Effects of Patient-Controlled Transcutaneous Electrical Acupoint Stimulation on Cancer Induced Bone Pain Relief in Patients with Non-Small Cell Lung Cancer: Study Protocol for a Randomized Controlled Trial.

Background: Transcutaneous Electrical Acupoint Stimulation (TEAS) therapy opens up the possibility for individuals with Cancer-induced bone pain (CIBP) to receive a home-based, patient-controlled approach to pain management. The aim of this study is designed to evaluate the efficacy of patient-controlled TEAS (PC-TEAS) for relieving CIBP in patients with non-small cell lung cancer (NSCLC). Methods/Design: This is a study protocol for a prospective, triple-blind, randomized controlled trial. We anticipate enrolling 188 participants with NSCLC bone metastases who are also using potent opioid analgesics from 4 Chinese medical centers. These participants will be randomly assigned in a 1:1 ratio to either the true PC-TEAS or the sham PC-TEAS group. All participants will receive standard adjuvant oncology therapy. The true group will undergo patient-controlled TEAS intervention as needed, while the sham group will follow the same treatment schedule but with non-conductive gel patches. Each treatment course will span 7 days, with a total of 4 courses administered. There will be 4 assessment time points: baseline, the conclusion of weeks 4, 8, and 12. The primary outcome of this investigation is the response rate of the average pain on the Brief Pain Inventory (BPI) scale at week 4 after treatment. Secondary outcomes include pain related indicators, quality of life scale, mood scales, and routine blood counts on the assessment days. Any adverse events will be promptly addressed and reported if they occur. We will manage trial data using the EDC platform, with a data monitoring committee providing regular quality oversight. Discussion: PC-TEAS interventions offer an attempt to achieve home-based acupuncture treatment and the feasibility of achieving triple blinding in acupuncture research. This study is designed to provide more rigorous trial evidence for the adjuvant treatment of cancer-related pain by acupuncture and to explore a safe and effective integrative medicine scheme for CIBP. Trial Registration: ClinicalTrials.gov NCT05730972, registered February 16, 2023.

Real-world advantage and challenge of post-autologous stem cell transplantation MRD negativity in high-risk patients with double-hit multiple myeloma.

BACKGROUND: Autologous stem-cell transplantation (ASCT) remains a beneficial approach for patients with newly diagnosed multiple myeloma (NDMM) in the age of novel therapeutic agents. Nevertheless, limited real-world data is available to establish criteria for identifying high-risk ASCT patients. METHODS: We analyzed outcomes for 168 NDMM patients who underwent ASCT at our center from December 2015 to December 2022. We investigated the impact of the number of high-risk cytogenetics (HRCA), defined as t(4;14), t(14;16), 1q21 gain/amplification, and del(17p), as well as the post-ASCT minimal residual disease (MRD) status as prognostic indicators. We assessed progression-free survival (PFS) and overall survival (OS), and focused on identifying risk factors. RESULTS: The cohort included 42% of patients (n = 71) with 0 HRCA, 42% (n = 71) with 1 HRCA, and 16% (n = 26) with ≥ 2 HRCA. After a median follow-up of 31 months, the median PFS was 53 months (95% CI, 37-69), and OS was not reached for the entire cohort. Despite similar rates of MRD-negativity post-ASCT, patients with ≥ 2 HRCA, termed "double hit" (DH), had a significantly higher risk of progression/mortality than those with 0 or 1 HRCA. Multivariate analysis highlighted DH (HR 4.103, 95% CI, 2.046-8.231) and MRD positivity post-ASCT (HR 6.557, 95% CI, 3.217-13.366) as adverse prognostic factors for PFS, with DH also linked to inferior OS. As anticipated, DH patients with post-ASCT MRD positivity displayed the poorest prognosis, with a median PFS of 7 months post-ASCT. Meanwhile, DH patients with MRD negativity post-ASCT showed improved prognosis, akin to MRD-negative non-DH patients. It is noteworthy to exercise caution, as DH patients who initially achieved MRD negativity experienced a 41% cumulative loss of that status within one year. CONCLUSIONS: This study strongly advocates integrating DH genetic assessments for eligible ASCT patients and emphasizes the importance of ongoing MRD monitoring, as well as considering MRD-based treatment adaptation for those patients in real-world settings.

Atom-based optical polarization modulator.

In this work, we employ 87Rb atoms as rotation media to manipulate the polarization of optical fields in both magnetic and magnetic-free environments. Employing the nonlinear magneto-optical rotation mechanism, we achieve a state-of-the-art magneto-optical rotation coefficient of 1.74×108 rad⋅T-1⋅m-1 which is four orders of magnitude higher than commonly employed materials. Additionally, in a magnetic-free environment, we achieve all-optical cross-polarization modulation between the pump and probe light via Rb atoms. The nonlinear magneto-optical rotation configuration introduces inventive techniques for a new type of magneto-optical modulator while the all-optical configuration paves the way for exploring photonic integrated circuit (PIC) devices free from disruptions caused by electrical or magnetic crosstalk.

Nomogram for personalized prognostic assessment of children with favorable histology Wilms tumor: A retrospective analysis.

OBJECTIVE: This retrospective study aimed to construct and validate a nomogram for personalized prognostic assessment of favorable histology Wilms tumor (FHWT) based on clinical and pathological variables. METHODS AND MATERIALS: This was a retrospective study collected data from patients who underwent surgery for FHWT between March 2007 and November 2022 at Beijing Children's Hospital. Univariate and multivariate Cox proportional hazards regression analyses were conducted to determine the significance variables and constructed the nomogram in predicting event-free survival (EFS) in FHWT patients. RESULTS: A total of 401 FHWT patients were included in the study, with the median age of the patients was 3.4 years. The overall 1-, 3-, and 5-year OS rates were 98.2%, 96.3%, and 93.9%. The 1-, 3-, and 5-year EFS rates were 91.2%, 88.2%, and 86.6%. Subgroup analysis revealed age greater than 2 years was associated with a worse prognosis than age less than or equal to 2 years (P < 0.001), and patients with high-risk Wilms tumors were associated with a higher rate of recurrence and death (P < 0.001). Multivariate analysis showed that age (HR: 2.449, 95%CI: 1.004-5.973), stage (HR: 1.970, 95% CI:1.408-2.756), and histological risk (HR:9.414, 95% CI: 4.318-20.525) were identified as independent predictors of EFS (P < 0.05) and used to construct the nomogram. The prognostic nomogram demonstrated good calibration, great clinical utility, and the time-dependent receiver operating curve analysis showed that the nomogram had precise predictability, with area under the curve values of 0.85(95CI:0.796-0.913), 0.85(95CI:0.80-0.91), and 0.88(95CI:0.839-0.937) for 1-,3-year and 5-year EFS. CONCLUSION: This study provides valuable insights into the clinical characteristics and outcomes of FHWT patients. Accurate staging and histological risk assessment are important in predicting outcomes, and the prognostic nomogram we developed can be a useful tool for clinicians to assess patient prognosis and make informed treatment decisions.

Characteristics of high frame frequency contrast-enhanced ultrasound in renal tumors.

OBJECTIVE: This study aims to analyze the characteristics of high frame rate contrast-enhanced ultrasound (H-CEUS) in renal lesions and to improve the ability for differential diagnosis of renal tumors. METHODS: A total of 140 patients with renal lesions underwent contrast-enhanced ultrasound (CEUS) examination in the First Affiliated Hospital of Nanchang University from July 2022 to July 2023. Based on the tumor pathology and the results of enhanced CT, tumor patients were divided into malignant and benign groups. All subjects were examined using gray-scale ultrasound, conventional contrast-enhanced ultrasound (C-CEUS), and H-CEUS, and their dynamic images were recorded. Two radiologists independently analyzed and recorded the results of ultrasound, C-CEUS, and H-CEUS images and statistically analyzed the features of C-CEUS and H-CEUS images. The independent sample t-test was used to compare the difference in age and maximum diameter of nodules between the benign and malignant groups. The χ2 test was used to compare the sex, mode of operation, gray-scale ultrasound characteristics, and enhancement characteristics of the two CEUS modes (enhancement mode, regression mode, enhancement degree, enhancement uniformity, enhancement or not, enhancement direction, post-enhancement boundary and range, and pseudocapsule) between the benign and malignant groups. The difference in vascular morphology of malignant nodules of varying sizes under two angiographic modes. RESULTS: There were significant differences in gender (χ2 = 10.408, P = 0.001), mode of operation (χ2 = 47.089, P < 0.001), nodule composition (χ2 = 7.481, P = 0.003), nodule echo (χ2 = 20.926, P < 0.001), necrosis (χ2 = 31.343, P < 0.001) and nodule blood flow (χ2 = 9.006, P = 0.029) between the benign and malignant groups. There were significant differences in the regression model (χ2 = 6.782, P = 0.034) and enhancement direction (χ2 = 13.771, P = 0.001) between the two radiographic techniques in the malignant group. There was a significant difference in the enhancement uniformity between the two CEUS techniques in the benign group (χ2 = 8.264, P = 0.004). There was a significant difference between the two CEUS techniques in displaying the vascular morphology in the malignant group with the maximum diameter of nodules ≤ 4.0 cm (χ2 = 11.421, P < 0.022). However, there was no significant difference between the two techniques in the malignant group with the maximum diameter of nodules > 4.0 cm. CONCLUSION: Increasing the frame rate of ultrasound images is helpful to accurately display the enhanced features and vascular morphology of renal tumors, especially for malignant tumors with a maximum diameter of ≤ 4.0 cm. Thus, H-CEUS can make up for the limitation of CEUS with regard to the display of vascular morphology.

MecVax supplemented with CFA MEFA-II induces functional antibodies against 12 adhesins (CFA/I, CS1-CS7, CS12, CS14, CS17, and CS21) and 2 toxins (STa, LT) of enterotoxigenic Escherichia coli (ETEC).

Enterotoxigenic Escherichia coli (ETEC) strains that produce various adhesins and one or two enterotoxins are the leading causes of children's diarrhea and travelers' diarrhea. MecVax, a multivalent ETEC vaccine candidate, consists of two proteins, an adhesin multiepitope fusion antigen (MEFA) that stimulates antibodies to the seven most important ETEC adhesins (CFA/I and CS1-CS6) and a toxoid fusion antigen which stimulates antibodies against ETEC enterotoxins (heat-labile toxin and heat-stable toxin). CFA MEFA-II, another polyvalent MEFA protein, has been demonstrated to stimulate antibodies to another five important ETEC adhesins (CS7, CS12, CS14, CS17, and CS21). We hypothesize that MecVax coverage and efficacy can be expanded if MecVax could stimulate antibodies to all 12 adhesins. In this study, we supplemented MecVax with CFA MEFA-II, examined broad immunity to the 12 targeted ETEC adhesins and 2 ETEC toxins (STa, LT) in mice, and assessed mouse antibody functions for inhibiting the adherence of the 12 adhesins and neutralizing the enterotoxicity of 2 toxins, thus assessing the potential application of a broadly protective pan-ETEC vaccine. Mice intramuscularly immunized with MecVax and CFA MEFA-II developed robust antibody responses to the 12 ETEC adhesins and 2 toxins; furthermore, mouse serum antibodies showed functional activities against the adherence from each of the targeted adhesins and the enterotoxicity of either toxin. Data also indicated that CFA MEFA-II was antigenically compatible with MecVax. These results demonstrated that the inclusion of CFA MEFA-II further expands MecVax broad immunogenicity and protection coverage, suggesting the feasibility of developing a vaccine against all important diarrheal ETEC strains.IMPORTANCEThere are no vaccines licensed for Enterotoxigenic Escherichia coli (ETEC), a leading cause of children's diarrhea and the most common cause of travelers' diarrhea. Since ETEC strains produce over 25 adhesins and 2 distinctive enterotoxins, heterogeneity is a key obstacle to vaccine development. MecVax, a multivalent ETEC vaccine candidate, induces protective antibodies against the seven most important adhesins (CFA/I and CS1-CS6) associated with two-thirds of ETEC clinical cases. However, ETEC prevalence shifts chronically and geographically, and other adhesins are also associated with clinical cases. MecVax would become a pan-ETEC vaccine if it also protects against the remaining important adhesins. This study demonstrated that MecVax supplemented with adhesin protein CFA MEFA-II induces functional antibodies against 12 important ETEC adhesins (CFA/I, CS1-CS7, CS12, CS14, CS17, and CS21), enabling the development of a more broadly protective ETEC vaccine and further validating the application of the MEFA vaccinology platform for multivalent vaccine development.

Improving Microbial Cell Factory Performance by Engineering SAM Availability.

Methylated natural products are widely spread in nature. S-Adenosyl-l-methionine (SAM) is the secondary abundant cofactor and the primary methyl donor, which confer natural products with structural and functional diversification. The increasing demand for SAM-dependent natural products (SdNPs) has motivated the development of microbial cell factories (MCFs) for sustainable and efficient SdNP production. Insufficient and unsustainable SAM availability hinders the improvement of SdNP MCF performance. From the perspective of developing MCF, this review summarized recent understanding of de novo SAM biosynthesis and its regulatory mechanism. SAM is just the methyl mediator but not the original methyl source. Effective and sustainable methyl source supply is critical for efficient SdNP production. We compared and discussed the innate and relatively less explored alternative methyl sources and identified the one involving cheap one-carbon compound as more promising. The SAM biosynthesis is synergistically regulated on multilevels and is tightly connected with ATP and NAD(P)H pools. We also covered the recent advancement of metabolic engineering in improving intracellular SAM availability and SdNP production. Dynamic regulation is a promising strategy to achieve accurate and dynamic fine-tuning of intracellular SAM pool size. Finally, we discussed the design and engineering constraints underlying construction of SAM-responsive genetic circuits and envisioned their future applications in developing SdNP MCFs.

PARP-1 inhibitor alleviates cerebral ischemia/reperfusion injury by reducing PARylation of HK-1 and LDH in mice.

Poly (ADP-ribose) polymerase-1 (PARP-1) activity significantly increases during cerebral ischemia/reperfusion. PARP-1 is an NAD+-consumption enzyme. PARP-1 hyperactivity causes intracellular NAD+ deficiency and bioenergetic collapse, contributing to neuronal death. Besides, the powerful trigger of PARP-1 causes the catalyzation of poly (ADP-ribosyl)ation (PARylation), a posttranslational modification of proteins. Here, we found that PARP-1 was activated in the ischemic brain tissue during middle-cerebral-artery occlusion and reperfusion (MCAO/R) for 24 h, and PAR accumulated in the neurons in mice. Using immunoprecipitation, Western blotting, liquid chromatography-mass spectrometry, and 3D-modeling analysis, we revealed that the activation of PARP-1 caused PARylation of hexokinase-1 and lactate dehydrogenase-B, which, therefore, caused the inhibition of these enzyme activities and the resulting cell energy metabolism collapse. PARP-1 inhibition significantly reversed the activity of hexokinase and lactate dehydrogenase, decreased infarct volume, and improved neuronal deficiency. PARP-1 inhibitor combined with pyruvate further alleviated MCAO/R-induced ischemic brain injury in mice. As such, we conclude that PARP-1 inhibitor alleviates neuronal death partly by inhibiting the PARylation of metabolic-related enzymes and reversing metabolism reprogramming during cerebral ischemia/reperfusion injury in mice. PARP-1 inhibitor combined with pyruvate might be a promising therapeutic approach against brain ischemia/reperfusion injury.

ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban.

BACKGROUND: Intracellular Ca2+ cycling determines myocardial contraction and relaxation in response to physiological demands. SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a) is responsible for the sequestration of cytosolic Ca2+ into intracellular stores during cardiac relaxation, and its activity is reversibly inhibited by PLN (phospholamban). However, the regulatory hierarchy of SERCA2a activity remains unclear. METHODS: Cardiomyocyte-specific ZBTB20 knockout mice were generated by crossing ZBTB20flox mice with Myh6-Cre mice. Echocardiography, blood pressure measurements, Langendorff perfusion, histological analysis and immunohistochemistry, quantitative reverse transcription-PCR, Western blot analysis, electrophysiological measurements, and chromatin immunoprecipitation assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Specific ablation of ZBTB20 in cardiomyocyte led to a significant increase in basal myocardial contractile parameters both in vivo and in vitro, accompanied by an impairment in cardiac reserve and exercise capacity. Moreover, the cardiomyocytes lacking ZBTB20 showed an increase in sarcoplasmic reticular Ca2+ content and exhibited a remarkable enhancement in both SERCA2a activity and electrically stimulated contraction. Mechanistically, PLN expression was dramatically reduced in cardiomyocytes at the mRNA and protein levels by ZBTB20 deletion or silencing, and PLN overexpression could largely restore the basal contractility in ZBTB20-deficient cardiomyocytes. CONCLUSIONS: These data point to ZBTB20 as a fine-tuning modulator of PLN expression and SERCA2a activity, thereby offering new perspective on the regulation of basal contractility in the mammalian heart.

Assessment of clinical prognosis improvement in children with concomitant anterior and posterior urethral valves: A case series report.

BACKGROUND: Concomitant anterior urethral valves (AUVs) and posterior urethral valves (PUVs) is an extremely rare congenital urologic anomaly, which may be easily overlooked in the clinic. OBJECTIVE: This study assessed the prognosis of children with concomitant PUVs and AUVs. METHODS: The clinical data of inpatients with concomitant AUVs and PUVs in our hospital were collected from January 1983 to June 2022. The clinical manifestations, auxiliary inspection, and treatment were described in detail. RESULTS: In total, 6 cases of concomitant AUVs and PUVs in boys were found in our hospital, with ages ranging from 3 months to 9 years; the main clinical manifestation was abnormal urination. Four patients exhibited concomitant AUVs and PUVs preoperatively and underwent simultaneous anterior and posterior urethral valvotomy. Follow-up studies showed that 3 patients' clinical symptoms substantially improved with well-maintained renal function. One patient died of renal failure. In the other 2 patients, PUVs were initially identified and excised, but their clinical symptoms did not show substantial improvement. Following voiding cystourethrography (VCUG), the AUVs were found and obstructions were then completely relieved. However, 2 patients died of renal failure. CONCLUSIONS: If urinary symptoms cannot be substantially relieved after posterior urethral valvotomy, VCUG and cystoscopy should be repeated to shorten the interval between anterior and posterior urethral valvotomies to improve patient prognosis.

Gender determination and long-time follow-up analysis of mixed gonadal dysgenesis.

INTRODUCTION: Mixed gonadal dysgenesis (MGD) is a rare disorder of sexual development. The management of MGD is challenging since the disease significantly impacts a patient's growth, hormone balance, and gonadal development. This article used a large population and a long follow-up period for its analysis. OBJECTIVES: This study aims to summarize the gender determination basis and analyze the long-term follow-up of mixed gonadal dysgenesis. METHODS: A total of 45 patients' clinical data were summarized and analyzed. Patients were divided by gender. Next, we followed up regarding the occurrence of complications after surgery, the patients' satisfaction with external genitalia appearance, the growth of the patients, counting the surgical pattern the incidence of surgical complications and the development of the patients' growth. All patients included in this study underwent chromosomal karyotype analysis, abdomen exploration, and pathological biopsy. After sex determination, 7 patients who were raised as female underwent clitoroplasty, and bilateral gonadectomy. 38 male patients underwent urethroplasty + one-sided gonadectomy. RESULTS: Patient follow-up started in the third month after surgery. Female patients reported no surgery-related complications, while 14 male patients showed surgery-related complications. Additionally, 20 male patients (60.6 %) had a lower height compared to normal peers, 12 of which (36.4 %) were lower than the second standard deviation of the height of normal peers. CONCLUSION: The clinical manifestations of mixed gonadal dysgenesis are variable, and the management is complicated. Children's gonadal function, external genital conditions, psychological evaluation, and parents' wishes should be considered before sex determination. In China, most patients are raised as males with a high incidence of postoperative complications. We found that short stature is a common feature in male patients, thus their height and growth should be carefully supervised. Patients should pay attention to their sexual function and sexual potential during adulthood.

Integrative multi-omics analysis reveals the critical role of the PBXIP1 gene in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder, and its strongest risk factor is aging. A few studies have explored the relationship between aging and AD, while the underlying mechanism remains unclear. We assembled data across multi-omics (i.e., epigenetics, transcriptomics, and proteomics, based on frozen tissues from the dorsolateral prefrontal cortex) and neuropathological and clinical traits from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). Aging was assessed using six DNA methylation clocks (including the Horvath clock, Hannum clock, Levine clock, HorvathSkin clock, Lin clock, and Cortical clock) that capture mortality risk in literature. After accounting for age, we first identified a gene module (including 263 genes) that was related to the integrated aging measure of six clocks, as well as three neuropathological traits of AD (i.e., ß-amyloid, Tau tangles, and tangle density). Interestingly, among 20 key genes with top intramodular connectivity of the module, PBXIP1 was the only one that was significantly associated with all three neuropathological traits of AD at the protein level after Bonferroni correction. Furthermore, PBXIP1 was associated with the clinical diagnosis of AD in both ROSMAP and three independent datasets. Moreover, PBXIP1 may be related to AD through its role in astrocytes and hippocampal neurons, and the mTOR pathway. The results suggest the critical role of PBXIP1 in AD and support the potential and feasibility of using multi-omics data to investigate mechanisms of complex diseases. However, more validations in different populations and experiments in vitro and in vivo are required in the future.

Fe Cluster Modified Co9 S8 Heterojunction: Highly Efficient Photoelectrocatalyst for Overall Water Splitting and Flexible Zinc-Air Batteries.

Designing bifunctional low-cost photo-assisted electrocatalysts for converting solar and electric energy into hydrogen energy remains a huge challenge. Herein, a heterojunction (Fe cluster modified Co9 S8 loaded on carbon nanotubes, Co9 S8 -Fe@CNT) for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) is demonstrated. Benefiting from the good electronic conductivity and spatial confinement of the carbon skeleton, as well as the electronic structure regulation of the Fe cluster, Co9 S8 -Fe@CNT exhibits excellent catalytic performance with a low overpotential of 150 mV for OER and 135 mV for HER at 10 mA cm-2 . Upon light irradiation, holes and electrons are generated in the valence band and conduction band of the Co9 S8 , respectively. Part of the charges are transferred to the interface to facilitate the catalytic reaction, while the remaining are transferred by the electrode. When working as a bifunctional catalyst for overall water splitting, the performance can reach 1.33 V at under light conditions, which is significantly better than 1.52 V in a dark environment. Theoretical calculations revealed lowered Gibbs free energy (∆GH *) of the heterojunction with the effect of Fe modification of Co9 S8 . This work sheds a new light in designing novel photoelectrochemical materials to convert solar and electric energy into chemical energy.

Ureteropelvic junction obstruction with polyps in children: clinical manifestations and supranormal preoperative differential renal function.

OBJECTIVE: To describe and analyze the clinical manifestation and pre-DRF of UPJO children with polyps and explore the possible influencing factors of supranormal pre-DRF. PATIENTS AND METHODS: All patients undergoing primary Anderson-Hynes pyeloplasty for UPJO due to polyp were retrospectively reviewed. Patients' characteristics, parameters of ultrasound and dynamic renograms (DR) were recorded in elaborate. Pre-DRF in groups of different age, weight, gender, pain, grade of hydronephrosis, anterio-posterior pelvic diameter (APD), length of kidney and postoperative ultrasonic parameters were compared. RESULTS: A total of 18 UPJO children with polyps were included. Five (27.78%) patients had SFU III grade of hydronephrosis. Seven (38.89%) patients were supranormal pre-DRF. All patients had pre-DRF > 40%. Drainage curve was delayed excretion in 12 (66.67%) patients and T1/2 < 20 min was in 4 (22.22%) patients. Among the 16 patients who underwent preoperative IVP examination, 15 (93.75%) patients had concentration of intrarenal pelvis contrast agent within 10 min. No significant difference in post-APD reduction rate and post-minPT increased was found between supranormal pre-DRF and non-supranormal pre-DRF groups. The supranormal pre-DRF was more likely to occur in young and low-weight children. CONCLUSION: The preoperative renal function of UPJO patients with polyps was well preserved, and 38.89% of them had supranormal pre-DRF. Patients with supranormal pre-DRF can be managed with the same strategies as those with normal renal function.

MiR-20 promotes cartilage repair in knee osteoarthritis rats via BMP2/Smad1 signaling pathway.

To explore the effect of micro ribonucleic acid (miR)-20b on knee osteoarthritis rats by regulating the bone morphogenetic protein 2 (BMP2)/Smad1 pathway, a total of 36 SD rats were randomly divided into normal group (n=12), model group (n=12) and miR-20b mimics group (n=12). The rats in normal group were fed normally, while those in model group and miR-20b mimics group were used to establish knee osteoarthritis models. After modeling, model group was not given any intervention, but miR-20b mimics group received intra-articular injection of miR-20b mimics once a day for 2 weeks. Basso, Beattie and Bresnahan (BBB) limb motor function scoring was performed at 1, 5, 7 and 14 days after the modeling, and samples were obtained after 2 weeks of intervention. Next, hematoxylin and eosin (H&E) staining was applied to observe tissue morphology, Markin's scoring was utilized to evaluate articular cartilage degeneration, and immunohistochemistry was employed to detect the expressions of BMP2 and Smad1. Thereafter, the expression of miR-20b was detected via qPCR, the content of cartilage oligomeric matrix protein (COMP) and C-telopeptide of type II collagen (CTX-II) was measured via enzyme-linked immunosorbent assay (ELISA), and the expressions of BMP2 and Smad1 proteins were examined via Western blotting (WB). BBB limb motor function scoring showed that compared with that in normal group, the BBB limb motor function score of rats in the other two groups was reduced (P<0.05). In comparison with that in model group, the BBB limb motor function score in miR-20b mimics group was increased from the 7th day after intervention (P<0.05). In addition, H&E staining results manifested that the articular surface in normal group was smooth and flat, with normal morphology, clear structure and no obvious damage. In model group, the articular surface was not smooth and uneven, and more articular cartilage fractures, morphological disorders and structural damages could be observed. Moreover, the articular surface in miR-20b mimics group was slightly damaged and smoother, and its morphology and structure were markedly improved in contrast to that in model group. The Markin's score in normal group was lower than that in model group and miR-20b mimics group (P<0.05), and it was overtly decreased in miR-20b mimics group in comparison with that in model group (P<0.05). Next, immunohistochemistry demonstrated that compared with normal group, the other two groups had lowered positive expressions of BMP2 and Smad1 (P<0.05). In comparison with model group, miR-20b mimics group exhibited notably raised positive expressions of BMP2 and Smad1 (P<0.05). Then it was found from qPCR results that the expression level of miR-20b in the other two groups was overtly reduced compared with that in normal group (P<0.05), and it was prominently elevated in miR-20b mimics group in contrast to that in model group (P<0.05). Besides, ELISA illustrated that the content of COMP and CTX-II in the cartilage tissues in the other two groups was evidently reduced compared with that in normal group (P<0.05), and it was increased prominently in miR-20b mimics group compared with that in model group (P<0.05). Finally, it was revealed by WB examination that the relative expression levels of BMP2 and Smad1 proteins in the other two groups markedly declined in comparison with those in normal group (P<0.05), and they were elevated in contrast to those in model group (P<0.05). MiR-20b can promote cartilage repair and improve articular function in knee osteoarthritis rats by up-regulating the BMP2/Smad1 signaling pathway.

Fructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal.

Arginase, a manganese (Mn)-dependent enzyme, is indispensable for urea generation and ammonia disposal in the liver. The potential role of fructose in Mn and ammonia metabolism is undefined. Here we demonstrate that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice. Fructose overexposure reduces liver Mn content as well as its activity of arginase and Mn-SOD, and impairs the clearance of blood ammonia under liver dysfunction. Mechanistically, fructose activates the Mn exporter Slc30a10 gene transcription in the liver in a ChREBP-dependent manner. Hepatic overexpression of Slc30a10 can mimic the effect of fructose on liver Mn content and ammonia disposal. Hepatocyte-specific deletion of Slc30a10 or ChREBP increases liver Mn contents and arginase activity, and abolishes their responsiveness to fructose. Collectively, our data establish a role of fructose in hepatic Mn and ammonia metabolism through ChREBP/Slc30a10 pathway, and postulate fructose dietary restriction for the prevention and treatment of hyperammonemia.

Transcutaneous electrical acupoint stimulation for cancer-related pain management in patients receiving chronic opioid therapy: a randomized clinical trial.

PURPOSE: The opioid crisis resulting from its use disorder and overdose poses additional challenges for cancer pain management. The American Society of Clinical Oncology Practice Guideline recommends acupuncture therapy for the management of adult cancer-related pain (CRP), but the effectiveness of transcutaneous electrical acupoint stimulation (TEAS) on CRP remains uncertain. METHODS: This 5-week prospective randomized clinical trial was conducted at 2 hospitals in China, and participants with CRP receiving chronic opioid therapy were randomized 1:1 into two groups between December 2014 and June 2018. The true TEAS group underwent 15 sessions of TEAS treatments over 3 consecutive weeks, while the control group received sham stimulation. The primary outcome was the numerical rating scale (NRS) score in the past 24h at week 3. The secondary outcomes included morphine equivalent daily dose, quality of life and adverse events. RESULTS: A total of 159 participants were included in the modified intention-to-treat population. The baseline characteristics were similar in both groups. The mean NRS scores were 0.98 points at week 3 in the true TEAS group and 1.41 points in the sham group, with the mean difference between groups of -0.43 points (P < 0.001; OR = 0.68, P < 0.05). The proportion of patients with NRS reduction more than thirty percentage at week 3 was 50.00% in the true TEAS group and 35.44% in the sham group (RD = 0.15, P > 0.05; RR = 1.41, P > 0.05). No significant difference in pain intensity between the two groups was observed during the follow-up period without TEAS intervention (week 4, OR = 0.83, P > 0.05; week 5, OR = 0.83, P > 0.05). The Karnofsky Performance Status value suggested that patients in the true TEAS group experienced an improved quality of life (Between-group differences: week 3, 3.5%, P < 0.05; week 4, 4.6%, P < 0.001; week 5, 5.6%, P < 0.001). CONCLUSIONS: The 3-week application of TEAS in patients with CRP receiving chronic opioid therapy resulted in a statistically significant reduction in pain scores, but the observed reduction was of uncertain clinical significance. The prolonged analgesic effect of TEAS was not confirmed in this trial. CLINICALTRIAL: GOV: ChiCTR-TRC-13003803.

Failure in Double-J stent inserting in laparoscopic pyeloplasty of ureteropelvic junction obstruction: the clinical features and outcomes.

BACKGROUND: Double-J (DJ) stent placement is an important procedure during laparoscopic pyeloplasty (LP). Failing to insert the DJ stent may indicate the patient was also complicated with uretero-vesical junction obstruction (UVJO), and surgeons have to change to another alternative drainage method. In the present study, we analyzed the risk factors of failure of DJ stent placement during the LP and reviewed the clinical outcomes of these challenging pyeloplasties. METHODS: We retrospectively analyzed the clinical data of patients with ureteropelvic junction obstruction (UPJO) who underwent LP in our department from January 2016 to September 2020. For patients who developed a difficult process of inserting the DJ stent, the externalized uretero-pyelostomy (EUP) stent was indwelled. Patients were finally divided into two groups: DJ group and EUP group. The primary outcomes were recurrent UPJO, postoperative uretero-vesical junction obstruction (UVJO) and complications. RESULTS: A total of 535 patients were included in the study, of which 37 patients (6.9%) failed to insert the DJ stent. Age was younger, and weight was lower (P < 0.05) in the EUP group. Within follow-up, recurrent UPJO occurred in ten (1.87%) patients, nine in the DJ group and one in the EUP group (P > 0.05). The incidence of postoperative UVJO in the EUP group was significantly higher than in the DJ group (10.8% vs. 0.2%, P < 0.01). 74 patients (13.8%) developed complications after surgery, 12 patients (32.4%) in the EUP group, significantly higher than that in the DJ group (32.4% vs. 12.4%, P < 0.01). Compared with the DJ group, the larger APD were observed in the EUP group at three months postoperatively (3.50 [3.02;4.58] vs. 2.20 [1.50;2.88], P < 0.05), but the difference vanished in further follow-up. CONCLUSION: The failure of DJ stent placement tends to occur in patients with younger age, lower weight, and larger preoperative APD. Failure may not increase the recurrent UPJO rate, but may indicate a higher probability of postoperative UVJO and may develop more postoperative complications and slower recovery.

Urethrocutaneous fistula and glans dehiscence formation of hypospadias surgery in patients receiving caudal block vs. non-caudal block: A meta-analysis.

BACKGROUND: This meta-analysis aimed to evaluate the difference in postoperative complications as urethrocutaneous fistula or glans dehiscence, in children undergoing primary hypospadias repair with caudal block (CB) versus non-caudal block (NCB). METHODS: Data were obtained from MEDLINE, Embase, Web of Science, and the Cochrane Library. Comparative studies of CB versus NCB were identified, with reports of complications published or presented until October 2022. Subgroup analyses were performed based on study type, meatal location (distal only), type of NCB, surgeon and technique, and concentration and dose of anesthetics. RESULTS: Compared to the reference group of NCB, CB was not significantly associated with the development of complications following primary hypospadias repair (OR 1.40, 95 % CI 0.88-2.23). After adjusting for confounding factors, such as type of study(OR 1.51, 95%CI: 0.29-7.91), type of NCB[PB (OR 1.82, 95 % CI: 0.87-3.84), GA (OR 1.26, 95 % CI: 0.39-4.04)], meatal location (distal only) (OR 1.22, 95 % CI: 0.61-2.43), surgeon and technique (OR 1.37, 95 % CI: 0.59-3.14) and concentration and dose of anesthetics(OR 2.74, 95 % CI: 0.82-9.20), subgroup analyses revealed no significant association between CB and NCB (P > 0.05). DISCUSSION: Previous studies have found a correlation between CB and increased incidence of postoperative complications (urethrocutaneous fistula or glans dehiscence) of hypospadias, but different literature have suggested that surgical technique, surgical duration and the severity of hypospadias, rather than CB, are closely related to the occurrence of complications. In order to reduce confounding factors, subgroup analyses were conducted. The results showed that no correlation could be found in postoperative complications and CB. CONCLUSIONS: This meta-analysis compared the incidence of urethrocutaneous fistula or glans dehiscence in the CB and NCB groups for primary hypospadias repair in children, indicating that no clear correlation could be found in postoperative complications and CB. Subgroup analyses on study type, type of NCB, meatal location (distal only), surgeon and technique, and regional anesthetic concentration and dose supported this conclusion.