Identification of an 8 HPV-related RNA signature as a novel prognostic biomarker for squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck (SCCHN) is a commonly detected cancer worldwide. Human papillomavirus (HPV) is emerging as an important risk factor affecting SCCHN prognosis. Therefore, identification of HPV status is essential for effective therapies in SCCHN. The aim of this study was to investigate the prognostic value of HPV-associated RNA biomarkers for SCCHN. The clinical data, survival data, and RNA-seq data of SCCHN were downloaded from The Cancer Genome Atlas database. Before the differential expression analysis, the heterogeneity between the 2 groups (HPV+ vs HPV-) of samples was analyzed using principal component analysis. The differentially expressed genes (DEGs) between HPV+ and HPV- SCCHN samples were analyzed using the R edgeR package. The Gene Ontology functional annotations, including biological process, molecular function and cellular component (CC), and Kyoto Encyclopedia of Genes And Genomes pathways enriched by the DEGs were analyzed using DAVID. The obtained matrix was analyzed by weighed gene coexpression network analysis. A total of 350 significant DEGs were identified through differential analysis, and these DEGs were significantly enriched in functions associated with keratinization, and the pathway of neuroactive ligand-receptor interaction. Moreover, 72 hub genes were identified through weighed gene coexpression network analysis. After the hub genes and DEGs were combined, we obtained 422 union genes, including 65 survival-associated genes. After regression analysis, a HPV-related prognostic model was established, which consisted of 8 genes, including Clorf105, CGA, CHRNA2, CRIP3, CTAG2, ENPP6, NEFH, and RNF212. The obtained regression model could be expressed by an equation as follows: risk score = 0.065 × Clorf105 + 0.012 × CGA + 0.01 × CHRNA2 + 0.047 × CRIP3 + 0.043 × CTAG2-0.034 × ENPP6 - 0.003 × NEFH - 0.068 × RNF212. CGA interacted with 3 drugs, and CHRNA2 interacted with 11 drugs. We have identified an 8 HPV-RNA signature associated with the prognosis of SCCHN patients. Such prognostic model might serve as possible candidate biomarker and therapeutic target for SCCHN.

Lactulose vs Polyethylene Glycol for Bowel Preparation: A Single-Center, Prospective, Randomized Controlled Study Based on BMI.

INTRODUCTION: Colonoscopy is currently considered as one of the principal techniques to diagnose the colorectal diseases. Admittedly, qualified bowel preparation before colonoscopy is a premise for high-quality examination. Lower quality bowel preparation might seriously impede visualization of the intestinal mucosa, resulting in missed and misdiagnosed intestinal lesions. Therefore, it is necessary to choose the appropriate oral laxative based on the guarantee of safety and efficacy. METHODS: This prospective randomized controlled study was conducted to compare lactulose oral solution and polyethylene glycol (PEG) electrolyte powder for bowel preparation using the following indicators: Boston Bowel Preparation Scale, Bowel Bubble Score, detection rate of adenoma and lesion, patients' satisfaction, and adverse effects. Our study investigated the suitability of 2 bowel preparation reagents for patients with different body mass indices mainly based on body mass index (BMI). RESULTS: In the lactulose group, there was a significant improvement in the quality of bowel preparation compared with those in the PEG group ( P < 0.05), especially in people with normal BMI and higher BMI. Compared with the PEG group, individuals in the lactulose group had a significantly higher adenoma detection rate (50% vs 33.5%, P < 0.05) and taste scores (8.82 vs 6.69, P < 0.05), as well as significantly fewer adverse reactions (6.5% vs 32.5%, P < 0.05). DISCUSSION: Lactulose oral solution is superior to PEG in bowel preparation quality and taste, especially in normal BMI and higher BMI groups. It can be used clinically as a potential and promising bowel preparation agent in the future. Clinical Trial registration number: ChiCTR2100054318.

Effect of follicle-stimulating hormone and luteinizing hormone on apoptosis, autophagy, and the release and reception of some steroid hormones in yak granulosa cells through miR-23a/ASK1 axis.

Follicle-stimulating hormone (FSH), luteinizing hormone (LH), miR-23a, apoptosis signal-regulating kinase 1(ASK1)/c-Jun N-terminal kinase (JNK), autophagy and apoptosis play crucial roles in follicular development. However, their role in yak granulosa cells (GCs) remains unknown. Therefore, we examined the effect of miR-23a, ASK1, FSH, and LH on apoptosis, autophagy, and the release and reception of some steroid hormones in these cells. Our results showed that miR-23a overexpression significantly increased the abundance of Beclin1, the LC3II/I ratio, and the number of Ad-mRFP-GFP-LC3-labeled autophagosomes, and decreased p62 abundance. Additionally, Bax abundance and the number of terminal deoxynucleotidyl transferase deoxynucleotide triphosphate nick end labeling-positive cells were reduced, while Bcl2 expression was increased. Overexpression of miR-23a also significantly increased the abundance of estradiol receptor α (ER-α) and ß (ER-ß) and the concentrations of estradiol (E2), progesterone (P4) in yak GCs. Here, treating yak GCs with miR-23a decreased ASK1 expression, which regulates ASK1/JNK-mediated apoptosis, autophagy, E2 and P4 levels, and ER-α/ß abundance. In contrast, treatment of yak GCs with FSH (10 µg/mL) and LH (100 µg/mL) increased miR-23a abundance, regulating the subsequent effect on ASK1/JNK-mediated apoptosis, autophagy, ER-α/ß abundance, and E2 and P4 concentrations. In conclusion, miR-23a enhances autophagy in yak GCs, attenuates apoptosis, and increases ER-α/ß abundance and E2 and P4 concentrations by downregulating ASK1. Additionally, FSH and LH can regulate these effects of miR-23a by altering its expression. These results provide important insights that can inform the development of strategies to reduce abnormal follicular atresia and improve the reproductive rate of yaks.

Targeting NR1D1 in organ injury: challenges and prospects.

Nuclear receptor subfamily 1, group D, member 1 (NR1D1, also known as REV-ERBα) belongs to the nuclear receptor (NR) family, and is a heme-binding component of the circadian clock that consolidates circadian oscillators. In addition to repressing the transcription of multiple clock genes associated with circadian rhythms, NR1D1 has a wide range of downstream target genes that are intimately involved in many physiopathological processes, including autophagy, immunity, inflammation, metabolism and aging in multiple organs. This review focuses on the pivotal role of NR1D1 as a key transcription factor in the gene regulatory network, with particular emphasis on the milestones of the latest discoveries of NR1D1 ligands. NR1D1 is considered as a promising drug target for treating diverse diseases and may contribute to research on innovative biomarkers and therapeutic targets for organ injury-related diseases. Further research on NR1D1 ligands in prospective human trials may pave the way for their clinical application in many organ injury-related disorders.

Thermal, photonic, and electrocatalysis in lignin depolymerization research.

In order to realize a sustainable bio-based future, it is essential to fully harness the potential of biomass, including lignin - a readily available biopolymer that ranks second in abundance and serves as a renewable source of aromatics. While lignin has traditionally been used for lower-value applications like fuel and power generation, unlocking its higher-value potential through diverse conversion and upgrading techniques is of paramount importance. This review focuses on the catalytic conversion of lignin, with a specific emphasis on selective depolymerization, a process that not only supports economically and environmentally sustainable biorefineries but also aligns with Green Chemistry principles, mitigating adverse environmental impacts. Furthermore, we provide a comprehensive discussion of reaction pathways and mechanisms, including C-O and C-C bond cleavage, among different catalysts. Lastly, we analyze and briefly discuss the prospects of rational catalyst design in biomass valorization.

Secure and Privacy-Preserving Intrusion Detection and Prevention in the Internet of Unmanned Aerial Vehicles.

In smart cities, unmanned aerial vehicles (UAVS) play a vital role in surveillance, monitoring, and data collection. However, the widespread integration of UAVs brings forth a pressing concern: security and privacy vulnerabilities. This study introduces the SP-IoUAV (Secure and Privacy Preserving Intrusion Detection and Prevention for UAVS) model, tailored specifically for the Internet of UAVs ecosystem. The challenge lies in safeguarding UAV operations and ensuring data confidentiality. Our model employs cutting-edge techniques, including federated learning, differential privacy, and secure multi-party computation. These fortify data confidentiality and enhance intrusion detection accuracy. Central to our approach is the integration of deep neural networks (DNNs) like the convolutional neural network-long short-term memory (CNN-LSTM) network, enabling real-time anomaly detection and precise threat identification. This empowers UAVs to make immediate decisions in dynamic environments. To proactively counteract security breaches, we have implemented a real-time decision mechanism triggering alerts and initiating automatic blacklisting. Furthermore, multi-factor authentication (MFA) strengthens access security for the intrusion detection system (IDS) database. The SP-IoUAV model not only establishes a comprehensive machine framework for safeguarding UAV operations but also advocates for secure and privacy-preserving machine learning in UAVS. Our model's effectiveness is validated using the CIC-IDS2017 dataset, and the comparative analysis showcases its superiority over previous approaches like FCL-SBL, RF-RSCV, and RBFNNs, boasting exceptional levels of accuracy (99.98%), precision (99.93%), recall (99.92%), and F-Score (99.92%).

Design strategy and research progress of multifunctional nanoparticles in lung cancer therapy.

INTRODUCTION: Lung cancer is one of the cancer types with the highest mortality rate, exploring a more effective treatment modality that improves therapeutic efficacy while mitigating side effects is now an urgent requirement. Designing multifunctional nanoparticles can be used to overcome the limitations of drugs and conventional drug delivery systems. Nanotechnology has been widely researched, and through different needs, suitable nanocarriers can be selected to load anti-cancer drugs to improve the therapeutic effect. It is foreseeable that with the rapid development of nanotechnology, more and more lung cancer patients will benefit from nanotechnology. This paper reviews the merits of various multifunctional nanoparticles in the treatment of lung cancer to provide novel ideas for lung cancer treatment. AREAS COVERED: This review focuses on summarizing various nanoparticles for targeted lung cancer therapy and their advantages and disadvantages, using nanoparticles loaded with anti-cancer drugs, delivered to lung cancer sites, enhancing drug half-life, improving anti-cancer drug efficacy and reducing side effects. EXPERT OPINION: The delivery mode of nanoparticles with superior pharmacokinetic properties in the in vivo circulation enhances the half-life of the drug, and provides tissue-targeted selectivity and the ability to overcome biological barriers, bringing a revolution in the field of oncology.

NADPH oxidase 4 facilitates progression of chondrosarcoma via generation of reactive oxygen species.

Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is an enzyme that regulates reactive oxygen species (ROS) generation, and its function in the development of chondrosarcoma remains unclear. In the present study, we studied NOX4 expression in chondrosarcoma by immunochemical examination, and analyzed the role of NOX4 in viability and apoptosis of human chondrosarcoma cell line SW1353 using NOX4 siRNA or NOX4 inhibitor GKT137831. NOX4 level significantly increased in tumor compared to that in para-carcinoma sample. The levels of NOX4 were positively correlated with histological grade and Musculoskeletal Tumor Society stage of the patients. NOX4 level was significantly increased in SW1353 compared with that in chondrocytes CHON-001. Knockdown of NOX4 or inhibition of NOX4 by GKT137831 both decreased generation of ROS, and induced growth inhibition and apoptosis in SW1353, accompanied with the activation of caspases (caspase-3, caspase-8 and caspses-9), upregulation of Bax, cytochrome C(cyt-c), cleaved-PARP and down-regulation of Bcl-2. Moreover, NOX4 siRNA and GKT137831 decreased the expression of p-Akt, p-ERK and p-p65 in SW1353 cells. In an in vivo study, NOX4 shRNA transfected SW1353 have shown impaired growth ability compared to the SW1353 when they were injected into the nude mice. Meanwhile, GKT137831 induced growth inhibition and apoptosis in SW1353 xenograft animals, together with increased expression of Bax, cyt-c, cleaved-PARP, and decreased expression of Bcl-2, p-Akt, p-ERK and p-p65. NOX4 plays a positive role in the development of chondrosarcoma and could serve as a promising target against chondrosarcoma clinically.

Role of ELK1 in regulating colorectal cancer progression: miR-31-5p/CDIP1 axis in CRC pathogenesis.

Background and Objective: Colorectal cancer (CRC) is a malignant tumor that affects the digestive system. With the increased of modernization of society, the incidence of colorectal cancer has increased throughout the world. As a transcription factor, ELK1 has been widely studied in colorectal cancer. However, there are still many unknown factors regarding its specific mechanism of action.This study explored the role of ELK1 and its downstream pathway in CRC pathogenesis. Methods: Based on clinical samples, this study examined miR-31-5p expression in CRC cells and its impact on malignant behaviors (migration, invasion, apoptosis) and autophagy. The promoter sequence of miR-31-5p was obtained from the UCSC database, and ELK1 was identified as its transcription factor. In ELK1-knockdown CRC cells, miR-31-5p was overexpressed, and its response in malignant behaviors and autophagy was analyzed. The target gene CDIP1 was predicted and verified using a dual-luciferase assay. The influence of CDIP1 on malignant behavior in CRC cells was assessed, and CDIP1 siRNA was used as a rescue treatment for miR-31-5p inhibition. The role of ELK1/miR-31-5p in tumor growth was validated in vivo. Results: miR-31-5p expression was upregulated in the colorectal cancer tissues and cells. The knockdown of miR-31-5p markedly inhibited cancer cells' malignant behaviors and mediated autophagy. ELK1 was confirmed to bind with the miR-31-5p promoter and enhance miR-31-5p transcription. miR-31-5p was found to bind with the CDIP1 3'UTR and inhibit CDIP1 expression. CDIP1 siRNA partially rescued the effects of miR-31-5p knockdown on cell metastatic ability, autophagy, and apoptosis. Based on the in vivo experiments, results showed that the ELK1/miR-31-5p axis positively regulated tumor growth in nude mice. Conclusion: Our findings indicate that ELK1 regulates the progression of colorectal cancer via an miR-31-5p/CDIP1 axis, and the ELK1/miR-31-5p/CDIP1 axis could be a therapeutic target for colorectal cancer.

Synergistic effect of schizandrin A and DNase I knockdown on high glucose induced beta cell apoptosis by decreasing intracellular calcium concentration.

OBJECTIVE: To explore the synergistic effect of deoxyribonuclease I (DNase I) knockdown combined with Schizandrin A (Sch A) in protecting islet beta-cells (ß-cells) from apoptosis under high-glucose (HG) conditions. METHODS: The concentration of Sch A was detected by Cell Counting Kit-8 (CCK-8). High glucose-cultured rat insulinoma beta cell line (RIN-M5F) cells were treated with Sch A and transfected with DNase I small interfering RNA (siRNA). Cell apoptosis rate and apoptosis-related protein level were examined by flow cytometry and Western blot method respectively. In addition, Na-K-adenosine triphosphatease (Na-K-ATPase) and Ca-Mg-ATPase activity, cell membrane potential, and intracellular Ca concentration was also examined respectively. RESULTS: Our study revealed that HG stimulation can cause a significant increase in DNase I level and cell apoptosis rate. However, Sch A combined with DNase I knockdown can significantly decrease the cell apoptosis rate and apoptosis-related protein levels such as BAX ( 0.05) and Caspase-3 ( 0.01). In addition, we also found that the combination of Sch A and DNase I knockdown can dramatically increase cell membrane potential level, Na-K-ATPase, and Ca-Mg-ATPase activity. Meanwhile, intracellular Ca concentration was also found to be significantly decreased by the synergistic effect of Sch A and DNase I knockdown. CONCLUSION: Overall, our study reveals a synergistic effect of Sch A and DNase I knockdown in protecting ß-cells from HG-induced apoptosis.

Compound heterozygous variants in CFTR with potentially reducing ATP-binding ability identified in Chinese infertile brothers with isolated congenital bilateral absence of vas deferens.

BACKGROUND: Isolated congenital bilateral absence of vas deferens (iCBAVD) in men results in obstructive azoospermia and is mainly caused by pathogenic variants in cystic fibrosis transmembrane conductance regulator (CFTR) or adhesion G protein-coupled receptor G2 (ADGRG2). METHODS: The next-generation sequencing (NGS) was used to screen the mutations in the proband, and Sanger sequencings were performed to validate the compound heterozygous variant of CFTR in his family members. Protein structure simulation was performed to discover the potential pathological mechanism. RESULTS: This study reported novel compound heterozygous CFTR mutations (NM:000492.4, Intron: 5T; c.3965_3969dupTTGGG: p.R1325Gfs*5) in two brothers with obstructive azoospermia. The compound heterozygous CFTR mutations were first screened out by NGS in an infertile male patient who exhibited iCBAVD from a nonconsanguineous Chinese family. Histological analysis of the testicular biopsy from this patient revealed normal spermatogenesis and mature spermatozoa were observed in the seminiferous tubules. Surprisingly, the same compound heterozygous CFTR mutations were also observed in his brothers who also exhibited iCBAVD, with their parents being a heterozygous carrier for the mutations, as verified by Sanger sequencing. Protein structure simulation revealed that these mutations potentially led to impaired ATP-binding ability of CFTR. CONCLUSION: We identified novel compound heterozygous CFTR mutations in two brothers and summarized the literature regarding CFTR mutation and male infertility. Our study may contribute to the genetic diagnosis of iCBAVD and future genetic counseling.

Bone resorption and incretin hormones following glucose ingestion in healthy emerging adults.

Background: Studies in adults indicate that macronutrient ingestion yields an acute anti-resorptive effect on bone, reflected by decreases in C-terminal telopeptide (CTX), a biomarker of bone resorption, and that gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), facilitate this response. There remain knowledge gaps relating to other biomarkers of bone turnover, and whether gut-bone cross-talk is operative during the years surrounding peak bone strength attainment. This study first, describes changes in bone resorption during oral glucose tolerance testing (OGTT), and second, tests relationships between changes in incretins and bone biomarkers during OGTT and bone micro-structure. Methods: We conducted a cross-sectional study in 10 healthy emerging adults ages 18-25 years. During a multi-sample 2-hour 75 g OGTT, glucose, insulin, GIP, GLP-1, CTX, bone-specific alkaline phosphatase (BSAP), osteocalcin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-ß ligand (RANKL), sclerostin, and parathyroid hormone (PTH) were assayed at mins 0, 30, 60, and 120. Incremental areas under the curve (iAUC) were computed from mins 0-30 and mins 0-120. Tibia bone micro-structure was assessed using second generation high resolution peripheral quantitative computed tomography. Results: During OGTT, glucose, insulin, GIP, and GLP-1 increased significantly. CTX at min 30, 60, and 120 was significantly lower than min 0, with a maximum decrease of about 53 % by min 120. Glucose-iAUC0-30 inversely correlated with CTX-iAUC0-120 (rho = -0.91, P < 0.001), and GLP-1-iAUC0-30 positively correlated with BSAP-iAUC0-120 (rho = 0.83, P = 0.005), RANKL-iAUC0-120 (rho = 0.86, P = 0.007), and cortical volumetric bone mineral density (rho = 0.93, P < 0.001). Conclusions: Glucose ingestion yields an anti-resorptive effect on bone metabolism during the years surrounding peak bone strength. Cross-talk between the gut and bone during this pivotal life stage requires further attention.

Factors Affecting the Quality of Bowel Preparation Before Colonoscopy in Outpatient: A Prospective Observational Study.

Colonoscopy is an effective method for screening colorectal cancer and adenoma, but the adenoma detection rate depends on the quality of bowel preparation. Our study investigates the influencing factors of the quality of bowel preparation before colonoscopy in outpatients and the influence of the number of walking steps on the quality of bowel preparation. We prospectively collected the clinical data of 150 outpatients undergoing colonoscopy in our department in 2019. Ordinal logistic regression shows that the overweight, not drinking, the number of walking steps before colonoscopy, and the time interval between start PEG and colonoscopy (4-6 hours) were independent factors affecting bowel preparation quality. There was a curving relationship between the reciprocal of Ottawa score and the number of walking steps before colonoscopy, and the regression equation is 1/ Ottawa score = -0.198 + 0.062 × ln steps (p = .035), a minimum of 5,270 walking steps before a colonoscopy is required for a high quality of bowel preparation.

CTRP family in diseases associated with inflammation and metabolism: molecular mechanisms and clinical implication.

C1q/tumor necrosis factor (TNF) related proteins (CTRPs) is a newly discovered adipokine family with conservative structure and ubiquitous distribution and is secreted by adipose tissues. Recently, CTRPs have attracted increasing attention due to the its wide-ranging effects upon inflammation and metabolism. To-date, 15 members of CTRPs (CTRP1-15) with the characteristic C1q domain have been characterized. Earlier in-depth phenotypic analyses of mouse models of CTRPs deficiency have also unveiled ample function of CTRPs in inflammation and metabolism. This review focuses on the rise of CTRPs, with a special emphasis on the latest discoveries with regards to the effects of the CTRP family on inflammation and metabolism as well as related diseases. We first introduced the structure of characteristic domain and polymerization of CTRPs to reveal its pleiotropic biological functions. Next, intimate association of CTRP family with inflammation and metabolism, as well as the involvement of CTRPs as nodes in complex molecular networks, were elaborated. With expanding membership of CTRP family, the information presented here provides new perspectives for therapeutic strategies to improve inflammatory and metabolic abnormalities.

Long-term outcome of transcatheter repair of paravalvular leak post surgical mitral valve replacement / 中华心血管病杂志

Objective: To explore the long-term clinical efficacy of transcatheter repair of mitral paravalvular leak (PVL) post surgical mitral valve replacement. Methods: This study is a retrospective study. Patients who completed transcatheter repair of paravalvular leak after surgical mitral valve replacement at Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine from March 2010 to December 2018 were included. Technical success was defined as the occluder being stably implanted in the paravalvular leak site without affecting the function of the mitral valve and surrounding tissues; and there were no intervention-related complications, such as new hemolysis or aggravated hemolysis, and echocardiography confirmed mitral paravalvular regurgitation reduced by more than 1 grade. Patients were followed up at 30 days, 1, and 3 years after the intervention. The main endpoints were all-cause death and re-surgery due to interventional failure or serious complications. The occurrence of occluder-mediated hemolysis and chronic renal insufficiency was recorded, and patients were monitored with echocardiography during follow up. Results: A total of 75 patients were included, aged (54.3±22.9) years old, and 38 patients were males. All patients had decreased cardiac function and/or hemolysis before intervention. Procedural success was achieved in 54 patients (72.0%). Incidence of device-mediated hemolysis was 18.7% (14/75). During the follow-up period, all-cause death occurred in 7 patients (9.3%), and 3 were cardiac deaths.The 3-year event-free survival rate was 81.3% (61/75). The need for cardiac surgery was 9.3% (7/75): 3 cases due to severe device-mediated hemolysis, 2 cases due to prosthetic valve failure and 2 cases due to moderate to severe residual regurgitation. The echocardiography follow-up results showed that the position of the occluder was stable, there was no impact on the artificial valve function and surrounding structures, and the residual regurgitation was stable without progressive increase in event-free patients. Compared with pre-intervention, the left ventricular end systolic diameter ((33.9±7.4)mm vs. (38.3±8.9) mm, P=0.036), end diastolic diameter ((53.7±8.3) mm vs. (58.4±9.1) mm, P=0.045) and left atrial diameter (59.3 (44.5, 90.7) mm vs. 64.3 (44.8, 96.6) mm, P=0.049) were significantly reduced, pulmonary artery systolic pressure was also significantly decreased ((36.5±15.8) mmHg vs. (46.3±14.9) mmHg, P=0.022, 1 mmHg=0.133 kPa). There was no significant difference between 3 years and 1 year after transcatheter repair of mitral paravalvular leak post surgical mitral valve replacement (all P>0.05). Conclusion: Transcatheter repair of mitral paravalvular leak post surgical mitral valve replacement is an effective treatment option in selective patients.

Chinese expert consensus on the diagnosis and treatment of osteoporotic periarticular fracture of the shoulder in the elderly (version 2023) / 中华创伤杂志

Periarticular fracture of the shoulder is a common type of fractures in the elderly. Postoperative adverse events such as internal fixation failure, humeral head ischemic necrosis and upper limb dysfunction occur frequently, which seriously endangers the exercise and health of the elderly. Compared with the fracture with normal bone mass, the osteoporotic periarticular fracture of the shoulder is complicated with slow healing and poor rehabilitation, so the clinical management becomes more difficult. At present, there is no targeted guideline or consensus for this type of fracture in China. In such context, experts from Youth Osteoporosis Group of Chinese Orthopedic Association, Orthopedic Expert Committee of Geriatrics Branch of Chinese Association of Gerontology and Geriatrics, Osteoporosis Group of Youth Committee of Chinese Association of Orthopedic Surgeons and Osteoporosis Committee of Shanghai Association of Chinese Integrative Medicine developed the Chinese expert consensus on the diagnosis and treatment of osteoporotic periarticular fracture of the shoulder in the elderly ( version 2023). Nine recommendations were put forward from the aspects of diagnosis, treatment strategies and rehabilitation of osteoporotic periarticular fracture of the shoulder, hoping to promote the standardized, systematic and personalized diagnosis and treatment concept and improve functional outcomes and quality of life in elderly patients with osteoporotic periarticular fracture of the shoulder.

Application of bedside ultrasound in the evaluation of volume responsiveness in patients with septic shock / 中国医师杂志

Objective:To evaluate the value of bedside ultrasound in evaluating volume responsiveness of patients with septic shock.Methods:A total of 102 patients with septic shock admitted to ICU of the First Affiliated Hospital of Hebei North University from April 2018 to February 2021 were selected. Patients were divided into response group and non-response group according to the value of stroke volume increase (ΔSV) after volume loading test (VE), and the hemodynamic parameters before and after VE were compared between the two groups. Pearson correlation was used to analyze the relationship between ΔSV and hemodynamic indexes. Receiver operating characteristic (ROC) curve was drawn to analyze the sensitivity and specificity of each hemodynamic index in evaluating volumetric reactivity in patients with septic shock.Results:Of the 102 patients, 54 responded and 48 did not. Before VE, the distensibility index of inferior vena cava (ΔIVC 1), espiratory variability index of inferior vena cava (ΔIVC 2), respiratory variability of aortic peak velocity (ΔVpeak AO), brachial artery maximum velocity variability (ΔVpeak BA) and respiratory rate of peak flow velocity of femoral artery (ΔVpeak CFA) in response group were higher than those in non-response group (all P<0.05), but there was no statistical significance in heart rate (HR), mean arterial pressure (MAP) and central venous pressure (CVP) between 2 groups (all P>0.05). After VE, the HR, ΔIVC 1, ΔIVC 2, ΔVpeak AO, ΔVpeak BA and ΔVpeak CFA in response group were significantly decreased, while MAP and CVP were significantly increased (all P<0.05). The CVP was significantly decreased in the non-response group ( P<0.05), while other indexes were not significantly changed. Before VE, the ΔIVC 1, ΔIVC 2, ΔVpeak AO, ΔVpeak BA and ΔVpeak CFA were positively correlated with ΔSV ( r=0.589, 0.647, 0.697, 0.621, 0.766; all P<0.05). There was no correlation between CVP and ΔSV ( r=-0.345, P>0.05). Before VE, the area under the curve of ΔIVC 1, ΔIVC 2, ΔVpeak AO, ΔVpeak BA and ΔVpeak CFA were all >0.7, indicating high sensitivity and specificity. Conclusions:Bedside ultrasound monitoring ΔIVC, ΔVpeak AO, ΔVpeak BA and ΔVpeak CFA can better evaluate the volume response of patients with septic shock, and can provide a reference basis for clinical fluid resuscitation treatment.

Construction and evaluation of a prognostic model for severe acute pancreatitis based on CT scores and inflammatory factors / 中华危重病急救医学

Objective:To construct a prognostic model for severe acute pancreatitis (SAP) based on CT scores and inflammatory factors, and to evaluate its efficacy.Methods:128 patients with SAP diagnosed admitted to the First Hospital Affiliated to Hebei North College from March 2019 to December 2021 were enrolled and given Ulinastatin combined with continuous blood purification therapy. The levels of C-reactive protein (CRP), procalcitonin (PCT), interleukins (IL-6, IL-8), tumor necrosis factor-α (TNF-α), and D-dimer were measured before and on the third day of treatment. An abdominal CT was performed on the third day of treatment to assess the modified CT severity index (MCTSI) and extra-pancreatic inflammatory CT score (EPIC). Patients were divided into the survival group ( n = 94) and the death group ( n = 34) according to the 28-day survival prognosis after admission. The risk factors for the SAP prognosis were analyzed using Logistic regression, which was then used to build nomogram regression models. The value of the model was evaluated using the concordance index (C-index), calibration curves and decision curve analysis (DCA). Results:Before treatment, the levels of CRP, PCT, IL-6, IL-8 and D-dimer in the death group were higher than those in the survival group. After treatment, the levels of IL-6, IL-8 and TNF-α in the death group were higher than those in the survival group. MCTSI and EPIC scores in the survival group were lower than those in the death group. Logistic regression analysis shows that, pre-treatment CRP > 140.70 mg/L, D-dimer > 2.00 mg/L, and post-treatment IL-6 > 31.28 ng/L, IL-8 > 31.04 ng/L, TNF-α > 31.04 ng/L, and MCTSI > 8 points were all independent risk factors for SAP prognosis [odds ratios ( OR) and 95% confidence intervals (95% CI) were 8.939 (1.792-44.575), 6.369 (1.368-29.640), 8.546 (1.664-43.896), 5.239 (1.108-24.769), 4.808 (1.126-20.525), 18.569 (3.931-87.725), all P < 0.05]. Model 1 (consisting of pre-treatment CRP, D-dimer, and post-treatment IL-6, IL-8 and TNF-α) had a lower C-index than that model 2 (consisting of pre-treatment CRP, D-dimer, and post-treatment IL-6, IL-8 and TNF-α, and MCTSI; 0.988 vs. 0.995). The mean absolute error (MAE) and mean square error (MSE) of model 1 (0.034, 0.003) were higher than those of model 2 (0.017, 0.001). When the threshold probability was in the range of 0-0.66 or 0.72-1.00, the net benefit of model 1 was lower than that of model 2. When the threshold probability was in the range of 0.66-0.72, the net benefit of model 1 was higher than that of model 2. In addition, model 2 had a higher C-index than acute physiology and chronic health evaluationⅡ (APACHE Ⅱ) and bedside index of acute pancreatitis severity (BISAP, 0.995 vs. 0.833, 0.751). Model 2 had a lower MAE (0.017) and MSE (0.001) than APACHEⅡ (0.041, 0.002). Model 2 had a lower MAE than BISAP (0.025). Model 2 had a higher net benefit than both APACHEⅡ and BISAP. Conclusion:The prognostic assessment model of SAP consisting of pre-treatment CRP, D-dimer, and post-treatment IL-6, IL-8 and TNF-α, and MCTSI has high discrimination, precision and clinical application value, and is superior to APACHEⅡ and BISAP.

First-in-class small molecule drugs in 2022 / 药学学报

2022 is the third year of the global COVID-19 pandemic, and its troubles on new drug discovery are gradually apparent. 37 new drugs were approved by the FDA's Center for Drug Evaluation and Research (CDER) last year, down from the peak of 50 new drug approvals in 2021. Notably, first-in-class drugs still occupy a dominant position this year, with a total of 21 drugs. Among them, 7 are first-in-class small molecule drugs. Although the total number of new drug approvals in 2022 sharply decreased, some first-in-class small molecule drugs were regarded as significant, including mitapivat, the first oral activator targeting the pyruvate kinase (PK); mavacamten, the first selective allosteric inhibitor targeting the myocardial β myosin ATPase; deucravacitinib, the first deuterated allosteric inhibitor targeting the tyrosine kinase 2 (TYK2); and lenacapavir, the first long-acting inhibitor targeting the HIV capsid. Generally, the research of first-in-class drugs needs to focus on difficult clinical problems and can treat some specific diseases through novel targets and biological mechanisms. There are tremendous challenges in the research processes of new drugs, including biological mechanism research, target selection, molecular screening, lead compound identification and druggability optimization. Therefore, the success of first-in-class drugs development has prominent guidance significance for new drug discovery. This review briefly describes the discovery background, research and development process and therapeutic application of 3 first-in-class small molecule drugs to provide research ideas and methods for more first-in-class drugs.