Evidence-based expert consensus on clinical management of safety of Bruton’s tyrosine kinase inhibitors(2024)

Bruton’s tyrosine kinase inhibitors(BTKis)have revolutionized the treatment of B-cell lymphomas.However,safety issues related to the use of BTKis may hinder treatment continuity and further affect clinical efficacy.A comprehensive and systematic expert consensus from a pharmacological perspective is lacking for safety issues associated with BTKi treatment.A multidisciplinary consensus working group was established,comprising 35 members from the fields of hematology,cardiovascular disease,cardio-oncology,clinical pharmacy,and evidencebased medicine.This evidence-based expert consensus was formulated using an evidence-based approach and the Delphi method.The Joanna Briggs Institute Critical Appraisal(JBI)tool and Grading of Recommendations Assessment,Development,and Evaluation(GRADE)approach were used to rate the quality of evidence and grade the strength of recommendations,respectively.This consensus provides practical recommendations for BTKis medication based on nine aspects within three domains,including the management of common adverse drug events such as bleeding,cardiovascular events,and hematological toxicity,as well as the management of drug-drug interactions and guidance for special populations.This multidisciplinary expert consensus could contribute to promoting a multi-dimensional,comprehensive and standardized management of BTKis.

Outcome and risk factors of ulcer healing after gastric endoscopic submucosal dissection: A systematic review and meta-analysis

BACKGROUND Endoscopic submucosal dissection(ESD)is widely utilized for the treatment of large adenomas,submucosal lesions,and early gastric cancer.A significant arti-ficial ulcer typically forms after ESD.Delayed or incomplete healing of these ulcers can result in complications such as delayed bleeding and perforation.However,a comprehensive review of the outcomes and risk factors related to ulcer healing following ESD is currently lacking.AIM To assess ulcer healing outcomes and identify risk factors associated with delayed ulcer healing.RESULTS Our analysis included 12 studies,involving a total of 3430 patients.The meta-analysis revealed an overall healing rate of 65.55%for ulcers following ESD[odds ratio(OR)=2.71;95%confidence interval(CI):2.45-3.00].The healing rate within eight weeks was 48.32%(OR=0.76;95%CI:0.35-1.66),while the rate beyond eight weeks was 88.32%(OR=6.73;95%CI:3.82-11.87).Risk factors included Helicobacter pylori(H.pylori)infection(OR:=5.32;95%CI:1.90-14.87;P=0.001),ulcer size(OR=2.08;95%CI:1.19-3.61;P=0.01),lesion site(OR=2.08;95%CI:1.19-3.11),and pathological type(OR=1.64;95%CI:1.06-2.52).Diabetes(OR=0.56;95%CI:0.05-5.80;P=0.63)and duration of operation(OR=1.00;95%CI:0.99-1.01;P=0.96)were not significant factors.CONCLUSION The healing rate of ulcers following ESD is high after eight weeks.Risk factors affecting the healing process include H.pylori infection,ulcer size,lesion site,and pathological type.

腹腔灌注治疗在晚期胃癌腹膜转移患者中的应用效果

目的:探讨腹腔灌注治疗对胃癌腹膜转移患者生存的影响。方法:回顾性分析2014年1月至2020年12月哈尔滨医科大学附属肿瘤医院收治的353例晚期胃癌合并腹膜转移患者临床资料。根据是否腹腔灌注给药分为灌注治疗组和未灌注治疗组,并对患者进行生存随访。Kaplan-Meier法绘制生存曲线,Cox风险比例模型分析影响患者预后的因素,根据病灶部位、分化程度等进行亚组分析。结果:灌注治疗组和未灌注治疗组中位总生存(overall survival,OS)期为9.50个月(95%CI:7.39~11.61)和7.83个月(95%CI:5.74~9.92,P=0.022)。体质量指数(BMI)>25及伴有腹水的胃癌腹膜转移患者更易从腹腔灌注中获益。多因素分析显示:腹腔积液(HR=1.52,95%CI:1.18~1.94)、全身系统治疗(HR=0.43,95%CI:0.33~0.56)、手术(HR=0.52,95%CI:0.39~0.70)、腹腔灌注治疗(HR=0.65,95%CI:0.52~0.82)是影响患者生存的因素。结论:胃癌伴有腹膜转移患者可进行腹腔灌注治疗,与未灌注治疗患者相比,其生存期明显延长。Cox多因素分析显示无腹水、接受手术治疗、接受全身系统治疗和腹腔灌注治疗的患者预后更佳。分层分析显示BMI>25及伴有腹水的胃癌腹膜转移患者更易从腹腔灌注治疗中获益。

Subretinal recombinant human tissue plasminogen activator injection using a 41G needle for the management of submacular hemorrhages:a 3-case report

Dear Editor,Submacular hemorrhage(SMH)is the accumulation of blood in the macular region caused by changes in retinal or choroidal circulation[1].SMH may be caused by age-related macular degeneration(AMD),pathological myopia,polypoid choroidal angiopathy(PCV)or retinal macroaneurysm[2].

Identification of UGT85A glycosyltransferases associated with volatile conjugation in grapevine(Vitis vinifera × Vitis labrusca)

Glycosylated volatiles are considered as hidden aroma precursors that affect fruit flavor and are involved in plant defense response. Several uridine-diphosphate(UDP)-glycosyltransferase(UGT) members related to the glycosylation of volatiles have been identified from grapevine berries. Although grapevine leaves produced much higher levels of glycosylated volatiles than berries, UGTs responsible for the production of glycosylated volatiles in leaves have not yet been identified. Here, eight novel UGT genes were cloned, among these four members that belong to UGT85A family(named UGT85A24, UGT85A25, UGT85A26, and UGT85A27) were localized in the cytoplasm and their recombinant proteins showed activity toward volatiles detected in grapevine, with geraniol as the preferred substrate in vitro. Two UGT genes with 98.1% homology differ in R/S-linalool selection. The UGT85A26-catalyzed substrate showed enrichment in S-linalool, whereas UGT85A27 showed a strong preference for R-linalool. UGT85A24 and UGT85A25 were expressed mainly in berries, and UGT85A26 and UGT85A27 were expressed predominantly in grapevine mature leaves and correlated with the highest content of glycosylated volatiles in the mature leaves. Methyl jasmonate(MeJA) induced the expression of UGT85A26 and UGT85A27 as well as the production of linalyl-β-glucoside, citronellyl-β-glucoside and phenethyl-β-glucoside. Transient overexpression of UGT85A26 and UGT85A27 in tobacco leaves led to the accumulation of linalyl-β-glucoside and an increase in citronellyl-β-glucoside in vivo. These results indicate that the expression of UGT85A26 and UGT85A27 is a major regulator affecting the content of glycosylated volatiles in grapevine.

3-N-Butylphthalide mitigates high glucose-induced injury to Schwann cells:association with nitrosation and apoptosis

A high glucose state readily causes peripheral axon atrophy, demyelination, loss of nerve fiber function, and delayed regeneration. However, few studies have examined whether nitration is also critical for diabetic peripheral neuropathy. Therefore, this study investigated the effects of high glucose on proliferation, apoptosis, and 3-nitrotyrosine levels of Schwann cells treated with butylphthalide. In addition, we explored potential protective mechanisms of butylphthalide on peripheral nerves. Schwann cells were cultured in vitro with high glucose then stimulated with the peroxynitrite anion inhibitors uric acid and 3-n-butylphthalide for 48 hours. Cell Counting Kit-8 and flow cytometry were used to investigate the effects of uric acid and 3-n-butylphthalide on proliferation and apoptosis of Schwann cells exposed to a high glucose environment. Effects of uric acid and 3-n-butylphthalide on levels of 3-nitrotyrosine in Schwann cells were detected by enzyme-linked immunosorbent assay. The results indicated that Schwann cells cultured in high glucose showed decreased proliferation, but increased apoptosis and intracellular 3-nitrotyrosine levels. However, intervention with uric acid or 3-n-butylphthalide could increase proliferation of Schwann cells cultured in high glucose, and inhibited apoptosis and intracellular 3-nitrotyrosine levels. According to our data, 3-n-butylphthalide may inhibit cell nitrification and apoptosis, and promote cell proliferation, thereby reducing damage to Schwann cells caused by high glucose.

Optimized analysis of sharpening characteristics of a compact RF pulse source based on a gyro-magnetic nonlinear transmission line for ultrawideband electromagnetic pulse application

We constructed a compact high-power RF pulse generator based on a gyro-magnetic nonlinear transmission line(GNLTL) to produce a high-voltage pulse with a sub-nanosecond rise time and a relatively high repetition rate, which shows great potential for application in the high-power ultrawideband electromagnetic effect, etc. The influence of incident pulse parameters(rise time and voltage amplitude) and line length on the sharpening characteristics of the GNLTL were investigated experimentally to optimize the rising rate of the modulated pulse front. Based on the GNLTL equivalent circuit model consisting of an LC ladder network, the rise time, the voltage conversion coefficient and the rising rate properties of a modulated pulse were also numerically analyzed in a wider range. The results show that a?>?90 k V RF pulse with a rise time of 350 ps and a repetition rate of 1 kHz in burst mode is produced by the GNLTL at an axial biasing magnetic field of 22 kA m^-1 and a line length of 30 cm under the condition of a 70 kV incident pulse. Applying a faster and higher incident pulse is conducive to improving the sharpening effect of the GNLTL. Furthermore, within a certain range, increasing the line length of the GNLTL not only reduces the rise time, but increases the voltage conversion coefficient and the rising rate of a modulated pulse. Furthermore, considering the energy loss of ferrite rings, there is an optimal line length to obtain the fastest rising rate of a modulated pulse front edge.

Control and Implementation of 2-DOF Lower Limb Exoskeleton Experiment Platform

In this study,a humanoid prototype of 2-DOF(degrees of freedom)lower limb exoskeleton is introduced to evaluate the wearable comfortable effect between person and exoskeleton.To improve the detection accuracy of the humanrobot interaction torque,a BPNN(backpropagation neural networks)is proposed to estimate this interaction force and to compensate for the measurement error of the 3D-force/torque sensor.Meanwhile,the backstepping controller is designed to realize the exoskeleton's passive position control,which means that the person passively adapts to the exoskeleton.On the other hand,a variable admittance controller is used to implement the exoskeleton's active followup control,which means that the person's motion is motivated by his/her intention and the exoskeleton control tries best to improve the human-robot wearable comfortable performance.To improve the wearable comfortable effect,serval regular gait tasks with different admittance parameters and step frequencies are statistically performed to obtain the optimal admittance control parameters.Finally,the BPNN compensation algorithm and two controllers are verified by the experimental exoskeleton prototype with human-robot cooperative motion.

Cronkhite-Canada syndrome with steroid dependency: A case report

BACKGROUND Cronkhite-Canada syndrome(CCS)is a rare nonhereditary disease characterized by chronic diarrhoea,diffuse gastrointestinal polyposis and ectodermal manifestations.The lethality of CCS can be up to 50%if it is untreated or if treatment is delayed or inadequate.More than 35%of the patients do not achieve long-term clinical remission after corticosteroid administration,with relapse occurring during or after the cessation of glucocorticoid use.The optimal strategy of maintenance therapy of this disease is controversial.CASE SUMMARY A 47-year-old man presented to the hospital with a 3-mo history of frequent watery diarrhoea,accompanied by macular skin pigmentation that included the palms and soles,and onychodystrophy of the fingernails and toenails.Gastroscopy and colonoscopy revealed numerous polyps in the stomach and colon.After other possibilities were ruled out by a series of examinations,CCS was diagnosed and treated with prednisone.The patient took prednisone for more than 1 year before achieving complete resolution of his symptoms and endoscopic findings.The patient was then given prednisone 5 mg/d for 6 mo of maintenance therapy.With clinical improvement and polyp regression,prednisone was discontinued.Eight mo after the discontinuation of prednisone,the diarrhoea and gastrointestinal polyps relapsed.Therefore,the patient was given the same dose of prednisone,and complete remission was achieved again.CONCLUSION It is necessary to extend the duration of prednisone maintenance therapy for CCS.Prednisone is still effective when readministered after relapse.Surveillance endoscopy at intervals of 1 year or less is recommended to assess mucosal disease activity.

Analysis and Perspective of Endodontics Standard Resident Training in China

As an important part of postgraduate education,Standard Resident Training(STR)plays a crucial role in the process of culturing a competent dental care provider who can independently treat the common oral infectious diseases.A systematic and comprehensive evaluation system is desiderating for realization of high-quality Endodontics resident training due to its discipline characteristics of highly specialized and strict operation.This paper analyzes the current status of resident training in our Endodontic Department and discusses how to improve the clinical skills and reasoning ability of residents,in order to construct a comprehensive resident training formative evaluation system in China.

Metabolome profiling of stratified seeds provides insight into the regulation of dormancy in Davidia involucrata

Dove tree(Davidia involucrata),a tertiary vestige species,is well-adapted to cool conditions.Dormancy in D.involucrata seed lasts for an extremely long period of time,typically between 3 and 4 years,and this characteristic makes the species an excellent model for studying the mechanisms of seed dormancy.The molecular mechanisms governing germination control in D.involucrata are still unknown.Seed stratification have been reported to enhance germination in recalcitrant seeds.We performed a widely targeted metabolome profiling to identify metabolites and associated pathways in D.involucrata seeds from six different moist sand stratification durations(0-30 months) using the ultra-high-performance liquid chromatography-Q Exactive Orbitrap-Mass spectrometry.There was an increasing germination rate with prolonged stratification durations(12-30 months).Furthermore,we detected 10,008 metabolites in the stratified seeds.We also detected 48 differentially accumulated metabolites(DAMs) between all stratification periods in the seeds,with 10 highly conserved metabolites.Most of the differentially accumulated metabolites between unstratified and stratified seeds were enriched in purine metabolism,pyrimidine metabolism,flavone and flavonol biosynthesis,phenylpropanoid biosynthesis,and arginine biosynthesis pathways.Key phytohormones,abscisic acid,indole-3 acetic acid,and sinapic acid were differentially accumulated in the seeds and are predicted to regulate dormancy in D.involucrata.We have provided extensive metabolic information useful for future works on dove tree germination study.

Robust Sliding Mode Control for a 2-DOF Lower Limb Exoskeleton Base on Linear Extended State Observer

For the 2-Degree of Freedom(DOF)lower limb exoskeleton,to ensure the system robustness and dynamic performance,a linearextended-state-observer-based(LESO)robust sliding mode control is proposed to not only reduce the influence of parametric uncertainties,unmodeled dynamics,and external disturbance but also estimate the unmeasurable real-time joint angular velocity directly.Then,via Lyapunov technology,the stability of the corresponding LESO and controller is proven.The appropriate and reasonable simulation was carried out to verify the effectiveness of the proposed LESO and exoskeleton controller.

视光与干眼联合诊疗模式的探索

干眼是一种常见的眼部疾病,会导致眼部不适和视功能障碍,严重影响患者的生活和工作质量。近年来,随着环境和生活方式的改变,干眼发病率逐年上升,特别是近视或者近视防控患者中配戴接触镜产生的干眼引发了广泛关注。但仅依靠现有眼科医疗资源难以满足全国干眼诊疗需求。因此,建立视光与干眼联合诊疗模式具有重要的意义。已有多个国家和地区进行了视光与干眼联合诊疗的实践,但国内仍处于初期探索阶段。笔者通过分析干眼诊疗现状及国际视光干眼联合诊疗的经验,为我国视光与干眼联合诊疗体系的建设提供参考。

Quasi-synchronous control of uncertain multiple electrohydraulic systems with prescribed performance constraint and input saturation

This article focuses on the high accuracy quasi-synchronous control issue of multiple electrohydraulic systems(MEHS).In order to overcome the negative effects of parameter uncertainty and external load interference of MEHS,a kind of finite-time disturbance observer(FTDO)via terminal sliding mode method is constructed based on the MEHS model to achieve fast and accuracy estimation and compensation ability.To avoid the differential explosion in backstepping iteration,the dynamic surface control is used in this paper to guarantee the follower electrohydraulic nodes synchronize to the leader motion with a better performance.Furthermore,a timevarying barrier Lyapunov function(tvBLF)is adopted during the controller design process to constraint the output tracking error of MEHS in a prescribed performance with time-varying exponential function.As the initial state condition is relax by tvBLF,the input saturation law is also adopted during the controller design process in this paper to restrain the surges of input signals,which can avoid the circuit and mechanical structure damage caused by the volatile input signal.An MEHS experimental bench is constructed to verify the effectiveness of the theoretical conclusions proposed in this paper and the advantages of the proposed conclusions in this paper are illustrated by a series of contradistinctive experimental results.

De novo biosynthesis of liquiritin in Saccharomyces cerevisiae

Liquiritigenin(LG),isoliquiritigenin(Iso-LG),together with their respective glycoside derivatives liquiritin(LN)and isoliquiritin(Iso-LN),are the main active flavonoids of Glycyrrhiza uralensis,which is arguably the most widely used medicinal plant with enormous demand on the market,including Chinese medicine prescriptions,preparations,health care products and even food.Pharmacological studies have shown that these ingredients have broad medicinal value,including anti-cancer and antiinflammatory effects.Although the biosynthetic pathway of glycyrrhizin,a triterpenoid component from G.uralensis,has been fully analyzed,little attention has been paid to the biosynthesis of the flavonoids of this plant.To obtain the enzyme-coding genes responsible for the biosynthesis of LN,analysis and screening were carried out by combining genome and comparative transcriptome database searches of G.uralensis and homologous genes of known flavonoid biosynthesis pathways.The catalytic functions of candidate genes were determined by in vitro or in vivo characterization.This work characterized the complete biosynthetic pathway of LN and achieved the de novo biosynthesis of liquiritin in Saccharomyces cerevisiae using endogenous yeast metabolites as precursors and cofactors for the first time,which provides a possibility for the economical and sustainable production and application of G.uralensis flavonoids through synthetic biology.

p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells

We have recently reported that Ginsenoside Rh2 （G- Rh2） induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. How- ever, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and cas- pase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process, Moreover, significant increases in Fas expression and caspase-8 activity temporally coin- cided with an increase in p53 expression in p53-non- mutated HeLa and SK-HEP-1 cells upon G-Rh2 treat- ment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation, These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immedi- ate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 ceils, p53-mediated Fas expression and sub- sequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti- tumor drug development.

Detection of serum IgM and IgG for COVID-19 diagnosis

Dear Editor,Infection with the novel coronavirus(SARS-CoV-2,which is the virus responsible for the coronavirus disease 2019(COVID-19))was first reported in Wuhan,China on December 31,2019.The outbreak of COVID-19 remains ongoing and was linked to more than 80,000 infected patients and more than 3,000 deaths in China as of March 7,2020(Holshue et al.,2020).

Genome-wide analysis identified 17 new loci influencing intraocular pressure in Chinese population

Intraocular pressure(IOP) is a major risk factor for glaucoma. Genetic determinants of intraocular pressure can provide critical insights into the genetic architecture of glaucoma and, as a result, open new avenues for therapeutic intervention. We performed a genome-wide association study and replication analysis of 8,552 Chinese participants. In the genome-wide association study, we identified 51 loci that surpassed the significance of P<9×10^(-7), and we formally replicated these loci. A combined discovery and replication meta-analysis identified 21 genome-wide loci that surpassed the genome-wide significance of P<5×10^(-8), including 4 previously reported loci: rs145063132(7 p21.2, ETV1/DGKB), rs548030386(7 q31.2, ST7 near CAV1/CAV2), rs7047871(9 p24.2, GLIS3), and rs2472494(9 q31.1, ABCA1/SLC44 A1). Of the 17 newly identified loci, five were reported to have ocular related phenotypes: PTCH2(rs7525308 in 1 p34.1), LRIF1/DRAM2(rs1282146 in 1 p13.3), COLEC11(rs201143466 in 2 p25.3),SPTBN1(rs4514918 in 2 p16.2), and CRK(rs11078446 in 17 p13.3). The genetic loci identified in this study not only increase our understanding of the genes involved in intraocular pressure but also provide important genetic markers to improve future genetic screening and drug discovery for intraocular pressure disorders.

Dielectric,magnetic and microwave absorbing properties of polyaniline-Co0.7Cr0.1Zn0.2Fe2O4 composites

The spinel cobalt chromium zinc ferrites（Co0.7Cr0.1Zn0.2Fe2O4） and the polyaniline（PANI）-Co0.7Cr0.1Zn0.2Fe2O4 composites were prepared by polyacrylamide gel and an in situ polymerization method,respectively.The structure of the synthesized material was characterized by X-ray diffraction（XRD） and Fourier transform infrared spectrometer（FTIR）,which shows that the spinel Co0.7Cr0.1Zn0.2Fe2O4 ferrites and the PANI Co0.7Cr0.1Zn0.2Fe2O4 composites are obtained.As a small amount of Co^2＋ in the octahedron ferrite is replaced by Cr^3＋,the lattice constant of Co0.8Cr0.2Zn0.2Fe2O4 ferrites reduces from0.8409 to 0.8377 nm.The magnetic properties of the two materials were investigated by vibrating sample magnetometer（VSM）.The VSM results confirm that the saturation magnetization（Ms）,remanent magnetization（Mr） and coercive force（Hc） of the PANI-Co0.7Cr0.1Zn0.2Fe2O4composites are 8.80 mA·m^2·g^-1,3.14 mA·m^2·g^-1 and37.22 kA·m^-1,respectively,which are smaller than those of the Co0.7Cr0.1Zn0.2Fe2O4 ferrites.The microwave absorbing capability of the two materials was studied by waveguide method.In the frequency range of 5-20 GHz,two reflection loss maximum values of the PANI-Co0.7Cr0.1Zn0.2Fe2O4 composites appear at 14.1 and 17.9 GHz with-13.17 and-15.36 dB,respectively,which are obviously higher than those of the Co0.7Cr0.1Zn0.2Fe2O4 ferrites.

新征税权对亚马逊公司在线商城商业模式的适用性探讨

近年来,亚马逊因利用在线商城商业模式进行远程跨境经营且极端避税,而被欧盟委员会调查。本文聚焦亚马逊在线商城商业模式的价值创造与价值实现过程,探讨"统一方法"新征税权对亚马逊在线商城商业模式的适用性,为我国更好应对数字经济税收挑战和完善数字经济税收治理提供借鉴。