Physiologically Based Pharmacokinetic Models Are Effective Support for Pediatric Drug Development.

Pediatric drug development faces many difficulties. Traditionally, pediatric drug doses are simply calculated linearly based on the body weight, age, and body surface area of adults. Due to the ontogeny of children, this simple linear scaling may lead to drug overdose in pediatric patients. The physiologically based pharmacokinetic (PBPK) model, as a mathematical model, contributes to the research and development of pediatric drugs. An example of a PBPK model guiding drug dose selection in pediatrics has emerged and has been approved by the relevant regulatory agencies. In this review, we discuss the principle of the PBPK model, emphasize the necessity of establishing a pediatric PBPK model, introduce the absorption, distribution, metabolism, and excretion of the pediatric PBPK model, and understand the various applications and related prospects of the pediatric PBPK model.

[Application Value of Indocyanine Green in the Localization of Small Pulmonary Nodules in Video-assisted Thoracoscopic Surgery].

Objective To investigate the application value of indocyanine green(ICG)in the localization of small pulmonary nodules in video-assisted thoracoscopic surgery(VATS). Methods We retrospectively analyzed the clinical data of 45 patients with small nodules(diameter<1 cm)who received preoperative localization with ICG and underwent VATS wedge resection from October 2020 to February 2021.The data for analysis included patients age,nodule diameter,distance from the parietal pleura,nodule density,success rate of localization,time of localization,incidence of complications,and pathological findings. Results The success rate of localization was 100%.The average nodule size was 6.3 mm,and the nodules were(10±11)mm from the parietal pleura.After localization of 59 nodules,13(22.0%)cases were found to have mild pneumothorax,and 4(6.7%)cases were found to have mild hemorrhage.The success rate of operation was 100%,and 43(72.9%)cases were confirmed adenocarcinoma by postoperative pathology. Conclusion ICG has a high success rate and good safety in the localization of small pulmonary nodules in VATS.

HIF1a Inhibitor Rescues Acute-on-Chronic Liver Failure.

INTRODUCTION AND OBJECTIVES: Hypoxia-inducible factor-1α is critically involved in the pathogenesis of liver diseases. Its inhibitor genistein attenuated D-galactosamine (D-GalN)-induced liver damage. However, the role of genistein in acute-on-chronic liver failure (ACLF) is unclear. The influence of genistein on reactive oxygen species (ROS) and hepatocyte functions were evaluated in a rat model of ACLF. MATERIAL AND METHODS: Genistein [20mg/ (kg. day)]/coenzyme Q10 [10mg/ (kg. day)]/lipoic acid [20mg/ (kg. day)] was administered via the intra-gastric route daily for 6 weeks as co-treatment to the rats in the experimental groups. Then, 100µg/kg LPS combined with 0.5g/kg D-GalN was injected intraperitoneally to attack the rats. RESULTS: Genistein significantly attenuated LPS/D-GalN-induced ACLF, characterized by ameliorated gross appearance and microscopic histopathology of liver, reduced AST level in serum, whereas increased levels of ATP, ADP/O, and respiratory control ratio (RCR) in mitochondria. Genistein suppressed necrosis and ROS production. CONCLUSION: These results suggested that genistein could protect against ACLF through inhibiting cellular ROS production and necrosis, improving RCR, and decreasing permeability transition pores in mitochondrial, which was similar as mitochondrial protective agent coenzyme Q10.

Pharmacokinetics and Tissue Distribution of Anwuligan in Rats after Intravenous and Intragastric Administration by Liquid Chromatography-Mass Spectrometry.

Anwuligan, a natural 2,3-dibenzylbutane lignan from the nutmeg mace of Myristica fragans, has been proved to possess a broad range of pharmacological effects. A rapid, simple, and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been established and successfully applied to the study of pharmacokinetics and tissue distribution of anwuligan after intravenous or intragastric administration. Sample preparation was carried out through a liquid-liquid extraction method with ethyl acetate as the extraction reagent. Arctigenin was used as the internal standard (IS). A gradient program was employed with a mobile phase consisting of 0.1% formic acid aqueous solution and acetonitrile. The mass spectrometer was operated in a positive ionization mode with multiple reaction monitoring. The transitions for quantification were m/z 329.0→205.0 for anwuligan and m/z 373.0→137.0 for IS, respectively. Calibration curves were linear over the ranges of 0.5-2000 ng/mL for both plasma samples and tissue samples (r > 0.996). The absolute bioavailability is 16.2%, which represented the existing of the obvious first-pass effect. An enterohepatic circulation was found after the intragastric administration. Anwuligan could be distributed rapidly and widely in different tissues and maintained a high concentration in the liver. The developed and validated LC-MS/MS method and the pharmacokinetic study of anwuligan would provide reference for the future investigation of the preclinical safety of anwuligan as a candidate drug.

Interaction Effects between Doxorubicin and Hernandezine on the Pharmacokinetics by Liquid Chromatography Coupled with Mass Spectrometry.

Doxorubicin (DOX) is an effective anti-tumor drug widely used in clinics. Hernandezine (HER), isolated from a Chinese medicinal herb, has a selective inhibitory effect on DOX multidrug resistance, making DOX more effective in treating cancer. The aim of this study was to investigate the effect of the interaction of HER and DOX on pharmacokinetics. Male Sparague-Dawley rats were randomly divided into three groups: a single DOX group, a single HER group, and a combination group. Plasma concentrations of DOX and HER were determined by the LC-MS/MS method at specified time points after administration, and the main pharmacokinetic parameters were estimated. The results showed that there were significant differences in the Cmax and AUC0-∞ of DOX in the single drug group and combined drug group, indicating that HER could improve the absorption of DOX. However, DOX in combination, in turn, reduced the free drug concentration of HER, possibly because DOX enhanced the HER drug-protein binding effect. The results could be used as clinical guidance for DOX and HER to avoid adverse reactions.

Pharmacokinetics and Tissue Distribution of Alnustone in Rats after Intravenous Administration by Liquid Chromatography-Mass Spectrometry.

Alnustone, a nonphenolic diarylheptanoid, first isolated from Alnus pendula (Betulaceae), has recently received a great deal of attention due to its various beneficial pharmacological effects. However, its pharmacokinetic profile in vivo remains unclear. The purpose of this study is to establish a fast and sensitive quantification method of alnustone using liquid chromatography tandem mass spectrometry (LC-MS/MS) and evaluate the pharmacokinetic and tissue distribution profiles of alnustone in rats. The sample was precipitated with acetonitrile with 0.5% formic acid and separated on BEH C18 Column. The mobile phase was composed of 0.1% formic acid in water and methanol at a flow rate of 0.3 mL/min. Alnustone and the internal standard (caffeine) were quantitatively monitored with precursor-to-product ion transitions of m/z 262.9→105.2 and m/z 195.2→138.0, respectively. The calibration curve for alnustone was linear from 1 to 2000 ng/mL. The intra- and inter-day assay precision (RSD) ranged from 1.1-9.0 % to 3.3-8.6%, respectively and the intra- and inter-day assay accuracy (RE) was between -8.2-9.7% and -10.3-9.9%, respectively. The validated method was successfully applied to the pharmacokinetic studies of alnustone in rats. After single-dose intravenous administration of alnustone (5 mg/kg), the mean peak plasma concentration (Cmax) value was 7066.36 ± 820.62 ng/mL, and the mean area under the concentration-time curve (AUC0-t) value was 6009.79 ± 567.30 ng/mL∙h. Our results demonstrated that the residence time of alnustone in vivo was not long and it eliminated quickly from the rat plasma. Meanwhile, the drug is mainly distributed in tissues with large blood flow, and the lung and liver might be the target organs for alnustone efficacy. The study will provide information for further application of alnustone.

Value of CT-Angiography in the Emergency Management of Severe Hemoptysis.

Objective To depict imaging anatomy of bronchial artery (BA) using multidetector CT-angiography (MDCTA) and evaluate the value of MDCTA for management of hemoptysis patients requiring admission to emergency room. Methods We retrospectively studied the clinical and radiological data of patients with severe hemoptysis (≥100 ml of expectorated blood in a 24-hour period) requiring admission to emergency room from Jan 1, 2013 to Dec 31, 2015. Patients' images of MDCTA, treatment modalities, and outcome were discussed. Results A total of 108 patients underwent MDCTA scans. Etiology of hemoptysis was mainly bronchiectasis (44%), tuberculosis sequelae (26%) and tumor (18%). MDCTA visualized 197 traceable BAs and also suggested the involvement of 35 nonbronchial systemic arteries. The mean diameter of BAs, measured at the level of the bronchial bifurcation in the mediastinum, was 2.8±1.2 mm. The mean diameter of BAs, for 52 patients who only received conservative treatment, was 2.9±1.1 mm, and was not significantly larger than that of BAs for 56 patients who underwent bronchial artery embolization (BAE) for continued bleeding which did not resolve after conservative treatment (2.7±1.1 mm, P = 0.94). The technical success rate of embolization was 95% (53/56). Clinical success rate during follow-up was achieved in 50 (94%) of 53 patients who had undergone embolization. Conclusions MDCTA provides useful information for identifying the anatomical characteristics of bleeding-related BAs and nonbronchial systemic arteries for the management of patients with severe hemoptysis. However, MDCTA could not determine the individuals who need BAE through measuring diameter of BAs.

[Clinical features of carotid-cavernous sinus fistulas in 23 patients].

OBJECTIVE: To analyze the clinical features of carotid-cavernous sinus fistulas (CCFs). METHODS: The medical records of 23 patients with CCFs, which was confirmed by conventional cerebral angiography, in Peking Union Medical College Hospital from January 1990 to October 2012 were retrospectively analyzed. Data including patient characteristics, clinical features on ophthalmic examination, neurological assessment, and imaging study were collected.The differences between the direct and the indirect CCFs were compared, and the reasons for misdiagnoses were analyzed. RESULTS: Most patients were presented with ocular symptoms (78.3%). The most common signs were conjunctival injection or chemosis (78.3%), proptosis (69.6%), and ocular motor palsies (56.5%). There were 13 (56.5%) direct CCFs and 1 0(43.5%) indirect CCFs, and a history of encephalic trauma was more frequently reported among the former (61.5%) than the latter (10.0%); also, intracranial vascular murmur was more prevalent in patients with direct CCFs (69.2%vs.20.0%). Nine patients were misdiagnosed as other ocular diseases. Nonspecific clinical symptoms and signs such as chemosis, elevated intraocular pressure, and diplopia were the common causes of the misdiagnoses. CONCLUSIONS: Misdiagnosis of CCFs remains common due to its diverse clinical manifestations.CCFs should be suspected in patients with refractory red eyes, intraocular pressure elevation, proptosis and/or ophthalmoplegia, and a detailed history-taking, careful physical examination, and adequate imaging may minimize the misdiagnosis.

[Nutritional risk assessment in patients with chronic liver disease].

OBJECTIVE: To use the European Nutritional Risk Screening (NRS)-2002 survey tool to investigate nutritional risk associated to different degrees of liver disease and to assess its ability to identify the nutritional risk of hospitalized patients with chronic liver disease. METHODS: A total of 366 hospitalized patients were assessed with the NRS-2002 on the day of admission. Patients who meet the criteria for malnourishment (NRS-2002 score of more than 3 points (severely impaired nutritional status with body mass index (BMI) less than 18.5 kg/m2) were selected for further study to determine liver function. Patients were classified according to liver dysfunction-related features, including cirrhosis status, Child-Pugh classification, and underlying disease causes (e.g.alcohol, hepatitis virus infection). Chi square test was used in statistical analysis of inter-group difference. RESULTS: The incidence of patients surveyed who were at nutritional risk was 41.0%, and the incidence of malnutrition was 7.6%. The patients with liver failure showed the highest rate of nutritional risk (72.8%). Moreover, among the 97 patients with liver cirrhosis, significantly more had Child-Pugh grade B than grade A (88.6% vs.33.1%; x2=24.019, P=0.000). The cause of liver failure with the highest incidence of nutritional risk was alcohol-related liver disease (66.7%). The overall malnutrition rate among the total 156 patients classified by the NRS-2002 as being at nutritional risk was 76.2%. CONCLUSION: The NRS-2002 is a suitable screening tool for use in Chinese patients with mild early liver disease, but it must be interpreted carefully as its findings alone may promote a false positive rate. The NRS-2002 is less accurate in patients with end-stage liver disease.

[Changes in mitochondria fusion protein-2 hepatic expression in conditions of liver cirrhosis and acute on chronic liver failure].

OBJECTIVE: To determine the differential protein and mRNA expressions of mitochondria fusion protein-2 (Mfn2) in hepatic tissues in conditions of cirrhosis and acute on chronic liver failure using rat model systems,and to determine the correlative effects on production of adenosine triphosphate (ATP) and reactive oxygen species (ROS). METHODS: A liver cirrhotic rat model (LC rats) was established by intraperitoneal injection of carbon tetrachloride (CCl4,in vegetable oil),and these mice were subsequently used (10 weeks later) to establish the acute on chronic liver failure rat model (LF rats) by injecting lipopolysaccharide and D-amino-galactose.Control groups (normal controls,NC rats) were established for each model by intraperitoneal injection of vegetable oil only.Protein expression of Mfn2 in liver was quantified by western blotting with fluorescence densitometry and immunofluorescence staining,and mRNA expression was measured by real-time fluorescence quantitative PCR.ROS levels in liver were measured by fluorescence spectrophotometry,and ATP content was measured by bioluminescence assay.Significance of inter-group differences was assessed by one-way ANOVA,and correlations were determined using bivariate statistical modeling. RESULTS: Mfn2 protein expression was significantly lower in the liver tissues from modeled rats than that from the control rats (LC:0.051+/-0.004 and LF:0.037+/-0.007 vs.NC:0.254+/-0.008;F=444.98,P less than 0.05).The mRNA expression followed the same trend of lower expression (LC:21.21+/-0.93 and LF:24.35+/-0.85 vs.NC:19.09+/-0.69; F=66.941,P less than 0.05).The ATP content in liver tissues was also significantly lower in the modeled rats (LC:2.07+/-0.05 mol/L and LF:1.81+/-0.11 mol/L vs.NC:3.24+/-0.08 mol/L; F =574.21,P less than 0.05).Lower Mfn2 expression was correlated with lower ATP content (r =0.982) and higher ROS content (r =0.803). CONCLUSION: Reduced Mfn2 expression in liver tissue may cause a decrease in ATP synthesis and increase in ROS generation,thereby disrupting metabolism and increasing oxidative stress in the liver under conditions of cirrhosis and liver failure.

Nitrogen-fixing and non-nitrogen-fixing legume plants differ in leaf nutrient concentrations and relationships between photosynthetic and hydraulic traits.

Legumes account for a significant proportion of plants in the terrestrial ecosystems. Nitrogen (N)-fixing capability of certain legumes is a pivotal trait that contributes to their ecological dominance. Yet, the functional traits and trait relationships between N-fixer and non-N-fixer legumes are poorly understood. Here, we investigated 27 functional traits associated with morphology, nutrients, hydraulic conductance and photosynthesis in 42 woody legumes (19 N-fixers and 23 non-N-fixers) in a common garden. Our results showed that N-fixers had higher specific leaf area, photosynthetic phosphorus (P)-use efficiency, leaf N, and iron concentrations on both area and mass basis, N/P ratio, and carbon (C) to P ratio, but lower wood density, area-based maximum photosynthetic rate (Aa), photosynthetic N-use efficiency, leaf mass- and area-based P and molybdenum and area-based boron concentrations, and C/N ratio, compared with non-N-fixers. The mass-based maximum photosynthetic rate (Am), stomatal conductance (gs), intrinsic water-use efficiency (WUEi), mass- and area-based leaf potassium and mass-based boron concentrations, leaf hydraulic conductance (Kleaf), and whole-shoot hydraulic conductance (Kshoot) showed no difference between N-fixers and non-N-fixers. Significant positive associations between all hydraulic and photosynthetic trait pairs were found in N-fixers, but only one pair (Kshoot-Aa) in non-N-fixers, suggesting that hydraulic conductance plays a more important role in mediating photosynthetic capacity in N-fixers compared with non-N-fixers. Higher mass-based leaf N was linked to lower time-integrated gs and higher WUEi among non-N-fixer legumes or all legumes pooled after phylogeny was considered. Moreover, mass-based P concentration was positively related to Am and gs in N-fixers, but not in non-N-fixers, indicating that the photosynthetic capacity and stomatal conductance in N-fixers were more dependent on leaf P status than in non-N-fixers. These findings expand our understanding of the trait-based ecology within and across N-fixer and non-N-fixer legumes in tropics.

Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma.

BACKGROUND: Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL. METHODS: Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells. RESULTS: A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy. CONCLUSIONS: The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile. TRIAL REGISTRATION NUMBERS: ChiCTR1900025419 and NCT04690192.

Efficacy and safety of combination therapies vs monotherapy of hypomethylating agents in accelerated or blast phase of Philadelphia negative myeloproliferative neoplasms: a systematic review and meta-analysis.

BACKGROUND: There is a lack of evidence regarding whether combination therapy of hypomethylating agents (HMAs) has better outcomes than HMA monotherapy in patients with Philadelphia chromosome-negative accelerated or blast phase myeloproliferative neoplasms (MPN-AP/BP). MATERIALS AND METHODS: Pubmed, Embase, Web of Science and Cochrane library databases were searched for studies from inception of each database until 31 December 2021. Data extraction and synthesis were conducted following the PRISMA reporting guideline. RESULTS: It was found that HMAs plus venetoclax therapy yielded a higher CR/CRi rate than HMAs alone [36% vs 19%, p = .0204] and a higher CR rate than HMAs plus ruxolitinib [22% vs 8%, p = .0313]. HMAs plus ruxolitinib combination showed a higher ORR than HMA monotherapy [45% vs 30%, p = .0395], but there was no improvement in CR/CRi. The one-year and two-year OS rate for patients treated with HMAs plus venetoclx/ruxolitinib demonstrated a trend towards prolonged survival than HMAs alone [HMAs plus venetoclax: 24% vs 11%, p = .1295 and 12% vs 3%, p = .2357; HMAs plus ruxolitinib: 25% vs 11%, p = .0774 and 33% vs 3%, p = .051]. CONCLUSION: It was confirmed that HMA in combination with venetoclax is an effective and well-tolerated option in MPN-AP/BP patients in pre- as well as post-haematopoietic stem cell transplantation settings. HMA plus ruxolitinib therapy was revealed to be effective in patients with MPN-AP.Key MessagesCombination therapy with HMAs and venetoclax/ruxolitinib was associated with improved outcomes than HMAs alone in MPN-AP/BP patients.Further large-scale randomized controlled trials are needed to confirm regarding to the optimal treatment for this patient population.

[Establishment of Patient-Derived Xenograft (PDX) Zebrafish Model of Multiple Myeloma and Its Application in Drug Screening].

OBJECTIVE: To establish a MM patient-derived tumor xenograft model (MM-PDX) in zebrafish, and to evaluate the anti-myeloma activity of indirubin-3'-monoxime(I3MO) using this model. METHODS: Zebrafish embryos 2 days after fertilization were transplanted with fluorescence labeled myeloma primary tumor cells, the survival of primary tumor cells in zebrafish was observed at 0,16 and 24 hours after cell injection. The zebrafish embryos after tumor cell transplantation were randomly divided into control group, BTZ treatment and I3MO treatment group. Before and 24 hours after treatment with BTZ and I3MO, the positive area with calcein or Dil in zebrafish were observed under fluorescence microscope to reflect the survival of tumor cells, and it was verified. RESULTS: MM patient derived tumor cells survived in zebrafish. The construction of MM-PDX was successful. Compared with control group, the fluo- rescence area of the BTZ and I3MO treatment groups in zebrafish were significantly decreased(P<0.05), and BTZ and I3MO significantly inhibited the survival of MM cells in zebrafish. CONCLUSION: MM-PDX model was successfully established. Zebrafish model derived from tumor cells of MM patients can be used as a tool for drug screening of MM.

Effect of the change in antiviral therapy indication on identifying significant liver injury among chronic hepatitis B virus infections in the grey zone.

Objective: In clinical practice, a substantial proportion of chronic hepatitis B virus (HBV) infections that do not fit into any of the usual immune states are considered to be in the "grey zone (GZ)". This study aimed to investigate the effect of the change in antiviral therapy indication on identifying significant hepatic injury among GZ patients. Methods: Patients with chronic HBV infections and a persistent normal alanine aminotransferase (ALT) level (PNALT) who underwent ultrasonography-guided percutaneous liver biopsy were examined retrospectively. Evidenced hepatic injury (EHI) was defined as an inflammation grade ≥2 (≥G2) and/or fibrosis stage ≥2 (≥F2). Complete clinical data, liver inflammation, and fibrosis grades were collected, and the levels of cytokines were detected by the Luminex technique, all of which were analysed to investigate the immune and histopathology states of the liver. Results: A total of 347 patients with chronic HBV infections and PNALT were categorized into immune tolerant (IT, n = 108), inactive HBV surface antigen (HBsAg) carrier (IHC, n = 61), GZ-1 (HBeAg positive in GZ, n = 92), and GZ-2 (HBeAg negative in GZ, n = 68) phases. Among them, 51.3% were in the GZ phase, and 50.1% presented with EHI. The IL-6 levels were higher in the EHI group than in the non-EHI group (2.77 vs. 1.53 pg/ml, Z = -13.32, p = 0.028). The monocyte chemoattractant protein 1 (MCP-1) level was positively correlated with HBV DNA (R = 0.64, p < 0.001) and HBeAg (R = 0.5, p < 0.001) but negatively correlated with fibrosis grade (R = -0.26, p = 0.048). The ratio of EHI in the GZ phase was 60.55%, which was significantly higher than that in patients in the IT (39.8%) and IHC phases (37.7%) (χ2 = 10.4, p = 0.006). A total of 46.69% of all patients exceeded the new ALT antiviral treatment threshold (30 U/L for men and 19 U/L for women). The EHI values in the IT and IHC phases below the new ALT threshold were 32.6% and 37.8%, respectively, whereas higher EHI values of 67.4% and 68.4% were seen in GZ-1 and GZ-2 patients, respectively, exceeding the new ALT threshold, and the difference was statistically significant (χ2 = 11.13, p < 0.001; χ2 = 14.22, p = 0.002). The median age in our cohort was 38.91 years, and only 21.03% were less than 30 years old. The EHI values in the IT and IHC patients <30 years old were 32.4% and 35.8%, respectively, while the ratio of EHI increased to 43.2% once patients were older than 30 years but still in the IT and IHC stages. Conclusion: Setting 30 years old as a cut-off and lowering the ALT threshold could facilitate screening for the presence of significant liver injury, especially for GZ patients. IL-6 was a good indicator of EHI, and MCP-1 was significantly positively correlated with HBV DNA but negatively correlated with liver fibrosis.

UK-based specialist dental professionals' experiences of working with autistic patients.

AIMS: Previous research has demonstrated that autistic individuals often experience difficulties accessing dental care, both as a result of autism specific difficulties and practitioners' attitudes towards autism. However, very little research exists that explores dental professionals' experiences of providing care to their autistic patients. The aim of this study was to investigate the strategies UK-based dental professionals' use when working with autistic patients METHODS AND RESULTS: In this study, dental professionals (n = 16) from a variety of specialty roles (special care, paediatrics, orthodontics) were interviewed. We asked participants to talk through, in depth, specific cases they had encountered in their practice, what sorts of accommodations they had provided, and what concerns had arisen during appointments. Thematic analysis was used to analyses the data and revealed four main themes: the unique dental needs associated with being autistic, effective adaptations to practice, the crucial role of the caregiver, and the importance of specialist knowledge CONCLUSION: Recommendations for how dentists can improve the dental experiences of autistic patients can be drawn from the specialist dentists' responses in this study. These include involving autistic patients in decisions about their treatment and being flexible and willing to work with autistic patients and their caregivers.

Indirubin-3'-monoxime acts as proteasome inhibitor: Therapeutic application in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in majority of newly diagnosed patients with myeloma. However, drug resistance remains the major obstacle causing treatment failure in clinical practice. Here, we investigated the effects of Indirubin-3'-monoxime (I3MO), one of the derivatives of Indirubin, in the treatment of MM. METHODS: MM patient primary samples and human cell lines were examined. I3MO effects on myeloma treatment and the underling molecular mechanisms were investigated via in vivo and in vitro study. FINDINGS: Our results demonstrated the anti-MM activity of I3MO in both drug- sensitive and -resistance MM cells. I3MO sensitizes MM cells to bortezomib-induced apoptosis. Mechanistically, I3MO acts as a multifaceted regulator of cell death, which induced DNA damage, cell cycle arrest, and abrogates NF-κB activation. I3MO efficiently down-regulated USP7 expression, promoted NEK2 degradation, and suppressed NF-κB signaling in MM. Our study reported that I3MO directly bound with and caused the down-regulation of PA28γ (PSME3), and PA200 (PSME4), the proteasome activators. Knockdown of PSME3 or PSME4 caused the inhibition of proteasome capacity and the overload of paraprotein, which sensitizes MM cells to bortezomib-mediated growth arrest. Clinical data demonstrated that PSME3 and PSME4 are over-expressed in relapsed/refractory MM (RRMM) and associated with inferior outcome. INTERPRETATION: Altogether, our study indicates that I3MO is agent triggering proteasome inhibition and represents a promising therapeutic strategy to improve patient outcome in MM. FUNDINGS: A full list of funding can be found in the acknowledgements.

Pharmacokinetics, tissue distribution and plasma protein binding rate of palmatine following intragastric and intravenous administration in rats using liquid chromatography tandem mass spectrometry.

Palmatine is a natural isoquinoline alkaloid widely found in traditional Chinese medicines. In this study, a simple, sensitive and rapid ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the quantification of palmatine in the plasma and tissue samples in rats. Sample preparation involved a simple protein precipitation extraction technique using acetonitrile as the precipitating solvent. Chromatographic separation was accomplished on an ACQUITY UPLC BEH C18 column with a mobile phase of acetonitrile-5 mM ammonium acetate solution (70:30, v/v) at a flow rate of 0.3 mL/min. Coptisine was selected as the internal standard. The protonated analytes were determined with MRM in the positive ion mode. The assay exhibited a linear dynamic range of 1.0-1000 ng/mL for palmatine in each biological matrix and the low limit of quantification was 1.0 ng/mL. Non-compartmental pharmacokinetic parameters indicated that there is a significant difference in the apparent distribution volume and half-life between intragastric and intravenous administration modes. Palmatine could be detected in different tissues and the content in liver and kidney is relatively high, suggesting that liver and kidney might be the targeting organs of palmatine. The plasma protein binding rate test showed that the percent binding of palmatine is medium, and was found to be higher in human than in rats.

Targeted Near-Infrared Fluorescence Imaging With Iodized Indocyanine Green in Preoperative Pulmonary Localization: Comparative Efficacy, Safety, Patient Perception With Hook-Wire Localization.

BACKGROUND: Precise preoperative localization is of great importance to improve the success rate and reduce the operation time of VATS surgery. This study aimed to assess the efficacy, safety, patient perception between CT-guided indocyanine green (ICG) preoperative localization of lung nodule and hook-wire localization. METHODS: 65 patients with 85 clinically suspicious pulmonary nodules underwent ICG preoperative localization in this study, and 92 patients with 95 nodules localized by conventional hook-wire served as controls. Both hook-wire localization and ICG injection were performed under CT guidance. Successful targeting rate, success rate in the operative field, incidence rate of complications and respiratory pain score were recorded and compared. RESULTS: The successful targeting rate for both groups is 100%, however, due to hook-wire dislodgement, the success rate in the VATS operation field of the hook-wire group (95.6%) is lower than that of the ICG group (100%), with no significant difference(p=0.056). The overall complication rate of the hook-wire group (37.0%) is significantly higher than the ICG group (35.4%) (p=0.038). The mean respiratory pain score of the hook-wire group is 3.70 ± 1.25, which is significantly higher than that of the ICG group (2.85 ± 1.05) (p<0.001). CONCLUSIONS: ICG composed with contrast mixture are superior to the conventional hook-wire preoperative lung nodule localization procedure, with a lower complication rate, lower pain score, and relatively higher success rate. ICG is a promising alternative method for pulmonary nodule preoperative localization.

An electrochemical sensing platform based on a new copper complex for the determination of hydrogen peroxide and nitrite.

A new copper(II) complex [Cu(C12H23N3)4Br2·2H2O] was synthesized and its structure was characterized by x-ray crystallography and elemental analysis. The copper atom had a distorted octahedron coordination involving two bromide anions and four nitrogen atoms from the 1-decyl-1H-[1,2,4]triazole ligands. Moreover, the electrochemical behavior and electrocatalysis of the carbon paste electrode (Cu-CPE) bulk-modified by the complex have been studied in detail. The Cu-CPE showed excellent electrocatalytic activities toward the reduction of hydrogen peroxide and nitrite, and the detection limit was much lower than that mentioned in earlier reports. This bulk-modified CPE has good reproducibility, long-term stability and surface renewability, which appear promising for constructing chemical sensors.