Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. METHODS: MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 µg/kg, then escalated to 570 µg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. FINDINGS: Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 µmol/L (95% CI -257 to -94) for maralixibat versus 11 µmol/L (-58 to 80) for placebo, also representing a significant difference of -187 µmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. INTERPRETATION: Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. FUNDING: Mirum Pharmaceuticals.

Construction of a gene model related to the prognosis of patients with gastric cancer receiving immunotherapy and exploration of COX7A1 gene function.

BACKGROUND: GC is a highly heterogeneous tumor with different responses to immunotherapy, and the positive response depends on the unique interaction between the tumor and the tumor microenvironment (TME). However, the currently available methods for prognostic prediction are not satisfactory. Therefore, this study aims to construct a novel model that integrates relevant gene sets to predict the clinical efficacy of immunotherapy and the prognosis of GC patients based on machine learning. METHODS: Seven GC datasets were collected from the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database and literature sources. Based on the immunotherapy cohort, we first obtained a list of immunotherapy related genes through differential expression analysis. Then, Cox regression analysis was applied to divide these genes with prognostic significancy into protective and risky types. Then, the Single Sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to score the two categories of gene sets separately, and the scores differences between the two gene sets were used as the basis for constructing the prognostic model. Subsequently, Weighted Correlation Network Analysis (WGCNA) and Cytoscape were applied to further screen the gene sets of the constructed model, and finally COX7A1 was selected for the exploration and prediction of the relationship between the clinical efficacy of immunotherapy for GC. The correlation between COX7A1 and immune cell infiltration, drug sensitivity scoring, and immunohistochemical staining were performed to initially understand the potential role of COX7A1 in the development and progression of GC. Finally, the differential expression of COX7A1 was verified in those GC patients receiving immunotherapy. RESULTS: First, 47 protective genes and 408 risky genes were obtained, and the ssGSEA algorithm was applied for model construction, showing good prognostic discrimination ability. In addition, the patients with high model scores showed higher TMB and MSI levels, and lower tumor heterogeneity scores. Then, it is found that the COX7A1 expressions in GC tissues were significantly lower than those in their corresponding paracancerous tissues. Meanwhile, the patients with high COX7A1 expression showed higher probability of cancer invasion, worse clinical efficacy of immunotherapy, worse overall survival (OS) and worse disease-free survival (DFS). CONCLUSIONS: The ssGSEA score we constructed can serve as a biomarker for GC patients and provide important guidance for individualized treatment. In addition, the COX7A1 gene can accurately distinguish the prognosis of GC patients and predict the clinical efficacy of immunotherapy for GC patients.

Bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells.

BACKGROUND: Gastric cancer (GC) is associated with high mortality rates. Bile acids (BAs) reflux is a well-known risk factor for GC, but the specific mechanism remains unclear. During GC development in both humans and animals, BAs serve as signaling molecules that induce metabolic reprogramming. This confers additional cancer phenotypes, including ferroptosis sensitivity. Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression. However, it is not fully defined if BAs can influence GC progression by modulating ferroptosis. AIM: To reveal the mechanism of BAs regulation in ferroptosis of GC cells. METHODS: In this study, we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis. We used gain and loss of function assays to examine the impacts of farnesoid X receptor (FXR) and BTB and CNC homology 1 (BACH1) overexpression and knockdown to obtain further insights into the molecular mechanism involved. RESULTS: Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells. This effect correlated with increased glutathione (GSH) concentrations, a reduced GSH to oxidized GSH ratio, and higher GSH peroxidase 4 (GPX4) expression levels. Subsequently, we confirmed that BAs exerted these effects by activating FXR, which markedly increased the expression of GSH synthetase and GPX4. Notably, BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR. Finally, our results suggested that FXR could significantly promote GC cell proliferation, which may be closely related to its anti-ferroptosis effect. CONCLUSION: This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSH-GPX4 axis in GC cells. This work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.

Immune-stealth VP28-conjugated heparin nanoparticles for enhanced and reversible anticoagulation.

Heparins are a family of sulfated linear negatively charged polysaccharides that have been widely used for their anticoagulant, antithrombotic, antitumor, anti-inflammatory, and antiviral properties. Additionally, it has been used for acute cerebral infarction relief as well as other pharmacological actions. However, heparin's self-aggregated macrocomplex may reduce blood circulation time and induce life-threatening thrombocytopenia (HIT) complicating the use of heparins. Nonetheless, the conjugation of heparin to immuno-stealth biomolecules may overcome these obstacles. An immunostealth recombinant viral capsid protein (VP28) was expressed and conjugated with heparin to form a novel nanoparticle (VP28-heparin). VP28-heparin was characterized and tested to determine its immunogenicity, anticoagulation properties, effects on total platelet count, and risk of inducing HIT in animal models. The synthesized VP28-heparin trimeric nanoparticle was non-immunogenic, possessed an average hydrodynamic size (8.81 ± 0.58 nm) optimal for the evasion renal filtration and reticuloendothelial system uptake (hence prolonging circulating half-life). Additionally, VP28-heparin did not induce mouse death or reduce blood platelet count when administered at a high dosein vivo(hence reducing HIT risks). The VP28-heparin nanoparticle also exhibited superior anticoagulation properties (2.2× higher prothrombin time) and comparable activated partial thromboplastin time, but longer anticoagulation period when compared to unfractionated heparin. The anticoagulative effects of the VP28-heparin can also be reversed using protamine sulfate. Thus, VP28-heparin may be an effective and safe heparin derivative for therapeutic use.

Age-stratified risk factors of re-intervention for uterine fibroids treated with high-intensity focused ultrasound.

OBJECTIVE: To estimate the rate and risk factors of re-intervention for patients with uterine fibroids (UFs) undergoing high-intensity focused ultrasound (HIFU) at different age distributions. METHOD: A retrospective cohort study was conducted in Nanchong Central Hospital, recruiting a total of 672 patients with UFs undergoing HIFU from June 2017 to December 2019. Using univariate and multivariate logistic regression, risk factors for re-intervention were assessed. RESULTS: Among 401 patients with UFs who completed the follow-up visits (median 47 months, range 34-61), 50 (12.46%) patients underwent re-intervention (such as high-intensity focused ultrasound, uterine artery embolization, myomectomy and hysterectomy). In the different age distributions, the re-intervention rate was 17.5% (34/194) in patients aged <45 years and 7.7% (16/207) in those aged ≥45 years. Regarding the younger patient group (aged <45 years), hypo- or iso-intensive fibroids in T2-weighted magnetic resonance imaging (T2WI) intensity may elevate the risk of re-intervention for UFs (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.37-6.62; P = 0.007). Among the older patient group (aged ≥45 years), preoperative anemic patients had an increased risk of re-intervention compared with those without anemia (OR 3.30, 95% CI 1.01-10.37; P = 0.041). CONCLUSION: The re-intervention rate of HIFU decreased with increasing age. Among those aged <45 years, T2WI intensity was the independent risk factor for re-intervention, and among those aged ≥45 years, preoperative anemic status may be related to re-intervention outcome.

Statin use reduces radiation-induced stroke risk in advanced nasopharyngeal carcinoma patients.

OBJECTIVE: This cohort study aimed to evaluate the impact of statin use on ischemic stroke risk in patients with advanced nasopharyngeal carcinoma (NPC) undergoing standard concurrent chemoradiotherapy (CCRT). METHODS: Using data from the Taiwan Cancer Registry Database, we conducted an inverse probability of treatment-weighted Cox regression analysis to examine the association between statin use during CCRT and ischemic stroke risk. RESULTS: The adjusted hazard ratio (aHR) for ischemic stroke in the statin group compared to the non-statin group was 0.70 (95 % CI: 0.54-0.92; P < 0.0107). This protective effect was observed across different statin classes, with hydrophilic statins such as pravastatin showing an aHR of 0.37 (95 % CI: 0.17-0.85) and lipophilic statins including atorvastatin displaying an aHR of 0.32 (95 % CI: 0.21-0.50) compared to non-statin use. Analysis of cumulative defined daily doses (cDDD) revealed a dose-response relationship, with lower stroke risk observed in higher quartiles of cDDD. Additionally, patients with a daily defined dose (DDD) > 1 had a reduced risk of stroke with an aHR of 0.49 (95 % CI: 0.31-0.63), while those with DDD ≤ 1 showed an aHR of 0.59 (95 % CI: 0.40-0.84). CONCLUSIONS: Our study provides evidence supporting the beneficial effects of statin use during the CCRT period in reducing radiation-induced stroke risk among patients with advanced NPC undergoing definitive CCRT. Notably, pravastatin and atorvastatin demonstrated significant reductions in stroke occurrence. Furthermore, the findings suggest a dose-response relationship, where higher cumulative doses and greater daily dose intensity of statin use were associated with a lower risk of stroke.

Video-assisted thoracic surgery drainage is feasible and safe for acute necrotizing mediastinitis: a retrospective cohort study.

Background: Acute necrotizing mediastinitis (ANM) is a severe infection of the mediastinal loose connective tissue. Traditionally, it has been treated with thoracotomy, but video-assisted thoracic surgery (VATS) is been increasingly used in patients with this condition. This study aimed to compare the outcomes of VATS and open thoracotomy in treating ANM. Methods: The medical records of patients with ANM who underwent surgery between March 2012 and April 2021 were retrieved. A retrospective screening was conducted based on clinical characteristics, bacterial pathogens, surgical approach, and outcomes. The patients were divided into a VATS group and an open thoracotomy (Open) group. The patient characteristics and surgical outcomes of the two groups were summarized and compared. Results: A total of 64 cases were enrolled in this study, including 48 in the VATS group (75%) and 16 in the Open group (25%). The most common site of infection was the neck (n=26, 40.6%). Streptococcus constellatus and Acinetobacter baumannii (A. baumannii) were the most frequently found pathogens in secretion culture. In sputum culture, the most common pathogens were Klebsiella pneumonia and A. baumannii. Postoperative outcomes, including blood transfusion (33.3% vs. 43.8%; P=0.45), duration of postoperative drainage {14 [1-47] vs. 17 [4-54] days; P=0.15}, length of antibiotic medication {14.5 [1-54] vs. 18 [4-54] days; P=0.29}, admission to intensive care unit (ICU) (87.5% vs. 75.0%; P=0.43), length of ICU stay {5 [1-58] vs. 8.5 [1-37] days; P=0.20}, postoperative hospital stay {17 [2-61] vs. 21 [5-56] days; P=0.22}, reoperation rate (12.5% vs. 6.25%; P=0.82), and mortality rate (14.6% vs. 12.5%; P>0.99) were comparable between the two groups. Conclusions: ANM treated by both the VATS and open approach had comparable outcomes. Therefore, VATS is a viable option for patients with ANM.

Mesobiliverdin IXα-enriched microalgae feed additive eliminates reliance on antibiotic tylosin to promote intestinal health of weaning piglets.

Weaning is a critical period in raising pigs. Novel animal feed additives that promote gut health and regulate immune function of piglets without antibiotics are needed. In this study, we aimed to test the ability of mesobiliverdin IXα-enriched microalgae (MBV IXα-enriched microalgae) to eliminate reliance on antibiotics to promote intestinal health in piglets. Eighty 28-day-old weaned piglets were randomly allocated to four groups each with four replicate pens and five piglets per pen. The dietary treatments were a basal diet as control (NC), basal diet plus 0.05% tylosin (PC), basal diet plus 0.1% or 0.5% MBV IXα-enriched microalgae as low (MBV-SP1) or high (MBV-SP2) dose respectively. All treated animals showed no significant differences in live weight, average daily gain and feed efficiency compared to control animals. Histological examination showed that MBV-SP1 and particularly MBV-SP2 increased the ratio of villus height to crypt depth in the jejunum and ileum compared to NC (p < 0.05). Similarly, tylosin treatment also increased villi lengths and the ratio of villus height to crypt depth in the jejunum and ileum compared to the NC (p < 0.05). MBV-SP1 and particularly MBV-SP2 reduced the levels of inflammatory cytokines interleukin-6 and tumour necrosis factor-alpha in the small intestine. MBV-SP2 and tylosin similarly reduced the lipid peroxidation marker (TBARS value) in the duodenum and ileum. In conclusion, feed supplementation with MBV IXα-enriched microalgae improved gut health by villus height and production of immunomodulators that correlated with down-regulated secretion of inflammatory cytokines.

HGF/c-Met signaling promotes the migration and proliferation of deer antler MSCs.

The complete regeneration of deer antlers is based on the proliferation and differentiation of stem cells. Mesenchymal stem cells (MSCs) of antlers have an important role in antler regeneration and rapid growth and development. HGF is mainly synthesized and secreted by mesenchymal cells. After binding to its receptor c-Met, which transduces signals into cells to stimulate cell proliferation and migration in various organs to promote tissue morphogenesis and angiogenesis. However, the role and mechanism of the HGF/c-Met signaling pathway on antler MSCs are still unclear. In this study, we established antler MSCs with overexpression and interference of HGF gene by lentivirus and small interference RNA, observed the effect of HGF/c-Met signal pathway on the proliferation and migration of antler MSCs, and detected the expression of downstream related signal pathway genes, to explore the mechanism of HGF/c-MET signal pathway on the proliferation and migration of antler MSCs. The results showed that the HGF/c-Met signal affects the expression of RAS, ERK and MEK genes, regulates the proliferation of pilose antler MSCs through Ras/Raf, MEK/ERK pathway, affects the expression of Gab1, Grb2, AKT and PI3K genes, and regulates the migration of MSCs of pilose antler through Gab1/Grb2 and PI3K/AKT pathway.

Elimination of methicillin-resistant Staphylococcus aureus biofilms on titanium implants via photothermally-triggered nitric oxide and immunotherapy for enhanced osseointegration.

BACKGROUND: Treatment of methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections in implant placement surgery is limited by the lack of antimicrobial activity of titanium (Ti) implants. There is a need to explore more effective approaches for the treatment of MRSA biofilm infections. METHODS: Herein, an interfacial functionalization strategy is proposed by the integration of mesoporous polydopamine nanoparticles (PDA), nitric oxide (NO) release donor sodium nitroprusside (SNP) and osteogenic growth peptide (OGP) onto Ti implants, denoted as Ti-PDA@SNP-OGP. The physical and chemical properties of Ti-PDA@SNP-OGP were assessed by scanning electron microscopy, X-ray photoelectron spectroscope, water contact angle, photothermal property and NO release behavior. The synergistic antibacterial effect and elimination of the MRSA biofilms were evaluated by 2',7'-dichlorofluorescein diacetate probe, 1-N-phenylnaphthylamine assay, adenosine triphosphate intensity, o-nitrophenyl-ß-D-galactopyranoside hydrolysis activity, bicinchoninic acid leakage. Fluorescence staining, assays for alkaline phosphatase activity, collagen secretion and extracellular matrix mineralization, quantitative real­time reverse transcription­polymerase chain reaction, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the inflammatory response and osteogenic ability in bone marrow stromal cells (MSCs), RAW264.7 cells and their co-culture system. Giemsa staining, ELISA, micro-CT, hematoxylin and eosin, Masson's trichrome and immunohistochemistry staining were used to evaluate the eradication of MRSA biofilms, inhibition of inflammatory response, and promotion of osseointegration of Ti-PDA@SNP-OGP in vivo. RESULTS: Ti-PDA@SNP-OGP displayed a synergistic photothermal and NO-dependent antibacterial effect against MRSA following near-infrared light irradiation, and effectively eliminated the formed MRSA biofilms by inducing reactive oxygen species (ROS)-mediated oxidative stress, destroying bacterial membrane integrity and causing leakage of intracellular components (P < 0.01). In vitro experiments revealed that Ti-PDA@SNP-OGP not only facilitated osteogenic differentiation of MSCs, but also promoted the polarization of pro-inflammatory M1 macrophages to the anti-inflammatory M2-phenotype (P < 0.05 or P < 0.01). The favorable osteo-immune microenvironment further facilitated osteogenesis of MSCs and the anti-inflammation of RAW264.7 cells via multiple paracrine signaling pathways (P < 0.01). In vivo evaluation confirmed the aforementioned results and revealed that Ti-PDA@SNP-OGP induced ameliorative osseointegration in an MRSA-infected femoral defect implantation model (P < 0.01). CONCLUSIONS: These findings suggest that Ti-PDA@SNP-OGP is a promising multi-functional material for the high-efficient treatment of MRSA infections in implant replacement surgeries.

New model of PIRADS and adjusted prostatespecific antigen density of peripheral zone improves the detection rate of initial prostate biopsy: a diagnostic study.

This study explored a new model of Prostate Imaging Reporting and Data System (PIRADS) and adjusted prostate-specific antigen density of peripheral zone (aPSADPZ) for predicting the occurrence of prostate cancer (PCa) and clinically significant prostate cancer (csPCa). The demographic and clinical characteristics of 853 patients were recorded. Prostate-specific antigen (PSA), PSA density (PSAD), PSAD of peripheral zone (PSADPZ), aPSADPZ, and peripheral zone volume ratio (PZ-ratio) were calculated and subjected to receiver operating characteristic (ROC) curve analysis. The calibration and discrimination abilities of new nomograms were verified with the calibration curve and area under the ROC curve (AUC). The clinical benefits of these models were evaluated by decision curve analysis and clinical impact curves. The AUCs of PSA, PSAD, PSADPZ, aPSADPZ, and PZ-ratio were 0.669, 0.762, 0.659, 0.812, and 0.748 for PCa diagnosis, while 0.713, 0.788, 0.694, 0.828, and 0.735 for csPCa diagnosis, respectively. All nomograms displayed higher net benefit and better overall calibration than the scenarios for predicting the occurrence of PCa or csPCa. The new model significantly improved the diagnostic accuracy of PCa (0.945 vs 0.830, P < 0.01) and csPCa (0.937 vs 0.845, P < 0.01) compared with the base model. In addition, the number of patients with PCa and csPCa predicted by the new model was in good agreement with the actual number of patients with PCa and csPCa in high-risk threshold. This study demonstrates that aPSADPZ has a higher predictive accuracy for PCa diagnosis than the conventional indicators. Combining aPSADPZ with PIRADS can improve PCa diagnosis and avoid unnecessary biopsies.

Mechanisms and Effects of Isorhamnetin on Imiquimod-Induced Psoriasiform Dermatitis in Mice.

Isorhamnetin (IRh), which has a wide range of pharmacological effects, is one of the most significant active components in the fruits of Hippophae rhamnoides L. and the leaves of Ginkgo biloba L. It protects the heart and brain, in addition to possessing anti-tumor, anti-inflammatory, antioxidant, organ protection, and anti-obesity properties. We sought to assess IRh's anti-psoriatic activity, explore its immunomodulatory properties in reducing the severity of psoriatic symptoms, and evaluate its potential immunotherapeutic effects. We used IRh to treat imiquimod (IMQ)-induced psoriasis in BALB/C mice and examined the underlying mechanisms. The outcomes demonstrated that IRh reduced epidermal hyperplasia, lowered PASI scores, and improved histopathological psoriasiform lesions in IMQ-induced mice. IRh attenuated the accumulation of malondialdehyde (MDA), and also reversed the reduction caused by IMQ of superoxide dismutase (SOD) and catalase (CAT) in skin tissues. Additionally, IRh effectively inhibited IMQ's ability to increase proinflammatory cytokines such as TNF-α, IL-6, IL-17A, and transcription factor NF-κB. Furthermore, IRh significantly reduced the percentage of Th1 and Th17 in the spleens of mice treated with IMQ and suppressed the maturation of splenic dendritic cells. Overall, our research suggests that IRh protects against oxidative stress and inflammation in the pathogenesis of psoriasis, with potential for the development of new and potent medication for the treatment of psoriasis.

[Determination of Dichloromethane in Blood with Headspace Gas Chromatography and Gas Chromatography-Mass Spectrometry].

Objective: To establish a method for qualitative determination of dichloromethane (DCM) in blood by gas chromatography-mass spectrometry (GC-MS) and quantitative determination of DCM in blood by headspace gas chromatography (HS-GC), and to provide reliable support for forensic examination and analysis of poisoning or deaths caused by DCM. Methods: 0.5 mL blood sample was collected, added into headspace vial with chloroform as the internal standard, and processed by heating at 65 °C and evacuation treatment. The intermediate gas in the headspace vial was analyzed by GC-MS for qualitative validation of the method and by HS-GC for quantitative validation of the method. The method was then applied in forensic case analysis. Results: Qualitative validation of the examination method by GC-MS found that the chromatographic peak and mass spectral characteristic ions were specific in samples added with DCM, and that no interference was observed in the blank negative samples. The limit of detection (LOD) was 5 µg/mL. Quantitative method validation by HS-GC found that the chromatographic peak of DCM was well separated from those of eight other volatile compounds, with the resolution>1.5 in all cases; the lower limit of quantification (LOQ) was 20 µg/mL and good linearity was shown within the range of 20 and 1000 µg/mL, R>0.999; the intra-day test precision and inter-day test precision were good (relative standard deviation, or RSD<15% for both) and test accuracy was high (relative error, or δ<15%). With the method established in the study, DCM was detected successfully in the blood of two fatal cases caused by DCM poisoning, with the blood concentration being 470 µg/mL and 915 µg/mL, respectively. Conclusion: This method is shown to be a rapid, stable and accurate approach to the qualitative and quantitative forensic and toxicological analysis of DCM in blood in DCM poisoning cases or deaths caused by DCM.

Functioning tailor-made 3D-printed vascular graft for hemodialysis.

BACKGROUND: The two ends of arteriovenous graft (AVG) are anastomosed to the upper limb vessels by surgery for hemodialysis therapy. However, the size of upper limb vessels varies to a large extent among different individuals. METHODS: According to the shape and size of neck vessels quantified from the preoperative computed tomography angiographic scan, the ethylene-vinyl acetate (EVA)-based AVG was produced in H-shape by the three-dimensional (3D) printer and then sterilized. This study investigated the function of this novel 3D-printed AVG in vitro and in vivo. RESULTS: This 3D-printed AVG can be implanted in the rabbit's common carotid artery and common jugular vein with ease and functions in vivo. The surgical procedure was quick, and no suture was required. The blood loss was minimal, and no hematoma was noted at least 1 week after the surgery. The blood flow velocity within the implanted AVG was 14.9 ± 3.7 cm/s. Additionally, the in vitro characterization experiments demonstrated that this EVA-based biomaterial is biocompatible and possesses a superior recovery property than ePTFE after hemodialysis needle cannulation. CONCLUSIONS: Through the 3D printing technology, the EVA-based AVG can be tailor-made to fit the specific vessel size. This kind of 3D-printed AVG is functioning in vivo, and our results realize personalized vascular implants. Further large-animal studies are warranted to examine the long-term patency.