and interleukin-1 receptor-like 2) were negatively associated with PCS. Similar findings were obtained after adjusting for classical CV risk factors. However, only higher levels of FGF23 was related to increased risk of ACS. In conclusion, IS and PCS were associated with several CV-related proteins involved in endothelial barrier function, complement system, cell adhesion, phosphate homeostasis, and inflammation. Multiplex proteomics seems to be a promising way to discover novel pathophysiology of the uremic toxin.

Objective: To compare the differences in sit-to-stand and stand-to-sit movements of older nonfalling males and older male fallers (also referred to herein as fallers) to contribute to the development of posture transfer–assisting devices or interventional therapies to prevent falls. Design: Controlled study. Setting: University research laboratory. Participants: Ten older men (mean age, 75.9±5.4 years) who had fallen or been unstable at least once in the past year and 10 nonfalling older men (mean age, 70.0±5.0 years) participated in this study. Interventions: Not applicable. Main Outcome Measures: Movement duration; sagittal trunk, hip, knee, and ankle joint range of motion (ROM); anteroposterior and mediolateral (ML) center of mass (COM) total trajectory. Results: During the sit-to-stand transition, fallers exhibited greater trunk joint ROM in the flexion and extension phase and smaller hip joint ROM in the extension phase as well as greater ML COM total trajectory. During stand-to-sit, older fallers exhibited greater trunk joint ROM in the flexion phase and smaller hip and knee joint ROM in the flexion phase as well as greater ML COM total trajectory. Older fallers took more time to perform the stand-to-sit and had greater ML COM total trajectory during the movement; additionally, they exhibited different proportional distributions of ROM for each joint compared with nonfaller. Conclusion: Older fallers had more difficulty performing stand-to-sit than sit-to-stand; they exhibited more body sway in COM motion and, in particular, were unable to control ML motion y. Older fallers were more likely to adopt trunk, hip, and knee joint flexion strategies to maintain balance during sit-to-stand and stand-to-sit than nonfaller participants were.

Background: Parkinson’s disease (PD) is characterized by intraneuronal α-synuclein aggregation called Lewy bodies and progressive dopaminergic neurodegeneration. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation. The molecular link on how neuroinflammation upregulates neuronal TLRs and induces accumulation of α-synuclein aggregates to drive synucleinopathy remains to be determined.Objective: Despite conditioned medium from microglia and TLR agonists were utilized to study their effects on neuronal cells, a Transwell coculture system, comprising lipopolysaccharide-activated microglia on top and retinoic acid-differentiated SH-SY5Y cells at the bottom more mimicking in vivo neuroinflammation, was employed to elucidate the mechanism of activated microglia on neuronal cells.Methods: Genetic variants of TLRs in PD patients were genotyped and the multiplex cytokines, sRAGE, and HMGB1were assessed. A coculture system was employed to measure α-synuclein aggregates and neurite shortening by confocal microscope. The expression of TLR2/4 and autophagy flux was detected by western blot and immunofluorescence.Results: PD patients showed higher plasma levels of proinflammatory cytokines and genetic TLR4 variant, c.896 A > G (p. D299G). Elevated proinflammatory cytokines in coculture medium was also seen. Phosphorylation and aggregation of α-synuclein, shortening of neurite, upregulation of TLR2/4 expression, activation of downstream p38 and JNK, and dampening of autophagic flux were seen in SH-SY5Y cells cocultured with activated microglia. Those were prevented by inhibiting TLR2/4 and p38/JNK signaling.Conclusion: Activated microglia-derived neuroinflammation induced neuronal TLR2/4-p38/JNK activation to perturb autophagy, causing accumulation of α-synuclein aggregates and neurite shortening. Targeting neuronal TLR2/4 pathway might be a mechanistic-based therapy for neurodegenerative disease, such as PD.

Background: This study aimed to examine social-cognitive impairments in patients with schizophrenia using the Eyes test. In contrast to previous methods using the correct answers, we developed the Taiwanese version of the Eyes test and constructed the response network to explore impairments in the emotional aspects of theory of mind in patients with schizophrenia. Methods: Eighteen patients with schizophrenia and 18 healthy controls were recruited to examine their performance of the Eyes test. To explore the internal structures of mental states, we used network analysis to construct the networks of choice patterns (i.e. participants' answers) by using two network indicators, including density (an index of structure diversity of a network) and centrality (an index of the choice patterns within a network). Moreover, we divided all the choices into negative, positive, and neutral item groups based on emotion polarity. Results: The patient group was slower and less accurate than the control group. Moreover, there was a negative correlation between accuracy and blunted affect, and there were positive correlations between reaction time and emotional withdrawal and apathetic social withdrawal. As compared to healthy controls, patients with schizophrenia showed larger density in the network structure and higher centrality than controls. Also, patients showed poorer performance on negative words than healthy controls. Conclusion: Our results demonstrated more diversity to recognize negative emotions from patients' choice patterns as compared to those in the control group. These findings suggest that deficits on recognizing negative emotions might be associated with the dysfunctions of mental states in schizophrenia. Keywords: Eyes test, Negative emotion, Network analysis, Schizophrenia, Social cognition

Background During the COVID-19 surge in Taiwan, the Far East Memorial Hospital established a system including a centralized quarantine unit and triage admission protocol to facilitate acute care surgical inpatient services, prevent nosocomial COVID-19 infection and maintain the efficiency and quality of health care service during the pandemics. Materials and methods This retrospective cohort study included patients undergoing acute care surgery. The triage admission protocol was based on rapid antigen tests, Liat® PCR and RT-PCT tests. Type of surgical procedure, patient characteristics, and efficacy indices of the centralized quarantine unit and emergency department (ED) were collected and analyzed before (Phase I: May 11 to July 2, 2021) and after (Phase II: July 3 to July 31, 2021) the system started. Results A total of 287 patients (105 in Phase I and 182 in Phase II) were enrolled. Nosocomial COVID-19 infection occur in 27 patients in phase I but zero in phase II. More patients received traumatological, orthopedic, and neurologic surgeries in phase II than in phase I. The patients’ surgical risk classification, median total hospital stay, intensive care unit (ICU) stay, intraoperative blood loss, operation time, and the number of patients requiring postoperative ICU care were similar in both groups. The duration of ED stay and waiting time for acute care surgery were longer in Phase II (397 vs. 532 minutes, p < 0.0001). The duration of ED stay was positively correlated with the number of surgical patients visiting the ED (median = 66 patients, Spearman’s ρ = 0.207) and the occupancy ratio in the centralized quarantine unit on that day (median = 90.63%, Spearman’s ρ = 0.191). Conclusions The triage admission protocol provided resilient quarantine needs and sustainable acute care surgical services during the COVID-19 pandemic. The efficiency was related to the number of medical staff dedicated to the centralized quarantine unit and number of surgical patients visited in ED.

Abstract Background Systemic sclerosis (SSc), a life-threatening autoimmune disease characterized by vasculopathy. Numerous SSc patients demonstrate gastrointestinal (GI) involvement but the delicate GI bleeding risk remains sparse. We aimed to explore the role of SSc in determining the long-term risk of GI bleeding, including bleedings of upper (peptic and non-peptic ulcers) and lower GI tracts. Methods Patients with SSc diagnosis were identified from the Catastrophic Illness Patient Database and the National Health Insurance Research Database from 1998 to 2007. Each SSc patient was matched with five SSc-free individuals by age, sex, and index date. All individuals (case = 3665, control = 18,325) were followed until the appearance of a GI bleeding event, death, or end of 2008. A subdistribution hazards model was assessed to evaluate the GI bleeding risk with adjustments for age, sex, and time-dependent covariates, comorbidity, and medications. Results The incidence rate ratios of GI bleeding were 2.38 (95% confidence interval [CI], 2.02–2.79), 2.06 (95% CI, 1.68–2.53), and 3.16 (95% CI, 2.53–3.96) for over-all, upper, and lower GI bleeding events in SSc patients. In the competing death risk in the subdistribution hazards model with time-covariate adjustment, SSc was an independent risk factor for over-all GI bleeding events (subdistribution hazard ratio [sHR] 2.98, 95% CI, 2.21–4.02), upper GI bleeding events (sHR 2.80, 95% CI, 1.92–4.08), and lower GI bleeding events (sHR 3.93, 95% CI, 2.52–6.13). Conclusion SSc patients exhibited a significantly higher risk of over-all and different subtype GI bleeding events compared with the SSc-free population. The prevention strategy is needed for these high GI bleeding risk groups.

Background: Contradictory messages regarding the necessity of long-term antipsychotic treatment after first episode psychosis arouse deliberations in clinical practice. We explored if there is an alternative beyond the dichotomy of maintenance treatment and discontinuation of medications.Methods: We conducted a retrospective observational study by reviewing medical records at the study hospital of a cohort of patients since their participation in an early psychosis study starting from 2006, with special interests in patients able to maintain good functioning under treatment with a low antipsychotic dose.Results: Of the 81 patients with first-episode psychosis, 55 patients (67.9%) had follow-up information for longer than 5 years. The majority (n = 46, 83.6%) had non-affective psychosis, 20 patients (36.4%) had full-time employment/education by the time of their latest visit; among them, 15 patients received dosage of antipsychotics no more than the minimum effective dose [chlorpromazine equivalent (CPZE) dose, 200 mg/day]. Besides, 10 of 55 patients (18.2%) only received very low dose antipsychotics (CPZE < 50 mg/day) during maintenance, which was significantly correlated to good functioning. Being male, having a history of hospitalization, and being on clozapine therapy were correlated to poorer functioning. Antipsychotic-free status was achieved only in two non-psychotic patients.Conclusions: A substantial proportion of patients could achieve good functioning under low-dose antipsychotic maintenance after first-episode psychosis, even if they could not completely withdraw antipsychotics in the long term. Optimizing the balance between preventing relapse and preserving functioning by fine-tuning antipsychotic dosage during maintenance is a challenge warranting more clinical attention.

High entropy alloy films of AlCoCrFeNi B2-ordered structure are formed during an ultrafast heating process by reactive Ni/Al multilayers. The self-propagating high-temperature reaction occurring in reactive Ni/Al multilayers after ignition represents an ultrafast heat source which is used for the transformation of a thin films Al/CoFe/CrNi multilayer structure into a single-phase high entropy alloy film. The materials design of the combined multilayers thus determines the phase formation.Conventional rapid thermal annealing transforms the multilayer into a film with multiple equilibrium phases. Ultrafast combustion synthesis produces films with ultrafine-grained single-phase B2-ordered compound alloy. The heating rates during the combustion synthesis are in the order of one million K/s, much higher than those of the rapid thermal annealing, which is about 7 K/s. The results are compared with differential scanning calorimetry experiments with heating rates ranging from about 100 K/s up to 25000 K/s. It is shown that the heating rate clearly determines the phase formation in the multilayers. The rapid kinetics of the combustion prevents long-range diffusion and promotes the run-away transformation. Thus, multilayer combustion synthesis using reactive Ni/Al multilayers as heat source represents a new pathway for the fabrication of single phase high-entropy alloy films.

Dihydromyricetin (DHM)-rich herbal mixture extracts, also called APF complex, comprised of Ampelopsis grossedentata, Pericarpium citri reticulatae, and Fructus crataegi. The content of DHM in APF complex was 362.7 ± 12.5 mg/g. The aims of this study were to investigate the therapeutic effects of APF complex on metabolic syndrome in rats fed a high-fat diet (HFD) and evaluate the subacute toxicity of APF complex in rats. HFD significantly increased body weight gain, fat tissue (epididymal fat, mesenteric fat, and perirenal fat) deposition, body fat index, and hepatic triglyceride (TG) and total cholesterol (TC) accumulation as well as caused abnormal blood biochemical parameters, including TC, TG, low-density lipoprotein-cholesterol (LDL-C), free fatty acid (FFA), and glucose. APF complex has a tendency but not significance to limit HFD-induced body weight gain. APF complex also significantly improved HFD-induced body fat accumulation, as evidenced by decreasing fat tissue deposition and body fat index. In addition, APF complex significantly ameliorated HFD-induced hyperlipidemia and hyperglycemia, as evidenced by reducing levels of blood TG and TC as well as blood glucose and FFA, respectively. Furthermore, APF complex significantly decreased HFD-induced hepatic TG and TC accumulation. In subacute toxicity assessment, APF complex exhibited no toxicological signs, as evidenced by without affecting mortality, food and water consumption, body weight changes, absolute organ weights, hematological system, blood lipids and nutritional status, and electrolyte balance as well as non-toxic to liver and renal function. Overall, APF complex was considered as a non-toxic herbal prescription and could act as adjuvant therapy for metabolic syndrome. Keywords: Dihydromyricetin, Herbal mixture extracts, High-fat diet, Metabolic syndrome, Subacute toxicity

Formaldehyde is one of the indoor air quality pollutants produced by indoor decoration. The World Health Organization has listed Formaldehyde as a primary carcinogen. Wood planks for house interior decoration are common sources of formaldehyde. Based on the technology research and development of monitoring and control of the smart home, the air quality should be effectively improved through emission and suppression. This study uses extremely unventilated student renters in Taiwan as simulation spaces. Two classes of wood plank construction materials, F1 and F3, which are classified according to as different concentrations of formaldehyde standard board grades by Taiwanese. Through three different temperature control experiments, each group of experiments use electrochemical formaldehyde detectors to measure at least two consecutive days of data to analyze the influence to which temperature, the control factor, affected formaldehyde emission rate. The results revealed that the F3 class wood planks can increase the rate of formaldehyde emission through heating, which has a significant effect on home environment control, but they need a temperature below 10 °C to barely maintain within the regulations in Taiwan. The F1 class wood planks have an emission rate of nearly zero in a low-temperature environment due to its low formaldehyde emission. The emission rate of the F1 in a high-temperature environment is not as effective as the F3. The addition of experimental data can be used as a reference basis for AI decision making, which is conducive to the establishment of indoor intelligent control systems.

Secondary hormone therapy, abiraterone and enzalutamide, has improved outcomes for metastatic castration-resistant prostate cancer (mCRPC) and prolonged patients’ lives significantly. Various studies have compared the cancer-related outcomes, adverse effects, and drug-induced comorbidities in patients with mCRPC who are treated with abiraterone or enzalutamide. However, few studies have explored associations between survival and comorbidities or comprehensive analyzed newly developed comorbidities during and after secondary hormone therapy. We attempted to clarify whether the Charlson comorbidity index (CCI) overall or itemized is predictive for overall survival, and we compared newly developed comorbidities between abiraterone and enzalutamide groups. We extracted data about expenses and comorbidities for patients who have mCRPC, received abiraterone and enzalutamide and met pre-examination operation criteria between September 2016 and December 2017 from the Taiwan National Health Insurance database. A total of 1153 patients with mCRPC who received abiraterone (n = 782) or enzalutamide (n = 371) with or without previous chemotherapy were included. We used the propensity score to match confounding factors, including age, pre-existing comorbidities, and precipitating factors for comorbidity (e.g., hypertension, hyperlipidemia), to eliminate selection bias in the comparison of newly developed comorbidities. Cox regression analysis was used for overall survival. We found that enzalutamide is superior to abiraterone with regard to overall survival. Our study revealed that there is no statistically significant difference in development of new comorbidities between abiraterone and enzalutamide group. Moreover, the CCI score, rather than any single item of the CCI, was a statistically significant predictor for overall survival.

This work investigated hydrogen trapping and hydrogen embrittlement (HE) in two press-hardened steels, 22MnB5 for 1,500 MPa grade and 34MnB5V for 2000 MPa grade, respectively. Superior to the 22MnB5 steel, the newly developed 34MnB5V steel has an ultimate tensile strength of over 2000 MPa without sacrificing ductility due to the formation of vanadium carbides (VCs). Simulated press hardening was applied to two steels, and hydrogen was induced by cathodic charging. Susceptibility to HE was validated by slow strain-rate tensile test. When hydrogen content was high, the 34MnB5V steel fractured in elastic regime. However, when hydrogen content was 0.8–1.0 ppmw, the 34MnB5V steel bore much higher stress than the 22MnB5 steel before fracture. The behavior of hydrogen trapping was investigated by thermal desorption analyses. Although the two steels trapped similar amounts of hydrogen after cathodic charging, their trapping mechanisms and effective trapping sites were different. In summary, a finer prior austenite grain size due to the pinning effect of VCs can also improve the toughness of 34MnB5V steel. Moreover, trapping hydrogen by grain boundary suppresses the occurrence of hydrogen-enhanced local plasticity. Microstructural refinement enhanced by VCs improves the resistance to HE in 34MnB5V steel. Importantly, the correlation between hydrogen trapping by VCs and improvement of HE is not significant. Hence, this work presents the challenge in designing irreversible trapping sites in future press-hardened steels.

Digoxin is commonly prescribed for heart failure and atrial fibrillation, but there is limited data on its safety in patients with chronic kidney disease (CKD). We conducted a population-based cohort study using the pre-end stage renal disease (ESRD) care program registry and the National Health Insurance Research Database in Taiwan. Of advanced CKD patient cohort (N = 31,933), we identified the digoxin user group (N = 400) matched with age and sex non-user group (N = 2,220). Multivariable Cox proportional hazards and sub-distribution hazards models were used to evaluate the association between digoxin use and the risk of death, cardiovascular events (acute coronary syndrome, ischemic stroke, or hemorrhagic stroke) and renal outcomes (ESRD, rapid decline in estimated glomerular filtration rate-eGFR, or acute kidney injury). Results showed that all-cause mortality was higher in the digoxin user group than in the non-user group, after adjusting for covariates (adjusted hazard ratio, aHR 1.63; 95% CI 1.23-2.17). The risk for acute coronary syndrome (sub-distribution hazard ratio, sHR 1.18; 95% CI 0.75-1.86), ischemic stroke (sHR 1.42; 95% CI 0.85-2.37), and rapid eGFR decline (sHR 1.00 95% CI 0.78-1.27) was not significantly different between two groups. In conclusion, our study demonstrated that digoxin use was associated with increased mortality, but not cardiovascular events or renal function decline in advanced CKD patients. This finding warns the safety of prescribing digoxin in this population. Future prospective studies are needed to overcome the limitations of cohort study design.

This study aimed at developing an instructional tool for the artificial intelligence education of young students, and used learning analytics to identify the sequential learning behavioral patterns of students during the process of learning with the instructional tool. The instructional experiment took 9 weeks. The first stage of the course was 5 weeks spent on individual learning of MIT App Inventor and Personal Image Classifier. The second stage was 4 weeks spent on cooperative learning to make a robot car and play a computational thinking board game. In the second stage, the students worked in pairs to make the robot car. Finally, they played the computational thinking board game with the personal image classification application they developed in the first stage and the robot car they made in the second stage. The innovative studies found meaningful behavioral patterns when the young students learned the application of artificial intelligence with the instructional tool developed and proposed in the study.

Kidney disease patients may have concurrent chronic kidney disease-associated mineral bone disorder and hypertension. Cardiovascular disease (CVD) and neuropathy occur due to kidney failure-induced accumulation of uremic toxins in the body. Indoxyl sulfate (IS), a product of indole metabolism in the liver, is produced from tryptophan by the intestinal flora and is ultimately excreted through the kidneys. Hemodialysis helps renal failure patients eliminate many nephrotoxins, except for IS, which leads to a poor prognosis. Although the impacts of IS on cardiac and renal development have been well documented using mouse and rat models, other model organisms, such as zebrafish, have rarely been studied. The zebrafish genome shares at least 70% similarity with the human genome; therefore, zebrafish are ideal model organisms for studying vertebrate development, including renal development. In this study, we aimed to investigate the impact of IS on the development of zebrafish embryos, especially cardiac and renal development. At 24 h postfertilization (hpf), zebrafish were exposed to IS at concentrations ranging from 2.5 to 10 mM. IS reduced survival and the hatching rate, caused cardiac edema, increased mortality, and shortened the body length of zebrafish embryos. In addition, IS decreased heart rates and renal function. IS affected zebrafish development via the ROS and MAPK pathways, which subsequently led to inflammation in the embryos. The results suggest that IS interferes with cardiac and renal development in zebrafish embryos, providing new evidence about the toxicity of IS to aquatic organisms and new insights for the assessment of human health risks. Accordingly, we suggest that zebrafish studies can ideally complement mouse model studies to allow the simultaneous and comprehensive investigation of the physiological impacts of uremic endotheliotoxins, such as IS, on cardiac and renal development.

Bilateral Filtering (BF) is an effective edge-preserving smoothing technique in image processing. However, an inherent problem of BF for image denoising is that it is challenging to differentiate image noise and details with the range kernel, thus often preserving both noise and edges in denoising. This letter proposes a novel Dual-Histogram BF (DHBF) method that exploits an edge-preserving noise-reduced guidance image to compute the range kernel, removing isolated noisy pixels for better denoising results. Furthermore, we approximate the spatial kernel using mean filtering based on column histogram construction to achieve constant-time filtering regardless of the kernel radius’ size and achieve better smoothing. Experimental results on multiple benchmark datasets for denoising show that the proposed DHBF outperforms other state-of-the-art BF methods.

Tooth loss or damage is a common problem affecting millions of people worldwide, and it results in significant impacts on one’s quality of life. Dental regeneration with the support of stem cell-containing scaffolds has emerged as an alternative treatment strategy for such cases. With this concept in mind, we developed various concentrations of calcium silicate (CS) in a gelatin methacryloyl (GelMa) matrix and fabricated human dental pulp stem cells (hDPSCs)-laden scaffolds via the use of a bioprinting technology in order to determine their feasibility in promoting odontogenesis. The X-ray diffraction and Fourier transform-infrared spectroscopy showed that the incorporation of CS increased the number of covalent bonds in the GelMa hydrogels. In addition, rheological analyses were conducted for the different concentrations of hydrogels to evaluate their sol–gel transition temperature. It was shown that incorporation of CS improved the printability and printing quality of the scaffolds. The printed CS-containing scaffolds were able to release silicate (Si) ions, which subsequently significantly enhanced the activation of signaling-related markers such as ERK and significantly improved the expression of odontogenic-related markers such as alkaline phosphatase (ALP), dentin matrix protein-1 (DMP-1), and osteocalcin (OC). The calcium deposition assays were also significantly enhanced in the CS-containing scaffold. Our results demonstrated that CS/GelMa scaffolds were not only enhanced in terms of their physicochemical behaviors but the odontogenesis of the hDPSCs was also promoted as compared to GelMa scaffolds. These results demonstrated that CS/GelMa scaffolds can serve as cell-laden materials for future clinical applications and use in dentin regeneration.

Background Galantamine has been approved for the treatment of Alzheimer’s disease (AD). However, there are few studies which have reported the association between cognitive responses and galantamine plasma concentration. The aim of this study was to determine the correlation between galantamine plasma concentration and the subsequent cognitive response following treatment in AD patients. Methods AD sufferers who continuously took 8 mg/d galantamine for at least 6 months without previous exposure to other kinds of AChEI such as donepezil, rivastigmine, or memantine were included in this cohort study. The assessments included the Mini Mental Status Examination (MMSE), Clinical Dementia Rating Scale (CDR) and the Cognitive Assessment Screening Instrument (CASI). Each subdomain of the CASI assessment was conducted at baseline and after 6 months of galantamine. The plasma concentrations of galantamine were measured by capillary electrophoresis after 6 months of the treatment. Logistic regression was performed to adjust for age, gender, apolipoprotein E ε4 genotype status, and baseline score to investigate the association between galantamine plasma concentrations and the cognitive response. Results The total sample consisted of 33 clinically diagnosed AD patients taking galantamine 8 mg/d for 6 months. There was no linear correlation between galantamine concentration and cognitive response in patients. However, 22 patients were responsive to the treatment in the long-term memory domain. In CASI subset domain, concentration improved during the 6 months follow up. Conclusions In the limited samples study, galantamine mostly benefitted the cognitive domain of long-term memory. The benefits were not related to the galantamine plasma concentration. Objective intra-individual evaluation of therapeutic response should be encouraged.

Background: Auditory event-related potentials (ERPs) have been utilized to study defective information processing of patients with schizophrenia. To delineate the pathophysiological processes from pre-psychotic state to first-episode psychosis, a study on subjects from ultra-high-risk (UHR) state to first-episode psychosis, ideally in an antipsychotic-free condition, can add important information to our understanding.Methods: Patients with UHR state or at their first-episode psychosis (FEP) who were drug-naive or only have been temporarily treated with antipsychotics were assessed by auditory ERPs measurement, including P50/N100 (sensory gating) and duration mismatch negativity (MMN; deviance detection). A group of age-matched healthy subjects served as their controls.Results: A total of 42 patients (23 UHR and 19 FEP) and 120 control subjects were recruited, including 21 pure drug-naive and 21 with very short exposure to antipsychotics. Collapsing FEP and UHR as a patient group, they exhibited significant sensory deficits manifested as larger P50 S2 amplitude, larger N100 ratio, and smaller N100 difference, and significantly less deviance detection response revealed by MMN. Such differences were less significant when treating FEP and UHR separately for comparisons. Comparisons of ERP results between drug-naive subjects and antipsychotic-short-exposure subjects revealed no significant difference in any P50/N100 and MMN parameter.Conclusion: Our study is one of the few studies focused on drug-naive or minimally treated patients at pre- or early-psychotic states. Our results exhibited impaired performance in sensory gating and deviance detection shown by certain parameters. A longitudinal study with larger sample sizes will be helpful to provide more evidence to elucidate the role of antipsychotics on an individual’s neurophysiological performance at different stages of psychosis.

BackgroundDepression is common in dialysis patients, but the clinical impact of this condition is poorly defined.MethodsOut of 57,703 patients starting dialysis during 2000-2007 recorded in the National Health Insurance Research Database of Taiwan, we identified 2,475 patients with a clinical diagnosis of depression, and compared them with 1:5 age- and sex-matched patients without a depression diagnosis (n = 12,375). Patients were followed up for hospitalisation due to severe infections, major adverse cardiovascular events (MACE) and death. Multivariable Cox regression and competing risk analyses (accounting for death when appropriate) were used to estimate risk associations.ResultsPatients with depression had a higher frequency of comorbidities. During a mean follow-up of 3.2 years, 1,140 severe infections, 806 MACE, and 1,121 deaths were recorded. Compared to controls, patients with depression were at increased risk of death (adjusted hazard ratio 1.24; 95%CI 1.16-1.33). Patients with depression were also at higher risk of severe (1.14; 1.06-1.22) and fatal infections (death within 30 days, 1.22; 1.09-1.35), attributed mainly to sepsis (1.19; 1.08-1.31), septic shock (1.36; 1.13-1.62) and pneumonia (1.19; 1.07-1.33). Conversely, no association was observed between depression and the MACE risk (1.04; 0.94-1.15).ConclusionDialysis patients with depression are associated with increased risk of infections and death.

Anti-acid drugs, proton pump inhibitor (PPI) and histamine-2 blocker (H2-blocker), are commonly prescribed to treat gastrointestinal disorders. These anti-acid drugs alter gut microbiota in the general population, but their effects are not known in hemodialysis patients. Hence, we investigated the microbiota composition in hemodialysis patients treated with PPIs or H2-blocker. Among 193 hemodialysis patients, we identified 32 H2-blocker users, 23 PPI users, and 138 no anti-acid drug subjects. Fecal samples were obtained to analyze the gut microbiome using 16S RNA amplicon sequencing. Differences in the microbial composition of the H2-blocker users, PPI users, and controls were assessed using linear discriminant analysis effect size and the random forest algorithm. The species richness or evenness (α-diversity) was similar among the three groups, whereas the inter-individual diversity (β-diversity) was different between H2-blocker users, PPI users, and controls. Hemodialysis patients treated with H2-blocker and PPIs had a higher microbial dysbiosis index than the controls, with a significant increase in the genera Provetella 2, Phascolarctobacterium, Christensenellaceae R-7 group, and Eubacterium oxidoreducens group in H2-blocker users, and Streptococcus and Veillonella in PPI users. In addition, compared to the H2-blocker users, there was a significant enrichment of the genera Streptococcus in PPI users, as confirmed by the random forest analysis and the confounder-adjusted regression model. In conclusion, PPIs significantly changed the gut microbiota composition in hemodialysis patients compared to H2-blocker users or controls. Importantly, the Streptococcus genus was significantly increased in PPI treatment. These findings caution against the overuse of PPIs.

Gut dysbiosis in patients with chronic kidney disease (CKD) may induce chronic inflammation and increase morbidity. Phosphate-binding agents, generally used in patients with CKD, may potentially change the composition of the gut microbiota. This study aimed to compare the microbiota composition in hemodialysis patients treated with ferric citrate or calcium carbonate. The stool microbiota was investigated in hemodialysis patients treated with ferric citrate (n = 8) and calcium carbonate (n = 46) using 16S rRNA gene amplicon sequencing profiling using linear discriminant analysis of effect size. Further predictive functional profiling of microbial communities was obtained with Tax4Fun in R. Hemodialysis patients treated with calcium carbonate had a significantly reduced microbial species diversity (Shannon index and Simpson index) and an increased microbial alteration ratio compared with patients treated with ferric citrate. A distinct microbial community structure was found in patients treated with ferric citrate, with an increased abundance of the Bacteroidetes phylum and a decreased abundance of the phylum Firmicutes. Members of the order Lactobacillales were enriched in patients treated with calcium carbonate, whereas taxa of the genera Ruminococcaceae UCG-004, Flavonifractor, and Cronobacter were enriched in patients treated with ferric citrate phosphate binder. In conclusion, Ferric citrate therapy results in a more diverse microbiome community compared to calcium carbonate therapy in hemodialysis patients with phosphate binder treatment. The gut microbiome reflects the phosphate binder choice in hemodialysis patients, further affecting the physiological environment in the gastrointestinal tract.

Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and ApcMin/+ CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC.

Repairing damaged articular cartilage is particularly challenging because of the limited ability of cartilage to perform self-repair. Intra-articular injections of N-acetylglucosamine (GlcNAc) comprise a method of repairing full-thickness articular cartilage defects in the rabbit knee joint model. To date, the effects of administration of GlcNAc and hyaluronic acid (HA) have been investigated only in the context of osteoarthritis treatment. Therefore, we evaluated the therapeutic effects of using cell-free porous poly lactic-co-glycolic acid (PLGA) graft implants and intra-articular injections of GlcNAc or HA in a rabbit model of osteochondral regeneration to investigate whether they have the potential for inducing osteochondral regeneration when used alone or simultaneously. Twenty-four rabbits were randomized into one of four groups: the scaffold-only group (PLGA), the scaffold with intra-articular injections of GlcNAc (PLGA+G) group, twice per week for four weeks; the scaffold with intra-articular injections of HA group (PLGA+HA) group, once per week for three weeks; and the scaffold with intra-articular injections of GlcNAc and HA (PLGA+G+HA) group, once per week for three weeks. Knees were evaluated at 4 and 12 weeks after surgery. At the end of testing, only the PLGA+G+HA group exhibited significant bone reconstruction, chondrocyte clustering, and good interactions with adjacent surfaces at 4 weeks. Additionally, the PLGA+G+HA group demonstrated essentially original hyaline cartilage structures that appeared to have sound chondrocyte orientation, considerable glycosaminoglycan levels, and reconstruction of the bone structure at 12 weeks. Moreover, the PLGA+G+HA group showed organized osteochondral integration and significantly higher bone volume per tissue volume and trabecular thickness. However, there were no significant differences between the PLGA+G and PLGA+HA groups except for gap formation on subchondral bone in the PLGA+G group. This study demonstrated that PLGA implantation combined with intra-articular injections of GlcNAc and HA allowed for cartilage and bone regeneration and significantly promoted osteochondral regeneration in rabbits without supplementation of exogenous growth factors. And the combination of this two supplements with PLGA scaffold could also prolong injection interval and better performance than either of them alone for the reconstruction of osteochondral tissue in the knee joints of rabbits.

Inadequate care of chronic kidney disease (CKD) is common and may be associated with adverse outcomes after dialysis. The nationwide pre-end-stage renal disease pay for performance program (P4P) has been implemented in Taiwan to improve quality of CKD care. However, the effectiveness of the P4P program in improving the outcomes of pre-dialysis care and dialysis is uncertain. We conducted a longitudinal cohort study. Patients who newly underwent long-term dialysis (≥3 mo) between 2007 and 2009 were identified from the Taiwan National Health Insurance Research Database. Based on the patient enrolment of the P4P program, they were categorized into P4P or non-P4P groups. We analysed pre-dialysis care, healthcare expenditures, and mortality between two groups. Among the 26 588 patients, 25.5% participated in the P4P program. The P4P group received significantly better quality of care, including a higher frequency of glomerular filtration rate measurement and CKD complications survey, a higher rate of vascular access preparation, and more frequent use of arteriovenous fistulas than the non-P4P group did. The P4P group had a 68.4% reduction of the 4-year total healthcare expenditure (excluding dialysis fee), which is equivalent to US$345.7 million, and a significant 22% reduction in three-year mortality after dialysis (hazard ratio 0.78, 95% confidence interval: 0.75-0.82, P < 0.001) compared with the non-P4P group. P4P program improves quality of pre-dialysis CKD care, and provide survival benefit and a long-term cost saving for dialysis patients.

The USA Food and Drug Administration (FDA) issued warnings regarding the use of antipsychotics in patients with dementia in 2003 and 2005. We aimed to study the dose and duration of antipsychotic treatment in dementia, and to examine whether physicians' prescription behaviors changed after the FDA warnings. Methods: Medical charts of outpatients who had Alzheimer's disease, vascular dementia, or mixed dementia were reviewed. Patients must have achieved a clinically stable state for at least 4 weeks after receiving antipsychotic treatment for agitation or psychosis. Demographics, clinical correlates, and duration of antipsychotic treatment were compared among different antipsychotic groups. Because the quetiapine group had the largest sample size, the optimal dose and duration of quetiapine treatment were compared among three time periods (before 2003, 2003–2005, after 2005). Results: Stable state was achieved in 215 patients (80 had Alzheimer's disease, 117 vascular dementia, and 18 mixed dementia). Most patients (177) took quetiapine, 25 took risperidone, and 13 took sulpiride. The whole sample had a long total duration of antipsychotic treatment (median 525 days, mean 707 days). The median dose and total duration of antipsychotic treatment were 1.0 mg/day and 238 days for risperidone, 100 mg/day and 390 days for sulpiride, and 25 mg/day and 611 days for quetiapine, respectively. The optimal dose and total duration of quetiapine treatment decreased significantly after FDA warning in 2005, although the duration remained long. Conclusion: The optimal doses of antipsychotics were not higher than those of western reports, but the total duration of antipsychotic treatment was quite long. Although our study suggests the prescription dosage and duration of antipsychotic treatment decreased significantly after FDA warning in 2005, the duration of treatment was still long. Given the serious safety concerns, more effort should be made to avoid unnecessary and prolonged prescription.