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Abstract Background This study aimed to explore the demographic characteristics, diagnostic challenges, treatment patterns, and caregiver burden of mitochondrial diseases. Methods This retrospective cross-sectional study enrolled patients diagnosed with mitochondrial diseases from the Department of Neurology at Peking University First Hospital between January 2010 and December 2021. A questionnaire covering demographic characteristics, diagnostic dilemma, treatment, economic aspects, and caregiver stress was administered, and disability was assessed using the modified Rankin Scale (mRS). Results A total of 183 patients (mean age: 16 (IQR: 12–25), 49.72% males) were enrolled, including 124 pediatric patients and 59 adult patients. MELAS (106. 57.92%) and Leigh syndrome (37, 20.22%) were predominant among the mitochondrial disease subtypes. Among them, 132 (72.13%) patients were initially misdiagnosed with other diseases, 58 (31.69%) patients visited 2 hospitals before confirmed as mitochondrial disease, and 39 (21.31%) patients visited 3 hospitals before confirmed as mitochondrial disease. Metabolic modifiers were the most common type of drugs used, including several dietary supplements such as L-carnitine (117, 63.93%), Coenzyme Q10 (102, 55.74%), idebenone (82, 44.81%), and vitamins (99, 54.10%) for proper mitochondrial function. Mothers are the primary caregivers for both children (36.29%) and adults (38.98%). The mRS score ranged from 0 to 5, 92.35% of the patients had different degrees of disability due to mitochondrial disease. The average monthly treatment cost was 3000 RMB for children and 3100 RMB for adults. Conclusions This study provided valuable insights into the characteristics and challenges of mitochondrial diseases, which underscores the need for improved awareness, diagnostic efficiency, and comprehensive support for patients and caregivers.

Abstract Background During the prolonged period from Human Papillomavirus (HPV) infection to cervical cancer development, Low-Grade Squamous Intraepithelial Lesion (LSIL) stage provides a critical opportunity for cervical cancer prevention, giving the high potential for reversal in this stage. However, there is few research and a lack of clear guidelines on appropriate intervention strategies at this stage, underscoring the need for real-time prognostic predictions and personalized treatments to promote lesion reversal. Methods We have established a prospective cohort. Since 2018, we have been collecting clinical data and pathological images of HPV-infected patients, followed by tracking the progression of their cervical lesions. In constructing our predictive models, we applied logistic regression and six machine learning models, evaluating each model’s predictive performance using metrics such as the Area Under the Curve (AUC). We also employed the SHAP method for interpretative analysis of the prediction results. Additionally, the model identifies key factors influencing the progression of the lesions. Results Model comparisons highlighted the superior performance of Random Forests (RF) and Support Vector Machines (SVM), both in clinical parameter and pathological image-based predictions. Notably, the RF model, which integrates pathological images and clinical multi-parameters, achieved the highest AUC of 0.866. Another significant finding was the substantial impact of sleep quality on the spontaneous clearance of HPV and regression of LSIL. Conclusions In contrast to current cervical cancer prediction models, our model’s prognostic capabilities extend to the spontaneous regression stage of cervical cancer. This model aids clinicians in real-time monitoring of lesions and in developing personalized treatment or follow-up plans by assessing individual risk factors, thus fostering lesion spontaneous reversal and aiding in cervical cancer prevention and reduction. Graphical Abstract

Abstract Within the intricate tapestry of molecular research, noncoding RNAs (ncRNAs) were historically overshadowed by a pervasive presumption of their inability to encode proteins or peptides. However, groundbreaking revelations have challenged this notion, unveiling select ncRNAs that surprisingly encode peptides specifically those nearing a succinct 100 amino acids. At the forefront of this epiphany stand lncRNAs and circRNAs, distinctively characterized by their embedded small open reading frames (sORFs). Increasing evidence has revealed different functions and mechanisms of peptides/proteins encoded by ncRNAs in cancer, including promotion or inhibition of cancer cell proliferation, cellular metabolism (glucose metabolism and lipid metabolism), and promotion or concerted metastasis of cancer cells. The discoveries not only accentuate the depth of ncRNA functionality but also open novel avenues for oncological research and therapeutic innovations. The main difficulties in the study of these ncRNA-derived peptides hinge crucially on precise peptide detection and sORFs identification. Here, we illuminate cutting-edge methodologies, essential instrumentation, and dedicated databases tailored for unearthing sORFs and peptides. In addition, we also conclude the potential of clinical applications in cancer therapy.

Abstract Background A few patients with inflammatory myopathy showed anti-mitochondrial antibody (AMA) positivity. This study aimed to report the clinical and pathological findings with vacuoles in 3 cases of such patients. Methods Three cases with myositis from the Myositis Clinical Database of Peking University First Hospital were identified with AMA positivity. Their clinical records were retrospectively reviewed and the data was extracted. All the 3 cases underwent muscle biopsy. Results Three middle-aged patients presented with chronic-onset weakness of proximal limbs, marked elevation of creatine kinase, and AMA-positivity. Two of the 3 cases meet the criteria of primary biliary cholangitis. All the 3 cases presented with cardiac involvement and proteinuria. Two cases developed type 2 respiratory failure. MRI of the thigh muscle showed multiple patches of edema bilaterally in both cases, mostly in the adductor magnus. Pathological findings include degeneration of muscle fibers, diffused MHC-I positivity, and complement deposits on cell membranes. Vacuoles without rims of different sizes were discovered under the membrane of the muscle fibers. A few RBFs were discovered in case 1, while a diffused proliferation of endomysium and perimysium was shown in case 2. Conclusions AMA-positive inflammatory myopathy is a disease that could affect multiple systems. Apart from inflammatory changes, the pathological findings of muscle can also present vacuoles.

Abstract Lung cancer is a deeply malignant tumor with high incidence and mortality. Despite the rapid development of diagnosis and treatment technology, abundant patients with lung cancer are still inevitably faced with recurrence and metastasis, contributing to death. Lymphatic metastasis is the first step of distant metastasis and an important prognostic indicator of non-small cell lung cancer. Tumor-induced lymphangiogenesis is involved in the construction of the tumor microenvironment, except promoting malignant proliferation and metastasis of tumor cells, it also plays a crucial role in individual response to treatment, especially immunotherapy. Thus, this article reviews the current research status of lymphatic metastasis in non-small cell lung cancer, in order to provide some insights for the basic research and clinical and translational application in this field.

Existing medical image segmentation methods may only consider feature extraction and information processing in spatial domain, or lack the design of interaction between frequency information and spatial information, or ignore the semantic gaps between shallow and deep features, and lead to inaccurate segmentation results. Therefore, in this paper, we propose a novel frequency selection segmentation network (FSSN), which achieves more accurate lesion segmentation by fusing local spatial features and global frequency information, better design of feature interactions, and suppressing low correlation frequency components for mitigating semantic gaps. Firstly, we propose a global-local feature aggregation module (GLAM) to simultaneously capture multi-scale local features in the spatial domain and exploits global frequency information in the frequency domain, and achieves complementary fusion of local details features and global frequency information. Secondly, we propose a feature filter module (FFM) to mitigate semantic gaps when we conduct cross-level features fusion, and makes FSSN discriminatively determine which frequency information should be preserved for accurate lesion segmentation. Finally, in order to make better use of local information, especially the boundary of lesion region, we employ deformable convolution (DC) to extract pertinent features in the local range, and makes our FSSN can focus on relevant image contents better. Extensive experiments on two public benchmark datasets show that compared with representative medical image segmentation methods, our FSSN can obtain more accurate lesion segmentation results in terms of both objective evaluation indicators and subjective visual effects with fewer parameters and lower computational complexity.

Abstract Background Pathogenic missense variants in the dystrophin (DMD) gene are rarely reported in dystrophinopathies. Most DMD missense variants are of uncertain significance and their pathogenicity interpretation remains complicated. We aimed to investigate whether DMD missense variants would cause aberrant splicing and re-interpret their pathogenicity based on mRNA and protein studies. Methods Nine unrelated patients who had an elevated serum creatine kinase level with or without muscle weakness were enrolled. They underwent a detailed clinical, imaging, and pathological assessment. Routine genetic testing and muscle-derived mRNA and protein studies of dystrophin and sarcoglycan genes were performed in them. Results Three of the 9 patients presented with a Duchenne muscular dystrophy (DMD) phenotype and the remaining 6 patients had a suspected diagnosis of Becker muscular dystrophy (BMD) or sarcoglycanopathy based on their clinical and pathological characteristics. Routine genetic testing detected only 9 predicted DMD missense variants in them, of which 6 were novel and interpreted as uncertain significance. Muscle-derived mRNA studies of sarcoglycan genes didn’t reveal any aberrant transcripts in them. Dystrophin mRNA studies confirmed that 3 predicted DMD missense variants (c.2380G > C, c.4977C > G, and c.5444A > G) were in fact splicing and frameshift variants due to aberrant splicing. The 9 DMD variants were re-interpreted as pathogenic or likely pathogenic based on mRNA and protein studies. Therefore, 3 patients with DMD splicing variants and 6 patients with confirmed DMD missense variants were diagnosed with DMD and BMD, respectively. Conclusion Our study highlights the importance of muscle biopsy and aberrant splicing for clinical and genetic interpretation of uncertain DMD missense variants.

Abstract Background Vast economic and healthcare status discrepancies exist among regions in China, contributing to different treatment patterns. This study was aimed to investigate the current status of pharmacotherapy for acute ischemic stroke (AIS) and outcomes in China and explore the geographic variation in stroke care. Methods This study was a multicenter prospective registry study, which collected the data of patients with AIS from 80 hospitals in 46 cities in 2015–2017 across China. Poor functional outcome defined as a modified Rankin Scale score of 3–6 was assessed at 3 and 12 months. Multivariate logistic regression was used. Results Among 9973 eligible patients, the number of receiving intravenous thrombolysis (IVT), antiplatelet agents, anticoagulants, statin and human urinary kallidinogenase was 429 (4.3%), 9363 (93.9%), 1063 (10.7%), 6828 (74.7%) and 5112 (51.2%), respectively. Multivariable analysis showed IVT use in northeastern was significantly more frequent than in eastern region (OR = 3.17, 95% CI, 2.53–3.99), while the antiplatelets agents use were less frequent (OR = 0.46, 95%CI: 0.38–0.57). The proportions of poor outcomes at 3 and 12 months were 20.7% and 15.8%, respectively. Multivariate analysis showed AIS patients from northeastern and central region had significantly lower risk of poor outcome at month 3 and 12 than those from eastern region (all P

Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P

Chemotherapy has already proven widely effective in treating cancer. Chemotherapeutic agents usually include DNA damaging agents and non-DNA damaging agents. Assessing genotoxic effect is significant during chemotherapy drug development, since the ability to attack DNA is the major concern for DNA damaging agents which relates to the therapeutic effect, meanwhile genotoxicity should also be evaluated for chemotherapy agents’ safety especially for non-DNA damaging agents. However, currently applicability of in vitro genotoxicity assays is hampered by the fact that genotoxicity results have comparatively high false positive rates. γ-H2AX has been shown to be a bifunctional biomarker reflecting both DNA damage response and repair. Previously, we developed an in vitro genotoxicity assay based on γ-H2AX quantification using mass spectrometry. Here, we employed the assay to quantitatively assess the genotoxic effects of 34 classic chemotherapy agents in HepG2 cells. Results demonstrated that the evaluation of cellular γ-H2AX could be an effective approach to screen and distinguish types of action of different classes of chemotherapy agents. In addition, two crucial indexes of DNA repair kinetic curve, i.e., k (speed of γ-H2AX descending) and t50 (time required for γ-H2AX to drop to half of the maximum value) estimated by our developed online tools were employed to further evaluate nine representative chemotherapy agents, which showed a close association with therapeutic index or carcinogenic level. The present study demonstrated that mass spectrometric quantification of γ-H2AX may be an appropriate tool to preliminarily evaluate genotoxic effects of chemotherapy agents.

This paper proposes a method for generating interferometric phase diagrams, which includes interferometric image registration based on Dot Trace Texture Information (DTTI) and interferometric phase filtering based on semantic segmentation. First, the InSAR images are sharpened according to the different backscattering characteristics of various pixel values, and DTTI is extracted to generate the Dot Trace Texture Map (DTTM). Second, SIFT feature points are extracted from two InSAR coherent complex images. They are then screened by comparison with DTTI. These selected points are used to calculate the registration relationship, ensuring precise registration of the two images. Third, the interferometric phase diagram is segmented by semantics based on correlation coefficients. For high-quality interferometric phase regions, we use two-dimensional frequency domain rotational symmetric Gaussian Laplace and wavelet domain filters successively. For low-quality regions, we use an average filter to smooth out noise. The superiority of the proposed algorithm was verified through comparative experiments.

Due to the rapid development of RNA sequencing techniques, a circular non-coding RNA (ncRNA) known as circular RNAs (circRNAs) has gradually come into focus. As a distinguished member of the circRNA family, circ_0003945 has garnered attention for its aberrant expression and biochemical functions in human diseases. Subsequent studies have revealed that circ_0003945 could regulate tumor cells proliferation, migration, invasion, apoptosis, autophagy, angiogenesis, drug resistance, and radio resistance through the molecular mechanism of competitive endogenous RNA (ceRNA) during tumorigenesis. The expression of circ_0003945 is frequently associated with some clinical parameters and implies a poorer prognosis in the majority of cancers. In non-malignant conditions, circ_0003945 also holds considerable importance in diseases pathogenesis. This review aims to recapitulate molecular mechanism of circ_0003945 and elucidates its potential as a diagnostic and therapeutic target in neoplasms and other diseases.

Abstract CTCF plays an important role in 3D genome organization by adjusting the strength of chromatin insulation at TAD boundaries, where clustered CBS (CTCF-binding site) elements are often arranged in a tandem array with a complex divergent or convergent orientation. Here, using Pcdh and HOXD loci as a paradigm, we look into the clustered CTCF TAD boundaries and find that, counterintuitively, outward-oriented CBS elements are crucial for inward enhancer-promoter interactions as well as for gene regulation. Specifically, by combinatorial deletions of a series of putative enhancer elements in mice in vivo or CBS elements in cultured cells in vitro, in conjunction with chromosome conformation capture and RNA-seq analyses, we show that deletions of outward-oriented CBS elements weaken the strength of long-distance intra-TAD promoter-enhancer interactions and enhancer activation of target genes. Our data highlight the crucial role of outward-oriented CBS elements within the clustered CTCF TAD boundaries in developmental gene regulation and have interesting implications on the organization principles of clustered CTCF sites within TAD boundaries.

In the present study, an investigation is conducted into the effect of different aging treatments on the hardening properties of the 6151 aluminum alloy sheet. According to the research results, the artificial aging hardening response of the pre-aging sheet is significantly stronger compared to natural aging after the solution treatment. In the stage of artificial aging, 120 oC pre-aging treatment produces a more significant strengthening effect than 80 oC and 100 oC pre-aging treatment. The longer the artificial time, the higher the hardness value. When the artificial aging temperature reaches 200 oC, the time taken to achieve peak aging is the shortest, and the occurrence of softening is evident in the over-aged state. When the artificial aging temperature is 200 oC, the softening effect becomes more significant. Natural aging can inhibit the strengthening effect of artificial aging. With the extension of natural aging, the hardening effect of artificial aging diminishes gradually.

Abstract Objective Anti‐mitochondrial antibodies (AMAs) are associated with idiopathic inflammatory myopathies (IIMs). We aimed to summarize the clinicopathological characteristics, assess circulating cell‐free mitochondrial DNA (ccf‐mtDNA), and circulating cell‐free nuclear DNA (ccf‐nDNA) in AMA‐associated IIMs. Methods Medical records of 37 IIMs patients with AMAs were reviewed. Circulating cell‐free mtDNA and ccf‐nDNA levels in sera from IIMs patients with AMAs (n = 21), disease controls (n = 66) and healthy controls (HCs) (n = 23) were measured and compared. Twenty‐eight immune‐mediated necrotizing myopathy (IMNM) patients, 23 dermatomyositis (DM) patients, and 15 anti‐synthetase syndrome (ASS) patients were enrolled as disease controls. Correlations between variables were analyzed. Results Limb weakness was observed in 75.7% and neck weakness in 56.8% of patients. Cardiac involvement occurred in 51.4% of patients. Muscle pathology revealed 81.1% of IMNM, 5.4% polymyositis, and 13.5% nonspecific myositis. Microinfarction was observed in 8.1% of patients. Serum ccf‐mtDNA levels in AMA‐associated IIMs were significantly higher than those in HCs (p

Abstract Background The coexistence of two myositis-specific autoantibodies (MSA) is considered extremely rare. We describe three patients with both anti-signal recognition particle (SRP) antibodies and another MSA in serum. Methods We performed a retrospective clinical data collection and follow-up studies of the clinical manifestations and treatment outcome of three patients positive with anti-SRP antibodies and other MSAs. IgG antibodies against MSAs were detected using commercial line immunoblot assay. Results The tests of MSA showed positive result of anti-SRP antibodies and another one MSA including anti-TIF1-γ, anti-Jo1, or anti-EJ antibodies, respectively. The proximal muscle weakness appeared in 2 patients; interstitial lung disease presented in 2 patients. The serum CK level was elevated in 1 patient. The muscle biopsy showed necrotizing myopathy in 1 patient and deposition of membrane attack complex on scattered myofibers in the other one patient. One of the two patients with interstitial lung disease died because of respiratory failure. One patient had completely improved and the other one showed partial remission after immunosuppressive therapy. Conclusions The patients with anti-SRP antibodies co-occurred with the other MSA may have various clinical characteristics. The clinicopathological phenotypes of these patients seem to be mainly caused by one of the MSAs, namely the responsible antibody.

Most pathogenic DMD variants are detectable and interpretable by standard genetic testing for dystrophinopthies. However, approximately 1∼3% of dystrophinopthies patients still do not have a detectable DMD variant after standard genetic testing, most likely due to structural chromosome rearrangements and/or deep intronic pseudoexon-activating variants. Here, we report on a boy with a suspected diagnosis of Becker muscular dystrophy (BMD) who remained without a detectable DMD variant after exonic DNA-based standard genetic testing. Dystrophin mRNA studies and genomic Sanger sequencing were performed in the boy, followed by in silico splicing analyses. We successfully detected a novel deep intronic disease-causing variant in the DMD gene (c.2380 + 3317A > T), which consequently resulting in a new dystrophin pseudoexon activation through the enhancement of a cryptic donor splice site. The patient was therefore genetically diagnosed with BMD. Our case report further emphasizes the significant role of disease-causing splicing variants within deep intronic regions in genetically undiagnosed dystrophinopathies.

CGG repeat expansion in NOTCH2NLC is the genetic cause of neuronal intranuclear inclusion disease (NIID). Previous studies indicated that the CGG repeats can be translated into polyglycine protein (N2CpolyG) which was toxic to neurons by forming intranuclear inclusions (IIs). However, little is known about the factors governing polyG IIs formation as well as its molecular pathogenesis. Considering that neurogenetic disorders usually involve interactions between genetic and environmental stresses, we investigated the effect of stress on the formation of IIs. Our results revealed that under hyperosmotic stress, N2CpolyG translocated from the cytoplasm to the nucleus and formed IIs in SH-SY5Y cells, recapitulating the pathological hallmark of NIID patients. Furthermore, N2CpolyG interacted/ co-localized with an RNA-binding protein FUS in the IIs of cellular model and NIID patient tissues, thereby disrupting stress granule formation in cytoplasm under hyperosmotic stress. Consequently, dysregulated expression of microRNAs was found both in NIID patients and cellular model, which could be restored by FUS overexpression in cultured cells. Overall, our findings indicate a mechanism of stress-induced pathological changes as well as neuronal damage, and a potential strategy for the treatment of NIID.

Abstract Objective The co‐morbidity of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)/autoimmune nodopathies with nephropathy has been gradually known in recent years. This study was intended to explore the clinical, serological and neuropathological features of seven patients with CIDP/autoimmune nodopathies and nephropathy. Methods Among 83 CIDP patients, seven were identified with nephropathy. Their clinical, electrophysiological and laboratory examination data were collected. The nodal/paranodal antibodies were tested. The sural biopsies were performed in all the patients, and renal biopsies were operated in 6 patients. Results Six patients had chronic onsets and one had an acute onset. Four patients exhibited peripheral neuropathy preceding nephropathy while two showed concurrent onset of neuropathy and nephropathy, and one started with nephropathy. All the patients showed demyelination in electrophysiological examination. Nerve biopsies showed mild to moderate mixed neuropathies including demyelinating and axonal changes in all patients. Renal biopsies showed membranous nephropathy in all 6 patients. Immunotherapy was effective in all patients, with two patients showing good response to corticosteroid treatment alone. Four of the patients were positive to anti‐CNTN1 antibody. Compared with anti‐CNTN1 antibody‐negative patients, antibody‐positive patients had a higher proportion of ataxia (3/4 vs. 1/3), autonomic dysfunction (3/4 vs. 1/3), less frequent antecedent infections (1/4 vs. 2/3), higher cerebrospinal fluid proteins (3.2 g/L vs. 1.69 g/L), more frequent conduction block on electrophysiological examination (3/4 vs. 1/3), higher myelinated nerve fiber density, and positive CNTN1 expression in the glomeruli of kidney tissues. Conclusion Anti‐CNTN1 antibody was the most frequent antibody in this group of patients with CIDP/autoimmune nodopathies and nephropathy. Our study suggested that there might be some clinical and pathological differences between the antibody positive and negative patients.

Abstract Background Type 2 diabetes mellitus (T2DM) is closely associated with the occurrence of cognitive impairment, imposing a heavy burden on the patient's family and society. Aerobic exercise and targeted memory strategies have been widely reported to improve cognitive function. Methods: A total of 122 T2DM patients with Montreal Cognitive Assessment Scale (MoCA) test scores of less than 26 received the aerobic exercise combined with memory strategy training. After 6 months of intervention, a final group of 113 patients entered the final evaluation and analysis. Diabetes‐specific quality of life scale (DSQL) and activities of daily living (ADL) assessments were performed to evaluate the life quality of the patients. Results The scores of MoCA and ADL were significantly upregulated, and the scores of DSQL were significantly reduced after the 6‐month intervention of T2DM patients. The levels of fasting plasma glucose (FPG), hemoglobin A1c, total cholesterol (TC), and triglyceride (TG) levels of T2DM patients with cognitive impairment significantly decreased post intervention. A significant decrease in low density lipoprotein cholesterol (LDL‐C) and an increase in high density lipoprotein cholesterol (HDL‐C) were observed. The FPG, HbA1, TC, TG, and LDL‐C levels were significantly lower, and the HDL‐C levels were significantly higher in patients with normal cognitive function than in patients with abnormal cognitive function. Conclusions Aerobic exercise combined with memory strategy training effectively improved the memory and cognitive function in patients with T2DM.

Abstract Background Intrathecal injection of medications can be challenging in spinal muscular atrophy (SMA) patients with severe scoliosis or after spine surgery. Here we report our experience with real-time ultrasound (US)-guided intrathecal administration of nusinersen in patients with SMA. Methods Seven patients (six children and one adult) with either spinal fusion or severe scoliosis were enrolled. We performed intrathecal injections of nusinersen under US guidance. The efficacy and safety of US-guided injection were explored. Results Five patients had undergone spinal fusion, while the other two presented severe scoliosis. Success was achieved in 19/20 lumbar punctures (95%), 15 of which were performed through the near-spinous process approach. The intervertebral space with a designated channel was selected for the five postoperative patients, while the interspaces with the smallest rotation angle were chosen for the other two patients with severe scoliosis. In 89.5% (17/19) of the punctures, the number of insertions was no more than two. No major adverse events were observed. Conclusion Given its safety and efficacy, real-time US guidance is recommended for SMA patients with spine surgery or severe scoliosis, and the near-spinous process view can be used as a interlaminar puncture approach for US guidance.

Introduction: Mitochondrial disease is a spectrum of debilitating disorders caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA that compromises the respiratory chain. Mitochondrial 3243A>G (m.3243 A>G) is the most common mutation showing great heterogeneity in phenotype. Previous studies have indicated that NADH: ubiquinone oxidoreductase (complex I) deficiency accompanied by a decreased nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) ratio may play a pivotal role in the pathogenesis of m.3243A>G mutation.Methods: To evaluate the potential effects of strategies targeting the imbalanced NAD+/NADH ratio in m.3243A>G mutation, we treated fibroblasts derived from patients with the m.3243 A>G mutation using nicotinamide riboside (NR) or mitochondria-targeted H2O-forming NADH oxidase (mitoLbNOX).Results: M.3243 A>G fibroblasts showed a significant reduction in complex I core subunit 6, complex I enzymatic activity, complex I-dependent oxygen consumption rate (OCR), and adenosine triphosphate (ATP) production compared to the controls. The NAD+/NADH ratio was also significantly reduced in m.3243 A>G fibroblasts, and, using fluorescence lifetime imaging microscopy, we also found that the NADH level was elevated in m.3243 A>G fibroblasts. After NR treatment, the NAD+/NADH ratio, complex I-dependent OCR, and ATP levels increased, whereas NADH levels remained unchanged. More excitingly, after treatment with mitoLbNOX, the NAD+/NADH ratio, complex I-independent OCR, and ATP levels increased more pronouncedly compared with the NR treatment group, accompanied by significantly reduced NADH levels.Discussion: The present study suggests that compared with repletion of NAD+ alone, the combination of this therapeutic modality with alleviation of NADH overload may amplify the treatment effect of restoring NAD+/NADH balance in m.3243A>G fibroblasts.

Abstract Objective The objective of this research was to study the clinical features, genetic characteristics, muscle imaging, and muscle pathological changes of a cohort of Chinese patients with mutations in the valosin‐containing protein (VCP) gene. Methods Nine patients from seven Chinese pedigrees were recruited. Variants were detected by next‐generation sequencing and confirmed by Sanger sequencing. Thigh muscle MRIs were performed in five patients. All the patients received muscle biopsies. Results Seven variants in VCP were identified, and two were novel. All the patients presented with adult‐onset muscle weakness. The appearance of “isolated island sign” or “contra‐isolated island sign” was observed in four of the five the patients on muscle MRIs. Muscle biopsies demonstrated the combination of neuropathic and myopathic changes in seven patients and muscle dystrophic changes in two patients. Notably, rimmed vacuoles and cytoplasmic VCP and p62‐positive protein aggregates were observed in all the patients. Conclusion Our finding of novel variants expanded the mutational spectrum of the VCP gene. This cohort of Chinese patients with VCP mutations mainly present with inclusion body myopathy with predominant limb–girdle distribution. The characteristic pattern of fatty infiltration, especially the “isolated island” and “contra‐isolated island” on muscle MRI, along with rimmed vacuoles in muscle biopsy, provides valuable clues for guiding genetic diagnostic workup.

Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents. The gut microbiota plays an important role in the pathophysiology of NAFLD through the gut–liver axis. Therefore, we aimed to investigate the genus and species of gut microbiota and their functions in children and adolescents with NAFLD. From May 2017 to July 2018, a total of 58 children and adolescents, including 27 abnormal weight (AW) (obese) NAFLD patients, 16 AW non-NAFLD children, and 15 healthy children, were enrolled in this study at Shenzhen Children’s Hospital. All of them underwent magnetic resonance spectroscopy (MRS) to quantify the liver fat fraction. Stool samples were collected and analysed with metagenomics. According to body mass index (BMI) and MRS proton density fat fraction (MRS-PDFF), we divided the participants into BMI groups, including the AW group (n = 43) and the Lean group (n = 15); MRS groups, including the NAFLD group (n = 27) and the Control group (n = 31); and BMI-MRS 3 groups, including NAFLD_AW (AW children with NAFLD) (n = 27), Ctrl_AW (n = 16) (AW children without NAFLD) and Ctrl_Lean (n = 15). There was no difference in sex or age among those groups (p > 0.05). In the BMI groups, at the genus level, Dialister, Akkermansia, Odoribacter, and Alistipes exhibited a significant decrease in AW children compared with the Lean group. At the species level, Megamonas hypermegale was increased in the AW group, while Akkermansia muciniphila, Dialister invisus, Alistipes putredinis, Bacteroides massiliensis, Odoribacter splanchnicus, and Bacteroides thetaiotaomicron were decreased in AW children, compared to the Lean group. Compared with the Control group, the genus Megamonas, the species of Megamonas hypermegale and Megamonas rupellensis, increased in the NAFLD group. Furthermore, the genus Megamonas was enriched in the NAFLD_AW group, while Odoribacter, Alistipes, Dialister, and Akkermansia were depleted compared with the Ctrl_Lean or Ctrl_AW group at the genus level. Megamonas hypermegale and Megamonas rupellensis exhibited a significant increase in NAFLD_AW children compared with the Ctrl_Lean or Ctrl_AW group at the species level. Compared with healthy children, the pathways of P461-PWY contributed by the genus Megamonas were significantly increased in NAFLD_AW. We found that compared to healthy children, the genus Megamonas was enriched, while Megamonas hypermegale and Megamonas rupellensis were enriched at the species level in children and adolescents with NAFLD. This indicates that the NAFLD status and/or diet associated with NAFLD patients might lead to the enrichment of the genus Megamonas or Megamonas species.

Abstract PLIN4‐myopathy is a recently identified autosomal dominant muscular disorder caused by the coding 99 bp repeat expansion in PLIN4, presenting with distal or proximal weakness. Here, we report one family and one sporadic case of adult‐onset PLIN4‐associated limb‐girdle weakness, whose diagnoses were achieved by a comprehensive genetic analysis workup. We provided additional evidence that the combination of subsarcolemmal/cytoplasmic ubiquitin/p62 positive deposits and rimmed vacuoles could serve as a strong indicator of PLIN4‐myopathy. Moreover, we found novel myopathological features that were ultrastructural subsarcolemmal filamentous materials and membrane‐bound granulofilamentous inclusions formed by the co‐deposition of disrupted lipid droplets and p62 protein aggregates.

Abstract Objective The present study was intended to analyze the characteristics of myelinated nerve fibers density (MFD) of transthyretin amyloid polyneuropathy (ATTR‐PN) and other similar neuropathies. Methods A total of 41 patients with ATTR‐PN, 58 patients of other common peripheral neuropathies, and 17 age‐and gender‐matched controls who visited the First Hospital of Peking University and performed sural nerve biopsy between June 2007 and August 2021 were included for analysis of MFD. Results Except the vasculitic neuropathy group, the total and small MFD of patients in the ATTR‐PN group were significantly lower than those of other disease groups. There was an obvious negative correlation between the total MFD and the disease course in the ATTR‐PN group. The disease course of early‐onset and late‐onset symptoms was similar, but the loss of large myelinated nerve fibers (MF) was more severe for the latter. In addition, all late‐onset and most early‐onset patients had severely reduced MFD after a 2 years' disease course. The MFD in ATTR‐PN patients was negatively correlated with Neuropathy Impairment Score (NIS) and Norfolk Quality of life‐diabetic neuropathy (Norfolk QOL‐DN) score. Conclusion MF is lost differently in ATTR‐PN and in other common peripheral neuropathies. The late‐onset and early‐onset ATTR‐PN patients have different patterns of loss of large and small MF.

Inflammatory bowel disease (IBD) mainly includes Crohn’s disease and ulcerative colitis. These diseases have a progressive course of chronic relapse and remission and affect a large number of children and adults worldwide. The burden of IBD is rising worldwide, with levels and trends varying greatly in countries and regions. Like most chronic diseases, the costs associated with IBD are high, including hospitalizations, outpatient and emergency visits, surgeries, and pharmacotherapies. However, there is no radical cure for it yet, and its therapeutic targets still need further study. Currently, the pathogenesis of IBD remains unclear. It is generally assumed that the occurrence and development of IBD are related to the environmental factors, gut microbiota, immune imbalance, and genetic susceptibility. Alternative splicing contributes to a various diseases, such as spinal muscular atrophy, liver diseases, and cancers. In the past, it has been reported that alternative splicing events, splicing factors, and splicing mutations were associated with IBD, but there were no reports on the practical application for clinical diagnosis and treatment of IBD using splicing-related methods. Therefore, this article reviews research progress on alternative splicing events, splicing factors, and splicing mutations associated with IBD.

It is well known that long non-coding RNAs (lncRNAs) play an important role in the regulation of tumor genesis and development. They can modulate gene expression of transcriptional regulation, epigenetic regulation of chromatin modification, and post-transcriptional regulation, thus influencing the biological behavior of tumors, such as cell proliferation, apoptosis, cell cycle, invasion, and migration. Tumor angiogenesis not only provides nutrients and helps excrete metabolites, but it also opens a pathway for tumor metastasis. Anti-angiogenic therapy has become one of the effective treatment methods for tumor. But its drug resistance leads to the limitation of clinical application. Recent studies have shown that lncRNAs are closely related to tumor angiogenesis and anti-angiogenic therapy resistance, which provides a new direction for tumor research. lncRNAs are expected to be new targets for tumor therapy. For the first time to our knowledge, this paper reviews advancement of lncRNAs in tumor angiogenesis and anti-angiogenic therapy resistance and further discusses their potential clinical application.

Abstract Distant spreading of metastatic tumor cells is still the leading cause of tumor death. Metastatic spreading is a complex process, in which epithelial-mesenchymal transition (EMT) is the primary and key event to promote it. Presently, extensive reviews have given insights on the occurrence of EMT at the primary tumor site that depends on invasive properties of tumor cells and the tumor-associated microenvironment. However, essential roles of circulation environment involved in tumor cell EMT is not well summarized. As a main constituent of the blood, platelet is increasingly found to work as an important activator to induce EMT. Therefore, this review aims to emphasize the novel role of platelet in EMT through signal communications between platelets and circulation tumor cells, and illustrate potent interventions aiming at their communications. It may give a complementary view of EMT in addition to the tissue microenvironment, help for better understand the hematogenous metastasis, and also illustrate theoretical and practical basis for the targeted inhibition. Video abstract

Abstract Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats in the 5’ untranslated region has been found in neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDMs). Although the upstream open reading frame has not been elucidated in OPML and OPDMs, polyglycine (polyG) translated by expanded CGG repeats is reported to be as a primary pathogenesis in FXTAS and NIID. Collectively, these findings indicate a new disease entity, the polyG diseases. In this review, we state the common clinical manifestations, pathological features, mechanisms, and potential therapies in these diseases, and provide preliminary opinions about future research in polyG diseases.

As oncogenes or tumor suppressor genes, lncRNAs played an important role in tumorigenesis and the progression of human cancers. The lncRNA SNHG15 has recently been revealed to be dysregulated in malignant tumors, suggesting the aberrant expression of which contributes to clinical features and regulates various oncogenic processes. We have selected extensive literature focused on SNHG15 from electronic databases, including studies relevant to its clinical significance and the critical events in cancer-related processes such as cell proliferation, apoptosis, autophagy, metastasis, and drug resistance. This review summarized the current understanding of SNHG15 in cancer, mainly focusing on the pathological features, known biological functions, and underlying molecular mechanisms. Furthermore, SNHG15 has been well-documented to be an effective diagnostic and prognostic marker for tumors, offering novel therapeutic interventions in specific subsets of cancer cells.

ObjectiveTo analyze the correlation between balance function and gait parameters of patients with basal ganglia infarction. And to observe the influence of balance function on plantar pressure and hemiplegia gait based on the Berg Balance Scale (BBS) score.MethodsOne hundred and forty patients with cerebral infarction hemiplegia in the basal ganglia region (a study group, n = 140) and healthy people (a control group, n = 140) were enrolled. The study group was evaluated with the BBS, the 10 m walking test (10MWT), and the timed up-and-go test (TUGT). The gait parameters and the peak plantar pressure were measured in both groups while walking, and the differences between the groups were compared. In addition, the characteristics of the plantar pressure curve of the hemiplegic and non-hemiplegic sides during walking and the correlation between the 10MWT, the TUGT, the plantar pressure peak, the gait parameters,and the BBS score were analyzed in the study group.ResultsThe peak plantar pressure of the forefoot and heel, stride length, lateral symmetry, stand phase, swing phase, and dual stand phase of both sides in the study group were significantly lower than those in the control group (P < 0.05). The BBS score negatively correlated with the 10MWT, the TUGT, the peak plantar pressure of the hemiplegic forefoot, midfoot, and the non-hemiplegic midfoot, the anterior to posterior position (ant/post position), hemiplegic stand phase, and the dual stand phase (P < 0.05). The BBS score positively correlated with the hemiplegic swing phase and stride length (P < 0.05).ConclusionA correlation was found between the forefoot plantar pressure and the stand phase of the hemiplegic limbs, the ant/post position, and the balance function after basal ganglion cerebral infarction. This association can be used in walking and balance assessment for stroke rehabilitation. Correcting forefoot pressure or the front and ant/post position can improve balance function.

Several studies have demonstrated the protective effect of dl-3-n-Butylphthalide (NBP) against cerebral ischemia, which may be related to the attenuation of mitochondrial dysfunction. However, the specific mechanism and targets of NBP in cerebral ischemia/reperfusion remains unclear. In this study, we used a chemical proteomics approach to search for targets of NBP and identified cytochrome C oxidase 7c (Cox7c) as a key interacting target of NBP. Our findings indicated that NBP inhibits mitochondrial apoptosis and reactive oxygen species (ROS) release and increases ATP production through upregulation of Cox7c. Subsequently, mitochondrial respiratory capacity was improved and the HIF-1α/VEGF pathway was upregulated, which contributed to the maintenance of mitochondrial membrane potential and blood brain barrier integrity and promoting angiogenesis. Therefore, our findings provided a novel insight into the mechanisms underlying the neuroprotective effects of NBP, and also proposed for the first time that Cox7c exerts a critical role by protecting mitochondrial function.

Abstract Many studies in recent years have found that dysregulation of long non-coding RNAs (lncRNAs) can contribute to disease. Small nucleolar RNA host gene 17 (SNHG17) is a novel cancer-related lncRNA of the SNHG family which is highly expressed in various tumors and may exert oncogenic functions. Several studies have demonstrated that SNHG17 is closely related to the proliferation, migration, invasion, apoptosis, and chemical drug resistance of tumor cells, and clinical studies have found an association between high SNHG17 expression and poor prognosis. In this review, we summarize relevant studies investigating SNHG17, focusing on its biological function as well as its potential value for clinical applications.

Abstract Objective A group of genes have been reported to be associated with myopathies with tubular aggregates (TAs). Many cases with TAs still lack of genetic clarification. This study aims to explore the genetic background of cases with TAs in order to improve our knowledge of the pathogenesis of these rare pathological structures. Methods Thirty‐three patients including two family members with biopsy confirmed TAs were collected. Whole‐exome sequencing was performed on 31 unrelated index patients and a candidate gene search strategy was conducted. The identified variants were confirmed by Sanger sequencing. The wild‐type and the mutant p.Ala11Thr of ALG14 were transfected into human embryonic kidney 293 cells (HEK293), and western blot analysis was performed to quantify protein expression levels. Results Eleven index cases (33%) were found to have pathogenic variant or likely pathogenic variants in STIM1, ORAI1, PGAM2, SCN4A, CASQ1 and ALG14. Among them, the c.764A>T (p.Glu255Val) in STIM1 and the c.1333G>C (p.Val445Leu) in SCN4A were novel. Western blot analysis showed that the expression of ALG14 protein was severely reduced in the mutant ALG14 HEK293 cells (p.Ala11Thr) compared with wild type. The ALG14 variants might be associated with TAs in patients with complex multisystem disorders. Interpretation This study expands the phenotypic and genotypic spectrums of myopathies with TAs. Our findings further confirm previous hypothesis that genes related with calcium signalling pathway and N‐linked glycosylation pathway are the main genetic causes of myopathies with TAs.

Abstract Background Congenital myopathies are a group of rare neuromuscular diseases characterized by specific histopathological features. The relationship between the pathologies and the genetic causes is complex, and the prevalence of myopathy-causing genes varies among patients from different ethnic groups. The aim of the present study was to characterize congenital myopathies with infancy onset among patients registered at our institution. Method This retrospective study enrolled 56 patients based on the pathological and/or genetic diagnosis. Clinical, histopathological and genetic features of the patients were analysed with long-term follow-up. Results Twenty-six out of 43 patients who received next-generation sequencing had genetic confirmation, and RYR1 variations (12/26) were the most prevalent. Eighteen novel variations were identified in 6 disease-causing genes, including RYR1, NEB, TTN, TNNT1, DNM2 and ACTA1. Nemaline myopathy (17/55) was the most common histopathology. The onset ages ranged from birth to 1 year. Thirty-one patients were followed for 3.83 ± 3.05 years (ranging from 3 months to 11 years). No patient died before 1 year. Two patients died at 5 years and 8 years respectively. The motor abilities were stable or improved in 23 patients and deteriorated in 6 patients. Ten (10/31) patients developed respiratory involvement, and 9 patients (9/31) had mildly abnormal electrocardiograms and/or echocardiograms. Conclusion The severity of congenital myopathies in the neonatal/infantile period may vary in patients from different ethnic groups. More concern should be given to cardiac monitoring in patients with congenital myopathies even in those with static courses.

Purpose To investigate the video-urodynamic and pelvic floor electrophysiological characteristics in patients with traumatic spinal cord injury (SCI). Methods This retrospective reviewed the clinical records, urodynamic and pelvic floor electrophysiological data of 647 patients with traumatic SCI and out of spinal shock. Patients were classified based on American Spinal Injury Association (ASIA) Impairment Scale and urodynamic findings. Results Of the 647 patients, detrusor overactivity (DO) with or without detrusor sphincter dyssynergia (DSD) was found in 79.5%, 61%, 35.2%, 35%, and 19.2% of patients with cervical, thoracic (T1–9), thoracic (T10–12), lumbar, and conical cauda injury, respectively. Other patients manifested detrusor areflexia (DA). Patients with DO and/or DSD had a longer duration of SCI at each injury level than patients with DA. In suprasacral injury patients with DA, 63.0% (58 of 92) had a normal bulbocavernosus reflex (BCR) response. Compared with patients without bladder sensation (BS), bladder capacity during urine leakage was far higher in those with BS. The manifestation of BCR and somatosensory-evoked potential (SEP) was associated with the level of injury. Conclusions This study showed a significant correlation between the level of SCI and video-urodynamic findings, but clinical examination cannot by predict bladder function; urodynamic testing is also necessary. In addition, the role of BCR and SEP for guiding bladder management is limited. Moreover, BS is important for urinary control in patients with traumatic SCI.

Abstract Background Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers. Results The as-synthesized nanoplatforms penetrated deeply into the interior region of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment. Conclusions This study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment. Graphical Abstract

Adult-onset neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder with high clinical heterogeneity. Previous studies indicated that the high-intensity signals in the corticomedullary junction on diffusion-weighted imaging (DWI) on brain MRI, known as the “ribbon sign,” could serve as a strong diagnostic clue. Here we used the explorative approach to study the undiagnosed rate of adult-onset NIID in a single center in China via searching for the ribbon sign in picture archive and communication system (PACS) and report the clinical and radiological features of initially undiagnosed NIID patients.Consecutive brain MRI of 21,563 adult individuals (≥18 years) in the PACS database in 2019 from a tertiary hospital were reviewed. Of them, 4,130 were screened out using the keywords “leukoencephalopathy” and “white matter demyelination.” Next, all 4,130 images were read by four neurologists. The images with the suspected ribbon sign were reanalyzed by two neuroradiologists. Those with the ribbon sign but without previously diagnosed NIID were invited for skin biopsy and/or genetic testing for diagnostic confirmation. The clinical features of all NIID patients were retrospectively reviewed.Five patients with high-intensity in the corticomedullary junction on DWI were enrolled. Three patients were previously diagnosed with NIID confirmed by genetic or pathological findings and presented with episodic encephalopathy or cognitive impairment. The other two patients were initially diagnosed with limb-girdle muscular dystrophy (LGMD) with rimmed vacuoles (RVs) and normal pressure hydrocephalus (NPH) in one each. Genetic analysis demonstrated GGC repeat expansion in the NOTCH2NLC gene of both, and skin biopsy of the first patient showed the presence of intranuclear hyaline inclusion bodies. Thus, five of the 21,563 adult patients (≥18 years) were diagnosed with NIID. The distinctive subcortical high-intensity signal on DWI was distributed extensively throughout the lobes, corpus callosum, basal ganglia, and brainstem. In addition, T2-weighted imaging revealed white matter hyperintensity of Fazekas grade 2 or 3, atrophy, and ventricular dilation. Distinctive DWI hyperintensity in the junction between the gray and white matter can help identify atypical NIID cases. Our findings highly suggest that neurologists and radiologists should recognize the characteristic neuroimaging pattern of NIID.

ObjectivesDermatomyositis (DM) and anti-synthetase syndrome (ASS) are autoimmune diseases with multisystem involvement. Despite sharing some clinical and myopathological features, these are two diseases with different pathogeneses and prognoses. We aimed to clarify and compare cytokine/chemokine profiles in both disorders, which may help in the differential diagnosis.Materials and methodsWe collected clinical data and serum samples of consecutive patients with DM and ASS. Quantibody® Human Inflammation Array 3 for cytokines/chemokines was performed in the serum of all participants. Receiver operating characteristic analysis with the area under the curve and Youden's index were performed.ResultsEight newly diagnosed and treatment-naïve patients with DM, nine newly diagnosed and treatment-naïve patients with ASS, and 14 healthy controls were enrolled. Serum C-C motif chemokine ligand (CCL) 2, CCL4, C-X-C motif chemokine ligand (CXCL) 13, and tumor necrosis factor receptor 2 (TNFR2) were increased in patients with both DM and ASS. Serum interleukin (IL)-1 receptor type 1 (IL-1ra), IL-1b, CCL1, CXCL11, and CCL3 were modulated in patients with DM only, and IL-8, CXCL9, and tissue inhibitors of metalloproteinases-1 (TIMP-1) in patients with ASS only. Serum CCL2, CXCL13, and TNFR2 accurately distinguished patients with DM and ASS from healthy controls, as shown by the area under the curve >0.80. Moreover, receiver operating characteristic analysis showed that, as biomarkers for discrimination between DM and ASS, the combination of IL-1ra and TIMP-1, had an area under the curve of 0.944, a sensitivity of 87.5%, and a specificity of 88.9%.ConclusionOur study demonstrated that serum levels of cytokines/chemokines showed a different pattern in newly diagnosed patients with DM and ASS, in which serum IL-1ra and TIMP-1 could be used to distinguish between the two diseases.

Objects: This study was intended to find out more about the clinical characterizations of patients carrying transthyretin (TTR) E61K (p.Glu81Lys) gene mutation and the biochemical characterization of this mutant protein.Materials and methods: Five patients who had been diagnosed with hereditary transthyretin amyloidosis and two asymptomatic carriers carrying TTR E61K gene mutation were reported. Biochemical and biophysical tests were conducted to observe the thermodynamic and kinetic stability. Fibril formation tests measured by turbidity assay were performed to explore the pathogenicity of this mutation. Kinetic stabilizer responsiveness was measured to determine the inhibitory effect on protein aggregation.Results: The average age of onset for the five patients was 62 years, and the course of the disease ranged from 2 to 10 years. Cardiac disease was prominent in this group of patients. Nerve pathology revealed a mildly to moderately reduced myelinated fiber density and muscle pathology showed predominant neurogenic impairment accompanied by possible myogenic impairment. E61K-TTR was characterized as a kinetically destabilized protein compared to WT-TTR but its thermodynamic stability was not compromised. In addition, the subunit exchange of E61K with WT-TTR further destabilized the heterozygous tetramer. Meanwhile, the E61K:WT heterozygous tetramer exhibited a poor response to kinetic stabilizers in the fibril formation assay. Finally, the serum TTR tetramer concentration was low in E61K-TTR symptomatic patients and in one asymptomatic gene carrier. Vyndamax (Tafamidis) could increase the TTR tetramer concentration.Conclusions: Patients with E61K mutation tended to be late-onset. The concentration of TTR tetramer in the serum might serve as a biomarker to monitor disease progress, therapeutic window time, and therapeutic response to TTR kinetic stabilizer drugs.

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder characterized by dementia, tremor, episodic encephalopathy and autonomic nervous dysfunction. To date, vestibular migraine (VM)-like attack has never been reported in cases with NIID. Here, we describe an 86-year-old patient with NIID who presented with recurrent vertigo associated with headache for more than 30 years. Case presentation An 86-year-old Chinese woman with vertigo, headache, weakness of limbs, fever, and disturbance of consciousness was admitted to our hospital. She had suffered from recurrent vertigo associated with headache since her 50 s,followed by essential tremor and dementia. On this admission, brain magnetic resonance imaging revealed high intensity signals along the corticomedullary junction on diffusion weighted imaging (DWI). Peripheral neuropathy of the extremities was detected through electrophysiological studies. We diagnosed NIID after detecting eosinophilic intranuclear inclusions in the ductal epithelial cells of sweat glands and identifying an abnormal expansion of 81 GGC repeats in the 5’UTR of NOTCH2NLC gene. Conclusions VM-like attack may be associated with NIID.

IntroductionIn China, the increasing number of people with Alzheimer's disease (AD) poses a great challenge to families and the country. Economic and cultural differences cause a urban-rural gap in medical resources. This multicenter survey aimed to investigate the real-world practice of disease treatment among people with AD.MethodsPeople with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for their treatment experience. Logistic regression was used to explore the factors that influence medication adherence in all areas, urban areas, and rural areas.ResultsIn this survey, 1,427 participants came from urban areas, and 539 participants came from rural areas. Patients in urban areas were older (mean age 74 vs. 70, p = 0.001), less frequently had mild AD (36.0 vs. 52.1%, p < 0.001), and more often were cared for at professional institutions (8.8 vs. 3.2%, p < 0.001). In terms of pharmacotherapy, 77.8% of people accepted taking lifelong medication, whereas 61.3% of patients insisted on taking medications. Although 72.0% of rural people believed in taking lifelong medication, only 30.0% adhered to drug use. The major factors that influenced medication adherence for all patients with AD were regional distribution (p < 0.001, OR = 6.18, 95% CI: 4.93–7.74) and family earnings (p = 0.003, OR = 1.22, 95% CI: 1.07–1.38). In rural areas, family earnings (p = 0.008, OR = 1.44, 95% CI: 1.10–1.89) and severity of AD (p = 0.033, OR = 1.31, 95% CI: 1.02–1.68) were the main factors. Family earnings (p = 0.038, OR = 1.16, 95% CI: 1.01–1.34) was the only factor among urban areas. Among all non-pharmaceutical activities except for cognitive intervention, the participation rates of rural patients were significantly higher than those of urban patients (p < 0.05).ConclusionAlthough national progress has been made in the public awareness of disease treatment, adequate diagnosis and medication adherence need to be prompted, especially in rural areas. Furthermore, lifelong treatment should be improved based on regional characteristics through the joint efforts of the government, health workers, and social volunteers.

ObjectiveThe diagnosis of neuronal intranuclear inclusion disease (NIID) is currently based on CGG repeat expansion in the 5′UTR of the NOTCH2NLC gene, or p62-positive intranuclear inclusions in skin biopsy. The purpose of this study is to explore the value of non-invasive pathological findings in urine sediment cells from NIID patients.Materials and methodsTen patients with clinically suspected NIID were enrolled for skin biopsy and gene screening. Morning urine (500 ml) was collected from each patient, and cell sediment was obtained by centrifugation. Urine cytology, including Giemsa staining, p62 immunostaining, and electron microscopic examination, were conducted on cell sediment.ResultsThe main clinical symptoms of 10 patients included episodic disturbance of consciousness, cognitive impairment, tremor, limb weakness, and so on. Cerebral MRI showed that 9 patients had linear DWI high signal in the corticomedullary junction. Genetic testing found that the number of CGG repeat ranged from 96 to 158 in the NOTCH2NLC gene. Skin biopsy revealed that all patients showed p62-positive intranuclear inclusions in 18.5 ± 6.3% of the duct epithelial cells of sweat gland. In contrast, urine sediment smears revealed that only 3 patients had p62 positive intranuclear inclusions in 3.5 ± 1.2% of the sedimentary cells. Ultrastructural examinations showed that intranuclear inclusions were also identified in the cell sediment of the 3 patients.ConclusionUrine cytology may be a new and non-invasive pathological diagnosis technique for some NIID patients, although the positive rate is not as high as that of skin biopsy, which is a sensitive and reliable pathological method for NIID.

The precise identification of pathogenic DMD variants is sometimes rather difficult, mainly due to complex structural variants (SVs) and deep intronic splice-altering variants. We performed genomic long-read whole DMD gene sequencing in a boy with asymptomatic hyper-creatine kinase-emia who remained genetically undiagnosed after standard genetic testing, dystrophin protein and DMD mRNA studies, and genomic short-read whole DMD gene sequencing. We successfully identified a novel pathogenic SV in DMD intron 1 via long-read sequencing. The deep intronic SV consists of a long interspersed nuclear element-1 (LINE-1) insertion/non-tandem duplication rearrangement causing partial exonization of the LINE-1, establishing a genetic diagnosis of Becker muscular dystrophy. Our study expands the genetic spectrum of dystrophinopathies and highlights the significant role of disease-causing LINE-1 insertions in monogenic diseases.

BackgroundPLA2G6-associated neurodegeneration (PLAN) is a heterogeneous group of neurodegenerative diseases caused by biallelic PLA2G6 mutations, covering diseases such as infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). The study aims to report the clinical and genetic features of a series of PLAN patients.MethodsThe clinical and radiological findings of five Chinese patients from three families were collected. Whole-exome next generation sequencing (NGS) was applied to identify the genetic causes. Co-segregation analysis of the detected candidate variants were performed in their families. The pathogenicity of identified novel variants was predicted by in silico analysis.ResultsNGS revealed compound heterozygous variants of PLA2G6 gene in all five patients. There were six PLA2G6 variants identified, including two known variants (c.116G>A, c.238G>A) and four novel variants (c.2120dupA, c.2071C>G, c.967G>A, c1534T>A). ACMG predicts c.2120dupA to be pathogenic, c.2071C>G and c.1534T>A to be likely pathogenic, and c1534T>A to be of uncertain significance. Clinically, four patients fell into the diagnosis of ANAD, and 1 into the diagnosis of AREP. Brain imaging revealed cerebellar atrophy, iron deposition in bilateral globus pallidus, and substantia nigra in three cases.ConclusionsFour novel pathogenic variants were discovered and the pathogenic variant spectrum of the PLA2G6 gene was expanded.

The effect of corona discharge from buildings or structures on the surrounding atmospheric electric field is very important in the measurement of urban atmospheric electric fields and the early warning of lightning. However, most previous studies were focused on independent buildings, with little research on three-dimensional building groups. Therefore, based on three-dimensional numerical simulation technology, this paper uses a double-needle system to simulate the characteristics of thunderstorm corona discharge from two equal-height buildings separated by a variable distance. The shielding effect of the double-needle system on the ground electric field is evaluated both with and without corona discharge, and the main conclusions are as follows: (1) The larger the distance between the two needles, the closer the peak corona current from each tip of the double-needle system is to that from an independent lightning rod at the same height. When the peak corona current from each tip of the double-needle system equals the peak corona current from an independent lightning rod at the same height to some level of approximation, the distance between the two needle systems is determined by the needle height at this time. (2) If the distance between the two needles is 0.1 m, the corona charge released by the double-needle system is almost equal to that released by an independent lightning rod. The corona charge released by the double-needle system is approximately twice as much as that released by an independent lightning rod when the distance between the two needles is increased to a certain value that increases with the needle height and the time of corona discharge. (3) The greater the value of the time of corona discharge, the stronger the shielding effect of the corona discharge on the ground electric field and the larger the shielding range, but the greater the value of the needle height, the smaller the shielding range. (4) Compared with the shielding effect with no corona discharge, that with corona discharge is greater, but the greater the value of the needle height, the less the enhancement. For example, for corona discharge with a time of 10 s, the needle height is 20 m, and the shielding range is ca. 70 m, which is 8.8 times that without corona discharge; however, for the needle height of 100 m, the shielding range is ca. 150 m, which is only 1.5 times that without corona discharge.