Idiopathic pulmonary fibrosis (IPF) is a progressive disease lacking effective therapy. Metformin, an antidiabetic medication, has shown promising therapeutic properties in preclinical fibrosis models; however, its precise cellular targets and associated mechanisms in fibrosis resolution remain incompletely defined. Most research on metformin's effects has focused on mesenchymal and inflammatory responses with limited attention to epithelial cells. In this study, we utilized Sftpc lineage-traced and Fgfr2b conditional knockout mice, along with BMP2/PPARγ and AMPK inhibitors, to explore metformin's impact on alveolar epithelial cells in a bleomycin-induced pulmonary fibrosis model and cell culture. We found that metformin increased the proliferation and differentiation of alveolar type 2 (AT2) cells, particularly the recently identified injury-activated alveolar progenitors (IAAPs)-a subpopulation characterized by low SFTPC expression but enriched for PD-L1. Single-cell RNA sequencing revealed a reduction in apoptosis among mature AT2 cells. Interestingly, metformin's therapeutic effects were not significantly affected by BMP2 or PPARγ inhibition, which blocked the lipogenic differentiation of myofibroblasts. However, Fgfr2b deletion in Sftpc lineage cells significantly impaired metformin's ability to promote fibrosis resolution, a process linked to AMPK signaling. In conclusion, metformin alleviates fibrosis by directly activating AT2 cells, especially the IAAPs, through a mechanism that involves AMPK and FGFR2b signaling, but is largely independent of BMP2/PPARγ pathways.

Objective:To investigate the current situation of the use of transjugular intrahepatic portosystemic shunt (TIPS) for portal hypertension, which should aid the development of TIPS in China.Methods:The China Portal Hypertension Alliance (CHESS) initiated this study that comprehensively investigated the basic situation of TIPS for portal hypertension in China through network research. The survey included the following: the number of surgical cases, main indications, the development of Early-TIPS, TIPS for portal vein cavernous transformation, collateral circulation embolization, intraoperative portal pressure gradient measurement, commonly used stent types, conventional anticoagulation and time, postoperative follow-up, obstacles, and the application of domestic instruments.Results:According to the survey, a total of 13 527 TIPS operations were carried out in 545 hospitals participating in the survey in 2021, and 94.1% of the hospital had the habit of routine follow-up after TIPS. Most hospitals believed that the main indications of TIPS were the control of acute bleeding (42.6%) and the prevention of rebleeding (40.7%). 48.1% of the teams carried out early or priority TIPS, 53.0% of the teams carried out TIPS for the cavernous transformation of the portal vein, and 81.0% chose routine embolization of collateral circulation during operation. Most of them used coils and biological glue as embolic materials, and 78.5% of the team routinely performed intraoperative portal pressure gradient measurements. In selecting TIPS stents, 57.1% of the hospitals woulel choose Viator-specific stents, 57.2% woulel choose conventional anticoagulation after TIPS, and the duration of anticoagulation was between 3-6 months (55.4%). The limitation of TIPS surgery was mainly due to cost (72.3%) and insufficient understanding of doctors in related departments (77.4%). Most teams accepted the domestic instruments used in TIPS (92.7%).Conclusions:This survey shows that TIPS treatment is an essential part of treating portal hypertension in China. The total number of TIPS cases is far from that of patients with portal hypertension. In the future, it is still necessary to popularize TIPS technology and further standardize surgical indications, routine operations, and instrument application.

OBJECTIVE: To assess the value of genetic screening by high-throughput sequencing (HTS) for the early diagnosis of neonatal diseases. METHODS: A total of 2 060 neonates born at Ningbo Women and Children's Hospital from March to September 2021 were selected as the study subjects. All neonates had undergone conventional tandem mass spectrometry metabolite analysis and fluorescent immunoassay analysis. HTS was carried out to detect the definite pathogenic variant sites with high-frequency of 135 disease-related genes. Candidate variants were verified by Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). RESULTS: Among the 2 060 newborns, 31 were diagnosed with genetic diseases, 557 were found to be carriers, and 1 472 were negative. Among the 31 neonates, 5 had G6PD, 19 had hereditary non-syndromic deafness due to variants of GJB2, GJB3 and MT-RNR1 genes, 2 had PAH gene variants, 1 had GAA gene variants, 1 had SMN1 gene variants, 2 had MTTL1 gene variants, and 1 had GH1 gene variants. Clinically, 1 child had Spinal muscular atrophy (SMA), 1 had Glycogen storage disease II, 2 had congenital deafness, and 5 had G6PD deficiency. One mother was diagnosed with SMA. No patient was detected by conventional tandem mass spectrometry. Conventional fluorescence immunoassay had revealed 5 cases of G6PD deficiency (all positive by genetic screening) and 2 cases of hypothyroidism (identified as carriers). The most common variants identified in this region have involved DUOX2 (3.93%), ATP7B (2.48%), SLC26A4 (2.38%), GJB2 (2.33%), PAH (2.09%) and SLC22A5 genes (2.09%). CONCLUSION Neonatal genetic screening has a wide range of detection and high detection rate, which can significantly improve the efficacy of newborn screening when combined with conventional screening and facilitate secondary prevention for the affected children, diagnosis of family members and genetic counseling for the carriers.
Child ; Infant, Newborn ; Humans ; Female ; Prospective Studies ; Connexins/genetics* ; Connexin 26/genetics* ; Glucosephosphate Dehydrogenase Deficiency ; Mutation ; Sulfate Transporters/genetics* ; DNA Mutational Analysis ; Genetic Testing/methods* ; Deafness/genetics* ; Neonatal Screening/methods* ; Hearing Loss, Sensorineural/genetics* ; High-Throughput Nucleotide Sequencing ; Solute Carrier Family 22 Member 5/genetics*

Objective:To distinguish the differences between Olibanum and Myrrha by using modern analytical methods such as Differential Scanning Calorimeter (DSC) and Fourier Transform InfraRed (FT-IR). Methods:By collecting Olibanum and Myrrha in different growing areas and different processed prosecures, this paper to analizes the influence of temperature increase and its speed , as well as the particle size on the DSC experiment. The DSC method was used to perform a differential thermal map of Olibanum and Myrrha scanning and analysis; FT-IR was used to scan and analyze 20 batches of Olibanum and Myrrha. Results:TThe results of DSC analysis showed that the DSC experimental condition ranged between 30-600 ℃; the speed of temperature increase was 30 ℃/min; the particle size was 100 mesh. The DSC spectra of of Olibanum and Myrrha were significantly different. Only the processed products of frankincense had endothermic peak near 297 ℃, and there was no characteristic peak in this temperature range. Their exothermic peaks are close at 326 ℃, but their enthalpy values are quite different. The position of endothermic peak near 100 ℃ is close to the size of peak shape. FT-IR test showed that the absorption peaks of Olibanum and Myrrha at wave numbers 2 925, 1 710, 1 454, 1 371, 1 242, 1 029 cm -1 appeared, and the positions of strong peaks were also similar. The intensity of the characteristic peak of Myrrha wave number 1 029 cm -1 is greater than that of Olibanum. Conclusion:The DSC spectra of Olibanum and Myrrha are significantly different, and the difference between the two FT-IR spectra is small. Differential scanning Calorimetry is an effective, fast, and simple way to identify resinous Chinese medicinal materials, and is worthy of further popularization.

Objective:To analyze the characteristics of pulse-step-sine (PSS) test in healthy people of different ages and to discuss its clinical value.Methods:From July 10, 2018 to December 9, 2020, a total of 78 healthy volunteers, including 40 males and 38 females, were enrolled and divided into youth group, middle age group and old age group. The I Portal NOTC rotational-chair system (NKI) was applied for PSS detection to analyze the clinical characteristics of gain, phase, asymmetry, and slope of step and sinusoidal components. Statistical analysis was performed using SPSS17.0 software.Results:In the same age group, there were no statistically significant differences in left and right step gain, slope gain and sine gain (All P values were greater than 0.05). Pairwise comparison between different age groups showed that there was no significant difference in the corresponding parameters between the youth group and the middle age group. Compared with young group, the old age group had a significantly lower step gain value in their left side ( P<0.01) but not in the right side ( P>0.05).The left and right slopes of the old age group were significantly lower than those of the young group and the middle group, and the differences were statistically significant (All P values<0.05). Conclusion:The PSS test can detect bilateral and unilateral horizontal semicircular canal function with good tolerance in different age groups, better than the traditional rotational chair examination to determine the well-compensated unilateral vestibular function. PSS test is a new vestibular detection method.

Objective:To observe the local reactions and efficacy of CD19 CAR-T therapy in recurrence/refractory B-cell non-Hodgkin's lymphoma (R/R NHL) patients with >7.5 cm lesions.Methods:32 R/R NHL patients with >7.5 cm lesions were enrolled and injected with CD19 CAR-T cells. Flow cytometry was used to detect and observe the amplification of CD19 CAR-T cells in vivo. Enzyme-linked immunosorbent assay (ELISA) was used to detect cytokines in peripheral blood of patients. The side effects of CD19 CAR-T cell therapy included systemic side effects and local reactions of tumor. The local side effects were observed by Ultrasound, Computed tomography and Magnetic resonance imaging. Treatment options included glucocorticoid, interleukin-6 antibody and drainage of exudate. Overall response rate (ORR) and overall survival rate (OS) were observed.Results:①Among the 32 patients, CR (40.63%) , PR (31.25%) and ORR (71.88%) were 13, 10 and 23, respectively. ②In all 23 patients received ORR, 13 patients had grade 1-2 CRS, while 10 patients had grade 3-4 CRS. All the 9 patients in the SD+PD group had grade 1-2 CRS ( P=0.030) . ③A total of 15 patients with tumor local reactions, included 9 patients with CR, 5 patients with PR and 1 patient with SD. The local reactions of the tumor included that the diameter of the superficial lesions increased with redness, swelling and heat pain. The deep lesions presented abdominal pain, abdominal distension, suffocation and local pain, and burning of the tumor. The deep lesions were enlarged or accompanied by local edema. The local exudative lesions were found in the abdominal cavity and pleural cavity. ④ Peak proportion of CD19 CAR-T cells in ORR group was higher than that of in SD+PD group[16.8% (5.3%-48.2%) vs 2.9% (1.5%-5.7%) , z=-4.297, P<0.001]. The peak proportion of CD19 CAR-T cells in ORR group with local reactions was higher than that of in patients without local reactions [22.2% (10.5%-48.2%) vs 12.6% (5.3%-21.6%) , z=-3.213, P=0.001]. The peak proportion of CD19 CAR-T cells in multiple lesion group was higher than that of in single lesion group [35.8% (1.5%-48.2%) vs 16.8% (10.5%-18.5%) , z=-2.023, P=0.040]. ⑤Occurrence of local reactions and tumor shrinkage time were both delayed compared with systemic side effects. ⑥In the ORR group, the OS of patients with tumor local reactions was longer than that of patients without tumor local reactions, but there was no difference in the two groups (75% vs 34.6%, P=0.169) . Conclusions:CD19 CAR-T cell therapy in R/R NHL patients with >7.5 cm lesions might cause tumor local reactions later than systemic side effects.Clinicaltrial::ChiCTR1800018059

Objective:To establish a disease risk prediction model for the newborn screening system of inherited metabolic diseases by artificial intelligence technology.Methods:This was a retrospectively study. Newborn screening data ( n=5 907 547) from February 2010 to May 2019 from 31 hospitals in China and verified data ( n=3 028) from 34 hospitals of the same period were collected to establish the artificial intelligence model for the prediction of inherited metabolic diseases in neonates. The validity of the artificial intelligence disease risk prediction model was verified by 360 814 newborns ' screening data from January 2018 to September 2018 through a single-blind experiment. The effectiveness of the artificial intelligence disease risk prediction model was verified by comparing the detection rate of clinically confirmed cases, the positive rate of initial screening and the positive predictive value between the clinicians and the artificial intelligence prediction model of inherited metabolic diseases. Results:A total of 3 665 697 newborns ' screening data were collected including 3 019 cases ' positive data to establish the 16 artificial intelligence models for 32 inherited metabolic diseases. The single-blind experiment ( n=360 814) showed that 45 clinically diagnosed infants were detected by both artificial intelligence model and clinicians. A total of 2 684 cases were positive in tandem mass spectrometry screening and 1 694 cases were with high risk in artificial intelligence prediction model of inherited metabolic diseases, with the positive rates of tandem 0.74% (2 684/360 814)and 0.46% (1 694/360 814), respectively. Compared to clinicians, the positive rate of newborns was reduced by 36.89% (990/2 684) after the application of the artificial intelligence model, and the positive predictive values of clinicians and artificial intelligence prediction model of inherited metabolic diseases were 1.68% (45/2 684) and 2.66% (45/1 694) respectively. Conclusion:An accurate, fast, and the lower false positive rate auxiliary diagnosis system for neonatal inherited metabolic diseases by artificial intelligence technology has been established, which may have an important clinical value.

Objective:To determine the efficacy and safety of sacral neuromodulation (SNM) in incomplete spinal cord injured (SCI) subjects affected by neurogenic lower urinary tract symptoms.Methods:Clinical data of 36 patients with incomplete spinal cord injury who underwent SNM from February 2015 to April 2019 were retrospectively analyzed and were divided into group NUR (16 cases neurogenic urinary retention group) and group NOAB (20 cases of neurogenic bladder overactive group). If at least 50% clinical improvement occurred, the patient would undergo a permanent SNM procedure. The patients were evaluated by using bladder diary, postvoid residual volume measurement, frequency of clean catheterization and urodynamic parameters before and during the test, and after the permanent SNM.Results:Among the 36 patients, 21 cases (58.3%) were tested effectively and received permanent stimulator implantation, 7(19.4%) in NUR group and 14(38.9%) in NOAB group. The residual urine volume of bladder, the average number of catheterization and the average number of urination in NUR group were improved in different degrees. After operation, the symptoms of frequent urination, urgency of urination and incontinence in NOAB group were relieved to varying degrees. During the follow-up, 2 patients with urinary retention failed the treatment. After the Ⅰ phase of the contralateral S3, the curative effect was recovered. A patient were infected after operation, and the wound healed after removal of the infection.Conclusions:The SNM is safe and effective in the treatment of neurogenic lower urinary tract symptoms in some incomplete spinal cord injury patients, and is helpful to protect renal function in patients with spinal cord injury. SNM can not improve all symptoms at times, but the SNM can be considered in patients with ineffective or intolerant traditional treatment.

Objective:To analyze the long-term efficacy and safety of re-irradiation for recurrent glioma.Methods:The data of 52 patients with recurrent gliomas were collected from 2009 to 2019. The median planned targetvolume (PTV) was 73.5 cm 3(49.9-102.7 cm 3) and the median dose was 45.0 Gy (43.0-48.8 Gy). Kaplan-Meier method was used for survival assessment, log-rank test for difference assessment, and Cox’s regression model for multivariate prognostic analysis. Results:The median follow-up time was 32.6 months. The median overall survival (OS) and progression-free survival (PFS) time were 16.1 months (95% CI, 4.1-28.1) and 8.0 months (95% CI, 4.0-12.0). The 1-, 2-and 3-year survival rates were 67%, 43% and 29%, respectively. The 6-month, 1-year and 2-year PFS rates were 67%, 40%, 26%, respectively. Multivariate analysis showed that KPS score and recurrence time significantly affected the OS ( P=0.012, P=0.001). KPS score and time interval between two radiotherapies significantly impacted the PFS ( P=0.003, P=0.018). Stratified analysis showed that KPS score was the independent prognostic factor of OS and PFS in patients with WHO grade Ⅱ initial pathology and reoperation after recurrence ( P<0.001, P=0.012); clinical manifestation was the independent prognostic factor of OS and PFS in patients with WHO grade Ⅲ and Ⅳ initial pathology ( P=0.006, P=0.044). The overall incidence of adverse reactions was 30.8%. Grade 1 adverse reactions accounted for 25.0%, and 5.8% for grade 2. Conclusions:Re-irradiation for recurrent glioma yields good long-term clinical efficacy and tolerable adverse reactions.