Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that Phocaeicola vulgatus abundance was approximately 12 times higher in nonresponders than in responders. P. vulgatus rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in P. vulgatus-colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for P. vulgatus-rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing P. vulgatus growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.

Objective:To compare the efficacy of minimally invasive steel plate combined with percutaneous hollow nail fixation through the sinus tarsi incision versus "L"-shaped incision steel plate fixation in the treatment of calcaneal fractures.Methods:A retrospective analysis was conducted on 103 cases of Sanders type II-IV calcaneal fractures treated with minimally invasive steel plate combined with percutaneous hollow nail fixation through sinus tarsi incision from January 2017 to March 2024 at the orthopedic department of Hangzhou Sir Run Run Shaw Hospital (minimally invasive group). An additional 103 cases treated with "L"-shaped incision steel plate fixation during the same period were included as controls (open group). The preoperative hospital stay, surgical time, postoperative hidden blood loss, postoperative hospital stay, postoperative infection rate, postoperative Bohler angle, Gissane angle, calcaneal mid-width, sustentacular effective fixation rate, and American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score at 6 and 12 months postoperatively were compared between the two groups.Results:There were no statistically significant differences in age, gender, diabetes, smoking history, and body mass index between the minimally invasive group and the open group ( P>0.05). In the minimally invasive group, the preoperative hospital stay (3.1±1.5 days), postoperative hospital stay (3.5±1.5 days), hidden blood loss (293.3±71.4 ml), surgical time (64.4±13.2 min), and AOFAS score at 6 months postoperatively (79.9±3.9) were superior to those in the open group (7.1±0.7 days, 5.6±0.9 days, 408.3±101.7 ml, 91.5±24.3 min, and 70.5±6.1, respectively) ( P<0.05), with no significant difference in AOFAS score at 1 year postoperatively ( P>0.05). Additionally, the preoperative hospital stay (3.7±1.5 days), postoperative hospital stay (4.0±2.0 days), hidden blood loss (336.3±75.3 ml), and AOFAS score at 6 months postoperatively (77.4±3.8) in the minimally invasive group were superior to those in the open group (7.6±0.9 days, 8.2±2.6 days, 441.3±89.2 ml, and 64.6±8.4, respectively) ( P<0.05), with no significant difference in surgical time and AOFAS score at 1 year postoperatively ( P>0.05). Within-group comparisons indicated that as fracture severity increased, preoperative ( P<0.05) and postoperative hospital stays ( P<0.05) increased in the open group, while surgical time increased in the minimally invasive group ( P<0.05). AOFAS scores at 6 months postoperatively varied between complex and simple fractures in both groups ( P<0.05). There were no statistically significant differences in postoperative Bohler angle, Gissane angle, and calcaneal mid-width between the two groups ( P>0.05). The sustentacular effective fixation rate in the minimally invasive group was 85.4%, superior to 47.4% in the open group for simple fractures ( P<0.05), with no statistically significant difference for complex fractures ( P>0.05). The incision infection rate was 0 in the minimally invasive group compared to 3 cases (3%) in the open group, with no statistically significant difference ( P=0.246). Conclusion:Minimally invasive steel plate combined with percutaneous hollow nail fixation through sinus tarsi incision for calcaneal fractures offers the advantages of shorter hospital stay, reduced surgical trauma, lower incision infection rate, and better short-term efficacy compared to open incision. It is suitable for most Sanders type II-IV calcaneal fractures.

Objective To retrieve,evaluate and summarize the best evidence on the management of ocular complications in intensive care patients ventilated in prone position,and to provide references for clinical practice.Methods Evidence on management of ocular complications in intensive care patients ventilated in prone position was systemically retrieved in the guideline websites,professional association websites and databases,such as the BMJ Best Practice,UpToDate,Cochrane Library,Joanna Briggs Institute,PubMed,Web of Science,Science Direct,Embase,CNKI,Wanfang and other databases,including guidelines,clinical decisions,evidence summaries,expert consensuses,group standards,systematic reviews and scoping reviews,published from January 2013 to June 2023.The guidelines were individually evaluated by 4 researchers,and the remaining literature was individually evaluated by 2 researchers.The literature that met the criteria was extracted and graded.Results A total of 15 articles were involved,including 6 guidelines,2 clinical decisions,2 evidence summaries,3 systematic reviews,1 scoping review and 1 group standard.Finally,6 evidence topics and 16 pieces of best evidence were formed,including organization and training,risk identification,eye assessment,eye protection,position management and regular observation.Conclusion This study summarized the best evidence on the management of ocular complications in intensive care patients ventilated in prone position.In the application,the best evidence should be selected according to the clinical situation,so as to reduce the incidence of ocular complications and improve the quality of life of patients.

Objective To explore the predictive value of CXC chemokine receptor 2(CXCR2)and Zonula occluden-1(ZO-1)for postoperative cerebral vasospasm in subarachnoid hemorrhage(SAH)patients with ruptured intracranial aneurysm.Methods A total of 215 SAH patients with ruptured intracranial aneurysm admitted to our hospital between May 2020 and October 2023 were recruited,and according to occurrence of postoperative cerebral vasospasm or not,they were separated into a spasm group(70 cases)and a non-spasm group(145 cases).The spasm group was further divided into mild,moderate and severe subgroups(14,38 and 18 cases,respectively).ELISA was applied to detect the serum levels of CXCR2 and ZO-1;Spearman and Pearson corre-lation analyses,multivariate logistic regression analysis,and ROC curve analysis were applied to test the correlation,influencing factors,and predictive value of indicators,and their AUC values were calculated.Results The spasm group had significantly higher CXCR2 and ZO-1 levels,inci-dence of intracranial hemorrhage,and larger proportions of Glasgow coma scale(GCS)score of 3-8 at admission,Hunt-Hess grade Ⅲ,and Fisher grades m and Ⅳ than the non-spasm group(P＜0.01).Intracranial hemorrhage volume,Hunt-Hess grade and Fisher grade were positively correlated with CXCR2 and ZO-1 levels,and the GCS score at admission was negatively correlated with the levels of the two indicators in the SAH patients with ruptured intracranial aneurysm(P＜0.01).CXCR2 and ZO-1 were independent risk factors for postoperative cerebral vasospasm in these patients(P＜0.01).The AUC value of CXCR2,ZO-1 and their combination in predicting postoperative cerebral vasospasm was 0.839(95％CI:0.780-0.898),0.813(95％CI:0.750-0.876),and 0.910(95％CI:0.869-0.951),with the combination showing better predictive per-formance(Z=2.391,Z=3.266,P＜0.05).The serum levels of CXCR2 and ZO-1 in the severe subgroup were significantly higher than those in the moderate subgroup and then followed by the mild subgroup in order,with statistical differences(P＜0.01).Conclusion Serum CXCR2 and ZO-1 levels are associated with postoperative cerebral vasospasm in SAH patients with ruptured intracranial aneurysm,and can be used as potential biomarkers for prognosis prediction.

Objectives:To explore the clinical use and observe the clinical efficacy of the Pivox system in oblique lateral interbody fusion(OLIF)in treating single-segment lumbar spinal diseases.Methods:The clini-cal data of patients with single-segment lumbar spinal diseases(Discogenic low back pain,lumbar spondylolis-thesis,lumbar spinal stenosis)who underwent OLIF without posterior instrumentation from May 2020 to Jan-uary 2021 in our hospital were collected,including 36 males and 33 females,aged 32-79 years old(59.1±5.9 years).And the patients were divided into OLIF stand-alone group(39 patients)and Pivox+OLIF group(30 pa-tients).The perioperative parameters of the two groups of patients were compared,including incision length,operative time,intraoperative blood loss,and length of hospital stay.The visual analogue scale(VAS)and Os-westry disability index(ODI)were assessed before operation,at 1 week,1,3,6 and 12 months after operation for clinical efficacy.The intervertebral disc height,foraminal height and foraminal area before and after oper-ation,and the fusion rate were evaluated and compared between the two groups.Complications were recorded and compared as well.Results:The patients were followed up for 14.0±0.3 months(12-18 months).No signif-icant differences were found between the two groups in gender,age,disease type,operative level,bone min-eral density(BMD),or body mass index(BMI)(P＞0.05).The operative time in OLIF group was shorter than that in Pivox+OLIF group(P＜0.05),while there were no significant differences in blood loss,incision length and hospital stay(P＞0.05).The VAS score and ODI index in both groups before surgery were higher than those at 1 week,1 month,3 months,6 months,and 12 months after surgery(P＜0.05).No significant differences in VAS and ODI were found at 1 week,1 month,3 months,6 months,and 12 months after surgery between the two groups,respectively(P＞0.05).The intervertebral disc height,foraminal height and foraminal area at postoperative 1 week,6 and 12 months were all greater than those before operation in both groups,while the increase values of intervertebral disc height,foraminal height and foraminal area in Pivox+OLIF group were greater than those in OLIF group at 1 week,and 6 and 12 months after surgery,but without statistical differ-ences(P＞0.05).Cage subsidence occurred in both groups,and cage displacement was noticed in two cases in the OLIF group,while none was there in the Pivox+OLIF group.There were no significant differences in fu-sion rate and incidence of complications between two groups(P＞0.05).Conclusions:The short-term effect of Pivox+OLIF procedure in the treatment of single-segment lumbar degenerative diseases is satisfactory,but comparing with stand-alone OLIF,Pivox+OLIF has no obvious advantage in spinal canal decompression and preventing cage subsidence.

Objectives:To investigate the effectiveness and safety of unilateral approach contralateral under-cutting decompression assisted with ultrasonic osteotome in treating severe degenerative lumbar spinal stenosis.Methods:174 patients with severe degenerative lumbar spinal stenosis who were treated with ultrasonic os-teotome assisted unilateral approach contralateral undercutting decompression between June 2018 and June 2021 were collected[unilateral approach bilateral decompression transforaminal lumbar interbody fusion(TLID group,group A],and 129 patients undergone bilateral transforaminal decompression during the same period were randomly selected as control(bilateral small incision TLIF group,group B).The perioperative parameters such as incision length,operative time,intraoperative blood loss,postoperative drainage,and length of hospital stay were recorded and compared between the two groups.Creatine phosphokinase(CPK)test was performed to evaluate muscle damage conditions,and visual analogue scale(VAS)and Oswestry disability index(ODI)were used to evaluate the postoperative therapeutic effects.The complications and fusion conditions were compared between the two groups.Results:There wasn't significant difference in average length of bilateral incisions and length of hospital stays between the two groups(P＞0.05).Group A was less significantly than group B in terms of operative time,intraoperative blood loss,and postoperative drainage,with statistical significance(P＜0.05).The preoperative CPK value was comparable between the two groups(P＞0.05),and on postoperative 1d and 3d it was statistically greater in group B than in group A(P＜0.05),but on postoperative 5d it wasn't sig-nificantly different between the two groups(P＞0.05).The postoperative VAS scores and ODI improved com-pared with the preoperative values in both groups on postoperative 3d,at 1 month,3 months,and 12 months(P＜0.05),and there was no statistical difference between the two groups respectively at the same follow-up period(P＞0.05),even though group A was better in ODI and VAS than group B at 12 months after operation.There was no significant difference between the two groups in postoperative complications such as dural tear,incision fat liquefaction,cerebrospinal fluid leakage and postoperative infection.Group A was less in the pro-portion of postoperative worsening lower limb numbness and rebound of hip/lower limb symptoms than in group B(P＜0.05).1 year after operation,12 cases in group A were not fused,and 8 cases in group B were not fused.There was no statistically significant difference in the bone graft fusion between the two groups(P＞0.05).Conclusions:Comparing with bilateral small incision TLIF,ultrasonic osteotome assisted unilateral ap-proach contralateral undercutting decompression also can achieve good treatment results,which features in less trauma,less effects on spinal stability,shorter operative time,and less intraoperative blood loss,and therefore worth in clinical promotion.

Objective To strengthen the management of rational medication for patients with rare diseases and improve the level of comprehensive medication support,in order to address the pain points in medication for rare diseases.Methods By leveraging mobile information technology,a mobile application for the Guangdong Shortage Drug Consultation Platform was developed and a smart and multifunctional pharmaceutical service information platform for rare disease patients was established.Results As the first big data platform in China integrating provincial-level rare disease medical resources,it innovatively realizes the closed-loop interaction among"treatment to medication"online and offline by establishing a comprehensive and professional rare disease mobile pharmaceutical service system.Conclusion The pharmaceutical service platform builds a bridge for rare disease patients to seek medical treatment and and medicine,and helps promote the high-quality development of Healthy China strategy.

OBJECTIVE To develop a population pharmacokinetic （PPK） model for mycophenolate mofetil active metabolite mycophenolic acid （MPA） in children with primary IgA nephropathy， explore the factors affecting the pharmacokinetic parameters of MPA， and provide a basis for clinical individualized therapy. METHODS Retrospective collection was conducted on 636 concentrations and clinical data from 47 pediatric patients with primary IgA nephropathy. PPK analysis was carried out by using the nonlinear mixed-effects model； the covariates were tested with a stepwise method. Goodness-of-fit plots， Bootstrap and visual predictive check were employed to evaluate the final model. RESULTS The pharmacokinetics of MPA in children with IgA nephropathy in vivo conformed to the first-order absorption and elimination two-compartment model （objective function value of 3 276.31）. Covariate analysis suggested that body weight and albumin （ALB） levels were significant influencing factors on apparent clearance rate and apparent distribution volume. The typical values of PPK parameters of MPA in the final model were as follows： the central room had a distributed volume of 5.79 L， the clearance rate was 4.06 L/h， the volume of peripheral ventricular distribution was 430.93 L， the clearance rate between compartments was 15.40 L/h， the oral absorption rate constant was 1.29 h－1. After verification， most of the predicted corrected observed concentration points were within the 90% confidence interval of the predicted corrected simulated concentration， indicating that the MPA final model had good predictive performance. CONCLUSIONS The PPK model of MPA in children with primary IgA nephropathy is established in this study， identifying body weight and ALB levels are significant factors affecting MPA metabolism.

Purpose: The purpose of this study was to optimize a peptide (nABP284) that binds to programmed cell death protein 1 (PD-1) by a computer-based protocol in order to increase its affinity. Then, this study aimed to determine the inhibitory effects of this peptide on cancer immune escape by coculturing improving cytokine-induced killer (ICIK) cells with cancer cells. Materials and Methods: nABP284 that binds to PD-1 was identified by phage display technology in our previous study. AutoDock and PyMOL were used to optimize the sequence of nABP284 to design a new peptide (nABPD1). Immunofluorescence was used to demonstrate that the peptides bound to PD-1. Surface plasmon resonance was used to measure the binding affinity of the peptides. The blocking effect of the peptides on PD-1 was evaluated by a neutralization experiment with human recombinant programmed death-ligand 1 (PD-L1) protein. The inhibition of activated lymphocytes by cancer cells was simulated by coculturing of human acute T lymphocytic leukemia cells (Jurkat T cells) with human tongue squamous cell carcinoma cells (Cal27 cells). The anticancer activities were determined by coculturing ICIK cells with Cal27 cells in vitro. Results: A high-affinity peptide (nABPD1, KD=11.9 nM) for PD-1 was obtained by optimizing the nABP284 peptide (KD=11.8 μM). nABPD1 showed better efficacy than nABP284 in terms of increasing the secretion of interkeulin-2 by Jurkat T cells and enhancing the in vitro antitumor activity of ICIK cells. Conclusion nABPD1 possesses higher affinity for PD-1 than nABP284, which significantly enhances its ability to block the PD-1/PD-L1 interaction and to increase ICIK cell-mediated antitumor activity by armoring ICIK cells.

【Objective】 To investigate the effects of one-stage additional posterior pedicle screws （PPS） internal fixation on early Cage subsidence after oblique lateral interbody fusion （OLIF）. 【Methods】 We made a retrospective analysis of 118 patients with lumbar degenerative diseases treated with OLIF at the Department of Orthopedics， Sir Run Run Shaw Hospital， School of Medicine， Zhejiang University， from January 2016 to December 2019. We divided the patients into OLIF stand-alone group （58 ones） and OLIF with PPS fixation group （60 ones） according to the surgical procedure. All the patients had preoperative frontal and lateral radiographs of the lumbar spine， and CT and MR scans were performed. The clinical outcomes and reoperation rates of the two groups were compared at immediate postoperative follow-up and at 1， 3， 6 and 12 months. X-ray and CT examinations were performed to assess Cage subsidence in both groups at each postoperative follow-up. 【Results】 There was no statistical difference between the two groups in baseline data and surgical segmentation. Of the 118 patients with 141 discs who underwent OLIF surgery， 58 patients with 68 discs received OLIF stand-alone surgery and 60 ones with 73 discs received OLIF with PPS fixation. There were no significant differences in intraoperative bleeding， complications， or postoperative clinical outcomes between the two groups （P>0.05）， and the Cage subsidence rate was 22.4% in OLIF stand-alone group and 5% in OLIF with PPS fixation group， with significant difference between the two groups （P<0.01）. 【Conclusion】 Both OLIF stand-alone and OLIF additional PPS fixation can achieve good early clinical outcomes， and first-stage additional PPS fixation can significantly reduce the occurrence of Cage subsidence in the early postoperative period after OLIF.