OBJECTIVE To provide valuable insights for the adjustment of anti-infectious regimens， identification of adverse reactions， and individualized pharmaceutical care in patients with critically severe scrub typhus. METHODS Clinical pharmacists actively participated in the pharmaceutical care process for a patient with severe scrub typhus leading to mixed shock undergoing continuous renal replacement therapy and extracorporeal membrane oxygenation. Initially， the patient received meropenem （1 g， q12 h， ivdrip）， in combination with doxycycline （0.1 g， q12 h， po）， which was later switched to meropenem （1 g， q8 h， ivdrip） along with omacycline （100 mg， qd， ivdrip） due to impaired gastrointestinal function. However， as the patient’s condition progressively deteriorated and the infection became uncontrolled， the clinical pharmacists recommended that the clinicians adjust the anti-infective regimen to meropenem （2 g， q8 h， ivdrip） combined with tigecycline （100 mg for first dose； 50 mg， q12 h for maintenance； ivdrip）. The clinicians followed the advice of the clinical pharmacists. After treatment， the patient’s symptoms exhibited significant improvement， accompanied by a notable decrease in inflammatory markers， indicating that the infection had been successfully controlled. However， due to continuously increasing bilirubin levels， in order to reduce the risk of drug-induced liver injury， the clinicians changed tigecycline to azithromycin （0.5 g， qd， ivdrip） following the recommendation of the clinical pharmacists. RESULTS Ultimately， metagenomic next-generation sequencing of the bronchoalveolar lavage fluid and blood specimens indicated that Orientia tsutsugamushi had been completely eradicated in the patient. CONCLUSIONS Tigecycline may be a viable therapeutic choice for patients with severe scrub typhus. In the context of critically ill patients with scrub typhus， combining tigecycline with azithromycin might potentially enhance the efficacy in eliminating Orientia tsutsugamushi.

BACKGROUND:Liuwei Dihuang Wan takes"three tonifying and three reducing effects"as its compatibility feature to nourish yin and tonify the kidneys,while Zuogui Wan takes"seeking yin in yang"as its compatibility feature to nourish yin and tonify the kidneys by promoting yang.Both of them belong to the same method of nourishing yin and tonifying the kidneys,and have better curative effects at the symptomatic and cellular molecular levels. OBJECTIVE:To observe the effects of Liuwei Dihuang Wan and Zuogui Wan in bone metabolism,and to explore their mechanism of action in the osteoprotegerin(OPG)/receptor activator of nuclear factor-κB ligand(RANKL)osteoblastic pathway. METHODS:Thirty-two Sprague-Dawley rats were randomized into model,Liuwei Dihuang Wan,Zuogui Wan,and sham operation group,with eight rats in each group.Osteoporosis models were prepared using removal of both ovaries in the first three groups.Starting at 30 days postoperatively,rats in the Liuwei Dihuang Wan group were gavaged with Liuwei Dihuang Wan 1.125 g/kg/d;rats in the Zuoqui Wan group were gavaged with Zuogui Wan 2.25 g/kg/d;and rats in the sham operation group and the model group were gavaged with saline 10 mL/kg/d.After 12 weeks of gavage,the rat tibia was taken to measure bone mineral density.The serum levels of estrogen,bone alkaline phosphatase,and cAMP/cGMP were measured using ELISA,and the expression of OPG/RANKL in the femur was detected using western blot. RESULTS AND CONCLUSION:Compared with the sham operation group,the model group showed a decrease in bone mineral density and levels of estrogen and bone alkaline phosphatase(P＜0.05)and an increase in cAMP/cGMP level(P＜0.05).Compared with the model group,the Liuwei Dihuang Wan group and the Zuogui Wan group significantly increased bone mineral density(P＜0.05)and bone alkaline phosphatase levels(P＜0.05);the Zuogui Wan group significantly decreased cAMP/cGMP levels(P＜0.05)and upregulated OPG expression(P＜0.05);the Liuwei Dihuang Wan group upregulated OPG expression and downregulated RANKL expression(P＜0.05);and both groups were unable to significantly increase estrogen levels(P＞0.05).To conclude,Zuogui Wan,which seeks yin from yang,can effectively increase the expression of OPG but cannot downregulate the expression of RANKL.However,Liuwei Dihuang Wan,which has three tonifying and three reducing effects,can bidirectionally regulate the expression of OPG and RANKL.This result suggests that Liuwei Dihuang Wan can significantly inhibit osteoclastic function compared with Zuogui Wan,and further research is needed to verify this conclusion.

BACKGROUND:Studies have reported that alendronate intake significantly increases bone mineral density in patients with osteoporosis. OBJECTIVE:To analyze and compare the changes in metabolites before and after alendronate intervention in ovariectomized rats by chromatography-mass spectrometry,and to further explore the specific mechanism and target of alendronate in the treatment of osteoporosis. METHODS:A total of 36 female Sprague-Dawley rats were randomly divided into model group,alendronate sodium group and sham operation group.The osteoporosis model was established by ovariectomy in the first two groups.Four weeks after modeling,the rats in the alendronate group were intragastrically given alendronate sodium,while those in the sham operation group and model group were given equal volume of normal saline.After 12 weeks of continuous gavage,the metabolites of the lumbar spine were analyzed by chromatography-mass spectrometry,and the common differential metabolites were obtained,which were analyzed by bioinformatics such as Kyoto Gene and Genome Encyclopedia pathway. RESULTS AND CONCLUSION:Totally 17 different metabolites were obtained in the three groups.The enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes showed that alendronate sodium could regulate unsaturated fatty acid biosynthesis,linoleic acid metabolism and other pathways to protect ovariectomized rats.These results indicate that alendronate sodium may exert its anti-osteoporosis effect by interfering with unsaturated fatty acid bioanabolism and linoleic acid metabolism,so as to achieve the purpose of preventing osteoporosis

BACKGROUND: Postoperative pulmonary complications (PPCs) are major adverse events in neurosurgical patients. This study aimed to develop and validate machine learning models predicting PPCs after neurosurgery. METHODS: PPCs were defined according to the European Perioperative Clinical Outcome standards as occurring within 7 postoperative days. Data of cases meeting inclusion/exclusion criteria were extracted from the anesthesia information management system to create three datasets: The development (data of Huashan Hospital, Fudan University from 2018 to 2020), temporal validation (data of Huashan Hospital, Fudan University in 2021) and external validation (data of other three hospitals in 2023) datasets. Machine learning models of six algorithms were trained using either 35 retrievable and plausible features or the 11 features selected by Lasso regression. Temporal validation was conducted for all models and the 11-feature models were also externally validated. Independent risk factors were identified and feature importance in top models was analyzed. RESULTS: PPCs occurred in 712 of 7533 (9.5%), 258 of 2824 (9.1%), and 207 of 2300 (9.0%) patients in the development, temporal validation and external validation datasets, respectively. During cross-validation training, all models except Bayes demonstrated good discrimination with an area under the receiver operating characteristic curve (AUC) of 0.840. In temporal validation of full-feature models, deep neural network (DNN) performed the best with an AUC of 0.835 (95% confidence interval [CI]: 0.805-0.858) and a Brier score of 0.069, followed by Logistic regression (LR), random forest and XGBoost. The 11-feature models performed comparable to full-feature models with very close but statistically significantly lower AUCs, with the top models of DNN and LR in temporal and external validations. An 11-feature nomogram was drawn based on the LR algorithm and it outperformed the minimally modified Assess respiratory RIsk in Surgical patients in CATalonia (ARISCAT) and Laparoscopic Surgery Video Educational Guidelines (LAS VEGAS) scores with a higher AUC (LR: 0.824, ARISCAT: 0.672, LAS: 0.663). Independent risk factors based on multivariate LR mostly overlapped with Lasso-selected features, but lacked consistency with the important features using the Shapley additive explanation (SHAP) method of the LR model. CONCLUSIONS: The developed models, especially the DNN model and the nomogram, had good discrimination and calibration, and could be used for predicting PPCs in neurosurgical patients. The establishment of machine learning models and the ascertainment of risk factors might assist clinical decision support for improving surgical outcomes. TRIAL REGISTRATION ChiCTR 2100047474; https://www.chictr.org.cn/showproj.html?proj=128279 .
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Algorithms ; Lung Diseases/etiology* ; Machine Learning ; Neurosurgical Procedures/adverse effects* ; Postoperative Complications/diagnosis* ; Risk Factors ; ROC Curve

Age-related macular degeneration (AMD) is a disease that affects the vision of elderly individuals worldwide. Although current therapeutics have shown effectiveness against AMD, some patients may remain unresponsive and continue to experience disease progression. Therefore, in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment. Recently, studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species (ROS) and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) innate immunity pathways, ultimately resulting in sterile inflammation and cell death in various cells, such as cardiomyocytes and macrophages. Therefore, combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management. Notably, emerging evidence indicates that natural products targeting mitochondrial quality control (MQC) and the cGAS/STING innate immunity pathways exhibit promise in treating AMD. Here, we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways, as well as their interconnected mediators, which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses, thereby hoping to offer new insights into therapeutic interventions for AMD treatment.

Objective To investigate the effect of melanoma associated antigen D1 (Mage-D1)on mouse femoral bone mass and mineralization ability of mouse bone marrow mesenchymal cells (BMSCs)and its potential molecular mechanism.Methods Female Mage-D1 gene knockout heterozygous mice and male wild-type (WT)mice were subjected as parent mice to breed Mage-D1 gene knockout homozygous (Mage-D1 KO)mice.PCR and agarose gel electrophoresis were used to identify male Mage-D1 knockout (Mage-D1 KO)mice and littermate male wild-type (WT)mice.Micro-CT scanning was performed to observe mouse femoral bone mass,and ELISA and chemical assay were employed to detect serum levels of calcium,phosphorus,calcitonin,and parathyroid hormone in mice.After primary cultured BMSCs were identified with flow cytometry,immunofluorescence staining was utilized to detect the expression of Mage-D1 in BMSCs.BMSCs were infected by Mage-D1 silencing lentivirus,and then the cells were divided into negative control group (sh-NC)and silencing group (sh-Mage-D1).Cell scratch assay was conducted to detect the migration ability of BMSCs,and flow cytometry and CCK-8 assay were conducted to detect the cycle change and proliferation ability of BMSCs.After mineralization induction,alkaline phosphatase (ALP) staining and alizarin red staining were performed;RT-qPCR and Western blotting were used to measure the expression levels of ALP,Runx2 and Col1.RT-qPCR was used to detect mineralization-related genes p75NTR and Msx1.Results Compared with the WT mice,the femoral cortical bone thickness,cortical bone mineral content,cancellous bone mineral content,trabecular number,and cancellous bone surface density were decreased,and trabecular separation was increased in the Mage-D1 knockout homozygous mice (P<0.05).There were no significant changes in the serum levels of calcium,phosphorus,calcitonin and parathyroid hormone in mice after Mage-D1 knockout.Mage-D1 was expressed in the whole BMSCs and was highly expressed in the nucleus and perinuclear regions.Compared with the sh-NC BMSCs,the sh-Mage-D1 group had decreased proliferation ability (P<0.01),enhanced migration ability (P<0.01),and decreased expression of ALP,Runx2 and Col1 genes (P<0.05)and protein (P<0.01)after mineralization induction,milder ALP and alizarin red stain,and lower expression levels of p75NTR and Msx1.Conclusion Mage-D1 knockout can significantly reduce femur bone mass in mice.It can promote the proliferation and inhibit migration of BMSCs,and positively regulate their mineralization in vitro,and the p75NTR-Dlx1/Msx1 signaling axis may be involved in the regulation of bone metabolism by Mage-D1.

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

BACKGROUND:The mechanisms and targets of alendronate in the treatment of osteoporosis still need to be investigated in depth. OBJECTIVE:To investigate the mechanism by which alendronate regulates bone metabolism in rats with osteoporosis and to perform a bioinformatics analysis of differentially expressed proteins. METHODS:Female Sprague-Dawley rats were randomly divided into three groups(n=12 per group):model group,alendronate group and sham-operated group.Animal models of osteoporosis were prepared using ovariectomy in the model and alendronate groups.At 4 weeks after modeling,rats in the alendronate group were gavaged with alendronate;the other two groups were given the equal volume of normal saline.After 12 weeks of continuous gavage,the bone mineral density of the tibia was measured and the lumbar spine of the rats was taken for proteomic analysis using Tandem mass tag-liquid chromatography-tandem mass spectrometry technique to identify differentially expressed proteins for gene ontology,Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction analysis. RESULTS AND CONCLUSION:There were 32 up-regulated proteins and 51 down-regulated proteins identified between the alendronate group and model group.Gene ontology enrichment analysis showed that the differentially expressed proteins were mainly involved in molecular functions,such as binding and catalytic activity,and in biological processes,such as cellular process and metabolic process.Kyoto Encylopedia of Genes and Genomes enrichment analysis showed that the differentially expressed proteins in the alendronate group and model group were mainly involved in the biosynthesis of pantothenate and coenzyme A.Protein-protein interaction analysis indicated that among the differentially expressed proteins in the alendronate group and model group,Hspa1l,Enpp3,Unc45a,Myh9 and Cant1 were located at the nodes of the protein-protein interaction network and were closely related to bone metabolism.Overall,these findings indicate that alendronate may regulate bone metabolism in the rat model of osteoporosis by regulating the expression of differentially expressed proteins and biosynthesis of pantothenate and coenzyme A.

OBJECTIVE To study the improvement effect and mechanism of Shuhou tongqi formula on intestinal injury in mice with postoperative ileus （POI）. METHODS Mice were randomly divided into sham operation group， model group， positive control group （Mosapride citrate tablets， 1.95 mg/kg）， and Shuhou tongqi formula group （1.88 g/kg）， with 6 mice in each group. Except for the sham operation group， POI model was induced in other groups by typical small intestinal interference. Each group was given relevant drug liquid/water， once a day， for consecutive 2 days. After the last medication， the percentage of carbon powder propulsion in small intestine was detected， and pathomorphological changes in ileum tissue of mice were observed. The serum levels of interleukin-6 （IL-6）， IL-10， tumor necrosis factor-α （TNF-α）， motilin （MTL） and somatostatin （SS） were all detected； the expression levels of Toll-like receptor 4 （TLR4）， nuclear factor κB （NF-κB p65） and p38 mitogen-activated protein kinase （p38 MAPK） were determined in ileal tissue of mice； the gut microbiota of colon contents was analyzed in each group of mice. RESULTS After the intervention of Shuhou tongqi formula， pathological damage such as intestinal wall atrophy and mucosal capillary congestion in ileum tissue were improved significantly； the percentage of carbon powder propulsion and the serum level of IL-10 and MTL were increased significantly （P＜0.05）； however， serum levels of TNF-α， IL-6 and SS， the expressions of TLR4， NF-κB p65 and p38 MAPK were decreased significantly （P＜0.05）. The analysis of gut microbiota showed that Shuhou tongqi formula could significantly increase ACE， Chao1， Shannon and PD indexes， and relative abundance of Akkermansia （P＜0.05）， but decreased relative abundance of Proteobacteria， Ligilactobacillus and Escherichia-Shigella significantly （P＜0.05）. CONCLUSIONS Shuhou tongqi formula can improve intestinal injury and inflammatory reaction of POI mice， the mechanism of which may be associated with inhibiting the activity of TLR4/ NF-κB/MAPK signaling pathway， regulating the levels of gastrointestinal hormones and improving the disturbance of intestinal flora in mice. E-mail：1643589936@qq.com

Objective To analyze the antibody types of autoimmune hemolytic anemia(AIHA)patients in Panyu dis-trict,Guangzhou and track the therapeutic effect of blood transfusion,so as to provide reference for clinical transfusion treat-ment strategy of AIHA patients.Methods From January 2021 to October 2023,96 ambiguous cross-matching blood sam-ples from Blood Transfusion Departments of local hospitals sent to Panyu Central Blood Station were analyzed,and 25 sam-ples of AIHA patients were identified.Then blood group identification,Rh system antigen phenotyping,antibody screening and cross-matching were further performed to analyze the correlation between antibody types and transfusion efficacy in AIHA patients.Results Among the 25 samples of AIHA patients,17 showed consistency between forward and reverse blood grouping and8 showed discrepancy.There were 19(19/25,76%)samples incompatible in cross match on the major side,of which 18(18/19,94.7%)were positive for direct Coombs test,autoantibodies and non-specific antibodies,and1(1/19,5.3%)was positive for autoantibody and alloantibody.There were 6(6/25,24%)samples compatible in cross match on the major side,of which 3(3/6,50%)were positive for autoantibodies,3(3/6,50%)were positive for au-toantibody and alloantibody.Of the 25 AIHA patients,20 received blood transfusion treatment and could be traced,and 5 patients did not receive blood transfusion treatment or transferred to other hospitals and could not be traced.Blood transfu-sion was effective in 11(11/20,55%)cases,partially effective in 6(6/20,30%)cases,and ineffective in 3(3/20,15%)cases.Among the ABO blood group incompatibility samples,transfusion was effective or partially effective in 17(17/20,85%)cases.Conclusion The transfusion efficacy of AIHA patients is not directly related to the results of cross-matc-hing.Under the premise of regulating the autoimmune environment and eliminating the ABO blood group incompatibility caused by unexpected alloantibodies,AIHA patients with incompatible cross-matching can be transfused when necessary,and transfusion of ABO and Rh system antigen homologous blood can improve the safety and efficiency of transfusion.