pH-dependent water permeability switching and its memory in MoS2 membranes.

Intelligent transport of molecular species across different barriers is critical for various biological functions and is achieved through the unique properties of biological membranes1-4. Two essential features of intelligent transport are the ability to (1) adapt to different external and internal conditions and (2) memorize the previous state5. In biological systems, the most common form of such intelligence is expressed as hysteresis6. Despite numerous advances made over previous decades on smart membranes, it remains a challenge to create a synthetic membrane with stable hysteretic behaviour for molecular transport7-11. Here we demonstrate the memory effects and stimuli-regulated transport of molecules through an intelligent, phase-changing MoS2 membrane in response to external pH. We show that water and ion permeation through 1T' MoS2 membranes follows a pH-dependent hysteresis with a permeation rate that switches by a few orders of magnitude. We establish that this phenomenon is unique to the 1T' phase of MoS2, due to the presence of surface charge and exchangeable ions on the surface. We further demonstrate the potential application of this phenomenon in autonomous wound infection monitoring and pH-dependent nanofiltration. Our work deepens understanding of the mechanism of water transport at the nanoscale and opens an avenue for the development of intelligent membranes.

Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy.

Hematopoietic stem cell transplantation (HSCT) is the only approved treatment for presymptomatic infantile globoid cell leukodystrophy (GLD [Krabbe disease]). However, correction of disease is not complete, and outcomes remain poor. Herein we evaluated HSCT, intravenous (IV) adeno-associated virus rh10 vector (AAVrh10) gene therapy, and combination HSCT + IV AAVrh10 in the canine model of GLD. While HSCT alone resulted in no increase in survival as compared with untreated GLD dogs (∼16 weeks of age), combination HSCT + IV AAVrh10 at a dose of 4E13 genome copies (gc)/kg resulted in delayed disease progression and increased survival beyond 1 year of age. A 5-fold increase in AAVrh10 dose to 2E14 gc/kg, in combination with HSCT, normalized neurological dysfunction up to 2 years of age. IV AAVrh10 alone resulted in an average survival to 41.2 weeks of age. In the peripheral nervous system, IV AAVrh10 alone or in addition to HSCT normalized nerve conduction velocity, improved ultrastructure, and normalized GALC enzyme activity and psychosine concentration. In the central nervous system, only combination therapy at the highest dose was able to restore galactosylceramidase activity and psychosine concentrations to within the normal range. These data have now guided clinical translation of systemic AAV gene therapy as an addition to HSCT (NCT04693598, NCT05739643).

Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

TFCP2L1, a potential differentiation regulator, predicts favorable prognosis and dampens thyroid cancer progression.

PURPOSE: Thyroid cancer has an overwhelming incidence in the population. Thus, there is an urgent need to understand the underlying mechanism of its occurrence and development, which may provide new insights into therapeutic strategies. The role and mechanism of TFCP2L1 in regulating the progression of thyroid cancer remains unclear. METHODS: Public databases and clinical samples were used to detect the expression of TFCP2L1 in cancer and non-cancer tissues. Kaplan-Meier and Cox regression analyses were used to compare the differences in survival probability of the TFCP2L1 highly expressing group and the TFCP2L1 lowly expressing group. Functional assays were used to evaluate the biological effect of TFCP2L1 on thyroid cancer cells. RNA sequencing and enrichment analyses were used to find out pathways that were activated or inactivated by TFCP2L1. RESULTS: We demonstrated that TFCP2L1 was significantly downregulated in thyroid cancer. Decreased expression of TFCP2L1 was associated with malignant clinicopathological characteristics. Kaplan-Meier and Cox regression analyses indicated that thyroid tumor patients with low TFCP2L1 expression presented shorter disease-free interval and progression-free interval. Additionally, TFCP2L1 expression was positively correlated with thyroid differentiation degree. Overexpression of TFCP2L1 in thyroid cancer cells inhibited cell growth and motility in vitro, and tumorigenicity and metastasis in vivo. Mechanistically, the NF-κB signaling pathway was found inactivated by overexpressing TFCP2L1. CONCLUSION: Our results suggest that TFCP2L1 is a tumor suppressor and potential differentiation regulator, and might be a potential therapeutic target in thyroid cancer.

[Clinical analysis of 10 patients with Fabry disease].

We aimed to analyze the clinical data of 10 patients (6 male and 4 female) with Fabry disease (FD). The mean age of the patients was (28.80±9.27) years. Seven patients had classical FD and three had delayed onset FD. Among the 10 patients, six had skin involvement and cutaneous angiokeratoma; five had hypohidrosis or anhidrosis; nine had intermittent neuralgia; and three had supraorbital ridge protrusion, forehead bulge, and lip thickening. Five patients had proteinuria, including one with chronic kidney disease stage 3 and one with chronic kidney disease stage 5. Cardiac involvement occurred in three patients, two had myocardial hypertrophy and one had valvular insufficiency. The activity of galactosidase decreased in seven patients (2.80-1.55 µmol·L-1·h-1). Plasma deacetyl-GL-3 was elevated in all 10 patients(3.12-120.00 ng/ml). Three patients underwent renal biopsy, wherein two cases of focal segmental glomerulosclerosis and one of mesangial proliferative glomerulonephritis was found. A large number of myeloid and zebra bodies were found in the podocytes in three patients, including a small number of myeloid and zebra bodies in the renal tubular epithelial cells in one patient with occasional zebra bodies in the renal interstitium. Nine patients had GLA gene mutations. One patient was c.102T>A, a de novo mutation. Four patients were treated with agalsidase α injection (0.2 mg/kg, intravenous infusion every 2 weeks), and their prognosis was good. FD has various clinical manifestations and multi-system involvement, which requires multidisciplinary cooperation. Detection of galactosidase activity, plasma globotriaosylsphingosine, and GLA gene mutation can help for accurate diagnosis.

Effects of Three Different Heating Devices on Patients Undergoing Surgery: A Network Meta-Analysis.

PURPOSE: Perioperative hypothermia is a common anesthesia-related complication that can result in negative outcomes. Intraoperative active heating can positively impact these outcomes. Therefore this study aimed to investigate the effectiveness of three common heating devices for controlling hypothermia, improving thermal comfort, and reducing anesthesia recovery time. DESIGN: Systematic review and meta-analysis. METHODS: Seven electronic literature databases were searched from the inception date of the databases to March 18, 2022. RevMan 5.4 and Stata 15.1 were used to perform meta-analyses on the obtained data, and the Cochrane Evaluation Manual was used for quality risk assessment of the included studies. FINDINGS: A total of 18 studies involving 1,511 patients undergoing surgery using heating devices were included. In this meta-analysis, a ranking method known as the Surface Under the Cumulative Ranking Curve (SUCRA) was used. SUCRA provides a numerical measure of the effectiveness of treatments, with higher values indicating superior efficacy. Findings demonstrated that the concurrent use of three heating devices led to an elevation in core body temperatures (SUCRA = 69.2%) and enhanced delayed recovery (SUCRA = 88.6%) as compared to the application of a single device. Furthermore, for thermal comfort, the employment of heating blankets proved to be the most effective (SUCRA = 87.8%). CONCLUSIONS: This study showed the core body temperatures and reductions in delayed recovery were greater when three heating devices were used together as compared to use one of them alone. Heating blankets was the most effective option for improving the thermal comfort of patients. Thus, clinicians should opt for appropriate heating equipment according to the type of surgery and the characteristics and needs of patients. The choice of appropriate heating equipment will ensure surgical safety, improve patient comfort, and reduce surgical risks.

Deficient chaperone-mediated autophagy in macrophage aggravates inflammation of nonalcoholic steatohepatitis by targeting Nup85.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH), a more severe subtype of nonalcoholic fatty liver disease, can cause cirrhosis and hepatocellular carcinoma. Macrophages play critical roles in initiating and maintaining NASH-induced liver inflammation and fibrosis. However, the underlying molecular mechanism of macrophage chaperone-mediated autophagy (CMA) in NASH remains unclear. We aimed to investigate the effects of macrophage-specific CMA on liver inflammation and identify a potential therapeutic target for NASH treatment. METHODS: The CMA function of liver macrophages was detected using Western blot, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and flow cytometry. By constructing myeloid-specific CMA deficiency mice, we evaluated the effects of deficient CMA of macrophages on monocyte recruitment, liver injury, steatosis and fibrosis in NASH mice. A label-free mass spectrometry was utilized to screen the substrates of CMA in macrophages and their mutual interactions. The association between CMA and its substrate was further examined by immunoprecipitation, Western blot and RT-qPCR. RESULTS: A typical hallmark in murine NASH models was impaired CMA function in hepatic macrophages. Monocyte-derived macrophages (MDM) were the dominant macrophage population in NASH, and CMA function was impaired in MDM. CMA dysfunction aggravated liver-targeted recruitment of monocyte and promoted steatosis and fibrosis. Mechanistically, Nup85 functions as a substrate for CMA and its degradation was inhibited in CMA-deficient macrophages. Inhibition of Nup85 attenuated the steatosis and monocyte recruitment caused by CMA deficiency in NASH mice. CONCLUSIONS: We proposed that the impaired CMA-induced Nup85 degradation aggravated monocyte recruitment, promoting liver inflammation and disease progression of NASH.

Development and multicenter validation of a novel radiomics-based model for identifying eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: Reliable noninvasive methods are needed to identify endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) to facilitate personalized therapy. Previous computed tomography (CT) scoring system has limited and inconsistent performance in identifying eosinophilic CRSwNP. We aimed to develop and validate a radiomics-based model to identify eosinophilic CRSwNP. METHODS: Surgical patients with CRSwNP were recruited from Tongji Hospital and randomly divided into training (n = 232) and internal validation cohort (n = 61). Patients from two additional hospitals served as external validation cohort-1 (n = 84) and cohort-2 (n = 54), respectively. Data were collected from October 2013 to May 2021. Eosinophilic CRSwNP was determined by histological criterion. The least absolute shrinkage and selection operator and the logistic regression (LR) algorithm were used to develop a radiomics model. Univariate and multivariate LR were employed to build models based on CT scores, clinical characteristics, and the combination of radiological and clinical characteristics. Model performance was evaluated by assessing discrimination, calibration, and clinical utility. RESULTS: The radiomics model based on 10 radiomic features achieved an area under the curve (AUC) of 0.815 in the training cohort, significantly better than the CT score model based on ethmoid-to-maxillary sinus score ratio with an AUC of 0.655. The combination of radiomic features and blood eosinophil count had a further improved performance, achieving an AUC of 0.903. The performance of these models was confirmed in all validation cohorts with satisfying predictive calibration and clinical application value. CONCLUSIONS: A CT radiomics-based model is promising to identify eosinophilic CRSwNP. This radiomics-based method may provide novel insights in solving other clinical concerns, such as guiding personalized treatment and predicting prognosis in patients with CRSwNP.

Assessing hydrological connectivity for natural-artificial catchment with a new framework integrating graph theory and network analysis.

Anthropogenic activities alter the underlying surface conditions and arrangements of landscape features in a drainage basin, interfering with the pollutant (e.g., dissolved nitrogen, phosphorus) transport network configuration and altering the hydrological response. Assessing the impact of anthropogenic activities on hydrological connectivity for natural-artificial catchment is critical to understand the hydrological-driven ecosystem processes, services and biodiversity. However, quantifying this impact at catchment scale remains challenging. In this study, a new framework was proposed to quantify the impact of anthropogenic activities on hydrological connectivity combined with graph theory and network analysis. This framework was exemplified in a natural-artificial catchment of the Yangtze River basin of China. Based on remote sensing and field-investigated data, three transport networks were constructed, including natural transport network (N1), ditch-road transport network (N2), and terrace-dominated transport network (N3), which reflected the different human intervention. The results showed that human intervention improved the connectivity of the nodes and enhanced the complexity of the catchment transport network structure. Anthropogenic activities significantly decreased the hydrological structural connectivity of the catchment. In particular, compared with the N1 network, the critical nodes for hydrological connectivity which were judged by connectivity indexes were reduced by 92.94% and 95.29% in the N2 and N3 network, respectively. Furthermore, the ditch-road construction had a greater impact than terraces in decreasing hydrological structural connectivity at catchment scale. This framework has proven effective in quantifying the hydrological connectivity analysis under different human intervention at the catchment scale and facilitates the improvement of catchment management strategies.

[Etiological analysis of a patient with multiple primary malignant neoplasms].

To investigate the etiology of multiple primary malignant neoplasms occurred in one patient. Retrospective analysis was performed on a 52-year-old female patient who was admitted to the Department of Endocrinology, the First Affiliated Hospital of Sun Yat-Sen University on October 7, 2021, due to "thyroid occupying lesion for one week". A complete systemic positron emission tomography examination of the patient indicated that the metabolic characteristics of the left thyroid nodules were consistent with medullary thyroid carcinoma, those of the right thyroid nodules were consistent with papillary thyroid carcinoma, and the metabolic characteristics of the T6-7 level were consistent with meningioma, and teratoma was found in the right ovarian region. Intradural subdural mass resection was performed on October 20, 2021, and bilateral total thyroidectomy, isthmus thyroidectomy, bilateral central lymph node dissection and left cervical lymph node dissection were performed on November 2, 2021. The postoperative pathologic diagnosises were meningioma (WHO Grade 1), medullary thyroid carcinoma (left side), and papillary thyroid carcinoma (right side).Whole exon gene sequencing revealed the presence of mutations in the ACAN and FLNB genes, which are associated with dysplasia, as well as mutations in the DDX41 and JAK2 genes, which are linked to active pro-proliferation signaling and tumor susceptibility. In this study, a gene mutation pattern which could lead to multiple primary malignant neoplasms was found.

[Explore the influence of vitamin D supplementation on clinical efficacy and drug retention rate of vedolizumab in patients with ulcerative colitis].

Objectives: To analyze the influence of vitamin D supplementation on clinical efficacy and drug retention rate of vedolizumab (VDZ) in patients with ulcerative colitis (UC). Methods: Retrospective study. By retrieving the clinical database of the Second Affiliated Hospital of Wenzhou Medical University, the patients with moderately to severely active UC were collected, who underwent VDZ treatment from January 2020 to June 2022. The modified Mayo score and Mayo endoscopic score (MES) were employed to evaluate disease activity and intestinal inflammation in UC patients, respectively. According to whether vitamin D was supplemented during VDZ treatment, the patients were divided into supplementary group and non-supplementary group. According to baseline serum 25(OH) D level, UC patients were divided into vitamin D deficiency group and non-deficiency group. According to whether vitamin D was supplemented, the patients of each group were divided into supplementary subgroup and non-supplementary subgroup, respectively. The clinical response rate, clinical remission rate and mucosal healing rate at week 30 after receiving VDZ treatment and the retention rate of VDZ at the 72nd week were observed. The effect of baseline serum 25 (OH) D level on the efficacy of vitamin D supplementation was analyzed by chi-square test. The effects of vitamin D supplementation on the clinical efficacy and drug retention of VDZ in UC were analyzed by chi-square test and Kaplan-Meier curve, respectively. Results: A total of 80 patients with moderately to severely active UC, who were aged (39.4±13.0) years(18-75 years), 37 male and 43 female, were included. There were 43 cases in supplementary group and 37 cases in non-supplementary group. There were 59 cases in the deficiency group, including 32 cases in the supplementary subgroup and 27 cases in the non-supplementary subgroup. There were 21 cases in the non-deficiency group, including 11 cases in the supplementary subgroup and 10 cases in the non-supplementary subgroup. At week 30, the average level of serum 25(OH) D was shown to be higher in supplementary group than that at week 0 [(24.5±5.4) vs (17.7±6.7) µg/L, P<0.001]. At week 30, in contrast with non-supplementary group, erythrocyte sedimentation rate(ESR)[75.0% (24.3%, 86.7%) vs 32.7% (-2.6%, 59.3%), P=0.005] and modified Mayo score [(4.7±2.8) vs (2.3±2.7) points, P<0.001] and MES score [(1.2±1.1) vs (0.4±0.9) points, P=0.001] were significantly reduced, clinical response rate [79.1%(34/43) vs 56.8%(21/37), P=0.032], clinical remission rate [67.4%(29/43) vs 29.7%(11/37), P=0.001] and mucosal healing rate [72.1%(31/43) vs 37.8%(14/37), P=0.002] were higher. At week 72, drug retention rate of VDZ was shown to be higher in supplementary group than in non-supplementary group [55.8%(24/43) vs 27.0%(10/37), P=0.004]. The further analysis showed that vitamin D supplementation could only improve clinical response rate[71.9%(23/32) vs 44.4%(12/27), P=0.033], clinical remission rate[62.5%(20/32) vs 14.8%(4/27), P<0.001], mucosal healing rate[68.8%(22/32) vs 22.2%(6/27), P<0.001] and drug retention rate [53.1%(17/32) vs 13.8%(4/27), P=0.001] in the patients with vitamin D deficiency. Conclusion: Vitamin D supplementation contributes to improving clinical response rate, clinical remission rate, mucosal healing rate and drug retention rate of VDZ in UC patients.

[Standardized diagnosis results of suspected local anesthetics allergy].

To review and investigate the diagnosis results of local anesthetics (LA) allergy and improve the understanding of LA allergy in clinician. From March 2017 to February 2022, a total of 24 patients were investigated in Allergy Center of West China Hospital,Sichuan University on suspicion of LA allergy. Clinical data and results of skin tests and drug provocation tests (DPT) with the suspected drugs were retrospectively evaluated. The value of standardized diagnostic protocol in the LA allergy were analyzed. The results showed that 24 patients (3 men/21 women) were included with age range from 20 to 74 years. Three cases (12.5%) were positive in previous LA skin tests and proved to be tolerated through standardized tests. Twenty-one patients were initially diagnosed as "LA allergy" because of adverse reactions after previous use of LA, including 20 cases of immediate-type reaction and 1 case of delayed-type reaction. Three cases were considered LA allergy through standardized diagnosis approaches, including skin tests and DPT. One patient was diagnosed with anaphylaxis caused by chlorhexidine. Of the remaining 17 patients, 7 were considered as psychosomatic reactions (29.1%), 3 of sympathetic nervous system conditions (12.5%), 1 of spontaneous urticaria (4.2%), 2 of vasovagal syncope (8.3%), drug side effects (8.3%), skin irritation (8.3%), respectively. In conclusion, true allergic reactions to LA are rare. Through standardized skin tests and DPT, allergy can be ruled out in the vast majority of patients who complain of "LA allergy". For patients who are highly suspected of LA inducing anaphylaxis, other local anesthetics that can be used as safe alternatives should be determined by diagnostic tests according to future needs.

B-Cell-Activating Factor Contributes to Elevation of the Content of Regulatory B Cells in Neonatal Sepsis.

We studied the role of B cell-activating factor (BAFF) in PI3K/AKT/mTOR signaling pathway in promoting proliferation and maintaining survival of regulatory B lymphocytes (Breg) in newborns with sepsis. The peripheral blood samples were collected from preterm neonates (n=40) diagnosed with sepsis on the day of diagnosis and on days 7, 14, and 21 after diagnosis, as well as from the matched preterm neonates without sepsis (n=40; control group). The peripheral blood mononuclear cells and B cells were isolated, cultured, and stimulated with LPS and immunostimulant CpG-oligodeoxynucleotide (CpG-ODN). Proliferation and differentiation of B-cells into CD19+CD24hiCD38hi Breg cells and the role of the PI3K/AKT/mTOR signaling pathway in these processes were studied by flow cytometry, real-time quantitative reverse transcription PCR (qRT-PCR), and Western blotting. BAFF levels in the peripheral blood of neonates with sepsis were significantly increased at one week after diagnosis in parallel with increasing trend of expression of BAFF receptor. When applied with LPS and CpG-ODN, BAFF promoted differentiation of B cells into CD19+CD24hiCD38hi Breg cells. Phosphorylation of 4E-BP1 factor and 70S6K kinase located downstream in PI3K/AKT/mTOR signaling pathway was significantly up-regulated when stimulated with BAFF in combination with LPS and CpG-ODN. Thus, increased level of BAFF activates PI3K/AKT/mTOR signaling pathway and induces in vitro differentiation of peripheral blood B cells into CD19+CD24hiCD38hi Breg cells.

Knockdown of Long Noncoding RNA CCAT2 Suppresses Malignant Phenotype in Human Laryngeal Squamous Cell Carcinoma.

This study aimed to explore the biological role and mechanism underlying the effects of colon cancer-associated transcript 2 (CCAT2), a long noncoding RNA (lncRNA) in human laryngeal squamous cell carcinoma (LSCC). CCAT2 expression levels in clinical LSCC samples and TU-212 cell line were evaluated by quantitative real-time PCR. The correlation of CCAT2 expression level with clinical-pathological characteristics of patients and their prognosis was analyzed. The functional role of CCAT2 in human LSCC was assessed by Cell Counting Kit-8, Transwell assay, flow cytometric analysis, and LSCC xenograft experiment in vivo. The expression of potential targeted proteins was detected by Western blotting and immunohistochemistry. We found that expression of CCAT2 was significantly elevated in LSCC tissues and TU-212 cells (p<0.05). Survival analysis showed that LSCC patients with high expression of CCAT2 had a shorter 5-year overall survival rate than those with low expression (p<0.05). In addition, CCAT2 silencing with short hairpin RNA significantly decreased the proliferative and invasive potential of TU-212 cells (p<0.05) and promoted their apoptosis. In Nude mice, CCAT2 knockdown suppressed the growth of tumor and decreased its volume and weight in comparison with the controls (p<0.05). In TU-212 cells, CCAT2 silencing with short hairpin RNA significantly down-regulated the expression of ß-catenin and CDK8 (p<0.05). Thus, knockdown of CCAT2 suppresses proliferation and invasion of the cells and inhibits Wnt/ß-catenin signaling pathway in LSCC, which indicates novel therapeutic targets and prognostic indicators in patients with LSCC.

[Clinical analysis of 66 cases of pseudo fever].

Some patients who present with a "fever" may only have a localized increase in body surface temperature, while their core body temperature remains normal. This phenomenon is commonly referred to as pseudo fever. A retrospective analysis of clinical data from January 2013 to January 2020 at our fever clinic showed that 66 adolescents were diagnosed with pseudo fever. These patients typically showed a gradual increase in axillary temperature after their cold symptoms had disappeared. Most patients reported no significant complaints other than mild dizziness. Laboratory tests showed no significant abnormalities, and antipyretics were ineffective in lowering their body temperature. Pseudo fever is a relatively independent clinical phenomenon that is distinct from functional fever or simulated fever, and its underlying mechanism remains to be studied.

A bibliometric analysis of primary ovarian insufficiency from 2010 to 2020.

OBJECTIVE: This study aimed to carry out a bibliometric analysis of primary ovarian insufficiency (POI) from 2010 to 2020 and to reveal the research status and hotspots in the future. METHOD: A total of 3087 articles and reviews related to POI published from 2010 to 2020 retrieved from the Web of Science Core Collection were used for bibliometric analysis. CiteSpace and VOSviewer were adopted to analyze countries and regions, organizations, authors, journals, keywords and co-cited references. RESULTS: The number of publications about POI increased year by year. The USA produced the largest number of publications and the most influence in this field. The main research directions of POI can be roughly divided into four aspects according to the analysis of keywords and co-cited references: genetic research of POI; stem cell therapy for patients with POI; prediction of ovarian function; and fertility preservation of cancer patients. Genetic research and stem cell therapy may become research hotspots in the future. CONCLUSION: This study might be the first bibliometric study to analyze publications of POI from multiple indicators, in order to provide new opinions for the research trends and possible hotspots of POI.

[The associations of cyclin-dependent kinase inhibitor 2B antisense RNA 1 gene polymorphisms with the risk of Crohn's disease in Chinese patients].

Objectives: The present study aimed to investigate the associations of cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) gene polymorphisms with the risk of Crohn's disease (CD) in Chinese patients. Methods: From January 2012 to January 2021, a total of 207 CD patients and 545 age-and gender-matched healthy controls were collected from the Department of Gastroenterology, the Second Affiliated Hospital of Wenzhou Medical University. The genotypes of CDKN2B-AS1 (rs1063192, rs10757274, rs10757278, rs1333048, rs2383207) were determined by matrix-assisted laser desorption ionization time-of-flight mass spectrometry technique. Unconditional logistic regression analysis was used to analyze the differences of CDKN2B-AS1 polymorphisms between CD patients and healthy controls, as well as their influences on the clinicopathologic characteristics of CD patients. The analyses for linkage disequilibrium and haplotype were further performed by Haploview 4.2 software. Results: The variant genotype (AG+GG) and variant allele (G) of rs1063192 were more prevalent in CD patients than in healthy controls (32.4% vs 24.8%, P=0.036; 18.8% vs 13.6%, P=0.011). The same conclusions were also drawn for homozygous variant genotype (GG) and variant allele (G) of rs10757274 when CD patients were compared with healthy controls (19.8% vs 12.8%, P=0.017; 45.2% vs 38.1%, P=0.012). According to the Montreal Classification Standards, CD patients were stratified into different subgroups. The homozygous variant genotype (GG) and variant allele (G) of rs10757278 were less frequent in the patients with stricturing CD or penetrating CD than in those with non-stricturing and non-penetrating CD (13.7% vs 29.9%, P=0.015; 37.7% vs 50.4%, P=0.022). However, all the correlations above were no longer significant after Bonferroni's correction (all P>0.05). The polymorphic loci of rs10757274, rs2383207, rs10757278, and rs1333048 were in close linkage disequilibrium with each other in CDKN2B-AS1 gene. Compared with healthy controls, the frequency of haplotype AGAC was decreased in CD patients (1.5% vs 4.5%, χ2=7.61, P=0.006), whereas the frequency of haplotype GGAC was obviously increased in CD patients (3.0% vs 0.6%, χ2=14.25, P<0.001). The stratified analysis further showed that the frequency of haplotype AGAC was higher in the patients with stricturing CD or penetrating CD than in those with non-stricturing and non-penetrating CD (3.1% vs 0.4%, χ2=5.31, P=0.021). Conclusions: The variations of CDKN2B-AS1 (rs1063192, rs10757274, rs10757278, rs1333048, rs2383207) may not independently affect the risk of CD. Among the haplotypes constructed by rs10757274, rs2383207, rs10757278, and rs1333048, the haplotype AGAC may reduce the risk of CD, whereas it may increase the risk of stricturing or penetrating in CD patients. In addition, the haplotype GGAC may increase the risk of CD.

[Clinical features of young inpatients with angle-closure glaucoma].

Objective: To analyze the composition of diagnosis in young inpatients with angle-closure glaucoma and to compare the clinical characteristics between primary angle-closure glaucoma (PACG) and secondary angle-closure glaucoma (SACG). Methods: This was a retrospective case series study. Angle-closure glaucoma patients aged 40 years or younger and hospitalized in Zhongshan Ophthalmic Center from January 2012 to December 2019 were included. The clinical diagnosis, gender, onset age, and results of general ophthalmic examination, A-scan ultrasonography measurements, ultrasound biomicroscopy, optical coherence tomography and visual field were recorded. The proportions and composition of PACG and SACG, as well as the misdiagnosis ratio, were analyzed. The onset age, visual acuity, visual field, and ocular parameters were compared between patients with PACG and SACG. Non-normally distributed data were represented by M (Q1, Q3). The difference between groups were compared by Mann-Whitney U test, Chi square test, and independent sample t test. Results: A total of 243 patients (243 eyes) were included in this study. The mean onset age was (28±9) years, and the male-to-female ratio was 1∶1.79. There were 93 patients (38.3%) in PACG group and 150 (61.7%) in SACG group. The age of PACG [34(28, 38)] was older than that of SACG [28(19, 34)], and the proportion of males in the SACG group (44.0%, 66/150) was significantly higher than that in the PACG group (22.6%, 21/93) (Z=-5.34, χ2=11.46; both P<0.01). Nanophthalmos (22.7%, 34 cases), autosomal recessive bestrophinopathy (ARB) (19.3%, 29 cases), uveitis (18.7%, 28 cases) and retinitis pigmentosa (14.0%, 21 cases) were the most common causes of SACG. The best corrected visual acuity (logarithm of the minimum angle of resolution) was 0.10 (0.00, 0.48) and 0.40 (0.06, 1.00), mean deviation of visual field was -8.07 (-27.49, -2.09) and -15.04 (-28.75, -5.97) dB, and subfoveal choroidal thickness was (452.3±130.7) and (396.3±120.9) µm in the PACG and SACG groups, respectively. The differences were statistically significant (Z=-4.86, -2.14; t=2.37; all P<0.05). There was no statistical difference in intraocular pressure, cup-to-disc ratio, extent of peripheral anterior synechia, central anterior chamber depth, lens thickness, mean retinal nerve fiber layer thickness between these two groups (all P>0.05). The misdiagnosis ratio was 10.7% (26/243) in all patients, while the misdiagnosis ratio of the SACG group (16.7%, 25/150) was higher than that of the PACG group (1.1%, 1/93) (χ²=14.61, P<0.001). Conclusions: PACG, nanophthalmos and ARB are the most common etiologies in young inpatients with angle-closure glaucoma. Compared to PACG, patients with SACG are younger, with worse visual acuity and more severe visual field defects, and easier to be misdiagnosed.

[Outcome comparison between LSA complete reconstruction and partial coverage with endovascular technique for patients with Stanford type B aortic dissection].

Objectives: To compare the short-term outcomes of branched stentgrafts for left subclavian artery (LSA) revascularization or partial LSA coverage without reconstruction in the treatment of type B aortic dissection with proximal tear close to LSA. Methods: A total of 125 type B aortic dissection patients were treated with thoracic endovascular aortic repair (TEVAR) in Xinqiao Hospital of the Army Medical University from January 2019 to March 2021. Their medical records were reviewed and the outcomes were followed up. According to the different treatment methodologies, the patients were divided into complete LSA coverage with reconstruction group (n=25) and partial LSA coverage without reconstruction group (n=100). The data of baseline characteristics, clinical outcomes, and incidence of postoperative in-hospital adverse events were collected and compared between the two groups. The adverse events during one-year follow-up were also compared between the two groups. Kaplan-Meier analysis and log-rank test were used to compare the cumulative survival rates between groups. Results: Compared with partial LSA coverage group, distance of proximal tear to LSA((8.69±2.32)mm vs. (13.77±1.71) mm) was shorter, in-hospital expenses[175 400(166 000-189 900) yuan vs. 143 700 (138 100-151 800) yuan] was higher, average length of stent [200.00 mm vs. 150.00 (150.00-150.00) mm] and operation time [155.00 (140.00-170.00) min vs. 95.00 (80.00-100.00) min] were longer, and volumes of contrast agent [300.00 (200.00-300.00) ml vs. 200.00 (200.00-300.00) ml] (P<0.05) were higher for patients in the complete LSA coverage with reconstruction group. The incidence of post-operative fever was significantly higher in complete LSA coverage with revascularization group than that in partial LSA partial coverage with reconstruction group (56% vs. 25%, P=0.003). There was no significant difference in the incidences of all-cause death, stroke, endoleak, paraplegia, and LSA branch vessel occlusion between the two groups during follow-up. Kaplan-Meier analysis showed that there was no significant difference in the cumulative survival rates between the two groups (log-rank test: P=0.572 5). Conclusion: The TEVAR with complete LSA revascularization or partial LSA coverage without reconstruction for type B aortic dissection close to LSA are safe and effective with high success rates. There is no significant difference between these two techniques in short-term outcomes.

Accurate diagnosis of colorectal cancer based on histopathology images using artificial intelligence.

BACKGROUND: Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients' treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses. METHODS: Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany. RESULTS: Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. CONCLUSIONS: This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.