OBJECTIVE To standardize the main processes and related technical links of the clinical comprehensive evaluation of drugs， and provide guidance and reference for improving the quality of comprehensive evaluation evidence and its transformation and application value. METHODS The construction of Guideline for the Workflow of Clinical Comprehensive Evaluation of Drugs was based on the standard guideline formulation method of the World Health Organization （WHO）， strictly followed the latest definition of guidelines by the Institute of Medicine of the National Academy of Sciences of the United States， and conformed to the six major areas of the Guideline Research and Evaluation Tool Ⅱ. Delphi method was adopted to construct the research questions； research evidence was established by applying the research methods of evidence-based medicine. The evidence quality classification system of the Chinese Evidence-Based Medicine Center was adopted for evidence classification and evaluation. The recommendation strength was determined by the recommendation strength classification standard formulated by the Oxford University Evidence-Based Medicine Center， and the recommendation opinions were formed through the expert consensus method. RESULTS & CONCLUSIONS The Guideline for the Workflow of Clinical Comprehensive Evaluation of Drugs covers 4 major categories of research questions， including topic selection， evaluation implementation， evidence evaluation， and application and transformation of results. The formulation of this guideline has standardized the technical links of the entire process of clinical comprehensive evaluation of drugs， which can effectively guide the high-quality and high-efficient development of this work， enhance the standardized output and transformation application value of evaluation evidence， and provide high-quality evidence support for the scientific decision-making of health and the rationalization of clinical medication.

The correlation between hearing loss (HL) and physical performance in patients receiving maintenance hemodialysis (MHD) remains poorly investigated. This study explored the association between HL and physical performance in patients on MHD. Methods: This multicenter cross-sectional study was conducted between July 2020 and April 2021 in seven hemodialysis centers in Shanghai and Suzhou, China. The hearing assessment was performed using pure-tone average (PTA). Physical performance was assessed using the Timed Up and Go Test (TUGT), handgrip strength, and gait speed. Results: Finally, 838 adult patients (male, 516 [61.6%]; 61.2 ± 2.6 years) were enrolled. Among them, 423 (50.5%) had mild to profound HL (male, 48.6% and female, 53.4%). Patients with HL had poorer physical performance than patients without HL (p < 0.001). TUGT was positively correlated with PTA (r = 0.265, p < 0.001), while handgrip strength and gait speed were negatively correlated with PTA (r = –0.356, p < 0.001 and r = –0.342, p < 0.001, respectively). Physical performance in patients aged <60 years showed significant dose-response relationships with HL. After adjusting for confounders, the odds ratios (95% confidence intervals) for HL across the TUGT quartiles (lowest to highest) were 1.00 (reference), 1.15 (0.73–1.81), 1.69 (1.07–2.70), and 2.87 (1.69–4.88) (p for trend = 0.005). Conclusion: Lower prevalence of HL was associated with a faster TUGT and a stronger handgrip strength in patients on MHD.

Nerve regeneration in adult mammalian spinal cord is poor because of the lack of intrinsic regeneration of neurons and extrinsic factors - the glial scar is triggered by injury and inhibits or promotes regeneration. Recent technological advances in spatial transcriptomics (ST) provide a unique opportunity to decipher most genes systematically throughout scar formation, which remains poorly understood. Here, we first constructed the tissue-wide gene expression patterns of mouse spinal cords over the course of scar formation using ST after spinal cord injury from 32 samples. Locally, we profiled gene expression gradients from the leading edge to the core of the scar areas to further understand the scar microenvironment, such as neurotransmitter disorders, activation of the pro-inflammatory response, neurotoxic saturated lipids, angiogenesis, obstructed axon extension, and extracellular structure re-organization. In addition, we described 21 cell transcriptional states during scar formation and delineated the origins, functional diversity, and possible trajectories of subpopulations of fibroblasts, glia, and immune cells. Specifically, we found some regulators in special cell types, such as Thbs1 and Col1a2 in macrophages, CD36 and Postn in fibroblasts, Plxnb2 and Nxpe3 in microglia, Clu in astrocytes, and CD74 in oligodendrocytes. Furthermore, salvianolic acid B, a blood-brain barrier permeation and CD36 inhibitor, was administered after surgery and found to remedy fibrosis. Subsequently, we described the extent of the scar boundary and profiled the bidirectional ligand-receptor interactions at the neighboring cluster boundary, contributing to maintain scar architecture during gliosis and fibrosis, and found that GPR37L1_PSAP, and GPR37_PSAP were the most significant gene-pairs among microglia, fibroblasts, and astrocytes. Last, we quantified the fraction of scar-resident cells and proposed four possible phases of scar formation: macrophage infiltration, proliferation and differentiation of scar-resident cells, scar emergence, and scar stationary. Together, these profiles delineated the spatial heterogeneity of the scar, confirmed the previous concepts about scar architecture, provided some new clues for scar formation, and served as a valuable resource for the treatment of central nervous system injury.
Mice ; Animals ; Gliosis/pathology* ; Cicatrix/pathology* ; Spinal Cord Injuries ; Astrocytes/metabolism* ; Spinal Cord/pathology* ; Fibrosis ; Mammals ; Receptors, G-Protein-Coupled

Objective To observe the effect of muscone in regulating fatty acid synthase(Fas)/fatty acid synthase ligand(FasL)signaling pathway on cardiomyocyte apoptosis in rats with diabetic car-diomyopathy(DCM),and explore the mechanism of Chen Shuquan's theory of"warming and clear-ing collaterals"in treating DCM.Methods SD rats were divided into blank group,DCM group,low-dose muscone group(0.68 mg/kg muscone),high-dose muscone group(2.72 mg/kg muscone),met-formin group(140 mg/kg metformin),and high-dose muscone+recombinant human FasL protein(rh-FasL)group(2.72 mg/kg muscone+0.017 mg/kg rh-FasL),with 12 rats in each group.Except for the blank group,rats in all other groups were fed with high-fat feed combined with intraperitoneal injection of streptozotocin to construct a DCM rat model.After successful modeling,the rats were administered once a day for 6 weeks.After the last treatment,the changes in fasting blood glucose,left ventricular ejection fraction(LVEF),and left ventricular short axis shortening rate(LVFS)in rats were detected;Hematoxylin-eosin(HE)staining and Masson staining were applied to detect pathological damage and fibrosis degree of myocardial tissue,respectively.Spectrophotometry was applied to detect the activity of superoxide dismutase(SOD)and the content of malondialdehyde(MDA)in myocardial tissue;TUNEL staining was applied to observe myocardial cell apoptosis;and Western blot was applied to detect the expression of cleaved aspartate specific cysteine protease-3(cleaved-caspase-3),Bcl-2 associated X protein(Bax),Fas,and FasL proteins in myocardial tis-sue.Results Compared with the blank group,the pathological damage to the myocardial tissue of rats in the DCM group was severe,the fasting blood glucose,MDA content,myocardial collagen ar-ea fraction and apoptosis rate of myocardial cell,and expression of cleaved-caspase-3,Bax,Fas,and FasL proteins increased,while the LVEF,LVFS,and activity of SOD decreased(P＜0.05);compared with DCM group,pathological damage of myocardial tissue was reduced in the low-dose muscone group,the high-dose muscone group and the metformin group,and fasting blood glucose,MDA content,myocardial collagen area fraction,myocardial apoptosis rate and cleaved-caspase-3,Bax,Fas and FasL protein expression were decreased,and the activities of LVEF,LVFS and SOD were increased(P＜0.05).Compared with low-dose muscone group,pathological damage of myocar-dial tissue was relieved in the high-dose muscone group and the metformin group,fasting blood glu-cose,MDA content,myocardial collagen area fraction,myocardial apoptosis rate,cleaved-caspase-3,Bax,Fas and FasL protein expression were decreased,and LVEF,LVFS and SOD activities were in-creased(P＜0.05).Compared with the high-dose muscone group,the pathological damage to the myocardial tissue of rats in the high-dose muscone+rh-FasL group was intensified,the fasting blood glucose,MDA content,and expression of cleaved-caspase-3,Bax,Fas,and FasL proteins increased,the LVEF,LVFS,and activity of SOD decreased(P＜0.05).Conclusion Muscone may inhibit oxidative stress and cardiomyocyte apoptosis in DCM rats by inhibiting the Fas/FasL pathway.

Diabetic neuropathic pain (DNP) is the most common disabling complication of diabetes. Emerging evidence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area; however, the underlying molecular events remain poorly understood. Here we found that an axon guidance molecule, Netrin-3 (Ntn-3), was expressed in the sensory neurons of mouse dorsal root ganglia (DRGs), and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model. Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice. In contrast, the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice. In conclusion, our studies identified Ntn-3 as an important regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons, indicating that Ntn-3 is a potential druggable target for DNP treatment.
Mice ; Animals ; Diabetes Mellitus, Experimental/metabolism* ; Axons/physiology* ; Diabetic Neuropathies ; Sensory Receptor Cells/metabolism* ; Neuralgia/metabolism*

Objective To observe the effect of muscone in regulating fatty acid synthase(Fas)/fatty acid synthase ligand(FasL)signaling pathway on cardiomyocyte apoptosis in rats with diabetic car-diomyopathy(DCM),and explore the mechanism of Chen Shuquan's theory of"warming and clear-ing collaterals"in treating DCM.Methods SD rats were divided into blank group,DCM group,low-dose muscone group(0.68 mg/kg muscone),high-dose muscone group(2.72 mg/kg muscone),met-formin group(140 mg/kg metformin),and high-dose muscone+recombinant human FasL protein(rh-FasL)group(2.72 mg/kg muscone+0.017 mg/kg rh-FasL),with 12 rats in each group.Except for the blank group,rats in all other groups were fed with high-fat feed combined with intraperitoneal injection of streptozotocin to construct a DCM rat model.After successful modeling,the rats were administered once a day for 6 weeks.After the last treatment,the changes in fasting blood glucose,left ventricular ejection fraction(LVEF),and left ventricular short axis shortening rate(LVFS)in rats were detected;Hematoxylin-eosin(HE)staining and Masson staining were applied to detect pathological damage and fibrosis degree of myocardial tissue,respectively.Spectrophotometry was applied to detect the activity of superoxide dismutase(SOD)and the content of malondialdehyde(MDA)in myocardial tissue;TUNEL staining was applied to observe myocardial cell apoptosis;and Western blot was applied to detect the expression of cleaved aspartate specific cysteine protease-3(cleaved-caspase-3),Bcl-2 associated X protein(Bax),Fas,and FasL proteins in myocardial tis-sue.Results Compared with the blank group,the pathological damage to the myocardial tissue of rats in the DCM group was severe,the fasting blood glucose,MDA content,myocardial collagen ar-ea fraction and apoptosis rate of myocardial cell,and expression of cleaved-caspase-3,Bax,Fas,and FasL proteins increased,while the LVEF,LVFS,and activity of SOD decreased(P＜0.05);compared with DCM group,pathological damage of myocardial tissue was reduced in the low-dose muscone group,the high-dose muscone group and the metformin group,and fasting blood glucose,MDA content,myocardial collagen area fraction,myocardial apoptosis rate and cleaved-caspase-3,Bax,Fas and FasL protein expression were decreased,and the activities of LVEF,LVFS and SOD were increased(P＜0.05).Compared with low-dose muscone group,pathological damage of myocar-dial tissue was relieved in the high-dose muscone group and the metformin group,fasting blood glu-cose,MDA content,myocardial collagen area fraction,myocardial apoptosis rate,cleaved-caspase-3,Bax,Fas and FasL protein expression were decreased,and LVEF,LVFS and SOD activities were in-creased(P＜0.05).Compared with the high-dose muscone group,the pathological damage to the myocardial tissue of rats in the high-dose muscone+rh-FasL group was intensified,the fasting blood glucose,MDA content,and expression of cleaved-caspase-3,Bax,Fas,and FasL proteins increased,the LVEF,LVFS,and activity of SOD decreased(P＜0.05).Conclusion Muscone may inhibit oxidative stress and cardiomyocyte apoptosis in DCM rats by inhibiting the Fas/FasL pathway.

ABSTRACT: Meningiomas are the most common primary intracranial neoplasm with diverse pathological types and complicated clinical manifestations. The fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), published in 2021, introduces major changes that advance the role of molecular diagnostics in meningiomas. To follow the revision of WHO CNS5, this expert consensus statement was formed jointly by the Group of Neuro-Oncology, Society of Neurosurgery, Chinese Medical Association together with neuropathologists and evidence-based experts. The consensus provides reference points to integrate key biomarkers into stratification and clinical decision making for meningioma patients. REGISTRATION Practice guideline REgistration for transPAREncy (PREPARE), IPGRP-2022CN234.
Humans ; Meningioma/pathology* ; Consensus ; Neurosurgical Procedures ; Meningeal Neoplasms/pathology*

Objective To investigate the expression and clinical significance of TM9SF3 in lung adenocarcinoma (LUAD). Methods TCGA and GEPIA databases were used to screen the differentially-expressed TM9SF family molecules and analyze their effects on patient prognosis with LUAD. The expression and localization of TM9SF3 in LUAD patients were verified by a human proteomic mapping database, Western blot assay, and polymerase chain reaction assay. Herein, the GSEA was used for the signal pathway enrichment analysis of TM9SF3-related genes. Meanwhile, the TIMER database and CIBERSORT algorithm were used to analyze the correlation between differentially-expressed TM9SF3 and the degree of immune cell infiltration. Results The expression of TM9SF3 in LUAD was significantly increased and had a significant adverse effect on the prognosis of LUAD patients. In addition, immunoblotting and polymerase chain reaction confirmed that TM9SF3 was highly expressed in LUAD. Meanwhile, the genes related to TM9SF3 expression were mainly enriched in cell signaling pathways regulating immune cell activity. The expression of TM9SF3 was significantly correlated with the expression changes of six immune cells. Conclusion TM9SF3 is differentially expressed in LUAD and may be used as a potential prognostic marker for LUAD patients. TM9SF3 can also change the level of immune cell infiltration in LUAD patients and is expected to be a new potential target for LUAD immunotherapy.

Hydrogen sulfide (H

Objective:To compare the clinical efficacy of transperitoneal robot assisted laparoscopic radical prostatectomy (RARP) versus extraperitoneal single port RARP.Methods:A retrospective analysis was perfoumed on 142 cases of RARP from July 2019 to June 2020 in Robotic Minimally Invasive Center of Sichuan Provincial People's Hospital, including 82 cases(Group A) , aged 70.0(65.6-78.0), undergoing transperitoneal RARP and 60 cases(Group B), aged 68.2 years old(60.1-79.2), undergoing extraperitoneal single port RARP. For group A, PSA was 12.9(5.6-64.0) ng/ml, with 26 cases of less than 10 ng/ml(31.7%), 40 cases of 10-20 ng/ml(48.8%), and 16 cases of more than 20 ng/ml(19.5%), the Gleason score was 7.2(6.0-10.0), with 14 cases(17.1%) of ≤6, 56 cases(68.3%) of 7, and 12 cases(14.6%) of ≥8, and the prostate volume was 61.3(29.0-112.0) ml. There were 49 cases with BMI≤25 kg/m 2, accounting for 59.8%, and 33 cases with BMI>25 kg/m 2, accounting for 40.2%. There were 17 cases(20.7%) of T 1, 44 cases(53.7%) of T 2 and 21 cases(25.6%) of T 3. The proportion of lymph node dissection was 17.1%, and 4 cases(4.9%)had a history of operation. For group B, the PSA was 12.2(1.0-42.6)ng/ml, with 20 cases (33.3%) of <10 ng/ml, 31 cases(51.7%)of 10-20 ng/ml, and 9 cases (15%) of >20 ng/ml. Gleason score was 7.1(6.0-9.0), with 12 cases (20.0%) of ≤6, 42 cases (70.0%) of 7, and 6 cases (10.0%)of ≥8. Prostate volume was 42.4(31.2-72.8)ml on average. There were 37 cases (61.7%) with BMI≤25 kg/m 2, and 23 cases (38.3%)with BMI >25 kg/m 2 . There were 17 cases(28.3%)of T 1, 32 cases(53.3%)of T 2 and 11 cases(18.3%)of T 3.The proportion of lymph node dissection was 11.7% and 4 cases (6.7%) had a history of operation.There was no statistically significant difference in term of age, PSA level, Gleason score, BMI, clinical stage, proportion of lymph node dissection or history of operation between the two groups( P>0.05), but there was statistically significant difference for prostate volume( P<0.05). All operations were performed by the same operator. Four different ways of bladder neck and urethral dissociation was selected according to the intraoperative conditions in Group A, include VIP style, T-shape incision style, VIP plus T-shape incision style or the style along the lateral side of the bladder neck. Small and single anterograde incision stripping of bladder neck was routinely performed in the Group B. Postoperative follow-up was performed to compare the operation time, intraoperative blood loss, bladder neck and urethral anastomosis time, postoperative hospital stay, postoperative exhaust time, postoperative complications, positive rate of surgical margin, indwelling time of urinary catheter, urinary continence satisfaction rate of immediately after operation, 3 months and 6 months after operation, wound healing and aesthetics. Results:All of the operations were successfully completed under robot-assisted laparoscopy, and there was no conversion to open surgery. The operation time was 56.0(45.0-112.0) min in the Group A and 65.4(55.5-96.8) min in the Group B, and there was no statistically significant difference( P>0.05). The intraoperative blood loss was 76.2(30.0-120.5) ml and 55.6(45.5-114.6) ml, respectively, and the difference was not statistically significant( P>0.05). The time of bladder neck urethral anastomosis was 18.9(12.6-25.6) min and 16.2(10.7-19.3) min, respectively, and the difference was not statistically significant( P>0.05). The postoperative hospital stay days were 9.3(8.0-16.0) d and 8.4(7.0-13.0) d, respectively, and the difference was not statistically significant( P>0.05). The postoperative exhaust time was 1.3(0.7-3.0) d and 3.4(2.0-7.0) d, respectively, and the difference was statistically significant( P<0.05). There was 1 case of anastomotic fistula with ureteral injury in Group A, and no serious complication in Group B, and the difference was not statistically significant( P>0.05). The number of positive surgical margin in the two groups was 13(15.9%)and 9(15.0%)respectively, and the difference was not statistically significant( P>0.05). The indwelling time of urinary catheter after operation was 9(7-21) d and 6(4-8) d, respectively, and the difference was statistically significant( P<0.05). The number of patients with satisfactory urinary continence immediately after surgery, 3 months and 6 months after surgery in the two groups were 8(9.8%), 51(62.2%), 62(75.6%) and 17(28.3%), 43(71.7%) and 54(90.0%), respectively. The differences were statistically significant( P<0.05). The total incision lengths in the two groups were 12.1(10.4-13.4) cm and 5.6(5.0-6.0) cm, respectively, and the difference was statistically significant( P<0.05). Conclusions:The extraperitoneal single port RARP is safe and feasible, and the postoperative effect is similar to that of transperitoneal RARP. It has the advantages of shorter recovery time, higher urinary continence satisfaction rate, neater and more beautiful incision. The long-term therapeutic effect needs further confirming by prospective study.