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IntroductionHyperlipidemia remains a major disease threatening global public health. The morbidity and mortality associated with cardiovascular diseases have been increasing. The inhibition of 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a key enzyme in the cholesterol synthesis pathway, can effectively reduce cholesterol levels.Methods and resultsIn this study, the most suitable protease for preparing HMGCR inhibitory peptides was screened using the evaluation indexes of peptide yield and HMGCR inhibition rate. Peptide sequences with molecular weights

PurposeThe split-elbow sign (SES), characterized by preferential dysfunction of the biceps brachii compared to the triceps, is a clinical feature observed in amyotrophic lateral sclerosis (ALS). However, the quantified SES index has not been extensively investigated, and its role in diagnosing ALS remains unknown. Therefore, this study aimed to investigate the split-elbow index (SEI) derived from compound muscle action potential (CMAP), motor unit number index (MUNIX), and echo intensity (EI) in ALS.MethodsA cohort comprising 70 individuals diagnosed with ALS, along with 41 disease controls and 40 healthy controls, was recruited for the study. The SEI was calculated by dividing the recorded values of CMAP, MUNIX, and EI obtained over the biceps brachii by the corresponding value measured in the triceps, resulting in SEICMAP, SEIMUNIX, and SEIEI, respectively. Receiver operating characteristic (ROC) curves of the three methods were used for comparison. Statistical analyses were performed using SPSS V.26.0 and R software.ResultsBoth SEICMAP and SEIMUNIX exhibited significant reductions in ALS patients compared to that in controls (PSEICMAp

BackgroundInfertility is increasingly recognized as a global health issue affecting couples of reproductive age, with male factors contributing to approximately 50% of infertility cases. However, the association between depression and anxiety-two of the most prevalent mental health conditions-and impaired male fertility remains a subject of ongoing debate.MethodsIn this cross-sectional study, male participants seeking fertility counseling at an IVF clinic were recruited. Symptoms of depression and anxiety were assessed using the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7), respectively. Generalized linear regression models (GLMs) were employed to investigate the relationships between mental health status and semen parameters.ResultsStatus of depression was negatively associated with semen quality parameters, whereas no statistically significant association was recognized between anxiety and semen quality except that sperm concentration was decreased by 25.60 (95% CI, 1.226 to 49.965, P=0.040) ×106/ml in moderate to severe anxiety group referring to normal group. Furthermore, when stratified by sleep duration, moderate to severe depression group showed a great decrease in progressive motility (PR), total motility, concentration and total sperm count (TSC) as referred to normal group in participants with sleep duration less than 7 hours.ConclusionThe present study revealed that depression rather than anxiety was a negative factor that affected semen quality, especially in individuals with shorter sleep duration.

The anti-nerve growth factor antibody class of drugs interrupts signaling by blocking NGF binding to TrkA receptors for the treatment of pain; however, this target class of drugs has been associated with serious adverse effects in the joints during clinical trials. DS002 is a novel anti-nerve growth factor antibody drug independently developed by Guangdong Dashi Pharmaceuticals. The main purpose of this study is to explore the correlation between DS002 and pain as well as cartilage and bone metabolism with the help of metabolomics technology and the principle of enzyme-linked reaction, and to examine whether DS002 will produce serious adverse effects in joints caused by its same target class of drugs, in order to provide more scientific basis for the safety and efficacy of DS002. Our results showed that DS002 mainly affected the metabolism of aromatic amino acids and other metabolites, of which six metabolites, l -phenylalanine, 5-hydroxytryptophan, 5-hydroxytryptamine hydrochloride, 3-indolepropionic acid, kynuric acid, and kynurenine, were significantly altered, which may be related to the effectiveness of DS002 in treating pain. In addition, there were no significant changes in biological indicators related to cartilage and bone metabolism in vivo, suggesting that DS002 would not have a significant effect on cartilage and bone metabolism, so we hypothesize that DS002 may not produce the serious adverse effects in joints caused by its fellow target analogs. Therefore, the Anti-NGF analgesic drug DS002 has the potential to become a promising drug in the field of analgesia, providing pain patients with an efficient treatment option without adverse effects.

Introduction: The liver is the only organ capable of full regeneration in mammals. However, the exact mechanism of gut microbiota and metabolites derived from them relating to liver regeneration has not been fully elucidated.Methods: To demonstrate how the gut-liver axis contributes to liver regeneration, using an LC-QTOF/MS-based metabolomics technique, we examine the gut microbiota-derived metabolites in the gut content of C57BL/6J mice at various points after 2/3 partial hepatectomy (PHx). Compound identification, multivariate/univariate data analysis and pathway analysis were performed subsequently. The diversity of the bacterial communities in the gastrointestinal content was measured using 16S rRNA gene sequencing. Then, the integration analysis of gut microbiota and metabolome was performed.Results: After 2/3 PHx, the residual liver proliferated quickly in the first 3 days and had about 90% of its initial weight by the seventh day. The results of PLS-DA showed that a significant metabolic shift occurred at 6 h and 36 h after 2/3 PHx that was reversed at the late phase of liver regeneration. The α and β-diversity of the gut microbiota significantly changed at the early stage of liver regeneration. Specifically, Escherichia Shigella, Lactobacillus, Akkermansia, and Muribaculaceae were the bacteria that changed the most considerably during liver regeneration. Further pathway analysis found the most influenced co-metabolized pathways between the host and gut bacteria including glycolysis, the TCA cycle, arginine metabolism, glutathione metabolism, tryptophan metabolism, and purine and pyrimidine metabolism. Specifically, steroid hormone biosynthesis is the most significant pathway of the host during liver regeneration.Discussion: These findings revealed that during liver regeneration, there was a broad modification of gut microbiota and systemic metabolism and they were strongly correlated. Targeting specific gut bacterial strains, especially increasing the abundance of Akkermansia and decreasing the abundance of Enterobacteriaceae, may be a promising beneficial strategy to modulate systemic metabolism such as amino acid and nucleotide metabolism and promote liver regeneration.

BackgroundAccurate tumor target contouring and T staging are vital for precision radiation therapy in nasopharyngeal carcinoma (NPC). Identifying T-stage and contouring the Gross tumor volume (GTV) manually is a laborious and highly time-consuming process. Previous deep learning-based studies have mainly been focused on tumor segmentation, and few studies have specifically addressed the tumor staging of NPC.ObjectivesTo bridge this gap, we aim to devise a model that can simultaneously identify T-stage and perform accurate segmentation of GTV in NPC.Materials and methodsWe have developed a transformer-based multi-task deep learning model that can perform two tasks simultaneously: delineating the tumor contour and identifying T-stage. Our retrospective study involved contrast-enhanced T1-weighted images (CE-T1WI) of 320 NPC patients (T-stage: T1-T4) collected between 2017 and 2020 at our institution, which were randomly allocated into three cohorts for three-fold cross-validations, and conducted the external validation using an independent test set. We evaluated the predictive performance using the area under the receiver operating characteristic curve (ROC-AUC) and accuracy (ACC), with a 95% confidence interval (CI), and the contouring performance using the Dice similarity coefficient (DSC) and average surface distance (ASD).ResultsOur multi-task model exhibited sound performance in GTV contouring (median DSC: 0.74; ASD: 0.97 mm) and T staging (AUC: 0.85, 95% CI: 0.82–0.87) across 320 patients. In early T category tumors, the model achieved a median DSC of 0.74 and ASD of 0.98 mm, while in advanced T category tumors, it reached a median DSC of 0.74 and ASD of 0.96 mm. The accuracy of automated T staging was 76% (126 of 166) for early stages (T1-T2) and 64% (99 of 154) for advanced stages (T3-T4). Moreover, experimental results show that our multi-task model outperformed the other single-task models.ConclusionsThis study emphasized the potential of multi-task model for simultaneously delineating the tumor contour and identifying T-stage. The multi-task model harnesses the synergy between these interrelated learning tasks, leading to improvements in the performance of both tasks. The performance demonstrates the potential of our work for delineating the tumor contour and identifying T-stage and suggests that it can be a practical tool for supporting clinical precision radiation therapy.

In this study, phosphoric acid activation was employed to synthesize nitrogen-doped mesoporous activated carbon (designated as MR1) from Lentinus edodes (shiitake mushroom) residue, while aiming to efficiently remove acetaminophen (APAP), carbamazepine (CBZ), and metronidazole (MNZ) from aqueous solutions. We characterized the physicochemical properties of the produced adsorbents using scanning electron microscopy (SEM), nitrogen adsorption isotherms, and X-ray photoelectron spectroscopy (XPS). MR1, MR2, and MR3 were prepared using phosphoric acid impregnation ratios of 1, 2, and 3 mL/g, respectively. Notably, MR1 exhibited a significant mesoporous structure with a volume of 0.825 cm3/g and a quaternary nitrogen content of 2.6%. This endowed MR1 with a high adsorption capacity for APAP, CBZ, and MNZ, positioning it as a promising candidate for water purification applications. The adsorption behavior of the contaminants followed the Freundlich isotherm model, suggesting a multilayer adsorption process. Notably, MR1 showed excellent durability and recyclability, maintaining 95% of its initial adsorption efficiency after five regeneration cycles and indicating its potential for sustainable use in water treatment processes.

Introduction: TT-01025-CL is an oral, irreversible small molecule that potently inhibits vascular adhesion protein-1 (VAP-1) for the treatment of inflammation associated with non-alcoholic steatohepatitis (NASH). The objectives of this study were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of TT-01025-CL, a VAP-1 inhibitor, in healthy Chinese volunteers.Methods: Double-blind, placebo-controlled, dose-escalation studies were conducted in subjects randomized to receive oral once-daily TT-01025-CL (ranges: 10–300 mg [single dose]; 20–100 mg for 7 days [multiple doses]) or placebo under fasting conditions. Safety and tolerability were monitored throughout the study. Pharmacokinetic (PK) parameters were determined using non-compartment analysis. The activity of semicarbazide-sensitive amine oxidase (SSAO)-specific amine oxidase and the accumulation of methylamine in plasma were evaluated as pharmacodynamic (PD) biomarkers.Results: A total of 36 (single-dose group) and 24 (multiple-dose group) subjects were enrolled in the study. No serious adverse events (AEs) were reported, and no subject discontinued due to an AE. All treatment-emergent adverse events (TEAEs) were mild and moderate in intensity. No dose-dependent increase in the intensity or frequency of events was observed. TT-01025-CL was rapidly absorbed after administration. In the single-ascending dose (SAD) study, median Tmax ranged from 0.5 to 2 h and mean t1/2z ranged from 2.09 to 4.39 h. PK was linear in the range of 100–300 mg. The mean Emax of methylamine ranged from 19.167 to 124.970 ng/mL, with mean TEmax ranging from 13.5 to 28.0 h. The complete inhibition (>90%) of SSAO activity was observed at 0.25–0.5 h post-dose and was maintained 48–168 h post-dose. In the multiple-ascending dose (MAD) study, a steady state was reached by day 5 in the 40 mg and 100 mg dose groups. Negligible accumulation was observed after repeated dosing. PK was linear in the range of 20–100 mg. Plasma methylamine appeared to plateau at doses of 20 mg and above, with mean Emax ranging from 124.142 to 156.070 ng/mL and mean TEmax ranging from 14.2 to 22.0 h on day 7. SSAO activity in plasma was persistently inhibited throughout the treatment period. No evident change in methylamine and SSAO activity was observed in the placebo groups.Conclusion: TT-01025-CL was safe and well-tolerated at a single dose of up to 300 mg and multiple doses of up to 100 mg once daily for 7 consecutive days. Absorption and elimination occurred rapidly in healthy volunteers. Linearity in plasma exposure was observed. TT-01025-CL inhibited SSAO activity rapidly and persistently in humans. The profile of TT-01025-CL demonstrates its suitability for further clinical development.

ObjectivesIn cardiovascular disease, previous studies have suggested young age as one of the reasons to explain the obesity paradox. This study attempts to provide a different opinion on this claim through unexpected findings.MethodsWe used a cross-sectional analysis of the US nationally representative data, total of 10,175 participants were recruited in 2013-2014 from NHANES. A total of 947 participants were selected to be included in this study through inclusion criteria and exclusion criteria for statistical analysis of the relationship between obesity and abdominal aortic calcification(AAC). Smooth curve fitting and multivariate regression analyses were conducted to examine the associations of obesity with AAC after adjusting for age, gender and associated variates.ResultsDepending on the age of the population, the relationship between obesity and AAC showed the different outcome. Obesity was associated with the lower risk of AAC among individuals older than 52 years of age. According to the difference of adjusted covariates, the AAC scores in the obesity group decreased by 0.92, 0.87, and 1.11 for 52 years old or older individuals. In particular, the risk of AAC was lower for patients with obesity with the following characteristics: male, low LDL, low triglyceride, DM, non-cancer patient, smoking, drinking, vigorous work activity, low annual household income, education of 9 – 11th grades and non-Hispanic white.ConclusionsIn US, adults aged 52 years or older, obesity was associated with decreased AAC risk. Older age may be one potential reason for the obesity paradox.

Introduction: Polysaccharides from Grifola frondosa (Dicks.) Gray (HSH) and Inonotus obliquus (Fr.) Pilat (BHR) showed noticeable effects on dextran sulfate sodium (DSS)-induced colitis, but their systemic modulation effects have not been fully revealed. This study aimed to investigate the regulation of the gut microbiota and systemic metabolism by HSH and BHR in DSS-induced colitis.Methods: C57BL/6J mice were given DSS (2.5%) in water and were treated with HSH and BHR (200 mg/kg/day) by gavage. Body weight and colon length were recorded, and H&E and AB-PAS staining of the colon were conducted to evaluate the model and the protective effect of the polysaccharides. Additionally, an LC-QTOF/MS-based untargeted metabolomic platform was used to identify the metabolites in the serum, colon tissue, gut contents, and faeces and investigate differential metabolites and metabolic pathways. 16S rDNA gene sequencing was used to measure the composition of bacterial communities.Results: The results showed that the mouse colitis model was established successfully, as evidenced by an increased disease activity index score [2.83 ± 0.62 vs. 0.06 ± 0.14 (p < 0.001)] and shortened colon length [5.43 ± 0.64 cm vs. 7.04 ± 0.29 cm (p < 0.001)], and HSH and BHR ameliorated DSS-induced colitis by improving the disease activity index (2.17 ± 0.28 and 1.83 ± 0.29, respectively) and restoring the colon length (6.12 ± 0.30 cm and 6.62 ± 0.35 cm, respectively). HSH and BHR significantly modulated metabolites involved in aromatic amino acid metabolism, the citrate cycle, purine metabolism, pyrimidine metabolism, etc. HSH and BHR increased the Chao1 index by 64.25% and 60.25%, respectively, and they increased the Shannon index by 13.02% and 10.23%, respectively. They both reversed the increase in the abundances of g_Odoribacter, g_Clostridium, g_AF12, g_Parabacteroides and g_Turicibacter and reversed the decrease in the abundance of g_unclassified_Bacteria induced by DSS. Specifically, HSH reversed the reductions in g_unclassified_Lactobacillales and g_Ruminococcus, and BHR reversed the decreases in g_unidentified_Coriobacteriaceae and g_unclassified_Firmicutes.Discussion: These results suggested that HSH and BHR may ameliorate DSS-induced colitis by global modulation of systemic metabolism and the gut microbiota. Targeting the gut microbiota may be a potentially effective strategy to modulate systemic metabolism and treat colitis.

Gastric cancer is a common malignant tumor of the digestive tract, with a low early diagnosis rate. N-methyl-N-nitro-N-nitroguanidine (MNNG) is one of the main risk factors for gastric cancer. Phytochemicals are healthy active substances derived from vegetables, fruits, nuts, tea, herbal medicines and other plants. Taking phytochemicals is a very promising strategy for the prevention and treatment of gastric cancer. Many studies have proved that phytochemicals have protective effects on MNNG induced gastric cancer via inhibiting cell proliferation, enhancing immunity, suppressing cell invasion and migration, inducing apoptosis and autophagy, blocking angiogenesis, inhibiting Helicobacter pylori infection as well as regulating metabolism and microbiota. The intervention and therapeutic effects of phytochemicals in MNNG induced gastric cancer have attracted more and more attention. In order to better study and explore the role, advantages and challenges of phytochemicals in MNNG induced gastric cancer, we summarized the intervention and therapeutic effects of phytochemicals in MNNG induced gastric cancer. This review may help to further promote the research and clinical application of phytochemicals in MNNG induced gastric cancer, and provide some new insights.

BackgroundThe etiology of amyotrophic lateral sclerosis (ALS) remains largely unknown. This study aimed to summarize the relationship between ALS and its genetic and non-genetic risk factors.MethodA search of relevant literature from PubMed, Embase, and Cochrane Database from inception to December 2022 was performed. Random-effects or fixed-effects models were performed by Stata MP 15.0 to pool multivariate or adjusted ratios (OR). PROSPERO registration number: CRD42022301549.Results230 eligible studies were included, of which 67 involved 22 non-genetic factors, and 163 involved genetic factors. Four aspects of non-genetic factors, including lifestyle, environmental and occupational exposures, pre-existing diseases/comorbidity and medical exposures, and others, were analyzed. Exposure to heavy metals (OR = 1.79), pesticides (OR = 1.46), solvents (OR = 1.37), previous head trauma (OR = 1.37), military service (OR = 1.29), stroke (OR = 1.26), magnetic field (OR = 1.22) and hypertension (OR = 1.04) are significant risk factors, but use of antidiabetics (OR = 0.52), high BMI (OR = 0.60 for obese and overweight vs. normal and underweight), living in urban (OR = 0.70), diabetes mellitus (OR = 0.83), and kidney disease (OR = 0.84) decrease the risk for ALS. In addition, eight common ALS-related genes were evaluated, the mutation frequencies of these genes were ranked from highest to lowest as SOD1 (2.2%), C9orf72 (2.1%), ATXN2 (1.7%), FUS (1.7%), TARDBP (0.8%), VCP (0.6%), UBQLN2(0.6%) and SQSTM1 (0.6%) in all the ALS patients.ConclusionsOur findings suggested that effective intervention for risk exposure and timely modification of lifestyle might prevent the occurrence of ALS. Genetic mutations are important risk factors for ALS and it is essential to detect genetic mutations correctly and scientifically.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=301549, identifier: CRD42022301549.

Electromagnetic induction can effectively induce abundant firing patterns in neurons. In modeling a neuron model with the electromagnetic induction effect, an electromagnetic induction current is frequently added to the state equation of membrane potential. To more properly reflect the non-uniform distribution of the ions inside and outside the neuron membrane, an ideal flux-controlled memristor with sinusoidal memductance function and non-linearly modulated input is raised to depict an electromagnetic induction effect on a Hindmarsh–Rose neuron model, and thereby, a three-dimensional (3D) memristive Hindmarsh–Rose (mHR) neuron model is built in this paper. The proposed mHR neuron model possesses no equilibrium point since the involvement of the ideal flux-controlled memristor, which induces the generation of hidden dynamics. Numerical results declare that the mHR neuron model can generate abundant hidden dynamics, i.e., periodic spiking, chaotic spiking, period-doubling bifurcation route, tangent bifurcation, and chaos crisis. These hidden dynamics are much related to the memristor coupling strength and externally applied stimulus. Afterward, the memristor initial condition-offset boosting behavior is revealed. This can trigger the generation of infinite multiple coexisting firing patterns along the memristor variable coordinate. These coexisting firing patterns have identical attractor topology but different locations in the phase plane. Finally, an analog circuit is designed for implementing the mHR neuron model, and PSIM-based circuit simulation is executed. The circuit-simulated results perfectly verify the generation of hidden infinite multiple coexisting initial condition-offset boosting firing patterns in the proposed mHR neuron model.

Introduction: The protective effects of astaxanthin against myocardial ischemia-reperfusion injuries are well documented, although the mechanisms are not defined.Methods: The anoxia-reoxygenation injury model was established after astaxanthin treated H9c2 cells for 24 h. Cell viability, lactate dehydrogenase, oxidative stress level and western blot were tested. Secondly, measured the effects of astaxanthin pretreatment on microRNA expression in a rat myocardial cell anoxia-reoxygenation injury model.Results: After anoxia-reoxygenation injury, in a dose dependent manner, astaxanthin increased cell viability, superoxide dismutase and glutathione peroxidase activity, decreased lactate dehydrogenase and malondialdehyde levels, downregulated protein expression of caspase-3, caspase-8, nuclear factor erythroid-2-related factor 2 and heme oxygenase-1, and upregulated the Bcl-2/Bax ratio. High-throughput sequencing and qPCR showed that microRNAs rno-miR-125b-5p and rno-let-7c-1-3p were differentially expressed (|log2| ≥ 0.585, q < 0.1) between the normal, anoxia-reoxygenation, and astaxanthin (1.25 μM) groups. Kyoto Encyclopedia of Genes and Genomes and GO Gene ontology pathway enrichment analyses showed that TNF signaling, axon guidance, NF-κB signaling pathway, and other pathways displayed differentially expressed microRNA target genes associated with myocardial injuries.Discussion: These results suggested that thetarget genes of rno-miR-125b-5p were enriched in inflammation and apoptosis-related signaling pathways. Also, the results imply that simultaneous targeting of these related signaling pathways could significantly prevent myocardial anoxia-reoxygenation injury in the presence of astaxanthin.

BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder (NDS) with unclear pathophysiology and few therapeutic options. Mutations in SOD1 and C9orf72 are the most common in Asian and Caucasian patients with ALS, respectively. Aberrant (microRNAs) miRNAs found in patients with gene-mutated ALS may be involved in the pathogenesis of gene-specific ALS and sporadic ALS (SALS). The aim of this study was to screen for differentially expressed miRNAs from exosomes in patients with ALS and healthy controls (HCs) and to construct a miRNA-based diagnostic model to classify patients and HCs.MethodsWe compared circulating exosome-derived miRNAs of patients with ALS and HCs using the following two cohorts: a discovery cohort (three patients with SOD1-mutated ALS, three patients with C9orf72-mutated ALS, and three HCs) analyzed by microarray and a validation cohort (16 patients with gene-mutated ALS, 65 patients with SALS, and 61 HCs) confirmed by RT-qPCR. The support vector machine (SVM) model was used to help diagnose ALS using five differentially expressed miRNAs between SALS and HCs.ResultsA total of 64 differentially expressed miRNAs in patients with SOD1-mutated ALS and 128 differentially expressed miRNAs in patients with C9orf72-mutated ALS were obtained by microarray compared to HCs. Of these, 11 overlapping dysregulated miRNAs were identified in both groups. Among the 14 top-hit candidate miRNAs validated by RT-qPCR, hsa-miR-34a-3p was specifically downregulated in patients with SOD1-mutated ALS, while hsa-miR-1306-3p was downregulated in ALS patients with both SOD1 and C9orf72 mutations. In addition, hsa-miR-199a-3p and hsa-miR-30b-5p were upregulated significantly in patients with SALS, while hsa-miR-501-3p, hsa-miR-103a-2-5p, and hsa-miR-181d-5p had a trend to be upregulated. The SVM diagnostic model used five miRNAs as features to distinguish ALS from HCs in our cohort with an area under receiver operating characteristic curve (AUC) of 0.80.ConclusionOur study identified aberrant miRNAs from exosomes of SALS and ALS patients with SOD1/C9orf72 mutations and provided additional evidence that aberrant miRNAs were involved in the pathogenesis of ALS regardless of the presence or absence of the gene mutation. The machine learning algorithm had high accuracy in predicting the diagnosis of ALS, shedding light on the foundation for the clinical application of blood tests in the diagnosis of ALS, and revealing the pathological mechanisms of the disease.

Background: Evidence from observational studies concerning the causal role of blood pressure (BP) and antihypertensive medications (AHM) on Parkinson’s disease (PD) remains inconclusive. A two-sample Mendelian randomization (MR) study was performed to evaluate the unconfounded association of genetic proxies for BP and first-line AHMs with PD.Methods: Instrumental variables (IV) from the genome-wide association study (GWAS) for BP traits were used to proxy systolic BP (SBP), diastolic BP, and pulse pressure. SBP-associated variants either located within encoding regions or associated with the expression of AHM targets were selected and then scaled to proxy therapeutic inhibition of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, and thiazides. Positive control analyses on coronary heart disease (CHD) and stroke were conducted to validate the IV selection. Summary data from GWAS for PD risk and PD age at onset (AAO) were used as outcomes.Results: In positive control analyses, genetically determined BP traits and AHMs closely mimicked the observed causal effect on CHD and stroke, confirming the validity of IV selection methodology. In primary analyses, although genetic proxies identified by “encoding region-based method” for β-blockers were suggestively associated with a delayed PD AAO (Beta: 0.115; 95% CI: 0.021, 0.208; p = 1.63E-2; per 10-mmHg lower), sensitivity analyses failed to support this association. Additionally, MR analyses found little evidence that genetically predicted BP traits, overall AHM, or other AHMs affected PD risk or AAO.Conclusion: Our data suggest that BP and commonly prescribed AHMs may not have a prominent role in PD etiology.

Purpose: To evaluate the safety, tolerability, pharmacokinetics and immunogenicity of DS002 injection, an anti-nerve growth factor (anti-NGF) monoclonal antibody for treating pain conditions, in healthy Chinese subjects.Methods: This study was a single-center, randomized, double-blind, single-dose escalation, placebo-controlled design (CTR20210155). A total of 53 healthy subjects, 27 male and 26 female, were enrolled in this study, and one subject withdrew from the study before administration. Seven dose groups were set up, which were 0.5 mg, 1.0 mg, 2.0 mg, 4.0 mg, 7.0 mg, 12.0 mg and 20.0 mg, respectively. The drug was administered by single subcutaneous injection. Four subjects were enrolled in the first dose group (0.5 mg) received DS002. Other dose groups enrolled eight subjects each, six of whom received DS002 while the other two received a placebo. Safety, tolerability, pharmacokinetic parameters and immunogenicity of DS002 were assessed.Results: DS002 was well tolerated; all adverse events were Grade 1–2, and did not reach the termination standard of dose increment within the range of 0.5–20.0 mg. Adverse event rates were generally similar across treatments. After a single subcutaneous injection, the median Tmax in different dose groups ranged 167.77–337.38 h; mean t1/2 ranged 176.80–294.23 h, the volume of distribution (Vz) ranged 5265.42–7212.00 ml, and the clearance rate (CL) ranged 12.69–24.75 ml/h. In the dose range of 0.5–20.0 mg, Cmax ranged from 51.83 ± 22.74 ng/ml to 2048.86 ± 564.78 ng/ml, AUC0-t ranged from 20615.16 ± 5698.28 h·ng/mL to 1669608.11 ± 387246.36 h·ng/mL, and AUC0-inf ranged from 21852.45 ± 5920.21 h·ng/mL to 1673504.66 ± 389106.13 h·ng/mL. They all increased with dose escalation, and Cmax and AUC0-t did not have a significant dose-linear relationship, whilst AUC0-t was not dose-dependent at all. anti-drug antibody test results of each group of all subjects in this trial were negative.Conclusion: DS002 showed satisfactory safety within the dose range of 0.5 mg–20.0 mg. The absorption and metabolism of DS002 were slow, it exhibited a low volume of distribution and the clearance rate was low. These data suggest that DS002, by blocking nerve growth factor, is expected to become a novel, safe and non-addictive treatment for pain conditions.

AimsTo investigate the changes in lung cancer-related serum tumor markers in patients with chronic kidney disease (CKD) and determine the upper reference limit for patients with different stages.MethodsIncluded inpatients diagnosed with CKD who did not receive dialysis temporarily in our hospital from March to September 2020. Changes in serum CA125, HE4, CYFRA21-1, SCCA, NSE and ProGRP in CKD patients were analyzed. The non-parametric method was used to estimate the upper reference limit of the above indicators in patients with CKD stages 2-5.ResultsThe serum levels of HE4, CYFRA21-1, SCCA, and ProGRP in the CKD group were significantly higher than those in the healthy control group; CA125 and NSE levels were not statistically different. The false positives of SCC, CYFRA21-1, ProGRP, and HE4 increased significantly with the CKD stage. Still, NSE and CA125 did not show a significant increasing trend. Both HE4 and ProGRP have independent upper reference limits from CKD2 to CKD5 stage, namely 220.8 pmol/l and 101.4 pg/ml in the CKD2 stage, 496.7 pmol/l and 168.63 pg/ml in CKD3 stage, 4592.4 pmol/l and 272.8 pmol/l for CKD4 stage, CKD5 stage was 4778.2 pmol/l and 491.6 pmol/l.ConclusionThis study preliminarily determined the upper reference limits of Lung cancer-related tumor markers in patients with different CKD stages and provided laboratory support for the rational use and interpretation of Lung cancer-related tumor markers in special populations.

Introduction and methodsAs a crucial antioxidant enzyme, catalase (CAT) could destroy the cellular hydrogen peroxide to mitigate oxidative stress. The current study aimed to investigate the effects of maternal CAT supplementation from late gestation to day 14 of lactation on antioxidant ability and fatty acids metabolism with regard to the sow-piglet-axis. On day 95 of gestation, forty sows were divided into control (CON) group (fed a basal diet) and CAT group (fed a basal diet supplemented with 660 mg/kg CAT), the feeding experiment ended on day 14 of lactation.ResultsThe lactating sows in the CAT group produced more milk, and had higher antioxidant enzymes activity including POD and GSH-Px (P < 0.05), lower content of serum LDL as well as plasmic C18:3n3 content (P < 0.05). Additionally, maternal CAT supplementation improved offspring's body weight at day 14 of nursing period and ADG (P < 0.05), and regulated the antioxidant ability as evidenced by decreased related enzymes activity such as T-AOC and CAT and changed genes expression level. It significantly affected lipid metabolism of suckling piglets manifested by increasing the serum ALT, CHOL, and LDL (P < 0.05) level and modulating plasma medium- and long-chain fatty acids (MCFAs and LCFAs), as well as regulating the genes expression involved in lipid metabolism.ConclusionMaternal CAT supplementation could regulate the fatty acid composition and enhance the antioxidant ability of sows and offspring during the lactating period and further promote the growth of suckling piglets. These findings might provide a reference value for the utilization of CAT as supplement for mother from late pregnancy to lactation period to promote the fatty acid metabolism of offspring.

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

Research and wider societal debates has explored the potentially transformative role of AI in extended social control and hyper-capitalist development in China. In this paper, we use those debates to reflect on experiments with Urban AI in China. The key issue is whether AI offers something distinctive or different compared with the logics and imaginaries of ideas of the smart city. Analysis of emblematic sites of urban AI management in the cities of Shanghai and Hangzhou demonstrates: the resonances and dissonances between urban AI and smart. But they also demonstrate distinctive and complex landscape of urban AI experiments that is not neatly captured in social control and free market applications perspectives on AI. Moreover, the urban experimental contexts in which AI is being rolled, reveal aspirations for creating new “digital empires,” exploring new limits on data power and potential social resistance. The paper makes a distinctive contribution by providing a new framework for comparing logics of computational urban management in the context of emerging AI applications. As such the paper provides a distinctive framework for situating future applications of urban AI management in China and identifies the future urban research priorities.

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.

Background/purposeWith improved cancer survivorship, non-cancer events, especially heart disease (HD), have become the underlying cause of death in cancer patients, but the risk of HD mortality in sarcoma patients remains poorly characterized. Therefore, our purpose was to: (1) identify sarcoma patients at the highest risk of fatal HD compared with the general population, (2) identify patients and sarcoma characteristics associated with a higher risk of HD death, and (3) determine if chemotherapy increased the risk of HD death in sarcoma patients.MethodsFrom 1975 to 2016, we identified patients diagnosed with bone and soft tissue sarcoma from the Surveillance, Epidemiology, and End Results (SEER) database in the US. Standardized mortality ratios (SMRs) were evaluated using mortality data from the general population collected by the National Center for Health Statistics. This was the largest retrospective cohort study of fatal HD in individuals with sarcoma.ResultsIn 80,905 sarcoma patients observed for 530,290 person-years, 3,350 deaths from HD were identified with a mortality of 631.7/100,000 person-years. The SMR of death from HD was 1.38 (95% CI: 1.33–1.42). The highest risks of death from HD were observed in patients with Ewing sarcoma (SMR = 5.44; 95% CI: 3.38–8.75) and osteosarcoma (SMR = 1.92; 95% CI: 1.55–2.38). Patients diagnosed at < 19 years old had the highest SMR in all age subgroups, and a higher risk of fatal HD relative to the general population was observed in sarcoma survivors diagnosed at < 85 years old. In patients diagnosed at < 19 years old, HD plurality occurred in those with Ewing sarcoma (29.4%) and osteosarcoma (32.4%) and at > 35 years old, HD plurality occurred in those diagnosed with liposarcoma (19.0%) and malignant fibro histiocytoma (MFH) (23.6%). For sarcoma survivors, HD mortality risks were highest within the first year after diagnosis (SMR = 1.31; 95% CI: 1.21–1.41), and this risk remained elevated throughout follow-up compared with the general population. Subgroup analyses indicated that chemotherapy significantly increased the risk of fatal HD in patients with localized osteosarcoma (Hazard ratio (HR) = 3.18; 95% CI: 1.24–8.13; P = 0.016), but not in patients with other histological sarcoma subtypes and clinical stages.ConclusionThe risk of death from HD mainly varied in patients with different histological sarcoma subtypes and clinical stages. Chemotherapy increased the risk of fatal HD in patients with localized osteosarcoma. To lower the risk of fatal HD in patients with sarcoma, we call for enhanced multidisciplinary cooperation, including cardiologists and orthopedic surgeons.

The intestinal microbiome is responsible for the fermentation of complex carbohydrates and orchestrates the immune system through gut microbiota-derived metabolites. In our previous study, we reported that supplementation of Enteromorpha polysaccharide (EP) and yeast glycoprotein (YG) in combination synergistically improved antioxidant activities, serum lipid profile, and fatty acid metabolism in chicken. However, the mechanism of action of these polysaccharides remains elusive. The present study used an integrated 16S-rRNA sequencing technology and untargeted metabolomics technique to reveal the mechanism of action of EP+YG supplementation in broiler chickens fed basal diet or diets supplemented with EP+YG (200mg/kg EP + 200mg/kg YG). The results showed that EP+YG supplementation altered the overall structure of caecal microbiota as evidenced by β diversities analysis. Besides, EP+YG supplementation changed the microbiota composition by altering the community profile at the phylum and genus levels. Furthermore, Spearman correlation analysis indicated a significant correlation between altered microbiota genera vs serum cytokine levels and microbiota genera vs volatile fatty acids production. Predicted functional analysis showed that EP+YG supplementation significantly enriched amino acid metabolism, nucleotide metabolism, glycan biosynthesis and metabolism, energy metabolism, and carbohydrate metabolism. Metabolomics analysis confirmed that EP+YG supplementation modulates a myriad of caecal metabolites by increasing some metabolites, including pyruvic acid, pyridoxine, spermidine, spermine, and dopamine, and decreasing metabolites related to lipid metabolisms such as malonic acid, oleic acid, and docosahexaenoic acid. The quantitative enrichment analysis results further showed that glycolysis/gluconeogenesis, citric acid cycle, tyrosine metabolism, glycine, serine, and threonine metabolism, and cysteine and methionine metabolism were the most important enriched pathways identified with enrichment ratio >11, whereas, fatty acid biosynthesis and biosynthesis of unsaturated fatty acids pathways were suppressed. Together, the 16S-rRNA and untargeted metabolomics results uncovered that EP+YG supplementation modulates intestinal microbiota and their metabolites, thereby influencing the important metabolism pathways, suggesting a potential feed additive.

Gastric cancer (GC) is a malignant cancer of the digestive tract and is a life-threatening disease worldwide. Ferroptosis is a newly discovered form of regulated cell death, which involves the accumulation of iron-dependent lipid peroxides. It has been found that ferroptosis plays an important regulatory role in the occurrence, development, drug resistance, and prognosis of GC. Non-coding RNAs (ncRNAs) play a critical role in the occurrence and progression of a variety of diseases including GC. In recent years, the role of ferroptosis and ferroptosis-related ncRNAs (miRNA, lncRNA, and circRNA) in the occurrence, development, drug resistance, and prognosis of GC has attracted more and more attention. Herein, we briefly summarize the roles and functions of ferroptosis and ferroptosis-related ncRNAs in GC tumorigenesis, development, and prognosis. We also prospected the future research direction and challenges of ferroptosis and ferroptosis-related ncRNAs in GC.

The anterior talofibular ligament is the weakest and most vulnerable lateral ligament to be injured, and it can replace anatomical position through anatomical reconstruction. The purpose of this study is to evaluate clinical outcomes after an autologous half-bundle peroneus longus tendon anatomical reconstruction. We conducted a retrospective analysis by enrolling 34 patients [22 male and 12 female, median age 21 (range 19–26) years] with anterior talofibular ligament injury from January 2018 to March 2020. All patients underwent a ligament anatomical reconstruction operation with autologous half-bundle peroneus longus tendon and followed up with an average time of 16.21 ± 3.20 (range 12–24) months, with no loss of patients to follow-up during the study period. The American Orthopedic Foot, Ankle Society Score (AOFAS), Visual Analogue Score (VAS), and Anterior Tibiotalar Translation were used to assess the curative effect. All the indexes were compared between the preoperative and at the final follow-up to discover the related statistical differences. The AOFAS score improved significantly from an average preoperative score of 56.91 ± 3.79 to 94.12 ± 2.51 at the final followed-up (p

BackgroundOvarian cancer (OC) is one of the most common types of gynecologic tumor over the world. The Glutathione S-transferase Mu (GSTM) has five members, including GSTM1-5. These GSTMs is involved in cell metabolism and detoxification, but their role in OC remains unknown.MethodsData from multiple public databases associated with OC and GSTMs were collected. Expression, prognosis, function enrichment, immune infiltration, stemness index, and drug sensitivity analysis was utilized to identify the roles of GSTMs in OC progression. RT-qPCR analysis confirmed the effect of AICAR, AT-7519, PHA-793887 and PI-103 on the mRNA levels of GSTM3/4.ResultsGSTM1-5 were decreased in OC samples compared to normal ovary samples. GSTM1/5 were positively correlated with OC prognosis, but GSTM3 was negatively correlated with OC prognosis. Function enrichment analysis indicated GSTMs were involved in glutathione metabolism, drug metabolism, and drug resistance. Immune infiltration analysis indicated GSTM2/3/4 promoted immune escape in OC. GSTM5 was significantly correlated with OC stemness index. GSTM3/4 were remarkedly associated with OC chemoresistance, especially in AICAR, AT-7519, PHA-793887 and PI-103.ConclusionGSTM3 was negatively correlated with OC prognosis, and associated with OC chemoresistance and immune escape. This gene may serve as potential prognostic biomarkers and therapeutic target for OC patients.

The varieties of black rice with different amylose contents (waxy; medium-amylose: 16.03%; high-amylose: 27.14%) were parboiled and then evaluated for physicochemical and digestible properties. The color, crystalline structure, and swelling property of parboiled rice were analyzed, and the water molecular mobility, texture, and starch digestibility of cooked parboiled rice were determined. The color of black rice was only slightly changed after the parboiling treatment. The crystalline structures of waxy and medium-amylose rice were severely damaged by the parboiling treatment, while the highly crystalline structure was retained in parboiled high-amylose rice. During heating in water, parboiled high-amylose rice had a lower water absorption ratio (WAR) and volume expansion ratio (VER) than the other two varieties. After cooking, parboiled high-amylose rice had higher water molecular mobility and harder texture compared with the other two varieties. Cooked parboiled high-amylose rice contained higher content of resistant starch than cooked parboiled waxy and medium-amylose rice.

Monoclonal gammopathies of clinical significance (MGCS)-associated myopathy is a group of muscular MGCS-based rare manifestations. It mainly includes amyloid light chain (AL) amyloidosis and sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance. When myopathy manifests as the initial or sole clinical symptom, it can often be delayed or misdiagnosed as other myopathies. We report the case of a 60-year-old man who initially presented with fatigue and muscle weakness of the symmetric proximal lower limbs. Muscle biopsy did not reveal mononuclear cell infiltration, atrophy, necrosis, or positive Congo red staining results. The results of serum protein electrophoresis and immunofixation electrophoresis were negative. No specific diagnosis was established. After 1 year, the patient was diagnosed with AL amyloidosis after myocardial and fat pad biopsies were performed and myopathy was diagnosed as AL amyloidosis-associated myopathy after reassessment. The patient received CyBorD regime chemotherapy and achieved hematological and organ remission. Therefore, we reviewed the clinical and pathological manifestations of MGCS-associated myopathies. Based on published articles and the present case, we conclude that comprehensive screening for MGCS in unexplained myopathy is essential to avoid misdiagnosis or delayed diagnosis.

ObjectivesRecent surveys have paid insufficient attention to the psychological status of medical residents, but medical residents, as a special group of medical workers, need to be focused on. This study aimed to investigate medical residents' levels of social support, psychological resilience, and coping style, and explore the mediating role of psychological resilience, which can ultimately provide a new theoretical basis for improving medical residents' psychological status and quality of work and life.MethodsA total of 577 medical residents from China were investigated by an online questionnaire, using convenience sampling. Associations between social support, psychological resilience, and coping styles were assessed using Pearson correlation analysis. The mediating effect of psychological resilience was tested using SPSS Process.ResultsPositive correlations between social support, psychological resilience and coping style were found (r = 0.474, P < 0.001; r = 0.473, P < 0.001; r = 0.353, P < 0.001). The mediating effect of psychological resilience in the relationship between social support and coping style was significant (95% CI: 0.168, 0.384), and accounted for 25.84%.ConclusionAttention should be paid to the psychological status of medical residents, and social support and psychological flexibility can be used to increase the enthusiasm for their coping style and promote their mental health.

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma with considerable heterogeneity and different clinical prognosis. However, plasma metabomics used to forecast occurrence and prognosis of DLBCL are rarely addressed.MethodA total of 65 volunteers including 22 healthy controls (Ctrl), 25 DLBCL patients newly diagnosed (ND), and 18 DLBCL patients achieving complete remission (CR) were enrolled. A gas chromatography mass spectrometry-based untargeted plasma metabolomics analysis was performed.ResultsMultivariate statistical analysis displayed distinct metabolic features among Crtl, ND, and CR groups. Surprisingly, metabolic profiles of newly diagnosed DLBCL patients undergoing different prognosis showed clear and distinctive clustering. Based on the candidate metabolic biomarkers (glucose and aspartate) and clinical indicators (lymphocyte, red blood count, and hemoglobin), a distinct diagnostic equation was established showing improved diagnostic performance with an area under curve of 0.936. The enrichment of citric acid cycle, deficiency of branched chain amino acid, methionine, and cysteine in newly diagnosed DLBCL patients was closely associated with poor prognosis. In addition, we found that malate and 2-hydroxy-2-methylbutyric acid were positively correlated with the baseline tumor metabolic parameters (metabolically active tumor volume and total lesion glycolysis), and the higher abundance of plasma malate, the poorer survival.ConclusionOur preliminary data suggested plasma metabolomics study was informative to characterize the metabolic phenotypes and forecast occurrence and prognosis of DLBCL. Malate was identified as an unfavorable metabolic biomarker for prognosis-prediction of DLBCL, which provided a new insight on risk-stratification and therapeutic targets of DLBCL. More studies to confirm these associations and investigate potential mechanisms are in the process.

Ultraviolet B (UVB) radiation leads to the excessive accumulation of reactive oxygen species (ROS), which subsequently promote inflammation, degradation of the extracellular matrix, and photoaging in skin. Thus antioxidant activity is particularly important when screening for active substances to prevent or repair photodamage. Marine fish-derived bioactive peptides have become a trend in cosmetics and functional food industries owing to their potential dermatological benefits. In this study, 1-diphenyl- 2-pycryl-hydrazyl (DPPH) scavenging activity was selected to optimize the hydrolysis conditions of sturgeon skin collagen peptides with antioxidant activity. The optimal hydrolysis conditions for sturgeon skin collagen hydrolysate (SSCH) were determined by response surface methodology, which comprised an enzyme dosage of flavorzyme at 6,068.4 U/g, temperature of 35.5°C, pH of 7, and hydrolysis time of 6 h. SSCH showed good radical-scavenging capacities with a DPPH scavenging efficiency of 95%. Then, the effect of low-molecular-weight SSCH fraction (SSCH-L) on UVB irradiation-induced photodamage was evaluated in mouse fibroblast L929 cells and zebrafish. SSCH-L reduced intracellular ROS levels and the malondialdehyde content, thereby alleviating the oxidative damage caused by UVB radiation. Moreover SSCH-L inhibited the mRNA expression of genes encoding the pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and Cox-2. SSCH-L treatment further increased the collagen Ⅰα1 content and had a significant inhibitory effect on matrix metalloproteinase expression. The phosphorylation level of JNK and the expression of c-Jun protein were significantly reduced by SSCH-L. Additionally, SSCH-L increased the tail fin area at 0.125 and 0.25 mg/ml in a zebrafish UVB radiation model, which highlighted the potential of SSCH-L to repair UVB-irradiated zebrafish skin damage. Peptide sequences of SSCH-L were identified by liquid chromatography-tandem mass spectrometry. Based on the 3D-QSAR modeling prediction, six total peptides were selected to test the UVB-protective activity. Among these peptides, DPFRHY showed good UVB-repair activity, ROS-scavenging activity, DNA damage-protective activity and apoptosis inhibition activity. These results suggested that DPFRHY has potential applications as a natural anti-photodamage material in cosmetic and functional food industries.

PurposeTo evaluate the value of dynamic monitoring of procalcitonin (PCT) as a biomarker for the early diagnosis of postoperative infections in patients undergoing cardiac surgery.MethodsIn total, 252 patients who underwent cardiac surgery were retrospectively included. The postoperative patients’ PCT level, change value (△PCT), and clearance rate (△PCTc) were compared between the infected and noninfected groups in adult and pediatric patients on postoperative days (PODs) 1, 3, and 5. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the diagnostic value.ResultsProcalcitonin concentration decreased progressively in the noninfected group in adult and pediatric patients; PCT concentration continued to rise until it peaked on POD 3 in the infected group. In adult patients, the AUC of PCT for diagnosis of infection on PODs 1, 3, and 5 were 0.626, 0.817, and 0.806, with the optimal cut-off values of 7.35, 3.63, and 1.73 ng/ml, respectively. The diagnostic efficiency of △PCT3 and △PCTC3 was significantly better than △PCT5 and △PCTC5, respectively. In pediatric patients, the AUC of PCT for diagnosis of infection on PODs 1, 3, and 5 were 0.677, 0.747, and 0.756, respectively, and the optimal cut-off values were 27.62, 26.15, and 10.20 ng/ml.ConclusionThis study showed that dynamic monitoring of PCT levels could be an effective clinical means to help to discover postoperative infection earlier. The PCT level and its change indicators on POD 3 in adult patients and the PCT level on POD 5 in children can indicate infection.

PurposeThe study aimed to evaluate the health-related quality of life (HRQoL) measured by the five-level EuroQol-5 dimensions (EQ-5D-5L) in patients with cervical dystonia, and to explore the determinants of HRQoL in patients with cervical dystonia.MethodsEQ-5D-5L health state profiles were converted into a single aggregated “health utility” score. A calibrated visual analog scale (EQ VAS) was used for self-rating of current health status. Multiple linear regression analysis was used to explore the factors associated with HRQoL in cervical dystonia.ResultsA total of 333 patients with cervical dystonia were enrolled in the analysis, with an average age of 44.3 years old. The most common impaired dimension of health was anxiety/depression (73.6%), followed by pain/discomfort (68.2%) and usual activities (48%). The median health utility score was 0.80, and the median EQ VAS score was 70.2. Multivariate linear regression analysis indicated that disease duration and the scores of the Hamilton Depression Rating Scale (HDRS), Pittsburgh sleep quality index (PSQI), Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Part I, and TWSTRS Part III were associated with the health utility scores. After adjusting other parameters, the TWSTRS Part III score and the HDRS score were significantly associated with the EQ VAS scores (p < 0.05).ConclusionThis study evaluated HRQoL in patients with cervical dystonia using the Chinese version of the EQ-5D-5L scale. We found that, besides motor symptoms, non-motor symptoms, including depression, pain, and sleep quality, could be greater determinants of HRQoL in patients with cervical dystonia. Management of non-motor symptoms, therefore, may help improve HRQoL in patients with cervical dystonia.

ObjectiveThis study aims to explore the incidence and clinical features of acute pancreatitis (AP) in patients with type 2 diabetes diabetic ketoacidosis (DKA) in the emergency department and discuss the predictive value of some pathological indicators for AP in DKA.MethodsInpatient medical data of DKA patients hospitalized to our hospital's emergency department between January 2017 and January 2021 were evaluated retrospectively. These DKA patients were split into two groups based on whether they had AP or not. We examined the two groups' epidemiologic features, baseline laboratory results, and clinical outcomes. The Bedside Index for Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation II (APACHE II), and Logistic Organ Failure System (LODS) scores were computed and compared across groups.ResultsThe prevalence of AP in DKA patients was 15.53%. The difference in Abdominal pain between the two groups of patients was statistically significant (p < 0.001), and there was no statistical difference in age, gender, and BMI. The DKA and AP group LOS (P < 0.001), ICU admission rate (P = 0.046), anion gap (P < 0.001), red blood cell (P = 0.002), hemoglobin (P < 0.001), hematocrit (P = 0.002), serum triglyceride (P < 0.001), serum cholesterol (P < 0.001), serum amylase (P = 0.004), random glucose (P = 0.028), plasma fibrinogen (P < 0.001), glycosylated hemoglobin [HbA1c (%); P = 0.008] higher than the DKA group, pH (P < 0.001), carbon dioxide combining power (CO2CP; P < 0.001), ionized calcium (Ca2+; P = 0.022), ionized sodium (Na+; P = 0.001), and correction Na (P = 0.034) lower than the DKA group. Multivariate analysis showed that low pH (P < 0.05), hypertriglyceridemia (P = 0.001), and hypercholesterolemia (P = 0.01) were risk factors for DKA combined with AP. ROC curve analysis showed that the three cut-off value: serum triglycerides of 10.52 mmol/L, serum cholesterol of 9.03 mmol/L, and pH of 7.214. Serum triglyceride has the largest area under the curve (0.93). Under this cut-off value, the sensitivity (80%) and specificity of serum triglyceride, the degree (93.7%) is the highest, while the positive predictive value (62.0%) and negative predictive value (94.7%) of serum cholesterol are the highest.ConclusionsA severe episode of DKA with significant acidosis and hyperlipidemia is more likely to be linked with AP. The frequently used critical illness score is ineffective in determining the severity of the condition. When the serum triglyceride cut-off value is 10.52mmol/L, it has a higher predicted value for AP in DKA.

PurposeSelf-stigma is common in patients with Parkinson's disease (PD) and may lead to social isolation and delayed search for medical help. We conducted a 3-year prospective longitudinal study to investigate the development and evolution of self-stigma in patients with early stage PD and to explore the associated and predictive factors of self-stigma in PD.MethodA total of 224 patients with early stage PD (disease duration

The treatment of inner ear disorders always remains a challenge for researchers. The presence of various physiological barriers, primarily the blood–labyrinth barrier (BLB), limits the accessibility of the inner ear and hinders the efficacy of various drug therapies. Yet despite recent advances in the cochlea for repair and regeneration, there are currently no pharmacological or biological interventions for hearing loss. Current research focuses on the localized drug-, gene-, and cell-based therapies. Drug delivery based on nanotechnology represents an innovative strategy to improve inner ear treatments. Materials with specific nanostructures not only exhibit a unique ability to encapsulate and transport therapeutics to the inner ear but also endow specific targeting properties to auditory hair cells as well as the stabilization and sustained drug release. Along with this, some alternative routes, like intratympanic drug delivery, can also offer a better means to access the inner ear without exposure to the BLB. This review discusses a variety of nano-based drug delivery systems to the ear for treating inner ear diseases. The main factors affecting the curative efficacy of nanomaterials are also discussed. With a deeper understanding of the link between these crucial factors and the clinical effect of nanomaterials, it paves the way for the optimization of the therapeutic activity of nanocarriers.

BackgroundCINtec® PLUS p16/Ki-67 dual-stained cytology (DS) is an alternative test to cytology in triaging human papillomavirus (HPV)-positive women. Dalton p16/Ki-67 Dual Stain kit employs the similar immunocytochemical detection and operating procedures with CINtec® PLUS, but its accuracy and efficacy in triaging HPV-positive women need to be evaluated.MethodsA total of 717 HPV-positive specimens of cervical exfoliated cells were included. Cytology, Dalton, and CINtec® PLUS were subsequently performed, and two DS tests were separately completed in each of the same specimens. The results of two DS tests were head-to-head compared, and their efficacies to identify high-grade cervical intraepithelial neoplasia (CIN) were evaluated, using histopathology of biopsy as the golden standard.ResultsThe overall positive rate of two DS tests were 28.31% for Dalton and 33.89% for CINtec® PLUS (p < 0.05); both rose with the increased severity of histopathological and cytological abnormalities. Compared to CINtec® PLUS, the positive rate of Dalton was significantly lower in the normal histopathology group (p < 0.05) and lower, but not significantly, in mild abnormal histopathology and cytology NILM and LSIL groups. Two DS tests showed a good consistency (Kappa value, 0.63; 95% CI, 0.557–0.688), with 100% of consistency in the cytology HSIL group. Inconsistency occurred mainly in the cytology NILM and LSIL groups, with more Dalton negative but CINtec® PLUS positive. Compared to CINtec® PLUS, Dalton showed similar sensitivity (94.59% vs. 91.89%), but significantly higher specificity (75.29% vs. 69.26%, p = 0.013) and accuracy (76.29% vs. 70.43%, p = 0.012), with a larger area under the curve (AUC) of 0.849 (95% CI, 0.800–0.899) for identifying CIN3+. The similar results were observed when identifying CIN2+.ConclusionsDalton presents the lower false positive rate and better efficacy in identifying high-grade CIN than CINtec® PLUS, suggesting that Dalton may be superior to CINtec® PLUS and an alternative technique for triaging primary HPV-positive women in cervical cancer screening.

Background: Few studies have focused on the cold hand sign (CHS), a red flag symptom, in multiple system atrophy (MSA).Objective: This study aimed to investigate the frequency and correlative factors of CHS in patients with MSA and the impact of its early occurrence on the survival of these patients.Methods: A total of 483 patients with MSA were enrolled in this study, and the motor and non-motor symptoms between patients with MSA with and without CHS were compared. Moreover, patients with disease duration ≤ 3 years at baseline were followed, and the association between CHS and survival of patients with MSA was examined.Results: The frequencies of CHS in patients with MSA were 20, 15.4, and 25.3% in MSA, MSA-parkinsonian subtype (MSA-P), and MSA-cerebellar subtype (MSA-C), respectively. Higher Unified Multiple System Atrophy Rating Scale (UMSARS) scores and higher Non-Motor Symptom Scale (NMSS) scores at baseline were associated with CHS in MSA. CHS was associated with shorter survival after adjusting for baseline diagnosis subtype, age at onset, sex, orthostatic hypotension, disease duration, autonomic onset, UMSARS total score, and NMSS score (p = 0.001; HR = 3.701; 95% CI = 1.765–7.760).Conclusion: CHS is not rare in patients with MSA. Greater disease severity and more severe non-motor symptoms were associated with CHS in patients with MSA. Patients with early occurrence of CHS had a poor prognosis.

Background: The association between inflammation and neurodegeneration has long been observed in parkinson’s disease (PD) and multiple system atrophy (MSA). Previous genome-wide association studies (GWAS) and meta-analyses have identified several risk loci in inflammation-associated genes associated with PD.Objective: To investigate whether polymorphisms in some inflammation-associated genes could modulate the risk of developing PD and MSA in a Southwest Chinese population.Methods: A total of 2,706 Chinese subjects comprising 1340 PD, 483 MSA and 883 healthy controls were recruited in the study. Three polymorphisms (rs2074404 GG/GT/TT, rs17425622 CC/CT/TT, rs34043159 CC/CT/TT) in genes linked to inflammation in all the subjects were genotyped by using the Sequenom iPLEX Assay.Results: The allele G of WNT3 rs2074404 can increase risk on PD (OR: 1.048, 95% CI: 1.182–1.333, p = 0.006), exclusively in the LOPD subgroup (OR: 1.166, 95% CI:1.025–1.327, p = 0.019), but not in EOPD or MSA. And the recessive model analysis also demonstrated an increased PD risk in GG genotype of this locus (OR = 1.331, p = 0.007). However, no significant differences were observed in the genotype distributions and alleles of HLA-DRB5 rs17425622 and IL1R2 rs34043159 between the PD patients and controls, between the MSA patients and controls, or between subgroups of PD or MSA and controls.Conclusion: Our results suggested the allele G of WNT3 rs2074404 have an adverse effect on PD and particularly, on the LOPD subgroup among a Chinese population.

Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis.Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency

Objectives: To explore the influencing factors of residents' psychological status during standardized training in COVID-19 for finding ways to promote their mental health.Methods: A total of 760 residents were surveyed with a structured questionnaire. Correlation analysis was used to analyze the influencing factors of psychological status of the residents, and a mediation model was constructed to verify the mediating role of satisfaction.Results: Age, willingness to study medicine, and satisfaction were positively correlated with negative psychological status (P < 0.05). And gender, only child or not, and annual household income (RMB) were negatively correlated with negative psychological status (P < 0.01). Residents' satisfaction with standardized training mode plays a complete mediating role between annual household income and negative psychological status.Conclusions: Our findings emphasize the importance of concentrating on resident's psychological status and family economic situation. And relative departments should take action to optimize the standardized training mode to improve the satisfaction.

Background: Branchio-oto-renal syndrome (BOR) and branchio-oto syndrome (BOS) are rare autosomal dominant disorders defined by varying combinations of branchial, otic, and renal anomalies. Here, we characterized the clinical features and genetic etiology of BOR/BOS in several Chinese families and then explored the genotypes and phenotypes of BOR/BOS-related genes, as well as the outcomes of auditory rehabilitation in different modalities.Materials and Methods: Probands and all affected family members underwent detailed clinical examinations. Their DNA was subjected to whole-exome sequencing to explore the underlying molecular etiology of BOR/BOS; candidate variants were validated using Sanger sequencing and interpreted in accordance with the American College of Medical Genetics guidelines. In addition, a literature review concerning EYA1 and SIX1 alterations was performed to explore the genotypes and phenotypes of BOR/BOS-related genes.Results: Genetic testing identified the novel deletion (c.1425delC, p(Asp476Thrfs*4); NM_000,503.6), a nonsense variant (c.889C > T, p(Arg297*)), and two splicing variants in the EYA1 gene (c.1050+1G > T and c.1140+1G > A); it also identified one novel missense variant in the SIX1 gene (c.316G > A, p(Val106Met); NM_005,982.4). All cases exhibited a degree of phenotypic variability between or within families. Middle ear surgeries for improving bone-conduction component hearing loss had unsuccessful outcomes; cochlear implantation (CI) contributed to hearing gains.Conclusion: This is the first report of BOR/BOS caused by the SIX1 variant in China. Our findings increase the numbers of known EYA1 and SIX1 variants. They also emphasize the usefulness of genetic testing in the diagnosis and prevention of BOR/BOS while demonstrating that CI for auditory rehabilitation is a feasible option in some BOR/BOS patients.

A loss-of-function variant in Lin-28 Homolog A gene (LIN28A p. R192G, rs558060339) has been identified in two East Asian ancestry patients with early-onset PD (EOPD). Functional studies revealed that such a variant could lead to developmental defects and PD-related phenotype, and the phenotypes could be rescued after correction of the variant. The aim of the study was to screen the variants of LIN28A in Chinese patients with EOPD. A total of 682 EOPD patients were sequenced with whole exome sequencing and the coding and flanking region of LIN28A were analyzed. We identified a rare coding variant, p. P182L, of LIN28A in a Chinese patient with EOPD. Moreover, we also found a 3′-UTR polymorphism (rs4659441) to be associated with an increased risk for PD. However, our rare variant burden analysis did not support a role for LIN28A as a major causal gene for PD.

Objective: Vascular risk factors have been reported to be associated with cognitive impairment (CI) in the general population, but their role on CI in multiple system atrophy (MSA) is unclear. This study aimed to explore the relationship between vascular risk factors and CI in patients with MSA.Methods: The clinical data and vascular risk factors were collected. The Montreal Cognitive Assessment tool was used to test the cognitive function of patients with MSA. Binary logistic regression was used to analyze the correlation between vascular risk factors and CI.Results: A total of 658 patients with MSA with a mean disease duration of 2.55 ± 1.47 years were enrolled. In MSA patients, hypertension was recorded in 20.2%, diabetes mellitus in 10.3%, hyperlipidemia in 10.2%, smoking in 41.2%, drinking in 34.8%, and obesity in 9.6%. The prevalence of CI in patients with MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C) was 45.0, 45.1, and 44.9%, respectively. In the binary logistic regression model, patients with more than one vascular risk factors were significantly more likely to have CI in MSA (OR = 4.298, 95% CI 1.456–12.691, P = 0.008) and MSA-P (OR = 6.952, 95% CI 1.390–34.774, P = 0.018), after adjusting for age, sex, educational years, disease duration, and total Unified multiple system atrophy rating scale scores.Conclusion: Multiple vascular risk factors had a cumulative impact on CI in MSA. Therefore, the comprehensive management of vascular risk factors in MSA should not be neglected.

Objective: To explore the frequency, evolution, associated factors, and risk factors of fatigue over 3-year of prospective follow-up in a cohort of patients with early Parkinson’s disease (PD).Methods: A total of 174 PD patients in the early stage were enrolled and quantitively assessed motor and non-motor symptoms using comprehensive scales including the Fatigue Severity Scale (FSS) annually. Each subject was categorized as PD with and without fatigue based on a cut-off mean value of 4 using FSS. The generalized estimating equation (GEE) was utilized to investigate the associated factors, and the stepwise binary logistic regression model was performed to explore the predictors.Results: The frequency of fatigue was slightly changed (ranging from 35.1 to 40.4%) during the 3-year follow-up. The changed pattern of the frequency of fatigue was similar to that of anxiety. Fatigue was significantly associated with nocturnal sleep disorders (B 2.446, P < 0.001), high Hamilton Anxiety Rating Scale (HAMA) score (B 1.072, P = 0.011), and high Unified PD Rating Scale (UPDRS) III score (B 1.029, P = 0.003) over time. High UPDRS III score [odds ratio (OR) 1.051, P = 0.015] at baseline increased the risk of developing fatigue after 1-year; high LEDD (OR 1.002, P = 0.037) increased the risk of developing fatigue after 2-year; and high LEDD (OR 1.003, P = 0.049) and high HAMA score (OR 1.077, P = 0.042) increased the risk of developing fatigue after 3-year.Conclusion: Our present study provided evidence of the longitudinal evolution of fatigue in patients with early PD and help clinical management of fatigue.

Objective: This study aimed to explore the prevalence and clinical correlates of pathological laughter and crying (PLC) in patients with amyotrophic lateral sclerosis (ALS).Methods: A total of 1,031 ALS patients were enrolled between August 2012 and August 2019. The PLC was recorded by a face-to-face interview. Other characteristics of patients, including depression, anxiety, cognition, and behavior function, were also evaluated. The potential associated factors of PLC were explored using forward binary regression analysis. Survival was analyzed in groups using propensity score matching (PSM) and Cox proportional hazards models.Results: The prevalence of PLC was 11.4% in all patients at baseline. Bulbar-onset and female patients had higher prevalence of PLC. The multivariate regression analysis indicated that PLC in ALS was associated with bulbar onset (p < 0.001), late disease stage (p < 0.001), and higher score in the Hamilton Depression Rating Scale (HDRS) (p = 0.012). The higher score of HDRS was significantly and independently associated with PLC occurrence in bulbar-onset patients (p = 0.032). The late disease stage was related to PLC occurrence in spinal-onset patients (p < 0.001). After comparison with matched pairs by using PSM, PLC at baseline had no impact on survival.Conclusion: PLC was not uncommon in ALS, especially in bulbar-onset and female patients. We highlighted that the emotional state other than cognitive function had possible relationship with PLC in ALS.

Fuzi (the lateral root of Aconitum carmichaelii Debx.) is a traditional Chinese medicine that is cultivated in more than eight provinces in China. However, it can be easily devastated by post-harvest rot, causing huge losses. Therefore, it is extremely important that the primary causal pathogens of post-harvest Fuzi rot are identified and appropriate detection methods for them are developed to prevent and control losses. In this study, two bacterial strains (X1 and X2) were isolated from rotten post-harvest Fuzi. Based on their morphological, physiological, and biochemical characteristics, housekeeping gene homologies, and matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF MS) results, these isolates were identified as Pseudomonas aeruginosa and Serratia marcescens. The pathogenicities of these isolates were confirmed by fulfilling Koch’s postulates demonstrating that they were post-harvest Fuzi rot pathogens. Two loop-mediated isothermal amplification (LAMP) methods targeting the gyrase B subunit (gyrB) gene of P. aeruginosa and the phosphatidylinositol glycan C (pigC) gene of S. marcescens were successfully developed, and it was found that the target genes were highly specific to the two pathogens. These LAMP methods were used to detect P. aeruginosa and S. marcescens in 46 naturally occurring Fuzi and their associated rhizosphere soil samples of unknown etiology. The two bacterial assays were positive in some healthy and rotten samples and could be accomplished within 1 h at 65°C without the need for complicated, expensive instruments. To our knowledge, this is the first report of P. aeruginosa and S. marcescens causing post-harvest Fuzi rot. The newly developed methods are expected to have applications in point-of-care testing for the two pathogens under different Fuzi planting procedures and will significantly contribute to the control and prevention of Fuzi rot.

CD35, an important molecule implicated in inflammation and immunity, is reportedly associated with several cancers. However, very few studies have investigated the relationship between CD35 polymorphisms and hepatocellular carcinoma (HCC). The current study was conducted to investigate the association between tag SNPs in CD35 and HCC susceptibility and postoperative recurrence, in an attempt to elucidate the gene-environment interactions in HCC. A total of 1233 Chinese Han people, including 647 healthy controls and 586 HCC cases, were sampled in this study. Six Tag SNPs (rs10494885, rs2296160, rs3737002, rs3849266, rs669117, and rs7525160) of CD35 were selected using the HaploView 4.2 program and genotyped by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Overall, the mutation genotypes CC/CG of CD35 rs7525160 significantly increased the risk of HCC. Stratification analysis indicated that CD35 rs7525160 CC/CG genotypes increased HCC risk in patients younger than 65 years and were closely related to the pathological type of poor prognosis of HCC. Cox proportional hazard ratio model analysis revealed that the rs7525160 CC/CG genotype remains a significant independent risk factor for postoperative recurrence of HCC. In conclusion, CD35 rs7525160 polymorphism may contribute to the susceptibility and prognosis of HCC in the Chinese Han population.

Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) caused by mutations in GTPBP3 gene is a rare mitochondrial disease, and this disorder identified from the Chinese population has not been described thus far. Here, we report a case series of three patients with COXPD23 caused by GTPBP3 mutations, from a severe to a mild phenotype. The main clinical features of these patients include lactic acidosis, myocardial damage, and neurologic symptoms. Whole genome sequencing and targeted panels of candidate human mitochondrial genome revealed that patient 1 was a compound heterozygote with novel mutations c.413C > T (p. A138V) and c.509_510del (p. E170Gfs∗42) in GTPBP3. Patient 2 was a compound heterozygote with novel mutations c.544G > T (p. G182X) and c.785A > C (p.Q262P), while patient 3 was a compound heterozygote with a previously reported mutation c.424G > A (p.E142K) and novel mutation c.785A > C (p.Q262P). In conclusion, we first describe three Chinese individuals with COXPD23, and discuss the genotype-phenotype correlations of GTPBP3 mutations. Our findings provide novel information in the diagnosis and genetic counseling of patients with mitochondrial disease.