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BACKGROUND: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. METHODS: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. FINDINGS: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. INTERPRETATION: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. FUNDING: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).

Background The integration of Traditional Chinese Medicine (TCM) and Western Medicine in a multidisciplinary approach is the future direction for the diagnosis and treatment of Cancer-Related Fatigue (CRF). However, the lack of standard criteria for syndrome differentiation and treatment selection limits the application of TCM in Western and international contexts. Patients with CRF often experience fatigue associated with metabolic and energy balance abnormalities, with thyroid function playing a critical role in the body's energy metabolism and regulation. Objective To analyze the TCM syndrome characteristics of CRF and explore their correlation with thyroid function levels, providing a reference for the integrated diagnosis and treatment of CRF and mechanism research in both TCM and western medicine. Methods The study included cancer patients who visited the oncology outpatient and inpatient departments of the China Academy of Chinese Medical Sciences Xiyuan Hospital in 2021. General information of the patients was collected. The Chinese version of the Revised Piper Fatigue Scale (RPFS-CV) was used to assess patients' fatigue. Thyroid function tests, including triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone, anti-thyroid peroxidase antibody (TPO-Ab), and thyroglobulin antibody, were collected on the day of or the day after enrollment. TCM syndrome characteristics of CRF patients were collected through a self-designed CRF TCM Four-Diagnostic Information Form. Spearman's rank correlation analysis was used to explore the correlation between RPFS-CV fatigue scores and thyroid function indicators. Point biserial correlation analysis was used to investigate the correlation between RPFS-CV fatigue scores, thyroid function indicators, and TCM syndrome characteristics of CRF. Results A total of 159 CRF patients were included. The most common types of cancer were lung cancer (50 cases, 31.4%), breast cancer (23 cases, 14.5%), head and neck tumors (21 cases, 13.2%), rectal cancer (21 cases, 13.2%), and colon cancer (18 cases, 11.3%). The median diagnosis duration was 2.15 (3.16) years; 88 patients (55.3%) experienced recurrence or metastasis, with 40 patients (45.5%) having local recurrence and 38 patients (43.2%) having oligometastasis. The median duration of metastasis was 1.50 (2.83) years; 91 patients (57.2%) were in advanced stages, 101 patients (63.5%) had received antitumor treatment, and 57 patients (35.8%) had undergone chemotherapy. In TCM syndromes, deficiency syndromes with a frequency over 10% were Qi deficiency, heart deficiency, and spleen deficiency; among excess syndromes, those occurring more than 20 times were Qi stagnation and damp-cold. Syndromes with a median RPFS-CV fatigue score over 4 were, in descending order, damp-cold, Qi stagnation, spleen deficiency, heart deficiency, liver deficiency, damp-heat, and Qi deficiency. RPFS-CV fatigue scores were positively correlated with Qi deficiency, spleen deficiency, heart deficiency, liver deficiency, damp-cold, and Qi stagnation (P

Abstract Background The most challenging aspect of rehabilitation is the repurposing of residual functional plasticity in stroke patients. To achieve this, numerous plasticity-based clinical rehabilitation programs have been developed. This study aimed to investigate the effects of motor imagery (MI)-based brain–computer interface (BCI) rehabilitation programs on upper extremity hand function in patients with chronic hemiplegia. Design A 2010 Consolidated Standards for Test Reports (CONSORT)-compliant randomized controlled trial. Methods Forty-six eligible stroke patients with upper limb motor dysfunction participated in the study, six of whom dropped out. The patients were randomly divided into a BCI group and a control group. The BCI group received BCI therapy and conventional rehabilitation therapy, while the control group received conventional rehabilitation only. The Fugl–Meyer Assessment of the Upper Extremity (FMA-UE) score was used as the primary outcome to evaluate upper extremity motor function. Additionally, functional magnetic resonance imaging (fMRI) scans were performed on all patients before and after treatment, in both the resting and task states. We measured the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), z conversion of ALFF (zALFF), and z conversion of ReHo (ReHo) in the resting state. The task state was divided into four tasks: left-hand grasping, right-hand grasping, imagining left-hand grasping, and imagining right-hand grasping. Finally, meaningful differences were assessed using correlation analysis of the clinical assessments and functional measures. Results A total of 40 patients completed the study, 20 in the BCI group and 20 in the control group. Task-related blood-oxygen-level-dependent (BOLD) analysis showed that when performing the motor grasping task with the affected hand, the BCI group exhibited significant activation in the ipsilateral middle cingulate gyrus, precuneus, inferior parietal gyrus, postcentral gyrus, middle frontal gyrus, superior temporal gyrus, and contralateral middle cingulate gyrus. When imagining a grasping task with the affected hand, the BCI group exhibited greater activation in the ipsilateral superior frontal gyrus (medial) and middle frontal gyrus after treatment. However, the activation of the contralateral superior frontal gyrus decreased in the BCI group relative to the control group. Resting-state fMRI revealed increased zALFF in multiple cerebral regions, including the contralateral precentral gyrus and calcarine and the ipsilateral middle occipital gyrus and cuneus, and decreased zALFF in the ipsilateral superior temporal gyrus in the BCI group relative to the control group. Increased zReHo in the ipsilateral cuneus and contralateral calcarine and decreased zReHo in the contralateral middle temporal gyrus, temporal pole, and superior temporal gyrus were observed post-intervention. According to the subsequent correlation analysis, the increase in the FMA-UE score showed a positive correlation with the mean zALFF of the contralateral precentral gyrus (r = 0.425, P

Objective To establish a human tonsil organoid model and investigate the immunological effects of this tonsil organoid infected by influenza virus. Methods Human tonsil tissue removed by adenoid hypertrophy surgery were subjected to gradient centrifugation, and then the obtain cells were cultured in vitro with using a 2.5D-Transwell chamber in combination with IL-2 and B cell activating factor (Baff) to construct a human tonsil organoid. Single cell transcriptome sequencing (scRNA-seq) was used to analyze the distribution of influenza virus receptors in different cell subsets of the tonsil organoid. Immunofluorescence assay and flow cytometry were applied to detect the immunological effects of the tonsil organoid in 48 h after influenza virus infection. Results The tonsil organoids were established successfully using this 2.5D-Transwell culture technique. scRNA-seq analysis showed that the receptors for influenza virus were extensively distributed in nearly all of cell subsets of tonsil organoids. In 48 h after influenza virus infection, the tonsil organoids could generate a large amount of plasma cells and memory B cells to produce specific IgG antibodies. In addition, direct infection of the virus promoted the production of TNF-α and IL-2 from CD8+ T cells and the secretion of TNF-α, IFN-γ and IL-2 by CD4+ T cells. Conclusion The tonsil organoids can be established successfully and reach maturity at about the 6th day after culture. The receptors for influenza virus are widely distributed in human tonsil organoids. Influenza virus directly infects human T cells, leading to T cell activation and cytokine releasing. Moreover, influenza virus infection also promotes B cells differentiate into plasma cells and induce the secretion of IgG as well as the formation of memory B cells.

Abstract This study investigated alterations in functional connectivity (FC) within cortico–basal ganglia–thalamo–cortical (CBTC) circuits and identified critical connections influencing poststroke motor recovery, offering insights into optimizing brain modulation strategies to address the limitations of traditional single‐target stimulation. We delineated individual‐specific parallel loops of CBTC through probabilistic tracking and voxel connectivity profiles‐based segmentation and calculated FC values in poststroke patients and healthy controls, comparing with conventional atlas‐based FC calculation. Support vector machine (SVM) analysis distinguished poststroke patients from controls. Connectome‐based predictive modeling (CPM) used FC values within CBTC circuits to predict upper limb motor function. Poststroke patients exhibited decreased ipsilesional connectivity within the individual‐specific CBTC circuits. SVM analysis achieved 82.8% accuracy, 76.6% sensitivity, and 89.1% specificity using individual‐specific parallel loops. Additionally, CPM featuring positive connections/all connections significantly predicted Fugl‐Meyer assessment of upper extremity scores. There were no significant differences in the group comparisons of conventional atlas‐based FC values, and the FC values resulted in SVM accuracy of 75.0%, sensitivity of 67.2%, and specificity of 82.8%, with no significant CPM capability. Individual‐specific parallel loops show superior predictive power for assessing upper limb motor function in poststroke patients. Precise mapping of the disease‐related circuits is essential for understanding poststroke brain reorganization.

Abstract Background The volumes of the hippocampal subfields are related to poststroke cognitive dysfunctions. However, it remains unclear whether contralesional hippocampal subfield volume contributes to cognitive impairment. This study aimed to investigate the volumetric differences in the contralesional hippocampal subfields between patients with left and right hemisphere strokes (LHS/RHS). Additionally, correlations between contralesional hippocampal subfield volumes and clinical outcomes were explored. Methods Fourteen LHS (13 males, 52.57 ± 7.10 years), 13 RHS (11 males, 51.23 ± 15.23 years), and 18 healthy controls (11 males, 46.94 ± 12.74 years) were enrolled. Contralesional global and regional hippocampal volumes were obtained with T1‐weighted images. Correlations between contralesional hippocampal subfield volumes and clinical outcomes, including the Montreal Cognitive Assessment (MoCA) and Mini‐Mental State Examination (MMSE), were analyzed. Bonferroni correction was applied for multiple comparisons. Results Significant reductions were found in contralesional hippocampal as a whole (adjusted p = .011) and its subfield volumes, including the hippocampal tail (adjusted p = .005), cornu ammonis 1 (CA1) (adjusted p = .002), molecular layer (ML) (adjusted p = .004), granule cell and ML of the dentate gyrus (GC‐ML‐DG) (adjusted p = .015), CA3 (adjusted p = .009), and CA4 (adjusted p = .014) in the RHS group compared to the LHS group. MoCA and MMSE had positive correlations with volumes of contralesional hippocampal tail (p = .015, r = .771; p = .017, r = .763) and fimbria (p = .020, r = .750; p = .019, r = .753) in the LHS group, and CA3 (p = .007, r = .857; p = .009, r = .838) in the RHS group, respectively. Conclusion Unilateral stroke caused volumetric differences in different hippocampal subfields contralesionally, which correlated to cognitive impairment. RHS leads to greater volumetric reduction in the whole contralesional hippocampus and specific subfields (hippocampal tail, CA1, ML, GC‐ML‐DG, CA3, and CA4) compared to LHS. These changes are correlated with cognitive impairments, potentially due to disrupted neural pathways and interhemispheric communication.

IntroductionLung cancer is a major global health concern. Patients undergo a substantial process of emotional transformation following a lung cancer diagnosis, during which subtle changes in brain function and/or structure may occur. As such, the present study aimed to investigate the neuroplastic changes induced by negative emotions in patients with early-stage lung cancer.MethodsThis cross-sectional study recruited 35 patients with early-stage lung cancer and 33 age- and sex-matched healthy control patients. All participants completed the Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), and functional magnetic resonance imaging (fMRI). Amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were used as the fMRI indices. Correlations between the clinical assessments and ALFF and ReHo values were calculated.ResultsOur analysis revealed no significant differences in HAMD and HAMA scores between patients and control patients (p > 0.05). However, significant alterations in ALFF and ReHo were observed in multiple brain regions in patients with early-stage lung cancer compared to healthy controls (PFalseDiscoveryRate < 0.05). Specifically, ALFF values were decreased in the right postcentral gyrus, calcarine, and left middle cingulate, while ReHo values increased in the right angular gyrus and decreased in the bilateral postcentral gyrus, insula, left calcarine, putamen, superior temporal gyrus, middle cingulate, and right Rolandic gyrus. The HAMD score was significantly correlated with the ALFF value in the right postcentral gyrus (P = 0.007).ConclusionThis study provides valuable insights into the adaptive responses of the brain following the early diagnosis of lung cancer, revealing potential disturbances in negative emotional processing. Harnessing neuroplasticity may open new avenues for the establishment of personalized treatment strategies and targeted interventions to support the emotional and mental health of patients with lung cancer.

Tongue coating affects cognition, and cognitive decline at early stage also showed relations to functional and structural remodeling of superior temporal sulcus (STS) in amnestic mild cognitive impairment (aMCI). The potential correlation between disparate cognitive manifestations in aMCI patients with different tongue coatings, and corresponding mechanisms of STS remodeling remains uncharted. In this case-control study, aMCI patients were divided into thin coating (n = 18) and thick coating (n = 21) groups. All participants underwent neuropsychological evaluations and multimodal magnetic resonance imaging. Group comparisons were conducted in clinical assessments and neuroimaging measures of banks of the STS (bankssts). Generalized linear models were constructed to explore relationships between neuroimaging measures and cognition. aMCI patients in the thick coating group exhibited significantly poorer immediate and delayed recall and slower information processing speed (IPS) (P < 0.05), and decreased functional connectivity (FC) of bilateral bankssts with frontoparietal cortices (P < 0.05, AlphaSim corrected) compared to the thin coating group. It was found notable correlations between cognition encompassing recall and IPS, and FC of bilateral bankssts with frontoparietal cortices (P < 0.05, Bonferroni's correction), as well as interaction effects of group × regional homogeneity (ReHo) of right bankssts on the first immediate recall (P < 0.05, Bonferroni's correction). aMCI patients with thick coating exhibited poor cognitive performance, which might be attributed to decreased FC seeding from bankssts. Our findings strengthen the understanding of brain reorganization of STS via which tongue coating status impacts cognition in patients with aMCI.

Objective To explore the context and hotspot changes of forensic mixed stain research through bibliometric approach. Methods The literature of forensic mixed stain included in the core collection of Web of Science database from 2011 to 2022 were collected as the study object, and the annual publication number, countrie （region）, institution, journal, keywords, etc. were bibliometrically and visually analyzed using the R-based Bibliometrix 1.1.6 package and VOSviewer 1.6.18 software. Results A total of 732 articles on forensic mixed stain were included from 2011 to 2022, with the annual number of articles published and the annual citation frequency showing a steady increase year by year. Among the 59 countries （regions） with the most published articles, the United States ranked first with 246 articles, followed by China with 153 articles. The literature came from 104 journals, and the total number of articles published in the top 10 journals was 633. FORENSIC SCI INT GENET ranked first with 307 articles. Visual analysis using VOSviewer software showed that keywords could be divided into four research clusters, namely the genetic marker development group （blue）, the mixed stain typing analysis theory group （red）, the sequencing analysis group （yellow）, and the case sample research group （green）. It can be divided into four development stages in terms of different time periods: early development （2011—2013）, middle development （2014—2016）, rapid development （2017—2020） and latest development （2021—2022）. Conclusion The number of publications by domestic and foreign scholars in the study of mixed stain in forensic science is showing a relatively stable trend. Machine learning, next generation sequencing and other research have been the hottest topics that have attracted the most attention in recent years, which is expected to further develop the theory of mixed stain typing and sequencing analysis in forensic mixed stain research.

目的 探讨多元化教学模式在提高缺血性脑血管病介入诊疗进修医师培训质量和效率方面的应用。 方法 选择2018年1月—2022年12月在南京大学医学院附属鼓楼医院神经内科接受脑血管介入培训的进修医师为研究对象，应用多元化教学模式，即将多种教学方法融合交叉的培训模式进行教学。采用问卷调查的形式对进修医师满意度及其在培训前后介入诊疗理论知识和实践操作能力进行评估。 结果 共纳入55名进修医师，年龄32～50岁，其中男性51名（92.73%）。89.09%的进修医师对多元化教学模式非常满意；分别有83.64%和85.45%的进修医师认为多元化教学模式激发了学习兴趣和自主学习能力。经过多元化教学模式培训后，能够独立完成颅外支架置入治疗的进修医师显著增加 (41.82% vs. 12.73%，P=0.002)。 结论 多元化教学模式是提高缺血性脑血管病介入进修医师培训质量和效率的有效手段。 Abstract: Objective To explore the application of multi-model teaching in improving the quality and efficiency of training in neurointerventional operation for ischemic cerebrovascular disease. Methods Subjects were selected as training doctors who received cerebrovascular interventional operation training in the Department of Neurology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School from January 2018 to December 2022. All training doctors received multi-model training, that is, a combination of multiple teaching methods and cross-training mode for teaching. Questionnaire survey was used to evaluate the training doctors’ satisfaction of multi-model teaching and the changes in theoretical knowledge and practical ability of intervention diagnosis and treatment before and after training. Results A total of 55 training doctors were included, aged from 32 to 50 years, including 51 males (92.73%). Among them, 89.09% were satisfied with the multi-model teaching. Meanwhile, 83.64% and 85.45% of training doctors believe that multi-model teaching has stimulated their learning interest and improved self-learning abilities, respectively. After training, a significant increase in the number of training doctors who can independently complete extracranial stent implantation was achieved (41.82% vs. 12.73%, P=0.001). Conclusions The muti-model teaching is an effective method to improve the quality and efficiency of training in neurointerventional operation for ischemic cerebrovascular disease.

Abstract Background Electroacupuncture (EA) has been shown to facilitate brain plasticity‐related functional recovery following ischemic stroke. The functional magnetic resonance imaging technique can be used to determine the range and mode of brain activation. After stroke, EA has been shown to alter brain connectivity, whereas EA's effect on brain network topology properties remains unclear. An evaluation of EA's effects on global and nodal topological properties in rats with ischemia reperfusion was conducted in this study. Methods and results There were three groups of adult male Sprague‐Dawley rats: sham‐operated group (sham group), middle cerebral artery occlusion/reperfusion (MCAO/R) group, and MCAO/R plus EA (MCAO/R + EA) group. The differences in global and nodal topological properties, including shortest path length, global efficiency, local efficiency, small‐worldness index, betweenness centrality (BC), and degree centrality (DC) were estimated. Graphical network analyses revealed that, as compared with the sham group, the MCAO/R group demonstrated a decrease in BC value in the right ventral hippocampus and increased BC in the right substantia nigra, accompanied by increased DC in the left nucleus accumbens shell (AcbSh). The BC was increased in the right hippocampus ventral and decreased in the right substantia nigra after EA intervention, and MCAO/R + EA resulted in a decreased DC in left AcbSh compared to MCAO/R. Conclusion The results of this study provide a potential basis for EA to promote cognitive and motor function recovery after ischemic stroke.

BackgroundLong-term skill learning can lead to structure and function changes in the brain. Different sports can trigger neuroplasticity in distinct brain regions. Volleyball, as one of the most popular team sports, heavily relies on individual abilities such as perception and prediction for high-level athletes to excel. However, the specific brain mechanisms that contribute to the superior performance of volleyball athletes compared to non-athletes remain unclear.MethodWe conducted a study involving the recruitment of ten female volleyball athletes and ten regular female college students, forming the athlete and novice groups, respectively. Comprehensive behavioral assessments, including Functional Movement Screen and audio-visual reaction time tests, were administered to both groups. Additionally, resting-state magnetic resonance imaging (MRI) data were acquired for both groups. Subsequently, we conducted in-depth analyses, focusing on the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) in the brain for both the athlete and novice groups.ResultsNo significant differences were observed in the behavioral data between the two groups. However, the athlete group exhibited noteworthy enhancements in both the ALFF and ReHo within the visual cortex compared to the novice group. Moreover, the functional connectivity between the visual cortex and key brain regions, including the left primary sensory cortex, left supplementary motor cortex, right insula, left superior temporal gyrus, and left inferior parietal lobule, was notably stronger in the athlete group than in the novice group.ConclusionThis study has unveiled the remarkable impact of volleyball athletes on various brain functions related to vision, movement, and cognition. It indicates that volleyball, as a team-based competitive activity, fosters the advancement of visual, cognitive, and motor skills. These findings lend additional support to the early cultivation of sports talents and the comprehensive development of adolescents. Furthermore, they offer fresh perspectives on preventing and treating movement-related disorders. Trial registrationRegistration number: ChiCTR2400079602. Date of Registration: January 8, 2024.