Recent advances in the development of tumor microenvironment-activatable nanomotors for deep tumor penetration.

Cancer represents a significant threat to human health, with the use of traditional chemotherapy drugs being limited by their harsh side effects. Tumor-targeted nanocarriers have emerged as a promising solution to this problem, as they can deliver drugs directly to the tumor site, improving drug effectiveness and reducing adverse effects. However, the efficacy of most nanomedicines is hindered by poor penetration into solid tumors. Nanomotors, capable of converting various forms of energy into mechanical energy for self-propelled movement, offer a potential solution for enhancing drug delivery to deep tumor regions. External force-driven nanomotors, such as those powered by magnetic fields or ultrasound, provide precise control but often necessitate bulky and costly external equipment. Bio-driven nanomotors, propelled by sperm, macrophages, or bacteria, utilize biological molecules for self-propulsion and are well-suited to the physiological environment. However, they are constrained by limited lifespan, inadequate speed, and potential immune responses. To address these issues, nanomotors have been engineered to propel themselves forward by catalyzing intrinsic "fuel" in the tumor microenvironment. This mechanism facilitates their penetration through biological barriers, allowing them to reach deep tumor regions for targeted drug delivery. In this regard, this article provides a review of tumor microenvironment-activatable nanomotors (fueled by hydrogen peroxide, urea, arginine), and discusses their prospects and challenges in clinical translation, aiming to offer new insights for safe, efficient, and precise treatment in cancer therapy.

Decoding the Qu-aroma of medium-temperature Daqu starter by volatilomics, aroma recombination, omission studies and sensory analysis.

Qu-aroma is of great significance for evaluation the quality of Daqu starter. This study aimed to decode the Qu-aroma of medium-temperature Daqu (MT-Daqu) via "top-down" and "bottom-up" approaches. Firstly, 52 aroma descriptors were defined to describe the MT-Daqu aroma by quantitative descriptive analysis. Secondly, 193 volatile organic compounds (VOCs) were identified from 42 MT-Daqu samples by HS-SPME-GC-MS, and 43 dominant VOCs were screened out by frequence of occurrence or abundance. By Thin Film (TF)-SPME-GC-O-MS, 27 odors and 90 VOCs were detected in MT-Daqu mixture, and 14 odor-active VOCs were screened out by odor intensity. Thirdly, a five-level MT-Daqu aroma wheel was constructed by matching 52 aroma descriptors and 37 aroma-active VOCs. Finally, Qu-aroma of MT-Daqu was reconstructed with 37 aroma-active VOCs and evaluated by omission experiments. Hereinto, 26 key aroma-active VOCs were determined by OAV value ≥1, including isovaleric acid, 1-hexanol, isovaleraldehyde, 2-octanone, trimethylpyrazine, γ-nonalactone, 4-vinylguaiacol, etc.

Causal relationship between immune cells and atrial fibrillation: A Mendelian randomization study.

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia, with recent research indicating a correlation between immune system characteristics and the development of AF. However, it remains uncertain whether the immunological response is the primary underlying component or a secondary consequence of AF. Initially, we investigated the effect of immune cells on AF by performing forward Mendelian randomization (MR) analyses with immune cells as the exposure variable and their associated genetic variants as instrumental variables. Subsequently, we performed reverse MR analyses with AF as the exposure variable and immune cells as the outcome variable to exclude the interference of reverse causality, to distinguish between primary and secondary effects, and to further elucidate the causal relationship between the immune system and AF. We discovered that membrane proteins on specific immune cells, such as CD25 on memory B cells-which functions as a part of the interleukin-2 receptor-may be risk factors for AF development, with odds ratios of 1.0233 (95% confidence interval: 1.0012-1.0458, P = .0383). In addition, certain immune cell counts, such as the CD4 regulatory T cell Absolute Count, play a protective factor in the development of AF (odds ratio: 0.9513, 95% confidence interval: 0.9165-0.9874; P = .0086). More detailed results are elaborated in the main text. Our MR study has yielded evidence that substantiates a genetically inferred causal association between the immune system and AF. Identifying the risk factors associated with AF is vital to facilitate the development of innovative pharmaceutical treatments.

Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins.

Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI-H1975 cells, and NCI-H1975-TM cells (IC50 = 0.009 µM, 0.49 µM and 3.24 µM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50 = 17.93 nM, 0.25 µM and 0.63 µM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.

Associations between genomic aberrations, increased nuchal translucency, and pregnancy outcomes: a comprehensive analysis of 2,272 singleton pregnancies in women under 35.

Objectives: Regarding increased nuchal translucency (NT), the cutoff values used are heterogeneous in clinical practice, this study aims to assess the efficacy of prenatal detection for chromosomal abnormalities and pregnancy outcomes in fetuses with varying NT thicknesses, in order to provide data that supports informed prenatal diagnosis and genetic counseling for such cases. Methods: We included 2,272 pregnant women under 35 with singleton pregnancies who underwent invasive prenatal diagnosis between 2014 and 2022. The cohort comprised 2,010 fetuses with increased NT (≥2.5 mm) and 262 fetuses with normal NT but exhibiting a single soft marker. Prenatal diagnoses were supported by chromosomal microarray (CMA) and copy number variation sequencing (CNV-seq) analyses. Results: The detection rates of numerical chromosomal abnormalities were 15.4% (309/2,010) and 17.3% (297/1,717) in the NT ≥2.5 and ≥ 3.0 groups, respectively. Pathogenic/likely pathogenic CNV incidence increased with NT thickness (χ2 = 8.60, p < 0.05), peaking at 8.7% (22/254) in the NT 4.5-5.4 mm group. Structural defects were found in 18.4% of fetuses with NT values between 2.5 mm and 2.9 mm. Chromosomal abnormality rates in the isolated increased NT groups of 2.5-2.9 mm and 3.0-3.4 mm were 6.7% (16/239) and 10.0% (47/470), respectively, with no statistical significance (χ2 = 2.14, p > 0.05). Fetuses with NT thickness between 2.5 and 2.9 mm combined with the presence of soft markers or non-lethal structural abnormalities exhibited a significantly higher chromosomal abnormality risk (19.0%) compared to fetuses with isolated increased NT ranging from 3.5 to 4.4 mm (13.0%). Pregnancy termination rates increased with NT thickness (χ2 = 435.18, p < 0.0001), ranging from 12.0% (30/249) in the NT 2.5-2.9 mm group to 87.0% (141/162) in the NT ≥ 6.5 mm group. Conclusion: CMA or CNV-seq exhibited good performance in identifying genomic aberrations in pregnancies with increased NT thickness. NT ranging from 2.5 mm to 2.9 mm elevated the risk of fetal chromosomal abnormalities, particularly when combined with other soft markers.

Clinical performance of metagenomic next-generation sequencing for diagnosis of pulmonary Aspergillus infection and colonization.

Background: Investigations assessing the value of metagenomic next-generation sequencing (mNGS) for distinguish Aspergillus infection from colonization are currently insufficient. Methods: The performance of mNGS in distinguishing Aspergillus infection from colonization, along with the differences in patients' characteristics, antibiotic adjustment, and lung microbiota, were analyzed. Results: The abundance of Aspergillus significantly differed between patients with Aspergillus infection (n=36) and colonization (n=32) (P < 0.0001). Receiver operating characteristic (ROC) curve result for bronchoalveolar lavage fluid (BALF) mNGS indicated an area under the curve of 0.894 (95%CI: 0.811-0.976), with an optimal threshold value of 23 for discriminating between Aspergillus infection and colonization. The infection group exhibited a higher proportion of antibiotic adjustments in comparison to the colonization group (50% vs. 12.5%, P = 0.001), with antibiotic escalation being more dominant. Age, length of hospital stay, hemoglobin, cough and chest distress were significantly positively correlated with Aspergillus infection. The abundance of A. fumigatus and Epstein-Barr virus (EBV) significantly increased in the infection group, whereas the colonization group exhibited higher abundance of A. niger. Conclusion: BALF mNGS is a valuable tool for differentiating between colonization and infection of Aspergillus. Variations in patients' age, length of hospital stay, hemoglobin, cough and chest distress are observable between patients with Aspergillus infection and colonization.

Eugenol Inhibits Ox-LDL-Induced Proliferation and Migration of Human Vascular Smooth Muscle Cells by Inhibiting the Ang II/MFG-E8/MCP-1 Signaling Cascade.

Objective: In this study, we investigated the effect and mechanism of action of eugenol on oxidized low-density lipoprotein (ox-LDL)-induced abnormal proliferation and migration of human vascular smooth muscle cells (HVSMCs). Methods: HVSMCs were treated with 100 ug/mL ox-LDL for 24 hours to establish a cell model. After 1-hour pretreatment, eugenol at concentrations of 5, 25, and 50 uM was added. Cell viability was assessed using an MTT assay, PCNA expression was detected using Western blot, cell cycle distribution was analyzed using flow cytometry, and cell migration ability was evaluated using wound healing and Transwell migration assays. To investigate the mechanisms, Ang II receptors were inhibited by 1000 nM valsartan, MFG-E8 was knocked down by shRNA, MCP-1 was inhibited by siRNA, and MFG-E8 was overexpressed using plasmids. Results: The findings from this study elucidated the stimulatory impact of ox-LDL on the proliferation and functionality of HVSMCs. Different concentrations of eugenol effectively mitigated the enhanced activity of HVSMCs induced by ox-LDL, with 50 uM eugenol exhibiting the most pronounced inhibitory effect. Flow cytometry and Western blot results showed ox-LDL reduced G1 phase cells and increased PCNA expression, while 50 uM eugenol inhibited ox-LDL-induced HVSMC proliferation. In wound healing and Transwell migration experiments, the ox-LDL group showed larger cell scratch filling and migration than the control group, both of which were inhibited by 50 uM eugenol. Inhibiting the Ang II/MFG-E8/MCP-1 signaling cascade mimicked eugenol's effects, while MFG-E8 overexpression reversed eugenol's inhibitory effect. Conclusion: Eugenol can inhibit the proliferation and migration of ox-LDL-induced HVSMCs by inhibiting Ang II/MFG-E8/MCP-1 signaling cascade, making it a potential therapeutic drug for atherosclerosis.

Improved Biocompatibility and Angiogenesis of the Bone Titanium Scaffold through ERK1/2 Signaling Mediated by an Attached Strontium Element.

The promotion of early osseointegration is crucial for the success of biomedical titanium implants. Physical and chemical modifications to the material surface can significantly compensate for the lack of biocompatibility and early osseointegration of the implant. In this study, we implanted strontium onto titanium plates and analyzed the effect of strontium-doped materials on angiogenesis and biocompatibility in the human bone structure. Our findings demonstrated that strontium-loaded titanium sheet materials effectively promote human umbilical vein endothelial cell (HUVEC) biocompatibility and vascular differentiation ability, as evidenced by proliferation-apoptosis assays, RT-qPCR for vascular neogenesis markers, ELISA for vascular endothelial growth factor (VEGF) levels, and nitric oxide (NO) analysis. Mechanism studies based on RNAseq and Western blotting analysis revealed that strontium can promote titanium material biocompatibility with HUVEC cells and vascular neovascularization ability by activating the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Meanwhile, blocking the ERK1/2 signaling pathway could reverse the promotional effect of vascular formation. Overall, we have successfully fabricated a multifunctional biocompatible bone implant with better histocompatibility and angiogenesis compared to uncoated implants.

REDH: A database of RNA editome in hematopoietic differentiation and malignancy.

BACKGROUND: The conversion of adenosine (A) to inosine (I) through deamination is the prevailing form of RNA editing, impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species. Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases, providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets. However, the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking. METHODS: We downloaded RNA sequencing (RNA-seq) data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used. We performed sequence alignment, identified RNA editing sites, and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases. RESULTS: We established a new database, "REDH", represents RNA editome in hematopoietic differentiation and malignancy. REDH is a curated database of associations between RNA editome and hematopoiesis. REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts (human). Through the Differentiation, Disease, Enrichment, and knowledge modules, each A-to-I editing site is systematically integrated, including its distribution throughout the genome, its clinical information (human sample), and functional editing sites under physiological and pathological conditions. Furthermore, REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control. CONCLUSIONS: REDH is accessible at http://www.redhdatabase.com/ . This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies. It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.

Comprehensive review on gene mutations contributing to dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is one of the most common primary myocardial diseases. However, to this day, it remains an enigmatic cardiovascular disease (CVD) characterized by ventricular dilatation, which leads to myocardial contractile dysfunction. It is the most common cause of chronic congestive heart failure and the most frequent indication for heart transplantation in young individuals. Genetics and various other factors play significant roles in the progression of dilated cardiomyopathy, and variants in more than 50 genes have been associated with the disease. However, the etiology of a large number of cases remains elusive. Numerous studies have been conducted on the genetic causes of dilated cardiomyopathy. These genetic studies suggest that mutations in genes for fibronectin, cytoskeletal proteins, and myosin in cardiomyocytes play a key role in the development of DCM. In this review, we provide a comprehensive description of the genetic basis, mechanisms, and research advances in genes that have been strongly associated with DCM based on evidence-based medicine. We also emphasize the important role of gene sequencing in therapy for potential early diagnosis and improved clinical management of DCM.

ADAR1 links R-loop homeostasis to ATR activation in replication stress response.

Unscheduled R-loops are a major source of replication stress and DNA damage. R-loop-induced replication defects are sensed and suppressed by ATR kinase, whereas it is not known whether R-loop itself is actively involved in ATR activation and, if so, how this is achieved. Here, we report that the nuclear form of RNA-editing enzyme ADAR1 promotes ATR activation and resolves genome-wide R-loops, a process that requires its double-stranded RNA-binding domains. Mechanistically, ADAR1 interacts with TOPBP1 and facilitates its loading on perturbed replication forks by enhancing the association of TOPBP1 with RAD9 of the 9-1-1 complex. When replication is inhibited, DNA-RNA hybrid competes with TOPBP1 for ADAR1 binding to promote the translocation of ADAR1 from damaged fork to accumulate at R-loop region. There, ADAR1 recruits RNA helicases DHX9 and DDX21 to unwind R-loops, simultaneously allowing TOPBP1 to stimulate ATR more efficiently. Collectively, we propose that the tempo-spatially regulated assembly of ADAR1-nucleated protein complexes link R-loop clearance and ATR activation, while R-loops crosstalk with blocked replication forks by transposing ADAR1 to finetune ATR activity and safeguard the genome.

MicroRNA-338-3p helps regulate ovarian function by affecting granulosa cell function and early follicular development.

BACKGROUND: Follicular development in mammalian ovaries is a complex and dynamic process, and the interactions and regulatory-feedback loop between the follicular microenvironment, granulosa cells (GCs), and oocytes can affect follicular development and normal ovary functions. Abnormalities in any part of the process may cause abnormal follicular development, resulting in infertility. Hence, exploring the pathogenesis of abnormal follicular development is extremely important for diagnosing and treating infertile women. METHODS: RNA sequencing was performed with ovarian cortical tissues established in vitro. In situ-hybridization assays were performed to study microRNA-338-3p (miR-338-3p) expressed in GCs and oocytes. In vitro culture models were established with GCs and neonatal mouse ovaries to study the biological effects of miR-338-3p. We also performed in vivo experiments by injecting adeno-associated virus vectors that drive miR-338-3p overexpression into the mouse ovarian bursae. RESULTS: Sequencing analysis showed that miR-338-3p was expressed at significantly higher levels in ovarian cortical tissues derived from patients with ovarian insufficiency than in cortical tissues derived from patients with normal ovarian function; miR-338-3p was also significantly highly expressed in the GCs of patients with diminished ovarian reserve (P < 0.05). In situ-hybridization assays revealed that miR-338-3p was expressed in the cytoplasm of GCs and oocytes. Using in vitro culture models of granulosa cells, we found that miR-338-3p overexpression significantly suppressed the proliferation and oestradiol-production capacity of GCs (P < 0.05). In vitro culture models of neonatal mouse ovaries indicated that miR-338-3p overexpression suppressed the early follicular development in mouse ovaries. Further analysis revealed that miR-338-3p might be involved in transforming growth factor ß-dependent regulation of granulosa cell proliferation and, thus, early follicular development. Injecting miR-338-3p-overexpression vectors into the mouse ovarian bursae showed that miR-338-3p down-regulated the oocyte mitochondrial membrane potential in mice and disrupted mouse oestrous cycles. CONCLUSION: miR-338-3p can affect early follicular development and normal ovary functions by interfering with the proliferation and oestradiol production of GCs. We systematically elucidated the regulatory effect of miR-338-3p on follicular development and the underlying mechanism, which can inspire new studies on the diagnosis and treatment of diseases associated with follicular development abnormalities.

Molecular mechanisms of endothelial dysfunction in coronary microcirculation dysfunction.

Coronary microvascular endothelial cells (CMECs) react to changes in coronary blood flow and myocardial metabolites and regulate coronary blood flow by balancing vasoconstrictors-such as endothelin-1-and the vessel dilators prostaglandin, nitric oxide, and endothelium-dependent hyperpolarizing factor. Coronary microvascular endothelial cell dysfunction is caused by several cardiovascular risk factors and chronic rheumatic diseases that impact CMEC blood flow regulation, resulting in coronary microcirculation dysfunction (CMD). The mechanisms of CMEC dysfunction are not fully understood. However, the following could be important mechanisms: the overexpression and activation of nicotinamide adenine dinucleotide phosphate oxidase (Nox), and mineralocorticoid receptors; the involvement of reactive oxygen species (ROS) caused by a decreased expression of sirtuins (SIRT3/SIRT1); forkhead box O3; and a decreased SKCA/IKCA expression in the endothelium-dependent hyperpolarizing factor electrical signal pathway. In addition, p66Shc is an adapter protein that promotes oxidative stress; although there are no studies on its involvement with cardiac microvessels, it is possible it plays an important role in CMD.

Early surgical outcomes and influencing factors of high tibial osteotomy.

Objective: To investigate the influencing factors of functional recovery after high tibial osteotomy (HTO). Methods: A retrospective research was carried on 98 patients who underwent HTO between January 2018 and December 2020. In each case, the medial proximal tibial angle (MPTA), joint line convergence angle (JLCA), femoral tibial angle (FTA), hip-knee-ankle (HKA), weight bearing line (WBL) ratio of the knee joint, opening gap, opening angle, American knee society knee score (KSS), US Hospital for Special Surgery (HSS) score, Lysholm score, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were measured to determine postoperative function and influential factors of pain through logistic regression analysis. Results: The follow-up time was between 18 and 42 months after operation with an average of 27.66 ± 12.9 per month. Overall functional scores were significantly improved. The influencing factors that may affect the postoperative effect of HTO include age and preoperative WBL ratio of the knee joint (WBL%). After incorporating these two factors into the multivariate logistic regression analysis, for every 1 unit increase in the preoperative WBL%, the probability of postoperative HSS being superior is 1.06 times higher than before [Exp(ß): 1.062, 95% CI: 1.01-1.1, p = 0.018]. For every year increase in age, the probability of an excellent HSS score after surgery was 0.84 times higher than that before surgery [Exp(ß): 0.843, 95% CI: 0.718-0.989, p = 0.036]. Preoperative WBL% ≥ 14.37 was 17.4 times more likely to be rated as excellent postoperative HSS than that <14.37 [Exp(ß): 17.406, 95% CI: 1.621-186.927, p = 0.018]. Conclusion: The postoperative functional scores of the patients significantly improved. Patients with preoperative WBL% ≥ 14.37% had better function after surgery.

Method to Measure Radial Thermal Conductivity for Cylindrical Samples.

Anisotropy is a prevailing property in most substances in the real world. The thermal conductivity characteristic of anisotropy must be determined for utilizing geothermal resources and assessing battery performances. Most core samples were primarily obtained by drilling and intended to be cylindrical in shape, with the cores resembling quantities of familiar batteries. Although Fourier's law could be used to measure the axial thermal conductivity of square or cylindrical samples, there is still a need to develop a new method to measure the radial thermal conductivity of cylindrical samples and evaluate their anisotropy. Thus, we established a testing method for cylindrical samples using the theory of complex variable functions following the heat conduction equation and implemented a numerical simulation to determine the difference between this method and typical ones via a finite element model for various samples. Results show that the method could perfectly gauge the radial thermal conductivity of cylindrical samples with more powerful availability.

Clinical study on prevention of atopic dermatitis by oral administration of probiotics in infants.

Introduction: This study aimed to investigate the preventive effects of oral administration of probiotics on the incidence and severity of atopic dermatitis (AD) in infants. Material and methods: A total of 396 full-term infants were enrolled in this study. Of these, 132 newborns without a family history of AD were assigned to group A, and the other 264 newborns were randomly divided into groups B and C. Infants in groups A and B were solely breastfed, while probiotics were administered to those in group C as well as breastfeeding. The information of all subjects was recorded, and the incidence of AD was followed up. The levels of serum IgE and IL-4 were measured at the age of 3 years. Results: The incidence of AD in infants in group B was higher than that in group A at 3 months, 4-6 months, and 7-36 months after birth, together with increased symptom scores. For infants in group C, the incidence of AD at 4-6 months and 7-36 months after birth and the SCORAD scores at 0-3 months and 4-6 months after birth were lower than those in group B. The levels of IgE and IL-4 in group B were higher than those in groups A and C at 36 months old. Conclusions: Adding probiotics could favor the establishment of the intestinal microecological balance in the neonatal period, thereby reducing the incidence of AD, decreasing the levels of serum immune indexes and alleviating the severity of the disease.

[Analysis of GNAS gene variant in a Chinese pedigree affected with pseudohypoparathyroidism].

OBJECTIVE: To explore the genetic etiology of a Chinese pedigree affected with pseudohypoparathyroidism. METHODS: Peripheral blood samples of the proband and his parents were collected and subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified among the pedigree and 50 randomly selected healthy individuals through analysis of restriction fragment length polymorphism. Short tandem repeat (STR) linkage analysis was used to verify the parental origin of the pathogenic variants. RESULTS: Trio-WES and Sanger sequencing showed that the proband and his mother had both harbored a c.121C>G (p.His41Asp) variant of the GNAS gene, which was not found in other family members and the 50 healthy controls. The variant was not found in international databases. Based on guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic. CONCLUSION: The novel c.121C>G variant of the GNAS gene probably underlay the disease in this pedigree. Above finding has enriched the spectrum of GNAS gene variants.

The therapeutic effect of glucocorticoids on type II respiratory failure, heart failure, and massive pericardial effusion caused by hypothyroidism: A case report.

Background: Hypothyroidism is a disease commonly observed in outpatient clinics but can occasionally cause severe cardiovascular and respiratory diseases requiring hospitalization. Case report: The patient reported herein suffered from heart failure, massive pericardial effusion, type II respiratory failure, and hypothyroidism. There was no related basic diseases of respiratory and cardiovascular system in the past. She failed to be weaned from invasive ventilation multiple times after routine treatment and was finally successfully weaned on day five of receiving the combination therapy of a high-dose methylprednisolone intravenous drip and levothyroxine oral administration. Conclusion: This case report indicates that hypothyroidism may be a cause of type II respiratory failure, heart failure, and massive pericardial effusion without cardiac tamponade and that a combination of levothyroxine and corticosteroids could effectively treat the disease. Clinical workers should consider the role of thyroid function in diagnosis, and the admission team should include this aspect in the monitoring scope. Moreover, the role of hormones in the treatment of patients with severe hypothyroidism should not be ignored, and timely treatment should be provided.

A case report and review of literature: Tuberculous pericarditis with pericardial effusion as the only clinical manifestation.

Tuberculosis is a main cause of pericardial disease in developing countries. However, in patients with atypical clinical presentation, it can lead to misdiagnosis, missed diagnosis, and delayed treatment. In this study, we report a case of a 61-year-old woman admitted to the cardiac intensive care unit with "weakness and loss of appetite" and a large pericardial effusion shown by echocardiography. After hospitalization, a pericardiocentesis was performed, and the pericardial fluid was hemorrhagic. However, the Xpert MTB/RIF and T-SPOT tests were negative, and repeated phlegm antacid smears and culture of pericardial fluid did not reveal antacid bacilli. The patient eventually underwent thoracoscopic pericardial biopsy, which revealed extensive inflammatory cells and significant granulomas. Combined with the fact that the patient's pericardial effusion was exudate, the patient was considered to be suspected of tuberculous pericarditis (TBP) and given empirical anti-tuberculosis treatment the patient's symptoms improved and the final diagnosis was TBP. In this case report, it is further shown that a negative laboratory test cannot exclude tuberculosis infection. In recurrent unexplained pericardial effusions, the pericardial biopsy is feasible. In countries with a high burden of tuberculosis, empirical antituberculosis therapy may be used to treat the pericardial effusion that excludes other possible factors.

Development and evaluation of an online training program based on the O-AMAS teaching model for community pharmacists in the post-COVID-19 era.

Background: Formerly, the community pharmacists' work was mainly focused on drug supply. However, during the COVID-19 epidemic outbreak, community pharmacists in Wuhan played an important role in control and prevention of SARS-CoV-2 and in providing pharmaceutical care. Due to a lack of adequate knowledge and skills, many community pharmacists were not able to cope with healthcare work timely and efficiently. To improve community pharmacists' specialized knowledge and enhance their professional competence through systemic training in the post-COVID-19 era. Methods: Based on the O-AMAS (Objective, Activation, Multi-learning, Assessment and Summary) teaching model and flipped classroom, an online continuing training program containing four sections was developed. It was a semi-experimental study with no control group. Quantitative tests before and after training as well as questionnaire were used to evaluate the outcome of this training program for community pharmacists. Results: A total of twenty-six community pharmacists were invited to participate in continuing education, and twenty-five trainees finished this training program with a completion rate of 96.2 %. Quantitative tests before and after training and anonymous questionnaires were carried out to comprehensively evaluate the outcomes of this training program. Compared with the test scores before training (61.6 ± 6.6), the score after training was statistically higher, reaching 80.9 ± 7.5 (P < 0.001). Twenty-three questionnaires were received (returns ratio, 92.0%). Notably, most of the pharmacists were satisfied with the training program. The percentage of positive responses for each item in this anonymous questionnaire was more than 85 %. Conclusion: It was suggested that the O-AMAS model and the flipped classroom-based continuing educational program achieved the expected training effects. It is a promising on-the-job training approach for pharmacy continuing education. Moreover, our study also demonstrated that online learning had advantages of no geographic constraints, flexible learning beyond time and easy interaction, over traditional face-to-face training style, especially in the post-pandemic era.