The modified Hardinge approach is not inferior to trochanteric flip osteotomy for Pipkin type IV femoral head fractures: a comparative study in 40 patients.

PURPOSE: To compare the modified Hardinge approach and trochanteric flip osteotomy for the treatment of Pipkin type IV femoral head fractures. METHODS:  This retrospective study included 40 patients who underwent surgical treatment for Pipkin type IV femoral head fractures between 2011 and 2020 and completed at least 1 year of follow-up. The clinical outcome of the Merle d'Aubigné-Postel score and radiological outcomes, including the quality of the fracture reduction, osteonecrosis of the femoral head, posttraumatic osteoarthritis, and heterotopic ossification, were compared between the two groups. Conversion to total hip replacement was recorded as the main outcome measure, analyzed by Kaplan-Meier curve and log-rank test. RESULTS: Nineteen and 21 patients were treated using the modified Hardinge approach (Group A) and trochanteric flip osteotomy (Group B), respectively. The estimated surgical blood loss was significantly higher in Group B (500.00 ± 315.44 mL vs. 246.32 ± 141.35 mL; P = 0.002). Two patients in Group B complained of discomfort caused by the trochanteric screws and requested implant removal. Radiographic outcomes did not differ significantly between the two groups. Clinical outcomes assessed using the Merle d'Aubigné-Postel score 1 year after injury were nearly identical (P = 0.836). Four (21.1%) patients in Group A and three (14.3%) patients in Group B underwent conversion to total hip replacement during the follow-up period; the log-rank test showed no significant difference (P = 0.796). CONCLUSIONS: The modified Hardinge approach resulted in reduced blood loss, with clinical and radiological outcomes similar to those of trochanteric osteotomy; thus, it is an acceptable alternative to trochanteric flip osteotomy.

Is Telemedicine Suitable for Patients with Chronic Inflammatory Skin Conditions? A Systematic Review.

Telemedicine, the provision of remote healthcare, has gained prominence, accelerated by the COVID-19 pandemic. It has the potential to replace routine in-person follow-up visits for patients with chronic inflammatory skin conditions. However, it remains unclear whether telemedicine can effectively substitute in-person consultations for this patient group. This systematic review assessed the effectiveness and safety of telemedicine compared with traditional in-person care for chronic inflammatory skin diseases. A comprehensive search in various databases identified 11 articles, including 5 randomized controlled trials (RCTs) and 1 clinical controlled trial (CCT). These studies evaluated telemedicine's impact on patients with psoriasis and atopic dermatitis, with varying methods like video consultations and digital platforms. The findings tentatively suggest that telemedicine does not seem to be inferior compared with in-person care, particularly in terms of condition severity and quality of life for patients with chronic inflammatory skin diseases. However, these results should be interpreted with caution due to the inherent uncertainties in the evidence. There are indications that telemedicine can offer benefits such as cost-effectiveness, time savings, and reduced travel distances, but it is important to recognize these findings as preliminary, necessitating further validation through more extensive research.

Early detection and prognosis evaluation for hepatocellular carcinoma by circulating tumour DNA methylation: A multicentre cohort study.

BACKGROUND: Early diagnosis of hepatocellular carcinoma (HCC) can significantly improve patient survival. We aimed to develop a blood-based assay to aid in the diagnosis, detection and prognostic evaluation of HCC. METHODS: A three-phase multicentre study was conducted to screen, optimise and validate HCC-specific differentially methylated regions (DMRs) using next-generation sequencing and quantitative methylation-specific PCR (qMSP). RESULTS: Genome-wide methylation profiling was conducted to identify DMRs distinguishing HCC tumours from peritumoural tissues and healthy plasmas. The twenty most effective DMRs were verified and incorporated into a multilocus qMSP assay (HepaAiQ). The HepaAiQ model was trained to separate 293 HCC patients (Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 224) from 266 controls including chronic hepatitis B (CHB) or liver cirrhosis (LC) (CHB/LC, 96), benign hepatic lesions (BHL, 23), and healthy controls (HC, 147). The model achieved an area under the curve (AUC) of 0.944 with a sensitivity of 86.0% in HCC and a specificity of 92.1% in controls. Blind validation of the HepaAiQ model in a cohort of 523 participants resulted in an AUC of 0.940 with a sensitivity of 84.4% in 205 HCC cases (BCLC stage 0/A, 167) and a specificity of 90.3% in 318 controls (CHB/LC, 100; BHL, 102; HC, 116). When evaluated in an independent test set, the HepaAiQ model exhibited a sensitivity of 70.8% in 65 HCC patients at BCLC stage 0/A and a specificity of 89.5% in 124 patients with CHB/LC. Moreover, HepaAiQ model was assessed in paired pre- and postoperative plasma samples from 103 HCC patients and correlated with 2-year patient outcomes. Patients with high postoperative HepaAiQ score showed a higher recurrence risk (Hazard ratio, 3.33, p < .001). CONCLUSIONS: HepaAiQ, a noninvasive qMSP assay, was developed to accurately measure HCC-specific DMRs and shows great potential for the diagnosis, detection and prognosis of HCC, benefiting at-risk populations.

Guiding function of positron emission tomography-computed tomography examination in the diagnosis and treatment of ocular adnexal mucosa associated lymphoid tissue lymphoma.

AIM: To explore the role of positron emission tomography-computed tomography (PET-CT) examination in the diagnosis and treatment of ocular adnexal mucosa associated lymphoid tissue lymphoma (OAML). METHODS: The general clinical data, postoperative PET-CT results, treatment regimens, and the prognosis of 21 histopathologically confirmed OAML patients between October 2017 and September 2021 were collected. Among the 21 patients, five patients underwent surgical treatment alone, 13 patients underwent surgical treatment combined with radiotherapy, and three patients underwent surgical treatment combined with chemotherapy. RESULTS: The follow-up period ranged from 8 to 79mo, with four cases of recurrence and no deaths. Through PET-CT examination, two patients exhibited both local ocular metabolic elevation and systemic metastasis, and one of these patients had cervical lymph node metastasis, while the other had submandibular and parotid gland metastasis. Nine patients showed only local ocular metabolic elevation, while 10 patients had no abnormal metabolic activity locally. CONCLUSION: PET-CT examination plays a crucial role in detecting residual lesions and recurrence following tumor resection, aiding in precise disease staging, and facilitating the development of personalized treatment plans, ultimately improving patient prognosis.

Association of circulating inflammatory proteins with type 2 diabetes mellitus and its complications: a bidirectional Mendelian randomization study.

Background: Increasing evidence indicates that immune response underlies the pathology of type 2 diabetes (T2D). Nevertheless, the specific inflammatory regulators involved in this pathogenesis remain unclear. Methods: We systematically explored circulating inflammatory proteins that are causally associated with T2D via a bidirectional Mendelian randomization (MR) study and further investigated them in prevalent complications of T2D. Genetic instruments for 91 circulating inflammatory proteins were derived from a genome-wide association study (GWAS) that enrolled 14,824 predominantly European participants. Regarding the summary-level GWASs of type 2 diabetes, we adopted the largest meta-analysis of European population (74,124 cases vs. 824,006 controls) and a prospective nested case-cohort study in Europe (9,978 cases vs. 12,348 controls). Summary statistics for five complications of T2D were acquired from the FinnGen R9 repository. The inverse variance-weighted method was applied as the primary method for causal inference. MR-Egger, weighted median and maximum likelihood methods were employed as supplementary analyses. Results from the two T2D studies were combined in a meta-analysis. Sensitivity analyses and phenotype-wide association studies (PheWAS) were performed to detect heterogeneity and potential horizontal pleiotropy in the study. Results: Genetic evidence indicated that elevated levels of TGF-α (OR = 1.16, 95% CI = 1.15-1.17) and CX3CL1 (OR = 1.30, 95% CI = 1.04-1.63) promoted the occurrence of T2D, and increased concentrations of FGF-21 (OR = 0.87, 95% CI = 0.81-0.93) and hGDNF (OR = 0.96, 95% CI = 0.95-0.98) mitigated the risk of developing T2D, while type 2 diabetes did not exert a significant influence on said proteins. Elevated levels of TGF-α were associated with an increased risk of ketoacidosis, neurological complications, and ocular complications in patients with T2D, and increased concentrations of FGF-21 were potentially correlated with a diminished risk of T2D with neurological complications. Higher levels of hGDNF were associated with an increased risk of T2D with peripheral vascular complications, while CX3CL1 did not demonstrate a significant association with T2D complications. Sensitivity analyses and PheWAS further ensure the robustness of our findings. Conclusion: This study determined four circulating inflammatory proteins that affected the occurrence of T2D, providing opportunities for the early prevention and innovative therapy of type 2 diabetes and its complications.

Simultaneous Enhancement of Strength and Sulfide Stress Cracking Resistance of Hot-Rolled Pressure Vessel Steel Q345 via a Quenching and Tempering Treatment.

Sulfide stress cracking (SSC) failure is a main concern for the pressure vessel steel Q345 used in harsh sour oil and gas environments containing hydrogen sulfide (H2S). Methods used to improve the strength of steel usually decrease their SSC resistance. In this work, a quenching and tempering (Q&T) processing method is proposed to provide higher strength combined with better SSC resistance for hot-rolled Q345 pressure vessel steel. Compared to the initial hot-rolled plates having a yield strength (YS) of ~372 MPa, the Q&T counterparts had a YS of ~463 MPa, achieving a remarkable improvement in the strength level. Meanwhile, there was a resulting SSC failure in the initial hot-rolled plates, which was not present in the Q&T counterparts. The SSC failure was not only determined by the strength. The carbon-rich zone, residual stress, and sensitive hardness in the banded structure largely determined the susceptibility to SSC failure. The mechanism of the property amelioration might be ascribed to microstructural modification by the Q&T processing. This work provides an approach to develop improved strength grades of SSC-resistant pressure vessel steels.

Novel Bioresorbable Drug-Eluting Mesh Scaffold for Therapy of Muscle Injury.

A novel bioresorbable drug-eluting polycaprolactone (PCL) mesh scaffold was developed, utilizing a solvent-cast additive manufacturing technique, to promote therapy of muscle injury. The degradation rate and mechanical properties strength of the PCL mesh were characterized after immersion in a buffer solution for different times. The in vitro release characteristics of vancomycin, ceftazidime, and lidocaine from the prepared mesh were evaluated using a high-performance liquid chromatography (HPLC) assay. In addition, the in vivo efficacy of PCL meshes for the repair of muscle injury was investigated on a rat model with histological examinations. It was found that the additively manufactured PCL meshes degraded by 13% after submission in buffered solution for four months. All PCL meshes with different pore sizes exhibited greater strength than rat muscle and survived through 10,000 cyclic loadings. Furthermore, the meshes could offer a sustained release of antibiotics and analgesics for more than 3 days in vitro. The results of this study suggest that drug-loaded PCL mesh exhibits superior ability to pure PCL mesh in terms of effectively promoting muscle repair in rat models. The histological assay also showed adequate biocompatibility of the resorbable meshes. The additively manufactured biodegradable drug-eluting meshes may be adopted in the future in humans for the therapy of muscle injuries.

Development of novel hybrid 3D-printed degradable artificial joints incorporating electrospun pharmaceutical- and growth factor-loaded nanofibers for small joint reconstruction.

Small joint reconstruction remains challenging and can lead to prosthesis-related complications, mainly due to the suboptimal performance of the silicone materials used and adverse host reactions. In this study, we developed hybrid artificial joints using three-dimensional printing (3D printing) for polycaprolactone (PCL) and incorporated electrospun nanofibers loaded with drugs and biomolecules for small joint reconstruction. We evaluated the mechanical properties of the degradable joints and the drug discharge patterns of the nanofibers. Empirical data revealed that the 3D-printed PCL joints exhibited good mechanical and fatigue properties. The drug-eluting nanofibers sustainedly released teicoplanin, ceftazidime, and ketorolac in vitro for over 30, 19, and 30 days, respectively. Furthermore, the nanofibers released high levels of bone morphogenetic protein-2 and connective tissue growth factors for over 30 days. An in vivo animal test demonstrated that nanofiber-loaded joints released high concentrations of antibiotics and analgesics in a rabbit model for 28 days. The animals in the drug-loaded degradable joint group showed greater activity counts than those in the surgery-only group. The experimental data suggest that degradable joints with sustained release of drugs and biomolecules may be utilized in small joint arthroplasty.

Prolonged oral intake of green tea polyphenols attenuates delirium-like behaviors in mice induced by anesthesia/surgery.

Postoperative delirium (POD) is a severe postoperative complication characterized by delirium-like symptoms. So far, no effective preventable strategy for POD prevention has been identified. Reports show that the consumption of green tea polyphenols (GTP) is associated with better cognitive function by modulating the composition of gut microbiota. Whether GTP also play a role in alleviating POD through gut microbiota is unknown. Herein, we studied the effect of prolonged (eight weeks) GTP intake on postoperative delirium in C57BL/6 mice with laparotomies under isoflurane anesthesia (anesthesia/surgery). We subsequently investigated anesthesia/surgery caused behavioral changes and increased the expression of malondialdehyde (MAD), an oxidative stress marker, and the activities of superoxide dismutase (SOD), an antioxidant marker, in the mice at 6 h after anesthesia/surgery. However, GTP administration reversed these changes and alleviated anesthesia/surgery-induced decrease in the abundance of gut bacterial genera, Roseburia. Further, fecal microbiota transplant demonstrated that compared with mice in the control group, treatment of C57BL/6 mice with feces from GTP-treated mice had a slight effect on the behavioral changes of mice. These data suggest that daily consumption of GTP could protect against anesthesia/surgery-induced behavioral changes, which is closely associated with gut microbiota modification by GTP.

Reduced Surface Trap States of PbS Quantum Dots by Acetonitrile Treatment for Efficient SnO2-Based PbS Quantum Dot Solar Cells.

The solution-phase ligand-exchange strategy offers a simple pathway to prepare PbS quantum dots (QDs) and their corresponding solar cells. However, the production of high-quality PbS QDs with reduced surface trap state density for efficient PbS QD solar cells (QDSCs) still faces challenges. As the hydroxyl group (-OH) has been demonstrated to be the primary source of the surface trap states on PbS QDs in the general oleic acid method, here, we present an effective and facile strategy for reducing the surface -OH content of PbS QDs by using acetonitrile (ACN) as precipitant to wash the surface of QDs, which significantly decreases the trap state density and enables the preparation of superior PbS QDs. The resulting solar cell with an ITO/SnO2/n-PbS/p-PbS/Au structure obtained an improved photoelectric conversion efficiency (PCE) from 8.53 to 10.49% with an enhanced air storage stability, realizing a high PCE for SnO2-based PbS QDSCs.

Matrine reduced intestinal stem cell damage in eimeria necatrix-infected chicks via blocking hyperactivation of Wnt signaling.

BACKGROUND: Coccidiosis is a rapidly spreading and acute parasitic disease that seriously threatening the intestinal health of poultry. Matrine from leguminous plants has anthelmintic and anti-inflammatory properties. PURPOSE: This assay was conducted to explore the protective effects of Matrine and the AntiC (a Matrine compound) on Eimeria necatrix (EN)-infected chick small intestines and to provide a nutritional intervention strategy for EN injury. STUDY DESIGN: The in vivo (chick) experiment: A total of 392 one-day-old yellow-feathered broilers were randomly assigned to six groups in a 21-day study: control group, 350 mg/kg Matrine group, 500 mg/kg AntiC group, EN group, and EN + 350 mg/kg Matrine group, EN + 500 mg/kg AntiC group. The in vitro (chick intestinal organoids, IOs): The IOs were treated with PBS, Matrine, AntiC, 3 µM CHIR99021, EN (15,000 EN sporozoites), EN + Matrine, EN + AntiC, EN + Matrine + CHIR99021, EN + AntiC + CHIR99021. METHODS: The structural integrity of chicks jejunal crypt-villus axis was evaluated by hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM). And the activity of intestinal stem cells (ISCs) located in crypts was assessed by in vitro expansion advantages of a primary in IOs model. Then, the changes of Wnt/ß-catenin signaling in jejunal tissues and IOs were detected by Real-Time qPCR,Western blotting and immunohistochemistry. RESULTS: The results showed that dietary supplementation with Matrine or AntiC rescued the jejunal injury caused by EN, as indicated by increased villus height, reduced crypt hyperplasia, and enhanced expression of tight junction proteins. Moreover, there was less budding efficiency of the IOs expanded from jejunal crypts of chicks in the EN group than that in the Matrine and AntiC group, respectively. Further investigation showed that AntiC and Matrine inhibited EN-stimulated Wnt/ß-catenin signaling. The fact that Wnt/ß-catenin activation via CHIR99021 led to the failure of Matrine and AntiC to rescue damaged ISCs confirmed the dominance of this signaling. CONCLUSION: Our results suggest that Matrine and AntiC inhibit ISC proliferation and promote ISC differentiation into absorptive cells by preventing the hyperactivation of Wnt/ß-catenin signaling, thereby standardizing the function of ISC proliferation and differentiation, which provides new insights into mitigating EN injury by Matrine and AntiC.

[Efficiency Characteristics and Evolution Patterns of Urban Carbon Metabolism of Production-Living-Ecological Space in Beijing-Tianjin-Hebei Region].

This study explored the carbon metabolism efficiency of a production-living-ecological space system, which is of great significance for regional factor integration and spatial optimization. In this study, the material flow analysis method was introduced to establish a framework for evaluating the carbon metabolism efficiency of the production-living-ecological space system, and the super-efficiency DEA model and Malmquist index were used to empirically analyze the spatio-temporal distribution, dynamic change, and evolution patterns of the carbon metabolism efficiency of production-living-ecological space in the Beijing-Tianjin-Hebei Region, China, from 2000 to 2020 on the basis of the urban metabolic perspective. The results showed that:① the carbon metabolism efficiency of the production-living-ecological space showed a fluctuating growth trend, indicating the significant spatial differentiation of carbon metabolism efficiency in each city. There was a low overall carbon metabolism efficiency level, with a distribution pattern of being high in the middle and low in the north and south. ② The Malmquist index showed that the Total Factor Productivity (TFP) of carbon metabolism efficiency was greater than 1, and both the Technical Change (TC) and Pure Efficiency Change (PEC) were less than 1, in which the TFP showed an increasing trend, whereas there was no significant contribution of technological progress or pure technical efficiency to carbon metabolism efficiency. The total factor productivity of more than 50% of the cities showed an improving trend, only 38.46% of which made technological progress in improving carbon metabolism efficiency, and more than half of the urban pure technical efficiency showed a decreasing trend, in which the technical efficiency change and scale efficiency change were greater than 1 in most cities. ③ There were different types of carbon efficiency characteristics in each city, and according to the movement rules of the corresponding points in the quartile map, the evolution patterns of tourism industry efficiency were classified into stable, reciprocating, progressive, and abrupt. Therefore, local governments should adopt differentiated strategies to reasonably allocate spatial resources of production-living-ecological space and improve the technical level and scale efficiency, so as to improve the efficiency of urban carbon metabolism.

Does a simultaneous ventral/dorsal approach provide better reduction quality in treating acetabular fracture involving both columns with displaced posterior wall?

INTRODUCTION: Various surgical techniques have been proposed to manage acetabular fractures involving both columns with posterior wall displacement. However, the optimal surgical approach to achieve satisfactory reduction quality remains controversial. MATERIALS AND METHODS: This retrospective study evaluated 34 patients with fractures who were treated at a single medical institution. The patients were divided into two groups according to the ventral/dorsal surgical approach employed: simultaneous (SI) and sequential (SE). Perioperative parameters, as well as radiological and functional outcomes, were analyzed and compared between the two groups. RESULTS: The SI and SE groups comprised 9 and 23 out of the 34 patients, respectively. The SI group exhibited a significantly shorter surgical time and lower estimated blood loss than the SE group (p = 0.04 and 0.03, respectively). The quality of reductions of the anterior and posterior columns was similar between the two groups; however, superior reduction in the fracture gap of the posterior wall was observed in the SI group, as revealed by axial and coronal computed tomography scans. CONCLUSIONS: A simultaneous ventral and dorsal approach through the pararectus and the modified Gibson approach confer clinical advantages in reducing the fracture gap, surgical time, and intraoperative blood loss when managing acetabular fractures involving both columns and a displaced posterior wall. Therefore, these surgical approaches may be considered to be optimal for achieving satisfactory reduction quality in such fractures.

KCNH6 channel promotes insulin exocytosis via interaction with Munc18-1 independent of electrophysiological processes.

Glucose-stimulated insulin secretion (GSIS) in pancreatic islet ß-cells primarily relies on electrophysiological processes. Previous research highlighted the regulatory role of KCNH6, a member of the Kv channel family, in governing GSIS through its influence on ß-cell electrophysiology. In this study, we unveil a novel facet of KCNH6's function concerning insulin granule exocytosis, independent of its conventional electrical role. Young mice with ß-cell-specific KCNH6 knockout (ßKO) exhibited impaired glucose tolerance and reduced insulin secretion, a phenomenon not explained by electrophysiological processes alone. Consistently, islets from KCNH6-ßKO mice exhibited reduced insulin secretion, conversely, the overexpression of KCNH6 in murine pancreatic islets significantly enhanced insulin release. Moreover, insulin granules lacking KCNH6 demonstrated compromised docking capabilities and a reduced fusion response upon glucose stimulation. Crucially, our investigation unveiled a significant interaction between KCNH6 and the SNARE protein regulator, Munc18-1, a key mediator of insulin granule exocytosis. These findings underscore the critical role of KCNH6 in the regulation of insulin secretion through its interaction with Munc18-1, providing a promising and novel avenue for enhancing our understanding of the Kv channel in diabetes mechanisms.

KCNH6 is essential for insulin secretion by regulating intracellular ER Ca2+ store.

Appropriate Ca2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca2+ signal, serves significant roles in physiological function of pancreatic ß cells. To maintaining ER homeostasis, Ca2+ movement across the ER membrane is always accompanied by a simultaneous K+ flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic ß-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 ß-cell-specific knockout (ßKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of ßKO mice, which contributed to ER stress and ER stress-induced apoptosis in ß cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic ß cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in ßKO mice, restored ER Ca2+ overload and attenuated ER stress in ß cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca2+ stores and protect ß cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes.

Efficacy and safety of transcranial direct current stimulation in the treatment of fibromyalgia: A systematic review and meta-analysis.

OBJECTIVES: To update a systematic review of the efficacy and safety of transcranial direct current stimulation (tDCS) for analgesia, for antidepressant effects, and to reduce the impact of fibromyalgia (FM), looking for optimal areas of stimulation. METHODS: We searched five databases to identify randomized controlled trials comparing active and sham tDCS for FM. The primary outcome was pain intensity, and secondary outcome measures included FM Impact Questionnaire (FIQ) and depression score. Meta-analysis was conducted using standardized mean difference (SMD). Subgroup analysis was performed to determine the effects of different regional stimulation, over the primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), opercular-insular cortex (OIC), and occipital nerve (ON) regions. We analyzed the minimal clinically important difference (MCID) by the value of the mean difference (MD) for an 11-point scale for pain, the Beck Depressive Inventory-II (BDI-II), and the Fibromyalgia Impact Questionnaire (FIQ) score. We described the certainty of the evidence (COE) using the tool GRADE profile. RESULTS: Twenty studies were included in the analysis. Active tDCS had a positive effect on pain (SMD= -1.04; 95 % CI -1.38 to -0.69), depression (SMD= -0.46; 95 % CI -0.64 to -0.29), FIQ (SMD= -0.73; 95 % CI -1.09 to -0.36), COE is moderate. Only group M1 (SD=-1.57) and DLPFC (SD=-1.44) could achieve MCID for analgesia; For BDI-II, only group DLPFC (SD=-5.36) could achieve an MCID change. Adverse events were mild. CONCLUSION: tDCS is a safe intervention that relieves pain intensity, reduces depression, and reduces the impact of FM on life. Achieving an MCID is related to the stimulation site and the target symptom.

Simultaneous determination of colistin sulfate and tigecycline in human plasma by liquid chromatography-tandem mass spectrometry method.

OBJECTIVE: To establish a high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS) to simultaneously determine colistin sulfate and tigecycline in human plasma. METHODS: Polymyxin B1 internal standard (20 µL) was added into 200 µL of plasma sample. The samples were treated with methanol-5% trichloroacetic acid (50:50, V/V) solution, and the protein precipitation method was adopted for post-injection analysis. The chromatographic column was a Dikma C18 (4.6 mm × 150 mm, 5 µm). For the mobile phase, 0.1% formic acid in aqueous solution was used for phase A, 0.1% formic acid in acetonitrile solution for phase B, and gradient elution was also applied. The flow rate was 0.8 mL/min, the column temperature was 40 °C, and the injection volume was 10 µL; Electrospray ionization and multiple reaction ion monitoring were adopted and scanned by the HPLC-MS/MS positive ion mode. RESULTS: The endogenous impurities in the plasma had no interference in the determination of the analytes. There existed a good linear relationship of colistin sulfate within the range of 0.1-10 µg/mL (R2 = 0.9986), with the lower limit of quantification (LLOQ) of 0.1 µg/mL. There existed a good linear relationship of tigecycline within the range of 0.05-5 µg/ mL (R2 = 0.9987), with the LLOQ of 0.05 µg/mL. The intra- and inter-day relative standard deviations of colistin sulfate and tigecycline were both less than 15%, and the accuracy was between 88.21% and 108.24%. The extraction had good stability, the extraction recovery rate was 87.75-91.22%, and the matrix effect was 99.40-105.26%. CONCLUSION: This study successfully established a method for simultaneously detecting colistin sulfate and tigecycline plasma concentrations. The method was simple, rapid, and highly sensitive and could be applied for therapeutic medication monitoring.

Cell-free DNA testing for early hepatocellular carcinoma surveillance.

BACKGROUND: Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains unpromising. METHODS: A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage Ⅰ cohort (510 HCCs and 2074 LCs) and Stage Ⅱ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage Ⅰ cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage Ⅱ cohort. FINDINGS: PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% [95% CI: 39.66%-62.84%] at 95.53% [95% CI: 94.62%-96.38%] specificity for PreCar Score; sensitivity of 23.68% [95% CI: 14.99%-35.07%] at 99.37% [95% CI: 98.91%-99.64%] specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening. INTERPRETATION: Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care. FUNDING: A full list of funding bodies that contributed to this study can be found in Acknowledgments section.

All-potassium channel CRISPR screening reveals a lysine-specific pathway of insulin secretion.

OBJECTIVE: Genome-scale CRISPR-Cas9 knockout coupled with single-cell RNA sequencing (scRNA-seq) has been used to identify function-related genes. However, this method may knock out too many genes, leading to low efficiency in finding genes of interest. Insulin secretion is controlled by several electrophysiological events, including fluxes of KATP depolarization and K+ repolarization. It is well known that glucose stimulates insulin secretion from pancreatic ß-cells, mainly via the KATP depolarization channel, but whether other nutrients directly regulate the repolarization K+ channel to promote insulin secretion is unknown. METHODS: We used a system involving CRISPR-Cas9-mediated knockout of all 83 K+ channels and scRNA-seq in a pancreatic ß cell line to identify genes associated with insulin secretion. RESULTS: The expression levels of insulin genes were significantly increased after all-K+ channel knockout. Furthermore, Kcnb1 and Kcnh6 were the two most important repolarization K+ channels for the increase in high-glucose-dependent insulin secretion that occurred upon application of specific inhibitors of the channels. Kcnh6 currents, but not Kcnb1 currents, were reduced by one of the amino acids, lysine, in both transfected cells, primary cells and mice with ß-cell-specific deletion of Kcnh6. CONCLUSIONS: Our function-related CRISPR screen with scRNA-seq identifies Kcnh6 as a lysine-specific channel.

In silico and in vitro analyses of a novel FoxO1 agonist reducing Aß levels via downregulation of BACE1.

AIMS: FoxO1 is an important target in the treatment of Alzheimer's disease (AD). However, FoxO1-specific agonists and their effects on AD have not yet been reported. This study aimed to identify small molecules that upregulate the activity of FoxO1 to attenuate the symptoms of AD. METHODS: FoxO1 agonists were identified by in silico screening and molecular dynamics simulation. Western blotting and reverse transcription-quantitative polymerase chain reaction assays were used to assess protein and gene expression levels of P21, BIM, and PPARγ downstream of FoxO1 in SH-SY5Y cells, respectively. Western blotting and enzyme-linked immunoassays were performed to explore the effect of FoxO1 agonists on APP metabolism. RESULTS: N-(3-methylisothiazol-5-yl)-2-(2-oxobenzo[d]oxazol-3(2H)-yl) acetamide (compound D) had the highest affinity for FoxO1. Compound D activated FoxO1 and regulated the expression of its downstream target genes, P21, BIM, and PPARγ. In SH-SY5Y cells treated with compound D, BACE1 expression levels were downregulated, and the levels of Aß1-40 and Aß1-42 were also reduced. CONCLUSIONS: We present a novel small-molecule FoxO1 agonist with good anti-AD effects. This study highlights a promising strategy for new drug discovery for AD.