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Mastery motivation is a multifaceted, psychological force that stimulates a child to master skills or tasks and is positively associated with language-related competences. Children with developmental delay might have lower levels of motivation, and their parents might face escalated parenting stress as well. The aims of this study were to identify the characteristics of mastery motivation in toddlers with language delay by intergroup and intragroup comparison, and to investigate the associations between specific components of parenting stress and toddler's mastery motivation. Eighty Chinese-speaking Taiwanese toddlers aged 19 to 42 months and their parents (fifty toddlers with language delay and thirty toddlers with typical development) participated in the study. The language delay group was selected based on maternal reports of vocabulary production with the Mandarin-Chinese Communicative Development Inventory and direct assessment with an individualized developmental test or intelligence test. The Revised Dimensions of Mastery Questionnaire (DMQ 18) with Preschool version, and the Parenting Stress Index Short Form were used to measure three domains of child mastery motivation and parents' components of parenting stress, respectively. Toddlers with language delay were rated as having lower gross motor and social mastery motivation than their peers with typical development; however, they showed the strength/weakness intragroup characteristics of higher gross motor motivation and lower social motivation with other children. Parental stress in the language delay group was significantly negatively correlated with mastery motivation, and the component of Parent-Child Dysfunctional Interaction was negatively associated with toddlers' Total Mastery Motivation, social motivation, and two indicators of expressive aspect after controlling for toddlers' age, cognitive ability, and family social-economic status. In conclusion, it is necessary for early interventionists to observe parenting stress and mastery motivation during the process of early intervention., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Pancreatic intraepithelial neoplasia (PanIN) and islet cell microadenoma are exocrine and endocrine neoplasms of human pancreas that have been linked to pancreatic ductal adenocarcinoma (PDAC) and neuroendocrine tumor, respectively. However, in health and at the surgical margin of pancreatic cancer, it remains unresolved how to simultaneously characterize duct and islet remodeling to investigate the exocrine-endocrine association in the lesion microenvironment. Here, we develop a new vibratome-based approach to detect, confirm, and analyze the two types of pancreas remodeling via stereo/three-dimensional (3-D) and classic/two-dimensional (2-D) histology. Surgical margins of PDAC ( n = 10, distal) and cadaveric donor pancreases ( n = 10, consecutive cases) were fixed, sectioned by vibratome (350 µm), and surveyed for PanIN and microadenoma via stereomicroscopy. After lesion detection, PanIN and microadenoma were analyzed with 3-D fluorescence imaging and clinical microtome-based histology for confirmation and assessment of microenvironment. Multimodal imaging of PDAC surgical margins and cadaveric donor pancreases detected the peri-PanIN islet aggregation with duct-islet cell clusters. Organ-wide survey of cadaveric donor pancreases shows a marked 2.3-fold increase in the lesion size with the PanIN-islet association vs. without the association. In the survey, we unexpectedly detected the islet cell microadenoma adjacent to (<2 mm) PanIN. Overall, among the 53 early lesions in the cadaveric donor pancreases (PanINs and microadenomas), 81% are featured with the associated exocrine-endocrine tissue remodeling. Multimodal 3-D/2-D tissue imaging reveals local and simultaneous duct and islet remodeling in the cancer surgical margin and cadaveric donor pancreas. In the cadaveric donor pancreas, the peri-PanIN islet aggregation and PanIN-microadenoma association are two major features of pancreas remodeling in the early lesion microenvironment. NEW & NOTEWORTHY We develop a new multimodal 3-D/2-D imaging approach (matched stereomicroscopic, fluorescence, and H&E signals) to examine human duct-islet association in the PDAC surgical margin and cadaveric donor pancreas. In both conditions, peri-PanIN islet aggregation with duct-islet cell clusters was identified. The PanIN-islet cell microadenoma association was unexpectedly detected in the donor pancreas. Our work provides the technical and morphological foundations to simultaneously characterize human islets and ducts to study their association in health and disease.

Metabolomics is an omics strategy to study the metabolite alteration in the biological system. Unbiased observation of the metabolite level is essential for targeted metabolite quantification and untargeted metabolic profiling. State-of-the-art instruments and versatile tools have been developed for accurate observation of metabolic alterations in various studies. Several analytical pitfalls, such as sample overloading and signal-saturation-induced bias, have been revealed and addressed. In this study, we proposed incomplete-metabolite-extraction-caused bias is also an important issue that results in biased observation when performing metabolomics. In the demonstration example, numerous metabolites exhibited no significant difference between extracted plasma samples with different plasma contents, which is attributed to incomplete-metabolite-extraction-caused bias and matrix effect. Matrix effect is a well-known factor that result in biased observation, it can be reduced by sample dilution and compensated by using stable isotope labelled internal standards. The detection of metabolite signals in the following consecutive extractions provided further evidence of incomplete metabolite extraction. The completeness of metabolite extraction is crucial for unbiased observation of metabolic profile changes. To address this issue, we optimized the extraction time and methanol volume to reduce the incomplete-metabolite-extraction-caused bias and evaluated the metabolite signals in consecutive extractions. Methanol extraction performed with a plasma-to-methanol ratio of 1:14 resulted in metabolite responses of less than 18.1 % in the second extractions observed by metabolomic profiling. Finally, the optimized sample preparation procedure and untargeted profiling platform were applied to detect metabolite alterations associated with patients with cerebrovascular diseases and several features with significant difference were successfully identified. This study revealed and evaluated the bias caused by incomplete metabolite extraction and matrix effect in the commonly used methanol extraction method for human plasma sample preparation for metabolomics. We anticipate the proposed metabolite extraction evaluation method could benefit more clinical and biological metabolomics studies., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Macrophage polarization is a process whereby macrophages acquire distinct effector states (M1 or M2) to carry out multiple and sometimes opposite functions. We show here that translational reprogramming occurs during macrophage polarization and that this relies on the Elongator complex subunit Elp3, an enzyme that modifies the wobble uridine base U34 in cytosolic tRNAs. Elp3 expression is downregulated by classical M1-activating signals in myeloid cells, where it limits the production of pro-inflammatory cytokines via FoxO1 phosphorylation, and attenuates experimental colitis in mice. In contrast, alternative M2-activating signals upregulate Elp3 expression through a PI3K- and STAT6-dependent signaling pathway. The metabolic reprogramming linked to M2 macrophage polarization relies on Elp3 and the translation of multiple candidates, including the mitochondrial ribosome large subunit proteins Mrpl3, Mrpl13, and Mrpl47. By promoting translation of its activator Ric8b in a codon-dependent manner, Elp3 also regulates mTORC2 activation. Elp3 expression in myeloid cells further promotes Wnt-driven tumor initiation in the intestine by maintaining a pool of tumor-associated macrophages exhibiting M2 features. Collectively, our data establish a functional link between tRNA modifications, mTORC2 activation, and macrophage polarization., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Human leukocyte antigen (HLA)-B*58:01 allele is a significant risk factor for allopurinol-induced severe cutaneous adverse reactions (SCARs) which is potentially fatal. In some studies, chronic kidney disease (CKD) was also implicated to compound the risk of SCARs. We aim to investigate if pre-treatment HLA-B*58:01 screening can prevent allopurinol-induced SCARs in Chinese patients with CKD and its cost-effectiveness. We prospectively recruited Chinese CKD patients who required allopurinol during 2011-2015 and performed pre-treatment HLA testing (HLA screening group). Patients tested positive for HLA-B*58:01 were refrained from allopurinol while those tested negative were prescribed allopurinol. The incidence of SCARs in the HLA screening group was compared with the historical control in previous 5 years and the cost-effectiveness of HLA testing was analyzed. In the historical control (2006-2010), 3605 patients on allopurinol were screened, 22 out of 1027 (2.14%) CKD Chinese patients newly started on allopurinol developed SCARs, including 6 SJS/TEN. In the HLA screening group, 28 out of 192 patients (14.6%) tested HLA-B*58:01 positive were advised to avoid allopurinol; 156 out of 164 HLA-B*58:01-negative patients received allopurinol and none developed SCARs. The incidence rate of SCARs was significantly lower in the HLA screening group compared with controls (0% vs 2.14% respectively, p = 0.037*). The targeted HLA screening approach was associated with lower healthcare costs compared with no HLA screening (US$ 92,430 vs US$ 281,226). Pre-treatment HLA-B*58:01 screening is cost-effective to target on patients with CKD in Chinese to prevent allopurinol-induced SCARs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Burns can cause cell death and irreversible tissue damage. We examined the pathway of human dermis fibroblasts cell death caused by skin burns and the roles of chloroquine in human skin keratinocytes HaCaT wound healing. Western blot assays were performed to assess expression of proteins associated with autophagy, apoptosis, and endoplasmic reticulum stress in skin cells following burns. Changes in apoptosis-related proteins were assessed using flow cytometry, and wound cell migration was examined using wound healing assays. The burn animal model was used to test whether chloroquine would promote wound healing. In human burned fibroblasts, expression of LC3B-II and Cleave-caspase-7 was increased, whereas expression of Beclin-1, p62, and Grp78 was decreased. Severe burn induced ER stress and ERK phosphorylation, but PD98059 or necrostatin-1 treatment cells did not affect expression of autophagy LC3B-II protein and can induce apoptosis. Even though added with TGF-β and FGF did not repair autophagy caused by burns. Suggesting that autophagy and apoptosis were involved in heat-injured mechanism. Recombinant Wnt3a protein can help restore expression of β-catenin which reduced following burns in keratinocytes. Wnt3a protein can promote migration of keratinocytes after burns. Interesting, chloroquine increased expression of LC3B-II protein and restored cell migration activity after 24 h of burns. Consistently, surgical dressing containing chloroquine promoted wound healing in a burn animal mode. Autophagy and Wnt/β-catenin is two signalling pathways that participate in cell repair and wound healing in human fibroblasts, keratinocytes. Surgical dressing containing chloroquine can recover wound healing in burned rats., Competing Interests: The authors have declared that no competing interests exist.

Human epidermal growth factor receptor isoform D (EGFR; isoform D) is a soluble protein from a 3 kb alternate mRNA transcript that arises from the human EGFR gene. Several studies have identified this circulating isoform of EGFR as a potential diagnostic biomarker for the detection of early stage of cancers. While the expression of the full-length EGFR (isoform A) is regulated by its cognate ligand, EGF, as well as by phorbol myristate acetate (PMA), no studies have examined the factors regulating the expression of EGFR isoform D. In this study, using breast cancer cell lines, we show that the HER receptor ligands, EGF and neuregulin (NRG-1β), as well as the phorbol ester, PMA, can increase the expression of EGFR isoform D, as well as isoform A. Our results, based on measurement of mRNA levels, suggest that EGF induced expression of both isoform A and isoform D occur through a mitogen activated protein kinase (MAPK)-dependent mechanism, and also suggest that protein kinase C is involved in PMA-induced regulation of both isoforms. We also demonstrate that NRG-1β increases isoform A and isoform D expression via the MAPK-dependent pathway, but this regulation occurs independently of phosphatidylinositol 3-kinase/Akt activation. These results suggest that regulation of EGFR isoform A and isoform D expression occur using similar mechanisms. Despite commonalities in the transcriptional regulation of these two EGFR isoforms, the half-lives of these two transcripts is quite different. Moreover, EGFR isoform D, unlike isoform A, is not post-transcriptionally modulated by EGFR activators in the breast cancer cell line MDA-MB-468., Competing Interests: The authors have no conflict of interest to declare., (© 2022 The Authors.)

Background and Objectives: This study investigated the cutaneous small fiber pathology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and its clinical significance, that is, the NOTCH3 deposition in cutaneous vasculatures and CNS neurodegeneration focusing on cognitive impairment., Methods: Thirty-seven patients with CADASIL and 59 age-matched healthy controls were enrolled to evaluate cutaneous small fiber pathology by quantitative measures of intraepidermal nerve fiber density (IENFD), sweat gland innervation, and vascular innervation. Cognitive performance of patients with CADASIL was evaluated by a comprehensive neuropsychological assessment, and its association with small fiber pathology was tested using multivariable linear regression analysis adjusted for age and diabetes mellitus. We further assessed the relationships of IENFD with cutaneous vascular NOTCH3 ectodomain (NOTCH3ECD) deposition and biomarkers of neurodegeneration including structural brain MRI measures, serum neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1., Results: Patients with CADASIL showed reduced IENFD (5.22 ± 2.42 vs 7.88 ± 2.89 fibers/mm, p = 0.0001) and reduced sweat gland ( p < 0.0001) and vascular ( p < 0.0001) innervations compared with age-matched controls. Reduced IENFD was associated with impaired global cognition measured by Mini-Mental State Examination ( B = 1.062, 95% CI = 0.370-1.753, p = 0.004), and this association remained after adjustment for age and diabetes mellitus ( p = 0.043). In addition, IENFD in patients with CADASIL was associated with mean cortical thickness (Pearson r = 0.565, p = 0.0023) but not white matter hyperintensity volume, total lacune count, or total microbleed count. Reduced IENFD was associated with cutaneous vascular NOTCH3ECD deposition amount among patients harboring pathogenic variants in exon 11 (mainly p.R544C) ( B = -0.092, 95% CI = -0.175 to -0.009, p = 0.031). Compared with those with normal cognition, patients with CADASIL with cognitive impairment had an elevated plasma NfL level regardless of concurrent small fiber denervation, whereas only patients with both cognitive impairment and small fiber denervation showed an elevated plasma GFAP level., Discussion: Cutaneous small fiber pathology correlates with cognitive impairment and CNS neurodegeneration in patients with CADASIL, indicating a peripheral neurodegenerative process related to NOTCH3ECD aggregation., (© 2022 American Academy of Neurology.)

Taxanes are the backbone cytotoxic agents that have been prescribed in most solid malignant treatments for decades. Taxane-induced peripheral neuropathy (PN) and drug resistance are inevitable. Novel taxanes include semisynthetic taxanes, taxane analogs, taxanes with a different drug-delivery method, taxanes without lipid carries, oral taxanes, taxanes with resistance to permeability glycoprotein (P-gp), and taxanes with easy penetration of the blood-brain barrier (BBB). Some taxanes have already shown promising activity in the clinic and have shown abilities to overcome the drug resistance commonly occurring with traditional taxane treatment. Predictive b for response to taxanes are being explored in order to offer precision medicine in cancer therapy. This review will focus on the history, current, and future directions of taxane development in breast cancer, especially that of novel taxanes such as oral taxanes. Clinical trials on novel taxanes, including the mature phase III trials of oral taxane and the recent setback, as well as the future direction of taxane research, will be discussed., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The previously published 2017 Taiwan Lipid Guidelines for High Risk Patients becomes the standard guidance of dyslipidemia management for patients with atherosclerotic cardiovascular disease (ASCVD) in Taiwan. New clinical trials of lipid lowering therapy were published successively after 2017. The study results changed the treatment concept of ASCVD. Therefore, an update focusing on the lipid treatment strategy for patients with ASCVD becomes necessary. In this focused update of the 2017 guideline, the treatment targets of low-density lipoprotein cholesterol (LDL-C) for patients with ASCVD were modified. The algorithm of LDL-C lowering therapy was revised. The recommendations in this focused update were made mainly based on the scientific evidence from recently published clinical trials and endorsed by the major medical societies in Taiwan., Competing Interests: Declaration of competing interest The guideline was supported by the Taiwan Society of Lipids and Atherosclerosis., (Copyright © 2022. Published by Elsevier B.V.)

To meet the requirement from the economy and society, China's emergency rescue has been developing towards specialization and professionalization. The working environment for emergency responders is special accompanying with tremendous challenges and uncertainties. To promote the research on occupational health and personal protection is an important guarantee for the workers in China to realize the goal of "decent work". This paper reviews the hazards that affect the occupational health of emergency rescue workers, the research progress of adverse outcomes caused from exposure to these hazards, and the related development issues of personal protection. In order to ensure the safety and health of emergency rescue workers, the direction of further research on occupational health of emergency rescue workers is put forward.

Background/purpose: Several risk scores have been developed to predict symptomatic intracerebral hemorrhage (SICH) after acute reperfusion therapy for ischemic stroke. We compared the performance of established risk scores in predicting SICH after EVT under different SICH criteria., Methods: A total of 258 patients with anterior circulation large vessel occlusion who received EVT in two medical centers of Taiwan were recruited. Three definitions of SICH, the European Collaborative Acute Stroke Study II (ECASS II), ECASS III, and the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), were used. The HAT, SITS-SICH, SEDAN, and TAG risk scores were applied. Logistic regression and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of each risk model., Results: In the 258 included patients (mean age, 71.9 ± 11.8 years; men, 48.1%), the observed rates of SICH according to ECASS II, ECASS III, and SITS-MOST criteria were 10.1%, 5.0%, and 4.7%, respectively. Higher glucose level (>160 mg/dL) and unsuccessful recanalization independently predicted SICH under all criteria. Among the different risk scores, only SEDAN and TAG consistently predicted SICH. SEDAN and TAG scores exhibited the highest AUC in predicting SICH for ECASS III (SEDAN 0.72, TAG 0.72) and SITS-MOST (SEDAN 0.73, TAG 0.70) criteria., Conclusion: Among various risk scores, the TAG and SEDAN scores best predict SICH after EVT. Higher glucose level and unsuccessful recanalization, which are included in the TAG and SEDAN scores, are independent risk factors of SICH in the present cohort, highlighting their detrimental effects., Competing Interests: Declaration competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

3D chromatin organization plays an important role in transcription regulation and gene expression. The 3D genome is highly maintained by several architectural proteins, such as CTCF, Yin Yang 1, and cohesin complex. This structural organization brings regulatory DNA elements in close proximity to their target promoters. In this review, we discuss the 3D chromatin organization of super-enhancers and their relationship to phase-separated condensates. Super-enhancers are large clusters of DNA elements. They can physically contact with their target promoters by chromatin looping during transcription. Multiple transcription factors can bind to enhancer and promoter sequences and recruit a complex array of transcriptional co-activators and RNA polymerase II to effect transcriptional activation. Phase-separated condensates of transcription factors and transcriptional co-activators have been implicated in assembling the transcription machinery at particular enhancers. Cancer cells can hijack super-enhancers to drive oncogenic transcription to promote cell survival and proliferation. These dysregulated transcriptional programs can cause cancer cells to become highly dependent on transcriptional regulators, such as Mediator and BRD4. Moreover, the expression of oncogenes that are driven by super-enhancers is sensitive to transcriptional perturbation and often occurs in phase-separated condensates, supporting therapeutic rationales of targeting SE components, 3D genome organization, or dysregulated condensates in cancer.

Acute lung injury (ALI) is a serious inflammatory lung disease. Imbalances in the polarization of classically activated (M1) and alternatively activated (M2) macrophages are closely related to ALI. Anisodamine has a promising therapeutic effect for septic shock. Nevertheless, the role of anisodamine in progression of ALI remains to be investigated. Our results showed that anisodamine significantly reduced lung damage, myeloperoxidase (MPO) activity, lung wet/dry ratio, total cell number, and protein concentrations in bronchoalveolar lavage fluid and decreased interleukin (IL)-6 level and the levels of M1 phenotypic markers, whereas it increased IL-10 level and the levels of M2 phenotypic markers in mice with a nasal instillation of lipopolysaccharide (LPS). Bone marrow-derived macrophages (BMDMs) were stimulated or transfected with LPS plus anisodamine or LPS plus G9a short hairpin RNA. Anisodamine and downregulation of G9a both promoted BMDM M2 polarization caused by IL-4 treatment and inhibited M1 polarization resulting from LPS treatment. Chromatin immunoprecipitation assay revealed that anisodamine inhibited G9a-mediated methylation and expression suppression on interferon regulatory factory 4 (IRF4). Overexpression of G9a or silence of IRF4 reversed the improvement effect of anisodamine on lung tissue injury, evidenced by an increase of MPO activity and the restoration of LPS-induced alterations of M1 and M2 polarization. In conclusion, anisodamine protected against LPS-induced ALI, during which anisodamine suppressed the LPS-stimulated alterations of macrophage M1 and M2 polarization through inhibiting G9a-mediated methylation of IRF4, suggesting that anisodamine was a potential therapeutic drug to alleviate ALI. SIGNIFICANCE STATEMENT: Anisodamine treatment was able to attenuate lung injury and pulmonary edema caused by lipopolysaccharide (LPS) stimulation, and the specific mechanism was that anisodamine reversed the LPS-induced alterations of M1 and M2 polarization by inhibiting G9a-mediated methylation and expression suppression of interferon regulatory factor 4, which suggests that anisodamine has the potential to alleviate acute lung injury., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Genome-wide association studies have identified a genetic variant rs17356907 in netrin 4 (NTN4) as a risk locus of breast cancer (BC) in Europeans. NTN4 is a target gene of miR-17-92 cluster that is an oncogenic miRNA in BC development. We aimed to replicate the rs17356907 in a Chinese population and examine the interaction of NTN4 and miR-17-92 on BC susceptibility., Materials and Methods: The rs17356907 in NTN4 and 3 additional polymorphisms in the promoter of miR-17-92 (ie, rs9588884, rs982873, and rs1813389) were determined in 415 patients with BC and 420 healthy controls using a TaqMan assay. The expression levels of NTN4 in BC and normal tissues were performed using the quantitative reverse transcription-PCR., Results: With reference to the rs17356907AA genotype, the GG genotype was associated with a decreased risk of BC with an adjusted OR of 0.38 (95% CI: 0.20-0.74). With reference to the rs17356907AA-rs982873CT/CC genotypes, the rs17356907 AG/GG-rs982873CT/CC genotypes were associated with a borderline decreased risk of BC with an adjusted OR of 0.67 (95% CI: 0.48-0.93). Gene-gene interaction analysis showed that the rs17356907-rs982873-rs9588884-rs1813389 was the best model on BC susceptibility. Furthermore, the rs17356907GG genotype displayed higher levels of NTN4 mRNA., Conclusions: The NTN4 rs17356907 may have a single and interactive effect with miR-17-92 polymorphisms on the risk of BC., (Copyright © 2021. Published by Elsevier Inc.)

Background: Since the publication of the 2015 Taiwan Stroke Society Blood Pressure for Treatment and Prevention of Stroke Guideline (2015 TSS BP Guideline), several new clinical studies have addressed whether a stricter blood pressure (BP) target would be effective for stroke prevention., Methods: TSS guideline consensus group provides recommendations on BP targets for stroke prevention based on updated evidences., Results: The present guideline covers five topics: (1) diagnosis of hypertension; (2) BP control and primary prevention of ischemic stroke; (3) BP control and secondary prevention of ischemic stroke; (4) BP control and secondary prevention of large artery atherosclerosis ischemic stroke; and (5) BP control and secondary prevention of small vessel occlusion ischemic stroke., Conclusion: The BP target for most stroke patients with hypertension is <130/80 mm Hg., Competing Interests: Conflicts of interest: Dr. Chi has been on the speaker's bureau for AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Pfizer, and Sanofi. Dr. Chung has been on the speakers bureau for AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Viatris, and Sanofi. Dr. Li has been on the speakers bureau for Bayer, Boehringer Ingelheim, Daiichi-Sankyo, and Pfizer. Dr. Wang has been on the speakers bureau for Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Cordis, Daiichi-Sankyo, GSK, Medtronic, MSD, Novartis, Pfizer, Sanofi, and Takeda. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in NOTCH3, is the most common cause of hereditary cerebral small vessel disease. Whether it will involve systemic vasculopathy such as retinal vessel remains unknown. Optical coherence tomography angiography (OCT-A) is a noninvasive technique for visualising retinal blood flow. We analysed vessel density and retinal thickness in patients with CADASIL and investigated their correlations with disease severity., Methods: This prospective study enrolled 35 patients with CADASIL (59 eyes) and 35 healthy controls (54 eyes). OCT-A was used to measure the vessel density of the macular region and the thickness of retinal layers. Patients with CADASIL were divided into stroke (n = 20) and nonstroke (n = 15) subgroups and underwent cognition and gait speed evaluation. Neuroimaging markers of cortical thickness, white matter hyperintensity, lacunae, and cerebral microbleeds were examined through brain magnetic resonance imaging., Results: The OCT-A parameters, including vessel density, were comparable between the patients with CADASIL and the controls. In patients with CADASIL, vessel density in the superficial retinal plexus in the macula as was inner retinal thickness was significantly lower in the stroke than the nonstroke subgroup. Macular vessel density and inner retinal thickness were positively correlated with gait speed, while negatively correlated with number of lacunae., Conclusions: OCT-A is potentially a useful tool for evaluating disease severity, ischaemic burden, and neurodegeneration in patients with advanced CADASIL., Competing Interests: The authors have declared that no competing interests exist.

Transforming growth factor-β (TGF-β) is a crucial pathogenic mediator of inflammatory diseases. In tissue fibrosis, TGF-β regulates the pathogenic activity of infiltrated immunocytes and promotes extracellular matrix production via de novo myofibroblast generation and kidney cell activation. In cancer, TGF-β promotes cancer invasion and metastasis by enhancing the stemness and epithelial mesenchymal transition of cancer cells. However, TGF-β is highly pleiotropic in both tissue fibrosis and cancers, and thus, direct targeting of TGF-β may also block its protective anti-inflammatory and tumor-suppressive effects, resulting in undesirable outcomes. Increasing evidence suggests the involvement of long non-coding RNAs (lncRNAs) in TGF-β-driven tissue fibrosis and cancer progression with a high cell-type and disease specificity, serving as an ideal target for therapeutic development. In this review, the mechanism and translational potential of TGF-β-associated lncRNAs in tissue fibrosis and cancer will be discussed.

Competing Interests: All authors have declared no conflict of interest.

Background/purpose: Recently optimized models for selecting the locations of hospitals capable of providing endovascular thrombectomy (EVT) did not consider the accuracy of the prehospital stroke scale assessment and possibility of secondary transport. Our study aimed to propose a new model for selecting existing hospitals with intravenous thrombolysis capability to become EVT-capable hospitals., Methods: A sequential order was provided to upgrade hospitals providing intravenous thrombolysis, using a mixed integer programming model based on current medical resource allocation. In addition, we drafted a centralized plan to redistribute existing EVT resources by redetermining locations of EVT-capable hospitals. Using historical data of 7679 on-scene patients with suspected stroke, the model was implemented to determine the hospital that maximizes the number of patients receiving EVT treatment within call-to-definitive-treatment time., Results: All suspected stroke patients were sent to EVT-capable hospitals directly under the current medical resource allocation model. After upgrading one additional hospital to become an EVT-capable hospital, the percentage of patients receiving definitive treatment within the standard call-to-definitive-treatment time was elevated from 68.82% to 72.97%. In the model, assuming that there is no hospital providing EVT, all patients suspected of stroke will be sent to EVT-capable hospitals directly after upgrading three or more hospitals to be able to provide treatment., Conclusion: All patients eligible for acute stroke treatment are sent to EVT-capable hospitals in the simulation under the current medical resource allocation model. This model can be utilized to provide insights for capacity redistribution in other regions., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background To mitigate uncertainty that may arise in the judgment of emergency medical technicians when relying on a prehospital stroke scale at the scene, we propose a hospital selection protocol that considers the uncertainty of a prehospital stroke scale and the actual door-to-treatment durations, and we have developed a web-based system to be used with mobile devices. Methods and Results This hospital selection protocol incorporates real-time, estimated transport time obtained from Google Maps, historical median door-to-treatment duration at hospitals that only provide the standard intravenous thrombolysis treatment, and at hospitals with endovascular thrombectomy for probable large-vessel occlusion cases. We have validated the efficiency of the proposed protocol and compared it with other strategies used by emergency medical technicians when deciding on a receiving hospital. Using the proposed protocol for the triage reduces the time from onset to receiving definitive treatment by nearly 11 minutes. We found that the nearest endovascular thrombectomy-capable hospital from the scene may not be the most ideal if the door-to-treatment durations are discriminative. The results show that, when the tolerable bypass transport threshold and administration time are reduced to 9 minutes and 30.5 minutes, respectively, 228 patients out of 7678 cases, whose receiving hospitals were changed to endovascular thrombectomy-capable hospitals, received definitive treatment in a shorter time. The results of our analysis give recommendations for appropriate allowable bypass transport time for regional planning. Conclusions By applying almost-real value parameters, we have validated a web-based model, which can be universally adapted for optimal, time-saving hospital selection for patients with stroke.

Objectives: To develop and validate an ultrasound elastography radiomics nomogram for preoperative evaluation of the axillary lymph node (ALN) burden in early-stage breast cancer., Methods: Data of 303 patients from hospital #1 (training cohort) and 130 cases from hospital #2 (external validation cohort) between Jun 2016 and May 2019 were enrolled. Radiomics features were extracted from shear-wave elastography (SWE) and corresponding B-mode ultrasound (BMUS) images. The minimum redundancy maximum relevance and least absolute shrinkage and selection operator algorithms were used to select ALN status-related features. Proportional odds ordinal logistic regression was performed using the radiomics signature together with clinical data, and an ordinal nomogram was subsequently developed. We evaluated its performance using C-index and calibration., Results: SWE signature, US-reported LN status, and molecular subtype were independent risk factors associated with ALN status. The nomogram based on these variables showed good discrimination in the training (overall C-index: 0.842; 95%CI, 0.773-0.879) and the validation set (overall C-index: 0.822; 95%CI, 0.765-0.838). For discriminating between disease-free axilla (N0) and any axillary metastasis (N + (≥ 1)), it achieved a C-index of 0.845 (95%CI, 0.777-0.914) for the training cohort and 0.817 (95%CI, 0.769-0.865) for the validation cohort. The tool could also discriminate between low (N + (1-2)) and heavy metastatic ALN burden (N + (≥ 3)), with a C-index of 0.827 (95%CI, 0.742-0.913) in the training cohort and 0.810 (95%CI, 0.755-0.864) in the validation cohort., Conclusion: The radiomics model shows favourable predictive ability for ALN staging in patients with early-stage breast cancer, which could provide incremental information for decision-making., Key Points: • Radiomics analysis helps radiologists to evaluate the axillary lymph node status of breast cancer with accuracy. • This multicentre retrospective study showed that radiomics nomogram based on shear-wave elastography provides incremental information for risk stratification. • Treatment can be given with more precision based on the model., (© 2021. European Society of Radiology.)

Long non-coding RNA (lncRNA) LINC00891 knockdown is associated with poor prognosis of lung adenocarcinoma, but the underlying mechanism remains to be further explored. Here, we found that LINC00891 expression is downregulated in lung cancer tissues and cell lines compared with that in adjacent normal tissues and normal lung epithelial cells. LINC00891 overexpression impedes cell proliferation, invasion, migration and epithelial-to-mesenchymal transition (EMT) process in lung cancer cells. Mechanistic research showed that GATA2 directly binds to LINC00891 promoter and transcriptionally regulates LINC00891 expression. Meanwhile, GATA2 was identified as a target of miR-128-3p, and it is negatively regulated by miR-128-3p. Moreover, overexpression of GATA2 suppresses lung cancer cell proliferation, invasion, migration, and EMT process. Furthermore, LINC00891 restrains the RhoA pathway activity, and treatment with CCG-1423 (a specific RhoA pathway inhibitor) antagonizes the promoting effect of LINC00891 knockdown on cell malignant behaviors. Additionally, silencing of LINC00891 promotes xenograft tumor growth, which can be reversed by administration with CCG-1423. In summary, LINC00891 regulated by the miR-128-3p/GATA2 axis restrains lung cancer cell malignant progression and hinders xenograft tumor growth by suppressing the RhoA pathway.

Background: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation to modulate cortical activity for improving motor function. However, the different tDCS applications for modulating cortical activity and dual task gait performance in chronic stroke have not yet been investigated. This study investigated the effects of different tDCS applications on dual task gait performance and contralesional M1 activation in chronic stroke., Methods: Forty-eight participants were randomized to anodal, bilateral, cathodal, and sham tDCS groups. Each group received 20 min of tDCS stimulation, except the sham group. Gait performance was measured by GaitRite system during cognitive dual task (CDT) walking, motor dual task (MDT) walking, and single walking (SW). Contralesional M1 activity of unaffected tibialis anterior (TA) was measured using transcranial magnetic stimulation (TMS). Intragroup difference was analyzed by Wilconxon sign ranks test with Bonferroni correction, and Kruskal-Wallis one-way analysis of variance by ranks was used for intergroup comparisons, followed by post-hoc Mann-Whitney U tests with Bonferroni correction., Results: The bilateral tDCS (p = 0.017) and cathodal tDCS (p = 0.010) improved the CDT walking speed more than sham group. The bilateral tDCS (p = 0.048) and cathodal tDCS (p = 0.048) also improved the MDT walking speed more than sham group. Furthermore, bilateral tDCS (p = 0.012) and cathodal tDCS (p = 0.040) increased the silent period (SP) more than the anodal and sham group. Thus, one-session of bilateral and cathodal tDCS improved dual task walking performance paralleled with increasing contralesional corticomotor inhibition in chronic stroke., Conclusions: Our results indicate that one-session of bilateral and cathodal tDCS increased contralesional corticomotor inhibition and improved dual task gait performance in chronic stroke., Trial Registration: Thai Clinical Trials Registry (TCTR20180116001). Registered prospectively on 16th Jan, 2018 at http://www.thaiclinicaltrials.org ., (© 2022. The Author(s).)

Background: Previous retrospective cohorts showed that Rehmannia-6 (R-6, Liu-wei-di-huang-wan) formulations were associated with significant kidney function preservation and mortality reduction among chronic kidney disease patients with diabetes. This study aimed to investigate the potential mechanism of action of common R-6 variations in a clinical protocol for diabetic nephropathy (DN) from a system pharmacology approach. Study Design and Methods: Disease-related genes were retrieved from GeneCards and OMIM by searching "Diabetic Nephropathy" and "Macroalbuminuria". Variations of R-6 were identified from a published existing clinical practice guideline developed from expert consensus and pilot clinical service program. The chemical compound IDs of each herb were retrieved from TCM-Mesh and PubChem. Drug targets were subsequently revealed via PharmaMapper and UniProtKB. The disease gene interactions were assessed through STRING, and disease-drug protein-protein interaction network was integrated and visualized by Cytoscape. Clusters of disease-drug protein-protein interaction were constructed by Molecular Complex Detection (MCODE) extension. Functional annotation of clusters was analyzed by DAVID and KEGG pathway enrichment. Differences among variations of R-6 were compared. Binding was verified by molecular docking with AutoDock. Results: Three hundred fifty-eight genes related to DN were identified, forming 11 clusters which corresponded to complement and coagulation cascades and signaling pathways of adipocytokine, TNF, HIF-1, and AMPK. Five variations of R-6 were analyzed. Common putative targets of the R-6 variations on DN included ACE, APOE, CCL2, CRP, EDN1, FN1, HGF, ICAM1, IL10, IL1B, IL6, INS, LEP, MMP9, PTGS2, SERPINE1, and TNF, which are related to regulation of nitric oxide biosynthesis, lipid storage, cellular response to lipopolysaccharide, inflammatory response, NF-kappa B transcription factor activity, smooth muscle cell proliferation, blood pressure, cellular response to interleukin-1, angiogenesis, cell proliferation, peptidyl-tyrosine phosphorylation, and protein kinase B signaling. TNF was identified as the seed for the most significant cluster of all R-6 variations. Targets specific to each formulation were identified. The key chemical compounds of R-6 have good binding ability to the putative protein targets. Conclusion: The mechanism of action of R-6 on DN is mostly related to the TNF signaling pathway as a core mechanism, involving amelioration of angiogenesis, fibrosis, inflammation, disease susceptibility, and oxidative stress. The putative targets identified could be validated through clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chan, Yu, Yiu, Xue, Lok, Li, Zou, Ma, Lai and Tang.)

Background To investigate the effectiveness and safety of withholding or restarting antithrombotic agents, and different antithrombotic therapies among patients with atrial fibrillation post-intracranial hemorrhage. Methods and Results This is a nationwide retrospective cohort study involving patients with atrial fibrillation receiving antithrombotic therapies who subsequently developed intracranial hemorrhage between January 1, 2011 and December 31, 2017. The risk of ischemic stroke (IS), recurrent intracerebral hemorrhage (ICH), and all-cause mortality were investigated between patients receiving no treatment versus patients reinitiating oral anticoagulants (OACs) or antiplatelet agents, and warfarin versus non-vitamin K antagonist OACs. We applied inverse probability of treatment weighting to balance the baseline characteristics and Cox proportional hazards model to estimate the hazard ratios (HRs) of different outcomes of interest. Compared with no treatment, OACs reduced the risk of IS (HR, 0.61; 0.42-0.89), without increase in the risk of ICH (1.15, 0.66-2.02); antiplatelet agent users showed a similar risk of IS (1.13, 0.81-1.56) and increased risk of ICH (1.81, 1.07-3.04). Use of OACs or antiplatelet agents did not reduce the risk of all-cause mortality (0.85, 0.72-1.01; and 0.88, 0.75-1.03, respectively). Compared with warfarin, non-vitamin K antagonist OAC users showed a similar risk of IS (0.92, 0.50-1.70), non-significantly reduced risk of ICH (0.53, 0.22-1.30), and significantly reduced all-cause mortality (0.60, 0.43-0.84). Conclusions OACs are recommended in patients with atrial fibrillation and intracranial hemorrhage because they reduced the risk of IS with no increase in the risk of subsequent ICH. Non-vitamin K antagonist OACs are recommended over warfarin owing to their survival benefits.

Metastatic HER2 + breast cancer is an expanding area of drug development and research, with three new drugs approved in 2020 alone. While first-line therapy is well-established for metastatic HER2 + breast cancer, the standard of care for second-line therapy will likely be changing soon based on the results of the DESTINY-Breast03 trial. In the third-line setting, many options are available. Considerations in choosing between regimens in the third-line include resistance to trastuzumab, the presence of brain metastases, and tolerability. High rates of resistance exist in this setting particularly due to expression of p95, a truncated form of HER2 that constitutively activates downstream signaling pathways. We suggest a tyrosine kinase inhibitor (TKI)-based regimen because of the activity of TKIs in brain metastases and in p95-expressing tumors. Attempts to overcome resistance to anti-HER2 therapies with PI3K inhibitors, mTOR inhibitors, and CDK 4/6 inhibitors are an active area of research. In the future, biomarkers are needed to help predict which therapies patients may benefit from the most. We review the many new drugs in development, including those with novel mechanisms of action., (© 2022. The Author(s).)

Objectives: Radiological diagnosis of subtypes of cerebral small vessel diseases remains challenging. This study aimed to explore the spatial distribution of cerebral microbleeds (CMBs) in cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) in contrast to cerebral amyloid angiopathy (CAA) in the lobar regions., Methods: Thirty-two patients with CADASIL and 33 patients with probable CAA were prospectively and consecutively included. On 3-Tesla susceptibility-weighted magnetic resonance images, CMBs were analyzed for incidence and volume within atlas-based regions of interest, followed by voxel-wise analysis using risk mapping. The distribution of CMBs was correlated with the status of hypertension. Correlation and group differences with a p-value less than 0.05 were considered to be significant., Results: As compared with the CAA group, the CADASIL group presents a larger CMB volume in hippocampus/amygdala and white matter (nonparametric analysis of covariance, p = 0.014 and 0.037, respectively), a smaller CMB volume in parietal lobe (p = 0.038), and a higher incidence in hippocampus/amygdala, white matter, and insula (logistic regression, p = 0.019, 0.024, and 0.30, respectively). As part of the exclusion criteria of probable CAA, thalamus, basal ganglia, and pons exhibit greater CMB volume/incidence in the CADASIL group. In CADASIL patients, hot spots of CMBs are identified in the putamen and posteromedial thalamus; hypertension is associated with larger CMB volumes in insula, basal ganglia, and pons., Conclusions: The spatial distribution of CMBs is differentiable between CADASIL and CAA in lobar regions. In CADASIL patients, hypertension has a region-dependent mediating effect on the CMB volume., Key Points: • The topological distribution of lobar CMBs is differentiable between CADASIL and CAA. • In CADASIL patients, hypertension mediates CMB volume and the mediation is region dependent. • CMB risk mapping allows for voxel-wise exploration of CMB distribution and reveals hot spots in the putamen and posteromedial thalamus in CADASIL., (© 2021. The Author(s).)

Background: Chronic exposure to ultraviolet (UV) rays causes severe skin damage by inducing oxidative stress and inflammation. Identifying a safe and natural substance for skin protection is a crucial research goal., Objective: The aim of this study was to clarify the effects of genistein on skin inflammation and photoaging by using 3 models (humans: skin parameters; animals: wrinkle formation; and cells: anti-inflammatory effects)., Methods: Food frequency questionnaire data and serum and skin parameter data from 120 volunteers (a group with a genistein-rich diet [RG group] and a control group). Human keratinocytes were pretreated with genistein before ultraviolet B (UVB) irradiation. Genistein was topically applied to the dorsal skin of rats., Results: The blood samples of the RG group had lower serum uric acid levels and blood urea nitrogen levels. The dynamic elasticity level in the RG group was higher than that in the controls. Genistein pretreatment suppressed the expression of proinflammatory cytokines (CXCL1, IL-1, MIF, and PLANH1) and the proteins released by UVB-treated keratinocytes. Topical application of genistein to the dorsal skin of rats reduced the severity of UVB-induced wrinkling. Both intake and topical application of genistein combated UVB-induced inflammation and aging., Conclusions: Genistein could be used as a safe and natural compound for use in novel anti-inflammatory agents for topical application. The experimental design procedure, including the skin parameter and blood serum measurements of 137 participants. Genistein-rich compounds provide protection against UVB-induced inflammation, as determined using in vitro and in vivo animal model experiments., (© 2022. The Author(s).)

Background: The efficacy and safety of intravenous alteplase administered 3-4.5 h after acute ischemic stroke have been demonstrated. However, whether responses differ between low-dose and standard-dose alteplase during this time window and whether certain subgroups benefit more remain unknown., Patients and Methods: The current analysis was based on a multicenter matched-cohort study conducted in Taiwan. The treatment group comprised 378 patients receiving intravenous alteplase 3-4.5 h after stroke onset, and the control group comprised 378 age- and sex-matched patients who did not receive alteplase treatment during the same period. Standard- and low-dose alteplase was administered to patients at the physician's discretion., Results: Overall, patients receiving alteplase exhibited more favorable outcomes than did controls [34.0 vs. 22.7%; odds ratio (OR): 1.75, 95% confidence interval (CI): 1.27-1.42], and the effectiveness was consistent in all subgroups. Although patients in the standard-dose group ( n = 182) were younger than those in the low-dose ( n = 192) group, the proportions of patients with favorable outcomes (36.3 vs. 31.8%; OR: 1.22, 95% CI: 0.80-1.88) and symptomatic hemorrhage (2.8 vs 4.2%; OR: 0.65, 95% CI: 0.21-2.02) were consistently comparable in a covariate-adjusted model and an age-matched cohort. In the subgroup analysis, patients with cardioembolism, atrial fibrillation, and hypercholesterolemia were more likely to achieve favorable outcomes after receiving standard-dose than low-dose alteplase., Conclusion: In the 3-4.5 h time window, the effectiveness and safety of standard-dose and low-dose alteplase may be comparable. A standard dose may be selected for patients with cardioembolism, atrial fibrillation, or hypercholesterolemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Tang, Chen, Chen, Tsai, Sung, Lin, Huang, Po, Sun, Chen, Chan, Wei, Lee, Hsieh, Lin, Lien and Jeng.)

Purpose: Treatment of breast cancer (BC) with borderline or low (1%-9%) estrogen and progesterone expression remains controversial, with recent data disputing ASCO/College of American Pathologists 2010 guidelines that lowered the threshold of receptor positivity from 10% to 1%. The objective of this retrospective study was to validate these guidelines at the Georgia Cancer Center with a high percentage of Black race., Methods: All female patients with invasive BC diagnosed between 2005 and 2010 at the Georgia Cancer Center were chart reviewed up to an 11-year follow-up with data cutoff at 2016. We used Cox regression to explore survival among three hormonal status (HS) groups (< 1%, 1%-9%, and ≥ 10%) adjusting for all known BC clinicopathologic variables. Fisher's exact test was used to evaluate response to endocrine therapy (ET)., Results: Among 431 patients with mean age 59 years, 24.75% had HS < 1%, 17.5% HS 1%-9%, and 57.75% HS ≥ 10%. Race was 43.75% Black and 54% White. Disease stages were early (I-IIIA) in 84.4% and advanced (IIIB-IV) in 15.56%. Mortality in HS < 1% was significantly higher than that in HS ≥ 10% (hazard ratio [HR]: 1.8; 95% CI, 1.07 to 3.02), whereas no significant mortality difference between HS 1%-9% and HS ≥ 10% (HR: 1.05; 95% CI, 0.48 to 2.30) was observed. ET was protective, and treated patients had higher predicted survival than untreated patients in the 1%-9% group (HR: 0.10; 95% CI, 0.01 to 0.85). There was no significant mortality difference between ET-treated HS 1%-9% and ≥ 10% groups., Conclusion: One percent cutoff predicted superior survival on treatment with ET compared with the other groups, and HS as low as 1%-9% was equiprognostic to HS ≥ 10%. Whether other factors such as lymphovascular invasion, grade, and other parameters change the behavior of the 1%-9% HS group remains to be explored.

Background and Purpose: NOTCH3 p.R544C mutation accounts for 5% of spontaneous intracerebral haemorrhage (ICH) in East Asian patients. We investigated whether certain CT features are associated with NOTCH3 -related ICH., Methods: Patients with spontaneous ICH from a prospective stroke registry were screened for NOTCH3 p.R544C mutation. The neuroimaging features on the initial non-contrast CT scans selected to predict NOTCH3 p.R544C mutation, including burden of white matter lesion (WML), degree of brain atrophy, number of lacunes, prominent juxtacortical WML and prominent lobar lacunes, were analysed by neuroradiologists blinded to the mutation status., Results: Of 299 patients with spontaneous ICH (mean age, 61 years; male, 68%; ICH volumes, 14.1±17.8 mL), 13 patients (4.3%) carried NOTCH3 p.R544C mutation. The clinical features, haematoma size and location were similar between NOTCH3 p.R544C mutation carriers and non-carriers. The CT scan revealed that patients with NOTCH3 p.R544C mutation had more severe WML and more frequently had prominent juxtacortical WML (69.2% vs 17.8%, p<0.001), and the effects were not driven by ageing as seen in patients without mutation. Prominent juxtacortical WML (area under receiver operating characteristic curve=0.76) outperformed the total WML score and prominent lobar lacunes and significantly predicted NOTCH3 p.R544C mutation in a multivariable-adjusted model (OR, 20.9; 95% CI 4.94 to 88.6)., Conclusion: In patients with spontaneous ICH, the severity and topographic distribution of WML can help in identifying potential NOTCH3 mutation-related ICH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Haglund's deformity, which is characterized by a bony prominence of the posterosuperior aspect of the calcaneus, causes posterior heel pain. To date, there is no standard radiographic parameter to diagnose symptomatic Haglund's deformity. Herein, we proposed novel radiographic measurements to distinguish between patients with and without symptomatic Haglund's deformity., Methods: We retrospectively evaluated ankle radiographs of 43 patients who underwent surgery for symptomatic Haglund's deformity (Haglund group) and 41 healthy individuals (control group) free of heel complaints. Fowler-Phillip angle (FPA), Heneghan-Pavlov parallel pitch lines (PPL), Haglund's deformity height, bump height, and bump-calcaneus ratio were measured and compared between the groups. Furthermore, the reliability and cut-off value of each parameter were validated via ICC and ROC curve analysis, respectively., Results: The bump height ( p < 0.001) and the bump-calcaneus ratio ( p < 0.001) showed significant differences between the control and Haglund groups, unlike FPA, PPL, and Haglund's deformity height. ROC curve analysis revealed that the AUC of bump-calcaneus ratio was larger than that of bump height. The optimal threshold was 4 mm or higher for bump height and 7.5% or higher for bump-calcaneus ratio. The intra- and inter- observer ICCs were, respectively, 0.965 and 0.898 for bump height and 0.930 and 0.889 for bump-calcaneus ratio., Conclusions: This study proposes two novel radiographic parameters to identify operatively treated Haglund's deformity, namely bump height and bump-calcaneus ratio. They are easy to measure and intuitive. Both of them are effective diagnostic parameters for Haglund's deformity. Furthermore, bump-calcaneus ratio is more reliable diagnostic parameter than bump height.

Background: Chemo-endocrine therapy is the standard adjuvant treatment strategy for hormone receptor-positive (HR+) early breast cancer. Our research aimed to compare the efficacy of adjuvant chemo-endocrine therapies, regarding different endocrinal regimens and integration sequences (sequential or concomitant), for HR+ early breast cancer., Methods: PubMed, Embase, the Cochrane Library and web of science were searched for articles published before October 2018 with Clinicaltrials.gov (https://clinicaltrials.gov) for registered clinical trials and ASCO, AACR, ESCO, SABCS meeting abstracts for addition. Randomized clinical trials (RCTs) comparing chemotherapy and/or endocrine therapy in the adjuvant treatment of primary breast cancer patients were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted and analyzed in Bayesian analysis. Patients were stratified by menopause status., Results: Thirty-three trials with 28,515 patients and 19 treatments were enrolled. Comparisons between regimens has seen better efficacy of ovarian function suppressor (OFS) + aromatase inhibitors (AI) than OFS + tamoxifen, either used concurrently [HR =0.69, 95% credible intervals (CrI): 0.47-1.02] or sequentially with chemotherapy (HR =0.72, 95% CrI: 0.49-1.06) in premenopausal patients. Adding OFS to tamoxifen was marginally better than tamoxifen used alone (DFS: HR =0.85, 95% CrI: 0.65-1.09; OS: HR =0.77, 95% CrI: 0.52-1.08). Comparisons between different sequences of chemo-endocrine therapy proved equal efficacy in premenopausal and postmenopausal patients. Recommendation was given based on ranking of treatments. Sequential and concurrent use of chemotherapy and OFS + AI ranked equally in premenopausal patients and were recommended as the best option. However, tamoxifen ranked higher when used concurrently with chemotherapy in both premenopausal and postmenopausal HR+ early breast cancer., Conclusions: In the adjuvant chemo-endocrine therapy for premenopausal HR+ early breast cancer, concurrent and sequential adjuvant chemo-endocrine therapy was demonstrated of equal efficacy in both postmenopausal and premenopausal HR+ early breast cancer., Trial Registration: PROSPERO CRD42018104889., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-21-3/coif). The authors have no conflicts of interest to declare., (2022 Translational Breast Cancer Research. All rights reserved.)

Subjects with comorbidities are at risk for neurodegeneration. There is a lack of a direct relationship between comorbidities and neurodegeneration. In this study, immunomagnetic reduction (IMR) assays were utilized to assay plasma Aβ 1-42 and total tau protein (T-Tau) levels in poststroke (PS, n = 27), family history of Alzheimer's disease (ADFH, n = 35), diabetes (n = 21), end-stage renal disease (ESRD, n = 41), obstructive sleep apnea (OSA, n = 20), Alzheimer's disease (AD, n = 65). Thirty-seven healthy controls (HCs) were enrolled. The measured concentrations of plasma Aβ 1-42 were 14.26 ± 1.42, 15.43 ± 1.76, 15.52 ± 1.60, 16.15 ± 1.05, 16.52 ± 0.59, 15.97 ± 0.54 and 20.06 ± 3.09 pg/mL in HC, PS, ADFH, diabetes, ESRD, OSA and AD groups, respectively. The corresponding concentrations of plasma T-Tau were 15.13 ± 3.62, 19.29 ± 8.01, 17.93 ± 6.26, 19.74 ± 2.92, 21.54 ± 2.72, 20.17 ± 2.77 and 41.24 ± 14.64 pg/mL. The plasma levels of Aβ 1-42 and T-Tau in were significantly higher in the PS, ADFH, diabetes, ESRD and OSA groups than controls (Aβ 1-42 in PS: 15.43 ± 1.76 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.005; T-Tau in PS: 19.29 ± 8.01 vs. 15.13 ± 3.62 pg/mL, p < 0.005, Aβ 1-42 in ADFH: 15.52 ± 1.60 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in ADFH: 17.93 ± 6.26 vs. 15.13 ± 3.62 pg/mL, p < 0.005, Aβ 1-42 in diabetes: 16.15 ± 1.05 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in diabetes: 19.74 ± 2.92 vs. 15.13 ± 3.62 pg/mL, p < 0.001, Aβ 1-42 in ESRD: 16.52 ± 0.59 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in ESRD: 21.54 ± 2.72 vs. 15.13 ± 3.62 pg/mL, p < 0.001, Aβ 1-42 in OSA: 15.97 ± 0.54 pg/mL vs. 14.26 ± 1.42 pg/mL, p < 0.001; T-Tau in OSA: 20.17 ± 2.77 vs. 15.13 ± 3.62 pg/mL, p < 0.001). This evidence indicates the high risk for dementia in these groups from the perspective of plasma biomarkers., (© 2022. The Author(s).)

The molecular mechanism of the tyrosine kinase inhibitor (TKI) resistant lung adenocarcinoma is currently unclear, and the role of methylated adenosine at the N6 position in the resistance of cancer stem cells (CSCs) therapy is unknown. This study identified a novel and effective strategy to enhance TKIs therapy response. We first confirmed the sensitization of Metformin enforcing on Osimertinib treatment and revealed the mature miRNAs signatures of the Osimertinib resistant H1975 and HCC827 cells. Let-7b expression was stimulated when adding Metformin and then increasing the therapy sensitivity by decreasing the stem cell groups expanding. Methyltransferase-like 3 (METTL3) increased the pri-Let-7b, decreased both the pre-Let-7b and mature Let-7b, attenuating the Let-7b controlling of stem cell renewal. The addition of Metformin increased the bindings of DNA methyltransferase-3a/b (DNMT3a/b) to the METTL3 promoter. With the help of the readers of NKAP and HNRNPA2B1, the cluster mediated m6A formation on pri-Let-7b processing increased the mature Let-7b, the key player in suppressing Notch signaling and re-captivating Osimertinib treatment. We revealed that the maturation processing signaling stimulated the methylation regulation of the miRNAs, and may determine the stemness control of the therapy resistance. Our findings may open up future drug development, targeting this pathway for lung cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Gao, Ma, Sun, Peng, Wu, Du, Ren, Tang and Sun.)

Recently, monoclonal antibody (mAb) therapy has gained increasing attention in the medical field due to its high specificity. Dried blood spots (DBSs) have been used in various clinical fields due to their unique characteristics, such as easy transportation, low invasiveness, and home sampling. However, hematocrit (HCT)-associated issues may lead to inaccurate quantification; moreover, the HCT value is required for converting the drug concentration from DBS to plasma. To simultaneously measure HCT levels and quantify mAb concentrations in DBS samples, this study used volumetrically applied 15 μL DBS, and combined protein G purification and ethanol precipitation approaches as the sample preparation method. Sixty-two clinical samples were used to investigate the HCT estimation ability by using hemoglobin (Hb) peptides. Four mAbs, bevacizumab, trastuzumab, nivolumab and tocilizumab, were selected to demonstrate our method, and pembrolizumab was used as the internal standard. The optimized method could measure four mAbs and Hb peptides simultaneously within 11 min. Moreover, a correlation study revealed that the correlation coefficient for the Hb peptides and the HCT value was larger than 0.9. The HCT estimation results revealed that for over 90% of the real DBS samples the HCT could be obtained within ±20% estimation error acceptance criteria. The method was validated in terms of accuracy and precision for the four mAbs. The developed method was further applied to simultaneously quantify mAb concentrations and estimate HCT values in six patient DBS samples to demonstrate its clinical applicability. It is believed that this newly developed method could facilitate various clinical studies and provide benefits for mAb therapies in clinical fields., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Unfavorable prognoses are often accompanied for hyperglycemic stroke patients. This study aimed to construct a hyperglycemia/diabetes-derived polygenic risk score (PRS) to improve the predictive performance for poor outcome risks after a stroke and to evaluate its potential clinical application., Methods: A hospital-based cohort study was conducted including 1320 first-ever acute ischemic stroke (AIS) patients and 1210 patients who completed the follow-up at 3 months. PRSs were calculated for hyperglycemia/diabetes mellitus using results from genome-wide association studies in Asians. An unfavorable functional outcome was defined as a modified Rankin Scale score of ≥3 at 3, 6, and 12 months of follow-up. The prediction of a poor prognosis was evaluated using measures of model discrimination, calibration, and net reclassification improvement (NRI)., Results: The second to fourth PRS quartiles (≥Q2) were significantly associated with higher risks of unfavorable outcomes at 3 months compared with the first quartile as the reference group after adjusting for age, baseline stroke severity, hypertension, diabetes, dyslipidemia, smoking, heart disease, and ischemic stroke subtype (p for trend <0.0001). The addition of the PRS to traditional risk predictors of poor outcomes after an AIS significantly improved the model fit (likelihood ratio test p < 0.0001) and enhanced measures of reclassification (NRI, 0.245; 95% confidence interval [CI], 0.195-0.596). The corrected C-index for the PRS combining traditional risk factors at 3 months after a stroke was 0.899 (95% CI, 0.878-0.980). Among hyperglycemic AIS patients, those who did not take an antidiabetic drug and whose PRS was ≥Q2 had higher risks of an unfavorable outcome at 3 months compared with patients who took the medicine., Conclusion: The hyperglycemia/diabetes-derived PRS was associated with poor outcomes after an AIS, but further studies are needed to validate its use for clinical applications., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

ERα signaling drives proliferation, survival and cancer initiation in the mammary gland. Therefore, it is critical to elucidate mechanisms by which ERα expression is regulated. We show that the tumor suppressor E3 ligase COP1 promotes the degradative polyubiquitination of the microtubule-associated protein HPIP. As such, COP1 negatively regulates estrogen-dependent AKT activation in breast cancer cells. However, COP1 also induces ERα expression and ERα-dependent gene transcription, at least through c-Jun degradation. COP1 and ERα levels are positively correlated in clinical cases of breast cancer. COP1 also supports the metabolic reprogramming by estrogens, including glycolysis. On the other hand, COP1 suppresses EMT in breast cancer cells. COP1 deficiency also contributes to Tamoxifen resistance, at least through protective autophagy. Therefore, COP1 acts as an oncogenic E3 ligase by promoting ERα signaling but also acts as a tumor suppressor candidate by preventing EMT, which reflects a dual role of COP1 in breast cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Diabetes and chronic kidney disease (CKD) are pandemic, requiring more therapeutic options. This retrospective cohort evaluated the effectiveness, safety profile and prescription pattern of a pilot integrative medicine service program in Hong Kong. Data from 38 patients with diabetes and CKD enrolled to receive 48-week individualized add-on Chinese medicine (CM) were retrieved from the electronically linked hospital database. A 1:1 cohort was generated with patients from the same source and matched by propensity score. The primary outcomes are the change of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) analyzed by analysis of covariance and mixed regression model adjusted for baseline eGFR, age, gender, duration of diabetes history, history of hypertension, diabetic retinopathy, and the use of insulin and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. The rate of adverse events and the change of key biochemical parameters were analyzed. After a median of 51 weeks, patients who received add-on CM had stabilized eGFR (difference in treatment period: 0.74 ml/min/1.73m 2 , 95% CI: -1.01 to 2.50) and UACR (proportional difference in treatment period: 0.95, 95% CI: 0.67 to 1.34). Add-on CM was associated with significantly preserved eGFR (Inter-group difference: 3.19 ml/min/1.73m 2 , 95%CI: 0.32 to 6.06, [Formula: see text] 0.030) compared to standard care. The intergroup ratio of UACR was comparable (0.70, 95% CI: 0.45 to 1.08, [Formula: see text] 0.104). The result is robust in sensitivity analysis with different statistical methods, and there was no interaction with CKD stage and UACR. The rate of serious adverse events (8.1% vs. 18.9%, [Formula: see text] 0.174), moderate to severe hyperkalemia (8.1% vs. 2.7%, [Formula: see text] 0.304) and hypoglycemia (13.5% vs. 5.4%, [Formula: see text] 0.223), and the levels of key biochemical parameters were comparable between groups. The top seven most used CMs contained two classical formulations, namely Liu-wei-di-huang-wan and Si-jun-zi-tang. Individualized add-on CM was associated with significant kidney function preservation and was well tolerated. Further randomized controlled trials using CM prescriptions based on Liu-wei-di-huang-wan and Si-jun-zi-tang are warranted.

Background/purpose: Sphingolipids are major constituents of eukaryotic cell membranes and play key roles in cellular regulatory processes. Our recent results in an experimental stroke animal model demonstrated changes in sphingolipids in response to acute ischemic brain injury. This study aimed to investigate the plasma levels of sphingosine-1-phosphate (S1P) and ceramides in acute ischemic stroke (AIS) patients and their associations with functional outcomes., Methods: Plasma samples were collected from patients with AIS at <48 and 48-72 h post stroke and from nonstroke controls. The levels of S1P and ceramides with different fatty acyl chain lengths were measured by the ultra-high-pressure liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). A poor functional outcome was defined as a modified Rankin Scale (mRS) score ≥2 at 3 months after AIS., Results: The results showed that S1P and very-long-chain ceramides were significantly decreased in AIS patients (n = 87; poor outcome, 56.3%) compared to nonstroke controls (n = 30). In contrast, long-chain ceramides were significantly increased in AIS patients. More importantly, higher levels of Cer(d18:1/18:0), Cer(d18:1/20:0), and Cer(d18:1/22:0) at 48-72 h were significantly associated with poor functional outcomes after adjusting for potential clinical confounders, including age, sex, hypertension, and National Institutes of Health Stroke Scale score at admission., Conclusion: Our study supported the dynamic metabolism of sphingolipids after the occurrence of AIS. Ceramides could be potential prognostic markers for patients with AIS., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Ischemic stroke with a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) or T2-weighted images indicates onset within 4.5 h, but the pathological substrates in the DWI-T2 mismatch and T2(+) areas remain elusive. In this study, proteomics was used to explore (1) the protein expression profiles in the T2(+), mismatch, and contralateral areas, and (2) the protein with the highest expression in the T2(+) area in the brains of male Sprague-Dawley rats within 4.5 h after middle cerebral artery occlusion (MCAO). The expression of the candidate protein was further validated in (1) rat brain subjected to MCAO, (2) rat primary cortical neuronal culture with oxygen-glucose deprivation (OGD), and (3) infarcted human brain tissues. This study showed that apoptosis was observed in the T2(+) and mismatch regions and necroptosis in the T2(+) region of rat brains after MCAO. We identified capping protein regulator and myosin 1 linker 3 (CARMIL3) as the candidate molecule in the T2(+) and mismatch areas, exclusively in neurons, predominantly in the cytoplasm, and most abundant in the mismatch area. The CARMIL3(+) neurons and neurites in the mismatch and T2(+) areas were larger than those in the control area, and associated with (1) increased expression of sulfonylurea receptor 1 (SUR1), indicating edema, (2) accumulation of p62, indicating impaired autophagy, and (3) increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG), indicating oxidative stress. The increased expression of CARMIL3 was validated in a cell model of cortical neurons after OGD and in infarcted human brain tissues. In conclusion, this study shows that the mismatch and T2(+) areas within 4.5 h after ischemia are characterized by upregulated expression of CARMIL3 in neurons, particularly the mismatch area, which is associated with neuronal edema, impaired autophagy, and oxidative stress, indicating that CARMIL3 serves as a molecular signature of brain ischemia., 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 © 2021 Yeh, Hsu, Yeh, Yang, Chang, Chiang, Tang, Tsai, Jeng and Hsieh.)

The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft-Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p < 0.001). CKD-EPI and MDRD estimates classified fewer patients as having GFR < 50 mL/min than CrCL in all 3 groups. Both CrCL and CKD-EPI were associated with higher-than-expected ranges of dabigatran or rivaroxaban concentrations. Nevertheless, none of the renal function equations was associated with higher-than-expected apixaban concentrations. For participants aged ≥ 75 years, CKD-EPI may be associated with higher-than-expected trough concentration of dabigatran. In conclusion, CrCL and CKD-EPI both can be used to identify patients with high trough concentrations of dabigatran or rivaroxaban. Among elderly patients who used dabigatran, CKD-EPI may be associated with increased drug concentration., (© 2021. The Author(s).)

The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11b lo migratory DC2s-a DC2 population unique to the dermis-required IL-13 signaling dependent on the transcription factors STAT6 and KLF4, whereas DC2s in lung and small intestine were STAT6-independent. Similarly, human DC2s in skin expressed an IL-4 and IL-13 gene signature that was not found in blood, spleen and lung DCs. In mice, IL-13 was secreted homeostatically by dermal innate lymphoid cells and was independent of microbiota, TSLP or IL-33. In the absence of IL-13 signaling, dermal DC2s were stable in number but remained CD11b hi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4 + GATA3 + helper T cells (T H ), whereas antifungal IL-17 + RORγt + T H cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Strengthening the gut epithelial barrier is a potential strategy for management of gut microbiota-associated illnesses. Here, we demonstrate that dual-specificity phosphatase 6 (Dusp6) knockout enhances baseline colon barrier integrity and ameliorates dextran sulfate sodium (DSS)-induced colonic injury. DUSP6 mutation in Caco-2 cells enhances the epithelial feature and increases mitochondrial oxygen consumption, accompanied by altered glucose metabolism and decreased glycolysis. We find that Dusp6-knockout mice are more resistant to DSS-induced dysbiosis, and the cohousing and fecal microbiota transplantation experiments show that the gut/fecal microbiota derived from Dusp6-knockout mice also confers protection against colitis. Further culturomics and mono-colonialization experiments show that one gut microbiota member in the genus Duncaniella confers host protection from DSS-induced injury. We identify Dusp6 deficiency as beneficial for shaping the gut microbiota eubiosis necessary to protect against gut barrier-related diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The safety of endovascular revascularization in patients with carotid artery near occlusion (CANO) is unknown. We aimed to evaluate the peri-procedural risk in CANO patients receiving carotid artery stenting (CAS). A prospective data base with retrospective review was performed to identify patients who underwent CAS with CANO from July 2006 to July 2020, and had at least 1-month clinical follow-up data. The primary endpoints were stroke, hyperperfusion syndrome, and death within 30 days after CAS. A total of 198 patients with carotid artery stenosis were enrolled including 92 patients with CANO and 106 age and sex-matched patients with 70-99% conventional carotid stenosis. Full distal carotid collapse was found in 45 CANO patients (45/92, 49%). The technical success rate was 100%. The CANO patients had significantly longer lesion lengths compared with those of the non-CANO group. The incidence of hyperperfusion syndrome was comparable (CANO: 2.2%, non-CANO: 0.9%, P = 0.598). The risks of ischemic stroke and death within 30 days were 1.1% and 0% in the CANO group; and 1.9% and 0.9%, in the non-CANO group, respectively, without statistical difference. In conclusion, CAS is safe for patients with CANO, with a similar low 30-day peri-procedural event rate comparable to those of non-CANO., (© 2021. The Author(s).)