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Background: Toxoplasma gondii is an intracellular protozoan parasite that is widely distributed in humans and warm-blooded animals. T. gondii chronic infections can cause toxoplasmic encephalopathy, adverse pregnancy, and male reproductive disorders. In male reproduction, the main function of the testis is to provide a stable place for spermatogenesis and immunological protection. The disorders affecting testis tissue encompass abnormalities in the germ cell cycle, spermatogenic retardation, or complete cessation of sperm development. However, the mechanisms of interaction between T. gondii and the reproductive system is unclear. The aims were to study the expression levels of genes related to spermatogenesis, following T. gondii infection, in mouse testicular tissue., Methods: RNA-seq sequencing was carried out on mouse testicular tissues from mice infected or uninfected with the T. gondii type II Prugniaud (PRU) strain and validated in combination with real-time quantitative PCR and immunofluorescence assays., Results: The results showed that there were 250 significant differentially expressed genes (DEGs) (P < 0.05, |log 2 fold change| ≧ 1). Bioinformatics analysis showed that 101 DEGs were annotated to the 1696 gene ontology (GO) term. While there was a higher number of DEGs in the biological process classification as a whole, the GO enrichment revealed a significant presence of DEGs in the cellular component classification. The Arhgap18 and Syne1 genes undergo regulatory changes following T. gondii infection, and both were involved in shaping the cytoskeleton of the blood-testis barrier (BTB). The number of DEGs enriched in the MAPK signaling pathway, the ERK1/2 signaling pathway, and the JNK signaling pathway were significant. The PTGDS gene is located in the Arachidonic acid metabolism pathway, which plays an important role in the formation and maintenance of BTB in the testis. The expression of PTGDS is downregulated subsequent to T. gondii infection, potentially exerting deleterious effects on the integrity of the BTB and the spermatogenic microenvironment within the testes., Conclusions: Overall, our research provides in-depth insights into how chronic T. gondii infection might affect testicular tissue and potentially impact male fertility. These findings offer a new perspective on the impact of T. gondii infection on the male reproductive system., (© 2024. The Author(s).)

Background: The immunocompetence handicap hypothesis suggests that males with a higher testosterone level should be better at developing male secondary traits, but at a cost of suppressed immune performance. As a result, we should expect that males with an increased testosterone level also possess a higher parasite load. However, previous empirical studies aimed to test this prediction have generated mixed results. Meanwhile, the effect of testosterone level on parasite load in female hosts remains poorly known., Methods: In this study, we tested this prediction by manipulating testosterone level in Daurian ground squirrels (Spermophilus dauricus), a medium-sized rodent widely distributed in northeast Asia. S. dauricus is an important host of ticks and fleas and often viewed as a considerable reservoir of plague. Live-trapped S. dauricus were injected with either tea oil (control group) or testosterone (treatment group) and then released. A total of 10 days later, the rodents were recaptured and checked for ectoparasites. Fecal samples were also collected to measure testosterone level of each individual., Results: We found that testosterone manipulation and sex of hosts interacted to affect tick load. At the end of the experiment, male squirrels subjected to testosterone implantation had an averagely higher tick load than males from the control group. However, this pattern was not found in females. Moreover, testosterone manipulation did not significantly affect flea load in S. dauricus., Conclusions: Our results only lent limited support for the immunocompetence handicap hypothesis, suggesting that the role of testosterone on regulating parasite load is relatively complex, and may largely depend on parasite type and gender of hosts., (© 2024. The Author(s).)

Background: G-protein coupled receptors (GPCRs) are recognized as attractive targets for drug therapy. However, it remains poorly understood how GPCRs, except for a few chemokine receptors, regulate the progression of liver fibrosis. Here, we aimed to reveal the role of GPR65, a proton-sensing receptor, in liver fibrosis and to elucidate the underlying mechanism., Methods: The expression level of GPR65 was evaluated in both human and mouse fibrotic livers. Furthermore, Gpr65-deficient mice were treated with either bile duct ligation (BDL) for 21 d or carbon tetrachloride (CCl 4 ) for 8 weeks to investigate the role of GPR65 in liver fibrosis. A combination of experimental approaches, including Western blotting, quantitative real-time reverse transcription‑polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA), confocal microscopy and rescue studies, were used to explore the underlying mechanisms of GPR65's action in liver fibrosis. Additionally, the therapeutic potential of GPR65 inhibitor in the development of liver fibrosis was investigated., Results: We found that hepatic macrophages (HMs)-enriched GPR65 was upregulated in both human and mouse fibrotic livers. Moreover, knockout of Gpr65 significantly alleviated BDL- and CCl 4 -induced liver inflammation, injury and fibrosis in vivo, and mouse bone marrow transplantation (BMT) experiments further demonstrated that the protective effect of Gpr65 knockout is primarily mediated by bone marrow-derived macrophages (BMMs). Additionally, in vitro data demonstrated that Gpr65 silencing and GPR65 antagonist inhibited, while GPR65 overexpression and application of GPR65 endogenous and exogenous agonists enhanced the expression and release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and transforming growth factor-β (TGF-β), all of which subsequently promoted the activation of hepatic stellate cells (HSCs) and the damage of hepatocytes (HCs). Mechanistically, GPR65 overexpression, the acidic pH and GPR65 exogenous agonist induced up-regulation of TNF-α and IL-6 via the Gαq-Ca 2+ -JNK/NF-κB pathways, while promoted the expression of TGF-β through the Gαq-Ca 2+ -MLK3-MKK7-JNK pathway. Notably, pharmacological GPR65 inhibition retarded the development of inflammation, HCs injury and fibrosis in vivo., Conclusions: GPR65 is a major regulator that modulates the progression of liver fibrosis. Thus, targeting GPR65 could be an effective therapeutic strategy for the prevention of liver fibrosis., (© 2023. The Author(s).)

Background: Hyperglycemic crises are associated with high morbidity and mortality. Previous studies have proposed methods to predict adverse outcomes of patients in hyperglycemic crises; however, artificial intelligence (AI) has never been used to predict adverse outcomes. We implemented an AI model integrated with the hospital information system (HIS) to clarify whether AI could predict adverse outcomes., Methods: We included 2,666 patients with hyperglycemic crises from emergency departments (ED) between 2009 and 2018. The patients were randomized into a 70%/30% split for AI model training and testing. Twenty-two feature variables from the electronic medical records were collected. The performance of the multilayer perceptron (MLP), logistic regression, random forest, Light Gradient Boosting Machine (LightGBM), support vector machine (SVM), and K-nearest neighbor (KNN) algorithms was compared. We selected the best algorithm to construct an AI model to predict sepsis or septic shock, intensive care unit (ICU) admission, and all-cause mortality within 1 month. The outcomes between the non-AI and AI groups were compared after implementing the HIS and predicting the hyperglycemic crisis death (PHD) score., Results: The MLP had the best performance in predicting the three adverse outcomes, compared with the random forest, logistic regression, SVM, KNN, and LightGBM models. The areas under the curves (AUCs) using the MLP model were 0.852 for sepsis or septic shock, 0.743 for ICU admission, and 0.796 for all-cause mortality. Furthermore, we integrated the AI predictive model with the HIS to assist decision making in real time. No significant differences in ICU admission or all-cause mortality were detected between the non-AI and AI groups. The AI model performed better than the PHD score for predicting all-cause mortality (AUC 0.796 vs. 0.693)., Conclusions: A real-time AI predictive model is a promising method for predicting adverse outcomes in ED patients with hyperglycemic crises. Further studies recruiting more patients are warranted., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The continuously developing pesticide resistance is a great threat to agriculture and human health. Understanding the mechanisms of insecticide resistance is a key step in dealing with the phenomenon. Insect cuticle is recently documented to delay xenobiotic penetration which breaks the previous stereotype that cuticle is useless in insecticide resistance, while the underlying mechanism remains scarce., Results: Here, we find the integument contributes over 40.0% to insecticide resistance via different insecticide delivery strategies in oriental fruit fly. A negative relationship exists between cuticle thickening and insecticide penetration in resistant/susceptible, also in field strains of oriental fruit fly which is a reason for integument-mediated resistance. Our investigations uncover a regulator of insecticide penetration that miR-994 mimic treatment causes cuticle thinning and increases susceptibility to malathion, whereas miR-994 inhibitor results in opposite phenotypes. The target of miR-994 is a most abundant cuticle protein (CPCFC) in resistant/susceptible integument expression profile, which possesses capability of chitin-binding and influences the cuticle thickness-mediated insecticide penetration. Our analyses find an upstream transcriptional regulatory signal of miR-994 cascade, long noncoding RNA (lnc19419), that indirectly upregulates CPCFC in cuticle of the resistant strain by sponging miR-994. Thus, we elucidate the mechanism of cuticular competing endogenous RNAs for regulating insecticide penetration and demonstrate it also exists in field strain of oriental fruit fly., Conclusions: We unveil a regulatory axis of lnc19419 ~ miR-994 ~ CPCFC on the cuticle thickness that leads to insecticide penetration resistance. These findings indicate that competing endogenous RNAs regulate insecticide resistance by modulating the cuticle thickness and provide insight into the resistance mechanism in insects., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The mechanisms underlying the occurrence and development of esophageal squamous cell carcinoma (ESCC) remains to be elucidated. The present study aims to investigate the roles and implications of IGF2BP1 overexpression in ESCC., Methods: IGF2BP1 protein expression in ESCC samples was assessed by immunohistochemistry (IHC), and the mRNA abundance of IGF2BP1 and INHBA was analyzed with TCGA datasets and by RNA in situ hybridization (RISH). The methylation level of the IGF2BP1 promoter region was detected by methylation-specific PCR (MSP-PCR). Cell viability, migration, invasion and in vivo metastasis assays were performed to explore the roles of IGF2BP1 overexpression in ESCC. RNA immunoprecipitation sequencing (RIP-seq) and mass spectrometry were applied to identify the target RNAs and interacting proteins of IGF2BP1, respectively. RIP-PCR, RNA pulldown, immunofluorescence (IF), gene-specific m 6 A PCR and RNA stability assays were used to uncover the molecular mechanisms underlying the malignant phenotypes of ESCC cells caused by IGF2BP1 dysregulation. BTYNB, a small molecular inhibitor of IGF2BP1, was evaluated for its inhibitory effect on the malignant phenotypes of ESCC cells., Results: IGF2BP1 overexpression was detected in ESCC tissues and associated with the depth of tumor invasion. In addition, IGF2BP1 mRNA expression in ESCC cells was negatively correlated with the level of its promoter methylation. Knockdown of IGF2BP1 inhibited ESCC cell invasion and migration as well as tumor metastasis. Mechanistically, we observed that IGF2BP1 bound and stabilized INHBA mRNA and then resulted in higher protein expression of INHBA, leading to the activation of Smad2/3 signaling, thus promoting malignant phenotypes. The mRNA level of INHBA was upregulated in ESCC tissues as well. Furthermore, IGF2BP1 interacted with G3BP stress granule assembly factor 1 (G3BP1). Knockdown of G3BP1 also down-regulated the INHBA-Smad2/3 signaling. BTYNB abolished this activated signaling and significantly attenuated the malignant phenotypes of ESCC cells., Conclusions: Elevated expression of IGF2BP1 is a frequent event in ESCC tissues and might be a candidate biomarker for the disease. IGF2BP1 overexpression promotes the invasion and migration of ESCC cells by activating the INHBA-Smad2/3 pathway, providing a potential therapeutic target for ESCC patients with high expression of IGF2BP1., (© 2023. YUMED Inc. and BioMed Central Ltd.)

Objective: This study aimed to investigate the relationship between the TyG (Triglyceride-glucose index) and the prognosis of patients with HOCM (hypertrophic obstructive cardiomyopathy) without diabetes., Research Design and Methods: A total of 713 eligible patients with HOCM were enrolled in this study and divided into two groups based on treatment: an invasive treatment group (n = 461) and a non-invasive treatment group (n = 252). The patients in both two groups were then divided into three groups based on their TyG index levels. The primary endpoints of this study were Cardiogenic death during long-term follow-up. Kaplan-Meier analysis was used to study the cumulative survival of different groups. Restricted cubic spline was used to model nonlinear relationships between the TyG index and primary endpoints. Myocardial perfusion imaging/Myocardial metabolic imaging examinations were performed to assess glucose metabolism in the ventricular septum of the HOCM patients., Results: The follow-up time of this study was 41.47 ± 17.63 months. The results showed that patients with higher TyG index levels had better clinical outcomes (HR, 0.215; 95% CI 0.051,0.902; P = 0.036, invasive treatment group; HR, 0.179; 95% CI 0.063,0.508; P = 0.001, non-invasive treatment group). Further analysis showed that glucose metabolism in the ventricular septum was enhanced in HOCM patients., Conclusions: The findings of this study suggest that the TyG index may serve as a potential protective factor for patients with HOCM without diabetes. The enhanced glucose metabolism in the ventricular septum of HOCM patients may provide a potential explanation for the relationship between the TyG index and HOCM prognosis., (© 2023. The Author(s).)

Background: To explore the hematological toxicity (HT) induced by neoadjuvant chemoradiotherapy (nCRT) compared with neoadjuvant chemotherapy (nCT) and to identify the appropriate vertebral body (VB) dosimetric parameters for predicting HT in patients with locally advanced gastric cancer (GC)., Methods: In the phase III study, 302 patients with GC from an ongoing multi-center randomized clinical trial (NCT01815853) were included. Patients from two major centers were grouped into training and external validation cohorts. The nCT group received three cycles of XELOX chemotherapy, while the nCRT received the same dose-reduced chemotherapy plus 45 Gy radiotherapy. The complete blood counts at baseline, during neoadjuvant treatment, and in the preoperative period were compared between the nCT and nCRT groups. The VB was retrospectively contoured and the dose-volume parameters were extracted in the nCRT group. Patients' clinical characteristics, VB dosimetric parameters, and HTs were statistically analyzed. Instances of HT were graded according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0). The receiver operating characteristic (ROC) curves were generated to identify the optimal cut-off points for dosimetric variables and verify the prediction efficiency of the dosimetric index in both training and external validation cohorts., Results: In the training cohort, 27.4% Grade 3 + HTs were noted in the nCRT group and 16.2% in the nCT group (P = 0.042). A similar result was exhibited in the validation cohort, with 35.0% Grade 3 + HTs in the nCRT group and 13.2% in the nCT group (P = 0.025). The multivariate analysis of the training cohort revealed that V 5 was associated with Grade 3 + leukopenia (P = 0.000), Grade 3 + thrombocytopenia (P = 0.001), and Grade 3 + total HTs (P = 0.042). The Spearman correlation analysis identified a significant correlation of V 5 with the white blood cell nadir (P = 0.0001) and platelet nadir (P = 0.0002). The ROC curve identified the optimal cut-off points for V 5 and showed that V 5 < 88.75% could indicate a decreased risk of Grade 3 + leukopenia, thrombocytopenia, and total HTs in the training as well as the external validation cohorts., Conclusions: Compared with nCT, nCRT could increase the risk of Grade 3 + HT in patients with locally advanced GC. Dose constraints of V 5 < 88.75% in irradiated VB could reduce the incidence of Grade 3 + HT., (© 2023. The Author(s).)

Background: The purpose of the study was to compare the efficacy of two novel obesity indices, lipid accumulation product (LAP) and visceral adiposity index (VAI), with traditional obesity indices in predicting early-onset type 2 diabetes (T2DM)., Methods: In this cross-sectional study, a total of 744 participants, including 605 patients newly diagnosed with T2DM and 139 non-diabetic control subjects, were enrolled from a tertiary care hospital in Tianjin, China. Participants with T2DM were divided into two groups based on their age at diagnosis, namely early-onset T2DM (age less than 40 years, n = 154) and late-onset T2DM (age 40 years or older, n = 451). The predictive power of each obesity index was evaluated using receiver operating characteristic (ROC) curve analysis. Furthermore, binary logistic regression analysis was conducted to examine the independent relationship between LAP and VAI with early-onset T2DM risk. The relationship between novel obesity indices and the age of T2DM onset was also evaluated through correlation and multiple linear regression analysis., Results: In males, LAP had the highest predictive power for early-onset T2DM with an area under the ROC curve (AUC) of 0.742 (95% CI 0.684-0.799, P < 0.001). In females, VAI had the highest AUC for early-onset T2DM with a value of 0.748 (95% CI 0.657-0.839, P < 0.001), which was superior to traditional indices. Patients in the 4th quartile of LAP and VAI had 2.257 (95% CI 1.116-4.563, P = 0.023) and 4.705 (95% CI 2.132-10.384, P < 0.001) times higher risk of T2DM before age 40, compared to those in the 1st quartile, respectively. A tenfold increase in LAP was associated with a decrease in T2DM onset age of 12.862 years in males (β = -12.862, P < 0.001) and 6.507 years in females (β = -6.507, P = 0.013). A similar decrease in T2DM onset age was observed for each tenfold increase in VAI in both male (β = -15.222, P < 0.001) and female (β = -12.511, P < 0.001) participants., Conclusions: In young Chinese individuals, LAP and VAI are recommended over traditional obesity indices for improved prediction of early-onset T2DM risk., (© 2023. The Author(s).)

Background: Information available to date regarding the pregnancy outcomes of intrauterine insemination (IUI) without ovarian stimulation (OS) in infertile patients with unilateral tubal occlusion remains scarce. The objectives of this study were to investigate for couples affected by unilateral tubal occlusion (diagnosed via hysterosalpingography (HSG)/transvaginal real-time three-dimensional hysterosalpingo-contrast sonography (TVS RT-3D-HyCoSy)) and male infertility: (1) whether significant differences exist in pregnancy outcomes between IUI with or without OS cycles, and (2) whether the pregnancy outcomes of IUI without OS in women with unilateral tubal occlusion were similar to those of women with bilateral patent tubes., Methods: 258 couples affected by male infertility completed 399 IUI cycles. The cycles were divided into three groups: group A, IUI without OS in women with unilateral tubal occlusion; group B, IUI with OS in women with unilateral tubal occlusion; and group C, IUI without OS in women with bilateral patent tubes. The main outcome measures, including clinical pregnancy rate (CPR), live birth rate (LBR), and first trimester miscarriage rate, were compared between either groups A and B or groups A and C., Results: Although the number of dominant follicles > 16 mm were significantly higher in group B than that in group A (group B vs. group A: 1.6 ± 0.6 vs. 1.0 ± 0.2, P < 0.001), the CPR, LBR, and first trimester miscarriage rate were comparable between these two groups. When comparing group C to group A, the duration of infertility was significantly longer in group C than that in group A (group A vs. group C: 2.3 ± 1.2 (year) vs. 2.9 ± 2.1 (year), P = 0.017). Except for the first trimester miscarriage rate, which was significantly higher in group A (42.9%, 3/7) than that in group C (7.1%, 2/28) (P = 0.044), no significant differences were observed in the CPR and LBR in these two groups. After adjusting for female age, body mass index, and the duration of infertility, similar results were obtained between groups A and C., Conclusions: In couples affected by unilateral tubal occlusion (diagnosed via HSG/TVS RT-3D-HyCoSy) and male infertility, IUI without OS might be an alternative treatment strategy. However, when compared to patients with bilateral patent tubes, the patients with unilateral tubal occlusion showed a higher first trimester miscarriage rate following IUI without OS cycles. Further studies are warranted to clarify this relationship., (© 2023. The Author(s).)

Background: Mealtime difficulties related to cognitive functioning negatively impact a patient's life during the various stages of dementia, and they typically cause a burden and stress on family caregivers. Most people with dementia live at home alone or are cared for by informal caregivers, typically their spouses or other family members. However, no suitable screening tools for home-dwelling patients with dementia have been developed, nor have measurements focused on executive and self-eating functions. This study aimed to develop and evaluate the psychometric properties of the Dietary Function Assessment Scale (DFAS) for community-dwelling persons with dementia., Methods: A mixed-method design was used to develop the instrument. Methods included a comprehensive literature review to identify the item pool and an expert panel to assess the initial item pool. We performed convenience sampling of 190 home-dwelling people with dementia for psychometrical evaluation. The psychometric properties tests included item and factor analyses, criterion-related validity testing, internal consistency reliability testing, and defining the optimal cut-off values. The study was conducted from 2018 to 2019., Results: Items were generated based on an extensive literature review and pre-existing scales related to mealtime and executive functions in persons with dementia. The S-CVI/Ave of the DFAS was 0.89. A Principal Component factor analysis demonstrated seven items, with a two-factor structure accounting for 56.94% of the total variance. The two extracted factors were Self-eating ability and Dietary executive function. The confirmatory factor analysis indicated a good model fit. The criterion-related validity was adequate (r = -0.528, p < 0.01). The reliability of Cronbach's alpha internal consistency was 0.74, and McDonald's Omega coefficient was 0.80; the optimal cut-off value of 13 points with an AUC of 0.74 was established to determine poor dietary functioning in persons with dementia., Conclusion: The DFAS was simple, user-friendly, and a valid and reliable instrument to assess dietary functioning in community-dwelling persons with dementia. This short scale can be helpful for caretakers, who can use it to identify the dietary needs of home-dwelling persons with dementia and improve their care and eating experience., (© 2023. The Author(s).)

Background: Unbalanced translocations can cause developmental delay (DD), intellectual disability (ID), growth problems, dysmorphic features, and congenital anomalies. They may arise de novo or may be inherited from a parent carrying a balanced rearrangement. It is estimated that 1/500 people is a balanced translocation carrier. The outcomes of different chromosomal rearrangements have the potential to reveal the functional consequences of partial trisomy or partial monosomy and can help guide genetic counseling for balanced carriers, and other young patients diagnosed with similar imbalances., Methods: We performed clinical phenotyping and cytogenetic analyses of two siblings with a history of developmental delay (DD), intellectual disability (ID) and dysmorphic features., Results: The proband, a 38-year-old female, has a history of short stature, dysmorphic features and aortic coarctation. She underwent chromosomal microarray analysis, which identified partial monosomy of 4q and partial trisomy of 10p. Her brother, a 37-year-old male, has a history of more severe DD, behavioral problems, dysmorphic features, and congenital anomalies. Subsequently, karyotype confirmed two different unbalanced translocations in the siblings: 46,XX,der(4)t(4;10)(q33;p15.1) and 46,XY,der(10)t(4;10)(q33;p15.1), respectively. These chromosomal rearrangements represent two possible outcomes from a parent who is a carrier for a balanced translocation 46,XX,t(4;10)(q33;p15.1)., Conclusion: To our knowledge, this 4q and 10p translocation has not been described in literature. In this report we compare clinical features due to the composite effects of partial monosomy 4q with partial trisomy 10p and partial trisomy 4q with partial monosomy 10p. These findings speak to the relevance of old and new genomic testing, the viability of these segregation outcomes, and need for genetic counseling., (© 2023. The Author(s).)

Objective: Gestational diabetes mellitus (GDM) is a serious complication in pregnancy. Despite controlling the plasma glucose levels with dietary intervention (GDM-D) or insulin therapy (GDM-I), children born of diabetic mothers suffer more long-term complications from childhood to early adulthood. Placental circulation and nutrient exchange play a vital role in fetal development. Additionally, placental endothelial function is an indicator of vascular health, and plays an important role in maintaining placental circulation for nutrient exchange. This study was conducted to assess changes in fetal endothelial dysfunction in GDM under different interventions during pregnancy., Methods: The primary human umbilical vein endothelial cells (HUVECs) were obtained from normal pregnant women (n = 11), GDM-D (n = 14), and GDM-I (n = 12) patients. LC-MS/MS was used to identify differentially expressed proteins in primary HUVECs among the three groups, after which Bioinformatics analysis was performed. Glucose uptake, ATP level, apoptosis, and differentially expressed proteins were assessed to investigate changes in energy metabolism., Results: A total of 8174 quantifiable proteins were detected, and 142 differentially expressed proteins were identified after comparing patients with GDM-D/GDM-I and healthy controls. Of the 142, 64 proteins were upregulated while 77 were downregulated. Bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes and signaling pathways related to cellular processes, biological regulation, and metabolic processes. According to the results from KEGG analysis, there were changes in the PI3K/AKT signaling pathway after comparing the three groups. In addition, there was a decrease in glucose uptake in the GDM-I (P < 0.01) group. In GDM-I, there was a significant decrease in the levels of glucose transporter 1 (GLUT1) and glucose transporter 3 (GLUT3). Moreover, glucose uptake was significantly decreased in GDM-I, although in GDM-D, there was only a decrease in the levels of GLUT1. ATP levels decreased in GDM-I (P < 0.05) and apoptosis occurred in both the GDM-D and GDM-I groups. Compared to the normal controls, the levels of phosphate AKT and phosphate AMPK over total AKT and AMPK were reduced in the GDM-I group., Conclusion: In summary, endothelial dysfunction occurred in pregnancies with GDM even though the plasma glucose levels were controlled, and this dysfunction might be related to the degree of glucose tolerance. The energy dysfunction might be related to the regulation of the AKT/AMPK/mTOR signaling pathway., (© 2023. The Author(s).)

Background: Many laboratories have described the in vitro isolation of multipotent cells with stem cell properties from the skin of various species termed skin-derived stem cells (SDSCs). However, the cellular origin of these cells and their capability to give rise, among various cell types, to male germ cells, remain largely unexplored., Methods: SDSCs were isolated from newborn mice skin, and then differentiated into primordial germ cell-like cells (PGCLCs) in vitro. Single-cell RNA sequencing (scRNA-seq) was then applied to dissect the cellular origin of SDSCs using cells isolated from newborn mouse skin and SDSC colonies. Based on an optimized culture strategy, we successfully generated spermatogonial stem cell-like cells (SSCLCs) in vitro., Results: Here, using scRNA-seq and analyzing the profile of 7543 single-cell transcriptomes from newborn mouse skin and SDSCs, we discovered that they mainly consist of multipotent papillary dermal fibroblast progenitors (pDFPs) residing in the dermal layer. Moreover, we found that epidermal growth factor (EGF) signaling is pivotal for the capability of these progenitors to proliferate and form large colonies in vitro. Finally, we optimized the protocol to efficiently generate PGCLCs from SDSCs. Furthermore, PGCLCs were induced into SSCLCs and these SSCLCs showed meiotic potential when cultured with testicular organoids., Conclusions: Our findings here identify pDFPs as SDSCs derived from newborn skin and show for the first time that such precursors can be induced to generate cells of the male germline., (© 2023. The Author(s).)

Background: Helicobacter pylori (H. pylori) infection is associated with remodeling of gut microbiota. Many studies have found H. pylori infection and eradication therapy can alter the gut microbiota. However, few studies explored the impact of eradication therapy containing minocycline and metronidazole on gut microbiota., Aim: The objective of the present study was to explore the changes of gut microbiota after H. pylori infection. Besides, learn more about the dynamic changes of gut microbiota during different stages of eradication treatment containing minocycline, metronidazole, bismuth agents and proton pump inhibitors., Methods: Sixty stool samples from the patients with H. pylori infection before eradication, 14 and 42 days after eradication, and ten stool samples from non-infected individuals were collected. Subsequently, we performed 16S rRNA gene amplicon sequencing to analyze these samples, and the results were evaluated by using alpha diversity, beta diversity and microbial composition analyses. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was also used to predict the metabolic pathways according to the Kyoto Encyclopedia of Genes and Genomes database., Results: The alpha and beta diversity of the microbiota changed significantly in H. pylori infected individuals, but returned to baseline 42 days after eradication therapy. At the genus level, the abundances of Bacteroidetes, [Ruminococcus]&#95;gnavus&#95;group, Ruminococcaceae&#95;Incertae&#95;Sedis, Tuzzrealla, Butyricicoccus were significantly lower in the H. pylori infected group. Bacterial abundance was also dynamically changing during eradication treatment. In addition, PICRUST analysis found the levels of uronic acid metabolism, uncharacterized transport system, and biosynthesis of unsaturated fatty acids were higher in H. pylori infected individuals than in the non-infected group., Conclusions: Intestinal microbiota diversity, composition, functional predictions altered significantly after H. pylori infection, and gradually returned to healthy control levels after the application of eradication therapy containing minocycline and metronidazole in one month and a half., (© 2022. The Author(s).)

Background: The effects of traumatic brain injury (TBI) can include physical disability and even death. The development of effective therapies to promote neurological recovery is still a challenging problem. 3D-printed biomaterials are considered to have a promising future in TBI repair. The injury-preconditioned secretome derived from human umbilical cord blood mesenchymal stem cells showed better stability in neurological recovery after TBI. Therefore, it is reasonable to assume that a biological scaffold loaded with an injury-preconditioned secretome could facilitate neural network reconstruction after TBI., Methods: In this study, we fabricated injury-preconditioned secretome/collagen/heparan sulfate scaffolds by 3D printing. The scaffold structure and porosity were examined by scanning electron microscopy and HE staining. The cytocompatibility of the scaffolds was characterized by MTT analysis, HE staining and electron microscopy. The modified Neurological Severity Score (mNSS), Morris water maze (MWM), and motor evoked potential (MEP) were used to examine the recovery of cognitive and locomotor function after TBI in rats. HE staining, silver staining, Nissl staining, immunofluorescence, and transmission electron microscopy were used to detect the reconstruction of neural structures and pathophysiological processes. The biocompatibility of the scaffolds in vivo was characterized by tolerance exposure and liver/kidney function assays., Results: The excellent mechanical and porosity characteristics of the composite scaffold allowed it to efficiently regulate the secretome release rate. MTT and cell adhesion assays demonstrated that the scaffold loaded with the injury-preconditioned secretome (3D-CH-IB-ST) had better cytocompatibility than that loaded with the normal secretome (3D-CH-ST). In the rat TBI model, cognitive and locomotor function including mNSS, MWM, and MEP clearly improved when the scaffold was transplanted into the damage site. There is a significant improvement in nerve tissue at the site of lesion. More abundant endogenous neurons with nerve fibers, synaptic structures, and myelin sheaths were observed in the 3D-CH-IB-ST group. Furthermore, the apoptotic response and neuroinflammation were significantly reduced and functional vessels were observed at the injury site. Good exposure tolerance in vivo demonstrated favorable biocompatibility of the scaffold., Conclusions: Our results demonstrated that injury-preconditioned secretome/collagen/heparan sulfate scaffolds fabricated by 3D printing promoted neurological recovery after TBI by reconstructing neural networks, suggesting that the implantation of the scaffolds could be a novel way to alleviate brain damage following TBI., (© 2022. The Author(s).)

Background: Although frailty is a common geriatric syndrome in old adults, a simple method to assess the degree of frailty in a person has not yet been established. In this study we have tried to establish the association between calf circumference (CC) and frailty among older Chinese people., Methods: We used the data obtained from the 2014 edition of the Chinese Longitudinal Healthy Longevity Survey; 1216 participants aged ≥60 years were included for the study. Body mass index, CC and waist circumference measurement data, and laboratory test results were collected. Frailty status was measured using the frailty index (FI). Participants were then classified into non-frail (FI < 0.25) and frail (FI ≥ 0.25) groups., Results: There were 874 participants (71.9%) in the non-frail group and 342 (28.1%) in the frail group. The CC was significantly different between the two groups (31.54 ± 4.16 versus 28.04 ± 4.53, P < 0.001). Logistic regression analysis revealed that CC (odds ratio = 0.947, 95% confidence interval: 0.904-0.993, P = 0.023) was an independent impact factor associated with frailty. The CC value of 28.5 cm was considered the best cut-off value in women with area under the curve (AUC) was 0.732 (P < 0.001) and 29.5 cm in men with AUC was 0.592 (P = 0.004);We created a simple prediction model for frailty that included age,sex and CC:[Formula: see text]P = e logit(P) /1 + e logit(P) , and AUC is 0.849 (P < 0.001)., Conclusions: CC is a convenient and predictable marker of frailty in older adults., (© 2022. The Author(s).)

Background and Objectives: Disruption of brain barriers is considered to be involved in the pathogenesis of neuronal surface antibody-associated autoimmune encephalitis (NSAE), but few studies have focused on their relationship. We aimed to explore the association between the integrity of brain barriers and clinical and paraclinical characteristics in patients with NSAE., Methods: This retrospective study consecutively recruited patients with NSAE. The cerebrospinal fluid (CSF) / serum albumin quotient (Qalb) was used to evaluate the function of brain barriers. The data on demographic information, clinical manifestations, magnetic resonance imaging (MRI), CSF findings and prognosis were collected and analyzed., Results: Of the 93 patients included, 33 (35.5%) patients were assigned to the elevated Qalb group and 60 (64.5%) patients to the normal Qalb group. Males and prodromal symptoms were more common in elevated Qalb group (both P < 0.05). The CSF white blood cell, protein, immunoglobulin G and albumin were significantly higher in elevated Qalb group (all P < 0.05). Patients with elevated Qalb were more likely to have brain lesions on MRI (60.6% versus 33.3%, P = 0.011). The modified Rankin Scale (mRS) scores at discharge and at last follow-up were significantly higher in patients with elevated Qalb than those with normal Qalb (both P < 0.05). After univariate and multivariate analyses, Qalb elevation (adjusted odds ratio = 3.96, 95% confidence interval = 1.15-13.59, P = 0.029) was demonstrated as the only independent risk factor for a poor prognosis., Discussion: Males, prodromal symptoms, brain lesions on MRI, CSF pleocytosis, and elevated CSF protein were more common in NSAE patients with increased Qalb. Qalb elevation was an independent prognostic indicator for a poor prognosis in NSAE., (© 2022. The Author(s).)

Background: Stroke is the leading cause of disability worldwide, resulting in severe damage to the central nervous system and disrupting neurological functions. There is no effective therapy for promoting neurological recovery. Growing evidence suggests that the composition of exosomes from different microenvironments may benefit stroke. Therefore, it is reasonable to assume that exosomes secreted in response to infarction microenvironment could have further therapeutic effects., Methods: In our study, cerebral infarct tissue extracts were used to pretreat umbilical cord mesenchymal stem cells (UCMSC). Infarct-preconditioned exosomes were injected into rats via tail vein after middle cerebral artery occlusion (MCAO). The effect of infarct-preconditioned exosomes on the neurological recovery of rats was examined using Tunel assay, 2,3,5-triphenyltetrazolium chloride (TTC) assay, magnetic resonance imaging (MRI) analyses, modified Neurological Severity Score (mNSS), Morris water maze (MWM), and vascular remodeling analysis. Mi-RNA sequencing and functional enrichment analysis were used to validate the signal pathway involved in the effect of infarct-preconditioned exosomes. Human umbilical vein endothelial cells (HUVECs) were co-cultured with the isolated exosomes. Cell Counting Kit-8 (CCK-8) assay, scratch healing, and Western blot analysis were used to detect the biological behavior of HUVECs., Results: The results showed that compared with normal exosomes, infarct-preconditioned exosomes further promoted vascular remodeling and recovery of neurological function after stroke. The function of upregulated miRNAs and their target genes which is beneficial to vascular smooth muscle cells verified the importance of vascular remodeling in improving stroke. Better resistance to oxygen-glucose deprivation/reoxygenation (OGD/R), reduced apoptosis, and enhanced migration were observed in infarct-preconditioned exosomes-treated umbilical vein endothelial cells., Conclusions: Our results demonstrated that infarct-preconditioned exosomes promoted neurological recovery after stroke by enhancing vascular endothelial remodeling, suggested that infarct-preconditioned exosomes could be a novel way to alleviate brain damage following a stroke., (© 2022. The Author(s).)

Background: Uniparental disomy (UPD) is a condition in which both chromosomes are inherited from the same parent, except for imprinting disorders. Uniparental isodisomy (UPiD) may result in a homozygous variant contributing to an autosomal recessive disorder in the offspring of a heterozygous carrier. Junctional epidermolysis bullosa intermediate (JEB intermediate) is an autosomal recessive inherited disease that is associated with a series of gene variants, including those of COL17A1., Case Presentation: We report the first case of complete paternal UPiD of chromosome 10 harbouring a novel homozygous variant in COL17A1: c.1880(exon23)delG (p.G627Afs*56). This variant led to the clinical phenotype of junctional epidermolysis bullosa intermediate in a 5-year-old child. Trio-whole exome sequencing (Trio-WES) and in silico data analysis were used for variant identification, Sanger sequencing was performed for variant validation, and pathological examination was performed as the gold standard for phenotype confirmation., Conclusions: We recommend the use of WES as a first-tier test for the diagnosis of epidermolysis bullosa, especially for paediatric patients. Moreover, UPD events should be detected and analysed routinely through WES data in the future., (© 2022. The Author(s).)

Background: Atopic dermatitis (AD) is a chronic relapsing skin disease that has long-term physical and mental health impacts on children with this condition. Current treatments mainly include anti-inflammatory, antibacterial, and anti-allergic interventions, systemic therapy, and recently emerging target-focused agents. However, these treatments have limited effectiveness and unwanted side effects. The use of traditional Chinese medicine (TCM) in the treatment of AD has a long history, with promising efficacies, low toxicity, and improvements in the quality of life of patients with AD. Longmu Tang granule, a TCM, has been used to effectively treat AD since 2008 through doctors' prescriptions. To scientifically evaluate the clinical efficacy and safety of Longmu Tang granule, we proposed to launch a single-centred, double-blinded, randomised, placebo-controlled trial., Methods: In this single-centred, double-blinded, randomised, placebo-controlled clinical trial conducted at Xiyuan Hospital of China Academy of Chinese Medical Sciences, a total of 60 participants will be randomly assigned (1:1) to receive the Longmu Tang granule or placebo granule for 8 weeks. The primary outcome will be evaluated using the index of Scoring Atopic Dermatitis. The secondary outcomes will be evaluated using the Children's Dermatology Life Quality Index and the number cancellation test. The mechanistic evidence will be the serum levels of inflammatory cytokines, including immunoglobulin E, tumour necrosis factor-α, interleukin-1, and interleukin-6., Discussion: The results of this trial will provide evidence of the efficacy and safety of the Longmu Tang granule and prove its anti-inflammatory action in patients with AD., Trial Registration: Chinese Clinical Trial Registry Chictr.org ID: ChiCTR2100041591 . Registered on 1 January 2021., (© 2022. The Author(s).)

Background: This study aims to develop a machine learning-based application in a real-world medical domain to assist anesthesiologists in assessing the risk of complications in patients after a hip surgery., Methods: Data from adult patients who underwent hip repair surgery at Chi-Mei Medical Center and its 2 branch hospitals from January 1, 2013, to March 31, 2020, were analyzed. Patients with incomplete data were excluded. A total of 22 features were included in the algorithms, including demographics, comorbidities, and major preoperative laboratory data from the database. The primary outcome was a composite of adverse events (in-hospital mortality, acute myocardial infarction, stroke, respiratory, hepatic and renal failure, and sepsis). Secondary outcomes were intensive care unit (ICU) admission and prolonged length of stay (PLOS). The data obtained were imported into 7 machine learning algorithms to predict the risk of adverse outcomes. Seventy percent of the data were randomly selected for training, leaving 30% for testing. The performances of the models were evaluated by the area under the receiver operating characteristic curve (AUROC). The optimal algorithm with the highest AUROC was used to build a web-based application, then integrated into the hospital information system (HIS) for clinical use., Results: Data from 4,448 patients were analyzed; 102 (2.3%), 160 (3.6%), and 401 (9.0%) patients had primary composite adverse outcomes, ICU admission, and PLOS, respectively. Our optimal model had a superior performance (AUROC by DeLong test) than that of ASA-PS in predicting the primary composite outcomes (0.810 vs. 0.629, p < 0.01), ICU admission (0.835 vs. 0.692, p < 0.01), and PLOS (0.832 vs. 0.618, p < 0.01)., Conclusions: The hospital-specific machine learning model outperformed the ASA-PS in risk assessment. This web-based application gained high satisfaction from anesthesiologists after online use., (© 2022. The Author(s).)

Background: The retina, as part of the central nervous system (CNS) with limited capacity for self-reparation and regeneration in mammals, is under cumulative environmental stress due to high-energy demands and rapid protein turnover. These stressors disrupt the cellular protein and metabolic homeostasis, which, if not alleviated, can lead to dysfunction and cell death of retinal neurons. One primary cellular stress response is the highly conserved unfolded protein response (UPR). The UPR acts through three main signaling pathways in an attempt to restore the protein homeostasis in the endoplasmic reticulum (ER) by various means, including but not limited to, reducing protein translation, increasing protein-folding capacity, and promoting misfolded protein degradation. Moreover, recent work has identified a novel function of the UPR in regulation of cellular metabolism and mitochondrial function, disturbance of which contributes to neuronal degeneration and dysfunction. The role of the UPR in retinal neurons during aging and under disease conditions in age-related macular degeneration (AMD), retinitis pigmentosa (RP), glaucoma, and diabetic retinopathy (DR) has been explored over the past two decades. Each of the disease conditions and their corresponding animal models provide distinct challenges and unique opportunities to gain a better understanding of the role of the UPR in the maintenance of retinal health and function., Method: We performed an extensive literature search on PubMed and Google Scholar using the following keywords: unfolded protein response, metabolism, ER stress, retinal degeneration, aging, age-related macular degeneration, retinitis pigmentosa, glaucoma, diabetic retinopathy., Results and Conclusion: We summarize recent advances in understanding cellular stress response, in particular the UPR, in retinal diseases, highlighting the potential roles of UPR pathways in regulation of cellular metabolism and mitochondrial function in retinal neurons. Further, we provide perspective on the promise and challenges for targeting the UPR pathways as a new therapeutic approach in age- and disease-related retinal degeneration., (© 2022. The Author(s).)

Background: Studies have revealed that patients with chronic kidney disease (CKD) have dietary patterns different from those of the general population. However, no studies have compared the dietary patterns of between patients with early-stages (stages 1-3a) and late-stages (stages 3b-5) of CKD. Our objective was to investigate the associations between dietary patterns in early and late-stage CKD., Methods: We analyzed 4480 participants with CKD at various stages based on the data recorded between 2007 and 2016 from the database of the American National Health and Nutrition Examination Survey., Results: In total, 3683 and 797 participants had early and late-stage CKD, respectively. Through principal components analysis, the dietary intake dimension was reduced from 63 variables to 3 dietary patterns. We adopted logistic regression for analysis. The three dietary patterns are as follows: (1) saturated fatty acids and mono-unsaturated fatty acids (MUFA); (2) vitamins and minerals; and (3) cholesterols and polyunsaturated fatty acids (PUFA). These 3 patterns explained > 50% of dietary nutrient intake. Results indicated that among participants with dietary patterns 2 (vitamins and minerals) and 3 (cholesterols and PUFA), those with low intakes were more likely to have late-stage CKD. The odds ratios for patterns 2 and 3 were 1.74 (95% CI: 1.21-2.50) and 1.66 (95% CI: 1.13-2.43), respectively., Conclusions: This study revealed that intakes of vitamins and minerals and cholesterols and PUFA were associated with the stages of CKD., (© 2022. The Author(s).)

Background: Traumatic brain injury (TBI) has been reported as a risk factor for brain cancer development. However, the magnitude of the impact of TBI on systemic cancer development has not been clarified., Methods: A retrospective longitudinal cohort study was conducted using the Taiwan Longitudinal Health Insurance Database between January 2000 and December 2011. A total of 35,306 patients were initially enrolled, and 14,795 patients with mild TBI and 14,795 patients with moderate/severe TBI were matched using the National Health Insurance Research Database in Taiwan. The Cox proportional hazard regression model was used to estimate the hazard ratio (HR) of TBI adjusted for potential confounding factors., Results: After matching, the results showed that patients with moderate/severe TBI had a high mortality rate (17.7% vs. 10.4%) and shorter time interval from TBI to death (mean 3.6 years vs. 5.8 years). No differences were observed in cancer incidence (4.1% vs. 4.1%) or risk factors for mortality between mild and moderate/severe TBI patients. However, patients aged between 46 and 55 years, female patients, and patients with pre-existing renal disease had a significant higher cancer incidence risk in moderate/severe TBI compared with mild TBI patients. The top 15 most common cancers showed that mild TBI patients had a higher percentage of head and neck cancer. The overall mortality rate in all TBI patients diagnosed with cancer was about 50%, and the cancer-specific mortality is approximately 85% in death of TBI patients with cancer., Conclusions: We concluded that the incidence risk of a new cancer diagnosis and mortality risk of TBI patients with cancer between the mild TBI and moderate/severe TBI patients were not significantly different., (© 2022. The Author(s).)

Background: Microwave ablation (MWA) is a popular therapy for liver malignant tumor in recent years. Few studies have been conducted on its use in the treatment of hepatic alveolar echinococcosis (HAE). The study aims to evaluate the efficacy and safety of MWA in the treatment of HAE., Methods: This study analyzed the data of 45 patients (mean age, 38 ± 2 years; 24 males) diagnosed with HAE and underwent MWA treatment between June 2014 to December 2019. The patients after MWA were examined by CT or MRI [follow-up: 32 months (IQR 23-48.5)] to determine whether the lesions were relapsed and to evaluate the therapeutic effect of MWA. The safety of MWA was evaluated by monitoring postoperative complications. Clinical data, such as patient demographics, imaging features of the lesions, relevant findings of laboratory tests before and after ablation, and information related to ablation, were collected and analyzed. Paired-sample t tests and paired-sample Wilcoxon signed-rank tests were used to compare relevant laboratory indicators before and after MWA., Results: MWA was applied to 57 HAE lesions in 45 patients. The median size of lesions was 3.42 cm (IQR2.85-4.41). The rate of complete ablation was 100% (57/57). The median follow-up time was 32 months (IQR 23-48.5). The recurrence rate was 13% (6/45), and the median time of recurrence was 22 months. The rate of minor complications was 11.1% (5/45), and there were no major complications and deaths. Compared to preoperative, ALB, RBC, HBG, and PLT were decreased (p < 0.001); ALT, TB, DB, and WBC were increased (p < 0.001); and no statistically difference in PT, APTT, and INR (p > 0.05)., Conclusions: MWA might be a safe and effective way to cure HAE. Meanwhile, it provides a new option and a new way of thinking about treatment for patients with HAE., (© 2022. The Author(s).)

Background: The assessment of preschoolers' motor skills is essential to know young children's motor development and evaluate the intervention effects of promotion in children's sports activities. The purpose of this study was to review the motor skills assessment tools in Chinese pre-school-aged children, compare them in the international context, and provide guidelines to find appropriate motor skill assessment tools for developing children in China., Methods: A comprehensive literature search was carried out using the WANFAGN, CNKI, VIP, ERIC, EMBASE, MEDLINE, and SPORT Discus databases. Relevant articles published between January 2000 and May 2020 were retrieved. Studies that described the discriminative and evaluative measures of motor skills among the population aged 3-6 years in China were included., Results: A total of 17 studies were included in this study describing seven tools, including four self-developed tools and three international tools used in China. TGMD-2 appeared in a large proportion of the studies. The international tools used in China were incomplete in terms of translation, verification of reliability and validity, item selection, and implementation. Regarding the self-constructed tools, the CDCC was the most utilized self-developed tool, but it was mainly applied in intellectual development assessment. By comparing Chinese self-constructed and international tools, the construction of the CDCC and the Gross Motor Development Assessment Scale contained relatively complete development steps. However, the test content, validity and reliability, implementation instruction, and generalizability of self-constructed tools are still lacking., Conclusions: Both international and self-developed motor skills assessment tools have been rarely applied in China. Available tools lack enough validation and appropriate adjustments. Cultural differences in motor development between Chinese and Western populations should be considered when constructing a Chinese localized motor skill assessment tool., (© 2022. The Author(s).)

Background: Chronic subdural haematoma (CSDH) is a common condition in the elderly that often requires neurosurgical management. For small CSDH, evidence has emerged that statins may reduce haematoma volume and improve outcomes, presumably by reducing local inflammation and promoting vascular repair. We wish to extend this evidence in a study that aims to determine the efficacy and safety of atorvastatin combined with low-dose dexamethasone in patients with CSDH., Methods: The second ATorvastatin On Chronic subdural Hematoma (ATOCH-II) study is a multi-centre, randomized, placebo-controlled, double-blind trial which aims to enrol 240 adult patients with a conservative therapeutic indication for CSDH, randomly allocated to standard treatment with atorvastatin 20 mg combined with low-dose dexamethasone (or matching placebos) daily for 28 days, and with 152 days of follow-up. The primary outcome is a composite good outcome defined by any reduction from baseline in haematoma volume and survival free of surgery at 28 days. Secondary outcomes include functional outcome on the modified Rankin scale (mRS) and modified Barthel Index at 28 days, surgical transition and reduction in haematoma volumes at 14, 28 and 90 days., Discussion: This multi-centre clinical trial aims to provide high-quality evidence on the efficacy and safety of the combined treatment of atorvastatin and low-dose dexamethasone to reduce inflammation and enhance angiogenesis in CSDH., Trial Registration: ChiCTR, ChiCTR1900021659 . Registered on 3 March 2019, http://www.chictr.org.cn/showproj.aspx?proj=36157 ., (© 2021. The Author(s).)

Background: This study aims to validate the diagnostic accuracy of the International Ovarian Tumor Analysis (IOTA) the Assessment of Different NEoplasias in the adneXa (ADNEX) model in the preoperative diagnosis of adnexal masses in the hands of nonexpert ultrasonographers in a gynaecological oncology centre in China., Methods: This was a single oncology centre, retrospective diagnostic accuracy study of 620 patients. All patients underwent surgery, and the histopathological diagnosis was used as a reference standard. The masses were divided into five types according to the ADNEX model: benign ovarian tumours, borderline ovarian tumours (BOTs), stage I ovarian cancer (OC), stage II-IV OC and ovarian metastasis. Receiver operating characteristic (ROC) curve analysis was used to evaluate the ability of the ADNEX model to classify tumours into different histological types with and without cancer antigen 125 (CA 125) results., Results: Of the 620 women, 402 (64.8%) had a benign ovarian tumour and 218 (35.2%) had a malignant ovarian tumour, including 86 (13.9%) with BOT, 75 (12.1%) with stage I OC, 53 (8.5%) with stage II-IV OC and 4 (0.6%) with ovarian metastasis. The AUC of the model to differentiate benign and malignant adnexal masses was 0.97 (95% CI, 0.96-0.98). Performance was excellent for the discrimination between benign and stage II-IV OC and between benign and ovarian metastasis, with AUCs of 0.99 (95% CI, 0.99-1.00) and 0.99 (95% CI, 0.98-1.00), respectively. The model was less effective at distinguishing between BOT and stage I OC and between BOT and ovarian metastasis, with AUCs of 0.54 (95% CI, 0.45-0.64) and 0.66 (95% CI, 0.56-0.77), respectively. When including CA125 in the model, the performance in discriminating between stage II-IV OC and stage I OC and between stage II-IV OC ovarian metastasis was improved (AUC increased from 0.88 to 0.94, P = 0.01, and from 0.86 to 0.97, p = 0.01)., Conclusions: The IOTA ADNEX model has excellent performance in differentiating benign and malignant adnexal masses in the hands of nonexpert ultrasonographers with limited experience in China. In classifying different subtypes of ovarian cancers, the model has difficulty differentiating BOTs from stage I OC and BOTs from ovarian metastases., (© 2021. The Author(s).)

Background: Follow-up care is crucial but challenging for disease management particularly in rural areas with limited healthcare resources and clinical capacity, yet few studies have been conducted from the perspective of rural primary care physicians (PCPs). We assessed the frequency of follow-up care delivered by rural PCPs for hypertension and type 2 diabetes - the two most common long-term conditions., Methods: We conducted a multi-centre, self-administered survey study built upon existing general practice course programmes for rural PCPs in four provinces. Information on follow-up care delivery were collected from rural PCPs attending centralised in-class teaching sessions using a set of close-ended, multiple choice questions. Binary logistic regression analysis was performed to examine physician-level factors associated with non-attainment of the target frequency of follow-up care for hypertension and type 2 diabetes, respectively. The final sample consisted of rural PCPs from 52 township-level regions. The Complex Samples module was used in the statistical analysis to account for the multistage sample design., Results: The overall response rate was 91.4%. Around one fifth of PCPs in rural practices did not achieve the target frequency of follow-up care delivery (18.7% for hypertension; 21.6% for type 2 diabetes). Higher education level of physicians, increased volume of daily patients seen, and no provision of home visits were risk factors for non-attainment of the target frequency of follow-up care for both conditions. Moreover, village physicians with less working experiences tended to have less frequent follow-up care delivery in type 2 diabetes management., Conclusions: Efforts that are solely devoted to enhancing rural physicians' education may not directly translate into strong motivation and active commitment to service provision given the possible existence of clinical inertia and workload-related factors. Risk factors identified for target non-attainment in the follow-up care delivery may provide areas for capacity building programmes in rural primary care practice., (© 2021. The Author(s).)

Background: There is no clear conclusion on the relationship between thyroid disease and obesity and lifestyle factors such as smoking and drinking. In this study, we analysed the association of body mass index (BMI), smoking and drinking with subclinical hypothyroidism (SHO) and thyroid nodules (TNs) with the results of a cross-sectional survey of urban residents in central China and discussed the potential mechanism linking these predictive factors and the two diseases., Methods: This study included 1279 participants who were recruited from a Chinese community in 2011 and 2012. A questionnaire, laboratory examination and ultrasound diagnosis were conducted on these participants. Binary logistic regression analysis was used to analyse these factors., Results: Overweight (BMI ≥ 25 kg/m 2 ) was closely related to SHO and TNs in univariate and multivariate logistic regression analyses. Smoking had a protective effect on SHO and TNs, while drinking had a protective effect on TNs in univariate logistic regression and multivariate logistic regression with some covariates, but there was no significant difference between smoking and drinking and the two kinds of thyroid diseases in multivariate logistic regression analysis with all the covariates. In subgroup analysis, BMI ≥ 25 kg/m2 was significantly associated with SHO in people with positive thyroid antibodies (odds ratio (OR) = 2.221, 95 % confidence interval (CI): 1.168-4.184, P = 0.015) and smokers (OR = 2.179, 95 % CI: 1.041-4.561, P = 0.039). BMI ≥ 25 kg/m2 was significantly associated with TNs in people over 60 years old (OR = 2.069, 95 % CI: 1.149-3.724, P = 0.015) and drinkers (OR = 3.065, 95 % CI: 1.413-6.648, P = 0.005). Drinking alcohol had a protective effect on TNs in smokers (OR = 0.456, 95 % CI: 0.240-0.865, P = 0.016) and people with BMI ≥ 25 kg/m 2 (OR = 0.467, 95 % CI: 0.236-0.925, P = 0.029). No significant association was found between smoking and the two thyroid diseases in different subgroups., Conclusions: Obesity is a risk factor for both TNs and SHO, especially in elderly individuals and people with positive thyroid autoantibodies. Obesity and metabolic syndrome may be more associated with TNs than SHO. Smoking may have a protective effect on thyroid disease, while drinking may have a protective effect only on TNs., (© 2021. The Author(s).)

Objective: Preexisting severe cervical spinal cord compression is a significant risk factor in cervical hyperextension injury, and the neurological function may deteriorate after a slight force to the forehead. There are few biomechanical studies regarding the influence of pathological factors in hyperextension loading condition. The aim of this study is to analyze the effects of preexisting different types of cervical disc herniation and different degrees of compression on the spinal cord in cervical hyperextension., Method: A 3D finite element (FE) model of cervical spinal cord was modeled. Local type with median herniation, local type with lateral herniation, diffuse type with median herniation, and diffuse type with lateral herniation were simulated in neutral and extention positions. The compressions which were equivalent to 10%, 20%, 30%, and 40% of the sagittal diameter of the spinal cord were modeled., Results: The results of normal FE model were consistent with those of previous studies. The maximum von Mises stresses appeared in the pia mater for all 32 loading conditions. The maximum von Mises stresses in extension position were much higher than in neutral position. In most cases, the maximum von Mises stresses in diffuse type were higher than in local type., Conclusion: Cervical spinal cord with preexisting disc herniation is more likely to be compressed in hyperextension situation than in neutral position. Diffuse type with median herniation may cause more severe compression with higher von Mises stresses concentrated at the anterior horn and the peripheral white matter, resulting in acute central cord syndrome from biomechanical point of view., (© 2021. The Author(s).)

Background: Migraine is a common neurological disease that is often accompanied by psychiatric comorbidities. However, the relationship between abnormal brain function and psychiatric comorbidities in migraine patients remains largely unclear. Therefore, the present study sought to explore the correlations between the resting-state functional deficits and psychiatric comorbidities in migraine without aura (MwoA) patients., Methods: Resting-state functional magnetic resonance images were obtained. In addition, the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values were obtained. Thereafter regional abnormalities in MwoA patients with and without anxiety (MwoA-A and MwoA-OA) were chosen as seeds to conduct functional connectivity (FC) analysis., Results: Compared to the healthy controls (HCs), the MwoA-A and MwoA-OA patients had abnormal ALFF and ReHo values in the right lingual gyrus (LG). They also had abnormal FC of the right LG with the ipsilateral superior frontal gyrus (SFG) and middle cingulate cortex (MCC). Additionally, the MwoA-A patients showed higher ReHo values in the left posterior intraparietal sulcus (pIPS) and abnormal FC of the right LG with ipsilateral pIPS and primary visual cortex, compared to the MwoA-OA patients. Moreover, the MwoA-OA patients showed an increase in the FC with the right posterior cingulate cortex/precuneus (PCC/PCUN), left middle frontal gyrus (MFG) and left inferior temporal gyrus (ITG) relative to the HCs. Furthermore, the ALFF values of the right LG positively were correlated with anxiety scores in MwoA-A patients. The abnormal LG-related FCs with the PCC/PCUN, MFG and ITG were negatively associated with the frequency of headaches in MwoA-OA patients., Conclusions: This study identified abnormal visual FC along with other core networks differentiating anxiety comorbidity from MwoA. This may therefore enhance the understanding of the neuropsychological basis of psychiatric comorbidities and provide novel insights that may help in the discovery of new marks or even treatment targets.

Although new developments of surgery, chemotherapy, radiotherapy, and immunotherapy treatments for cancer have improved patient survival, the emergence of chemoresistance in cancer has significant impacts on treatment effects. The development of chemoresistance involves several polygenic, progressive mechanisms at the molecular and cellular levels, as well as both genetic and epigenetic heterogeneities. Chemotherapeutics induce epigenetic reprogramming in cancer cells, converting a transient transcriptional state into a stably resistant one. Super-enhancers (SEs) are central to the maintenance of identity of cancer cells and promote SE-driven-oncogenic transcriptions to which cancer cells become highly addicted. This dependence on SE-driven transcription to maintain chemoresistance offers an Achilles' heel for chemoresistance. Indeed, the inhibition of SE components dampens oncogenic transcription and inhibits tumor growth to ultimately achieve combined sensitization and reverse the effects of drug resistance. No reviews have been published on SE-related mechanisms in the cancer chemoresistance. In this review, we investigated the structure, function, and regulation of chemoresistance-related SEs and their contributions to the chemotherapy via regulation of the formation of cancer stem cells, cellular plasticity, the microenvironment, genes associated with chemoresistance, noncoding RNAs, and tumor immunity. The discovery of these mechanisms may aid in the development of new drugs to improve the sensitivity and specificity of cancer cells to chemotherapy drugs.

Background: Predicting outcomes in older patients with influenza in the emergency department (ED) by machine learning (ML) has never been implemented. Therefore, we conducted this study to clarify the clinical utility of implementing ML., Methods: We recruited 5508 older ED patients (≥65 years old) in three hospitals between 2009 and 2018. Patients were randomized into a 70%/30% split for model training and testing. Using 10 clinical variables from their electronic health records, a prediction model using the synthetic minority oversampling technique preprocessing algorithm was constructed to predict five outcomes., Results: The best areas under the curves of predicting outcomes were: random forest model for hospitalization (0.840), pneumonia (0.765), and sepsis or septic shock (0.857), XGBoost for intensive care unit admission (0.902), and logistic regression for in-hospital mortality (0.889) in the testing data. The predictive model was further applied in the hospital information system to assist physicians' decisions in real time., Conclusions: ML is a promising way to assist physicians in predicting outcomes in older ED patients with influenza in real time. Evaluations of the effectiveness and impact are needed in the future.

Background: No Canadian studies to date have examined the experiences of people who decline aspects of care during pregnancy and birth. The current analysis bridges this gap by describing comments from 1123 people in British Columbia (BC) who declined a test or procedure that their care provider recommended., Methods: In the Changing Childbirth in BC study, childbearing people designed a mixed-methods study, including a cross-sectional survey on experiences of provider-patient interactions over the course of maternity care. We conducted a descriptive quantitative content analysis of 1540 open ended comments about declining care recommendations., Results: More than half of all study participants (n = 2100) declined care at some point during pregnancy, birth, or the postpartum period (53.5%), making this a common phenomenon. Participants most commonly declined genetic or gestational diabetes testing, ultrasounds, induction of labour, pharmaceutical pain management during labour, and eye prophylaxis for the newborn. Some people reported that care providers accepted or supported their decision, and others described pressure and coercion from providers. These negative interactions resulted in childbearing people feeling invisible, disempowered and in some cases traumatized. Loss of trust in healthcare providers were also described by childbearing people whose preferences were not respected whereas those who felt informed about their options and supported to make decisions about their care reported positive birth experiences., Conclusions: Declining care is common during pregnancy and birth and care provider reactions and behaviours greatly influence how childbearing people experience these events. Our findings confirm that clinicians need further training in person-centred decision-making, including respectful communication even when choices fall outside of standard care.

Background: Both keratoconus (KCN) and chronic kidney disease (CKD) are multifactorial conditions with multiple aetiologies and share several common pathophysiologies. However, the few studies that have described the relationship between KCN and CKD are limited to case reports and small case series. This study aimed to evaluate the association between KCN and CKD., Methods: The study cohort included 4,609 new-onset keratoconus patients ≥ 12 years identified by the International Classification of Diseases, Ninth Revision, Clinical Modification, code 371.6 and recruited between 2004 and 2011 from the Taiwan National Health Insurance Research Database. The age-, sex-, and comorbidity-matched control group included 27,654 non-KCN patients, selected from the Taiwan Longitudinal Health Insurance Database, 2000. Information for each patient was collected and tracked from the index date until December 2013. The incidence and risk of CKD were compared between the two groups. The adjusted hazard ratios (HRs) for CKD were calculated with Cox proportional hazard regression analysis. Kaplan-Meier analysis was used to calculate the cumulative CKD incidence rate., Results: The incidence rate of CKD was 1.36 times higher in KCN patients than in controls without statistically significant difference (95 % confidence interval [CI] = 0.99-1.86, p = 0.06). In total, 29 male KCN patients and 90 male controls developed CKD during the follow-up period. The incidence rate of CKD was 1.92 times (95 % [CI] = 1.26-2.91; p = 0.002) higher in male KCN patients than in controls. After adjusting for potential confounders, including age, hypertension, hyperlipidaemia, and diabetes mellitus, male KCN patients were 1.75 times (adjusted HR = 1.75, 95 % [CI] = 1.14-2.68, p < 0.05) more likely to develop CKD., Conclusions: We found that male KCN patients have an increased risk of CKD. Therefore, it is recommended that male KCN patients should be aware of CKD.

Background: Some studies have stated that intrauterine insemination (IUI) with controlled ovarian stimulation (COS) might increase the pregnancy rate, while others suggest that IUI in the natural cycle (NC) should be the first line of treatment. It remains unclear whether it is necessary to use COS at the same time when IUI is applied to treat isolated male factor infertility. Thus, we aimed to investigate efficacy of IUI with COS for isolated male factor infertility., Methods: A total of 601 IUI cycles from 307 couples who sought medical care for isolated male factor infertility between January 2010 and February 2020 were divided into two groups: NC-IUI and COS-IUI. The COS-IUI group was further divided into two subgroups according to the number of pre-ovulatory follicles on the day of HCG: cycles with monofollicular development (one follicle group) and cycles with at least two pre-ovulatory follicles (≥ 2 follicles group). The IUI outcomes, including clinical pregnancy, live birth, spontaneous abortion, ectopic pregnancy, and multiple pregnancy rates were compared., Results: The clinical pregnancy, live birth, spontaneous abortion, and ectopic pregnancy rates were comparable between the NC-IUI and COS-IUI group. Similar results were also observed among the NC-IUI, one follicle, and ≥ 2 follicles groups. However, with respect to the multiple pregnancy rate, a trend toward higher multiple pregnancy rate was observed in the COS-IUI group compared to the NC-IUI group (8.7% vs. 0, P = 0.091), and a significant difference was found between the NC-IUI and ≥ 2 follicles group (0 vs. 16.7%, P = 0.033)., Conclusion: In COS cycles, especially in those with at least two pre-ovulatory follicles, the multiple pregnancy rate increased without a substantial gain in overall pregnancy rate; thus, COS should not be preferred in IUI for isolated male factor infertility. If COS is required, one stimulated follicle and one healthy baby should be the goal considering the safety of both mothers and foetuses.

Background: Olfactory systems take on important tasks to distinguish salient information from a complex olfactory environment, such as locating hosts, mating, aggression, selecting oviposition sites, and avoiding predators. The olfactory system of an adult insect consists of two pairs of main olfactory appendages on the head, the antennae, and the palps, which are covered with sensilla. Benzothiazole and 1-octen-3-ol could elicit oviposition behavior in gravid B. dorsalis are regarded as oviposition stimulants. However, the mechanism for how B. dorsalis percepts benzothiazole and 1-octen-3-ol still remains unknown., Results: We conducted a comparative analysis of the antennal transcriptomes in different genders of B. dorsalis using Illumina RNA sequencing (RNA-seq). We identified a total of 1571 differentially expressed genes (DEGs) among the two sexes, including 450 female-biased genes and 1121 male-biased genes. Among these DEGs, we screened out 24 olfaction-related genes and validated them by qRT-PCR. The expression patterns of these genes in different body parts were further determined. In addition, we detected the expression profiles of the screened female-biased chemosensory genes in virgin and mated female flies. Furthermore, the oviposition stimulants-induced expression profilings were used to identify chemosensory genes potentially responsible for benzothiazole and 1-octen-3-ol perception in this fly., Conclusions: The results from this study provided fundamental data of chemosensory DEGs in the B. dorsalis antenna. The odorant exposure assays we employed lay a solid foundation for the further research regarding the molecular mechanism of benzothiazole and 1-octen-3-ol mediated oviposition behavior in B. dorsalis.

Psychological stress can cause adverse health effects in animals and humans. Accumulating evidence suggests that psychological stress in female mice is associated with ovarian developmental abnormalities accompanied by follicle and oocyte defects. Oocyte and early embryonic development are impaired in mice facing psychological stress, likely resulting from hormone signalling disorders, reactive oxygen species (ROS) accumulation and alterations in epigenetic modifications, which are primarily mediated by the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian (HPO) axes. The present evidence suggests that psychological stress is increasingly becoming the most common causative factor for female subfertility. Here, we review recent progress on the impact of psychological stress on female reproduction, particularly for oocyte and early embryonic development in female mice. This review highlights the connection between psychological stress and reproductive health and provides novel insight on human subfertility.

Background: Although effective results of many studies support the use of spinal cord stimulation in chronic pain patients, no randomized controlled trial has been undertaken in China to date. CITRIP is a multicenter, prospective, randomized, withdrawal study designed to evaluate the clinical effectiveness and safety of spinal cord stimulation plus remote programming management in patients with intractable trunk or limb pain., Method: Participants will be recruited in approximately 10 centers across China. Eligible participants with intractable trunk or limb and an average visual analog scale (VAS) score ≥ 5 will undergo a spinal cord stimulation test. Participants with VAS score reduction ≥ 50% could move forward to receive implantation of an implanted pulse generator. In the withdrawal period at 3-month follow-up visit, participants randomized to the experimental group (EG) will undergo continuous stimulation while ceasing the stimulation in the control group (CG). The outcome assessment will occur at baseline and at 1, 3 (pre- and post-randomization), and 6 months. The primary outcome is the difference of maximal VAS score between EG and CG in the withdrawal period compared with baseline before the withdrawal period. Additional outcomes include VAS score change at 1-, 3-, and 6-month follow-ups; responder rate (VAS score improving by 50%); achievement rate of a desirable pain state (VAS score ≤ 4); awake times during sleep; Beck Depression Inventory for depression evaluation; short-form 36 for quality of life evaluation; drug usage; and satisfaction rating of the device. Adverse events will be collected. The primary analysis will follow the intention-to-treat principle., Discussion: The CITRIP study seeks to evaluate the effectiveness and safety of a randomized withdrawal trial of spinal cord stimulation for patients with intractable trunk or limb pain., Trial Registration: ClinicalTrials.gov NCT03858790 . Registered on March 1, 2019, retrospectively registered.

Background: A big-data-driven and artificial intelligence (AI) with machine learning (ML) approach has never been integrated with the hospital information system (HIS) for predicting major adverse cardiac events (MACE) in patients with chest pain in the emergency department (ED). Therefore, we conducted the present study to clarify it., Methods: In total, 85,254 ED patients with chest pain in three hospitals between 2009 and 2018 were identified. We randomized the patients into a 70%/30% split for ML model training and testing. We used 14 clinical variables from their electronic health records to construct a random forest model with the synthetic minority oversampling technique preprocessing algorithm to predict acute myocardial infarction (AMI) < 1 month and all-cause mortality < 1 month. Comparisons of the predictive accuracies among random forest, logistic regression, support-vector clustering (SVC), and K-nearest neighbor (KNN) models were also performed., Results: Predicting MACE using the random forest model produced areas under the curves (AUC) of 0.915 for AMI < 1 month and 0.999 for all-cause mortality < 1 month. The random forest model had better predictive accuracy than logistic regression, SVC, and KNN. We further integrated the AI prediction model with the HIS to assist physicians with decision-making in real time. Validation of the AI prediction model by new patients showed AUCs of 0.907 for AMI < 1 month and 0.888 for all-cause mortality < 1 month., Conclusions: An AI real-time prediction model is a promising method for assisting physicians in predicting MACE in ED patients with chest pain. Further studies to evaluate the impact on clinical practice are warranted.

Background: Exercise improves glycemic control and functional capacity in elderly people with diabetes; however, its effect on health-related quality of life (HRQoL) and medical resource use remains unclear. This study aims to clarify the effect of exercise., Methods: Using the data from National Health and Nutrition Examination Survey between 2007 and 2016, we identified 1572 elderly people with diabetes for this cross-sectional population-based study. Demographic characteristics, health conditions, comorbidities, HRQoL, and medical resource were compared among four groups (no exercise, low-intensity exercise, moderate-intensity exercise, and high-intensity exercise)., Results: The mean age of all participants was between 71.5 and 73.3 years. Male participants with higher education performed more exercise than their counterparts. The moderate- and high-intensity groups reported better general health condition than the no exercise group. Depression and worse health were more common in the no exercise group. Participants in the moderate-intensity exercise group had lower risk for depression than those in the no exercise group (adjusted odds ratio: 0.13, 95% confidence interval: 0.02-0.92) after adjusting for demographic characteristics, health conditions, and comorbidities, whereas participants in the low- and high-intensity exercise did not have a lower risk. The no exercise group had the highest proportions of emergency, hospitalization, and total healthcare visits., Conclusions: Exercise is associated with better HRQoL, and lack of exercise is associated with higher medical resource use in elderly people with diabetes. Encouraging exercise is recommended in this population.

Background: Long non-coding RNAs (lncRNAs) are involved in many fundamental biological processes, such as transcription regulation, protein degradation, and cell differentiation. Information on lncRNA in the melon fly, Zeugodacus cucurbitae (Coquillett) is currently limited., Results: We constructed 24 RNA-seq libraries from eight tissues (midgut, Malpighian tubules, fat body, ovary, and testis) of Z. cucurbitae adults. A total of 3124 lncRNA transcripts were identified. Among those, 1464 were lincRNAs, 1037 were intronic lncRNAs, 301 were anti-sense lncRNAs, and 322 were sense lncRNAs. The majority of lncRNAs contained two exons and one isoform. Differentially expressed lncRNAs were analyzed between tissues, and Malpighian tubules versus testis had the largest number. Some lncRNAs exhibited strong tissue specificity. Specifically expressed lncRNAs were identified and filtered in tissues of female and male Z. cucurbitae based on their expression levels. Four midgut-specific lncRNAs were validated by quantitative real-time polymerase chain reaction (RT-qPCR), and the data were consistent with RNA-seq data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of targets of midgut-specific lncRNAs indicated an enrichment of the metabolic process., Conclusions: This was the first systematic identification of lncRNA in the melon fly. Expressions of lncRNAs in multiple adult tissues were evaluated by quantitative transcriptomic analysis. These qualitative and quantitative analyses of lncRNAs, especially the tissue-specific lncRNAs in Z. cucurbitae, provide useful data for further functional studies.

Background: Long-term mechanical ventilation with hyperoxia can induce lung injury. General anesthesia is associated with a very high incidence of hyperoxaemia, despite it usually lasts for a relatively short period of time. It remains unclear whether short-term mechanical ventilation with hyperoxia has an adverse impact on or cause injury to the lungs. The present study aimed to assess whether short-term mechanical ventilation with hyperoxia may cause lung injury in rats and whether deferoxamine (DFO), a ferrous ion chelator, could mitigate such injury to the lungs and explore the possible mechanism., Methods: Twenty-four SD rats were randomly divided into 3 groups (n = 8/group): mechanical ventilated with normoxia group (MV group, FiO 2  = 21%), with hyperoxia group (HMV group, FiO 2  = 90%), or with hyperoxia + DFO group (HMV + DFO group, FiO 2  = 90%). Mechanical ventilation under different oxygen concentrations was given for 4 h, and ECG was monitored. The HMV + DFO group received continuous intravenous infusion of DFO at 50 mg•kg - 1 •h - 1 , while the MV and HMV groups received an equal volume of normal saline. Carotid artery cannulation was carried out to monitor the blood gas parameters under mechanical ventilation for 2 and 4 h, respectively, and the PaO 2 /FiO 2 ratio was calculated. After 4 h ventilation, the right anterior lobe of the lung and bronchoalveolar lavage fluid from the right lung was sampled for pathological and biochemical assays., Results: PaO 2 in the HMV and HMV + DFO groups were significantly higher, but the PaO 2 /FiO 2 ratio were significantly lower than those of the MV group (all p < 0.01), while PaO 2 and PaO 2 /FiO 2 ratio between HMV + DFO and HMV groups did not differ significantly. The lung pathological scores and the wet-to-dry weight ratio (W/D) in the HMV and HMV + DFO groups were significantly higher than those of the MV group, but the lung pathological score and the W/D ratio were reduced by DFO (p < 0.05, HMV + DFO vs. HMV). Biochemically, HMV resulted in significant reductions in Surfactant protein C (SP-C), Surfactant protein D (SP-D), and Glutathion reductase (GR) levels and elevation of xanthine oxidase (XOD) in both the Bronchoalveolar lavage fluid and the lung tissue homogenate, and all these changes were prevented or significantly reverted by DFO., Conclusions: Mechanical ventilation with hyperoxia for 4 h induced oxidative injury of the lungs, accompanied by a dramatic reduction in the concentrations of SP-C and SP-D. DFO could mitigate such injury by lowering XOD activity and elevating GR activity.

Background: Patisiran, an RNA interference therapeutic, has demonstrated robust reduction of wild-type and mutant transthyretin protein and was able to improve polyneuropathy and quality of life following 18 months of treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. In this 24-month Phase II open-label extension study, we evaluated the effects of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on safety, serum transthyretin levels, and clinical parameters. Efficacy assessments included modified Neuropathy Impairment Score +7 (mNIS+7) and multiple disease-relevant measures. Cardiac assessments were performed in a pre-specified cardiac subgroup., Results: Twenty-seven patients entered this study, including 12 (44%) with ambulation difficulties due to their neuropathy and 11 (41%) who met criteria for the cardiac subgroup. During treatment, the majority of adverse events were mild/moderate in severity; there were no drug-related adverse events leading to treatment discontinuation. The most common drug-related adverse events were flushing and infusion-related reactions (22% each). Patisiran resulted in rapid, robust (~ 82%), and sustained reduction of mean transthyretin levels over 24 months. A mean 6.95-point decrease (improvement) in mNIS+7 from baseline was observed at 24 months. Patisiran's impact on mNIS+7 was irrespective of concomitant tafamidis or diflunisal use, sex, or age. Clinical assessments of motor function, autonomic symptoms, disease stage, and quality of life remained stable over 24 months. No significant changes were observed for echocardiographic measures or cardiac biomarkers in the cardiac subgroup. Exploratory analyses demonstrated improvements in nerve-fiber density with corresponding reductions in amyloid burden observed in skin biopsies over 24 months., Conclusions: Long-term treatment with patisiran had an acceptable safety profile and was associated with halting/improvement of polyneuropathy progression in patients with hATTR amyloidosis., Trial Registration: The study was registered at ClinicalTrials.gov (identifier: NCT01961921 ) on October 14, 2013.

Background: The effects of C-type natriuretic peptide (CNP) and fibroblast growth factor (FGF)-23 appear to oppose each other during the process of bone formation, whereas few studies exist on the interaction between CNP and FGF-23. The main objective of the present study is to probe whether CNP is directly responsible for the regulation of osteoblast or via antagonizing FGF-23., Methods: Osteoblasts were cultured in the absence or presence of CNP (0, 10, and 100 pmol/L) for 24 h, 48 h and 72 h, respectively., Results: The findings of the present study indicated that: (1) CNP significantly stimulated osteoblastic proliferation and collagen (Col)-X expression; (2) both osteoblastic (osteocalcin, procollagen type I carboxy-terminal propeptide, total alkaline phosphatase and bone-specific alkaline phosphatase) and osteolytic (tartrate-resistant acid phosphatase and cross-linked carboxyterminal telopeptide of type I collagen) bone turnover biomarkers were up-regulated by CNP in osteoblasts; (3) FGF-23 mRNA and protein were significantly down-regulated at 24 h by CNP in osteoblasts, but the expression of FGF receptor-1/Klotho had no significant change., Conclusions: CNP stimulates osteoblastic proliferation and Col-X expression via the down-regulation of FGF-23 possibly in vitro. However, the specific mechanisms of the interaction between CNP and FGF-23 in osteoblasts are still unclear according to our findings. A further study on osteoblasts cultured with CNP and FGF-23 inhibitor will be undertaken in our laboratory.

Background: Recent studies reported that patients with coronavirus disease-2019 (COVID-19) might have liver injury. However, few data on the combined analysis and change patterns of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) have been shown., Methods: This is a single-center retrospective study. A total of 105 adult patients hospitalized for confirmed COVID-19 in Beijing Ditan Hospital between January 12, and March 17, 2020 were included, and divided into mild group (n = 79) and severe group(n = 26). We compared liver functional test results between the two groups. Category of ALT change during the disease course was also examined., Results: 56.2% (59/105) of the patients had unnormal ALT, AST, or total TBil throughout the course of the disease, but in 91.4% (96/105) cases the level of ALT, AST or TBil ≤3 fold of the upper limit of normal reference range (ULN). The overall distribution of ALT, AST, and TBil were all significantly difference between mild and severe group (P <  0.05). The percentage of the patients with elevated both ALT and AST was 12.7% (10/79) in mild cases vs. 46.2% (12/26) in severe cases (P = 0.001). 34.6% (9/26) severe group patients started to have abnormal ALT after admission, and 73.3% (77/105) of all patients had normal ALT before discharge., Conclusions: Elevated liver function index is very common in patients with COVID-19 infection, and the level were less than 3 × ULN, but most are reversible. The abnormality of 2 or more indexes is low in the patients with COVID-19, but it is more likely to occur in the severe group.