OBJECTIVE To investigate the efficacy and safety of doxycycline in the treatment of macrolide-unresponsive Mycoplasma pneumoniae pneumonia （MUMPP） in children under 8 years of age. METHODS The medical records of children with MUMPP admitted to the Women and Children’s Hospital Affiliated to Ningbo University were collected from January 1st， 2023 to December 31st， 2023. They were divided into doxycycline group （44 cases）， doxycycline combined with methylprednisolone group （35 cases）， and azithromycin combined with methylprednisolone group （35 cases） according to the treatment methods. Doxycycline group was given Doxycycline hyclate enteric-coated capsules； doxycycline combined with methylprednisolone group was given Doxycycline hyclate enteric-coated capsules and Methylprednisolone sodium succinate for injection； azithromycin combined with methylprednisolone group was given Azithromycin for injection and Methylprednisolone sodium succinate for injection. Treatment courses of 3 groups lasted for 10 d. The fever reduction rate， the time of fever reduction and improvement rate of lung infection absorption were compared among the three groups. The occurrence of adverse drug reactions was recorded during their hospitalization and followed up within 5 months after discharge. RESULTS The fever reduction rats 48， 72 h after treatment and improvement rate of lung infection absorption in doxycycline group and doxycycline combined with methylprednisolone group were significantly higher than azithromycin combined with methylprednisolone group； the time of fever reduction was significantly shorter than azithromycin combined with methylprednisolone group （P＜0.05）； there was no statistical significance in the difference between the doxycycline group and the doxycycline combined with methylprednisolone group （P＞0.05）. There was no statistical significance in the incidence of rash， vomiting， abdominal pain， diarrhea， and elevated transaminases among the three groups during hospitalization and within 5 months after discharge （P＞0.05）. None of the children treated with doxycycline suffered from tooth discoloration or enamel hypoplasia. CONCLUSIONS Doxycycline has good efficacy and safety in therapy of MUMPP in children under 8 years of age； adjunctive coadministration of low-dose glucocorticoids does not necessarily result in significant additional efficacy.

BACKGROUND:Eucommia ulmoides has a certain osteogenic effect,which can promote the proliferation and differentiation of osteoblasts.However,it is unclear whether Eucommia ulmoides has effects on alveolar bone formation and Wnt/β-Catenin signaling pathway. OBJECTIVE:To investigate the mechanism by which Eucommia ulmoides promotes alveolar bone formation in ovariectomized rats based on the Wnt/β-Catenin signaling pathway. METHODS:Sixty female Sprague-Dawley rats were selected and randomly divided into five groups:blank control group,sham-operation group,model group,low-dose group Eucommia ulmoides group,and high-dose Eucommia ulmoides group,with twelve rats in each group.Osteoporosis animal models were constructed by bilateral oophorectomy in the model group and the low-dose and high-dose Eucommia ulmoides groups.The sham-operation group underwent the same method to remove adipose tissue of equal mass around the bilateral ovaries.Three months after surgery,the low-and high-dose Eucommia ulmoides groups were given 2.1 g/kg/d and 4.2 g/kg/d Eucommia ulmoides by gavage,respectively.The sham-operation group and model group were given the same amount of physiological saline by gavage.After 12 weeks of drug intervention,the changes in alveolar bone mass of rats in each group were observed through Micro-CT;hematoxylin-eosin staining was used to observe the pathological structural changes of alveolar bone in rats;enzyme linked immunosorbent assay was used to detect the expression levels of alkaline phosphatase and osteocalcin in the serum of rats;western blot was used to detect the expression levels of β-Catenin and Frizzled9 receptor proteins in the alveolar bone of rats;and real-time fluorescence quantitative PCR was used to detect the expression of osteocalcin,Runt-related transcription factor 2(Runx2),alkaline phosphatase,β-catenin,and frizzled9 mRNAs in alveolar bone tissues of rats. RESULTS AND CONCLUSION:Compared with the blank control group,bone volume fraction,trabecular number,trabecular thickness,and bone mineral density were reduced in the model group(P＜0.05),and trabecular separation was elevated(P＜0.05).Pathological observation showed that the arrangement of trabeculae was disordered and irregular,the trabeculae were thinned or broken,and the marrow cavity was enlarged in the model group,with a significant reduction in bone volume;the level of alkaline phosphatase in the serum was increased(P＜0.05),and the level of osteocalcin was decreased(P＜0.05);mRNA expression of alkaline phosphatase,osteocalcin,Runx2,β-catenin,and frizzled9 were decreased(P＜0.05);protein expression of β-Catenin and Frizzled9 was decreased(P＜0.05).Compared with the model group,the low-and high-dose Eucommia ulmoides groups showed an increase in bone volume fraction,trabecular number,trabecular thickness,and bone mineral density(P＜0.05)and a decrease in trabecular separation(P＜0.05).In the low-and high-dose Eucommia ulmoides groups,bone trabeculae were slightly aligned and thickened,with a significant increase in bone mass.Compared with the model group,the serum level of alkaline phosphatase was reduced(P＜0.05)and the serum level of osteocalcin was elevated(P＜0.05)in the low-and high-dose Eucommia ulmoides groups.Compared with the model group,the mRNA expression of alkaline phosphatase,osteocalcin,Runx2,β-catenin,and frizzled9 were increased in the low-and high-dose Eucommia ulmoides groups(P＜0.05).Compared with the model group,the protein expression of Frizzled9 was increased in the low-dose Eucommia ulmoides group(P＜0.05),while the protein expression of β-Catenin and Frizzled9 was increased in the high-dose Eucommia ulmoides group(P＜0.05).Compared with the low-dose Eucommia ulmoides group,the high-dose Eucommia ulmoides group had a more significant improvement in the above indexes.To conclude,Eucommia ulmoides can effectively promote the alveolar bone formation,and its mechanism of action might be related to the activation of the Wnt/β-catenin signaling pathway.

Protozoan infections (e.g., malaria, trypanosomiasis, and toxoplasmosis) pose a considerable global burden on public health and socioeconomic problems, leading to high rates of morbidity and mortality. Due to the limited arsenal of effective drugs for these diseases, which are associated with devastating side effects and escalating drug resistance, there is an urgent need for innovative antiprotozoal drugs. The emergence of drug repurposing offers a low-cost approach to discovering new therapies for protozoan diseases. In this review, we summarize recent advances in drug repurposing for various human protozoan diseases and explore cost-effective strategies to identify viable new treatments. We highlight the cross-applicability of repurposed drugs across diverse diseases and harness common chemical motifs to provide new insights into drug design, facilitating the discovery of new antiprotozoal drugs. Challenges and opportunities in the field are discussed, delineating novel directions for ongoing and future research.

OBJECTIVE: To develop and validate a predictive model for the risk of bloodstream infection (BSI) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). METHODS: A literature search was conducted in PubMed, Cochrane Library, and Embase databases from inception to July 2022 to identify studies reporting statistically significant risk factors for CRKP-BSI. Relative risks (RR) were extracted and pooled. Based on factor weights, a risk-scoring model was established. For external validation, hospitalized CRKP-infected patients from January 2016 to January 2022 at Shanghai First People's Hospital were included. Clinical data were used to calculate individual risk scores. The predictive accuracy was assessed using receiver operator characteristic curve (ROC curve). Patients were stratified into low-to-intermediate-risk and high-risk groups based on the optimal cut-off, and CRKP BSI incidence was compared between groups. RESULTS: The literatures related to the risk factors of CRKP-BSI published from database inception to July 2022 was retrieved and screened from PubMed, Cochrane Library, and Embase. Fourteen risk factors were included in the scoring model: cardiovascular disease, severe neutropenia or immunosuppression, intensive care unit (ICU) stay history, prior hospitalization, carbapenem exposure, aminoglycoside exposure, antifungal exposure, endotracheal intubation or tracheostomy, mechanical ventilation, hemodialysis, central venous catheter, indwelling urinary catheter, CRKP colonization, and Klebsiella pneumoniae positivity at non infection sites. The total score ranged from 0 to 173.5 points. In the validation cohort of 230 CRKP-infected patients, 41 developed CRKP BSI. The model yielded an area under the curve (AUC) of 0.783 (95%CI was 0.689-0.876). The optimal cut off was 81.25 points, with sensitivity of 75.6% and specificity of 81.0%. Based on this cut off, 163 patients were categorized as low-to-intermediate risk and 67 patients as high risk. The incidence of CRKP BSI in the high-risk group was significantly higher than in the low-to-intermediate-risk group [64.2% (43/67) vs. 4.9% (8/163); RR = 13.175 (95%CI was 5.920-29.319), P < 0.001]. CONCLUSIONS The model, based on 14 routinely available clinical parameters, demonstrated good performance in predicting CRKP BSI risk and may assist clinicians in early identification of high risk patients.
Humans ; Klebsiella pneumoniae/drug effects* ; Klebsiella Infections/microbiology* ; Carbapenems/pharmacology* ; Risk Factors ; Bacteremia/microbiology* ; ROC Curve ; Carbapenem-Resistant Enterobacteriaceae

Compared with conventional transdermal drug delivery systems, dissolving microneedles significantly enhance drug bioavailability by penetrating the stratum corneum barrier and achieving intradermal drug delivery. In order to improve the transdermal bioavailability of dexmedetomidine hydrochloride, in this study, a novel microneedle delivery system was developed for dexmedetomidine hydrochloride based on 3D printing combined with micro-molding. By systematically optimizing the microneedle geometrical parameters, array arrangement, and preparation process parameters, we determined the optimal ratio of drug-carrying matrix as 15% PVP (polyvinyl pyrrolidone) K90. The microneedles exhibited significant drug loading gradients, with mean content of (209.99±27.56) μg/patch, (405.31±30.31) μg/patch, and (621.61±34.43) μg/patch. They showed a regular pyramidal structure under SEM and handheld electron microscopy, and their mechanical strength allowed effective penetration into the stratum corneum. The surface contact angles were all < 90°, indicating excellent hydrophilicity. The microneedles dissolved completely within 10 min after skin insertion, achieving a cumulative release rate of 90% (Higuchi model, r=0.996) during 2 hours of in vitro transdermal permeation. The cytotoxicity test and hemolysis test verified good biocompatibility. Pharmacodynamic evaluation showed that the microneedle group demonstrated pain-relieving effect within 15 min, with the pain threshold at the time point of 60 min being 3 times that in the transdermal cream group. The microneedle system developed in this study not only offers an efficient drug delivery option for patients but also establishes an innovative platform for rapid percutaneous delivery of hydrophilic drugs, demonstrating significant potential in perioperative pain management.
Dexmedetomidine/pharmacokinetics* ; Printing, Three-Dimensional ; Needles ; Drug Delivery Systems/methods* ; Administration, Cutaneous ; Animals ; Microinjections/instrumentation* ; Skin Absorption ; Skin/metabolism*

Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells, vascular smooth muscle cells, and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.
Humans ; Vascular Endothelial Growth Factor A/metabolism* ; Endothelial Cells/metabolism* ; Transcription Factors/metabolism* ; Gene Expression Regulation ; Hypoxia/metabolism* ; Cell Hypoxia/physiology*

Objective To explore the correlation between the incidence of foodborne diseases and meteorological factors in Jinan, and to provide targeted measures for the prevention and control of foodborne diseases. Methods Data from the reporting systems of two sentinel hospitals for active surveillance of foodborne diseases from 2013 to 2021 in Jinan were collected. The meteorological data in the same period in Jinan were also collected. The generalized additive model was used to explore the nonlinear relationship between meteorological factors and the incidence of foodborne diseases, and threshold function analysis was use to perform subsection regression. Results The incidence of foodborne diseases was positively correlated with daily average temperature (r_s=0.23), relative humidity (r_s=0.05), and daily average wind speed (r_s=0.01), and negatively correlated with daily average air pressure (r_s=-0.19). Based on the GAM results and segmented regression analysis of meteorological factors, it was found that when the daily average temperature was below or above the threshold of 24.63°C, for every 1°C increase in daily average temperature, the incidence of foodborne diseases correspondingly increased by 0.04% and 0.18%. When the daily average wind speed was above the threshold of 2.26 m/s, the incidence of foodborne diseases decreased by 0.36% for every 1 m/s increase in the daily average wind speed. Conclusion Nine years of observation and data analysis have shown that meteorological factors such as daily average temperature, relative humidity, air pressure, and wind speed are related to the incidence of foodborne diseases. These findings suggest that meteorological factors may be important factors leading to foodborne diseases, which provides an important scientific basis for formulating effective prevention and control measures.

Objective:To explore the effectiveness and safety of endoscopic ultrasound-guided pancreatic duct drainage (EUS-PD).Methods:A retrospective analysis was conducted on data of 16 patients who underwent EUS-PD because of endoscopic retrograde pancreatography (ERP) failure, poor effectiveness or anatomical changes and couldn't undergo the routine ERP in Nanjing Drum Tower Hospital from June 2018 to July 2022. The technical success of EUS-PD, clinical efficacy and post-procedure adverse events were analyzed.Results:In the 16 patients, there were 14 males and 2 females, with age of 50.69±12.95 years. A total of 19 times of EUS-PD operations were included, 3 of them were rendezvous-assisted endoscopic retrograde pancreatography (RV-ERP), 15 transgastric or transenteric EUS-guided stent placement and 1 was EUS-guided nasopancreatic duct placement. Technical success was achieved in 84.21% (16/19) patients, and among whom 93.75% (15/16) achieved clinical success. The overall incidence of postoperative adverse events was 52.63% (10/19) including 47.37% (9/19) abdominal pain, 15.79% (3/19) fever and 15.79% (3/19) postoperative pancreatitis. All adverse effects were relieved after general conservative treatment and no primary disease or surgery-related death occurred. The mean follow-up was 17.6 (8.2,22.3) months and 93.75% (15/16) of the patients were followed up. By the time of follow-up, 76.92% (10/13) of the patients who had successfully received EUS-PD had no recurrence of abdominal pain or distension.Conclusion:EUS-PD is a safe and effective alternative therapy for those with pancreatic diseases with ERP failure, poor efficacy or anatomical changes.