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Abstract Background Gangrene and perforation are severe complications of acute appendicitis, associated with a higher mortality rate compared to uncomplicated appendicitis. Accurate preoperative identification of Gangrenous or perforated appendicitis (GPA) is crucial for timely surgical intervention. Methods This retrospective multicenter study includes 796 patients who underwent appendectomy. Univariate and multivariate logistic regression analyses are used to develop a nomogram model for predicting GPA based on laboratory tests and computed tomography (CT) findings. The model is validated using an external dataset. Results Seven independent predictors were included in the nomogram: white blood cell count, lymphocyte count, D-dimer, serum glucose, albumin, maximum outer diameter of the appendix, and presence of appendiceal fecalith. The nomogram achieved good discrimination and calibration in both the training and testing sets. In the training set, the AUC was 0.806 (95%CI: 0.763–0.849), and the sensitivity and specificity were 82.1% and 66.9%, respectively. The Hosmer-Lemeshow test showed good calibration (P = 0.7378). In the testing set, the AUC was 0.799 (95%CI: 0.741–0.856), and the sensitivity and specificity were 70.5% and 75.3%, respectively. Decision curve analysis (DCA) confirmed the clinical utility of the nomogram. Conclusion The laboratory test-CT nomogram model can effectively identify GPA patients, aiding in surgical decision-making and improving patient outcomes.

Background: Brain structure, oxygenation and perfusion are important factors in aging. Coupling between regional cerebral oxygen consumption and perfusion also reflects functions of neurovascular unit (NVU). Their trajectories and sex differences during normal aging important for clinical interpretation are still not well defined. In this study, we aim to investigate the relationship between brain structure, functions and age, and exam the sex disparities.Method: A total of 137 healthy subjects between 20∼69 years old were enrolled with conventional MRI, structural three-dimensional T1-weighted imaging (3D-T1WI), 3D multi-echo gradient echo sequence (3D-mGRE), and 3D pseudo-continuous arterial spin labeling (3D-pCASL). Oxygen extraction fraction (OEF) and cerebral blood flow (CBF) were respectively reconstructed from 3D-mGRE and 3D-pCASL images. Cerebral metabolic rate of oxygen (CMRO2) were calculated as follows: CMRO2=CBF·OEF·[H]a, [H]a=7.377 μmol/mL. Brains were segmented into global gray matter (GM), global white matter (WM), and 148 cortical subregions. OEF, CBF, CMRO2, and volumes of GM/WM relative to intracranial volumes (rel_GM/rel_WM) were compared between males and females. Generalized additive models were used to evaluate the aging trajectories of brain structure and functions. The coupling between OEF and CBF was analyzed by correlation analysis. P or PFDR < 0.05 was considered statistically significant.Results: Females had larger rel_GM, higher CMRO2 and CBF of GM/WM than males (P < 0.05). With control of sex, CBF of GM significantly declined between 20 and 32 years, CMRO2 of GM declined subsequently from 33 to 41 years and rel_GM decreased significantly at all ages (R2 = 0.27, P < 0.001; R2 = 0.17, P < 0.001; R2 = 0.52, P < 0.001). In subregion analysis, CBF declined dispersedly while CMRO2 declined widely across most subregions of the cortex during aging. Robust negative coupling between OEF and CBF was found in most of the subregions (r range = -0.12∼-0.48, PFDR < 0.05).Conclusion: The sex disparities, age trajectories of brain structure and functions as well as the coupling of NVU in healthy individuals provide insights into normal aging which are potential targets for study of pathological conditions.

Abstract In the era of 5G, billions of terminal devices achieve global interconnection and intercommunication, which leads to the generation of massive data. However, the existing cloud‐based data‐sharing mechanism faces challenges such as sensitive information leakage and data islands, which makes it difficult to achieve secure sharing across domains. In this paper, the authors propose a fine‐grained data‐sharing scheme based on blockchain and ciphertext policy attribute‐based encryption, and design a verifiable outsourced computation method to reduce the computational pressure of end users. Second, the authors comprehensively consider the user's identity privacy and transaction privacy, and propose a multi‐level privacy protection method based on ring signature and garbled bloom filter, which enhance the user's data privacy and availability, and prevent the traceability of requests. Finally, the authors design a set of interconnected smart contracts, and verify that their scheme can achieve secure and efficient data sharing through security analysis and performance testing.

Abstract Parkinson’s disease (PD) is a heterogeneous movement disorder with different motor subtypes including tremor dominant (TD), indeterminate and postural instability, and gait disturbance (PIGD) motor subtypes. Plasma glial fibrillary acidic protein (GFAP) was elevated in PD patients and may be regarded as a biomarker for motor and cognitive progression. Here we explore if there was an association between plasma GFAP and different motor subtypes and whether baseline plasma GFAP level can predict motor subtype conversion. Patients with PD classified as TD, PIGD or indeterminate subtypes underwent neurological evaluation at baseline and 2 years follow-up. Plasma GFAP in PD patients and controls were measured using an ultrasensitive single molecule array. The study enrolled 184 PD patients and 95 control subjects. Plasma GFAP levels were significantly higher in the PIGD group compared to the TD group at 2-year follow-up. Finally, 45% of TD patients at baseline had a subtype shift and 85% of PIGD patients at baseline remained as PIGD subtypes at 2 years follow-up. Baseline plasma GFAP levels were significantly higher in TD patients converted to PIGD than non-converters in the baseline TD group. Higher baseline plasma GFAP levels were significantly associated with the TD motor subtype conversion (OR = 1.283, P = 0.033) and lower baseline plasma GFAP levels in PIGD patients were likely to shift to TD and indeterminate subtype (OR = 0.551, P = 0.021) after adjusting for confounders. Plasma GFAP may serve as a clinical utility biomarker in differentiating motor subtypes and predicting baseline motor subtypes conversion in PD patients.

BackgroundThe overlapping clinical manifestations in parkinsonian variant of multiple system atrophy (MSA-P) and Parkinson’s Disease (PD) can complicate clinical diagnostic accuracy, particularly in the early stage. The study aims to uncover the patterns of brain function in the initial phase of the two conditions.MethodsWe recruited 24 MSA-P patients, 34 PD patients and 27 healthy controls (HC). Voxel-wise fractional amplitude of low-frequency fluctuation (fALFF) was compared to characterize regional brain function, followed by seed-based functional connectivity (FC) analysis. Receiver operating characteristic (ROC) analyses were used to examine the diagnostic accuracy of fALFF.ResultsCompared to HC, decreased fALFF was observed in the bilateral basal ganglia (BG) of MSA-P patients, while decreased fALFF was identified in the left BG of PD patients. Additionally, elevated fALFF was found in the superior cerebellum for MSA-P patients and the temporo-occipital cortex for PD patients. Furthermore, PD patients exhibited increased FC in the cortico-striatal loop compared to MSA-P patients. The fALFF of the left caudate distinguished MSA-P from HC with an area under the curve (AUC) of 0.838 (p

BackgroundA number of studies have explored the link between neurodegenerative disorders (NDDs) and albumin, the main protein in human plasma. However, the results have been inconsistent, highlighting the necessity for a detailed systemic analysis.MethodsUtilizing data from the United Kingdom Biobank, we investigated the relationship between baseline levels of serum and urine albumin and the occurrence of common NDDs, including Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and dementia, employing Cox proportional hazards regression analysis.ResultsOur results reveal that elevated baseline serum albumin levels are linked to a decreased risk of developing dementia (beta = −0.024, SE = 0.004, p

BackgroundRecent research has indicated the significance of immune activation in amyotrophic lateral sclerosis (ALS). However, the impact of peripheral immunity on cognitive impairment in sporadic ALS remains poorly characterized. Therefore, we aim to assess the relationship between peripheral immune parameters and cognitive impairment in patients with sporadic ALS.MethodsA case–control study involving 289 patients with sporadic ALS was conducted. All participants underwent cognitive assessment and measurements of blood immune parameters. The main outcomes included adjusted odds ratios (ORs) in multivariate logistic regression analysis and adjusted coefficients in a multivariate linear regression model. Sensitivity analysis was performed with stratification by the King’s clinical stage.ResultsCognitive impairment was observed in 98 (33.9%) patients. Higher counts of leukocyte (OR, 0.53; 95% CI, 0.29 to 0.95; p = 0.03), neutrophil (OR, 0.48; 95% CI, 0.26 to 0.88; p = 0.02), and monocyte (OR, 0.33; 95% CI, 0.18 to 0.60; p

Background: The calcium channel has been considered to have great potential as a drug target for neuroprotective therapy in Parkinson’s disease (PD), but previous studies yielded inconsistent results. Objectives: This study aimed to conduct a systematic review and meta-analysis to assess the relationship between using calcium channel blockers (CCBs) and the risk and progression of PD. Data sources and methods: The terms such as ‘Parkinson’s disease’, ‘PD’, ‘calcium channel blockers’, and ‘CCB’ were used to search the literature published before 1 May 2023 in English databases, including PubMed, Embase, and Cochrane Library, for studies on CCB and PD. Data analysis was performed using Review Manager 5.3 software. Results: A total of 190 works of literature were preliminarily retrieved, and 177 works of literature were excluded by eliminating duplicates, reading abstracts, and reading full texts. A total of nine studies were finally included in the meta-analysis of the CCB and the risk of PD, and five studies were included in the systematic review of the CCB and the progression of PD. A total of 2,961,695 participants were included in the meta-analysis. The random-effects model was used for analysis due to significant heterogeneity. The main results of the meta-analysis showed that the use of CCB could reduce the risk of PD (relative risk 0.78, 95% confidence interval 0.62–0.99). Conclusion: CCB use was associated with a significantly reduced risk of PD. Whether CCB use has a disease-modifying effect on PD needs further study. Registration: PROSPERO: CRD42024508242.

Myotonic dystrophy (DM) encompasses a spectrum of neuromuscular diseases characterized by myotonia, muscle weakness, and wasting. Recent research has led to the recognition of DM as a neurological disorder. Cognitive impairment is a central nervous system condition that has been observed in various forms of DM. Neuroimaging studies have increasingly linked DM to alterations in white matter (WM) integrity and highlighted the relationship between cognitive impairment and abnormalities in WM structure. This review aims to summarize investigations into cognitive impairment and brain abnormalities in individuals with DM and to elucidate the correlation between these factors and the potential underlying mechanisms contributing to these abnormalities.

Abstract Background Reactive astrogliosis has been demonstrated to have a role in Parkinson’s disease (PD); however, astrocyte-specific plasma glial fibrillary acidic protein (GFAP)’s correlation with PD progression remains unknown. We aimed to determine whether plasma GFAP can monitor and predict PD progression. Methods A total of 184 patients with PD and 95 healthy controls (HCs) were included in this prospective cohort study and followed-up for 5 years. Plasma GFAP, amyloid-beta (Aβ), p-tau181, and neurofilament light chain (NfL) were measured at baseline and at 1- and 2-year follow-ups. Motor and non-motor symptoms, activities of daily living, global cognitive function, executive function, and disease stage were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III, UPDRS-I, UPDRS-II, Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), and Hoehn and Yahr (H&Y) scales at each visit, respectively. Results Plasma GFAP levels were higher in patients with PD (mean [SD]: 69.80 [36.18], pg/mL) compared to HCs (mean [SD]: 57.89 [23.54], pg/mL). Higher levels of GFAP were observed in female and older PD patients. The adjusted linear mixed-effects models showed that plasma GFAP levels were significantly associated with UPDRS-I scores (β: 0.006, 95% CI [0.001–0.011], p = 0.027). Higher baseline plasma GFAP correlated with faster increase in UPDRS-I (β: 0.237, 95% CI [0.055–0.419], p = 0.011) and UPDRS-III (β: 0.676, 95% CI [0.023–1.330], p = 0.043) scores and H&Y stage (β: 0.098, 95% CI [0.047–0.149], p < 0.001) and faster decrease in MoCA (β: − 0.501, 95% CI [− 0.768 to − 0.234], p < 0.001) and FAB scores (β: − 0.358, 95% CI [− 0.587 to − 0.129], p = 0.002). Higher baseline plasma GFAP predicted a more rapid progression to postural instability (hazard ratio: 1.009, 95% CI [1.001–1.017], p = 0.033). Conclusions Plasma GFAP might be a potential biomarker for monitoring and predicting disease progression in PD.

Abstract Background The progression of sleep disturbances remains unclear in patients with early multiple system atrophy (MSA). We aimed to explore the frequency, severity, and coexistence of 2-year longitudinal changes of sleep disturbances including REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and Parkinson’s disease-related sleep problems (PD-SP) in early MSA. Methods MSA patients with a disease duration

Abstract Background Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown. Methods To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox proportional hazards model in 2,841 patients with ALS (Ndiscovery = 2,272, Nreplication = 569) in the Chinese population. We further conducted colocalization analysis using public cis-eQTL dataset, and Mendelian randomization analysis to identify risk factors for AAO of ALS. Finally, functional experiments including dual-luciferase reporter assay and RT-qPCR were performed to explore the regulatory effect of the target variant. Results The total heritability of AAO of ALS was ~ 0.24. One novel locus rs10128627 (FRMD8) was significantly associated with earlier AAO by ~ 3.15 years (P = 1.54E-08, beta = 0.31, SE = 0.05). This locus was cis-eQTL of NEAT1 in multiple brain tissues and blood. Colocalization analysis detected association signals at this locus between AAO of ALS and expression of NEAT1. Furthermore, functional exploration supported the variant rs10128627 was associated with upregulated expression of NEAT1 in cell models and patients with ALS. Causal inference suggested higher total cholesterol, low-density lipoprotein, and eosinophil were nominally associated with earlier AAO of ALS, while monocyte might delay the AAO. Conclusions Collective evidence from genetic, bioinformatic, and functional results suggested NEAT1 as a key player in the disease progression of ALS. These findings improve the current understanding of the genetic role in AAO of ALS, and provide a novel target for further research on the pathogenesis and therapeutic options to delay the disease onset.

Abstract Tamoxifen-based endocrine therapy remains a major adjuvant therapy for estrogen receptor (ER)-positive breast cancer (BC). However, many patients develop tamoxifen resistance, which results in recurrence and poor prognosis. Herein, we show that fatty acid oxidation (FAO) was activated in tamoxifen-resistant (TamR) ER-positive BC cells by performing bioinformatic and functional studies. We also reveal that CPT1A, the rate-limiting enzyme of FAO, was significantly overexpressed and that its enzymatic activity was enhanced in TamR cells. Mechanistically, the transcription factor c-Jun was activated by JNK kinase-mediated phosphorylation. Activated c-Jun bound to the TRE motif in the CPT1A promoter to drive CPT1A transcription and recruited CBP/P300 to chromatin, catalysing histone H3K27 acetylation to increase chromatin accessibility, which ensured more effective transcription of CPT1A and an increase in the FAO rate, eliminating the cytotoxic effects of tamoxifen in ER-positive BC cells. Pharmacologically, inhibiting CPT1A enzymatic activity with the CPT1 inhibitor etomoxir or blocking c-Jun phosphorylation with a JNK inhibitor restored the tamoxifen sensitivity of TamR cells. Clinically, high levels of phosphorylated c-Jun and CPT1A were observed in ER-positive BC tissues in patients with recurrence after tamoxifen therapy and were associated with poor survival. These results indicate that the assessment and targeting of the JNK/c-Jun-CPT1A-FAO axis will provide promising insights for clinical management, increased tamoxifen responses and improved outcomes for ER-positive BC patients.

Objective Although it is an effective fixation technique for an unstable odontoid, anterior fixation remains challenging in pediatric populations. Our study measures the anatomical parameters of the odontoid to identify the feasibility of anterior fixation with a single screw for children. Methods We retrospectively collected data from 112 normal male and female children (aged between 2 and 18) in our institute from January 1, 2022 to December 31, 2022. Subjects were divided into a youth group (2–6 years old), a juvenile group (7–12 years old), and an adolescent group (13–18 years old). Sagittal and coronal computed tomography images of the upper cervical spine were used to measure the screw length, angle, and inner and outer diameters of the odontoid. One‐way analysis of variance with the Tukey test was used to analyze the parameters among the groups, while the t‐test was used to analyze gender differences. Correlations between parameters and age were assessed using Pearson's test. Results There were significant differences between male and female subjects in screw length and inner and outer diameters (of both sagittal and coronal views) but not in screw angle. The narrowest diameter of the odontoid was 4.0 ± 1.5 mm in the youth group, 5.5 ± 1.5 mm in the juvenile group, and 5.6 ± 1.1 mm in the adolescent group, respectively. There were significant differences among the three groups in screw length (p 4 mm. Screw length and inner and outer diameters in lateral view were positively correlated with age, and screw angle was negatively correlated with age. Conclusion It is feasible to insert a standard single screw (Φ 3.5 mm) into the odontoid of children aged 7–18 years old but not those aged 2–6 years old. How the anatomical parameters of the odontoid change with age, especially the narrowest diameters, is worthy of attention.

Objective To evaluate the biomechanical stability of anterior transarticular crossing screw (ATCS) and compare it with anterior transarticular screw (ATS) which may provide basic evidence for clinical application. Methods Eight human fresh cadaveric specimens (occiput-C4) were tested with 5 conditions including the intact status, the injury status (type II odontoid fracture), the injury+ATS fixation status (traditional bilateral ATS fixation); the injury+unilateral ATCS fixation status; and the injury+bilateral ATCS fixation status. Specimens were applied to a pure moment of 1.5 Nm in flexion-extension, lateral bending, and axial rotation, respectively. The range of motions (ROMs) and the neutral zones (NZs) of C1 to C2 segment were calculated and compared between 5 status. Results ATS and ATCS fixations significantly reduced the motions in all directions when compared with the intact and injury statues (p < 0.05). In flexion-extension, the ROMs of ATS, unilateral ATCS, and bilateral ATCS were 4.7° ±2.5°, 4.1° ±1.9°, and 3.2° ±1.2°, respectively. Bilateral ATCS resulted in a significant decrease in ROM in flexion-extension when compared with ATS and unilateral ATCS (p = 0.035 and p = 0.023). In lateral bending and axial rotation, there was no significant difference in ROM between the 3 fixations (p > 0.05). Three fixations resulted in similar NZs in all directions (p > 0.05). Conclusion ATCS is a biomechanically effective alternative or supplemental method for atlantoaxial instability.

BackgroundCystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown.MethodsA total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan–Meier curve and Cox regression model were used for survival analysis.ResultsCysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p

Abstract Objectives High visit‐to‐visit blood pressure variability (BPV) was found to be associated with cognitive decline in the elderly. This study aimed to investigate the impact of visit‐to‐visit BPV on cognition in patients with early‐stage Parkinson's disease (PD). Design This is a retrospective analysis of a prospective cohort. Setting and participants A total of 297 patients with early‐stage PD (103 mild cognitive impairments [PD‐MCI] and 194 normal cognitions [PD‐NC] at baseline) were included from the Parkinson's Progression Markers Initiative study. Methods Variation independent of mean (VIM) of the first year was used as the indicator of BPV. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Patients were divided into PD‐MCI and PD‐NC according to the MoCA score at baseline. Longitudinal cerebrospinal fluid (Aβ‐42, Aβ, α‐synuclein, neurofilament light protein, tau phosphorylated at the threonine 181 position, total tau, glial fibrillary acidic protein) and serum (neurofilament light protein) biomarkers were assessed. The Bayesian linear growth model was used to evaluate the relationship between baseline BPV and the rate of change in cognition and biomarkers. Results Higher systolic VIM of the first year was related to a greater rate of decline in MoCA score in the following years in PD‐MCI (β = −.15 [95% CI −.29, −.01]). No association was found between BPV and biomarkers. Conclusion and implications Higher systolic VIM predicted a steeper decline in cognitive tests in PD‐MCI independently from the mean value of blood pressure, orthostatic hypotension, and supine hypertension.

Abstract We modified the original Unified Multiple System Atrophy Rating Scale (UMSARS) for remote video-based visits by excluding ocular motor dysfunction, increased tone, and body sway, resulting in a 23-item UMSARS (mUMSARS-23). The mUMSARS-23 demonstrated excellent reliability and strong validity when compared to the original scale, making it a promising tool for conducting video-based virtual assessments in patients with multiple system atrophy.

Abstract Background Recently, several rare variants of SPTLC1 were identified as disease cause for juvenile amyotrophic lateral sclerosis (ALS) by disrupting the normal homeostatic regulation of serine palmitoyltransferase (SPT). However, further exploration of the rare variants in large cohorts was still necessary. Meanwhile, SPTLC2 plays a similar role as SPTLC1 in the SPT function. Methods To explore the genetic role of SPTLC1 and SPTLC2 in ALS, we analyzed the rare protein-coding variants in 2011 patients with ALS and 3298 controls from the Chinese population with whole exome sequencing. Fisher’s exact test was performed between each variant and disease risk, while at gene level over-representation of rare variants in patients was examined with optimized sequence kernel association test (SKAT-O). Results Totally 33 rare variants with minor allele frequency

ObjectivesMutations in glucocerebrosidase (GBA1) can change the clinical phenotype of Parkinson’s disease (PD). This study aimed to explore the clinical characteristics of freezing of gait (FOG) in PD patients with GBA1 mutations.MethodsA whole-exome sequencing analysis was used to identify the GBA1 mutations (pathogenic or likely pathogenic) and exclude other PD-related gene mutations. A forward binary logistic regression model was conducted to identify the associated factors of FOG. The stepwise multiple linear regression analysis models were used to explore the effect of FOG on quality of life.ResultsThe prevalence of FOG in patients with GBA1 mutations (30/95, 31.6%) was significantly higher than those in patients without GBA1 mutations (152/760, 20%) (p = 0.009). A higher (i.e., worse) Unified PD Rating Scale part III score (OR = 1.126, 95%CI = 1.061–1.194, p

Abstract. Background:. Essential tremor (ET) and Parkinson's disease (PD) are common movement disorders. ET-PD syndrome is characterized by the occurrence of PD in patients with a previous history of ET, which may be an independent phenotype distinct from PD. This study aims to identify clinical characteristics and subtypes in ET-PD. Methods:. A total of 93 newly diagnosed ET-PD patients and 93 newly diagnosed PD patients matched for age, sex, education, and disease duration of PD were selected using propensity score matching analysis. The K-means cluster analysis was performed for 11 variables derived from the ET-PD group, and cluster profiles were established through statistical analysis of demographic and clinical variables. Results:. The ET-PD group consisted of a high number of patients with a family history of ET exhibiting evident tremor with milder hypokinesia and postural instability symptoms, as compared to the PD group. Through the cluster analysis, two clusters of ET-PD patients were identified. The ET-PD cluster 1 (n = 34) had a shorter ET duration before PD onset, lower number of patients with a family history of ET, higher unified PD rating scale instability scores, higher non-motor symptoms scores (non-motor symptoms scale D1 scores, Hamilton depression scale scores, Hamilton anxiety scale scores, and PD sleep scale-2 scores), and higher Chinese version of the PD questionnaire-39 scores relative to the ET-PD cluster 2 (n = 59). Conclusion:. ET-PD patients had significantly different characteristics for motor symptoms as compared to PD patients, and may be distinctly divided into two clinical subtypes, namely, the ET-PD complex type and the ET-PD simple type.

Abstract Background Recently, several rare variants of TP73 were identified as potential disease cause for amyotrophic lateral sclerosis (ALS) in the European population. However, further replication was still necessary, especially in cohorts with different ethnic backgrounds. Methods To explore the genetic role of TP73 in ALS in the Asian population, we analyzed the rare protein-coding variants in 2011 patients with ALS and 3298 controls with whole-exome sequencing. Fisher’s exact test was performed between each variant and disease risk, while at gene level over-representation of rare variants in patients was examined with optimized sequence kernel association test. Results Totally 24 rare variants with minor allele frequency

Abstract Background The progression of motor and non-motor symptoms (NMS) and the sensitivity of each item of the Unified Multiple System Atrophy Rating Scale (UMSARS) to change remain unclear in Chinese patients with early-stage multiple system atrophy (MSA). We investigated the evolution of motor symptoms and NMS in early-stage MSA and the sensitivity of each item included in the UMSARS to change over a 2-year follow-up. Methods Motor symptoms and NMS were recorded at baseline and at 1- and 2-year follow-ups based on the UMSARS and the NMS scale. Generalized estimating equation models were used. The sensitivity of an item included in the UMSARS to change was assessed by calculating a standardized effect using the mean annual change divided by the standard deviation of the change. Results We enrolled 246 consecutive patients with MSA and 97 MSA completed the 2-year follow-up. The mean total UMSARS score increased by 11.90 and 22.54 points at the 1- and 2-year follow-ups, respectively. UMSARS-I items associated with motor functions were more sensitive to change and those associated with autonomic dysfunction showed less sensitivity to change. Items 4 (tremor at rest), 5 (action tremor), and 3 (ocular motor dysfunction) of the UMSARS-II were less sensitive to change. The prevalence and severity of NMS significantly increased over the 2-year follow-up. Conclusions We observed significant progression in motor symptoms and NMS in patients with early-stage MSA. Our results provide useful information to support the revision of the UMSARS.

BackgroundBrain gray matter alterations in patients with trigeminal neuralgia (TN) have been detected in prior neuroimaging studies, but the results are heterogeneous. The current study conducted coordinate-based meta-analyses across neuroimaging studies, aiming to find the pattern of brain anatomic and functional alterations in patients with TN.MethodsWe performed a systematic literature search of PubMed, Embase, and Web of Science to identify relevant publications. A multimodal meta-analysis for whole-brain voxel-based morphometry (VBM) studies and functional imaging studies in TN was performed using anisotropic effect size-based signed differential mapping.ResultsThe meta-analysis comprised 10 VBM studies with 398 TN patients and 275 healthy controls, and 13 functional magnetic resonance imaging studies with 307 TN patients and 264 healthy controls. The multimodal meta-analysis showed conjoint structural and functional brain alterations in the right fusiform gyrus and inferior temporal gyrus, bilateral thalamus, left superior temporal gyrus, left insula, and inferior frontal gyrus. The unimodal meta-analysis showed decreased gray matter volume alone in the left putamen, left postcentral gyrus, and right amygdala as well as only functional abnormalities in the left cerebellum, bilateral precuneus, and left middle temporal gyrus.ConclusionThis meta-analysis revealed overlapping anatomic and functional gray matter abnormalities in patients with TN, which may help provide new insights into the neuropathology and potential treatment biomarkers of TN.

PurposeIncreasing neuroimaging studies have revealed gray matter (GM) and white matter (WM) anomalies of several brain regions by voxel-based morphometry (VBM) studies on patients with spinocerebellar ataxia type 3 (SCA3); however, the findings of previous studies on SCA3 patients by VBM studies remain inconsistent. The study aimed to identify consistent findings of gray matter (GM) and white matter (WM) changes in SCA3 patients by voxel-wise meta-analysis of whole-brain VBM studies.MethodsVBM studies comparing GM or WM changes in SCA3 patients and healthy controls (HCs) were retrieved from PubMed, Embase, Web of Science, and Medline databases from January 1990 to February 2023. Manual searches were also conducted, and authors of studies were contacted for additional data. The coordinates with significant differences in GM and WM between SCA3 patients and HCs were extracted from each cluster. A meta-analysis was performed using anisotropic effect size-based signed differential mapping (AES-SDM) software.ResultsA total of seven studies comprising 160 SCA3 patients and 165 HCs were included in the GM volume meta-analysis. Three studies comprising 57 SCA3 patients and 63 HCs were included for WM volume meta-analysis. Compared with HC subjects, the reduced GM volume in SCA3 patients was found in the bilateral cerebellar hemispheres, cerebellar vermis, pons, right lingual gyrus, and right fusiform gyrus. The decreased WM volume was mainly concentrated in the bilateral cerebellar hemispheres, right corticospinal tract, middle cerebellar peduncles, cerebellar vermis, and left lingual gyrus. No increased density or volume of any brain structures was found. In the jackknife sensitivity analysis, the results remained largely robust.ConclusionOur meta-analysis clearly found the shrinkage of GM and WM volume in patients with SCA3. These lesions are involved in ataxia symptoms, abnormal eye movements, visual impairment, cognitive impairment, and affective disorders. The findings can explain the clinical manifestations and provide a morphological basis for SCA3.

BackgroundThe 2008 criteria for the diagnosis of multiple system atrophy (MSA) has been widely used for more than 10 years, but the sensitivity is low, particularly for patients in the early stage. Recently, a new MSA diagnostic criteria was developed.ObjectiveThe objective of the study was to assess and compare the diagnostic utility of the new movement disorder society (MDS) MSA criteria with the 2008 MSA criteria.MethodsThis study included patients diagnosed with MSA between January 2016 and October 2021. All patients underwent regular face-to-face or telephonic follow-ups every year until October 2022. A total of 587 patients (309 males and 278 females) were retrospectively reviewed to compare the diagnostic accuracy of the MDS MSA criteria to that of the 2008 MSA criteria (determined by the proportion of patients categorized as established or probable MSA). Autopsy is the gold standard diagnosis of MSA, which is not available in clinical practice. Thus, we applied the 2008 MSA criteria at the last review as the reference standard.ResultsThe sensitivity of the MDS MSA criteria (93.2%, 95% CI = 90.5–95.2%) was significantly higher than that of the 2008 MSA criteria (83.5%, 95% CI = 79.8–86.6%) (P < 0.001). Additionally, the sensitivity of the MDS MSA criteria was maintained robustly across different subgroups, defined by diagnostic subtype, disease duration, and the type of symptom[s] at onset. Importantly, the specificities were not significantly different between the MDS MSA criteria and the 2008 MSA criteria (P > 0.05).ConclusionThe present study demonstrated that the MDS MSA criteria exhibited good diagnostic utility for MSA. The new MDS MSA criteria should be considered as a useful diagnostic tool for clinical practice and future therapeutic trials.

Deep-sea sediments enriched in rare earth elements and yttrium (REY-rich sediments) are widely distributed on the deep-sea floor, and their formation mechanism remains elusive. Although studies have recognized the link between seamounts and REY-rich sediments, in-depth analysis of the specific roles and effects of seamounts in the formation of REY-rich sediments is lacking. In this study, we analyzed surface sediments from the Marcus-Wake Seamounts for grain size, geochemistry, and mineral composition and classified the samples into three types: samples with moderate REY content and dominated by terrestrial detritus; samples with high REY and authigenic mineral content; and samples rich in CaCO3 but poor in REY. The REY in the sediments of the study area partly originate from Asian dust input and partly from seawater and/or pore water, and are mainly enriched in REY carrier particles including bioapatite fossils and micronodules. The amount of REY carrier particles influences the REY content in the sediments. The current field, primary productivity, weathering process, and depositional environment around seamounts are different from those of abyssal plains, which are conducive to the formation of REY-rich sediments. Strong bottom currents may exist in the southeastern direction of some large seamounts (e.g., Niulang Guyot), leading to the selective accumulation of REY-rich bioapatite fossils and micronodules, resulting in the formation of REY-rich sediments.

Abstract Emerging evidence has suggested a close correlation between COVID-19 and neurodegenerative disorders. However, whether there exists a causal association and the effect direction remains unknown. To examine the causative role of COVID-19 in the risk of neurodegenerative disorders, we estimated their genetic correlation, and then conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of susceptibility, hospitalization, and severity of COVID-19, as well as six major neurodegenerative disorders including Alzheimer’s disease (AD), amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body dementia, multiple sclerosis, and Parkinson’s disease. We identified a significant and positive genetic correlation between hospitalization of COVID-19 and AD (genetic correlation: 0.23, P = 8.36E–07). Meanwhile, hospitalization of COVID-19 was significantly associated with a higher risk of AD (OR: 1.02, 95% CI: 1.01–1.03, P: 1.19E–03). Consistently, susceptibility (OR: 1.05, 95% CI: 1.01–1.09, P: 9.30E–03) and severity (OR: 1.01, 95% CI: 1.00–1.02, P: 0.012) of COVID-19 were nominally associated with higher risk of AD. The results were robust under all sensitivity analyses. These results demonstrated that COVID-19 could increase the risk of AD. Future development of preventive or therapeutic interventions could attach importance to this to alleviate the complications of COVID-19.

ObjectivveThis study aimed to explore the prevalence and clinical correlates of apathy in amyotrophic lateral sclerosis (ALS) in a cohort of Chinese patients.MethodsA total of 1,013 ALS patients were enrolled in this study. Apathy was recorded during face-to-face interviews using Frontal Behavioral Inventory, and other patient characteristics, including depression, anxiety, and cognitive function, were collected using Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Chinese version of Addenbrooke’s Cognitive Examination-revised. Health-related quality of life of ALS patients and their caregivers was also evaluated, and the potential factors associated with apathy were explored using forward binary regression analysis. Survival was analyzed using the Cox proportional hazards model.ResultsThe prevalence of apathy in all patients was 28.9%. Patients in the late disease stage had a higher prevalence of apathy than those in the early disease stage. Furthermore, patients with apathy had a lower ALS Functional Rating Scale revised (ALSFRS-R) score, higher HDRS score, HARS score and higher proportion of reported problems in the anxiety/depression. Additionally, their caregivers had higher score of depression and higher Zarit-Burden Interview scores. Multivariate regression analysis revealed that apathy in ALS was associated with the onset region (p = 0.027), ALSFRS-R score (p = 0.007), depression (p = 0.001) and anxiety (p

IntroductionFunctional neuroimaging could provide abundant information of underling pathophysiological mechanisms of the clinical triad including motor, cognitive and psychiatric impairment in Huntington's Disease (HD).MethodsWe performed a voxel-based meta-analysis using anisotropic effect size-signed differential mapping (AES-SDM) method.Results6 studies (78 symptomatic HD, 102 premanifest HD and 131 healthy controls) were included in total. Altered resting-state brain activity was primarily detected in the bilateral medial part of superior frontal gyrus, bilateral anterior cingulate/paracingulate gyrus, left insula, left striatum, right cortico-spinal projections area, right inferior temporal gyrus area, right thalamus, right cerebellum and right gyrus rectus area. Premanifest and symptomatic HD patients showed different alterative pattern in the subgroup analyses.DiscussionThe robust and consistent abnormalities in the specific brain regions identified in the current study could help to understand the pathophysiology of HD and explore reliable neuroimaging biomarkers for monitoring disease progression, or even predicting the onset of premanifest HD patients.

Abstract Background Epidemiological and clinical studies have suggested comorbidity between frontotemporal dementia (FTD) and psychiatric disorders. FTD patients carrying specific mutations were at higher risk for some psychiatric disorders, and vice versa, implying potential shared genetic etiology, which is still less explored. Methods We examined the genetic correlation using summary statistics from genome-wide association studies and analyzed their genetic enrichment leveraging the conditional false discovery rate method. Furthermore, we explored the causal association between FTD and psychiatric disorders with Mendelian randomization (MR) analysis. Results We identified a significant genetic correlation between FTD and schizophrenia at both genetic and transcriptomic levels. Meanwhile, robust genetic enrichment was observed between FTD and schizophrenia and alcohol use disorder. Seven shared genetic loci were identified, which were mainly involved in interleukin-induced signaling, synaptic vesicle, and brain-derived neurotrophic factor signaling pathways. By integrating cis-expression quantitative trait loci analysis, we identified MAPT and CADM2 as shared risk genes. MR analysis showed mutual causation between FTD and schizophrenia with nominal association. Conclusions Our findings provide evidence of shared etiology between FTD and schizophrenia and indicate potential common molecular mechanisms contributing to the overlapping pathophysiological and clinical characteristics. Our results also demonstrate the essential role of autoimmunity in these diseases. These findings provide a better understanding of the pleiotropy between FTD and psychiatric disorders and have implications for therapeutic trials. Graphical abstract

Due to the outstanding penetrating detection performance of low-frequency electromagnetic waves, through-wall radar (TWR) has gained widespread applications in various fields, including public safety, counterterrorism operations, and disaster rescue. TWR is required to accomplish various tasks, such as people detection, people counting, and positioning in practical applications. However, most current research primarily focuses on one or two tasks. In this paper, we propose a multitask network that can simultaneously realize people counting, action recognition, and localization. We take the range–time–Doppler (RTD) spectra obtained from one-dimensional (1D) radar signals as datasets and convert the information related to the number, motion, and location of people into confidence matrices as labels. The convolutional layers and novel attention modules automatically extract deep features from the data and output the number, motion category, and localization results of people. We define the total loss function as the sum of individual task loss functions. Through the loss function, we transform the positioning problem into a multilabel classification problem, where a certain position in the distance confidence matrix represents a certain label. On the test set consisting of 10,032 samples from through-wall scenarios with a 24 cm thick brick wall, the accuracy of people counting can reach 96.94%, and the accuracy of motion recognition is 96.03%, with an average distance error of 0.12 m.

Objective To investigate the characteristics of functional muscle and muscle size in patients with basilar invagination (BI) and explore the effects of atlantoaxial dislocation. Methods Eighty BI patients (BI group) and 80 age- and sex-matched asymptomatic people (control group) were included. Axial T2 magnetic resonance imaging image was used to measure the cross-sectional area (CSA) and functional CSA (FCSA). The sternocleidomastoid (SCM), longus capitis and longus colli (LCap & LC), trapezius (Trap), splenius capitis (SpCap), splenius cervicis (SpC), semispinalis capitis (SSCap), semispinalis cervicis (SSC), multifidus (MS), levator scapulae (LS) and posterior deep layer muscles (PDLM) were evaluated. Correlations between age, atlantodental interval (ADI), Chamberlain distance and muscles were observed. Results BI group (39.4 ± 18.4 years; 33 males/47 females) exhibited significantly lower FCSA/CSA ratios than the control group in all extensor and flexor muscles, and presented smaller CSAs on the right and left Trap, SSC, LS, SCM, and left LCap & LC. FCSA/CSA ratios were significantly lower in BI patients with dislocation on the right Trap, SpCap, SpC, SSCap, MS, LS, LCap & LC, and PDLM, and the left SSCap, MS, and LCap & LC than in patients without deformity. Additionally, functional muscles of all parameters decreased with age in BI patients. Excluding children, the Trap, SpC, MS, and LS muscle sizes of BI patients tended to increase with age. ADI and Chamberlain distance tended to correlate negatively with FCSA/CSA ratio. Conclusion The BI patients, especially those with atlantoaxial dislocation, had less functional muscles compared with the control group. Moreover, their functional muscles decreased with age more obviously.

Recent years have witnessed tremendous progress in creating and manipulating ground-state ultracold polar molecules. However, the two-body loss regardless of the chemical reactivities is still a hurdle for many future explorations. Here, we investigate the loss suppression of nonreactive bosonic ^{23}Na^{87}Rb molecules with a circularly polarized microwave blue detuned to the rotational transition. We achieve suppression of the loss by 2 orders of magnitude with the lowest two-body loss rate coefficient reduced to 3×10^{-12} cm^{3}/s. Meanwhile, the elastic collision rate coefficient is increased to the 10^{-8} cm^{3}/s level. The large good-to-bad collision ratio has allowed us to carry out evaporative cooling of ^{23}Na^{87}Rb with an efficiency of 1.7(2), increasing the phase-space density by a factor of 10. With further improvements, this technique holds great promises for creating a Bose-Einstein condensate of ultracold polar molecules.

PurposeThe stability of fixation is crucial for the development of visual function. In this study, we quantify the deviation of visual target during fixational and saccadic tasks using eye-tracking technology, reflecting the control ability and characteristics of fixational displacement among healthy adults in a convenient method.MethodsOne hundred healthy participants aged between 18 and 55 years were recruited in the study. All participants underwent a complete ophthalmic assessment. The eye positions in the fixational and saccadic tasks were documented and analyzed by the Tobii eye-tracking system. Participants were grouped by age and gender. Targeting displacement (TD), defined as the average displacement between visual target and the mean of fixation points corresponding to that stimuli, was used to quantitatively observe fixational displacement in the horizontal and vertical directions.ResultThere was a strong reproducibility of TD as an indicator of fixation (ICC 0.812 to 0.891, p < 0.001). The TD in fixational task was significantly smaller than that of the saccadic task (3.884 ± 0.525 vs. 4.484 ± 0.509, p < 0.001) among normal people. Moreover, the difference of TD in the horizontal and vertical meridians was related to the nature of the task: In the fixational task, the TD in horizontal was smaller than that in the vertical (p < 0.001), whereas the TD in horizontal was larger than that in vertical in the saccadic task (p = 0.003). In the different age and gender groups: There was no significant difference between different gender and age groups in fixational task. However, during the saccadic task, males had smaller TD in the vertical direction than females (4.061 ± 0.495 vs. 4.404 ± 0.484, p = 0.002), and the average TD increased with age, mainly in the vertical direction (all p < 0.05). The fixation stability decreased significantly in the group over 50-years-old.ConclusionBy reporting the fixational displacement of different genders and ages in fixational and saccadic tasks, as well as different longitude lines among normal people, our study might provide an objective, quantitative and convenient reference index for the evaluation of fixation stability in visual impairment diseases and aging phenomenon of visual function.

Objective: The predictive factors for wheelchair dependence in patients with multiple system atrophy (MSA) are unclear. We aimed to explore the predictive factors for early-wheelchair dependence in patients with MSA focusing on clinical features and blood biomarkers. Methods: This is a prospective cohort study. This study included patients diagnosed with MSA between January 2014 and December 2019. At the deadline of October 2021, patients met the diagnosis of probable MSA were included in the analysis. Random forest (RF) was used to establish a predictive model for early-wheelchair dependence. Accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the model. Results: Altogether, 100 patients with MSA including 49 with wheelchair dependence and 51 without wheelchair dependence were enrolled in the RF model. Baseline plasma neurofilament light chain (NFL) levels were higher in patients with wheelchair dependence than in those without (P = 0.037). According to the Gini index, the five major predictive factors were disease duration, age of onset, Unified MSA Rating Scale (UMSARS)-II score, NFL, and UMSARS-I score, followed by C-reactive protein (CRP) levels, neutrophil-to-lymphocyte ratio (NLR), UMSARS-IV score, symptom onset, orthostatic hypotension, sex, urinary incontinence, and diagnosis subtype. The sensitivity, specificity, accuracy, and AUC of the RF model were 70.82 %, 74.55 %, 72.29 %, and 0.72, respectively. Conclusion: Besides clinical features, baseline features including NFL, CRP, and NLR were potential predictive biomarkers of early-wheelchair dependence in MSA. These findings provide new insights into the trials regarding early intervention in MSA.

Abstract Background The current study was to compare the management and clinical outcome between women and men with acute coronary syndrome (ACS). Method This was a retrospective study. Patients with ACS presented to the emergency department were enrolled. Management and clinical outcomes (including mortality and acute decompensated heart failure [ADHF]) were compared between women and men. Results A total of 686 patients were included and women accounted for 38.5% (n = 264). Women were less likely to receive ticagrelor at the emergency department (18.2% vs 25.1%). Duration from arrival at the emergency department to undergo electrocardiogram was longer in women (7.5 min vs 5.3 min). The duration from symptom onset to undergo percutaneous coronary intervention was longer in women (14.4 h vs 7.2 h). After adjusting for covariates, odds ratio (OR) for cardiovascular mortality was 0.42 (95% confidence interval [CI] 0.37–1.02) and ADHF was 0.63 (95% CI 0.55–1.01) for women vs men. Socioeconomic status, duration from symptom onset to arrive at the emergency department, and management at the emergency department were the important factors contributing to the sex-differences in clinical outcome. Conclusion Among ACS patients undergoing PCI, there was no sex-difference in in-hospital clinical outcome after adjusting for covariates. Future studies are needed to evaluate whether improving management at the emergency department can improve clinical outcomes in women and men with ACS.

Hepatitis B virus (HBV) middle surface antigen (MHBs) mutation or deletion occurs in patients with chronic HBV infection. However, the functional role of MHBs in HBV infection is still an enigma. Here, we reported that 7.33% (11/150) isolates of CHB patients had MHBs start codon mutations compared with 0.00% (0/146) in acute hepatitis B (AHB) patients. Interestingly, MHBs loss accounted for 11.88% (126/1061) isolates from NCBI GenBank, compared with 0.09% (1/1061) and 0.00% (0/1061) for HBV large surface antigen (LHBs) loss and HBV small surface antigen (SHBs) loss, respectively. One persistent HBV clone of genotype B (B56, MHBs loss) from a CHB patient was hydrodynamically injected into BALB/c mice. B56 persisted for >70 weeks in BALB/c mice, whereas B56 with restored MHBs (B56M+) was quickly cleared within 28 days. Serum cytokine assays demonstrated that CXCL1, CXCL2, IL-6 and IL-33 were significantly increased during rapid HBV clearance in B56M+ mice. Furthermore, the enhancers and promoters of B56 were proved to be required for B56 persistence in mice. Ablating MHBs expression improved the persistence of a new clone (HBV1.3, genotype B) which was recreated by using enhancers and promoters of B56. These data demonstrated that MHBs deletion can promote the persistence of specific HBV variants in a hydrodynamic mouse model. MHBs re-expression restored a rapid clearance of HBV, which was accompanied by cytokine responses including the elevation of CXCL1, CXCL2, IL-6 and IL-33.

ObjectivesA micro service-based architecture design method for ship industrial software is presented to improve the scalability and reliability of traditional industrial software.MethodsBased on traditional Internet software architecture, micro service technology is applied through future demand analysis. Ship industrial micro service software architecture is then presented for application in the entire ship industrial chain such as ship design, building and equipment manufacturing.ResultsThe proposed architecture is modeled and formally verified via π calculation. It is proven that the proposed architecture is correct and reasonable.ConclusionsThis research can lay a foundation for the development of next-generation ship industrial Internet software.

Background: Variants in the annexin A11 gene (ANXA11) have been reported to be associated with amyotrophic lateral sclerosis (ALS). These variants may be involved in the pathogenesis of ALS by causing defects in intracellular protein trafficking. However, the genetic spectrum and clinical characteristics of ALS patients with ANXA11 variants are largely unknown. Methods: Genetic analysis was performed on 1587 Chinese patients with ALS. Eight software packages were used to predict the deleteriousness of missense variants. In addition, we searched PubMed, Embase, and Web of Science for relevant literature and meta-analysed variant frequencies. Results: In our ALS cohort, we identified 20 non-synonymous variants in 29 ALS patients, including one stop-gain, one frameshift, and 18 rare missense variants with seven predicted pathogenic variants. In a literature review of 11 reported studies that included 69 patients, 37 ANXA11 variants were reported, with a frequency of 1.7%, which was similar to that in our cohort (1.8%). Both our cohort and previous reports showed that ANXA11 carriers were more commonly males than females (12/17 vs. 19/31). Patients carrying ANXA11 variants affecting the C-terminal of the protein had earlier disease onset and shorter survival times than those carrying variants affecting the N-terminal. We found a relatively longer median survival time than that previously reported (53.6 months vs. 46.0 months). Additionally, Caucasian ANXA11 carriers were more likely to have cognitive impairment, typically frontotemporal dementia (FTD) than their Asian counterparts (20.0% vs. 14.3%). While more than half of the patients in our cohort had cognitive impairment, none had FTD. Conclusion: In our and previously published cases, ALS-associated ANXA11 variants predominantly affected the N- and C-terminal conserved domains. ANXA11 variant carriers are typically male and cognitively impaired. Our study extends the genotypic and phenotypic spectra of ALS patients with ANXA11 variants. Further expansion of the sample size is needed to analyse the clinical and non-motor symptom characteristics of patients and to deepen the understanding of the pathogenesis of ANXA11-associated ALS.

Abstract Idiopathic blepharospasm shows a female predominance in prevalence, whether there are sex-related differences in distributions of nonmotor symptoms (NMSs) and predictors of quality of life are unknown. Four hundred and twenty-five patients with idiopathic blepharospasm were consecutively recruited, and underwent assessments including dystonia severity, mood disturbances, sleep disturbances, cognition, ocular symptoms, and quality of life. Frequencies and distributions of NMSs, and predictors of quality of life in female and male patients were investigated. NMSs existed in majority of male (94.0%) and female (95.8%) patients. The frequencies of depression, cognition dysfunction, and poor sleep quality were higher in female patients, while the frequency of excessive daytime sleepiness was higher in male patients. More female (79.5%) patients had multiple NMS domains affected than male (70.1%) patients (p = 0.040). Quality of life was associated with depression, anxiety and motor severity for female patients (adjusted R2 = 0.367, p

BackgroundAccumulating evidence has suggested that cystatin C is associated with cognitive impairment in patients with neurodegenerative diseases. However, the association between cystatin C and cognitive decline in patients with multiple system atrophy (MSA) remains largely unknown.ObjectivesThe objective was to determine whether cystatin C was independently associated with cognitive decline in patients with early-stage MSA.MethodsPatients with MSA underwent evaluation at baseline and the 1-year follow-up. Cognitive function was evaluated with Montreal cognitive assessment (MoCA). Changes in the MoCA score and the absolute MoCA score at the 1-year assessment were considered the main cognitive outcome. The cystatin C concentrations in patients with MSA and age, sex, and body mass index matched-healthy controls (HCs) were measured. A multiple linear regression model was used to test the association between cystatin C and cognitive decline.ResultsA total of 117 patients with MSA and 416 HCs were enrolled in the study. The cystatin C levels were significantly higher in patients with MSA than in HCs (p

BackgroundThe different clinical characteristics and prognostic values of the motor-nonmotor subtypes of Parkinson’s disease (PD) have been established by previous studies. However, the consistency of motor-nonmotor subtypes in patients with early-stage Parkinson’s disease required further investigation. The present study aimed to evaluate the consistency of motor-nonmotor subtypes across five years of follow-up in a longitudinal cohort.Materials and methodsPatients were classified into different subtypes (mild-motor–predominant, intermediate, diffuse malignant; or tremor-dominant, indeterminate, postural instability and gait difficulty) according to previously verified motor-nonmotor and motor subtyping methods at baseline and at every year of follow-up. The agreement between subtypes was examined using Cohen’s kappa and total agreement. The determinants of having the diffuse malignant subtype as of the fifth-year visit were explored using logistic regression.ResultsA total of 421 patients were included. There was a fair degree of agreement between the baseline motor-nonmotor subtype and the subtype recorded at the one-year follow-up visit (κ = 0.30 ± 0.09; total agreement, 60.6%) and at following years’ visits. The motor-nonmotor subtype had a lower agreement between baseline and follow-up than did the motor subtype. The baseline motor-nonmotor subtype was the determinant of diffuse malignant subtype at the fifth-year visit.ConclusionMany patients experienced a change in their motor-nonmotor subtype during follow-up. Further studies of consistency in PD subtyping methods should be conducted in the future.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of the upper and lower motor neurons from the motor cortex, brainstem, and spinal cord. Most ALS cases are sporadic, with 5–10% having a positive family history. Autosomal dominant polycystic kidney disease (ADPKD) is a heritable renal disease that eventually results in end-stage kidney disease. PKD1 is the most prevalent causative gene for ADPKD, accounting for ~85% of cases. Both diseases are currently considered untreatable. In this study, we report a large family that includes 10 patients with ALS phenotype, 3 asymptomatic SOD1-H47R carriers, and 6 with the ADPKD phenotype. Using whole exome sequencing, we found a novel likely pathogenic variant (p.R2787P) in PKD1 among patients with ADPKD, and a pathogenic variant (p.H47R) in SOD1 among patients with ALS. This study highlights the possibility that two different autosomal dominantly inherited diseases can co-exist independently within the same family. Phenotype—genotype correlations among these patients are also described. This research contributes novel phenotype and genotype characteristics of ALS with SOD1 mutations and ADPKD with PKD1 mutations.

Abstract Background Multiple system atrophy (MSA) is an incurable neurodegenerative disease. We aimed to investigate the health‐related quality of life (HRQoL) and the determinants of HRQoL in patients with MSA. Methods The five‐level EuroQol five‐dimensional questionnaire (EQ‐5D‐5L) was used to evaluate patients’ HRQoL. The results of HRQoL were indicated by the EQ‐5D‐5L index values and visual analog scale (EQ VAS) scores. Specific scales were used to measure disease severity, cognition, frontal lobe function, anxiety, depression, fatigue, and sleep disorders. The beta mixture model and the linear regression model were used to explore the determinants of HRQoL in patients with MSA. Results A total of 205 patients with cerebellar variants (MSA‐C; 53.9%) and 175 patients with parkinsonian variants (MSA‐P; 46.1%) were included in this cross‐sectional study. The mean values of the EQ‐5D‐5L index values and EQ VAS scores were .558 and 59.5, respectively. Problem with mobility was the problem reported by the highest proportion of patients (92.1%), followed by problems with usual activities (88.7%), self‐care (81.3%), anxiety/depression (72.1%), and pain/discomfort (53.9%). The determinants of the lower EQ‐5D‐5L index values in patients with MSA were greater disease severity, fatigue, Parkinson's disease‐related sleep problems (PD‐SP), depressive mood, and anxious mood. Greater disease severity, fatigue, and depressive mood were associated with lower EQ VAS scores. Conclusion The problem reported most frequently by Chinese individuals with MSA was mobility. In addition to the greater disease severity of MSA, fatigue, PD‐SP, depression, and anxiety were determinants of poor HRQoL.

Multiple evidence from epidemiological studies has suggested association between physical activity and risk of multiple sclerosis (MS). However, the conclusion was still controversial between studies, and whether the association was causal or confounded is elusive. To evaluate the role of physical activity with different intensities in the risk of MS, we first estimated their genetic correlation, and then conducted two-sample and multivariable Mendelian randomization analyses based on summary statistics from previous large genome-wide association studies. A significant genetic correlation was identified between moderate physical activity and the risk of MS (genetic correlation: -0.15, SE=0.05, P=2.9E-03). Meanwhile, higher moderate physical activity was significantly associated with a reduced risk of MS (OR:0.87, 95% CI:0.80-0.96, P=3.45E-03). Such association was further verified using summary statistics from another study on overall physical activity (OR:0.36, 95% CI:0.17-0.76, P=6.82E-03). The results were robust under all sensitivity analyses. Current results suggested moderate physical activity could reduce the risk of MS. These findings help better understand the role of physical activity in MS, and provide some lifestyle recommendations for individuals susceptible to MS.

Background: Cuprotosis is a new form of programmed cell death induced by copper. We explored the correlation of cuprotosis with clear cell renal cell carcinoma (ccRCC) and constructed a cuprotosis-related signature to predict the prognosis of patients with ccRCC.Methods: The clinical and transcriptomic data of ccRCC patients were downloaded from The Cancer Genome Atlas (TCGA), cBioPortal, and GEO databases, and cuprotosis-related gene sets were contained in the previous study. A cuprotosis-related signature was developed based on data from TCGA and verified by data from cBioPortal and GEO databases. The immune cell infiltrates and the corresponding signature risk scores were investigated. Two independent cohorts of clinical trials were analyzed to explore the correlation of the signature risk score with immune therapy response.Results: A signature containing six cuprotosis-related genes was identified and can accurately predict the prognosis of ccRCC patients. Patients with downregulated copper-induced programmed death had a worse overall survival (hazard ratio: 1.90, 95% CI: 1.39–2.59, p < 0.001). The higher signature risk score was significantly associated with male gender (p = 0.026), higher tumor stage (p < 0.001), and higher histological grade (p < 0.001). Furthermore, the signature risk score was positively correlated with the infiltration of B cells, CD8+ T cells, NK cells, Tregs, and T cells, whereas it was negatively correlated with eosinophils, mast cells, and neutrophils. However, no correlation between cuprotosis and response to anti-PD-1 therapy was found.Conclusion: We established a cuprotosis signature, which can predict the prognosis of patients with ccRCC. Cuprotosis was significantly correlated with immune cell infiltrates in ccRCC.

BackgroundThe upregulation of amino acid metabolism is an essential form of metabolic reprogramming in cancer. Here, we developed an amino acid metabolism signature to predict prognosis and anti-PD-1 therapy response in clear cell renal cell carcinoma (ccRCC).MethodsAccording to the amino acid metabolism-associated gene sets contained in the Molecular Signature Database, consensus clustering was performed to divide patients into two clusters. An amino acid metabolism-associated signature was identified and verified. Immune cell infiltrates and their corresponding signature risk scores were investigated. Two independent cohorts of clinical trials were analyzed to explore the correspondence between the signature risk score and the immune therapy response.ResultsTwo clusters with different amino acid metabolic levels were identified by consensus clustering. The patients in the two clusters differed in overall survival, progression-free survival, amino acid metabolic status, and tumor microenvironment. We identified a signature containing eight amino acid metabolism-associated genes that could accurately predict the prognosis of patients with ccRCC. The signature risk score was positively correlated with infiltration of M1 macrophages, CD8+ T cells, and regulatory T cells, whereas it was negatively correlated with infiltration of neutrophils, NK cells, and CD4+ T cells. Patients with lower risk scores had better overall survival but worse responses to nivolumab.ConclusionAmino acid metabolic status is closely correlated with tumor microenvironment, response to checkpoint blockade therapy, and prognosis in patients with ccRCC. The established amino acid metabolism-associated gene signature can predict both survival and anti-PD-1 therapy response in patients with ccRCC.

The laser parameters and additive materials were investigated for the laser–additive manufacturing of titanium alloys. A pre–placed metal–strip–based method for 3D printing titanium components was proposed. Before laser processing, the metal strips were fixed to a Grade 5 titanium substrate using resistance spot welding. The effect of the processing conditions (laser power: 1.5–3.0 kW; scanning speed: 3–9 mm·s−1; one or three layers; 1, 6, or 12 passes; Grade 2 and Grade 5 as additives) on the microstructures, oxidation resistance, and wear resistance of the as–printed samples was investigated. The results showed that the microstructure consisted of α′ martensite, oxygen–stabilized α, transformed β that contains coarse and fine acicular α, titanium oxides, and carbides. Cracks were observed, particularly near the upper surface of the three–layer samples. The cracks were suggested to have formed due to cumulative residual stresses and the formation of oxygen–stabilized α and α′ martensite that might cause embrittlement. Both oxidation and wear tests were conducted to verify the improved performance. After 55 h of oxidation, the as–printed samples showed mass gains of 0.029–0.035 g·cm−2, which were smaller than those of the substrate (0.039 g·cm−2).