Search

Yao-Ching Huang,1 Wu-Chien Chien,2– 5,* Chi-Hsiang Chung,2– 4 Hsin-An Chang,6,7 Yu-Chen Kao,6,8 Fang-Jung Wan,6 Shi-Hao Huang,1 Ren-Jei Chung,1,* Richard S Wang,9 Bing-Long Wang,2,* Nian-Sheng Tzeng,7,8,* Chien-An Sun10,11 1Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei, Taiwan; 2School of Public Health, National Defense Medical Center, Taipei, Taiwan; 3Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 4Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan; 5Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; 6Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 7Student Counseling Center, National Defense Medical Center, Taipei, Taiwan; 8Department of Psychiatry, Tri-Service General Hospital, Song-Shan Branch, National Defense Medical Center, Taipei, Taiwan; 9Program of Data Analytic and Business Computing, Stern School of Business, New York University, USA; 10Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; 11Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan*These authors contributed equally to this workCorrespondence: Nian-Sheng TzengDepartment of Psychiatry, School of Medicine, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Cheng-Gung Road, Nei-Hu District, Taipei, Taiwan, Republic of ChinaTel +886-2-87923311 Ext 17484Fax +886-2-87927221Email pierrens@mail.ndmctsgh.edu.twBing-Long WangDepartment of Public Health, National Defense Medical Center, 116, Section 6, Minchuan E. Road, Nei-Hu District, Taipei, Taiwan, Republic of ChinaTel +886-980-794951Email billwang1203@gmail.comBackground: Multiple sclerosis (MS) is a demyelinating disease that can damage neurons in the brain and spinal cord and is associated with several psychiatric disorders. However, few studies have evaluated the risk of psychiatric disorders in patients with MS by using a nationwide database. This study investigated the association between MS and the risk of psychiatric disorders.Methods: Using data from the Taiwan National Health Insurance Research Database from 2000 to 2015, we identified 1066 patients with MS. After adjustment for confounding factors, Fine and Gray’s competing risk model was used to compare the risk of psychiatric disorders during 15 years of follow-up.Results: Of the patients with MS, 531 (4622.86 per 105 person years) developed psychiatric disorders; by contrast, 891 of the 3198 controls (2485.31 per 105 person years) developed psychiatric disorders. Fine and Gray’s competing risk model revealed an adjusted hazard ratio (HR) of 5.044 (95% confidence interval = 4.448– 5.870, p < 0.001) after adjustment for all the covariates. MS was associated with depression, anxiety, bipolar disorder, sleep disorders, schizophrenia, schizophreniform disorder, and other psychotic disorders (adjusted HR: 12.464, 4.650, 6.987, 9.103, 2.552, 2.600, 2.441, and 2.574, respectively; all p < 0.001). Some disease-modifying drugs were associated with a lower risk of anxiety or depression.Conclusion: Patients with MS were determined to have a higher risk of developing a wide range of psychiatric disorders.Keywords: multiple sclerosis, psychiatric disorders, depression, anxiety

Shih-Chun Hsing,1,2 Yo-Ting Jin,3,4 Nian-Sheng Tzeng,5,6 Chi-Hsiang Chung,7– 9 Tien-Yu Chen,5,10,11 Hsin-An Chang,5,6 Yu-Chen Kao,5,12 Wu-Chien Chien4,7– 9 1Center for Healthcare Quality Management, Cheng Hsin General Hospital, Taipei, Taiwan; 2Department of Health Care Management, College of Health Technology, National Taipei University of Nursing and Heath Sciences, Taipei, Taiwan, Republic of China; 3Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan; 4Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; 5Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 6Student Counseling Center, National Defense Medical Center, Taipei, Taiwan; 7Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 8School of Public Health, National Defense Medical Center, Taipei, Taiwan; 9Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan; 10Department of Psychiatry, Tri-Service General Hospital, Keelung Branch, National Defense Medical Center, Taipei, Taiwan; 11Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; 12Department of Psychiatry, Tri-Service General Hospital, Song-Shan Branch, National Defense Medical Center, Keelung, TaiwanCorrespondence: Nian-Sheng TzengDepartment of Psychiatry, School of Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, No. 325, Section 2, Cheng-Gung Road, Nei-Hu District, Taipei, TaiwanTel +886 2-87923311, ext. 17484Fax +886-2-87927221Email pierrens@mail.ndmctsgh.edu.twWu-Chien ChienDepartment of Medical Research, Tri-Service General Hospital, National Defense Medical Center, 7115R, No. 325, Section 2, Cheng-Gung Road, Nei-Hu District, Taipei, TaiwanTel +886 2-87923311, ext. 19189Fax +886 2-87927235Email chienwu@ndmctsgh.edu.twBackground: To examine the association between the usage of agomelatine in patients with major depressive disorder and the usage of sedative-hypnotics.Methods: This population-based, cross-sectional study used Taiwan’s National Health Insurance Research Database (NHIRD) between 2012 and 2015. The agomelatine-only group and matched control (1:3) with the usage of other antidepressants were enrolled. The association between the usage of the agomelatine and other antidepressants and the usage of sedative-hypnotics in the patients were also assessed.Results: A total of 7961 subjects were enrolled comprising 1985 with the usage of agomelatine only, and 5976 with other antidepressants. In the present study, a total of 3322 subjects who used the sedative-hypnotics were recorded, with 811 (40.86%) from the agomelatine-only group and 2511 (42.02%) from the non-agomelatine group, which have used sedative-hypnotics. After adjusting for covariates, the odds ratio (OR) of the usage of sedative-hypnotics in the agomelatine only-group was 0.892 (95% CI: 0.306– 1.601, p = 0.533), in comparison to the controls, and the relative risk (RR) of the usage of sedative-hypnotics in the agomelatine only-group was 0.892 0.910 (95% CI: 0.312– 1.633, p = 0.452), in comparison to the controls. No matter as to whether the treatment duration was < 30 days or ≧ 30 days of agomelatine treatment was not associated with the increased usage of the sedative-hypnotics. The OR or RR for usage of the sedative-hypnotics was associated with the Charlson Comorbidity Index (CCI) scores as 2, 3, and ≧ 4, and the medical care from the medical center and regional hospital.Conclusion: Patients with the agomelatine-only group were not associated with the usage of sedative-hypnotics in comparison to the group using other antidepressants.Keywords: agomelatine, insomnia, antidepressant, major depressive disorder, National Health Insurance Research Database

Yueh-Er Chiou,1,2 Wu-Chien Chien,3– 5,* Chi-Hsiang Chung,3,4,6 Hsin-An Chang,7,8 Yu-Chen Kao,7,9 Pei-Kwei Tsay,10,* Nian-Sheng Tzeng7,8,* 1Department of Nursing, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 2Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; 3Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 4School of Public Health, National Defense Medical Center, Taipei, Taiwan; 5Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; 6Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan; 7Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 8Student Counseling Center, National Defense Medical Center, Taipei, Taiwan; 9Department of Psychiatry, Tri-Service General Hospital, Song-Shan Branch, National Defense Medical Center, Taipei, Taiwan; 10Department of Public Health and Center of Biostatistics, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan*These authors contributed equally to this workCorrespondence: Pei-Kwei TsayDepartment of Public Health and Center of Biostatistics, College of Medicine, Chang Gung University, Tao-Yuan 333, TaiwanTel +886-3-211-8800 # 5068 (PKT)Email Tsay@mail.cgu.edu.twNian-Sheng TzengJoint Program for Geriatric Psychiatry and Psychosomatic Medicine, Department of Psychiatry, School of Medicine, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Cheng-Gung Road, Nei-Hu District, Taipei, Taiwan, Republic of ChinaTel +886-2-87923311, Ext 17484Fax +886-2-87927221Email pierrens@mail.ndmctsgh.edu.twBackground: Herbal medicine containing aristolochic acids (HMCAA) was used for inflammatory and infectious diseases. This study aimed to investigate the association between the usage of HMCAA and the risk of dementia.Methods: A total of 199 new users of HMCAA were enrolled, along with 597 controls without the usage of HMCAA, at a ratio of 1:3 – matched by age, sex, and comorbidity, between 2000 and 2003 – from the National Health Research Institutes Database (NHRID) of Taiwan, which contains two million randomly sampled subjects, in this cohort study. We used Fine and Gray’s survival analysis (competing with mortality) to compare the risk of developing dementia during a 15-year follow-up period (2000– 2015).Results: In general, HMCAA was not significantly associated with dementia (adjusted subdistribution hazard ratio [SHR] = 0.861, 95% confidence interval [CI] = 0.484– 1.532, p = 0.611) for the HMCAA-cohort, although differential risk was observed among the groups at risk. The patients with usage of HMCAA aged ≧ 85 years were associated with a higher risk in dementia (adjusted SHR: 6.243, 95% CI=1.258– 21.084, p = 0.001), in comparison to those aged 50– 54 years. Furthermore, the patients with usage of HMCAA that had cerebrovascular accidents were associated with an increased risk of dementia.Conclusion: The usage of HMCAA was associated with the risk of developing dementia in the patients aged ≧ 85 years.Keywords: herbal medicine containing aristolochic acids, traditional Chinese herbal medicines, dementia

Chuan-Chi Yang,1,2 Wu-Chien Chien,3–5 Chi-Hsiang Chung,3,4,6 Yia-Ping Liu,2,7–9 Chin-Bin Yeh,2 Kuang-Huei Chen,1 Szu-Nian Yang,1,9,10 Hsin-An Chang,2,11 Yu-Chen Kao,2,12 Wan-Chun Lu,2 Nian-Sheng Tzeng2,11 1Department of Psychiatry, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan, ROC; 2Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC; 3Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC; 4School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC; 5Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC; 6Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan, ROC; 7Department of Psychiatry, Chen-Hsin General Hospital, Taipei, Taiwan, ROC; 8Institute of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, ROC; 9Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC; 10Headquarters, Tri-Service General Hospital, Beitou Branch, National Defense Medical Center, Taipei, Taiwan, ROC; 11Student Counseling Center, National Defense Medical Center, Taipei, Taiwan, ROC; 12Department of Psychiatry, Tri-Service General Hospital, Song-Shan Branch, National Defense Medical Center, Taipei, Taiwan, ROCCorrespondence: Nian-Sheng TzengDepartment of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, 325, Chung-Gung Road, Sec 2, Nei-Hu District 114, Taipei, Taiwan, ROCTel +886-2-87927299 ext 13674Email pierrens@mail.ndmctsgh.edu.twBackground: The associations between the human immunodeficiency virus (HIV) and dementias are as yet to be studied in Taiwan. The aim of this study is to clarify as to whether HIV infections are associated with the risk of dementia.Methods: A total of 1,261 HIV-infected patients and 3,783 controls (1:3) matched for age and sex were selected between January 1 and December 31, 2000 from Taiwan’s National Health Insurance Research Database (NHIRD). Fine and Gray’s survival analysis (competing with mortality) analyzed the risk of dementias during the 15-year follow up. The association between the highly active antiretroviral therapy (HAART) and dementia was analyzed by stratifying the HAART status among the HIV subjects.Results: During the follow-up period, 25 in the HIV group (N= 1,261) and 227 in the control group (N= 3,783) developed dementia (656.25 vs 913.15 per 100,000 person-years). Fine and Gray’s survival analysis revealed that the HIV patients were not associated with an increased risk of dementia, with the adjusted hazard ratio (HR) as 0.852 (95% confidence interval [CI]: 0.189–2.886, p=0.415) after adjusting for sex, age, comorbidities, geographical region, and the urbanization level of residence. There was no significant difference between the two groups of HIV-infected patients with or without HAART in the risk of dementia.Conclusion: This study found that HIV infections, either with or without HAART, were not associated with increased diagnoses of neurodegenerative dementias in patients older than 50 in Taiwan.Keywords: human immunodeficiency virus, highly active antiretroviral therapy, dementia, National Health Insurance Research Database, cohort study

Yi-Chien Hsu,1,2 Yu-Ching Chou,3 Hsin-An Chang,1,2,4 Yu-Chen Kao,1,2,5 San-Yuan Huang,1,2 Nian-Sheng Tzeng1,2,4 1Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan; 2School of Medicine, 3School of Public Health, 4Student Counseling Center, National Defense Medical Center, Taipei, Taiwan; 5Department of Psychiatry, Tri-Service General Hospital, Song-Shan Branch, Taipei, Taiwan Objectives: Refractory major depressive disorder (MDD) is a serious problem leading to a heavy economic burden. Antipsychotic augmentation treatment with aripiprazole and quetiapine is approved for MDD patients and can achieve a high remission rate. This study aimed to examine how psychiatrists in Taiwan choose medications and how that choice is influenced by health insurance payments and administrative policy.Design: Descriptive study.Outcome measures: Eight questions about the choice of treatment strategy and atypical antipsychotics, and the reason to choose aripiprazole.Intervention: We designed an augmentation strategy questionnaire for psychiatrists whose patients had a poor response to antidepressants, and handed it out during the annual meeting of the Taiwanese Society of Psychiatry in October 2012. It included eight questions addressing the choice of treatment strategy and atypical antipsychotics, and the reason whether or not to choose aripiprazole as the augmentation antipsychotic.Results: Choosing antipsychotic augmentation therapy or switching to other antidepressant strategies for MDD patients with an inadequate response to antidepressants was common with a similar probability (76.1% vs 76.4%). The most frequently used antipsychotics were aripiprazole and quetiapine, however a substantial number of psychiatrists chose olanzapine, risperidone, and sulpiride. The major reason for not choosing aripiprazole was cost (52.1%), followed by insurance official policy audit and deletion in the claims review system (30.1%).Conclusion: The prescribing behavior of Taiwanese psychiatrists for augmentation antipsychotics is affected by health insurance policy. Keywords: major depressive disorder, aripiprazole, psychiatrists, prescribing behavior, anti­psychotic augmentation, National Health Insurance program

Background: Everolimus was the first orally targeted therapy for certain cancers. It was introduced before CDK4/6 inhibitors and is widely used to treat advanced hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. This study presents comprehensive findings including updated data and long-term survival analyses focusing on patients with HR+/HER2- metastatic breast cancer who received everolimus-based treatment. The objectives were to assess the impact of everolimus on overall survival (OS) and progression-free survival (PFS) by treatment line, and to evaluate its role in therapeutic strategies in a real-world setting., Methods: We included 299 women aged over 20 years with histologically confirmed HR+/HER2- breast cancer who received everolimus-based treatment from multiple medical centers in Taiwan. Survival curves were generated using the Kaplan-Meier method, with the log-rank test for comparisons. Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events version 5.0., Results: The median PFS was 5.6 months, and the median OS was 60.1 months. Patients receiving everolimus treatment in three or more lines and those who underwent chemotherapy prior to everolimus-based treatment had a significantly shorter PFS but longer OS. Patients with liver and central nervous system metastases had significantly shorter PFS and OS. The disease control rate was 51.5%, and the overall response rate was 8.0%., Conclusion: These findings support current guidelines and advocate for the inclusion of everolimus in treatment plans for patients with metastatic HR+/HER2- breast cancer, particularly in late-line treatment, with careful consideration of the benefit-risk profile for each patient., Competing Interests: Conflicts of interest: Dr. Chun-Yu Liu and Dr. Ling-Ming Tseng, editorial board member at the Journal of the Chinese Medical Association, had no role in the peer review process or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Importance: Viloxazine is a novel nonstimulant medication approved for the treatment of attention-deficit/hyperactivity disorder (ADHD)., Objectives: To investigate the whether viloxazine is associated with effective and acceptable outcomes when treating children and adolescents with ADHD and to evaluate these outcomes' associations with viloxazine doses and duration of treatment., Data Sources: The MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycINFO, and ClinicalTrial.gov databases were searched from database inception to June 23, 2024., Study Selection: Two reviewers independently screened for double-blind, fixed-dose randomized clinical trials (RCTs) that compared viloxazine with placebo for pediatric patients with ADHD., Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Data extraction was completed independently by 2 authors and cross-checked for errors. Random-effects pairwise and dose-response meta-analyses were conducted., Main Outcomes and Measures: The primary outcome was the improvement of ADHD symptoms (measured by ADHD Rating Scale-5), and the secondary outcomes were all-cause discontinuation, dropout due to adverse effects, and serious adverse effects., Results: A total of 5 dose-response RCTs were included, with 1560 participants (1011 [64.8%] male; mean [SD] age, 10.6 [6.7] years). Viloxazine was associated with better outcomes in ADHD treatment compared with placebo (mean difference, 5.47 points; 95% CI, 4.03-6.91 points). The dose-response curve was bell-shaped, suggesting that doses greater than 400 mg or greater than 7 mg/kg might not be associated with more efficacy. The temporal trends analysis showed ascent curves tapering off at approximately weeks 4 to 6. The curve for 100 mg/d declined more rapidly, while the curves for 200 mg/d and 400 mg/d declined more gradually. The overall discontinuation rate due to adverse effects was 4.15% in the viloxazine group (45 of 1084), while viloxazine compared with placebo was associated with 2.48-fold higher risk of discontinuation due to adverse effects (risk ratio, 2.48; 95% CI, 1.26-4.88)., Conclusions and Relevance: In this meta-analysis, viloxazine was associated with better efficacy in treating children and adolescents with ADHD than placebo. A moderate dose (200-400 mg or 6-8 mg/kg) may provide optimal treatment outcomes. Future studies are warranted to assess the long-term effect of viloxazine. Viloxazine was relatively well tolerated for children and adolescents with ADHD.

Traumatic brain injury (TBI) presents substantial clinical challenges, as existing treatments are unable to reverse damage or effectively promote brain tissue regeneration. Although implantable biomaterials have been proposed to support tissue repair by mitigating the adverse microenvironment in injured brains, many fail to replicate the complex composition and architecture of the native extracellular matrix (ECM), resulting in only limited therapeutic outcomes. This study introduces an innovative approach by developing a mesenchymal stem cell (MSC) spheroid-derived three-dimensional (3D) decellularized ECM (dECM) that is enriched with the MSC-derived matrisome and secretome, offering a promising solution for TBI treatment and brain tissue regeneration. Proteomic and cytokine array analyses revealed that 3D dECM retained a diverse array of MSC spheroid-derived matrisome proteins and secretome components, which are crucial for replicating the complexity of native ECM and the therapeutic capabilities of MSCs. These molecules were found to underlie the observed effects of 3D dECM on immunomodulation, proneuritogenesis, and proangiogenesis in our in vitro functional assays. Implantation of 3D dECM into TBI model mice effectively mitigated postinjury tissue damage and promoted brain repair, as evidenced by a reduced brain lesion volume, decreased cell apoptosis, alleviated neuroinflammation, reduced glial scar formation, and increased of neuroblast recruitment to the lesion site. These outcomes culminated in improved motor function recovery in animals, highlighting the multifaceted therapeutic potential of 3D dECM for TBI. In summary, our study elucidates the transformative potential of MSC spheroid-derived bioactive 3D dECM as an implantable biomaterial for effectively mitigating post-TBI neurological damage, paving the way for its broader therapeutic application., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Chieh-Cheng Huang reports financial support was provided by National Science and Technology Council. Chieh-Cheng Huang reports financial support was provided by National Tsing Hua University. Chieh-Cheng Huang reports financial support was provided by National Health Research Institutes. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Different study designs of psychedelic trials may impact the blinding and expectance, leading to biased treatment effects. This study aimed to examine the association between antidepressant efficacy and study designs in psychedelic trials. Six databases were systematically searched. Eligible trials were required to investigate the efficacy of psychedelics (psilocybin, lysergic acid diethylamide [LSD], 3,4-Methylenedioxymethamphetamine [MDMA], and ayahuasca) in adult patients with depressive symptoms. We only considered oral psychedelic-assisted therapy without concomitant use of antidepressants. The primary outcome was the change in depressive symptoms. There were five study designs of psychedelic trials, including non-active-drug-as-placebo, active-drug-as-placebo, waitlist-as-control, fixed-order, and pre-post designs. In non-active-drug -as-placebo design, psilocybin (k = 4, Hedges' g [g] = 0.87, 95 % confidence intervals[CIs] = 0.58 to 1.16) and MDMA (k = 2, g = 0.65, 95%CIs = 0.26 to 1.05) were associated with large and medium effect sizes, respectively. In active-drug-as-placebo design, both psilocybin (k = 2, g = 0.71, 95%CIs = -0.01 to 1.43) and MDMA (k = 3, g = 0.53, 95%CIs = -0.23 to 1.28) were not statistically significant. In pre-post single-arm (k = 3, g = 2.51, 95%CIs = 1.00 to 4.02) and waitlist-as-control (k = 1, g = 2.88, 95%CIs = 1.75 to 4.00) designs, psilocybin showed a large effect size of antidepressant effect. Ayahuasca also showed a large effect size in both pre-post (k = 2, g = 1.88, 95%CIs = 1.18 to 2.57) and non-active-drug-as-placebo (k = 1, g = 1.60, 95%CIs = 0.84 to 2.36) designs. LSD was associated with a significant antidepressant effect only in non-active-drug-as-placebo design (k = 1, g = 1.49, 95%CIs = 0.80 to 2.17) but not in active-drug-as-placebo design (k = 1, g = 0.44, 95%CIs = -0.90 to 1.78). The antidepressant effects of psychedelics may be overestimated in studies with pre-post single-arm, non-active-drugs-as placebo, and waitlist-control designs. Restricted sample size, difficulty with establishing blinding for participants, and over expectancy limit the estimation of the antidepressant effect of psychedelic-assisted therapy., Competing Interests: Declaration of competing interest All authors have no financial relationships relevant to this article to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Self-management programs can help patients with rheumatoid arthritis develop strategies to address their disease-related problems. However, accessibility to traditional self-management programs is often limited., Purpose: This study was developed to assess the effectiveness, feasibility, and acceptability of a smartphone-delivered self-management program application (app) for adults with rheumatoid arthritis., Methods: A two-arm (intervention vs. control) randomized controlled trial was used. Adult patients with rheumatoid arthritis were recruited from the rheumatology departments of a medical center. Study enrollment capabilities were limited by current pandemic restrictions. The patients who met the inclusion criteria and agreed to participate (N = 46) were enrolled as participants and randomly assigned either to the intervention group (n = 25), which received instructions on the use of a smartphone app designed to facilitate the self-management of rheumatoid arthritis, or to the control group (n = 21), which received instructions on related self-management only. The outcome variables were assessed at baseline and at 8 and 12 weeks. Differences in between-group outcomes over time were analyzed using generalized estimating equations. Feasibility and acceptability were also evaluated. Data were collected between August 1, 2020, and July 31, 2022., Results: At baseline, no differences were detected between the two groups in terms of the demographic and disease characteristics of concern. Outcome measures for the intervention group improved significantly more than the control group for self-efficacy of pain at 8 weeks (B = 6.39, p < .05) and for both of self-efficacy of pain and self-management behavior at 12 weeks (B = 9.16, p < .05, and B = 4.25, p < .001, respectively). Factors related to app ease of use included limiting pop-ups and windows and having no time restrictions. Most of the participants reported the app as acceptable and easy to use, although challenges relating to using technology limited the usability of the app for some., Conclusions/implications for Practice: The smartphone app was shown to improve self-efficacy of pain and self-management behaviors. However, an accurate assessment of the effectiveness of the app and generalizability of the findings is limited by the smaller-than-desired sample size due to the COVID-19 pandemic and technological challenges. A greater understanding of how to overcome technological challenges is needed to optimize the delivery of self-management programs via smartphone-based apps. Studies reevaluating this app on a larger sample size should be conducted., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

Introduction: In-person cognitive behavioral therapy (CBT) can reduce self-reported anxiety in older adults. However, studies are limited for remote CBT. We assessed the effectiveness of remote CBT in mitigating self-reported anxiety in older adults., Methods: We conducted a systematic review and meta-analysis based on a literature search of PubMed, Embase, PsycInfo, and Cochrane databases up to March 31, 2021, for randomized controlled clinical trials comparing the effectiveness of remote CBT versus non-CBT controls on mitigating self-reported anxiety in older adults. We calculated within-group pre-to-post-treatment standardized mean difference using Cohen's d , obtained the difference between a remote CBT group and a non-CBT control group as our effect size for cross-study comparison, and conducted a random-effects meta-analysis. Changes in scores on self-reported anxiety symptoms (Generalized Anxiety Disorder-7 item Scale, Penn State Worry Questionnaire, or Penn State Worry Questionnaire - Abbreviated), and self-reported depressive symptoms (Patient Health Questionnaire-9 item Scale or Beck Depression Inventory) were primary and secondary outcomes, respectively., Results: Six eligible studies, containing 633 participants with a pooled mean age of 66.6 years, were included in the systematic review and meta-analysis. There was a significant mitigating effect of intervention on self-reported anxiety, favoring remote CBT over non-CBT controls (between-group effect size: -0.63; 95% CI: -0.99 to -0.28). We also found a significant mitigating effect of intervention on self-reported depressive symptoms (between-group effect size: -0.74; 95% CI: -1.24 to -0.25)., Discussion: Remote CBT is more effective in reducing self-reported anxiety and depressive symptoms than non-CBT control in older adults., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: Schizophrenia, a debilitating mental disorder, is characterized by persistent negative symptoms such as avolition and anhedonia. Currently, there are no effective treatments available for these symptoms. Thus, our study aims to assess the efficacy of online high-definition transcranial direct current stimulation (online HD-tDCS) in addressing the negative symptoms of schizophrenia, utilizing a double-blind, randomized, sham-controlled trial design., Methods: Fifty-nine patients with schizophrenia were randomized to receive either active HD-tDCS or sham stimulation, targeting the left dorsolateral prefrontal cortex. Outcomes were measured by changes in the Positive and Negative Syndrome Scale Factor Score for Negative Symptom (PANSS-FSNS). Exact low-resolution electromagnetic tomography was used to assess the functional connectivity., Results: All 59 participants, including 50.84% females with an average age of 43.36 years, completed the trial. In the intention-to-treat analysis, patients receiving active HD-tDCS showed greater improvement in PANSS-FSNS scores compared to those receiving the sham procedure. The differences were 2.34 (95% confidence interval [CI], 1.28-3.40), 4.28 (95% CI, 2.93-5.62), and 4.91 (95% CI, 3.29-6.52) after the intervention, as well as at 1-week and 1-month follow-ups, respectively. A tingling sensation on the scalp was more common in the active group (63.3%) compared to the sham group (10.3%). Additionally, HD-tDCS was associated with a decrease in delta-band connectivity within the default mode network., Conclusions: High-definition transcranial direct current stimulation was effective and safe in ameliorating negative symptoms in patients with schizophrenia when combined with online functional targeting., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences © 2024 Japanese Society of Psychiatry and Neurology.)

Objective: To evaluate the comparative effectiveness and acceptability of oral monotherapy using psychedelics and escitalopram in patients with depressive symptoms, considering the potential for overestimated effectiveness due to unsuccessful blinding., Design: Systematic review and Bayesian network meta-analysis., Data Sources: Medline, Cochrane Central Register of Controlled Trials, Embase, PsycINFO, ClinicalTrial.gov, and World Health Organization's International Clinical Trials Registry Platform from database inception to 12 October 2023., Eligibility Criteria for Selecting Studies: Randomised controlled trials on psychedelics or escitalopram in adults with depressive symptoms. Eligible randomised controlled trials of psychedelics (3,4-methylenedioxymethamphetamine (known as MDMA), lysergic acid diethylamide (known as LSD), psilocybin, or ayahuasca) required oral monotherapy with no concomitant use of antidepressants., Data Extraction and Synthesis: The primary outcome was change in depression, measured by the 17-item Hamilton depression rating scale. The secondary outcomes were all cause discontinuation and severe adverse events. Severe adverse events were those resulting in any of a list of negative health outcomes including, death, admission to hospital, significant or persistent incapacity, congenital birth defect or abnormality, and suicide attempt. Data were pooled using a random effects model within a Bayesian framework. To avoid estimation bias, placebo responses were distinguished between psychedelic and antidepressant trials., Results: Placebo response in psychedelic trials was lower than that in antidepression trials of escitalopram (mean difference -3.90 (95% credible interval -7.10 to -0.96)). Although most psychedelics were better than placebo in psychedelic trials, only high dose psilocybin was better than placebo in antidepression trials of escitalopram (mean difference 6.45 (3.19 to 9.41)). However, the effect size (standardised mean difference) of high dose psilocybin decreased from large (0.88) to small (0.31) when the reference arm changed from placebo response in the psychedelic trials to antidepressant trials. The relative effect of high dose psilocybin was larger than escitalopram at 10 mg (4.66 (95% credible interval 1.36 to 7.74)) and 20 mg (4.69 (1.64 to 7.54)). None of the interventions was associated with higher all cause discontinuation or severe adverse events than the placebo., Conclusions: Of the available psychedelic treatments for depressive symptoms, patients treated with high dose psilocybin showed better responses than those treated with placebo in the antidepressant trials, but the effect size was small., Systematic Review Registration: PROSPERO, CRD42023469014., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from National Science and Technology Council for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Psilocybin-assisted therapy has shown promising efficacy on clinical depressive symptoms. However, diverse psychological support or psychotherapy was performed with psilocybin treatment. This study aimed to explore the association of psychological protocols with the efficacy of psilocybin-assisted therapy for depressive symptoms., Method: Five major databases were systemic searched for clinical trials addressing psilocybin-assisted therapy for patients with clinical depressive symptoms. A Bayesian random-effects meta-analysis and meta-regression were performed. The effect size was mean difference (with 95% credible interval) measured by 17-Item Hamilton Depression Rating Scale., Results: There were 10 eligible studies including 515 adult patients with clinically diagnosed depression. The psychological protocols could be categorized into four types: (i) manualized directive psychotherapy(k=1); (ii) manualized nondirective psychological support(k=3), (iii) non-manualized nondirective psychological support(k=5); and (iv) non-manualized supportive psychotherapy(k=1). The pooled standard mean difference of psilocybin-assisted therapy was 10.08 (5.03-14.70)., Conclusion: Compared with manualized nondirective psychological support, the other three psychological approaches did not differ significantly. The improvement of depressive symptoms was not associated with the psychological protocols in adult patients receiving psilocybin-assisted therapy., Systemic Review Registration: Open Science Framework: identifier (osf.io/3YUDV)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Cheng, Kao, Tseng, Hsu, Yu, Yang, Thompson, Hsu and Liang.)

The depression response trajectory after a course of repetitive transcranial magnetic stimulation(rTMS) remains understudied. We searched for blinded randomized controlled trials(RCTs) that examined conventional rTMS over left dorsolateral prefrontal cortex(DLPFC) for major depressive episodes(MDE). The effect size was calculated as the difference in depression improvement, between active and sham rTMS. We conducted a random-effects dose-response meta-analysis to model the response trajectory from the beginning of rTMS to the post-treatment follow-up phase. The area under curve (AUC) of the first 8-week response trajectory was calculated to compare antidepressant efficacy between different rTMS protocols. We included 40 RCTs(n = 2012). The best-fitting trajectory model exhibited a logarithmic curve(X 2 =17.7, P < 0.001), showing a gradual ascent with tapering off around the 3-4th week mark and maintaining until week 16. The maximum effect size was 6.1(95 %CI: 1.25-10.96) at week 16. The subgroup analyses showed distinct trajectories across different rTMS protocols. Besides, the comparisons of AUC showed that conventional rTMS protocols with more pulse/session group or more total pulses were associated with greater efficacy than those with fewer pulse/session or fewer total pulses, respectively. A course of conventional left DLPFC rTMS could lead to both acute antidepressant effects and sustained after-effects, which were modeled by different rTMS protocols in MDE., Competing Interests: Declaration of competing interest All authors declared no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

DUSP22 rearrangements are genetic alterations observed in a subset of systemic anaplastic large cell lymphoma (S-ALCL), primary cutaneous anaplastic large cell lymphoma (C-ALCL), and lymphomatoid papulosis (LyP). Previous investigations have shown that the LEF1+/TIA1- immunoprofile and MSC E116K mutations are highly associated with DUSP22 rearrangement in ALCL. However, the existing literature primarily focuses on S-ALCL. Our understanding of the LEF1/TIA1 immunoprofile and MSC mutation status in C-ALCL/LyP is still limited. In this study, we aimed to assess LEF1/TIA1 expression and MSC mutations in a cohort of 23 C-ALCL/LyP cases, along with a control group of histological mimickers. DUSP22 rearrangements were detected by fluorescence in situ hybridization in eight cases (6/10 C-ALCL, 2/13 LyP). We found LEF1 expression in five out of eight (63%) DUSP22-rearranged cases (3/6 C-ALCL, 2/2 LyP), and none of the 15 cases lacking DUSP22 rearrangements. Furthermore, we also found frequent LEF1 expression in adult T-cell leukemia/lymphoma (ATLL; 10 of 11, 91%) within the control group. TIA1 expression was consistently negative in all DUSP22-rearranged C-ALCL/LyP and ATLL cases tested. MCS E116K mutation was identified in one of five DUSP22-rearranged C-ALCL cases. RNA sequencing of a DUSP22-rearranged C-ALCL revealed a novel DUSP22::SNHG fusion coexisting with a CD58::WNT2B fusion. In conclusion, our findings demonstrated a lower rate of LEF1 expression in DUSP22-rearranged C-ALCL/LyP compared to previous reports that predominantly focused on S-ALCL. Moreover, we observed that the majority of ATLL cases also expressed LEF1, suggesting that the LEF1+/TIA1- immunoprofile does not differentiate DUSP22-rearranged C-ALCL/LyP from ATLL., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Quantum mechanics/molecular mechanics (QM/MM) simulations offer an efficient way to model reactions occurring in complex environments. This study introduces a specialized set of charge and Lennard-Jones parameters tailored for electrostatically embedded QM/MM calculations, aiming to accurately model both adsorption processes and catalytic reactions in zirconium-based metal-organic frameworks (Zr-MOFs). To validate our approach, we compare adsorption energies derived from QM/MM simulations against experimental results and Monte Carlo simulation outcomes. The developed parameters showcase the ability of QM/MM simulations to represent long-range electrostatic and van der Waals interactions faithfully. This capability is evidenced by the prediction of adsorption energies with a low root mean square error of 1.1 kcal mol -1 across a wide range of adsorbates. The practical applicability of our QM/MM model is further illustrated through the study of glucose isomerization and epimerization reactions catalyzed by two structurally distinct Zr-MOF catalysts, UiO-66 and MOF-808. Our QM/MM calculations closely align with experimental activation energies. Importantly, the parameter set introduced here is compatible with the widely used universal force field (UFF). Moreover, we thoroughly explore how the size of the cluster model and the choice of density functional theory (DFT) methodologies influence the simulation outcomes. This work provides an accurate and computationally efficient framework for modeling complex catalytic reactions within Zr-MOFs, contributing valuable insights into their mechanistic behaviors and facilitating further advancements in this dynamic area of research.

A vertical-type InGaN light-emitting diode with a resonant cavity was demonstrated with a 9 μm aperture size and a short cavity formed by hybrid distributed Bragg reflectors (DBRs). The approach involved designing epitaxial structures and utilizing an electrochemical etching process to convert heavily doped n-type gallium nitride (n + -GaN) layers into porous GaN layers as a porous-GaN DBR structure. Thirteen pairs of the conductive porous-GaN:Si/GaN:Si DBR structure provided a vertical current path in a vertical-type light-emitting diodes (LED) structure. The LED epitaxial layers were separated from sapphire for membrane-type LED structures through a laser lift-off process. During the free-standing membrane fabrication process, the dielectric DBR deposited on ITO/p-GaN:Mg layers was inverted from top to bottom, thereby establishing the concept of higher reflectivity for the bottom DBR compared to the porous-GaN DBR. The physical cavity length was reduced from about 2.3 μm for the LED membrane to 0.74 μm for the membrane-type LED with the embedded porous-GaN DBR structure. The divergent angles and line width of EL emission light were reduced from 124°/31.7 nm to 44°/3.3 nm due to the resonant cavity effect. The membrane-type LED structures with hybrid DBRs consisted of small divergent angles, narrow line width, and vertical current injection properties that have potential for directional emission light sources and vertical-cavity surface-emitting diode laser applications., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

This study aimed to evaluate the association of the six parameters, namely stimulation intensity, stimulation frequency, pulses per session, treatment duration, number of sessions, and total number of pulses with the efficacy of conventional transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex for patients with treatment-resistant depression (TRD). A random-effects dose-response meta-analysis of blinded randomized controlled trials (RCTs) involving 2391 participants were conducted to examine the dose-effect relationship of six stimulation parameters. Any of the six parameters significantly individually predicted proportion of variance in efficacy: pulses per session (R²=52.7%), treatment duration (R²=51.2%), total sessions (R²=50.9%), frequency (R²=49.6%), total pulses (R²=49.5%), and intensity (R²= 40.4%). Besides, we identified frequency as a potential parameter interacting with the other five parameters, resulting in a significant increase in variance(ΔR 2 ) ranging from 5.0% to 16.7%. Finally, we found that RCTs using frequency > 10 Hz compared to those of 10 Hz showed better dose-effect relationships. We conclude that the six stimulation parameters significantly predict the dose-effect relationship of conventional rTMS on TRD. Besides, higher stimulation frequency, higher stimulation intensity, and adequate number of pulses were associated with treatment efficacy., Competing Interests: Declaration of Competing Interest All authors declared no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The SARS-CoV-2 virus has been a global public health threat since December 2019. This study aims to investigate the neurological characteristics and risk factors of coronavirus disease 2019 (COVID-19) in Taiwanese children, using data from a collaborative registry., Methods: A retrospective, cross-sectional, multi-center study was done using an online network of pediatric neurological COVID-19 cohort collaborative registry., Results: A total of 11160 COVID-19-associated emergency department (ED) visits and 1079 hospitalizations were analyzed. Seizures were the most common specific neurological symptom, while encephalitis and acute disseminated encephalomyelitis (ADEM) was the most prevalent severe involvement. In ED patients with neurological manifestations, severe neurological diagnosis was associated with visual hallucination, seizure with/without fever, behavior change, decreased GCS, myoclonic jerk, decreased activity/fatigue, and lethargy. In hospitalized patients with neurological manifestations, severe neurological diagnosis was associated with behavior change, visual hallucination, decreased GCS, seizure with/without fever, myoclonic jerk, fatigue, and hypoglycemia at admission. Encephalitis/ADEM was the only risk factor for poor neurological outcomes at discharge in hospitalized patients., Conclusion: Neurological complications are common in pediatric COVID-19. Visual hallucination, seizure, behavior change, myoclonic jerk, decreased GCS, and hypoglycemia at admission are the most important warning signs of severe neurological involvement such as encephalitis/ADEM., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Aim: Large language models (LLMs) have been suggested to play a role in medical education and medical practice. However, the potential of their application in the psychiatric domain has not been well-studied., Method: In the first step, we compared the performance of ChatGPT GPT-4, Bard, and Llama-2 in the 2022 Taiwan Psychiatric Licensing Examination conducted in traditional Mandarin. In the second step, we compared the scores of these three LLMs with those of 24 experienced psychiatrists in 10 advanced clinical scenario questions designed for psychiatric differential diagnosis., Result: Only GPT-4 passed the 2022 Taiwan Psychiatric Licensing Examination (scoring 69 and ≥ 60 being considered a passing grade), while Bard scored 36 and Llama-2 scored 25. GPT-4 outperformed Bard and Llama-2, especially in the areas of 'Pathophysiology & Epidemiology' (χ 2  = 22.4, P < 0.001) and 'Psychopharmacology & Other therapies' (χ 2  = 15.8, P < 0.001). In the differential diagnosis, the mean score of the 24 experienced psychiatrists (mean 6.1, standard deviation 1.9) was higher than that of GPT-4 (5), Bard (3), and Llama-2 (1)., Conclusion: Compared to Bard and Llama-2, GPT-4 demonstrated superior abilities in identifying psychiatric symptoms and making clinical judgments. Besides, GPT-4's ability for differential diagnosis closely approached that of the experienced psychiatrists. GPT-4 revealed a promising potential as a valuable tool in psychiatric practice among the three LLMs., (© 2024 The Authors. Psychiatry and Clinical Neurosciences © 2024 Japanese Society of Psychiatry and Neurology.)

High channel current of the high electron mobility transistors (HEMTs) and high relative responsivity of the photodetectors (PDs) were demonstrated in the AlGaN/AlN/GaN channel-stacking epitaxial structures. The interference properties of the X-ray curves indicated high-quality interfaces of the conductive channels. The AlGaN/AlN/GaN interfaces were observed clearly in the transmission electron microscope micrograph. The saturation I ds currents of the HEMT structures were increased by adding a number of channels. The conductive properties of the channel-stacking structures corresponded to the peaks of the transconductance ( g m ) spectra in the HEMT structures. The depletion-mode one- and two-channel HEMT structures can be operated at the cutoff region by increasing the reverse V gs bias voltages. Higher I ds current in the active state and lower current in the cutoff state were observed in the two-channel HEMT structure compared with one- and three-channel HEMT structures. For the channel-stacking metal-semiconductor-metal photodetector structures, the peak responsivity was observed at almost 300 nm incident monochromic light, which was increased by adding a number of channel layers. The channel current of the HEMT devices and the photocurrent in the PD devices were increased by adding a number of two-dimensional electron gas (2DEG) channels. By using a flat gate metal layer, the two-channel AlGaN/AlN/GaN HEMT structures exhibited a high I ds current, a low cutoff current, and a high peak g m value and have the potential for GaN-based power devices, fast portable chargers, and ultraviolet PD applications., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Salvage treatment for refractory metastatic colorectal cancer (mCRC) has yet to be identified. We aimed to evaluate the efficacy of a salvage lenvatinib-based regimen for refractory mCRC. In total, 371 patients were categorized into lenvatinib-based and non-lenvatinib-based groups. In the lenvatinib-based group, patients who received lenvatinib at a dosage of 10 mg/day were categorized into lenvatinib/chemotherapy and lenvatinib/immunotherapy subgroups. We reported overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. OS1 was used to measure the time from disease progression after TAS-102 and regorafenib treatment to death, while OS2 was used to measure the time from TAS-102 or regorafenib treatment to death. Propensity score matching analysis was employed to compare the characteristics between the lenvatinib-based and non-lenvatinib-based groups. Next-generation sequencing (NGS) information was analyzed using R software. The lenvatinib-based group exhibited longer OS than did the non-lenvatinib-based group (OS1, 11.4 vs. 3.7 months; OS2, 27.2 vs. 8.2 months). The disease control rate (DCR) and objective response rate (ORR) of the lenvatinib-based regimens were 69.4% and 6.1%, respectively. Lenvatinib/chemotherapy and lenvatinib/immunotherapy had similar PFS, OS, DCR, and ORR. The adverse effects were manageable. After propensity score matching, the lenvatinib-based group continued to exhibit significantly longer OS1 and OS2 than did the non-lenvatinib-based group. NGS analysis revealed that GNAS and KRAS alterations were associated with a worse treatment response and prolonged survival, respectively. In conclusion, a moderate-dose salvage lenvatinib-based regimen demonstrated promising clinical activity and tolerability in treating refractory mCRC., Competing Interests: None., (AJCR Copyright © 2024.)

Aims: Risk stratification of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), diagnosed using breast biopsy, has great clinical significance. Clinical trials are currently exploring the possibility of active surveillance for low-risk lesions, whereas axillary lymph node staging may be considered during surgical planning for high-risk lesions. We aimed to develop a machine-learning algorithm based on whole-slide images of breast biopsy specimens and clinical information to predict the risk of upstaging to invasive breast cancer after wide excision., Methods and Results: Patients diagnosed with ADH/DCIS on breast biopsy were included in this study, comprising 592 (740 slides) and 141 (198 slides) patients in the development and independent testing cohorts, respectively. Histological grading of the lesions was independently evaluated by two pathologists. Clinical information, including biopsy method, lesion size, and Breast Imaging Reporting and Data System (BI-RADS) classification of ultrasound and mammograms, were collected. Deep DCIS consisted of three deep neural networks to evaluate nuclear grade, necrosis, and stromal reactivity. Deep DCIS output comprised five parameters: total patches, lesion extent, Deep Grade, Deep Necrosis, and Deep Stroma. Deep DCIS highly correlated with the pathologists' evaluations of both slide- and patient-level labels. All five parameters of Deep DCIS were significantly associated with upstaging to invasive carcinoma in subsequent wide excisional specimens. Using multivariate logistic regression, Deep DCIS predicted upstaging to invasive carcinoma with an area under the curve (AUC) of 0.81, outperforming pathologists' evaluation (AUC, 0.71 and 0.69). After including clinical and hormone receptor status information, performance further improved (AUC, 0.87). This combined model retained its predictive power in two subgroup analyses: the first subgroup included unequivocal DCIS (excluding cases of ADH and DCIS suspicious for microinvasion) (AUC, 0.83), while the second excluded cases of high-grade DCIS (AUC, 0.81). The model was validated in an independent testing cohort (AUC, 0.81)., Conclusion: This study demonstrated that deep-learning models can refine histological evaluation of ADH and DCIS on breast biopsies, which may help guide future treatment planning., (© 2024 John Wiley & Sons Ltd.)

The primary goal of this study is to develop a wearable system for providing CNC machine operators with visual and tactile perception of triaxial cutting forces, thereby assisting operators in industrial environments to enhance work efficiency and prevent mechanical failures. To achieve this goal, we successfully integrated a virtual machining tool simulator with the remote-control wearable system (RCWS). Using the 'King Path' milling parameters, we employed the simulation software developed by the AIM-HI team to calculate static and dynamic cutting forces, converting this data into vibrational commands for the RCWS to generate corresponding tactile feedback. Furthermore, we conducted extensive experiments, testing various data conversion methods, including three sampling techniques and two data compression strategies, aiming to provide accurate tactile feedback related to cutting forces under different operating conditions., (© 2024. The Author(s).)

Mangroves are transition areas connecting land, freshwater, and the ocean, where a great amount of organic carbon accumulates in the soil, forming a considerable carbon sink. However, the soil might also be a source of greenhouse gas (GHG) emissions. This study hypothesized that measuring GHG emissions solely during low tides can represent diurnal GHG emissions in mangroves. Methane (CH 4 ) and carbon dioxide (CO 2 ) emissions were quantified during tidal cycles using an ultraportable gas analyzer in Kandelia obovata (without pneumatophores) and Avicennia marina (with pneumatophores) mangroves in summer and fall. The results showed that the CH 4 fluxes varied greatly during tidal cycles, from -1.25 to 96.24 μmol CH 4 m -2  h -1 for K. obovata and from 2.86 to 2662.00 μmol CH 4 m -2  h -1 for A. marina. The CO 2 fluxes ranged from -4.23 to 20.65 mmol CO 2 m -2  h -1 for K. obovata and from 0.09 to 24.69 mmol CO 2 m -2  h -1 for A. marina. The diurnal variation in GHG levels in mangroves is predominantly driven by tidal cycles. The peak emissions of CH 4 and CO 2 were noted at the beginning of the flooding tide, rather than during daytime or nighttime. While the patterns of the CO 2 fluxes during tidal cycles were similar between K. obovata and A. marina mangroves, their CH 4 flux patterns during the tidal cycles differed. Possibly due to different transport mechanisms, CO 2 emissions are primarily influenced by surface soils, whereas CH 4 is predominantly emitted from deeper soils, thus being influenced by root structures. To reduce the uncertainty in measuring GHG emissions in mangrove soils during a tidal cycle, it is advisable to increase the number of GHG flux measurements during the period spanning 30 min before and after the beginning of the flooding and ebbing tides., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The understanding of schwannoma tumorigenesis has been reshaped by the recent identification of SH3PXD2A::HTRA1 fusion in 10% of intracranial/spinal schwannomas. Nonetheless, pathologic features of schwannomas harboring this fusion, as well as its prevalence outside intracranial/spinal locations, have not been characterized. We screened 215 consecutive schwannomas for their clinicopathologic characteristics and fusion status using reverse-transcriptase polymerase chain reaction (RT-PCR). Among 29 (13.5%) fusion-positive schwannomas, the most prevalent location was peripheral somatic tissue (30.7%, 19/62), followed by spinal/paraspinal (18.4%, 7/38), body cavity/deep structures (10%, 2/20), intracranial (1.3%, 1/75), and viscera (0/13). All 8 cellular, 4 microcystic/reticular, and 3 epithelioid schwannomas were fusion-negative, as were 41/42 nonschwannomatous peripheral nerve sheath tumors. Remarkably, a distinct 'serpentine' palisading pattern, comprising ovoid/plump cells shorter than usual schwannian cells in a hyalinized stroma, was identified in most fusion-positive cases and the schwannomatous component of the only fusion-positive malignant peripheral nerve sheath tumor. To validate this finding, 60 additional cases were collected, including 36 with (≥10% arbitrarily) and 24 without appreciable serpentine histology, of which 29 (80.6%) and 2 (8.3%) harbored the fusion, respectively. With percentages of 'serpentine' areas scored, 10% was determined as the optimal practical cut-off to predict the fusion status (sensitivity, 0.950; specificity, 0.943). Fusion positivity was significantly associated with serpentine histology, smaller tumors, younger patients, and peripheral somatic tissue, while multivariate logistic linear regression analysis only identified serpentine histology and location as independent fusion-predicting factors. RNA in situ hybridization successfully detected the fusion junction, highly concordant with RT-PCR results. Gene expression profiling on 18 schwannomas demonstrated segregation largely consistent with fusion status. Fusion-positive cases expressed significantly higher HTRA1 mRNA abundance, perhaps exploitable as a biomarker. In summary, we systematically characterize a series of 60 SH3PXD2A::HTRA1 fusion-positive schwannomas, showing their distinctive morphology and location-specific prevalence for the first time., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Limited evidence exists about suicide risk in persons with polycystic ovary syndrome (PCOS)., Objective: To assess suicide risk in persons with PCOS, accounting for psychiatric comorbid conditions and age group., Design: Cohort study., Setting: Data from the Taiwanese nationwide database from 1997 to 2012., Patients: A cohort of 18 960 patients diagnosed with PCOS, each matched with control participants in a 1:10 ratio on the basis of age, psychiatric comorbid conditions, urbanization level, and income. Suicide attempts were evaluated using Cox regression models., Measurements: Suicide risk with hazard ratios (HRs)., Results: Participants with PCOS had a notable 8.47-fold increase in risk for suicide attempt compared with the control group (HR, 8.47 [95% CI, 7.54 to 9.51]), after adjustment for demographic characteristics, psychiatric comorbid conditions, Charlson Comorbidity Index scores, and frequency of all-cause clinical visits. The elevated risk was evident across the adolescent (HR, 5.38 [CI, 3.93 to 7.37]), young adult (<40 years; HR, 9.15 [CI, 8.03 to 10.42]), and older adult (HR, 3.75 [CI, 2.23 to 6.28]) groups. Sensitivity analyses involving the exclusion of data from the first year or the first 3 years of observation yielded consistent results., Limitation: Potential underestimation of PCOS and mental disorder prevalence due to use of administrative claims data; lack of clinical data, such as body mass index and depressive symptoms; and no assessment of a confounding effect of valproic acid exposure., Conclusion: This study underscores the heightened risk for suicide attempt that persons with PCOS face, even after adjustment for demographics, psychiatric comorbid conditions, physical conditions, and all-cause clinical visits. This suggests the importance of routine monitoring of mental health and suicide risk in persons diagnosed with PCOS., Primary Funding Source: Taipei Veterans General Hospital, Yen Tjing Ling Medical Foundation, and Ministry of Science and Technology of Taiwan., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2240.

Although the remission of self-limited epilepsy with centrotemporal spikes (SeLECTS) usually occurs by adolescence, deficits in cognition and behavior are not uncommon. Several functional magnetic resonance imaging (fMRI) studies have revealed connectivity disturbances in patients with SeLECTS associated with cognitive impairment. However, the disadvantages of fMRI are expensive, time-consuming, and motion sensitive. In the current study, we used a partial directed coherence (PDC) method to analyze electroencephalogram (EEG) for exploring brain connectivity in patients with SeLECTS. This study enrolled 38 participants (19 patients with SeLECTS and 19 healthy controls) for PDC analysis. Our results demonstrated that the controls had significantly higher PDC inflow connectivity in the F7, T3, FP1, and F8 channels than patients with SeLECTS. By contrast, the patients with SeLECTS demonstrated significantly higher PDC inflow connectivity than did the controls in the T5, Pz, and P4 channels. We also compared the PDC connectivity in different Brodmann areas between the patients with SeLECTS and the controls. The results revealed that the inflow connectivity in the BA9&#95;46&#95;L area was significantly higher in the controls than in the patients with SeLECTS, whereas the inflow connectivity in the MIF&#95;L area 4 was significantly higher in the patients with SeLECTS than in the controls. Our proposed approach of combining EEG with PDC provides a convenient and useful tool for investigating functional connectivity in patients with SeLECTS. This approach is time-saving and inexpensive compared with fMRI, but it achieves similar results to fMRI., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: This study aimed to examine dose-effects of total pulses on improvement of depressive symptoms in patients with treatment-resistant depression (TRD) receiving repetitive transcranial magnetic stimulation (rTMS) over the left dorsal lateral prefrontal cortex (DLPFC)., Materials and Methods: The MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, PsycINFO, and ClinicalTrial.gov databases were systematically searched. We included randomized, double-blind, placebo-controlled trials (RCT) that used rTMS over left DLPFC in patients with TRD. Excluded studies were non-TRD, non-RCTs, or combined other brain stimulation interventions. The outcome of interest was the difference between rTMS arms and sham controls in improvement of depressive symptoms in a dose-response manner. A random-effects meta-analysis and dose-response meta-analysis(DRMA) was used to examine antidepressant efficacy of rTMS and association with total pulses., Results: We found that rTMS over left DLPFC is superior to sham controls (reported as standardized mean difference[SMD] with 95% confidence interval: 0.77; 0.56-0.98). The best-fitting model of DRMA was bell-shaped (estimated using restricted cubic spline model; R 2 =0.42), indicating that higher doses (>26,660 total pulses) were not associated with increased improvement of depressive symptoms. Stimulation frequency(R 2 =0.53) and age(R 2 =0.51) were significant moderators for the dose-response curve. Furthermore, 15-20 Hz rTMS was superior to 10 Hz rTMS (0.61, 0.15-1.10) when combining all doses., Conclusions: Our findings suggest higher doses(total pulses) of rTMS were not always associated with increased improvement of depressive symptoms in patients with TRD, and that the dose-response relationship was moderated by stimulation frequency and age. These associations emphasize the importance of determining dosing parameters to achieve maximum efficacy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Infant-type hemispheric glioma (IHG) is a rare pediatric brain tumor with variable response to chemotherapy and radiotherapy. Molecular insights into IHG can be useful in identifying potentially active targeted therapy. A male fetus was found to have congenital hydrocephalus at the gestational age of 37 weeks. Fetal MRI showed a 2.6 × 2.0-cm tumor located at the frontal horn of the left lateral ventricle, involving the left basal nuclei and thalamus. Tumor biopsy at the age of 2 days revealed an IHG consisting of spindle tumor cells with strong expression of GFAP and ALK. Targeted RNA sequencing detected a novel fusion gene of SOX5::ALK. After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 3 months of treatment, reduction of tumor size was observed. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.

Mitochondrial division inhibitor 1 (Mdivi-1) is a well-known synthetic compound aimed at inhibiting dynamin-related protein 1 (Drp1) to suppress mitochondrial fission, making it a valuable tool for studying mitochondrial dynamics. However, its specific effects beyond Drp1 inhibition remain to be confirmed. In this study, we employed integrative proteomics and phosphoproteomics to delve into the molecular responses induced by Mdivi-1 in SK-N-BE(2)C cells. A total of 3070 proteins and 1945 phosphorylation sites were identified, with 880 of them represented as phosphoproteins. Among these, 266 proteins and 97 phosphorylation sites were found to be sensitive to the Mdivi-1 treatment. Functional enrichment analysis unveiled their involvement in serine biosynthesis and extrinsic apoptotic signaling pathways. Through targeted metabolomics, we observed that Mdivi-1 enhanced intracellular serine biosynthesis while reducing the production of C24:1-ceramide. Within these regulated phosphoproteins, dynamic dephosphorylation of proteasome subunit alpha type 3 serine 250 (PSMA3-S250) occurred after Mdivi-1 treatment. Further site-directed mutagenesis experiments revealed that the dephosphorylation-deficient mutant PSMA3-S250A exhibited a decreased cell survival. This research confirms that Mdivi-1's inhibition of mitochondrial division leads to various side effects, ultimately influencing cell survival, rather than solely targeting Drp1 inhibition.

Aims: Akr1A1 is a glycolytic enzyme catalyzing the reduction of aldehyde to alcohol. This study aims to delineate the role of Akr1A1 in regulating the adipo-osteogenic lineage differentiation of mesenchymal stem cells (MSCs)., Main Methods: MSCs derived from human bone marrow and Wharton Jelly together with gain- and loss-of-function analysis as well as supplementation with the S-Nitrosoglutathione reductase (GSNOR) inhibitor N6022 were used to study the function of Akr1A1 in controlling MSC lineage differentiation into osteoblasts and adipocytes., Key Findings: Akr1A1 expression, PKM2 activity, and lactate production were found to be decreased in osteoblast-committed MSCs, but PGC-1α increased to induce mitochondrial oxidative phosphorylation. Increased Akr1A1 inhibited the SIRT1-dependent pathway for decreasing the expressions of PGC-1α and TAZ but increasing PPAR γ in adipocyte-committed MSCs, hence promoting glycolysis in adipogenesis. In contrast, Akr1A1 expression, PKM2 activity and lactate production were all increased in adipocyte-differentiated cells with decreased PGC-1α for switching energy utilization to glycolytic metabolism. Reduced Akr1A1 expression in osteoblast-committed cells relieves its inhibition of SIRT1-mediated activation of PGC-1α and TAZ for facilitating osteogenesis and mitochondrial metabolism., Significance: Several metabolism-involved regulators including Akr1A1, SIRT1, PPARγ, PGC-1α and TAZ were differentially expressed in osteoblast- and adipocyte-committed MSCs. More importantly, Akr1A1 was identified as a new key regulator for controlling the MSC lineage commitment in favor of adipogenesis but detrimental to osteogenesis. Such information should be useful to develop perspective new therapeutic agents to reverse the adipo-osteogenic differentiation of BMSCs, in a way to increase in osteogenesis but decrease in adipogenesis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The current study aimed to determine the safety profile of intra-articular-injected allogeneic adipose-derived mesenchymal stem cells (ADSCs) GXCPC1 in subjects with knee osteoarthritis (OA) and its preliminary efficacy outcome. The 3 + 3 phase I study was designed with two dose-escalation cohorts: low dose (6.7 × 10 6 GXCPC1, N = 5) and high dose (4 × 10 7 GXCPC1, N = 6). The primary endpoint was safety, which was evaluated by recording adverse events throughout the trial; the secondary endpoints included total, pain, stiffness, and function subscales of the Western Ontario and McMaster Universities Arthritis Index (WOMAC), Visual Analogue Scale (VAS) for pain, and 12-Item Short Form (SF-12) health survey questionnaire. The GXCPC1 treatment was found to be safe after 1 year of follow-up with no treatment-related severe adverse events observed. When compared to baseline, subjects in both the low- and high-dose cohorts demonstrated improving trends in pain and knee function after receiving GXCPC1 treatment. Generally, the net change in pain (95% confidence interval (CI) = -7.773 to -2.561t at 12 weeks compared to baseline) and knee function (95% CI = -24.297 to -10.036t at 12 weeks compared to baseline) was better in subjects receiving high-dose GXCPC1. Although this study included a limited number of subjects without a placebo arm, it showed that the intra-articular injection of ADSCs was safe and well-tolerated in subjects with therapeutic alternatives to treat knee OA. However, a larger scale study with an appropriate control would be necessary for clinical efficacy in the following study., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A series of di-functional benzoxazine (BZ) monomers was synthesized, specifically the double-decker silsesquioxane (DDSQ) cage structure (DDSQ-BZ). Comparative analyses were conducted between DDSQ-BZ monomers and the most commonly utilized bisphenol A-functionalized bifunctional benzoxazine (BPA-BZ) monomer. DDSQ-BZ compounds possess better thermal properties such as high char yield and high thermal decomposition temperature ( T d10 ) after thermal ring-opening polymerization (ROP) because the inorganic DDSQ cage nanostructure features a nano-reinforcement effect. In addition, blending inorganic DDSQ-BZ compounds with epoxy resin was explored to form organic/inorganic hybrids with enhanced thermal and mechanical properties following thermal ROP. The improvement in mechanical properties is primarily attributed to the network structure formed by the cross-linking between DDSQ-BZ and the epoxy resin during thermal ROP, as well as hydrogen bonding interactions formed between the hydroxyl groups generated during thermal ROP and the Si-O-Si bonds in the DDSQ structure.

The prognosis for postinjury peripheral nerve regeneration remains suboptimal. Although transplantation of exogenous Schwann cells (SCs) has been considered a promising treatment to promote nerve repair, this strategy has been hampered in practice by the limited availability of SC sources and an insufficient postengraftment cell retention rate. In this study, to address these challenges, SCs were aggregated into spheroids before being delivered to an injured rat sciatic nerve. We found that the three-dimensional aggregation of SCs induced their acquisition of a repair phenotype, as indicated by enhanced levels of c-Jun expression/activation and decreased expression of myelin sheath protein. Furthermore, our in vitro results demonstrated the superior potential of the SC spheroid-derived secretome in promoting neurite outgrowth of dorsal root ganglion neurons, enhancing the proliferation and migration of endogenous SCs, and recruiting macrophages. Moreover, transplantation of SC spheroids into rats after sciatic nerve transection effectively increased the postinjury nerve structure restoration and motor functional recovery rates, demonstrating the therapeutic potential of SC spheroids. In summary, transplantation of preassembled SC spheroids may hold great potential for enhancing the cell delivery efficiency and the resultant therapeutic outcome, thereby improving SC-based transplantation approaches for promoting peripheral nerve regeneration., Competing Interests: The authors declare no conflict of interests., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Phosphaturic mesenchymal tumors (PMT) are uncommon neoplasms that cause hypophosphatemia/osteomalacia mainly by secreting fibroblast growth factor 23. We previously identified FN1::FGFR1/FGF1 fusions in nearly half of the PMTs and frequent KL (Klotho or α-Klotho) overexpression in only those with no known fusion. Here, we studied a larger cohort of PMTs for KL expression and alterations. By FN1 break-apart fluorescence in situ hybridization (FISH) and reappraisal of previous RNA sequencing data, 6 tumors previously considered "fusion-negative" (defined by negative results of FISH for FN1::FGFR1 fusion and FGF1 break-apart and/or of RNA sequencing) were reclassified as fusion-positive PMTs, including 1 containing a novel FN1::ZACN fusion. The final cohort of fusion-negative PMTs included 33 tumors from 32 patients, which occurred in the bone (n = 18), soft tissue (n = 10), sinonasal tract (n = 4), and brain (n = 1). In combination with previous work, RNA sequencing, RNA in situ hybridization, and immunohistochemistry showed largely concordant results and demonstrated KL/α-Klotho overexpression in 17 of the 28 fusion-negative and none of the 10 fusion-positive PMTs studied. Prompted by a patient in this cohort harboring germline KL upstream translocation with systemic α-Klotho overexpression and multifocal PMTs, FISH was performed and revealed KL rearrangement in 16 of the 33 fusion-negative PMTs (one also with amplification), including 14 of the 17 cases with KL/α-Klotho overexpression and none of the 11 KL/α-Klotho-low fusion-negative and 11 fusion-positive cases studied. Whole genomic sequencing confirmed translocation and inversion in 2 FISH-positive cases involving the KL upstream region, warranting further investigation into the mechanism whereby these rearrangements may lead to KL upregulation. Methylated DNA immunoprecipitation and sequencing suggested no major role of promoter methylation in KL regulation in PMT. Interestingly, KL-high/-rearranged cases seemed to form a clinicopathologically homogeneous group, showing a predilection for skeletal/sinonasal locations and typically matrix-poor, cellular solitary fibrous tumor-like morphology. Importantly, FGFR1 signaling pathways were upregulated in fusion-negative PMTs regardless of the KL status compared with non-PMT mesenchymal tumors by gene set enrichment analysis, perhaps justifying FGFR1 inhibition in treating this subset of PMTs., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The coronavirus disease pandemic has had a tangible impact on bronchoscopy for burn inpatients due to isolation and triage measures. We utilised the machine-learning approach to identify risk factors for predicting mild and severe inhalation injury and whether patients with burns experienced inhalation injury. We also examined the ability of two dichotomous models to predict clinical outcomes including mortality, pneumonia, and duration of hospitalisation., Methods: A retrospective 14-year single-centre dataset of 341 intubated patients with burns with suspected inhalation injury was established. The medical data on day one of admission and bronchoscopy-diagnosed inhalation injury grade were compiled using a gradient boosting-based machine-learning algorithm to create two prediction models: model 1, mild vs. severe inhalation injury; and model 2, no inhalation injury vs. inhalation injury., Results: The area under the curve (AUC) for model 1 was 0·883, indicating excellent discrimination. The AUC for model 2 was 0·862, indicating acceptable discrimination. In model 1, the incidence of pneumonia (P < 0·001) and mortality rate (P < 0·001), but not duration of hospitalisation (P = 0·1052), were significantly higher in patients with severe inhalation injury. In model 2, the incidence of pneumonia (P < 0·001), mortality (P < 0·001), and duration of hospitalisation (P = 0·021) were significantly higher in patients with inhalation injury., Conclusions: We developed the first machine-learning tool for differentiating between mild and severe inhalation injury, and the absence/presence of inhalation injury in patients with burns, which is helpful when bronchoscopy is not available immediately. The dichotomous classification predicted by both models was associated with the clinical outcomes., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Molecular recognition of complex isomeric biomolecules remains challenging in surface-enhanced Raman scattering (SERS) spectroscopy due to their small Raman cross-sections and/or poor surface affinities. To date, the use of molecular probes has achieved excellent molecular sensitivities but still suffers from poor spectral specificity. Here, we induce "charge and geometry complementarity" between probe and analyte as a key strategy to achieve high spectral specificity for effective SERS molecular recognition of structural analogues. We employ 4-mercaptopyridine (MPY) as the probe, and chondroitin sulfate (CS) disaccharides with isomeric sulfation patterns as our proof-of-concept study. Our experimental and in silico studies reveal that "charge and geometry complementarity" between MPY's binding pocket and the CS sulfation patterns drives the formation of site-specific, multidentate interactions at the respective CS isomerism sites, which "locks" each CS in its analogue-specific complex geometry, akin to molecular docking events. Leveraging the resultant spectral fingerprints, we achieve > 97 % classification accuracy for 4 CSs and 5 potential structural interferences, as well as attain multiplex CS quantification with < 3 % prediction error. These insights could enable practical SERS differentiation of biologically important isomers to meet the burgeoning demand for fast-responding applications across various fields such as biodiagnostics, food and environmental surveillance., (© 2023 Wiley-VCH GmbH.)