Research Progress on Frailty in Elderly People.

Global aging is rapidly accelerating, which significantly influences the health systems worldwide. Frailty emerges as the most conspicuous hallmark of aging, imposing novel global health challenges. Characterized by a multifaceted decline across physiological system, frailty diminishes an individual's capacity to maintain equilibrium in the presence of stressors, which leads to adverse outcomes such as falls, delirium, and disability. Several screening tools and interventions have been developed to mitigate the harm caused by frailty to human health, but research on frailty in mainland China commences belatedly with scant studies conducted. Therefore, it is imperative to explore screening methods and treatment modalities tailored to the Chinese context, thereby enhancing the older adults' quality of life and advancing social medicine. This review aims to elucidate the evolution, diagnosis, and management of frailty, alongside the challenges it poses, with the overarching goal of guiding future diagnostic and therapeutic endeavors. Specifically, we summarized the mechanisms of frailty and intervention strategies in elderly people, and meanwhile, we evaluated the advantages and disadvantages of different measurement tools.

Unlocking the therapeutic potential of P2X7 receptor: a comprehensive review of its role in neurodegenerative disorders.

The P2X7 receptor (P2X7R), an ATP-gated ion channel, has emerged as a crucial player in neuroinflammation and a promising therapeutic target for neurodegenerative disorders. This review explores the current understanding of P2X7R's structure, activation, and physiological roles, focusing on its expression and function in microglial cells. The article examines the receptor's involvement in calcium signaling, microglial activation, and polarization, as well as its role in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. The review highlights the complex nature of P2X7R signaling, discussing its potential neuroprotective and neurotoxic effects depending on the disease stage and context. It also addresses the development of P2X7R antagonists and their progress in clinical trials, identifying key research gaps and future perspectives for P2X7R-targeted therapy development. By providing a comprehensive overview of the current state of knowledge and future directions, this review serves as a valuable resource for researchers and clinicians interested in exploring the therapeutic potential of targeting P2X7R for the treatment of neurodegenerative disorders.

Cortical morphological alterations in cognitively normal Parkinson's disease with severe hyposmia.

Olfactory dysfunction is a common non-motor symptom of Parkinson's disease(PD) and may hold valuable insights into the disease's underlying pathophysiology. This study aimed to investigate cortical morphometry alterations in PD patients with severe hyposmia(PD-SH) and mild hyposmia(PD-MH) using surface-based morphometry(SBM) methods. Participants included 36 PD-SH patients, 38 PD-MH patients, and 40 healthy controls(HCs). SBM analysis revealed distinct patterns of cortical alterations in PD-SH and PD-MH patients. PD-MH patients exhibited reduced cortical thickness in the right supramarginal gyrus, while PD-SH patients showed widespread cortical thinning in regions including the bilateral pericalcarine cortex, bilateral lingual gyrus, left inferior parietal cortex, left lateral occipital cortex, right pars triangularis, right cuneus, and right superior parietal cortex. Moreover, PD-SH patients displayed reduced cortical thickness in the right precuneus compared to PD-MH patients. Fractal dimension analysis indicated increased cortical complexity in PD-MH patients' right superior temporal cortex and right supramarginal gyrus, as well as decreased complexity in the bilateral postcentral cortex, left superior parietal cortex, and right precentral cortex. Similarly, cortical gyrification index and cortical sulcal depth exhibited heterogeneous patterns of changes in PD-SH and PD-MH patients compared to HCs. These findings underscore the multifaceted nature of olfactory impairment in PD, with distinct patterns of cortical morphometry alterations associated with different degrees of hyposmia. The observed discrepancies in brain regions showing alterations reflect the complexity of PD's pathophysiology. These insights contribute to a deeper understanding of olfactory dysfunction in PD and provide potential avenues for early diagnosis and targeted interventions.

Diagnostic Significance of Serum Long Noncoding HOX Antisense Intergenic Ribonucleic Acid in Patients with Hepatitis B Virus Related Hepatocellular Carcinoma.

BACKGROUND/AIMS:  Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer-related mortality. Extensive literature suggests that long noncoding RNAs play a role in the progression of HCC and hold potential as diagnostic biomarkers for this disease. MATERIALS AND METHODS:  We examined the serum levels of HOX antisense intergenic RNA (HOTAIR) in 49 hepatitis patients, 31 liver cirrhosis (LC), and 37 HCC patients using quantitative real-time polymerase chain reaction. Correlations between serum HOTAIR levels and clinical data were evaluated in HCC patients. The receiver operating characteristic curve was utilized to analyze the diagnostic potency of HOTAIR. RESULTS:  The HOTAIR levels in serum were significantly higher in HCC patients compared to those with hepatitis (P = .003) and LC patients (P = .048). There was a significant association between the serum levels of HOTAIR and positivity of hepatitis B e antigen (HBeAg) (P = .039) as well as portal vein tumor thrombus (P = .040) in HCC patients. The area under the curve (AUC) for HOTAIR for distinguishing HCC from hepatitis and LC was 0.697. The combined AUC for HOTAIR, HBeAg, and alpha-fetoprotein (AFP) was 0.777. CONCLUSION:  Serum HOTAIR functions as a potential diagnostic marker for hepatitis B virus-related HCC. Combining HOTAIR with clinical data and AFP can reinforce the diagnostic precision on HCC.

A lumen-tunable triangular DNA nanopore for molecular sensing and cross-membrane transport.

Synthetic membrane nanopores made of DNA are promising systems to sense and control molecular transport in biosensing, sequencing, and synthetic cells. Lumen-tunable nanopore like the natural ion channels and systematically increasing the lumen size have become long-standing desires in developing nanopores. Here, we design a triangular DNA nanopore with a large tunable lumen. It allows in-situ transition from expanded state to contracted state without changing its stable triangular shape, and vice versa, in which specific DNA bindings as stimuli mechanically pinch and release the three corners of the triangular frame. Transmission electron microscopy images and molecular dynamics simulations illustrate the stable architectures and the high shape retention. Single-channel current recordings and fluorescence influx studies demonstrate the low-noise repeatable readouts and the controllable cross-membrane macromolecular transport. We envision that the proposed DNA nanopores could offer powerful tools in molecular sensing, drug delivery, and the creation of synthetic cells.

Application of chitosan as nano carrier in the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is characterized by persistent and recurrent gastrointestinal inflammation. Conventional IBD therapies often involve the use of antibiotics, NSAIDs, biological agents, and immunomodulators. While these medications can mitigate acute inflammatory symptoms, their long-term efficacy is frequently compromised due to cumulative toxic effects. In recent years, significant attention has shifted toward nanoparticle (NP)-based therapies as potential alternatives for IBD management. Various drug delivery strategies, including those targeting microbiota interactions, ligand-receptor binding, pH sensitivity, biodegradability, pressure response, and specific charge and size parameters, have been explored and optimized in animal studies. This review provides a comprehensive overview of the current landscape of chitosan NP-mediated drug delivery systems for IBD treatment. Additionally, it will discuss the prevailing challenges and propose future research directions to advance chitosan NP-based therapeutic strategies for IBD.

Differentiation of tuberculous and brucellar spondylitis using conventional MRI-based deep learning algorithms.

PURPOSE: To investigate the feasibility of deep learning (DL) based on conventional MRI to differentiate tuberculous spondylitis (TS) from brucellar spondylitis (BS). METHODS: A total of 383 patients with TS (n = 182) or BS (n = 201) were enrolled from April 2013 to May 2023 and randomly divided into training (n = 307) and validation (n = 76) sets. Sagittal T1WI, T2WI, and fat-suppressed (FS) T2WI images were used to construct single-sequence DL models and combined models based on VGG19, VGG16, ResNet18, and DenseNet121 network. The area under the receiver operating characteristic curve (AUC) was used to assess the classification performance. The AUC of DL models was compared with that of two radiologists with different levels of experience. RESULTS: The AUCs based on VGG19, ResNet18, VGG16, and DenseNet121 ranged from 0.885 to 0.973, 0.873 to 0.944, 0.882 to 0.929, and 0.801 to 0.933, respectively, and VGG19 models performed better. The diagnostic efficiency of combined models outperformed single-sequence DL models. The combined model of T1WI, T2WI, and FS T2WI based on VGG19 achieved optimal performance, with an AUC of 0.973. In addition, the performance of all combined models based on T1WI, T2WI, and FS T2WI was better than that of two radiologists (P<0.05). CONCLUSION: The DL models have potential guiding value in the diagnosis of TS and BS based on conventional MRI and provide a certain reference for clinical work.

Tris(triazolo)triazine-Based Covalent Organic Frameworks for Efficiently Photocatalytic Hydrogen Peroxide Production.

Two-dimensional covalent organic frameworks (2D-COFs) have recently emerged as fascinating scaffolds for solar-to-chemical energy conversion because of their customizable structures and functionalities. Herein, two tris(triazolo)triazine-based COF materials (namely COF-JLU51 and COF-JLU52) featuring large surface area, high crystallinity, excellent stability and photoelectric properties were designed and constructed for the first time. Remarkably, COF-JLU51 gave an outstanding H2O2 production rate of over 4200 µmol g-1 h-1 with excellent reusability in pure water and O2 under one standard sun light, that higher than its isomorphic COF-JLU52 and most of the reported metal-free materials, owing to its superior generation, separation and transport of photogenerated carriers. Experimental and theoretical researches prove that the photocatalytic process undergoes a combination of indirect 2e- O2 reduction reaction (ORR) and 4e- H2O oxidation reaction (WOR). Specifically, an ultrahigh yield of 7624.7 µmol g-1 h-1 with apparent quantum yield of 18.2 % for COF-JLU52 was achieved in a 1 : 1 ratio of benzyl alcohol and water system. This finding contributes novel, nitrogen-rich and high-quality tris(triazolo)triazine-based COF materials, and also designate their bright future in photocatalytic solar transformations.

Effect of microwaves combined with peracetic acid to improve the dewatering performance of residual sludge.

The activated sludge process plays a crucial role in modern wastewater treatment plants. During the treatment of daily sewage, a large amount of residual sludge is generated, which, if improperly managed, can pose burdens on the environment and human health. Additionally, the highly hydrated colloidal structure of biopolymers limits the rate and degree of dewatering, making mechanical dewatering challenging. This study investigates the impact and mechanism of microwave irradiation (MW) in conjunction with peracetic acid (PAA) on the dewatering efficiency of sludge. Sludge dewatering effectiveness was assessed through capillary suction time (CST) and specific resistance to filtration (SRF). Examination of the impact of MW-PAA treatment on sludge dewatering performance involved assessing the levels of extracellular polymeric substances (EPS), employing three-dimensional excitation-emission matrix (3D-EEM), Fourier transform-infrared spectroscopy (FT-IR), and scanning electron microscopy. Findings reveal that optimal dewatering performance, with respective reductions of 91.22% for SRF and 84.22% for CST, was attained under the following conditions: microwave power of 600 W, reaction time of 120 s, and PAA dosage of 0.25 g/g MLSS. Additionally, alterations in both sludge EPS composition and floc morphology pre- and post-MW-PAA treatment underwent examination. The findings demonstrate that microwaves additionally boost the breakdown of PAA into •OH radicals, suggesting a synergistic effect upon combining MW-PAA treatment. These pertinent research findings offer insights into employing MW-PAA technology for residual sludge treatment.

Therapeutic effects of Lingguizhugan decoction in a rat model of high-fat diet-induced insulin resistance.

BACKGROUND: Lingguizhugan (LGZG) decoction is a widely used classic Chinese medicine formula that was recently shown to improve high-fat diet (HFD)-induced insulin resistance (IR) in animal studies. AIM: To assess the therapeutic effect of LGZG decoction on HFD-induced IR and explore the potential underlying mechanism. METHODS: To establish an IR rat model, a 12-wk HFD was administered, followed by a 4-wk treatment with LGZG. The determination of IR status was achieved through the use of biochemical tests and oral glucose tolerance tests. Using a targeted meta-bolomics platform to analyze changes in serum metabolites, quantitative real-time PCR (qRT-PCR) was used to assess the gene expression of the ribosomal protein S6 kinase beta 1 (S6K1). RESULTS: In IR rats, LGZG decreased body weight and indices of hepatic steatosis. It effectively controlled blood glucose and food intake while protecting islet cells. Metabolite analysis revealed significant differences between the HFD and HFD-LGZG groups. LGZG intervention reduced branched-chain amino acid levels. Levels of IR-related metabolites such as tryptophan, alanine, taurine, and asparagine decreased significantly. IR may be linked to amino acids due to the contemporaneous increase in S6K1 expression, as shown by qRT-PCR. CONCLUSIONS: Our study strongly suggests that LGZG decoction reduces HFD-induced IR. LGZG may activate S6K1 via metabolic pathways. These findings lay the groundwork for the potential of LGZG as an IR treatment.

Recurrent Cerebral Venous Sinus Thrombosis Occurred in an Acute Lymphoblastic Leukemia Child with Mutated Lipoprotein Lipase Gene during Asparaginase Therapy.

Cerebral venous sinus thrombosis (CVST) and hyperlipidemia are severe complications of L-Asparaginase (L-Asp) during the treatment of B-cell acute lymphoblastic leukemia (B-ALL). Herein, we reported a 9-year-old B-ALL boy who underwent abnormal hypertriglyceridemia and CVST presenting as seizures and disturbance of consciousness twice during the induction therapy. Fortunately, he survived treatment with anticoagulant and lipid-lowering therapy. No thrombophilia-related gene mutation was detected, but a heterozygous mutation in lipoprotein lipase (LPL) gene was identified. His neurological symptoms were managed with short-term anticoagulant therapy and long-term lipid-lowering therapy. This case illustrated the manifestation and potential pathogenesis of CVST and highlighted the essentiality of screening baseline lipid profile and dyslipidemia- and thrombophilia-related gene mutation.

Diagnostic Value of Hounsfield Units for Osteoporotic Thoracolumbar Vertebral Non-Compression Fractures in Elderly Patients with Low-Energy Injuries.

Background: Thoracolumbar vertebral fractures are common pathological fractures caused by osteoporosis in the elderly. These fractures are challenging to detect. This study aimed to evaluate the diagnostic value of Hounsfield units for osteoporotic thoracolumbar vertebral non-compression fractures in elderly patients with low-energy fractures. Methods: The retrospective case-control study included elderly patients diagnosed with osteoporotic thoracolumbar vertebral fractures and non-fractured patients who underwent computed tomography examinations for lumbar vertebra issues during July 2017 and June 2020. Results: This study included 216 patients with fractures (38 males and 178 females; average age: 77.28±8.68 years) and 124 patients without fractures (21 males and 103 females; average age: 75.35±9.57 years). The difference in Hounsfield units of the target (intermediate) vertebral body significantly differed between the two groups (54.74 ± 21.84 vs 5.86 ± 5.14; p<0.001). The ratios of Hounsfield units were also significantly different between the two groups (1.38 ± 1.60 vs 0.13 ± 0.23; p<0.001). The cut-off value for the difference in Hounsfield units to detect osteoporotic spine fractures was 25.35, with high sensitivity (98.5%), specificity (99.9%), and the area under the curve (AUC) (0.999, 95% CI: 0.999-1). The cut-off value for the odds ratio of Hounsfield units was 0.260, with high sensitivity (99.1%), specificity (92.7%), and AUC (0.970, 95% CI: 0.949-0.992). Conclusion: The difference between Hounsfield units and the odds ratio of Hounsfield units might help diagnose osteoporotic thoracolumbar vertebral non-compression fractures in elderly patients with low-energy fractures.

Recent Advances in Whiskers: Properties and Clinical Applications in Dentistry.

Whiskers are nanoscale, high-strength fibrous crystals with a wide range of potential applications in dentistry owing to their unique mechanical, thermal, electrical, and biological properties. They possess high strength, a high modulus of elasticity and good biocompatibility. Hence, adding these crystals to dental composites as reinforcement can considerably improve the mechanical properties and durability of restorations. Additionally, whiskers are involved in inducing the value-added differentiation of osteoblasts, odontogenic osteocytes, and pulp stem cells, and promoting the regeneration of alveolar bone, periodontal tissue, and pulp tissue. They can also enhance the mucosal barrier function, inhibit the proliferation of tumor cells, control inflammation, and aid in cancer prevention. This review comprehensively summarizes the classification, properties, growth mechanisms and preparation methods of whiskers and focuses on their application in dentistry. Due to their unique physicochemical properties, excellent biological properties, and nanoscale characteristics, whiskers show great potential for application in bone, periodontal, and pulp tissue regeneration. Additionally, they can be used to prevent and treat oral cancer and improve medical devices, thus making them a promising new material in dentistry.

Efficacy and safety of mycophenolate mofetil versus cyclophosphamide therapy for Henoch schonlein purpura nephritis in children: A meta-analysis.

OBJECTIVE: The objective of this meta-analysis was to compare the efficacy and safety between glucocorticoids combined with mycophenolate mofetil (MMF) versus glucocorticoids combined with cyclophosphamide (CTX) for henoch schonlein purpura nephritis (HSPN) in children. METHODS: Databases including PubMed, EMbase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang database were searched from the inception to April 5th, 2024. Eligible studies comparing glucocorticoids combined with MMF versus glucocorticoids combined with CTX for HSPN in children were included. Data were analyzed using Review Manager Version 5.3. RESULTS: Ten studies were included in the meta-analysis. Six randomized controlled trials (RCTs) and 4 non-randomized studies involving 675 patients were identified. Compared with CTX therapeutic schedule, MMF therapeutic schedule had a higher complete remission (CR) within the 6 months (OR 1.61, 95%CI 1.16-2.22, P = .004) and CR within the 12 months (OR 1.73, 95%CI 1.00-2.97, P = .05). However, there was no significant difference between MMF and CTX therapeutic schedule concerning total remission (TR) within the 6 months (OR 1.54, 95%CI 0.82-2.92, P = .18) and TR within the 12 months (OR 2.08, 95%CI 0.86-5.01, P = .10). In addition, incidences of gastrointestinal discomfort (OR 0.33, 95%CI 0.19-0.56, P < .0001), liver function injury (OR 0.28, 95%CI 0.09-0.87, P = .03), myelosuppression (OR 0.15, 95%CI 0.06-0.41, P = .0001), alopecia (OR 0.25, 95%CI 0.07-0.91, P = .03) in MMF therapeutic schedule were all lower than CTX therapeutic schedule. There was no statistically significant difference between the 2 therapeutic schedules concerning infection (OR 0.90, 95%CI 0.50-1.61, P = .72), rash (OR 0.38, 95%CI 0.07-2.04, P = .26). CONCLUSION: Glucocorticoids combined with MMF had a higher CR and lower incidence of adverse effects compared with glucocorticoids combined with CTX in the treatment of HSPN in children.

Interpretable machine learning models for predicting clinical pregnancies associated with surgical sperm retrieval from testes of different etiologies: a retrospective study.

BACKGROUND: The relationship between surgical sperm retrieval of different etiologies and clinical pregnancy is unclear. We aimed to develop a robust and interpretable machine learning (ML) model for predicting clinical pregnancy using the SHapley Additive exPlanation (SHAP) association of surgical sperm retrieval from testes of different etiologies. METHODS: A total of 345 infertile couples who underwent intracytoplasmic sperm injection (ICSI) treatment with surgical sperm retrieval due to different etiologies from February 2020 to March 2023 at the reproductive center were retrospectively analyzed. The six machine learning (ML) models were used to predict the clinical pregnancy of ICSI. After evaluating the performance characteristics of the six ML models, the Extreme Gradient Boosting model (XGBoost) was selected as the best model, and SHAP was utilized to interpret the XGBoost model for predicting clinical pregnancies and to reveal the decision-making process of the model. RESULTS: Combining the area under the receiver operating characteristic curve (AUROC), accuracy, precision, recall, F1 score, brier score, and the area under the precision-recall (P-R) curve (AP), the XGBoost model has the best performance (AUROC: 0.858, 95% confidence interval (CI): 0.778-0.936, accuracy: 79.71%, brier score: 0.151). The global summary plot of SHAP values shows that the female age is the most important feature influencing the model output. The SHAP plot showed that younger age in females, bigger testicular volume (TV), non-tobacco use, higher anti-müllerian hormone (AMH), lower follicle-stimulating hormone (FSH) in females, lower FSH in males, the temporary ejaculatory disorders (TED) group, and not the non-obstructive azoospermia (NOA) group all resulted in an increased probability of clinical pregnancy. CONCLUSIONS: The XGBoost model predicts clinical pregnancies associated with testicular sperm retrieval of different etiologies with high accuracy, reliability, and robustness. It can provide clinical counseling decisions for patients with surgical sperm retrieval of various etiologies.

Non-nitrogen-containing bisphosphonates and nitrogen-containing bisphosphonates for the treatment of atherosclerosis and vascular calcification: A meta-analysis.

BACKGROUND: The role of non-nitrogen-containing bisphosphonates (non-N-BPs) and nitrogen-containing bisphosphonates (N-BPs) in the treatment of atherosclerosis (AS) and vascular calcification (VC) is uncertain. This meta-analysis was conducted to evaluate the efficacy of non-N-BPs and N-BPs in the treatment of AS and VC. METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched from their inception to July 5th, 2023. Eligible studies comparing bisphosphonates (BPs) versus no BPs in the treatment of AS and VC were included. The data were analyzed using Review Manager Version 5.3. RESULTS: Seventeen studies were included in this meta-analysis. Twelve were randomized control trials (RCTs), and 5 were nonrandomized studies. Overall, 813 patients were included in the BPs group, and 821 patients were included in the no BPs group. Compared with no BP treatment, non-N-BP or N-BP treatment did not affect serum calcium (P > .05), phosphorus (P > .05) or parathyroid hormone (PTH) levels (P > .05). Regarding the effect on serum lipids, non-N-BPs decreased the serum total cholesterol (TC) level (P < .05) and increased the serum triglyceride (TG) level (P < .01) but did not affect the serum low-density lipoprotein cholesterol (LDL-C) level (P > .05). N-BPs did not affect serum TC (P > .05), TG (P > .05) or LDL-C levels (P > .05). Regarding the effect on AS, non-N-BPs did not have a beneficial effect (P > .05). N-BPs had a beneficial effect on AS, including reducing the intima-media thickness (IMT) (P < .05) and plaque area (P < .01). For the effect on VC, non-N-BPs had a beneficial effect (P < .01), but N-BPs did not have a beneficial effect (P > .05). CONCLUSION: Non-N-BPs and N-BPs did not affect serum calcium, phosphorus or PTH levels. Non-N-BPs decreased serum TC levels and increased serum TG levels. N-BPs did not affect serum lipid levels. Non-N-BPs had a beneficial effect on VC, and N-BPs had a beneficial effect on AS.

Metal-doped carbon dots for biomedical applications: From design to implementation.

Carbon dots (CDs), as a new kind of fluorescent nanomaterials, show great potential for application in several fields due to their unique nano-size effect, easy surface functionalization, controllable photoluminescence, and excellent biocompatibility. Conventional preparation methods for CDs typically involve top-down and bottom-up approaches. Doping is a major step forward in CDs design methodology. Chemical doping includes both non-metal and metal doping, in which non-metal doping is an effective strategy for modulating the fluorescence properties of CDs and improving photocatalytic performance in several areas. In recent years, Metal-doped CDs have aroused the interest of academics as a promising nano-doping technique. This approach has led to improvements in the physicochemical and optical properties of CDs by altering their electron density distribution and bandgap capacity. Additionally, the issues of metal toxicity and utilization have been addressed to a large extent. In this review, we categorize metals into two major groups: transition group metals and rare-earth group metals, and an overview of recent advances in biomedical applications of these two categories, respectively. Meanwhile, the prospects and the challenges of metal-doped CDs for biomedical applications are reviewed and concluded. The aim of this paper is to break through the existing deficiencies of metal-doped CDs and fully exploit their potential. I believe that this review will broaden the insight into the synthesis and biomedical applications of metal-doped CDs.

Critical assessment of missense variant effect predictors on disease-relevant variant data.

Regular, systematic, and independent assessment of computational tools used to predict the pathogenicity of missense variants is necessary to evaluate their clinical and research utility and suggest directions for future improvement. Here, as part of the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, we assess missense variant effect predictors (or variant impact predictors) on an evaluation dataset of rare missense variants from disease-relevant databases. Our assessment evaluates predictors submitted to the CAGI6 Annotate-All-Missense challenge, predictors commonly used by the clinical genetics community, and recently developed deep learning methods for variant effect prediction. To explore a variety of settings that are relevant for different clinical and research applications, we assess performance within different subsets of the evaluation data and within high-specificity and high-sensitivity regimes. We find strong performance of many predictors across multiple settings. Meta-predictors tend to outperform their constituent individual predictors; however, several individual predictors have performance similar to that of commonly used meta-predictors. The relative performance of predictors differs in high-specificity and high-sensitivity regimes, suggesting that different methods may be best suited to different use cases. We also characterize two potential sources of bias. Predictors that incorporate allele frequency as a predictive feature tend to have reduced performance when distinguishing pathogenic variants from very rare benign variants, and predictors supervised on pathogenicity labels from curated variant databases often learn label imbalances within genes. Overall, we find notable advances over the oldest and most cited missense variant effect predictors and continued improvements among the most recently developed tools, and the CAGI Annotate-All-Missense challenge (also termed the Missense Marathon) will continue to assess state-of-the-art methods as the field progresses. Together, our results help illuminate the current clinical and research utility of missense variant effect predictors and identify potential areas for future development.

Abnormal Functional Connectivity Intra- and Inter-Network in Resting-State Brain Networks of Patients with Toothache.

Objective: To separate the resting-state network of patients with dental pain using independent component analysis (ICA) and analyze abnormal changes in functional connectivity within as well as between the networks. Patients and Methods: Twenty-three patients with dental pain and 30 healthy controls participated in this study. We extracted the resting-state functional network components of both using ICA. Functional connectivity differences within 14 resting-state brain networks were analyzed at the voxel level. Directional interactions between networks were analyzed using Granger causality analysis. Subsequently, functional connectivity values and causal coefficients were assessed for correlations with clinical parameters. Results: Compared to healthy controls, we found enhanced functional connectivity in the left superior temporal gyrus of anterior protrusion network and the right Rolandic operculum of auditory network in patients with dental pain (p<0.01 and cluster-level p<0.05, Gaussian random field corrected). In contrast, functional connectivity of the right precuneus in the precuneus network was reduced, and were significantly as well as negatively correlated to those of the Visual Analogue Scale (r=-4.93, p=0.017), Hamilton Anxiety Scale (r=-0.46, p=0.027), and Hamilton Depression Scale (r=-0.563, p<0.01), using the Spearman correlation analysis. Regarding the causal relationship between resting-state brain networks, we found increased connectivity from the language network to the precuneus in patients with dental pain (p<0.05, false discovery rate corrected). However, the increase in causal coefficients from the verbal network to the precuneus network was independent of clinical parameters. Conclusion: Patients with toothache exhibited abnormal functional changes in cognitive-emotion-related brain networks, such as the salience, auditory, and precuneus networks, thereby offering a new imaging basis for understanding central neural mechanisms in dental pain patients.