Search

Abstract Objectives To study the correlations between facial profile markers and crown-lump length (CRL) in a Chinese population, and to evaluate the clinical value of these markers for abnormal fetuses during the first trimester (11 to 13+6 gestational weeks). Methods The facial profile markers were as followings: inferior facial angle (IFA), maxilla-nasion-mandible (MNM) angle, facial maxillary angle (FMA), frontal space (FS) distance and profile line (PL) distance. These markers were measured in facial mid-sagittal section through ViewPoint 6 software. The diagnostic value of these markers for abnormal fetuses was assessed by receiver operating characteristic (ROC) curves. Results According to the first-trimester scanning (FTS) and follow-up, 31 fetuses were enrolled in the abnormal group, including 14 cases of trisomy 21, 7 cases of trisomy 18, 10 cases with cleft lip and palate (CLP), and 1000 normal fetuses were selected. Among the normal fetuses, the IFA, FS distance and PL distance had negative correlations with CRL. The MNM angle and FMA had positive correlations with CRL. The mean IFA values for fetuses with trisomy 21 and trisomy 18 were 74.11° (standard deviation (SD) 7.48) and 69.88° (SD 7.08), respectively, which were significantly smaller than the normal fetuses (p = 0.013; p = 0.003). The mean MNM angle of fetuses with trisomy 18 and CLP were 6.98° (SD 2.61) and 9.41° (SD 2.57), respectively, which were significantly greater than the normal fetuses (p = 0.005; p

Eosinophilia may result from three main causes: secondary (reactive), primary (clonal), and/or idiopathic. The diagnosis of idiopathic eosinophilia must be made based on excluding all reactive or clonal causes. However, some causes may be very rare so as to be misdiagnosed as idiopathic. We present the case of eosinophilia caused by aggressive systemic mastocytosis, originally recognized as idiopathic. Lymphadenopathy, dysmyelopoiesis, and hepatosplenomegaly gradually appeared and deteriorated with increasing eosinophils. This case carried KIT D816V mutation. The BCR::ABL fusion gene and the mutations in JAK2 V617F, PDGFRα , and PDGFRβ in bone marrow were all negative. PHF6, PPM1D , and TET2 mutations were demonstrable. The patient was prescribed to avapritinib. The condition was effectively controlled. However, the patient discontinued medication for economic reasons 5 months later. Disease progression happened and died 10 months after diagnosis. Our study indicates that gene mutation detection at diagnosis is helpful for patient accurate diagnosis and targeted therapy of such patients.

Aucuba japonica Thunb is an evergreen woody ornamental plant with significant economic and ecological values. It also produces aucubin, showing a variety of biological activities. It is widely planted in the southwest region of China, including karst landscape areas in Guizhou Province. In January 2022, a serious leaf blight disease was observed on the leaves of A. japonica in the outdoor gardens of Guizhou University, Guiyang, Guizhou, China. The causal agent was identified as Colletotrichum aenigma through amplification and sequencing of the internal transcribed spacer (ITS) region, translation of the chitin synthase (CHS) and actin (ACT) genes, and morphological characterizations. Koch’s postulates were confirmed by its pathogenicity on healthy leaves, including re-isolation and identification. To our knowledge, this is the first report of C. aenigma causing leaf blight on A. japonica worldwide. To identify pathogen characteristics that could be utilized for future disease management, the effects of temperature and light on mycelial growth, conidia production, and conidial germination, and the effects of humidity on conidial germination were studied. Optimal temperatures for mycelial growth of C. aenigma BY827 were 25–30°C, while 15°C and 35°C were favorable for conidia production. Concurrently, alternating 10-h light and 14-h dark, proved to be beneficial for mycelial growth and conidial germination. Additionally, conidial germination was enhanced at 90% humidity. In vitro screenings of ten chemical pesticides to assess their efficacy in suppressing C. aenigma representative strain BY827. Among them, difenoconazole showed the best inhibition rate, with an EC50 (concentration for 50% of maximal effect) value of 0.0148 μg/ml. Subsequently, field experiment results showed that difenoconazole had the highest control efficiency on A. japonica leaf blight (the decreasing rate of disease incidence and decreasing rate of disease index were 44.60 and 47.75%, respectively). Interestingly, we discovered that C. aenigma BY827 may develop resistance to mancozeb, which is not reported yet among Colletotrichum spp. strains. In conclusion, our study provided new insights into the causal agent of A. japonica leaf blight, and the effective fungicides evaluated provided an important basis and potential resource for the sustainable control of A. japonica leaf blight caused by C. aenigma in the field.

AimsTo verify whether the oral insulin N11005 is administered as a prandial insulin by assessing the pharmacokinetics (PK), pharmacodynamics (PD), and safety profiles of N11005 with a short-acting biosynthetic human insulin (Novolin R) as reference.MethodsThis was a randomized, open-label, single-dose, crossover hyperinsulinemic-euglycemic clamp study in healthy Chinese male subjects. A total of 12 subjects were enrolled in the test (T) group (N11005, 300 IU, p.o.) and the reference (R) group (Novolin R, 0.1 IU/Kg, i.h.) with a washout period of 14 days. All subjects were administered on the same day of the clamp study. Glucose Infusion Rates (GIR), serum insulin, and C-peptide concentration were determined during every 8-hour clamp cycle. Trial registration: Clinicaltrials.gov identifier NCT04975022.ResultsAfter administration, the ratios of mean serum C-peptide concentration to baseline concentration in both T and R groups were lower than 50%, which confirmed the stability of the clamp platform. T group (N11005) showed a more rapid onset of action (tGIR10%max≈11 min) and a comparable duration of action to the R group, which was basically in line with the characteristics of prandial insulins. No adverse events (AEs) occurred throughout the study, which demonstrated that N11005 and Novolin R are safe and well-tolerated.ConclusionsThe PD profiles of the single-dose N11005 in the human body are similar to those of prandial insulins, with an excellent safety profile.Clinical trial registrationClinicaltrials.gov, identifier NCT04975022.

Background and AimsNeedle injection and needle-free injection were proven effective in improving glycated hemoglobin (HbA1c) in type 2 diabetes mellitus (T2DM) patients. However, it is unclear if needle-free and needle injections of insulin during intensive insulin therapy in hospitalized patients provide similar efficacy and safety benefits.MethodsA self-controlled cross-over study was conducted on 62 patients with T2DM who received intensive long-acting and short-acting insulin injections with or without needles. The 7-point blood glucose test was performed on the 6th day after insulin administration and the injection method switched on the 7th day of hospitalization. The difference was compared in 7-point blood glucose levels.ResultsThe blood glucose levels at fasting (mean difference=-1.09 ± 2.38mmol/L, 95% CI, -1.69 to -0.48, p=0.0007) and post-breakfast (-1.14 ± 3.02mmol/L, 95%CI, -1.91 to -0.37, p=0.004) were better when patients were receiving needle-free injections compared to when receiving a needle injection. Indeed, daily blood glucose fluctuation, which presented as the area under the curve of glycemia, was decreased in needle-free injection periods (-0.3.48 ± 9.64, 95%CI, -5.95 to -1.01, p=0.0065). There was no significant difference in the dose of long-acting insulin between the two injection methods (-0.32 ± 2.69, 95%CI, -0.99 to 0.37, p>0.05). The dose of fast-acting insulin during the needle-free period was lower than that of when patients received needle injections (-1.66 ± 6.45, 95%CI, -3.29 to -0.025, p

BackgroundGround-glass opacities (GGOs) appearing in computed tomography (CT) scans may indicate potential lung malignancy. Proper management of GGOs based on their features can prevent the development of lung cancer. Electronic health records are rich sources of information on GGO nodules and their granular features, but most of the valuable information is embedded in unstructured clinical notes. ObjectiveWe aimed to develop, test, and validate a deep learning–based natural language processing (NLP) tool that automatically extracts GGO features to inform the longitudinal trajectory of GGO status from large-scale radiology notes. MethodsWe developed a bidirectional long short-term memory with a conditional random field–based deep-learning NLP pipeline to extract GGO and granular features of GGO retrospectively from radiology notes of 13,216 lung cancer patients. We evaluated the pipeline with quality assessments and analyzed cohort characterization of the distribution of nodule features longitudinally to assess changes in size and solidity over time. ResultsOur NLP pipeline built on the GGO ontology we developed achieved between 95% and 100% precision, 89% and 100% recall, and 92% and 100% F1-scores on different GGO features. We deployed this GGO NLP model to extract and structure comprehensive characteristics of GGOs from 29,496 radiology notes of 4521 lung cancer patients. Longitudinal analysis revealed that size increased in 16.8% (240/1424) of patients, decreased in 14.6% (208/1424), and remained unchanged in 68.5% (976/1424) in their last note compared to the first note. Among 1127 patients who had longitudinal radiology notes of GGO status, 815 (72.3%) were reported to have stable status, and 259 (23%) had increased/progressed status in the subsequent notes. ConclusionsOur deep learning–based NLP pipeline can automatically extract granular GGO features at scale from electronic health records when this information is documented in radiology notes and help inform the natural history of GGO. This will open the way for a new paradigm in lung cancer prevention and early detection.

Abstract Background Bladder cancer (BCa) shows its potential immunogenity in current immune-checkpoint inhibitor related immunotherapies. However, its therapeutic effects are improvable and could be affected by tumor immune microenvironment. Hence it is interesting to find some more prognostic indicators for BCa patients concerning immunotherapies. Methods In the present study, we retrospect 129 muscle-invasive BCa (MIBC) patients with radical cystectomy in Shanghai General Hospital during 2007 to 2018. Based on the results of proteomics sequencing from 9 pairs of MIBC tissue from Shanghai General Hospital, we focused on 13 immune-related differential expression proteins and their related genes. An immune-related prognostic signature (IRPS) was constructed according to Cancer Genome Atlas (TCGA) dataset. The IRPS was verified in ArrayExpress (E-MTAB-4321) cohort and Shanghai General Hospital (General) cohort, separately. A total of 1010 BCa patients were involved in the study, including 405 BCa patients in TCGA cohort, 476 BCa patients in E-MTAB-4321 cohort and 129 MIBC patients in General cohort. Result It can be indicated that high IRPS score was related to poor 5-year overall survival and disease-free survival. The IRPS score was also evaluated its immune infiltration. We found that the IRPS score was adversely associated with GZMB, IFN-γ, PD-1, PD-L1. Additionally, higher IRPS score was significantly associated with more M2 macrophage and resting mast cell infiltration. Conclusion The study revealed a novel BCa prognostic signature based on IRPS score, which may be useful for BCa immunotherapies.

Abstract Background Diabetic nephropathy (DN) is prevalent in patients with diabetes. N 6-methyladenosine (m6A) methylation has been found to cause modification of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3, which is involved in cell pyroptosis and inflammation. WTAP is a key gene in modulating NLRP3 m6A. Methods In this study, WTAP was silenced or overexpressed in high glucose (HG)-treated HK-2 cells to determine its influence on pyroptosis, NLRP3 inflammasome-related proteins, and the release of pro-inflammatory cytokines. NLRP3 expression and m6A levels were assessed in the presence of WTAP shRNA (shWTAP). WTAP expression in HK-2 cells was examined with the introduction of C646, a histone acetyltransferase p300 inhibitor. Results We found that WTAP expression was enhanced in patients with DN and in HG-treated HK-2 cells. Knockdown of WTAP attenuated HG-induced cell pyroptosis and NLRP3-related pro-inflammatory cytokines in both HK-2 cells and db/db mice, whereas WTAP overexpression promoted these cellular processes in HK-2 cells. WTAP mediated the m6A of NLRP3 mRNA that was stabilized by insulin-like growth factor 2 mRNA binding protein 1. Histone acetyltransferase p300 regulated WTAP expression. WTAP mRNA levels were positively correlated with NLRP3 inflammasome components and pro-inflammatory cytokines. Conclusion Taken together, WTAP promotes the m6A methylation of NLRP3 mRNA to upregulate NLRP3 inflammasome activation, which further induces cell pyroptosis and inflammation.

Abstract Background Glucose can be involved in metabolic activities as a structural substance or signaling molecule and plays an important regulatory role in fruit development. Glucose metabolism is closely related to the phenylpropanoid pathway, but the specific role of glucose in regulating lignin biosynthesis in pear fruit is still unclear. The transcriptome of pear calli generated from fruit and treated with glucose was analyzed to investigate the role of glucose in lignin biosynthesis. Results The treatment of exogenous glucose significantly enhanced the accumulation of lignin in pear calli. A total of 6566 differentially expressed genes were obtained by transcriptome sequencing. Glycolysis was found to be the pathway with significant changes. Many differentially expressed genes were enriched in secondary metabolic pathways, especially the phenylpropanoid pathway. Expression of structural genes (PbPAL, PbHCT, PbCOMT, PbPRX) in lignin biosynthesis was up-regulated after glucose treatment. In addition, glucose might regulate lignin biosynthesis through interactions with ABA, GA, and SA signaling. Several candidate MYB transcription factors involved in glucose-induced lignin biosynthesis have also been revealed. The qRT-PCR analyses showed that the expression pattern of PbPFP at early developmental stage in ‘Dangshansuli’ fruits was consistent with the trend of lignin content. Transient expression of PbPFP resulted in a significant increase of lignin content in ‘Dangshansuli’ fruits at 35 days after full bloom (DAB) and tobacco leaves, indicating that PbPFP (Pbr015118.1) might be associated with the enhancement of lignin biosynthesis in response to glucose treatment. Conclusions PbPFP plays a positive role in regulating lignin biosynthesis in response to glucose treatment. This study may reveal the regulatory pathway related to lignin accumulation in pear calli induced by glucose.

Abstract Psychoanalysis and infant research have strengthened cooperation in the current interdisciplinary dialog. The theoretical significance of infant research for psychoanalysis includes the consideration of individual “sociality” from birth, as opposed to the traditional psychoanalytic hypothesis of the “autistic” infant; such research creates openness in existing psychoanalytic mental models. It can also provide reliable evidence for the early development of various abilities and childhood amnesia, support psychoanalysis beyond linear causality, and create a framework for the theoretical integration of psychoanalysis. Infant research for psychoanalysis may present evidence of the healing effect of analyst–client relationships, encourage analysts to prioritize nonverbal information during treatment, and create opportunities for new psychoanalytic therapy technologies.

Osteoarthritis (OA) is the most common joint disease; thus, understanding the pathological mechanisms of OA initiation and progression is critical for OA treatment. MicroRNAs (miRNAs) have been shown to be involved in the progression of osteoarthritis, one candidate is microRNA-378 (miR-378), which is highly expressed in the synovium of OA patients during late-stage disease, but its function and the underlying mechanisms of how it contributes to disease progression remain poorly understood. In this study, miR-378 transgenic (TG) mice were used to study the role of miR-378 in OA development. miR-378 TG mice developed spontaneous OA and also exaggerated surgery-induced disease progression. Upon in vitro OA induction, miR-378 expression was upregulated and correlated with elevated inflammation and chondrocyte hypertrophy. Chondrocytes isolated from articular cartilage from miR-378 TG mice showed impaired chondrogenic differentiation. The bone marrow mesenchymal stem cells (BMSCs) collected from miR-378 TG mice also showed repressed chondrogenesis compared with the control group. The autophagy-related protein Atg2a, as well as chondrogenesis regulator Sox6, were identified as downstream targets of miR-378. Ectopic expression of Atg2a and Sox6 rescued miR-378-repressed chondrocyte autophagy and BMSC chondrogenesis, respectively. Anti-miR-378 lentivirus intra-articular injection in an established OA mouse model was shown to ameliorate OA progression, promote articular regeneration, and repress hypertrophy. Atg2a and Sox6 were again confirmed to be the target of miR-378 in vivo. In conclusion, miR-378 amplified OA development via repressing chondrocyte autophagy and by inhibiting BMSCs chondrogenesis, thus indicating miR-378 may be a potential therapeutic target for OA treatments.

ObjectiveDiabetic peripheral neuropathy (DPN) causes significant illness in patients and has a negative impact on the economy. The objective of this study is to evaluate the cost and quantity of anti-diabetic drugs needed by patients with or without DPN, as well as their variation trends in Beijing between 2016 and 2018.MethodsThis observational cross-sectional study used data on diabetic patients with outpatient medication records obtained from Beijing Medical Insurance from 2016 to 2018. The medications, comorbidities, diabetes-related complications, treatment strategies, and costs of drug treatment were compared between DPN patients and non-DPN patients.ResultsOf the 28,53,036 diabetic patients included in the study, 3,75,216 (13.15%) had DPN and 1,87,710 (50.03%) of the DPN patients were women. Compared with non-DPN patients, DPN patients used more mediations (4.7 ± 2.47 vs. 3.77 ± 2.32, p < 0.0001, in 2018) to treat related complications and comorbidities (2.03 ± 1.2 vs. 1.71 ± 1.05; 2.68 ± 1.93 vs. 2.06 ± 1.86, p < 0.0001, respectively, in 2018). The total annual costs of drug treatment were higher in DPN patients than in non-DPN patients (¥12583.25 ± 10671.48 vs. ¥9810.91 ± 9234.14, p < 0.0001, in 2018). The usage of DDP4i increased from 2.55 to 6.63% in non-DPN patients and from 4.45 to 10.09% in DPN patients from 2017 to 2018.ConclusionsThe number of comorbidities, diabetic complications, medications, and annual drug treatment costs were greater in DPN patients than in non-DPN patients.

Objective This study aimed to investigate the preferences regarding risks, benefits and other treatment attributes of patients with type 2 diabetes mellitus (T2DM) in China when selecting a second-line anti-hyperglycaemic medicine.Methods A discrete choice experiment with hypothetical anti-hyperglycaemic medication profiles was performed using a face-to-face survey administered to patients with T2DM. The medication profile was described using seven attributes: treatment efficacy, hypoglycaemia risk, cardiovascular benefits, gastrointestinal (GI) adverse events, weight change, mode of administration and out-of-pocket cost. Participants chose between medication profiles by comparing attributes. Data were analysed using a mixed logit model with marginal willingness to pay (mWTP) and maximum acceptable risk (MAR) calculated. The preference heterogeneity within the sample was explored using a latent class model (LCM).Results A total of 3327 respondents from five major geographical regions completed the survey. Treatment efficacy, hypoglycaemia risk, cardiovascular benefits and GI adverse events were major concerns among the seven attributes measured. Weight change and mode of administration were of lesser concern. Regarding mWTP, respondents would pay ¥236.1 (US$36.6) for an anti-hyperglycaemic medication with an efficacy of 2.5% points reduction in HbA1c, while they were willing to accept a weight gain of 3 kg only if they received a compensation of ¥56.7 (US$8.8). Respondents were willing to accept a relatively large increase in hypoglycaemia risk (MAR=15.9%) to improve treatment efficacy from intermediate (1.0% points) to high (1.5% points). LCM identified the following four unobserved subgroups: trypanophobia, cardiovascular-benefits-focused, safety-focused and efficacy-focused and cost-sensitive.Conclusion Patients with T2DM prioritised free out-of-pocket costs, highest efficacy, no hypoglycaemia risk and cardiovascular benefits over weight change and mode of administration. There exists great preference heterogeneity among patients, which should be taken into account in healthcare decision-making processes.

Gas emitted from landfills contains a large quantity of volatile organic compounds (VOCs) and semi-volatile organic compounds (SVOCs), some of which are carcinogenic, teratogenic, and mutagenic, thereby posing a serious threat to the health of landfill workers and nearby residents. However, the global hazards of VOCs and SVOCs in landfill gas to human health remain unclear. To quantify the global risk distributions of these pollutants, we collected the composition and concentration data of VOCs and SVOCs from 72 landfills in 20 countries from the core database of Web of Science and assessed their human health risks as well as analyzed their influencing factors. Organic compounds in landfill gas were found to primarily result from the biodegradation of natural organic waste or the emissions and volatilization of chemical products, with the concentration range of 1 × 10-1–1 × 106 μg/m3. The respiratory system, in particular, lung was the major target organ of VOCs and SVOCs, with additional adverse health impacts ranging from headache and allergies to lung cancer. Aromatic and halogenated compounds were the primary sources of health risk, while ethyl acetate and acetone from the biodegradation of natural organic waste also exceeded the acceptable levels for human health. Overall, VOCs and SVOCs affected residents within 1,000 m of landfills. Air temperature, relative humidity, air pressure, wind direction, and wind speed were the major factors that influenced the health risks of VOCs and SVOCs. Currently, landfill risk assessments of VOCs and SVOCs are primarily based on respiratory inhalation, with health risks due to other exposure routes remaining poorly elucidated. In addition, potential health risks due to the transport and transformation of landfill gas emitted into the atmosphere should be further studied.

The weak adhesion between nanocarriers and the intestinal mucosa was one of the main reasons caused the failure in oral delivery. Inspired by the “antiskid tires” with complex chiral patterns, mesoporous silica nanoparticles AT-R@CMSN exhibiting geometrical chiral structure were designed to improve the surface/interface roughness in nanoscale, and employed as the hosting system for insoluble drugs nimesulide (NMS) and ibuprofen (IBU). Once performing the delivery tasks, AT-R@CMSN with rigid skeleton protected the loaded drug and reduced the irritation of drug on gastrointestinal tract (GIT), while their porous structure deprived drug crystal and improved drug release. More importantly, AT-R@CMSN functioned as “antiskid tire” to produce higher friction on intestinal mucosa and substantively influenced multiple biological processes, including “contact”, “adhesion”, “retention”, “permeation” and “uptake”, compared to the achiral S@MSN, thereby improving the oral adsorption effectiveness of such drug delivery systems. By engineering AT-R@CMSN to overcome the stability, solubility and permeability bottlenecks of drugs, orally administered NMS or IBU loaded AT-R@CMSN could achieve higher relative bioavailability (705.95% and 444.42%, respectively) and stronger anti-inflammation effect. In addition, AT-R@CMSN displayed favorable biocompatibility and biodegradability. Undoubtedly, the present finding helped to understand the oral adsorption process of nanocarriers, and provided novel insights into the rational design of nanocarriers.

Background: Instead of only practicing these perfectly matched end-to-side anastomoses in microsurgical laboratories, we must learn how to perform these so-called “imperfect” end-to-side anastomoses in the laboratory.MethodsThree types of end-to-side microvascular anastomoses using the rat common iliac artery (CIA), one with the proximal end of the CIA to the contralateral side of the CIA, another with the distal end of the CIA to the contralateral side of the CIA, and the third with the distal end of the CIA to the ipsilateral side of the common iliac vein (CIV), were presented to simulate different end-to-side anastomosis situations in a microsurgical laboratory. Diameters of CIA and CIV, distances between temporary clips, the length of arteriotomy or venotomy, and the distribution of stitches were recorded. The patency rates were evaluated immediately after the anastomosis was completed and 30 min later. After animal euthanasia, the donor vessel was cut close to the anastomotic site, and the orifice size and intimal attachment were evaluated by inspecting them through inside the vessel.ResultsThe diameters of the CIA and CIV were 0.8–1.2 mm and 1.2–1.5 mm, respectively. The end-to-side microvascular anastomosis arteriotomy or venotomy is approximately 2.00–2.50 mm, the distance between the aneurysm clips on the recipient CIA or CIV is approximately 4.00–7.00 mm, and the distance between the corner of the arteriotomy or venotomy and the temporary aneurysm clip was 1.00–3.00 mm. Three types of end-to-side anastomoses using the CIA were successfully performed, and 100% patency rates were achieved immediately and 30 min postoperatively. Good distribution of stitches, wide orifice, and intimal attachment were recorded in the study in all groups.ConclusionsThree types of end-to-side anastomoses using rat CIAs could be efficiently used to mimic three different anastomotic situations.

Abstract To study the noise spectrum characteristics of marine pump units induced by different excitation sources, a computational aeroacoustic (CAA) model of the internal and external field noise of a marine pump was established. The coupled acoustic-vibration method was used to obtain the spectrum characteristics of internal and external field noise. The accuracy and feasibility of the simulation method for noise prediction were confirmed through a noise test. Due to the different mediums in the internal and external fields of the marine pump, an external field acoustic model was established based on the automatically matched layer (AML) technology. The spectral characteristics of different excitation sources and the spatial distribution of the radiated sound field were analyzed, and the contribution of different sound source excitations to the internal and external sound field was revealed. The results show that the main frequency of the internal field noise generated by different excitations is at the blade passing frequency, and the internal field noise induced by the dipole acoustic excitations dominates at 180.6 dB. For the external field noise, the main frequency is still located at the blade passing frequency. The radiation noise induced by the fluid excitation (139.2 dB) is higher than that induced by the dipole excitations (surface dipole, 136.3 dB; rotating dipole, 137.3 dB).

Abstract Background Although moderate weight loss improves outcomes of type 2 diabetes mellitus (T2DM) in young and middle-aged adults, there is a lack of high-quality evidence to support the strong relationship between obesity and T2DM in older people. This study aims to investigate whether the association of obesity with T2DM changes with aging. Methods In this cross-sectional study, we recruited 63,180 Chinses and US subjects from 3 datasets. Subjects were divided into young & middle-aged (≤59 years), young-old (60–75 years), and old-old (≥75 years). Logistic regression was used to determine the odds ratio (OR) and 95% confidence intervals (95% CI) for the association between obesity and T2DM, stratified by common confounders. A sliding-window based algorithm and restricted cubic splines were used to smoothly estimate the changes with aging. Results The OR (95% CI) for the associations between general obesity and T2DM were decreased from the young & middle-aged group (OR, 5.91; 95% CI, 5.33–6.56) to the young-old group (OR, 3.98; 95% CI, 3.56–4.45) and then to the old-old group (OR, 3.06; 95% CI, 2.57–3.66). The trend for this reduced association with aging persisted after stratification by obesity type, region, gender, recruiting time, hypertension, and hyperlipidemia in both Chinese and Americans. We also identified a weakened gender disparity for this association between the young & middle-aged subjects (P for disparity

Objective: Investigation of the regulatory mechanisms of cell stemness in cholangiocarcinoma (CCA) is essential for developing effective therapies to improve patient outcomes. The purpose of this study was to investigate the function and regulatory mechanism of m6A modifications in CCA cell stemness. Methods: Interleukin 6 (IL-6) treatment was used to induce an inflammatory response, and loss-of-function studies were conducted using mammosphere culture assays. Chromatin immunoprecipitation, polysome profiling, and methylated RNA immunoprecipitation analyses were used to identify signaling pathways. The in vitro findings were verified in a mice model. Results: We first identified that m6A writers were highly expressed in CCAs and further showed that STAT3 directly bound to the gene loci of m6A writers, showing that IL-6/STAT3 signaling regulated expressions of m6A writers. Downregulating m6A writers prevented cell proliferation and migration in vitro and suppressed CCA tumorigenesis in vivo. Notably, the knockdown of m6A writers inhibited CCA cell stemness that was triggered by IL-6 treatment. Mechanistically, IGF2BP2 was bound to CTNNB1 transcripts, significantly enhancing their stability and translation, and conferring stem-like properties. Finally, we confirmed that the combination of m6A writers, IGF2BP2, and CTNNB1 distinguished CCA tissues from normal tissues. Conclusions: Overall, this study showed that the IL-6-triggered inflammatory response facilitated the expressions of m6A writers and cell stemness in an m6A-IGF2BP2-dependent manner. Furthermore, the study showed that m6A modification was a targetable mediator of the response to inflammation factor exposure, was a potential diagnostic biomarker for CCA, and was critical to the progression of CCA.

Abstract Background Influenza A viruses (IAVs) are zoonotic, segmented negative-stranded RNA viruses. The rapid mutation of IAVs results in host immune response escape and antiviral drug and vaccine resistance. RUNX1 is a transcription factor that not only plays essential roles in hematopoiesis, but also functions as a regulator in inflammation. However, its role in the innate immunity to IAV infection has not been well studied. Methods To investigate the effects of RUNX1 on IAV infection and explore the mechanisms that RUNX1 uses during IAV infection. We infected the human alveolar epithelial cell line (A549) with influenza virus A/Puerto Rico/8/34 (H1N1) (PR8) and examined RUNX1 expression by Western blot and qRT-PCR. We also knocked down or overexpressed RUNX1 in A549 cells, then evaluated viral replication by Western blot, qRT-PCR, and viral titration. Results We found RUNX1 expression is induced by IAV H1N1 PR8 infection, but not by poly(I:C) treatment, in the human alveolar epithelial cell line A549. Knockdown of RUNX1 significantly inhibited IAV infection. Conversely, overexpression of RUNX1 efficiently promoted production of progeny viruses. Additionally, RUNX1 knockdown increased IFN-β and ISGs production while RUNX1 overexpression compromised IFN-β and ISGs production upon PR8 infection in A549 cells. We further showed that RUNX1 may attenuate the interferon signaling transduction by hampering the expression of IRF3 and STAT1 during IAV infection. Conclusions Taken together, we found RUNX1 attenuates type I interferon signaling to facilitate IAV infection in A549 cells.

Abstract Background Vestibular symptoms are frequently reported in patients with chronic migraine (CM). However, whether vestibular symptoms arise through overlapping neurobiology of migraine remains to be elucidated. The neuropeptide calcitonin gene-related peptide (CGRP) and CGRP1 receptor play important pathological roles in facilitating central sensitization in CM. Therefore, we aimed to investigate whether CGRP1 receptor contributes to vestibular dysfunction after CM by improving synaptic transmission in the vestibular nucleus (VN). Methods A CM rat model was established by recurrent intermittent administration of nitroglycerin (NTG). Migraine- and vestibular-related behaviors were assessed. CGRP1 receptor specific antagonist, BIBN4096BS, and protein kinase C (PKC) inhibitor chelerythrine chloride (CHE) were administered intracerebroventricularly. The expressions of CGRP and CGRP1 receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were evaluated by western blot, immunofluorescent staining and quantitative real-time polymerase chain reaction in the vestibular nucleus (VN). Synaptic associated proteins and synaptic morphological characteristics were explored by western blot, transmission electron microscope, and Golgi-cox staining. The expressions of PKC, phosphorylated extracellular signal regulated kinase (p-ERK), phosphorylated cAMP response element-binding protein at serine 133 site (p-CREB-S133) and c-Fos were detected using western blot or immunofluorescent staining. Results The expressions of CGRP, CLR and RAMP1 were significantly upregulated in CM rats. CLR and RAMP1 were expressed mainly in neurons. BIBN4096BS treatment and PKC inhibition alleviated mechanical allodynia, thermal hyperalgesia and vestibular dysfunction in CM rats. Additionally, BIBN4096BS treatment and PKC inhibition markedly inhibited the overexpression of synaptic associated proteins and restored the abnormal synaptic structure in VN after CM. Furthermore, BIBN4096BS treatment dysregulated the expression levels of PKC, p-ERK and p-CREB-S133, and attenuated neuronal activation in VN after CM. Conclusions The present study demonstrated that CGRP1 receptor inhibition improved vestibular function after CM by reversing the aberrant synaptic transmission via downregulating PKC/ERK/CREB signaling pathway. Therapeutic interventions by inhibiting CGRP/CGRP1 signaling may be a new target for the treatment of vestibular symptoms in CM.

Aims: Treatment for delayed wound healing resulting from peripheral vascular diseases and diabetic foot ulcers remains a challenge. A novel surgical technique named ‘tibial cortex transverse transport’ (TTT) has been developed for treating peripheral ischaemia, with encouraging clinical effects. However, its underlying mechanisms remain unclear. In the present study, we explored the potential biological mechanisms of TTT surgery using various techniques in a rat TTT animal model. Methods: A novel rat model of TTT was established with a designed external fixator, and effects on wound healing were investigated. Laser speckle perfusion imaging, vessel perfusion, histology, and immunohistochemistry were used to evaluate the wound healing processes. Results: Gross and histological examinations showed that TTT technique accelerated wound closure and enhanced the quality of the newly formed skin tissues. In the TTT group, haematoxylin and eosin (H&E) staining demonstrated a better epidermis and dermis recovery, while immunohistochemical staining showed that TTT technique promoted local collagen deposition. The TTT technique also benefited to angiogenesis and immunomodulation. In the TTT group, blood flow in the wound area was higher than that of other groups according to laser speckle imaging with more blood vessels observed. Enhanced neovascularization was seen in the TTT group with double immune-labelling of CD31 and α-Smooth Muscle Actin (α-SMA). The number of M2 macrophages at the wound site in the TTT group was also increased. Conclusion: The TTT technique accelerated wound healing through enhanced angiogenesis and immunomodulation. Cite this article: Bone Joint Res 2022;11(4):189–199.

With the rapid development of urbanization and industrialization, human activities have caused marine pollution in three ways: land source, air source, and sea source, leading to the problem of marine environments. Remote sensing, with its wide coverage and fast and accurate monitoring capability, continues to be an important tool for marine environment monitoring and evaluation research. This paper focuses on the three types of marine pollution, namely marine seawater pollution, marine debris and microplastic pollution, and marine air pollution. We review the application of remote sensing technology methods for monitoring marine pollution and identify the limitations of existing methods. Marine seawater pollution can be effectively monitored by remote sensing technology, especially where traditional monitoring methods are inadequate. For marine debris and microplastic pollution, the monitoring methods are still in the early stages of development and require further research. For marine air pollution, more air pollution parameters are required for accurate monitoring. Future research should focus on developing marine remote sensing with data, technology, and standard sharing for three-dimensional monitoring, combining optical and physical sensors with biosensors, and using multi-source and multi-temporal monitoring data. A marine multi-source monitoring database is necessary to provide an immediately available basis for coastal and marine governance, improve marine spatial planning, and help coastal and marine protection.

Abstract Background Central sensitization is an important pathophysiological mechanism of chronic migraine (CM), and microglia activation in trigeminocervical complex (TCC) contributes to the development of central sensitization. Emerging evidence implicates that blocking sphingosine-1-phosphate receptor 1 (S1PR1) can relieve the development of chronic pain and inhibit the activation of microglia. However, it is unclear whether S1PR1 is involved in the central sensitization of CM. Therefore, the purpose of this study is to explore the role of S1PR1 and its downstream signal transducers and activators of transcription 3 (STAT3) signaling pathway in the CM, mainly in inflammation. Methods Chronic intermittent intraperitoneal injection of nitroglycerin (NTG) established a mouse model of CM. First, we observed the changes and subcellular localization of S1PR1 in the trigeminocervical complex (TCC). Then, W146, a S1PR1 antagonist; SEW2871, a S1PR1 agonist; AG490, a STAT3 inhibitor were applied by intraperitoneal injection to investigate the related molecular mechanism. The changes in the number of microglia and the expression of calcitonin gene-related peptide (CGRP) and c-fos in the TCC site were explored by immunofluorescence. In addition, we studied the effect of S1PR1 inhibitors on STAT3 in lipopolysaccharide-treated BV-2 microglia. Results Our results showed that the expression of S1PR1 was increased after NTG injection and S1PR1 was colocalized with in neurons and glial cells in the TCC. The S1PR1 antagonist W146 alleviated NTG-induced hyperalgesia and suppressed the upregulation of CGRP, c-fos and pSTAT3 in the TCC. Importantly, blocking S1PR1 reduced activation of microglia. In addition, we found that inhibiting STAT3 signal also attenuated NTG-induced basal mechanical and thermal hyperalgesia. Conclusions Our results indicate that inhibiting S1PR1 signal could alleviate central sensitization and inhibit microglia activity caused by chronic NTG administration via STAT3 signal pathway, which provide a new clue for the clinical treatment of CM.

This study develops an adaptive Super-Twisting sliding mode control (STSMC) approach using an output feedback fuzzy neural network (OFFNN) for dynamic systems. The OFFNN approximator is designed to approach the model uncertainty, and a signal feedback loop could provide better data learning capabilities and more reasonable learning rate, therefore the proposed controller has full regulation and high approximation accuracy. Real-time experimental studies of an active power filter are accomplished to show the proposed controller has better harmonic suppression and steady-state and dynamic property than existing methods.

Driven by the Internet of Everything, one of the main goals in human–computer interaction is to achieve intuitive, effortless, and easy‐to‐learn communication. Thus, senseless optoelectronic devices with high response performance under ambient environment have an extensive application space in improving the interfacing between users and computers. Herein, a concept of wearable perovskite‐based shadow recognition sensor is demonstrated for ambient and nonobtrusive human–computer interaction. The multidimensional ordered nucleation and growth of perovskite crystals are promoted by introducing the self‐driving effect of liquid crystal (LC) oligomers. The resulted LC‐doped perovskite film (LC‐PVK) with micrometer‐sized grains can output relatively high photocurrent under indoor ambient light (≈500 lux). The LC‐based device exhibits over a hundred times of on–off ratio and fast response of millisecond level even after storage for more than 1200 h. The device also shows an ultratrace Pb2+ leakage of 1.02 μg L−1 in water, and still retains more than 90% of the photocurrent intensity after thousands of bending strains. Accordingly, a novel human–computer interaction is achieved by identifying external action commands with the recognition of shadows, which can provide a “haptic” perception for robots.

Abstract Background Previous studies have confirmed that the microglial activation and subsequent inflammatory responses in the trigeminal nucleus caudalis (TNC) are involved in the central sensitization of chronic migraine (CM). MicroRNA-155-5p has been shown to modulate the polarization of microglia and participate in inflammatory processes in a variety of neurological diseases. However, its role in CM remains unclear. The purpose of this study was to determine the precise role of miR-155-5p in CM. Methods A model of CM in C57BL/6 mice was established by recurrent intraperitoneal injection of nitroglycerin (NTG). Mechanical and thermal hyperalgesia were evaluated by Von Frey filaments and radiant heat. The expression of miR-155-5p was examined by qRT-PCR, and the mRNA and protein levels of silent information regulator 1(SIRT1) were measured by qRT-PCR, Western blotting (WB) and immunofluorescence (IF) analysis. The miR-155-5p antagomir, miR-155-5p agomir, SRT1720 (a SIRT1 activator) and EX527 (a SIRT1 inhibitor) were administered to confirm the effects of miR-155-5p and SIRT1 on neuroinflammation and the central sensitization of CM. ELISA, WB and IF assays were applied to evaluate the expression of TNF-α, myeloperoxidase (MPO), IL-10, p-ERK, p-CREB, calcitonin gene-related peptide (CGRP), c-Fos and microglial activation. The cellular localization of SIRT1 was illustrated by IF. Results After the NTG-induced mouse model of CM was established, the expression of miR-155-5p was increased. The level of SIRT1 was decreased, and partly colocalized with Iba1 in the TNC. The miR-155-5p antagomir and SRT1720 downregulated the expression of p-ERK, p-CREB, CGRP, and c-Fos, alleviating microglial activation and decreasing inflammatory substances (TNF-α, MPO). The administration of miR-155-5p agomir or EX527 exacerbated neuroinflammation and central sensitization. Importantly, the miR-155-5p agomir elevated CGRP and c-Fos expression and microglial activation, which could subsequently be alleviated by SRT1720. Conclusions These data demonstrate that upregulated miR-155-5p in the TNC participates in the central sensitization of CM. Inhibiting miR-155-5p alleviates neuroinflammation by activating SIRT1 in the TNC of CM mice.

Abstract. Background:. The chaperonin containing t-complex (CCT) proteins play an important role in cell cycle-related protein degradation in yeast and mammals. The role of the chaperonin containing t-complex 4 (CCT4), one subtype of CCT proteins, in the progress of hepatocellular carcinoma (HCC) was not fully elucidated. Here, we aimed to explore the mechanisms of CCT4 in HCC. Methods:. In this study, we used the UALCAN platform to analyze the relationship between CCT4 and HCC, and the association of CCT4 with the overall survival (OS) of HCC patients was also analyzed. CCT4 expression in HCC tumor tissues and normal tissues was also determined by western blot (WB) assay. Lentivirus vector was used to knock down the CCT4 expression, and quantitative polymerase chain reaction and WB were used to determine the level of CCT4 in HCC cell lines. Cell counting kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EdU) assays were used to detect the cell proliferation, and flow cytometry (FCM) was performed to evaluate the effect of CCT4 on the apoptosis of HCC cells. Co-immunoprecipitation (co-IP) assay and WB were used to explore the mechanisms of CCT4 regulating the growth of HCC. Data were calculated from at least three replicate experiments and expressed as mean ± standard deviation. Student's t test, paired t test, and Kaplan–Meier analysis were used to compare across different groups. Results:. We found CCT4 was upregulated in HCC tissues compared with normal tissues, and its high expression was associated with poor prognosis (P

Abstract. Lack of clarity of the mechanisms that underlie leukemogenesis obstructs the diagnosis, prognosis, and treatment of leukemia. Research has found that small nuclear RNA (snoRNA) plays an essential role in leukemia. These small non-coding RNAs are involved in ribosome biogenesis, including the 2′-O-methylation and pseudouridylation of precursor ribosomal RNA (pre-rRNA), and pre-rRNA splicing. Recently, many snoRNAs were found to be orphans that have no predictable RNA modification targets, but these RNAs have always been found to be located in different subcellular organelles, and they play diverse roles. Using high-throughput technology, snoRNA expression profiles have been revealed in leukemia, and some of the deregulated snoRNAs may regulate the cell cycle, differentiation, proliferation, and apoptosis in leukemic cells and confer drug resistance during leukemia treatment. In this review, we discuss the expression profiles and functions of snoRNAs, particularly orphan snoRNAs, in leukemia. It is possible that the dysregulated snoRNAs are promising diagnosis and prognosis markers for leukemia, which may serve as potential therapeutic targets in leukemia treatment.

Abstract Background Interferon-alpha (IFN-α) is a general therapeutic regimen to be utilized in hepatocellular carcinoma (HCC). However, regulatory mechanisms of IFN-α on competing endogenous RNAs (ceRNAs) level in anti-HCC relapse are rarely understood. Methods HCC patients with and without IFN-α treatment were calculated to analyze the expression profile of mRNA, long non-coding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA) by RNA sequence, and significant differential expression (DE) of these types of RNAs were selected for further analysis. A ceRNA regulatory network was constructed to explore the potential mechanisms of IFN-α intervention on anti-HCC relapse. Finally, the potential prognostic associated genes among these DE RNAs were identified. Results Totally, 556 mRNAs, 120 circRNAs, 87 lncRNAs, and 96 miRNAs were differentially expressed in patients who received IFN-α treatment. A ceRNA regulatory network including a circRNA-miRNA-mRNA network which composed of 4 up- and 10 down-regulated circRNAs, 8 up- and 5 down-regulated miRNAs, 28 up- and 9 down-regulated mRNAs, and a lncRNA-miRNA-mRNA network which composed of 10 up- and 3 down-regulated lncRNAs, 11 up- and 5 down-regulated miRNAs, 28 up- and 10 down-regulated mRNAs was constructed. Gene enrichment and pathway analysis revealed that the ceRNA network was associated with immune-related pathway and corresponding molecular function in patients who accepted IFN-α treatment. Next, we identified 3 most relevant to IFN-α treatment to HCC among these DE RNAs, namely FAM20A, IGFBP4 and MARCH3, as the prognostic associated genes for HCC. Furthermore, MARCH3 expression correlated with infiltrating levels of tumor infiltrating immune cells (TICCs) in HCC. MARCH3 expression also showed strong correlations with the gene markers of diverse immune cells in HCC. Conclusion Our data discovered a novel ceRNA network in HCC patients receiving IFN-α therapy, which might lay the foundation for better understand the regulatory mechanism of IFN-α treatment.

Abstract Background DNA Polymerase Theta (POLQ) is a DNA polymerase involved in error-prone translesion DNA synthesis (TLS) and error-prone repair of DNA double-strand breaks (DSBs), whose function in hepatocellular carcinoma has not been investigated. Methods In the present study, both the data collected from the Cancer Genome Atlas (TCGA) and our group’s results showed higher POLQ expression in HCC tissues than the para-cancerous tissues, which was associated with higher malignancy and poor prognosis. POLQ knockdown HCC cell model (shPOLQ) was constructed along with the corresponding negative control (shCtrl) through lentivirus infection for loss-of-function study. Results We found that, upon knockdown of POLQ, the proliferation and migration of HCC cells decreased and apoptosis percentage increased. Moreover, the percentage of cells in G2 phase significantly increased in shPOLQ group compared with shCtrl group. Xenografts in mice grafted with shPOLQ cells grew much slower than that transplanted with shCtrl cells, and expressed lower Ki67 level. Furthermore, an apoptosis-related signaling array was used to explore the involvement of downstream signaling pathways, suggesting the enhanced phosphorylation of HSP27 and JNK, and the de-activation of mTOR, PRAS40, ERK1/2 and STAT3 pathways. Conclusions Collectively, our study revealed that POLQ may participate in the development of HCC, depletion of which may be a promising treatment strategy for HCC.

Driven by the clinical demand on improving the oral bioavailability and reducing the side effects of insoluble drug, aminoated mesoporous silica xerogel (named L/d-BPEIN-MSX) with chiral surface topology was constructed through a facile, economical, and biomimetic strategy within 2 min, and served as the carrier of indomethacin (IMC). In the synthetic process, L/d-tartaric acid (L/d-TA) self-assembled with branched polyethyleneimine (BPEI) to endow chirality and synergistic promoted silica deposition, while 3-aminopropyl triethoxysilane (APTES) polycondensated with the silica source to form aminoated mesostructure. By premixed strategy, IMC can be in situ loaded into L/d-BPEIN-MSX with high efficiency, which then became active in circular dichroism (CD) spectra owing to induced chirality. Noteworthy, IMC-L/d-BPEIN-MSX significantly improved the release rate of IMC with multiple controlled release manners. That is, d-BPEIN-MSX had favorable drug release behavior which could respond to the chiral stimuli, whereas l-BPEIN-MSX exhibited advantageous chiral surface topology that was beneficial for bio-processes related to oral adsorption. Undoubtedly, they increased the bioavailability of IMC to 8–9 times, displayed good anti-inflammatory effect, and reduced the gastrointestinal irritation of IMC. In addition, L/d-BPEIN-MSX had low toxicity and irritation, and was proven to be biodegradable and biocompatible, which could meet the requirement for biomedical applications.

Background DNA binding with one finger (Dof) proteins are plant-specific transcription factor (TF) that plays a significant role in various biological processes such as plant growth and development, hormone regulation, and resistance to abiotic stress. The Dof genes have been identified and reported in multiple plants, but so far, the whole genome identification and analysis of Dof transcription factors in blueberry (Vaccinium corymbosum L.) have not been reported yet. Methods Using the Vaccinium genome, we have identified 51 VcDof genes in blueberry. We have further analyzed their physicochemical properties, phylogenetic relationships, gene structure, collinear analysis, selective evolutionary pressure, cis-acting promoter elements, and tissue and abiotic stress expression patterns. Results Fifty-one VcDof genes were divided into eight subfamilies, and the genes in each subfamily contained similar gene structure and motif ordering. A total of 24 pairs of colinear genes were screened; VcDof genes expanded mainly due to whole-genome duplication, which was subjected to strong purifying selection pressure during the evolution. The promoter of VcDof genes contains three types of cis-acting elements for plant growth and development, phytohormone and stress defense responsiveness. Expression profiles of VcDof genes in different tissues and fruit developmental stages of blueberry indicated that VcDof2 and VcDof45 might play a specific role in anthesis and fruit growth and development. Expression profiles of VcDof genes in different stress indicated that VcDof1, VcDof11, and VcDof15 were highly sensitive to abiotic stress. This study provides a theoretical basis for further clarifying the biological function of Dof genes in blueberry.

Introduction Although molecular testing is crucial for many patients with lung cancer, the decision to carry out molecular testing is not easy to make in actual clinical scenarios. Using a specific decision aid (DA) to conduct shared decision-making (SDM) may help ameliorate this problem. However, no DA currently exists for lung cancer molecular testing (DA_LCMT). We aim to develop an evidence-based, iteratively refined DA, which may facilitate SDM and improve the quality of SDM.Methods and analysis After considering the Ottawa Decision Support Framework, International Patient Decision Aid Standards and Food and Drug Administration guidance about methods to identify what is important to patients, semistructured interviews with qualitative research methods will be used to generate the decision-making needs of patients with lung cancer diagnosed with lung adenocarcinoma by intraoperative frozen pathological sections. Input will be provided by patients and other stakeholders, including thoracic surgeons, nurses, hospital administrators, molecular testing company staff and insurance company staff. Then, a modified Delphi method will be used to develop the DA_LCMT V.1.0 (DA_LCMT 1.0). Structured interviews with qualitative research methods will be used in the cognitive debriefing (alpha tests) and field testing (beta tests) to revise and improve the DA_LCMT from version 1.0 to the final version, version 3.0. Descriptive statistics will be used to summarise the baseline characteristics of the patients and other stakeholders. Qualitative data will be analysed using the three steps of grounded theory: generate a codebook, update the codebook and create a comprehensive list of related items.Ethics and dissemination Ethics Committee for Medical Research and New Medical Technology of Sichuan Cancer Hospital approved this study. This protocol is based on the latest version 1.0, dated 31 October 2021. The study was also approved by the Ethics Committees of The Third People’s Hospital of Chengdu, Zigong First People’s Hospital and Jiangyou People’s Hospital. The results of this study will be presented at medical conferences and published in peer-reviewed journals.Trial registration number NCT05191485.

Background: To explore the effectiveness of standardized first-trimester ultrasound screening (FTS) in detecting fetal structural abnormalities in a non-selective population. Methods: A retrospective study was performed on 7523 fetuses (6376 single and 569 twin pregnancies) who underwent FTS between 11 and 13+6 weeks’ gestation. All fetuses received anatomy scans using a standardized protocol. Results: 147 fetuses (133 single and 7 twin pregnancies) were lost to follow up. Of the remaining 7376 fetuses, 119 (1.61%, 119/7376) developed structural malformations, with 64 cases (53.8%, 64/119) identified during the first trimester. The remaining cases were detected during the second trimester (24.4%, 29/119), the third trimester (1.68%, 2/119), and postnatally (20.2%, 24/119). There were 4 cases of suspected ventricular septal defect (VSD) by FTS, which were later confirmed to be normal. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for FTS were 54.2%, 99.9%, 94.1%, and 99.3%, respectively. Forty eight fetuses, accounting for 10.6% of the total (452), with thickened nuchal translucency (NT) (above the 95th percentile) showed structural malformations. This was significantly higher than the prevalence of structural abnormalities found in fetuses with normal NT (1.0%, 71/6924) (p < 0.01). Conclusions: Standardized FTS is highly effective in detecting fetal structural malformations early, with impressive specificity, PPV, and NPV. Increased NT suggests detailed anatomy screening and helps guide treatment. However, while standardized FTS is an invaluable tool, it cannot fully replace the sensitivity of second- and third-trimester ultrasound screening. Clinical Trial Registration: The study was registered at https://www.chictr.org.cn (registration number ChiCTR-SOC-17010976).

Abstract Background Central sensitization is one of the characters of chronic migraine (CM). Aberrant synaptic plasticity can induce central sensitization. Oxytocin (OT), which is a hypothalamic hormone, plays an important antinociceptive role. However, the antinociceptive effect of OT and the underlying mechanism in CM remains unclear. Therefore, we explored the effect of OT on central sensitization in CM and its implying mechanism, focusing on synaptic plasticity. Methods A CM mouse model was established by repeated intraperitoneal injection of nitroglycerin (NTG). Von Frey filaments and radiant heat were used to measure the nociceptive threshold. Repeated intranasal OT and intraperitoneal L368,899, an oxytocin receptor (OTR) antagonist, were administered to investigate the effect of OT and the role of OTR. The expression of calcitonin gene-related peptide (CGRP) and c-fos were measured to assess central sensitization. N-methyl D-aspartate receptor subtype 2B (NR2B)-regulated synaptic-associated proteins and synaptic plasticity were explored by western blot (WB), transmission electron microscope (TEM), and Golgi-Cox staining. Results Our results showed that the OTR expression in the trigeminal nucleus caudalis (TNC) of CM mouse was significantly increased, and OTR was colocalized with the postsynaptic density protein 95 (PSD-95) in neurons. Repeated intranasal OT alleviated the NTG-induced hyperalgesia and prevented central sensitization in CM mouse. Additionally, the OT treatment inhibited the overexpression of phosphorylated NR2B and synaptic-associated proteins including PSD-95, synaptophysin-1 (syt-1), and synaptosomal-associated protein 25 (snap25) in the TNC of CM mouse and restored the abnormal synaptic structure. The protective effect of OT was prevented by L368,899. Furthermore, the expression of adenylyl cyclase 1 (AC1)/ protein kinase A (PKA)/ phosphorylation of cyclic adenosine monophosphate response element-binding protein (pCREB) pathway was depressed by OT and restored by L368,899. Conclusions Our findings demonstrate that repeated intranasal OT eliminates central sensitization by regulating synaptic plasticity via OTR in CM. The effect of OT has closely associated with the down-regulation of AC1/PKA/pCREB signaling pathway, which is activated in CM model. Repeated intranasal OT may be a potential candidate for CM prevention.

ABSTRACT With the demographic changes, more and more elderly people have chosen to spend their retirement life in a senior care facility. The elderly people in senior care facility are commonly suffering from various geriatric syndromes, including declined daily living activities, cognitive dysfunction, frailty, comorbidities, and polypharmacy, which make them vulnerable to adverse effects, like hypoglycemia and fall. Therefore, layered management is necessary for this population with group disparities. However, the staff in senior care facility vary greatly in concepts and skills on management of senile diabetic population, which needs urgently to be standardized and improved. For this purpose, based on literature review and panel discussion, 28 recommendations are proposed in respect of the standardized management of blood glucose, covering the comprehensive assessment, layered management and grouping, exercise, nutrition, glucose monitoring, identification and treatment of severe hyperglycemia, identification of macrovascular and microvascular complications, management of hypoglycemic drugs, falls and choking and other common problems, blood glucose screening, hypoglycemia prevention, and blood glucose management in major public health events or serious natural disasters. This guideline aims to standardize management skills of medical staff and caregivers in senior care facility for the blood glucose of elderly people and improve their quality of life.

AimsThe cost of drug regimens prescribed to Chinese patients has not been evaluated. This study aims to evaluate the medical costs and hypoglycemic agents for diabetes mellitus patients with or without chronic respiratory disease in Beijing, and to investigate the changes in the costs and number of antidiabetic medications used for diabetes patients with chronic respiratory disease from 2016 to 2018.MethodsThis observational, retrospective study included diabetes patients with outpatient medication records from Beijing Medical Insurance between 2016 and 2018. The medications, including hypoglycemic and nonhypoglycemic drugs, insulin dosage, comorbidities, diabetes-related complications, treatment strategies, and annual medical costs, were recorded.ResultsThis study included 2,853,036 diabetes patients from 2016 to 2018. About 18.95%–20.53% of patients with chronic respiratory disease were predominantly distributed among those aged 45–84 years (88.7%–89.1%). Diabetes patients with chronic respiratory disease used more medications (4.48 ± 2.41 vs. 3.76 ± 2.33) and had higher total annual drug costs (¥12,286 ± 10,385 vs. ¥9700 ± 9202) to treat more comorbidities (2.52 ± 1.53 vs. 2.05 ± 1.85) than those without chronic respiratory disease (p

ObjectiveTo study the effects of liraglutide or lifestyle interventions combined with other antidiabetic drugs on glucose metabolism and abdominal fat distribution in patients with obesity and type 2 diabetes mellitus (T2DM).MethodsFrom April 30, 2020, to April 30, 2022, a prospective randomized controlled study was carried out at the Endocrinology Department of Beijing Hospital, the National Center of Gerontology. According to the in- and exclusion criteria and by the random table method, revisited T2DM patients were selected as the research subjects and were allocated into a Study group (taking liraglutide) and a Control group (underwent lifestyle interventions). All patients received continuous 12-weeks interventions to the endpoint, and the changes of value [Δ=(endpoint)-(baseline)] of physical measurements, blood tests, the energy spectrum CT examination results, and body composition analysis results were analyzed and compared.ResultsA total of 85 people completed this study, and among them, 47 were in the Study group and 38 were in the Control group. Compared with the Control group, the changes of hemoglobin A1c (HbA1c) level (-0.78 ± 1.03% vs. -1.57 ± 2.00%, P=0.025), visceral fat area (0.91 ± 16.59 cm2 vs. -7.1 ± 10.17 cm2, P=0.011), and subcutaneous fat area of abdomen [0 (-18.75, 15.5) cm2 vs. -16.5 (-41.75, -2.25) cm2, P=0.014] were all greater in the Study group. The adverse events caused by liraglutide were mainly concentrated in the gastrointestinal system and all of them were minor adverse events.ConclusionLiraglutide can be the drug of choice for weight management and reduction of abdominal fat distribution in patients with obesity and T2DM.

Angioimmunoblastic T-cell lymphoma (AITL) genomic abnormalities are highly disease-specific, and the ras homology family member A (RHOA) gene is one of the most recurrent mutated genes, especially for RHOA G17V mutation site. Here, we identified a rare RHOA A161E mutation in an AITL patient through gene sequencing platforms. The patient presented with persistent hypereosinophilia, asymptomatic or symptomatic mildly for over 3 years. At diagnosis, this patient manifested night sweats, weight loss, multiple lymphadenopathies, and enlargement of the liver and spleen. We performed a retrospective genetic mutation analysis by whole-exome sequencing (WES) and droplet digital PCR (ddPCR) on serial gastric, intestinal, and lymph node specimens. The genetic mutation testing result demonstrated that a rare RHOA A161E mutation was found, which was elevated significantly on diagnosis related to AITL pathogenesis. Our case confirms that genetic mutation testing is helpful for diagnostic classification in AITL and dynamic monitoring of gene mutations at multiple time points may facilitate early detection of disease diagnosis.

ObjectiveThe study aimed to screen key genes in early diabetic kidney disease (DKD) and predict their biological functions and signaling pathways using bioinformatics analysis of gene chips interrelated to early DKD in the Gene Expression Omnibus database.MethodsGene chip data for early DKD was obtained from the Gene Expression Omnibus expression profile database. We analyzed differentially expressed genes (DEGs) between patients with early DKD and healthy controls using the R language. For the screened DEGs, we predicted the biological functions and relevant signaling pathways by enrichment analysis of Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Using the STRING database and Cytoscape software, we constructed a protein interaction network to screen hub pathogenic genes. Finally, we performed immunohistochemistry on kidney specimens from the Beijing Hospital to verify the above findings.ResultsA total of 267 differential genes were obtained using GSE142025, namely, 176 upregulated and 91 downregulated genes. GO functional annotation enrichment analysis indicated that the DEGs were mainly involved in immune inflammatory response and cytokine effects. KEGG pathway analysis indicated that C-C receptor interactions and the IL-17 signaling pathway are essential for early DKD. We identified FOS, EGR1, ATF3, and JUN as hub sites of protein interactions using a protein–protein interaction network and module analysis. We performed immunohistochemistry (IHC) on five samples of early DKD and three normal samples from the Beijing Hospital to label the proteins. This demonstrated that FOS, EGR1, ATF3, and JUN in the early DKD group were significantly downregulated.ConclusionThe four hub genes FOS, EGR1, ATF3, and JUN were strongly associated with the infiltration of monocytes, M2 macrophages, and T regulatory cells in early DKD samples. We revealed that the expression of immune response or inflammatory genes was suppressed in early DKD. Meanwhile, the FOS group of low-expression genes showed that the activated biological functions included mRNA methylation, insulin receptor binding, and protein kinase A binding. These genes and pathways may serve as potential targets for treating early DKD.

Research works on the synergistic effect of surface modified bioactive molecules and bone metal implants have been highlighted. N-cadherin is regarded as a key factor in directing cell–cell interactions during the mesenchymal condensation preceding the osteogenesis in the musculoskeletal system. In this study, the N-cadherin mimetic peptide (Cad) was biofunctionalized on the titanium metal surface via the acryloyl bisphosphonate (Ac-BP). To learn the synergistic effect of N-cadherin mimetic peptide, when tethered with titanium substrates, on promoting osteogenic differentiation of the seeded human mesenchymal stem cells (hMSCs) and the osseointegration at the bone-implant interfaces. Results show that the conjugation of N-cadherin mimetic peptide with Ac-BP promoted the osteogenic gene markers expression in the hMSCs. The biofunctionalized biomaterial surfaces promote the expression of the Wnt/β-catenin downstream axis in the attached hMSCs, and then enhance the in-situ bone formation and osseointegration at the bone-implant interfaces. We conclude that this N-cadherin mimetic peptide tethered on Ti surface promote osteogenic differentiation of hMSCs and osseointegration of biomaterial implants in vitro and in vivo. These findings demonstrate the importance of the development-inspired surface bioactivation of metal implants and shed light on the possible cellular mechanisms of the enhanced osseointegration.

Abstract Background To establish reference ranges of fetal facial profile markers and study their correlations with crown-rump length (CRL) during the first trimester (11 ~ 13+ 6 weeks’ gestation) in a Chinese population. Methods Ultrasonographic images of measuring fetal nuchal translucency (NT) were retrospectively selected randomly in normal fetuses whose parents were both Chinese. The facial markers included inferior facial angle (IFA), maxilla-nasion-mandible (MNM) angle, facial maxillary angle (FMA) and profile line (PL) distance. These markers were measured through ViewPoint 6 software by two experienced sonographers. Results Three hundred and eighty fetuses were selected. The ICCs (95 % CI) of intra-operator 1 reproducibility of IFA, MNM angle, FMA, PL distance were 0.944 (0.886 ~ 0.973), 0.804 (0.629 ~ 0.902), 0.834 (0.68 ~ 0.918) and 0.935 (0.868 ~ 0.969), respectively. The ICCs (95 % CI) of intra-operator 2 reproducibility of IFA, MNM angle, FMA, PL distance were 0.931 (0.857 ~ 0.967), 0.809 (0.637 ~ 0.904), 0.786 (0.600 ~ 0.892) and 0.906 (0.813 ~ 0.954), respectively. The ICCs (95 % CI) of inter-operator reproducibility of IFA, MNM angle, FMA, PL distance were 0.885 (0.663 ~ 0.953), 0.829 (0.672 ~ 0.915), 0.77 (0.511 ~ 0.891) and 0.844 (0.68 ~ 0.925), respectively. The average ± SD of IFA, MNM angle, FMA and PL distance were 80.2°±7.25°, 4.17°±1.19°, 75.36°±5.31°, 2.78 ± 0.54 mm, respectively. IFA and PL distance significantly decreased with CRL, while MNM angle and FMA significantly increased with CRL. Conclusions It was feasible to measure fetal facial markers during the first trimester. In Chinese population, the reference ranges of IFA, MNM angle, FMA and PL distance were 80.2°±7.25°, 4.17°±1.19°, 75.36°±5.31°, 2.78 ± 0.54 mm, respectively, and the measurements were found to correlate with CRL.

Background: Distraction osteogenesis (DO) is a functional tissue engineering approach that applies gradual mechanical traction on the bone tissues after osteotomy to stimulate bone regeneration. However, DO still has disadvantages that limit its clinical use, including long treatment duration Methods: Review the current methods of promoting bone formation and consolidation in DO with particular interest on biometal. Results: Numerous approaches, including physical therapy, gene therapy, growth factor-based therapy, stem-cell-based therapy, and improved distraction devices, have been explored to reduce the DO treatment duration with some success. Nevertheless, no approach to date is widely accepted in clinical practice due to various reasons, such as high expense, short biologic half-life, and lack of effective delivery methods. Biometals, including calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cu), manganese (Mn), and cobalt (Co) have attracted attention in bone regeneration attributed to their biodegradability and bioactive components released during in vivo degradation. Conclusion: This review summarizes the current therapies accelerating bone formation in DO and the beneficial role of biometals in bone regeneration, particularly focusing on the use of biometal Mg and its alloy in promoting bone formation in DO. Translational potential: The potential clinical applications using Mg-based devices to accelerate DO are promising. Mg stimulates expression of multiple intrinsic biological factors and the development of Mg as an implantable component in DO may be used to argument bone formation and consolidation in DO.

Abstract Microvascular anastomosis is a critical procedure in cerebral bypass surgeries. In some rare cases, the extraluminal interrupted technique is not optimal because the vessels are immobile and cannot be rotated, and anastomosis can be performed effectively through the intraluminal continuous suturing technique. The authors reported the application of the intraluminal continuous suturing technique in microanastomosis training with silicone tube, rat’s common iliac arteries and abdominal aorta. A silicone tube with a diameter of 1.5 mm was used to practice microanastomosis in intraluminal continuous suturing technique. Then the technique was applied in side-to-side, end-to-side anastomoses of common iliac arteries and the end-to-end abdominal aorta anastomoses of rat. The suturing time and patency rates were compared with an alternative intraluminal continuous suturing technique and one-way-up interrupted suturing technique in silicone tube and rat vessel anastomoses. The intraluminal continuous suturing technique could be gained through practicing with silicone tube, and the technique has also been demonstrated effective in side-to-side, end-to-side anastomoses of common iliac arteries of rat and the abdominal aorta end-to-end anastomoses. In all the animal experimental groups with different suturing techniques, there was no difference between the patency rates, all the immediate patency rate was 100%. There was no significant suturing time difference between the two intraluminal continuous suturing techniques, but the two intraluminal continuous suturing techniques were faster than the interrupted technique. The intraluminal continuous suturing technique described in the study could be used as an efficient method for side-to-side, end-to-side and end-to-end anastomosis, especially under the situation the posterior wall of the anastomosis could not be rotated. Proficiency of the technique could be achieved through practicing in laboratory with silicone tube and live animals.

This paper provides a multi-feedback feature selection fuzzy neural network (MFFSFNN) based on super-twisting sliding mode control (STSMC), aiming at compensating for current distortion and solving the harmonic current problem in an active power filter (APF) system. A feature selection layer is added to an output feedback neural network to attach the characteristics of signal filtering to the neural network. MFFSFNN, with the designed feedback loops and hidden layer, has the advantages of signal judging, filtering, and feedback. Signal filtering can choose valuable signals to deal with lumped uncertainties, and signal feedback can expand the learning dimension to improve the approximation accuracy. The STSMC, as a compensator with adaptive gains, helps to stabilize the compensation current. An experimental study is implemented to prove the effectiveness and superiority of the proposed controller.

Abstract Background Hypothermic machine perfusion (HMP) improves the quality of donor livers for transplantation, both in animal models and in clinical practice. Treatment with SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), can suppress the JNK signaling pathway to alleviate donor liver ischemia–reperfusion injury (IRI). We performed the present study with the objective of exploring the protective effects exerted by a combination of HMP and SP600125 on liver xenograft viability for donation after cardiac death (DCD) in a porcine model. Methods 54 adult BAMA mini-pigs were randomly assigned to 5 groups, including sham, cold storage for 4 h (CS 4 h), CS 4 h + SP600125, CS 2 h + HMP 2 h, and CS 2 h + HMP 2 h + SP600125 groups. Donor livers in the CS 4 h and CS 4 h + SP600125 groups were conventionally cold preserved for 4 h, whereas donor livers in the CS 2 h + HMP 2 h and CS 2 h + HMP 2 h + SP600125 groups were cold preserved for 2 h and then treated with HMP for 2 h. The preservation and perfusion solutions contained SP600125 (20 µM). Follow-up was conducted for 5 days after liver transplantation to compare the surgical outcomes by means of serological examination, pathological results, and survival rate. Results The most satisfactory outcome after liver transplantation was observed in the CS 2 h + HMP 2 h + SP600125 group, which presented with minimal damage of donor livers during 5 days’ follow-up. Additionally, serological examination, pathological results, and survival rate concurred in showing better results in the CS 2 h + HMP 2 h ± SP600125 group than in the CS 4 h ± SP600125 group. Conclusion HMP in combination with SP600125 has hepatoprotective properties and improves the quality and viability of porcine livers collected after DCD, thus improving prognosis after liver transplantation.

Abstract Background Paracrine signaling from endothelial progenitor cells (EPCs) is beneficial for angiogenesis and thus promotes tissue regeneration. Microgravity (MG) environment is found to facilitate the functional potentials of various stem or progenitor cells. The present study aimed to elucidate the effects of MG on pro-angiogenic properties and fracture repair capacities of conditioned media (CM) from EPCs. Methods Human peripheral blood-derived EPCs were cultured under MG or normal gravity (NG) followed by analysis for angiogenic gene expression. Furthermore, the serum-free CM under MG (MG-CM) or NG (NG-CM) were collected, and their pro-angiogenic properties were examined in human umbilical vein endothelial cells (HUVECs). In order to investigate the effects of MG-CM on fracture healing, they were injected into the fracture gaps of rat models, and radiography, histology, and mechanical test were performed to evaluate neovascularization and fracture healing outcomes. Results MG upregulated the expression of hypoxia-induced factor-1α (HIF-1α) and endothelial nitric oxide synthase (eNOS) and promoted NO release. Comparing to NG-CM, MG-CM significantly facilitated the proliferation, migration, and angiogenesis of HUVECs through NO-induced activation of FAK/Erk1/2-MAPK signaling pathway. In addition, MG-CM were verified to improve angiogenic activities in fracture area in a rat tibial fracture model, accelerate fracture healing, and well restore the biomechanical properties of fracture bone superior to NG-CM. Conclusion These findings provided insight into the use of MG bioreactor to enhance the angiogenic properties of EPCs’ paracrine signals via HIF-1α/eNOS/NO axis, and the administration of MG-CM favored bone fracture repair. Graphical abstract

Our study aimed to evaluate the exposure–response relationship between incretin-based medications and the risk of major adverse cardiovascular events (MACE) using cardiovascular outcome trials (CVOTs). Eleven CVOTs with incretin-based medications were included. The median follow-up time, percentage of time exposure, and hazard ratio (HR) of MACE were obtained from each CVOT. The pharmacokinetic parameters of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitor (DPP-4) were obtained from published studies. Regression analysis was performed to assess the relationship between drug exposure and MACE HR. Cutoff values were determined from the ROC curves. The linear regression results indicated that log Cmax, log AUC0–24h, and log AUCCVOT are negatively correlated with MACE HR (R2 = 0.8494, R2 = 0.8728, and R2 = 0.8372, respectively; all p < 0.0001). The relationship between drug exposure (log Cmax, log AUC0–24h, and log AUCCVOT) and MACE HR strongly corresponded with the log (inhibitor) vs. response curve (R2 = 0.8383, R2 = 0.8430, and R2 = 0.8229, respectively). The cutoff values in the ROC curves for log Cmax, log AUC0–24h, and log AUCCVOT, were 2.556, 3.868, and 6.947, respectively (all p = 0.007). A Fisher’s exact test revealed that these cutoff values were significantly related to cardiovascular benefits (all p < 0.05). Our study revealed a linear exposure–response relationship between drug exposure and MACE HR. We conclude that the cardiovascular benefits of incretin-based therapies may occur with higher doses of GLP-1 RAs and with increased exposure.