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Background: Cognitive impairment is common in the elderly population. Exploring patterns of white matter damage at the microstructural level would give important indications for the underlying mechanisms. Objective: To investigate the spatial patterns of white matter microstructure and structural network alternations in relation to different cognition domains Methods: Participants from the community-based Shunyi Study were included to investigate the association between white matter measurements and cognition cross-sectionally, via both global and local analysis. Cognitive functions were assessed using digit span, trail making test (TMT)-A/B, Fuld object Memory, and 12-Word Philadelphia Verbal Learning Test (PVLT). White matter measurements including fractional anisotropy (FA), mean diffusivity (MD), and structural network parameters were calculated based on diffusion tensor imaging. Results: Of the 943 participants included, the mean (SD) age was 55.8 (9.1) years, and the mean (SD) education level was 6.7 (3.2) years. We found the whole set of cognitive measurements was related to diffused white matter microstructural integrity damage and lower global efficiency. Poor executive functions (TMTA/B complete time) were related to lower FA and higher MD predominantly on the anterior white matter skeleton, while verbal memory loss (PVLT test scores) was related to sub-network dysconnectivity in the midline and the right temporal lobe. Conclusion: The anterior brain is dominantly involved in executive dysfunction, while midline and right temporal brain disconnection are more prominent in verbal memory loss. Global and regional disruption of white matter integrity and network connectivity is the anatomical basis of the cognitive impairment in the aging population.

The use of biologic agents has become the cornerstone of therapy for moderate to severe IBD. Few studies have investigated the efficacy of vedolizumab (VDZ) induction for ulcerative colitis (UC) in Asian patients in a real practice setting.To evaluate the efficacy and safety of VDZ induction therapy for moderate to severe UC in Taiwan.This was a retrospective and observational study. Selected moderate to severe UC patients received VZD 300 mg i.v. at weeks 0, 2, and 6 as induction therapy. Mayo scores were calculated to evaluate the efficacy.A total of 37 patients with UC who received VDZ and completed the induction therapy at Chang Gung Memorial Hospital (2017/10-2021/5) were included. The mean age was 46.5 year-old and the male to female ratio was 1:1 (19/18). 81.8% of the patients were biologic-naive. At weeks 8-10, a clinical response, clinical remission and endoscopic remission with VDZ induction therapy were achieved in 56.8% (21/37), 32.4% (12/37) and 58.3% (7/12) of the patients, respectively. 54.1% (20/37) were able to taper off at week 8. Overall, only 10.8% (4/37) of the patients were primary non-responders during induction therapy. No obvious VDZ-related severe adverse events were noted. Overall, 58.9% (11/19) of the patients relapsed after stopping VDZ, and the relapse rate after VDZ discontinuation was 42.1% (8/19) within first 6 months and 52.6% (10/19) within the first year.In real-world experience, induction therapy with VDZ showed promising clinical benefits and safety profile for patients with UC.

To investigate the technological innovation, safety, operational advantages, and clinical application value of direct percutaneous computed tomography (CT)-guided enterostomy.This retrospective study included patients who underwent direct percutaneous CT-guided enterostomy (n = 52), percutaneous endoscopic gastrojejunostomy (PEG-J, n = 39), or laparoscopic jejunostomy (n = 68) at Fujian Provincial Hospital between October 2019 and July 2021. The study indices included stoma surgery success rate, operation time, complication rate, and postoperative pain score. We concurrently analyzed the technological innovation of direct percutaneous CT-guided enterostomy and the changes in body mass index (BMI), serum albumin, prealbumin, and C-reactive protein (CRP) levels and patient-generated subjective global assessment (PG-SGA) scores after patients received 2 months of nutritional support.Direct percutaneous CT-guided enterostomy had a high success rate (100%) and low postoperative complication rate (5.77%). Compared to laparoscopic jejunostomy, direct percutaneous CT-guided enterostomy had a shorter operation time (36.92 ± 10.60) minutes, lower postoperative pain score (4.06 ± 2.02), lower anesthesia risk, and lower operative cost. The anesthetic risk for direct percutaneous CT-guided enterostomy is lower than that for PEG-J and has wider applications. After 2 months of postoperative nutritional support, patients had increased BMI, serum albumin level, and serum prealbumin level and decreased PG-SGA scores and CRP level with statistically significant differences compared to the preoperative state ( p0.05).Direct percutaneous CT-guided enterostomy is an important method of establishing an enteral nutrition therapy pathway, especially when endoscopic jejunostomy is not possible. It has a high safety profile and few complications, has unique advantages, and deserves further promotion of its application in clinical practice.

Andrographolide(ADE) has been demonstrated to inhibit tumor growth through direct cytotoxicity on tumor cells. However, its potential activity on tumor microenvironment (TME) remains unclear. Tumor-associated macrophages (TAMs), composed mainly of M2 macrophages, are the key cells that create an immunosuppressive TME by secretion of cytokines, thus enhancing tumor progression. Re-polarized subpopulations of macrophages may represent vital new therapeutic alternatives. Our previous studies showed that ADE possessed anti-metastasis and anoikis-sensitization effects. Here, we demonstrated that ADE significantly suppressed M2-like polarization and enhanced M1-like polarization of macrophages. Moreover, ADE inhibited the migration of M2 and tube formation in HUVECs under M2 stimulation. In vivo studies showed that ADE restrained the growth of MDA-MB-231 and HCC1806 human breast tumor xenografts and 4T-1 mammary gland tumors through TAMs. Wnt5a/β-catenin pathway and MMPs were particularly associated with ADE's regulatory mechanisms to M2 according to RNA-seq and bioinformatics analysis. Moreover， western blot also verified the expressions of these proteins were declined with ADE exposure. Among the cytokines released by M2, PDGF-AA and CCL2 were reduced. Our current findings for the first time elucidated that ADE could modulate macrophage polarization and function through Wnt5a signaling pathway, thereby playing its role in inhibition of triple-negative breast cancer.

Background and purposeAlthough inflammation has been proposed to be a candidate risk factor for cerebral small vessel disease (CSVD), previous findings remain largely inconclusive and vary according to disease status and study designs. The present study aimed to investigate possible associations between inflammatory biomarkers and MRI markers of CSVD.MethodsA group of 15 serum inflammatory biomarkers representing a variety of those putatively involved in the inflammatory cascade was grouped and assessed in a cross-sectional study involving 960 stroke-free subjects. The biomarker panel was grouped as follows: systemic inflammation (high-sensitivity C reactive protein (hsCRP), interleukin 6 and tumour necrosis factor α), endothelial-related inflammation (E-selectin, P-selectin, intercellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), CD40 ligand, lipoprotein-associated phospholipase A2, chitinase-3-like-1 protein and total homocysteine (tHCY)) and media-related inflammation (matrix metalloproteinases 2, 3 and 9, and osteopontin). The association(s) between different inflammatory groups and white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs), enlarged perivascular space (PVS) and the number of deep medullary veins (DMVs) were investigated.ResultsHigh levels of serum endothelial-related inflammatory biomarkers were associated with both increased WMH volume (R2=0.435, p=0.015) and the presence of lacunes (R2=0.254, p=0.027). Backward stepwise elimination of individual inflammatory biomarkers for endothelial-related biomarkers revealed that VCAM-1 was significant for WMH (β=0.063, p=0.005) and tHCY was significant for lacunes (β=0.069, p2=0.032, p=0.006), and backward stepwise elimination of individual systemic-related inflammatory biomarkers revealed that hsCRP (β=−0.162, p=0.007) was significant.ConclusionWMH and lacunes were associated with endothelial-related inflammatory biomarkers, and fewer DMVs were associated with systemic inflammation, thus suggesting different underlying inflammatory processes and mechanisms.

BACKGROUND/PURPOSE Decorin is a small leucine-rich proteoglycan rich in extracellular matrix with potential antitumor activity. However, the role of decorin in hematological malignancies remains unclear, especially in the case of multiple myeloma (MM), a bone marrow (BM) stroma-dependent plasma cell neoplasm. METHODS We measured decorin levels in BM plasma samples from 270 patients with newly diagnosed MM (NDMM) using enzyme-linked immunosorbent assays. RESULTS Patients were divided into high decorin (H-DCN, > 18.99 ng/mL) and low decorin (L-DCN

Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph

This study aimed to investigate the diagnostic value of doing a second ultrasound-guided fine-needle aspiration (US-FNA) for thyroid nodules of different sizes that could not be diagnosed by the first US-FNA.One hundred and forty-three patients (162 nodules) were diagnosed with suspected malignant thyroid nodules in a routine ultrasound examination, but since the diagnosis could not be confirmed by the cytology of the samples collected in the first US-FNA, the patients underwent US-FNA again 3 months later. The ultrasound results, cytology results, and postoperative pathology of these nodules were collected. The nodules were divided into three groups according to the largest diameter (L) of the thyroid nodules: Group 1, L 0.5 cm, 26 nodules; Group 2, L = 0.5-1.0 cm, 76 nodules; and Group 3, L 1.0 cm, 60 nodules.In the second US-FNA, the overall diagnosis rate of the 162 thyroid nodules that could not be given a definitive diagnosis by the first US-FNA was 51.8% (84/162). The definitive diagnosis rates of the nodules in Groups 1, 2, and 3 were 30.8% (8/26), 67.1% (51/76), and 41.7% (25/60), respectively. The diagnosis rate was the highest in Group 2, and the differences between this group and the other two groups were statistically significant (χSecond US-FNA is highly recommended for such nodules.

Capillary electrophoresis with fluorescence detection (CE-F) is a powerful method to measure enzyme activation in single cells. However, cellular enzymatic assays used in CE-F routinely utilize reporter substrates that possess a bulky fluorophore that may impact enzyme kinetics. To address these challenges, we describe a "fix and click" method utilizing an alkyne-terminated enzyme activation reporter, aldehyde-based fixation, and a click chemistry reaction to attach a fluorophore prior to analysis by single-cell CE-F. The "fix and click" strategy was utilized to investigate sphingolipid signaling in both immortalized cell lines and primary human colonic epithelial cells. When the sphingosine alkyne reporter was loaded into cells, this reporter was metabolized to ceramide (31.6 ± 3.3% peak area) without the production of sphingosine-1-phosphate. In contrast, when the reporter sphingosine fluorescein was introduced into cells, sphingosine fluorescein was converted to sphingosine-1-phosphate and downstream products (32.8 ± 5.7% peak area) without the formation of ceramide. Sphingolipid metabolism was measured in single cells from both differentiated and stem/proliferative human colonic epithelium using "fix and click" paired with CE-F to highlight the diversity of sphingosine metabolism in single cells from primary human colonic epithelium. This novel method will find widespread utility for the performance of single-cell enzyme assays by virtue of its ability to temporally and spatially separate cellular reactions with alkyne-terminated reporters, followed by the assay of enzyme activation at a later time and place.

Lymph node metastases (LNM) are an indicator for recurrence in papillary thyroid carcinoma (PTC) patients. However, prophylactic neck dissection (ND) cannot improve survival or recurrence rate because of increased surgical complications and occult LNM. Biomarkers are needed for the prediction of high-risk of LNM to avoid unnecessary operation and reduce the missed malignant lymph nodules. GEO database was searched for the differentially expressed genes (DEGs) between PTC patients with LNM (N1) and those without LNM (N0), transcriptional and methylation data of DEGs in THCA were examined from databases. The expression and methylation of TM4SF1 in fresh and paraffin tissues of PTC patients were examined by qRT-PCR, IHC, and MSP. TM4SF1 was the only one significantly associated with LNM. UALCAN revealed that TM4SF1 was overexpressed and hypomethylated in LNM patients. MEXPRESS presented a negative correlation between gene expression and promoter methylation of TM4SF1. DEGs were enriched in multiple pathways and the Extracellular Matrix (ECM)-receptor interaction pathway showed the greatest correlation with LNM. IHC and qRT-PCR of tissues demonstrated that the expression of TM4SF1 in the N1 group was 4.5-fold higher than that in the N0 group (p0.05). MSP exhibited that the positive rate of aberrant promoter methylation of TM4SF1 was 8.38% in N1 and 66.7% in N0 group (p0.05). Hyper-expression and hypomethylation of TM4SF1 are associated with lymph node metastases in PTC patients.

Apoptosis of alveolar epithelial cells during acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a critical pathological event that seriously endangers the health of patients. Suppressing apoptosis of alveolar epithelial cells was shown to alleviate functional damage of lung, and modulator of the reactive oxygen species (ROS)-induced apoptosis becomes a promising approach to the ALI therapy. Previous little studies showed that DHCR24 possessed anti-oxidative and anti-apoptotic property in ALI. Thus, H2O2 was utilized to mimic oxidative damage in vitro in alveolar epithelial cell line A549 in the present study. Our results exhibited that H2O2 treatment of A549 cells reduced the level of SOD and increased the level of ROS. Moreover, H2O2 inhibited Bcl-2 expression in A549 cells, but increased Bax and the activity of Caspase-3. In addition, the apoptosis rate in the H2O2 treatment group also increased significantly. And the expression of 24-dehydrocholesterol reductase (DHCR24) was markedly reduced in the H2O2 treatment group. Overexpression of DHCR24 can remarkably inhibit H2O2-induced oxidative stress and apoptosis. We found that overexpression of DHCR24 increased the phosphorylation level of PI3K and AKT, however, the PI3K inhibitor LY294002 (LY) eliminated the protective effect of DHCR24 in ALI. DHCR24 was down-regulated in H2O2-induced ALI, and overexpression of DHCR24 could inhibit H2O2-induced oxidative stress and apoptosis of A549 cells by activating the Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/AKT) signaling pathway. The above exhibited a protective effect of DHCR24 on alveolar epithelial cells exposed to oxidative stress-mediated apoptosis and provided a novel therapeutic method for ALI.

Our aim is to investigate the association of cerebral deep medullary veins (DMVs) with white matter microstructural integrity and regional brain atrophy in MRI. In a community-based cohort of 979 participants (mean age 55.4 years), DMVs were identified on susceptibility-weighted imaging. Brain structural measurements including gray matter and hippocampus volumes, as well as diffusion tensor metrics, were evaluated. The mean (SD)number of DMVs was 19.0 (1.7). A fewer number of DMVs was related to lower fractional anisotropy and higher mean diffusivity in multiple voxels on the white matter skeleton (threshold-free cluster enhancement corrected p

Background/purpose Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative therapy for acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), but advanced age with multiple comorbidities limits the eligibility for allo-HSCT. We conducted a retrospective study to investigate the comorbidities assessments and prognostic factors that predict outcomes for these patients. Methods Clinical data of patients older than 50 years who had received diagnoses of AML or MDS and underwent allo-HSCT were obtained. Information on patient characteristics, including age, gender, allogeneic transplant type, conditioning regimens, Charlson comorbidity index (CCI), and presence of acute graft-versus-host disease (GVHD) or chronic GVHD, were collected and analyzed. Results Two hundred fifty-five elderly patients with a median age at allo-HSCT of 57 years were included. The significant prognostic factors associated with worse overall survival (OS) were CCI ≥3 (hazard ratio: 1.88) and grade III–IV acute GVHD (3.18). Similar findings were noted in the non-relapse mortality analysis. To investigate the effects of chronic GVHD on patient outcomes, OS analysis was performed for those with survival >100 days after transplantation. The results revealed CCI ≥3 (1.88) and grade III–IV acute GVHD (2.73) remained poor prognostic factors for OS, whereas mild chronic GVHD (0.43) was associated with better OS. Conclusion This cohort study suggests that CCI ≥3 predicts poor outcomes, primarily due to a higher NRM risk. Careful management of GVHD after transplantation could improve outcomes in elderly patients with AML or MDS after allo-HSCT.

The outbreak of coronavirus disease 2019 (COVID‐19) has globally strained medical resources and caused significant mortality. This study was aimed to develop and validate a prediction model based on clinical features to estimate the risk of patients with COVID‐19 at admission progressing to critical patients. Patients admitted to the hospital between January 16, 2020, and March 10, 2020, were retrospectively enrolled, and they were observed for at least 14 days after admission to determine whether they developed into severe pneumonia. According to the clinical symptoms, all patients were divided into four groups: mild, normal, severe, and critical. A total of 390 patients with COVID‐19 pneumonia were identified, including 212 severe patients and 178 nonsevere patients. The least absolute shrinkage and selection operator (LASSO) regression reduced the variables in the model to 6, which are age, number of comorbidities, computed tomography severity score, lymphocyte count, aspartate aminotransferase, and albumin. The area under curve of the model in the training set is 0.898, and the specificity and sensitivity were 89.7% and 75.5%. The prediction model, nomogram might be useful to access the onset of severe and critical illness among COVID‐19 patients at admission, which is instructive for clinical diagnosis.

Background: Few studies have investigated the association between cognition and brain volume associated with cerebral small vessel disease (CSVD). Objective: We investigated the association between cognition and brain volume and neuroimaging markers of CSVD in a community-dwelling population. Methods: Participants (n = 993, age≥35 years) from the community-based Shunyi Study were included to investigate the association between neuroimaging markers and cognition cross-sectionally. Magnetic resonance imaging markers included brain volume measurements of the total cerebrum, white matter, gray matter, and CSVD imaging markers. Cognitive performance was assessed using neuropsychological tests of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Fuld Object Memory, digit span, Trail Making Test (TMT)-A, and TMT-B. Results: For brain volume measurement, subcortical white matter fraction was positively associated with MMSE score (β= 0.034, p = 0.0062) and MoCA score (β= 0.034, p = 0.0174), and negatively associated with TMT-A and TMT-B completion time (β= –2.319, p = 0.0002; β= –2.827, p = 0.0073, respectively). For evaluation of CSVD imaging markers, the presence of lacunes was positively associated with TMT-B completion time (β= 17.241, p = 0.0028). Conclusion: In community-dwelling populations, reduced white matter volumes, as a consequence of aging and vascular damage, are associated with worse global cognition and executive function. Our findings provide potential insights into the correlation between cognition and CSVD-associated subcortical white matter injury.

The mutant burden of FLT3-ITD modulates its prognostic impact on patients with acute myeloid leukemia (AML). However, for patients with low allelic ratio (AR) FLT3-ITD (FLT3-ITDlow, AR

Purpose To evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of single and multiple doses of PF-06881894 (pegfilgrastim-apgf; Nyvepria™), a biosimilar to reference pegfilgrastim (Neulasta®), in women with non-distantly metastatic breast cancer. Methods In Phase I (Cycle 0) of this Phase I/II study, the PD response (absolute neutrophil count [ANC]; CD34 + count), PK profile, and safety of a single 3- or 6-mg subcutaneous dose of PF-06881894 were assessed in chemotherapy-naïve patients before definitive breast surgery. In Phase II (Cycles 1–4), the PD response (duration of severe neutropenia [DSN, Cycle 1], ANC [Cycles 1 and 4]) and PK profile (Cycles 1 and 4) of single and multiple 6-mg doses of PF-06881894 concomitant with chemotherapy and after definitive breast surgery were assessed. Results Twenty-five patients (mean age 59 years) were enrolled (Cycle 0, n = 12; Cycles 1–4, n = 13). In Cycle 0, PD responses and PK values were lower with 3-mg versus 6-mg PF-06881894. In Cycles 1 and 4, mean DSN was 0.667 days after single or multiple 6-mg doses of PF-06881894, respectively. In Cycle 4 versus Cycle 1, PD responses were more robust; PK values (mean area under the curve, maximum concentration) were lower; and clearance values were higher. The safety profile of PF-06881894 was similar to that for reference pegfilgrastim. Conclusion PF-06881894 as a single 3- or 6-mg dose prior to definitive surgery, or multiple 6-mg/cycle doses postoperatively, with/without myelosuppressive chemotherapy, was consistent with the clinical pharmacology and safety profile of reference pegfilgrastim. Trial registration October 2017. ClinicalTrials.gov Identifier: NCT02650193. EudraCT Number: 2015-002057-35.

Computed tomography (CT)-guided percutaneous stylomastoid foramen puncture radiofrequency ablation for the treatment of hemifacial spasm has a significant clinical effect; however, related risk factors for recurrence have not been studied.To investigate the risk factors for the recurrence of hemifacial spasm after radiofrequency ablation and construct a model for predicting recurrence.This is a single-center retrospective observational study.The study was conducted at the Pain Department of the Affiliated Hospital of Jiaxing College in Jiaxing, China.A retrospective analysis was performed on 99 patients diagnosed with primary hemifacial spasm (HFS) admitted to the Affiliated Hospital of Jiaxing University between August 2018 and December 2021. All patients underwent CT-guided percutaneous stylomastoid foramen radiofrequency ablation. Kaplan-Meier survival analysis, log-rank test, and Cox proportional risk regression model were used to analyze the clinical factors that affect the recurrence of patients with HFS after radiofrequency ablation, and a recurrence prediction model was established.Follow-up was 3-12 months; recurrence rates were 20.2%, 36.4%, and 71.9% at 3, 6, and 12 months postoperatively, respectively. Univariate analysis showed that puncture approach, operation time, and facial paralysis level were factors influencing recurrence in patients with HFS after radiofrequency ablation (P0.05). The multivariate Cox proportional risk regression model showed that the operative time and facial paralysis grade were independent factors for recurrence after radiofrequency ablation in patients with facial spasms. The recurrence risk function model of patients with facial spasms after radiofrequency ablation was expressed as h(t) = h0exp(-0.619X1-2.589X2), where X1 and X2 represent the operation time and facial paralysis grade, respectively. The likelihood ratio of the model was statistically significant (chi squared = 55.769, P0.001).We look forward to increasing the sample size in follow-up studies and exploring relevant conclusions in randomized controlled trials.Long operation times and high-grade facial paralysis can reduce the risk of recurrence in patients with facial spasms. The constructed recurrence prediction model could serve as a reference for clinical diagnosis and treatment.

Hemifacial spasm (HFS) is mainly characterized by paroxysmal involuntary twitches of one side of the facial muscles. We developed an awake CT-guided percutaneous puncture of the stylomastoid foramen for radiofrequency ablation (RFA) therapy for the treatment of hemifacial spasm and successfully used it in our clinic.We aimed to compare anterior or posterior mastoid approaches in CT-guided percutaneous RFA at the stylomastoid foramen for the treatment of HFS.Prospective, clinical research study.Department of Anesthesiology and Pain Medical Center, Ningbo, China.Sixty-eight patients with HFS were recruited. They were divided into 2 groups: anterior mastoid approach and posterior mastoid approach. With the patient were under minimal sedation, a radiofrequency needle was used to reach the stylo-mastoid foramen on the affected side by an anterior approach or posterior approach; the facial nerve was localized using a low-frequency stimulation current. Ablation stopped when the patient's hemifacial contracture resolved. The puncture depth, angle, intraoperative and postoperative complications, and the short-term and long-term efficacy of the 2 puncture approaches were recorded.The HFS disappeared completely in 37 and 24 cases of the anterior and posterior group, but cases of both groups exhibited a House-Brackmann Facial Paralysis Scale Grade II or Grade III. During one-24 months of follow-up, 5 cases and 3 cases recurred respectively in the two groups. After 6 months of follow-up, the facial paralysis symptoms of patients in both groups disappeared.There was no difference in the operation time or efficacy between the 2 approaches. The anterior mastoid approach is easier to perform and is recommended based on our experience.

Pulsed radiofrequency (PRF) is a commonly used, minimally invasive method to treat herpes zoster neuralgia, but the intensity of standard voltage PRF is limited, resulting in patients not getting a lasting therapeutic effect. The therapeutic effect of repeated high-voltage long-duration PRF on acute herpes zoster neuralgia has not been studied.How to effectively reduce the incidence of postherpetic neuralgia is a serious challenge for clinicians. The purpose of this study was to investigate the clinical efficacy of repeated high-voltage long-duration pulsed radiofrequency therapy for patients with acute herpetic neuralgia and its preventive effect on postherpetic neuralgia.This is a retrospective study.The study was carried out in the Pain Department of the affiliated Hospital of Jiaxing College in Jiaxing, China.Eighty-one patients with acute herpetic neuralgia, who underwent minimally invasive treatment in the Pain Department of Jiaxing First Hospital from January 2020 through December 2020 were retrospectively analyzed. Patients were divided into 3 groups (n = 27 each group) according to treatment method: standard voltage PRF (group S); high-voltage long-duration PRF (group H), and repeated high-voltage long-duration PRF (group R). Pain was assessed according to Numeric Rating Scale (NRS-11) scores and analgesic drug doses were recorded. Blood galectin-3 (gal-3) and interleukin (IL)-6 levels among the 3 groups were compared before treatment and at one, 2, and 4 weeks posttreatment. The incidence of postherpetic neuralgia (PHN) and complications in the 3 groups were recorded.Pain intensity, blood levels of gal-3 and IL-6, and the dose of orally administered gabapentin capsules and morphine were reduced in all patients after treatment. Compared to group S, patients in group R exhibited lower NRS-11 scores, blood levels of gal-3 and IL-6, and dosages of oral gabapentin capsules after treatment. The incidence of PHN was significantly lower at weeks 4, 8, and 12. No adverse reactions occurred in the 3 groups posttreatment.Our small sample size is a limitation; we look forward to increasing the sample size in follow-up studies and exploring relevant conclusions in randomized controlled trials.Repeated high-voltage long-duration PRF therapy was an effective treatment for acute herpetic neuralgia and may prevent the occurrence of PHN.

Background We externally validated Fujimoto's post-transplant lymphoproliferative disorder (PTLD) scoring system for risk prediction by using the Taiwan Blood and Marrow Transplant Registry Database (TBMTRD) and aimed to create a superior scoring system using machine learning methods. Materials and Methods Consecutive allogeneic hematopoietic cell transplant (HCT) recipients registered in the TBMTRD from 2009 to 2018 were included in this study. The Fujimoto PTLD score was calculated for each patient. The machine learning algorithm, least absolute shrinkage and selection operator (LASSO), was used to construct a new score system, which was validated using the fivefold cross-validation method. Results We identified 2,148 allogeneic HCT recipients, of which 57 (2.65%) developed PTLD in the TBMTRD. In this population, the probabilities for PTLD development by Fujimoto score at 5 years for patients in the low-, intermediate-, high-, and very-high–risk groups were 1.15%, 3.06%, 4.09%, and 8.97%, respectively. The score model had acceptable discrimination with a C-statistic of 0.65 and a near-perfect moderate calibration curve (HL test p = .81). Using LASSO regression analysis, a four–risk group model was constructed, and the new model showed better discrimination in the validation cohort when compared with The Fujimoto PTLD score (C-statistic: 0.75 vs. 0.65). Conclusion Our study demonstrated a more comprehensive model when compared with Fujimoto's PTLD scoring system, which included additional predictors identified through machine learning that may have enhanced discrimination. The widespread use of this promising tool for risk stratification of patients receiving HCT allows identification of high-risk patients that may benefit from preemptive treatment for PTLD. Implications for Practice This study validated the Fujimoto score for the prediction of post-transplant lymphoproliferative disorder (PTLD) development following hematopoietic cell transplant (HCT) in an external, independent, and nationally representative population. This study also developed a more comprehensive model with enhanced discrimination for better risk stratification of patients receiving HCT, potentially changing clinical managements in certain risk groups. Previously unreported risk factors associated with the development of PTLD after HCT were identified using the machine learning algorithm, least absolute shrinkage and selection operator, including pre-HCT medical history of mechanical ventilation and the chemotherapy agents used in conditioning regimen.

This study was performed to investigate the relationship between the aspartate transaminase and/or alanine transaminase ratio (DRR) and long-term mortality of patients diagnosed with sepsis or septic shock.We conducted a retrospective study among adult septic patients who were admitted to the surgical intensive care unit (ICU) of the Chinese People's Liberation Army (PLA) General Hospital from January 2014 to December 2018. Baseline characteristics were compared between survivors and non survivors. We performed univariate and multivariate Cox regression analyses to evaluate the relation of DRR with 180-day mortality. The potential prognostic value of DRR in predicting mortality rate was assessed by receiver operating characteristic (ROC) curve analysis. In addition, we conducted subgroup analysis by the optimal DRR cutoff value.We included a total of 183 patients in the current study, and 44 (24%) patients died within 180 days of hospitalization. Univariate and multivariate Cox analyses revealed that DRR was an independent predictor of 180-day mortality (hazard ratio [HR] 1.421, 95% confidence interval [CI] 1.073-1.883, P = 0.014). The predictive accuracy of DRR for 180-day mortality was presented as an ROC curve, which had an area under the curve (AUC) of 0.708 (95% CI 0.629-0.786, P0.001). After we stratified all enrolled patients into two groups by using the optimal cutoff value of 1.29, we observed a significantly higher mortality in patients with a relatively high DRR.An elevated DRR was associated with higher 180-day mortality among septic patients, and DRR might be an optimal marker for predicting the long-term mortality of sepsis. More prospective and randomized trials are needed to confirm the prognostic value of DRR.

Background. Treating advanced colon cancer remains challenging in clinical settings because of the development of drug resistance and distant metastasis. Mechanisms underlying the metastasis of colon cancer are complex and unclear. Methods. Computational analysis was performed to determine genes associated with the exosomal long noncoding (lncRNA) plasmacytoma variant translocation 1 (PVT1)/vascular endothelial growth factor A (VEGFA) axis in patients with colon cancer. The biological importance of the exosomal lncRNA PVT1/VEGFA axis was examined in vitro by using HCT116 and LoVo cell lines and in vivo by using a patient-derived xenograft (PDX) mouse model through knockdown (by silencing of PVT1) and overexpression (by adding serum exosomes isolated from patients with distant metastasis (M-exo)). Results. The in silico analysis demonstrated that PVT1 overexpression was associated with poor prognosis and increased expression of metastatic markers such as VEGFA and epidermal growth factor receptor (EGFR). This finding was further validated in a small cohort of patients with colon cancer in whom increased PVT1 expression was correlated with colon cancer incidence, disease recurrence, and distant metastasis. M-exo were enriched with PVT1 and VEGFA, and both migratory and invasive abilities of colon cancer cell lines increased when they were cocultured with M-exo. The metastasis-promoting effect was accompanied by increased expression of Twist1, vimentin, and MMP2. M-exo promoted metastasis in PDX mice. In vitro silencing of PVT1 reduced colon tumorigenic properties including migratory, invasive, colony forming, and tumorsphere generation abilities. Further analysis revealed that PVT1, VEGFA, and EGFR interact with and are regulated by miR-152-3p. Increased miR-152-3p expression reduced tumorigenesis, where increased tumorigenesis was observed when miR-152-3p expression was downregulated. Conclusion. Exosomal PVT1 promotes colon cancer metastasis through its association with EGFR and VEGFA expression. miR-152-3p targets both PVT1 and VEGFA, and this regulatory pathway can be explored for drug development and as a prognostic biomarker.

Background Intestinal perforations and fistulas are common complications of Crohn’s disease. However, chronic perforation with peritoneal space to rectal and vaginal fistulas have not been previously reported. Case presentation A 38-year-old female suffered from progressive lower abdominal pain, diarrhea and weight loss. Terminal ileal chronic perforation with intra-abdominal abscess, peritoneal space to rectal and vaginal fistulas were noted. The patient received surgical resection of the cecum and terminal ileum, and then vedolizumab treatment. Three months later, she had complete fistula closure, and her body mass index had increased from 13 to 22. Conclusion Vedolizumab combined with stool diversion is effective at treating Crohn’s disease with chronic perforation and complex peritoneal space to rectal and vaginal fistulas.

Pigment epithelium-derived factor (PEDF) has complex functions in tumor metastasis, but little is known about the roles of PEDF and its receptors in hepatocellular carcinoma (HCC). Here we found that high expression of PEDF is associated with shorter overall survival in HCC patients. Forced expression of PEDF enhanced HCC cell aggressive behavior in vitro and in vivo, whereas silencing PEDF expression reduced migration and invasion. Furthermore, PEDF expression led to changes in cell morphology and the expression of epithelial-mesenchymal transition (EMT)-related markers via ERK1/2 signaling pathway, including the upregulation of N-cadherin and slug, and the downregulation of E-cadherin in HCC cells. Our results further showed that PEDF could interact with laminin receptor (LR) and LR knockdown attenuated PEDF-induced migration, invasion and the change of EMT-related markers. More importantly, in clinical HCC specimens, we found that PEDF expression was correlated with subcellular localization of LR, and that high expression of PEDF and positive expression of LR predicted a poor prognosis. In conclusion, our results demonstrate a novel functional role of PEDF/LR axis in driving metastasis through ERK1/2-mediated EMT in HCC and provided a promising prognostic marker in HCC.

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

There are differences in the clinical treatment schemes for patients with different severities of herpes zoster (HZ). Therefore, effective and accurate evaluation of disease severity is of great significance for the formulation of treatment plans. Postherpetic neuralgia (PHN) with long-term chronic pain leads to anxiety, depression, and even suicidal thoughts, which place a heavy burden on society and the family. Therefore, identifying risk factors and taking early intervention to reduce the occurrence of PHN is meaningful. Electromyography (EMG) can provide technical support for the early diagnosis of peripheral neuropathy. However, the application of EMG in HZ and PHN has rarely been reported. The purpose of this study was to compare the detection indices of EMG in patients with different severities and prognoses of HZ and to analyze the application of EMG in severity and prognosis of HZ.This study aimed to explore the relationship between EMG and severity and prognosis of upper limb HZ.A retrospective, observational study.The study was carried out in the Pain Department of the affiliated Hospital of Jiaxing College in Jiaxing, China.A total of 91 patients with upper limb HZ at the First Hospital of Jiaxing between January 2015 and August 2021 were enrolled. The patients were divided into mild, moderate, and severe HZ groups according to their numeric rating scale (NRS) scores. The occurrence of PHN was defined as a poor prognosis. The patients were divided into non-PHN and PHN groups according to the occurrence of PHN. Motor and sensory conduction indices of the median nerve were measured in each group. Spearman's correlation analysis was used to analyze the relationship between the EMG-related data of the median nerve and the NRS score and muscle strength. Univariate and multivariate logistic regression analyses were used to determine the independent influencing factors of PHN in patients with upper limb HZ, and the receiver operating characteristic (ROC) curve was drawn to evaluate the predictive value of EMG-related data in patients with upper limb HZ.Among 91 patients, there were 29 patients in the mild HZ group, 31 in the moderate HZ group, and 31 in the severe HZ group. The sensory nerve action potential (SNAP) amplitude of the median nerve in the severe and moderate HZ groups was lower than that in the mild HZ group, and that in the severe HZ group was lower than that in the moderate HZ group (F = 22.192, P0.05). Through Spearman's correlation analysis, it was found that the compound muscle action potential (CMAP) and SNAP amplitudes of the median nerve on the affected limb were negatively correlated with the NRS score (r = -0.266, P = 0.011; r = -0.778, P0.001), and there was no significant correlation between each index and muscle strength (P0.05). Among 91 patients, 44 and 47 were in the non-PHN and PHN groups, respectively. Univariate and multivariate logistic regression analyses showed that the CMAP amplitude of the median nerve on the affected limb (OR = 0.241, 95% CI: 0.098-0.567, P = 0.001) and SNAP amplitude (OR = 0.268, 95% CI: 0.110-0.628, P = 0.002) were independent influencing factors of PHN. Through the analysis of the ROC curve, it was found that the CMAP and SNAP amplitudes of the median nerve on the affected limb had a high predictive value for PHN (AUC = 0.657, P = 0.010; AUC = 0.773, P0.001). The cutoff values were 5.45 mV and 10.80 mV, respectively; and the predictive value of the 2 indices combined was the highest (AUC = 0.785, P0.001).The nonrandomized, single-center, small sample size, and retrospective design are major limitations of this study.The CMAP and SNAP amplitudes of the median nerve on the affected limb were related to the degree of pain in patients with upper limb HZ. The CMAP and SNAP amplitudes of the median nerve on the affected limb can be used as prognostic factors for patients with upper limb HZ, and CMAP amplitude combined with SNAP amplitude is more valuable in predicting prognosis.

Extending the benefits of tumor molecular profiling for all cancer patients requires a comprehensive analysis of tumor genomes across distinct patient populations worldwide. In this study, we perform deep next-generation DNA sequencing (NGS) from tumor tissues and matched blood specimens from over 10,000 patients in China by using a 450-gene comprehensive assay, developed and implemented under international clinical regulations. We perform a comprehensive comparison of somatically altered genes, the distribution of tumor mutational burden (TMB), gene fusion patterns, and the spectrum of various somatic alterations between Chinese and American patient populations. Here, we show 64% of cancers from Chinese patients in this study have clinically actionable genomic alterations, which may affect clinical decisions related to targeted therapy or immunotherapy. These findings describe the similarities and differences between tumors from Chinese and American patients, providing valuable information for personalized medicine.

BackgroundSepsis is considered an intractable dysfunction that results from the disordered host immune response to uncontrolled infection. Even though the precise mechanism of sepsis remains unclear, scientific advances have highlighted the key role of various programmed cell death processes in the pathophysiology of sepsis. The current study aims to explore the worldwide research trend on programmed cell death in the setting of sepsis and assesses the achievements of publications from various countries, institutions, journals, and authors globally.Material and methodsAssociated publications during 2002–2022 with the topical subject of sepsis and programmed cell death were extracted from the Web of Science. VOSviewer was utilized to evaluate and map the published trend in the relevant fields.ResultsAll 2,037 relevant manuscripts with a total citation of 71,575 times were screened out by the end of 1 January 2022. China accounted for the largest number of publications (45.07%) and was accompanied by corporate citations (11,037) and H-index (48), which ranked second globally. The United States has been ranked first place with the highest citations (30,775) and H-index (88), despite a low publication number (29.95%), which was subsequent to China. The journal Shock accounted for the largest number of publications in this area. R. S. Hotchkiss, affiliated with Washington University, was considered to have published the most papers in the relevant fields (57) and achieved the highest citation frequencies (9,523). The primary keywords on the topic of programmed cell death in sepsis remarkably focused on “inflammation” “immunosuppression”, and “oxidative stress”, which were recognized as the core mechanisms of sepsis, eventually attributing to programmed cell death. The involved research on programmed cell death induced by immune dysregulation of sepsis was undoubtedly the hotspot in the pertinent areas.ConclusionsThe United States has been academically outstanding in sepsis-related research. There appears to be an incompatible performance between publications and quantity with China. Frontier advances may be consulted in the journal Shock. The leading-edge research on the scope of programmed cell death in sepsis should preferably focus on immune dissonance-related studies in the future.

At present, there are many surgical treatments for primary hyperhidrosis (PH), but their medium- and long-term effects remain unclear.To evaluate and compare the efficacy of radiofrequency sympathectomy (RFS) and percutaneous ethanol sympatholysis (PES) in the treatment of PH.A retrospective study.This study was performed at the Affiliated Hospital of Jiaxing University, China.Patients who underwent RFS and PES at The First Affiliated Hospital of Jiaxing University for PH were retrospectively reviewed from January 2016 through December 2018 and were divided into an RFS group and a PES group. The Hyperhidrosis Disease Severity Scale was evaluated at the following time points: before the operation, immediately after the operation, 12 months and 24 months after the operation. The effective rate, patient satisfaction, and compensatory hyperhidrosis were also evaluated.A total of 94 patients diagnosed with primary hyperhidrosis were included (RFS group, n = 45; PES group, n = 49). RFS yielded a postprocedure 24-month effective rate of 53.33% in treating hyperhidrosis compared to PES (24.49%, P0.05). There were no significant differences between the 2 groups regarding patient satisfaction (P = 0.927) and compensatory hyperhidrosis (P = 0.711).This was a single-center study.This is the first clinical study to evaluate the efficacy of RFS and compare it with PES in treating primary hyperhidrosis. RFS significantly decreased hyperhidrosis and had a higher 2-year effective rate compared to PES.

BackgroundTo investigate the dynamic changes of urine N6-methyladenosine (m6A) levels in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) and evaluate the clinical significance.MethodsFirst, the levels of urine m6A were examined and compared among 62 patients with T2DM, 70 patients with DN, and 52 age- and gender-matched normal glucose tolerant subjects (NGT) by using a MethyIFIashTM Urine m6A Quantification Kit. Subsequently, we compared the concentrations of urine m6A between different stages of DN. Moreover, statistical analysis was performed to evaluate the association of urine m6A with DN.ResultsThe levels of m6A were significantly decreased in patients with DN [(16.10 ± 6.48) ng/ml], compared with NGT [(23.12 ± 7.52) ng/ml, P < 0.0001] and patients with T2DM [(20.39 ± 7.16) ng/ml, P < 0.0001]. Moreover, the concentrations of urine m6A were obviously reduced with the deterioration of DN. Pearson rank correlation and regression analyses revealed that m6A was significantly associated with DN (P < 0.05). The areas under the receiver operator characteristics curve (AUC) were 0.783 (95% CI, 0.699 – 0.867, P < 0.0001) for the DN and NGT groups, and 0.737 (95% CI, 0.639 – 0.835, P < 0.0001) for the macroalbuminuria and normoalbuminuria groups, and the optimal cutoff value for m6A to distinguish the DN from NGT and the macroalbuminuria from normoalbuminuria cases was 0.4687 (diagnostic sensitivity, 71%; diagnostic specificity, 76%) and 0.4494 (diagnostic sensitivity, 79%; diagnostic specificity, 66%), respectively.ConclusionsThe levels of urine m6A are significantly decreased in patients with DN and change with the deterioration of DN, which could serve as a prospective biomarker for the diagnosis of DN.

Next-generation sequencing (NGS) has been applied to measurable/minimal residual disease (MRD) monitoring after induction chemotherapy in patients with acute myeloid leukemia (AML), but the optimal time point for the test remains unclear. In this study, we aimed to investigate the clinical significance of NGS MRD at 2 different time points. We performed targeted NGS of 54 genes in bone marrow cells serially obtained at diagnosis, first complete remission (first time point), and after the first consolidation chemotherapy (second time point) from 335 de novo AML patients. Excluding DNMT3A, TET2, and ASXL1 mutations, which are commonly present in individuals with clonal hematopoiesis of indeterminate potential, MRD could be detected in 46.4% of patients at the first time point (MRD1st), and 28.9% at the second time point (MRD2nd). The patients with detectable NGS MRD at either time point had a significantly higher cumulative incidence of relapse and shorter relapse-free survival and overall survival. In multivariate analysis, MRD1st and MRD2nd were both independent poor prognostic factors. However, the patients with positive MRD1st but negative MRD2nd had a similar good prognosis as those with negative MRD at both time points. The incorporation of multiparameter flow cytometry and NGS MRD revealed that the presence of NGS MRD predicted poorer prognosis among the patients without detectable MRD by multiparameter flow cytometry at the second time point but not the first time point. In conclusion, the presence of NGS MRD, especially after the first consolidation therapy, can help predict the clinical outcome of AML patients.

Background and purposeThis study aimed to investigate the association of metabolic syndrome (MetS) with both intracranial atherosclerotic stenosis (ICAS) and imaging markers of cerebral small vessel disease (CSVD) in a community-based sample.MethodsThis study included 943 participants (aged 55.6±9.2 years, 36.1% male) from the community-based Shunyi cohort study. MetS was defined according to the joint interim criteria and quantified by the MetS severity Z-score. ICAS was evaluated by brain magnetic resonance angiography. The MRI markers of CSVD, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces (EPVS), were assessed. Multiple regression models were used to investigate the association of MetS severity Z-score with ICAS and these CSVD markers.ResultsWe found that risk of ICAS (OR=1.75, 95% CI 1.39 to 2.21, pConclusionsOur findings suggest that WMH and lacunes share risk factors with atherosclerosis of the cerebral artery, whereas the impact of glucose and lipid metabolic disorder to CMB or EPVS might be weak.

To analyze clinical characteristics of patients with novel coronavirus Omicron variant of concern infection, and to provide practical data and experience for subsequent clinical treatment.A retrospective analysis was performed for the clinical data of 5 cases with novel coronavirus Omicron variant of concern infection treated in the First Hospital of Jiaxing from December 18, 2021 to January 28, 2022. The patients' clinical data were recorded, including gender, age, length of hospital stay, vaccination status, clinical symptoms, laboratory indicators [white blood cell count (WBC), lymphocyte count (LYM), eosinophil count (EOS), hypersensitivity C-reactive protein (hs-CRP), novel coronavirus antibody immunoglobulin (IgG and IgM)], chest CT, treatment course and disease outcome.All 5 patients were male, aged 24-37 years old. Four patients were vaccinated with novel coronavirus vaccine (one patient received 3 doses of the vaccine and 3 patients received only the first 2 doses of the vaccine), and no infection was found in chest CT. Laboratory examination showed that WBC, LYM, EOS and hs-CRP levels were normal, and only showed mild symptoms of upper respiratory tract infection. One patient was not vaccinated with novel coronavirus vaccine, and signs of viral pneumonia could be seen in chest CT, laboratory examination showed that WBC and hs-CRP levels increased, suggesting that bacterial infection, fever, cough, sputum and other respiratory symptoms were obvious, and the treatment time was long. All 5 patients were treated with Chinese medicine Lotus antipyretic and Baihu Yinqiao decoction based on routine antiviral therapy.Patients with novel coronavirus Omicron variant of concern infection vaccinated with the novel coronavirus vaccine have milder clinical symptoms, with less obvious chest CT findings and faster recovery. Chinese medicine Lotus antipyretic and Baihu Yinqiao decoction has obvious therapeutic effect on such patients.

Sepsis represents a life-threatening organ dysfunction due to an aberrant host response. Of note is that majority of patients have experienced a severe immune depression during and after sepsis, which is significantly correlated with the occurrence of nosocomial infection and higher risk of in-hospital death. Nevertheless, the clinical sign of sepsis-induced immune paralysis remains highly indetectable and ambiguous. Given that, specific yet robust biomarkers for monitoring the immune functional status of septic patients are of prominent significance in clinical practice. In turn, the stratification of a subgroup of septic patients with an immunosuppressive state will greatly contribute to the implementation of personalized adjuvant immunotherapy. In this review, we comprehensively summarize the mechanism of sepsis-associated immunosuppression at the cellular level and highlight the recent advances in immune monitoring approaches targeting the functional status of both innate and adaptive immune responses.

The objective of our study was to measure DLEU7-AS1 expression in de novo acute myeloid leukemia (AML) whilst also analyzing its clinical relevance. We used gene expression data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Cancer Cell Line Encyclopedia (CCLE) and Genotype-Tissue Expression project (GTEx) to assess the expression profile of DLEU7-AS1 in pan-cancers, cancer cell lines and normal tissues. Reverse transcription-quantitative PCR was used to measure DLEU7-AS1 expression in bone marrow from 30 normal individuals and 110 patients with de novo AML. DLEU7-AS1 expression was found to be markedly reduced in the AML samples of the TCGA pan-cancer datasets. In our PCR validation, DLEU7-AS1 expression was significantly decreased in the AML samples compared with that in controls (P

Cancer-induced bone pain (CIBP) is a common pain in clinics, which can reduce the quality of life and increase the mortality of patients, but the treatment of CIBP is limited. This study was designed to investigate the analgesic effect of α-cobratoxin on CIBP and further to explore the molecular target and potential signal pathway. As shown by the mechanical allodynia test in a CIBP rat model, administration of α-cobratoxin produced significant analgesia in a dose-dependent manner, and the analgesic effects were blocked by pretreatment with an intrathecal injection of M4 mAChR-siRNA or intraperitoneal injection of tropicamide, an antagonist of M4 muscarinic cholinergic receptor. Whole-cell patch-clamp recording showed that α-cobratoxin can decrease the spontaneous firing and spontaneous excitatory postsynaptic currents of SDH neurons in CIBP rats. In primary lumber SDH neurons, intracellular calcium measurement revealed that α-cobratoxin decreased intracellular calcium concentration, and immunofluorescence demonstrated that M4 muscarinic cholinergic receptor and CaMKII/CREB were co-expressed. In the CIBP model and primary SDH neurons, Western blot showed that the levels of p-CaMKII and p-CREB were increased by α-cobratoxin and the effect of α-cobratoxin was antagonized by M4 mAChR-siRNA. The quantitative polymerase chain reaction (qPCR) results showed that α-cobratoxin downregulated the expression of proinflammatory cytokines through M4 muscarinic cholinergic receptor in SDH. These results suggest that α-cobratoxin may activate M4 muscarinic cholinergic receptor, triggering the inhibition of SDH neuronal excitability via CaMKII signaling pathway, thereby resulting in antagonistic effects in the CIBP rat model.

The treatment regimen for early gastric cancer (EGC) with mixed histologic type remains controversial. We aimed to clarify the relationship between mixed histologic type and lymph node metastasis (LNM) in EGC, with emphasis on submucosal invasive EGC.We collected data on 730 consecutive EGC patients at Nanjing Drum Tower hospital between June 2010 and May 2019. Risk factors of LNM and overall survival were analyzed to compare the prognostic differences between different histologic types.Mixed-type EGC patients had higher LNM rates than differentiated-type patients (29.2 % versus 10.6 %, P 0.001), while no significant difference was found between mixed-type and undifferentiated-type EGC patients (29.2% versus 24.0%, P = 0.225). Multivariate analyses identified tumor location (cardiac and bottom versus antrum), larger tumor size, submucosal invasion, histologic differentiation (undifferentiated-type, mixed-type versus differentiated-type), and lymphovascular invasion as independent risk factors for LNM in EGC patients. Subgroup analysis further elucidated that mixed histologic type was associated with LNM in submucosa invasive EGC, but not in mucosa-confined EGC. There was no statistical significance in overall survival and disease-specific survival of submucosal invasive EGC patients who underwent radical gastrectomy with lymphadenectomy between different histologic types (P = 0.151).Mixed histologic type may be an independent risk factor for LNM in submucosal invasive EGC. Curative resection with lymphadenectomy should be considered the appropriate treatment for submucosal invasive EGC with mixed histologic type.

Methylglyoxal, a major precursor of advanced glycation end products, is elevated in the plasma of patients with type 2 diabetes mellitus. Islet β-cell function was recently shown to be regulated by N

Background: Mechanisms through which arterial stiffness impacts cognitive function are crucial for devising better strategies to prevent cognitive decline. Objective: To examine the associations of arterial stiffness with white matter integrity and cognition in community dwellings, and to investigate whether white matter injury was the intermediate of the associations between arterial stiffness and cognition. Methods: This study was a cross-sectional analysis on 952 subjects (aged 55.5±9.1 years) who underwent diffusion tensor imaging and measurement of brachial-ankle pulse wave velocity (baPWV). Both linear regression and tract-based spatial statistics were used to investigate the association between baPWV and white matter integrity. The association between baPWV and global cognitive function, measured as the mini-mental state examination (MMSE) was evaluated. Mediation analysis was performed to assess the influence of white matter integrity on the association of baPWV with MMSE. Results: Increased baPWV was significantly associated with lower mean global fractional anisotropy (β= –0.118, p

AKR1C3 is an enzyme belonging to the aldo-ketoreductase family, the members of which catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. AKR1C3 plays an important role in tumor progression and metastasis, however, little is known about the function and the molecular mechanism underlying the role of AKR1C3 in hepatocellular carcinoma (HCC). In this study, we report that AKR1C3 is significantly upregulated in HCC and that increased AKR1C3 is associated with poor survival. AKR1C3 positively regulated HCC cell proliferation and metastasis in vitro and in vivo. AKR1C3 promoted tumor proliferation and metastasis by activating NF-κB signaling. Furthermore, AKR1C3 regulated NF-κB activity by modulating TRAF6 and inducing its autoubiquitination in HCC cells. Activation of NF-κB released proinflammatory factors that facilitated the phosphorylation of STAT3 and increased tumor cell proliferation and invasion. Gain- and loss-of-function experiments showed that AKR1C3 promoted tumor proliferation and invasion via the IL6/STAT3 pathway. STAT3 also directly bound the AKR1C3 promoter and increased transcription of AKR1C3, thereby establishing a positive regulatory feedback loop. Treatment with the AKR1C3 inhibitors indocin and medroxyprogesterone acetate inhibited tumor growth and invasion and promoted apoptosis in HCC cells. Collectively, these results indicate that a AKR1C3/NF-κB/STAT3 signaling loop results in HCC cell proliferation and metastasis and could be a promising therapeutic target in HCC. Significance: These findings elucidate a novel AKR1C3-driven signaling loop that regulates proliferation and metastasis in HCC, providing potential prognostic and therapeutic targets in this disease.

Objectives This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non‐small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD‐L1). Materials and Methods Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB‐high (TMB‐H) was defined as ≥10 mutations/Mb. PD‐L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal. Results EGFR‐sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD‐L1+/TMB‐H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD‐L1+/TMB‐H proportions than wild‐type genotypes. Histone‐lysine N‐methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD‐L1 expression, as well as higher PD‐L1+/TMB‐H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD‐L1+/TMB‐H proportions than wild‐type patients. The median progression‐free survival (PFS) was 5.47 months (95% CI 2.5–NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6–4.27) in wild‐type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co‐mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24–0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26–0.81, p = 0.007). Conclusion We found that tumors with different alterations in actionable target genes had variable expression of PD‐L1 and TMB in NSCLC. TP53/KMT2C co‐mutation might serve as a predictive biomarker for ICI responses in NSCLC. Implications for Practice Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non‐small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next‐generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD‐L1 expression. Our study demonstrated that KMT2C/TP53 co‐mutation might be an accurate, cost‐effective, and reliable biomarker to predict responses to PD‐1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy., Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), is epoch‐making in non‐small cell lung cancer (NSCLC), but only a proportion of patients can derive durable benefits from it, more accurate biomarkers are thus highly needed. Samples of 637 Chinese patients with NSCLC were analyzed through next‐generation sequencing and IHC to characterize the unique features of genomic alterations, TMB, and PD‐L1 expression. The results showed that the alteration subtypes of common driver genes including EGFR G719X, KRAS G12C, MET amplification, and SNVs/INDELs of ALK, RET, and ROS1 in NSCLC are associated with higher PD‐L1 expression or higher TMB value. Furthermore, our study first demonstrated that KMT2C/TP53 co‐mutation might be an accurate, cost‐effective, and reliable biomarker to predict the responses to PD‐1 blockade therapy in NSCLC patients, and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.

Burnout syndrome is a condition marked by emotional exhaustion, deterioration in motivation and lack of commitment, resulting from long-lasting workplace stress, characterized by exhaustion, negative feelings towards one's work and reduced professional efficacy. Healthcare workers are at particularly high risk for burnout due to high levels of stress. Our objectives were to determine the prevalence of burnout syndrome among doctors in Sabah and factors associated with it. This multi-centre cross-sectional study was carried out among doctors working in five Sabah main hospitals. Data were collected by using self-administered questionnaires consisting of basic socio-demographic information and Copenhagen Burnout Inventory (CBI). Overall, a total of 523 doctors consented to participate in this study. The prevalence of personal burnout, work-related burnout, and patient-related burnout among doctors were 57.1%, 48.8%, and 30.4% respectively. Chi-square analysis showed factors that were associated to personal burnout and work-related burnout, were marital status, duration of service and position in the service. Duration of service was the only factor associated with patient-related burnout. The prevalence of burnout syndrome in Sabah should not to be overlooked and more researches are indicated to look into prevention of burnout syndrome in Malaysian setting.

Introduction Gastric cancer (GC) has a high incidence and mortality rate, especially in East Asians, and about 90% of GCs are adenocarcinomas. Histological and etiological heterogeneity and ethnic diversity make molecular subtyping of GC complicated, thus making it difficult to determine molecular division systems and standard treatment modalities. Limited cohorts from South Korea, Singapore, Australia, and Japan have been studied; however, the mutational landscape of gastric adenocarcinomas in Chinese patients is still unknown. Methods We performed a targeted sequencing panel focusing on cancer‐related genes and tumor‐associated microorganisms of 529 gastric adenocarcinoma samples with matched blood controls. We identified 449 clinically relevant gene mutations. Results Approximately 47.1% of Chinese patients with GC harbored at least one actionable mutation. The top somatic mutations were TP53, ARID1A, LRP1B, PIK3CA, ERBB2, CDH1, KRAS, FAT4, CCNE1, and KMT2D. Truncation mutations of ARID1A, KMT2D, RNF43, TGFBR2, and CIC occurred in patients with high tumor mutational burden. Gene amplifications of ERBB2, CCNE1, CDK12, and CCND1 were detected in patients with low tumor mutational burden. Pathway analysis revealed common gene alterations in the Wnt and PI3K/Akt signaling pathways. The ratio of patients with high microsatellite instability was significantly lower than other cohorts, and high microsatellite instability and Epstein‐Barr virus (EBV)–positive features seemed mutually inclusive in Chinese patients with GC. In 44 (8.3%) patients, 45 germline mutations were identified, among which SPINK1 mutations, all SPINK1 c.194 + 2T > C, were present in 15.9% (7/44) of patients. Microorganisms found in Chinese patients with GC included Helicobacter pylori, EBV, hepatitis B virus, and human papillomavirus types 16 and 18. Conclusion Identification of varied molecular features by targeted next‐generation sequencing provides more insight into patient stratification and offers more possibilities for both targeted therapies and immunotherapies of Chinese patients with GC. Implications for Practice This study investigated the genomic alteration profile of 529 Chinese patients with gastric adenocarcinoma by deep targeting sequencing, which might be the largest Chinese cohort on the genomic research of gastric adenocarcinoma up to now., Novel molecular targeted therapies for gastric cancer are urgently needed. This article explores the mutational landscape covering somatic, germline, and microorganisms among a cohort of Chinese patients with gastric cancer. Findings provide insight on patient stratification and potential molecular targets, and for developing new treatment strategies for patients in China and worldwide.

Background and aims Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1α (PGC1α) is a key regulator of mitochondrial biogenesis and respiration. PGC1α is involved in the carcinogenesis, progression, and metabolic state of cancer. However, its role in the progression of hepatocellular carcinoma (HCC) remains unclear. Approach and results In this study, we observed that PGC1α was down-regulated in human HCC. A clinical study showed that low levels of PGC1α expression were correlated with poor survival, vascular invasion, and larger tumor size. PGC1α inhibited the migration and invasion of HCC cells with both in vitro experiments and in vivo mouse models. Mechanistically, PGC1α suppressed the Warburg effect through down-regulation of pyruvate dehydrogenase kinase isozyme 1 (PDK1) mediated by the WNT/β-catenin pathway, and inhibition of the WNT/β-catenin pathway was induced by activation of PPARγ. Conclusions Low levels of PGC1α expression indicate a poor prognosis for HCC patients. PGC1α suppresses HCC metastasis by inhibiting aerobic glycolysis through regulating the WNT/β-catenin/PDK1 axis, which depends on PPARγ. PGC1α is a potential factor for predicting prognosis and a therapeutic target for HCC patients.

Cerebral amyloid angiopathy-related inflammation (CAA-RI) is a rare but increasingly recognized subtype of CAA. CAA-RI consists of two subtypes: inflammatory cerebral amyloid angiopathy and amyloid β (Aβ)-related angiitis. Acute or subacute onset of cognitive decline or behavioral changes is the most common symptom of CAA-RI. Rapid progressive dementia, headache, seizures, or focal neurological deficits, with patchy or confluent hyperintensity on T2 or fluid-attenuated inversion recovery sequences and evidence of strictly lobar microbleeds or cortical superficial siderosis on susceptibility-weighted imaging imply CAA-RI. The gold standard for diagnosis is autopsy or brain biopsy. However, biopsy is invasive; consequently, most clinically diagnosed cases have been based on clinical and radiological data. Other diagnostic indexes include the apolipoprotein E ε4 allele, Aβ and anti-Aβ antibodies in cerebral spinal fluid and amyloid positron emission tomography. Many diseases with similar clinical manifestations should be carefully ruled out. Immunosuppressive therapy is effective both during initial presentation and in relapses. The use of glucocorticoids and immunosuppressants improves prognosis. This article reviews the pathology and pathogenesis, clinical and imaging manifestations, diagnostic criteria, treatment, and prognosis of CAA-RI, and highlights unsolved problems in the existing research.

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human cancers, can be divided into head and body/tail cancers anatomically. We previously reported a prognostic relevance of tumour location in resectable PDAC. This study aimed to further explore the mechanism underlying the molecular diversity between the head and body/tail of PDACs. We detected tumour genomes in 154 resectable (surgery) and non‐resectable (biopsy) PDACs using a next‐generation sequencing panel. Wilcoxon's rank test or Fisher's exact test was used for evaluating associations between clinical characteristics, mutation frequency and survival probability between the two cohorts. Compared with pancreatic head cancers, pancreatic body/tail cancers showed significantly more enriched genomic alterations in KRAS (97.1% vs 82.4%, P = 0.004) and SMAD4 (42.0% vs 21.2%, P = 0.008). At early stages (I‐II), the SMAD4 mutation rate was significantly higher in pancreatic body/tail cancers than pancreatic head cancers (56.0% vs 26.5%, P = 0.021). At late stages (III‐IV), pancreatic body/tail cancers presented significantly higher KRAS mutation rate (100.0% vs 75.8%, P = 0.001), higher frequency of MAPK pathway mutation (100% vs 87.8%, P = 0.040) and lower rates of druggable genomic alterations (30.8% vs 57.6%, P = 0.030) than pancreatic head cancers. Our work points out that pancreatic body/tail cancer seems to be more malignant than pancreatic head cancer at late stages.

Sepsis is a systemic inflammatory response caused by infection and is a major cause of neonatal death. This study explored the miR-455-5p in neonatal sepsis, and further investigated the diagnostic and prognostic value of miR-455-5p in neonatal sepsis (NS). The levels of serum miR-455-5p in 88 healthy controls and 90 NS patients were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Pearson correlation coefficient was used to evaluate the correlation between miR-455-5p and clinical features. Receiver operating characteristic (ROC) curve analysis was performed for the diagnostic evaluation on miR-455-5p. The prognostic value of miR-455-5p in NS was analyzed by Kaplan–Meier survival curve and multivariate Cox regression. The expression of serum miR-455-5p in NS patients was highly expressed in comparison to healthy controls (P, GRAPHICAL ABSTRACT

Aims: The relationship between central arterial stiffness and aging-related intracranial arteriopathy is not well investigated in the general population. In a population-based study, we investigated arterial stiffness in relation to intracranial atherosclerotic stenosis and intracranial arterial dolichoectasia. Methods: This study was a cross-sectional analysis on 1,123 subjects (aged 56.0 ± 9.3 years, 37.9% men) of the population-based Shunyi study in China. Arterial stiffness was assessed by measuring brachial-ankle pulse wave velocity (baPWV). Intracranial atherosclerotic stenosis and intracranial arterial dolichoectasia were evaluated via brain magnetic resonance angiography. Multivariate regression models were constructed to investigate the association between baPWV and intracranial large artery diseases. Results: Increased baPWV was significantly associated with higher prevalence of intracranial atherosclerotic stenosis (odds ratio for the highest quartile of baPWV compared with the lowest quartile, 3.66 [95% confidence interval, 1.57–8.54]), after adjustment for cardiovascular risk factors in multivariate analysis. BaPWV was not associated with the presence of basilar artery dolichoectasia and dilation of basilar artery and internal carotid artery. When the diameters of intracranial arteries were regarded as continuous variables, increased baPWV was inversely related to the internal carotid artery diameter in fully adjusted models (β ± SE, −0.083 ± 0.042, p = 0.047). Conclusions: This population-based study demonstrates that arterial stiffness was more likely associated with intracranial stenotic arteriopathy other than intracranial dilative arteriopathy.

Background: Primary intestinal lymphomas (PILs) are rare, and this study compared the clinical outcomes of aggressive primary intestinal B-cell lymphomas (aB-PILs) and T/natural killer-cell lymphomas (T/NK-PILs). Methods: The clinical information of patients diagnosed with aggressive PILs at our institution between 1995 and 2015 were retrospectively investigated. Pathological subtypes were confirmed according to the 2016 revision of the World Health Organization classification. The correlation between clinicopathological features and overall survival (OS) was determined using univariate and multivariate analyses. Results: Cases of T/NK-PILs had higher initial bowel perforation incidence (67% vs. 7%, P