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OP0079 A RANDOMIZED, DOUBLE-BLIND, PLACEBO-AND-TOCILIZUMAB CONTROLLED PHASE II TRIAL OF VDJ-001, A HIGH-AFFINITY IL-6R ANTAGONIST ANTIBODY, FOR THE TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS
Objectives:VDJ-001 is a novel humanized IgG1 monoclonal antibody designed to enhance the therapeutic index of Tocilizumab. Based on a random B-cell hyper-mutation and display technology, which mimics the native mechanism of antibody affinity maturation in vivo, VDJ-001 has been selected for its higher-affinity and more potent biological activities in comparison with Tocilizumab. The present study is to assess the comparative efficacy and safety of VDJ-001 in patients with rheumatoid arthritis following its pre-clinical and early clinical evaluation.Methods:In this double-blind, placebo and positive drug-controlled phase II study, 180 adult patients with moderate-to-severe active rheumatoid arthritis who had inadequate response to methotrexate (MTX) were randomly assigned to 4-treatment arms in 1:1:1:1 ratio, i.e., 4 mg/kg and 6 mg/kg of VDJ-001, 8 mg/kg of Tocilizumab, or placebo, i.v. q4w. All patients also received standard dose of methotrexate treatment. The primary endpoint was to compare the proportion of patients achieving ACR20 response at week 12; while secondary endpoint included the comparative analysis of patients achieving ACR50 and ACR70 responses at week 12 (NCT05957107, CTR20220613).Results:Both doses of VDJ-001 are safe and well-tolerated in 90 patients, most of them with low grade I-II of adverse reaction. Their safety profile is similar to Tocilizumab arm, which could be managed very well even during Covid-19 restriction period. In comparison with placebo arm (<60% responders), patients treated with both doses of VDJ-001 and Tocilizumab all reached a similar significant efficacy (p<0.05) on ACR20 response (>80% responders). Moreover, a clear trend on the potency ranking has been observed on ACR50/70 responders, i.e. VDJ-001 6mg/kg (64.3%) > Tocilizumab 8mg/kg (55.8%) > VDJ-001 4mg/kg (42.9%) > placebo (8.1%) for ACR50 responders; while VDJ-001 6mg/kg (33.3%) > Tocilizumab 8mg/kg (25.6%) > VDJ-001 4mg/kg (16.7%) > placebo (0%) for ACR70 response rates. There is a good correlation between pharmacokinetics and pharmacodynamics (sIL-6R) of VDJ-001 and Tocilizumab in a dose-dependent manner; while the disease biomarker change (ESR) is highly correlated with their corresponding efficacy.Conclusion:VDJ-001 is safe and effective in patients with rheumatoid arthritis. Its higher affinity and higher biological activity seem to be associated with the tendency of higher efficacy. The highly competitive rate (33.3%) on ACR70 response makes VDJ-001 6 mg/kg one of the best treatment options for RA patients.REFERENCES:NIL.Acknowledgements:Beijing VDJBio Co., Ltd.Disclosure of Interests:None declared.
Journal Article
Probability & statistics for engineers & scientists
This classic text provides a rigorous introduction to basic probability theory and statistical inference, illustrated by relevant applications. It assumes a background in calculus and offers a balance of theory and methodology.
Book
A peculiarly short-duration gamma-ray burst from massive star core collapse
Gamma-ray bursts (GRBs) have been phenomenologically classified into long and short populations based on the observed bimodal distribution of duration
1
. Multi-wavelength and multi-messenger observations in recent years have revealed that in general long GRBs originate from massive star core collapse events
2
, whereas short GRBs originate from binary neutron star mergers
3
. It has been known that the duration criterion is sometimes unreliable, and multi-wavelength criteria are needed to identify the physical origin of a particular GRB
4
. Some apparently long GRBs have been suggested to have a neutron star merger origin
5
, whereas some apparently short GRBs have been attributed to genuinely long GRBs
6
whose short, bright emission is slightly above the detector’s sensitivity threshold. Here, we report the comprehensive analysis of the multi-wavelength data of the short, bright GRB 200826A. Characterized by a sharp pulse, this burst shows a duration of 1 second and no evidence of an underlying longer-duration event. Its other observational properties such as its spectral behaviours, total energy and host galaxy offset are, however, inconsistent with those of other short GRBs believed to originate from binary neutron star mergers. Rather, these properties resemble those of long GRBs. This burst confirms the existence of short-duration GRBs with stellar core-collapse origin
4
, and presents some challenges to the existing models.
A gamma-ray burst (GRB) is reported to show a sharp 1-second spike, characteristic of short GRBs, but with other observational properties resembling those of long GRBs. This burst may belong to a class of core-collapse-origin GRBs with genuinely short durations.
Journal Article
It’s time to re-examine medical professionalism in medical education
[...]behaviours that serve to buy extra time for the individual—such as avoiding responsibilities or finding ways to leave work early—seem to be increasingly prevalent among some.3 These concerning values and behaviours have gained considerable traction among medical students and residents. Developing a more inclusive and adaptable definition of medical professionalism The definition of MP, endorsed by over 100 national professional societies worldwide, was proposed by the American Board of Internal Medicine in 2002.4The Canadian Medical Education Directives for Specialists, the Accreditation Council for Graduate Medical Education, and the General Medical Council have proposed definitions of MP that are relatively well-recognised.5 A common limitation of these definitions is that they either focus on values with specific social and cultural contexts or concentrate on competencies related to clinical tasks.5 Consequently, they lack a comprehensive framework with broad inclusivity and adaptability. [...]I propose a more inclusive and adaptable definition of MP, structured as a comprehensive framework comprising two principal modules: a set of ethical values and adaptive clinical capabilities. [...]each country could establish its own ethical values for MP.6 7 8 Second, it is important to consider the impact of technological advances and civilisational developments when examining the evolution of clinical competence. [...]it would help all stakeholders—including policymakers, educators, students, physicians, and patients—better understand and agree on the concept of MP. Applying interdisciplinary theory to address the hidden curriculum's limitations in reproducibility and assessability In MP training, a substantial proportion of learning occurs within the hidden curriculum.9 Despite educational research confirming its influence on the values and behaviours of trainees during clinical training, the hidden curriculum is highly variable, shaped by interactions among educators, staff, and trainees.9 Consequently, the hidden curriculum is neither replicable nor can its effects be accurately assessed. [...]MP, as the cornerstone of physicians' ability to fulfil their commitments to society and patients, cannot be overemphasised.
Journal Article
Transition of dislocation nucleation induced by local stress concentration in nanotwinned copper
Metals with a high density of nanometre-scale twins have demonstrated simultaneous high strength and good ductility, attributed to the interaction between lattice dislocations and twin boundaries. Maximum strength was observed at a critical twin lamella spacing (∼15 nm) by mechanical testing; hence, an explanation of how twin lamella spacing influences dislocation behaviours is desired. Here, we report a transition of dislocation nucleation from steps on the twin boundaries to twin boundary/grain boundary junctions at a critical twin lamella spacing (12–37 nm), observed with
in situ
transmission electron microscopy. The local stress concentrations vary significantly with twin lamella spacing, thus resulting in a critical twin lamella spacing (∼18 nm) for the transition of dislocation nucleation. This agrees quantitatively with the mechanical test. These results demonstrate that by quantitatively analysing local stress concentrations, a direct relationship can be resolved between the microscopic dislocation activities and macroscopic mechanical properties of nanotwinned metals.
Metallic materials with a nanometre-scaled lamella structure can have properties that are very different from their coarser-grained counterparts. Here, the authors demonstrate how dislocations in such a material—nanotwinned copper—can nucleate in two distinctly different mechanisms depending on local stress
Journal Article
The Relative Importance of Innate Immune Priming in Wolbachia-Mediated Dengue Interference
The non-virulent Wolbachia strain wMel and the life-shortening strain wMelPop-CLA, both originally from Drosophila melanogaster, have been stably introduced into the mosquito vector of dengue fever, Aedes aegypti. Each of these Wolbachia strains interferes with viral pathogenicity and/or dissemination in both their natural Drosophila host and in their new mosquito host, and it has been suggested that this virus interference may be due to host immune priming by Wolbachia. In order to identify aspects of the mosquito immune response that might underpin virus interference, we used whole-genome microarrays to analyse the transcriptional response of A. aegypti to the wMel and wMelPop-CLA Wolbachia strains. While wMel affected the transcription of far fewer host genes than wMelPop-CLA, both strains activated the expression of some immune genes including anti-microbial peptides, Toll pathway genes and genes involved in melanization. Because the induction of these immune genes might be associated with the very recent introduction of Wolbachia into the mosquito, we also examined the same Wolbachia strains in their original host D. melanogaster. First we demonstrated that when dengue viruses were injected into D. melanogaster, virus accumulation was significantly reduced in the presence of Wolbachia, just as in A. aegypti. Second, when we carried out transcriptional analyses of the same immune genes up-regulated in the new heterologous mosquito host in response to Wolbachia we found no over-expression of these genes in D. melanogaster, infected with either wMel or wMelPop. These results reinforce the idea that the fundamental mechanism involved in viral interference in Drosophila and Aedes is not dependent on the up-regulation of the immune effectors examined, although it cannot be excluded that immune priming in the heterologous mosquito host might enhance the virus interference trait.
Journal Article
Malnutrition Prolongs the Hospitalization of Patients with COVID-19 Infection: A Clinical Epidemiological Analysis
During the 2019 Coronavirus disease (COVID-19) outbreak, malnutrition may contribute to COVID-19 adverse outcomes. We conducted a clinical epidemiological analysis to investigate the association of malnutrition with hospitalized duration in patients with COVID-19.
Retrospective survey study.
Taikang Tongji (Wuhan) hospital in Wuhan, China.
139 patients with COVID-19.
In total, 139 patients with COVID-19 from patients in the Infection Department of Taikang Tongji (Wuhan) hospital from February 2020 to April 2020 were analyzed retrospectively. We used the “Global leadership Initiative on Malnutrition(GLIM)” assessment standard published in 2019 to assess nutritional status. Prolonged hospitalization was lasting more than the median value of the hospitalized days (17 days) in this population.
According to the assessment results of GLIM nutrition assessment, the patients were divided into malnutrition group and normal nutrition group. Compared with the patients in the normal nutrition group, the hospitalization time was longer(15.67±6.26 days versus 27.48±5.04 days, P = 0.001). Kaplan-Meier analysis showed patients with malnutrition were more likely to be hospitalized longer compared with those normal nutrition (mean with 95% confidence interval [CI]: 28.91[27.52–30.30] versus 22.78[21.76–23.79], P = 0.001). COX regression analysis showed that malnutrition (hazard ratio [HR] = 3.773, P for trend = 0.001) was proportional associated with being discharged from hospital delayed.
Present findings suggested that malnutrition contributed to predicting a probability of prolonged hospitalization in patients with COVID-19 infection, to whom extra attentions and precautions should be paid during clinical treatments. Based on the existing results, it is recommended that inpatients with nutritional risk or malnutrition start nutritional support treatment as soon as possible.
Journal Article
The human Vδ2+ T-cell compartment comprises distinct innate-like Vγ9+ and adaptive Vγ9- subsets
Vδ2
+
T cells form the predominant human γδ T-cell population in peripheral blood and mediate T-cell receptor (TCR)-dependent anti-microbial and anti-tumour immunity. Here we show that the Vδ2
+
compartment comprises both innate-like and adaptive subsets. Vγ9
+
Vδ2
+
T cells display semi-invariant TCR repertoires, featuring public Vγ9 TCR sequences equivalent in cord and adult blood. By contrast, we also identify a separate, Vγ9
−
Vδ2
+
T-cell subset that typically has a CD27
hi
CCR7
+
CD28
+
IL-7Rα
+
naive-like phenotype and a diverse TCR repertoire, however in response to viral infection, undergoes clonal expansion and differentiation to a CD27
lo
CD45RA
+
CX
3
CR1
+
granzymeA/B
+
effector phenotype. Consistent with a function in solid tissue immunosurveillance, we detect human intrahepatic Vγ9
−
Vδ2
+
T cells featuring dominant clonal expansions and an effector phenotype. These findings redefine human γδ T-cell subsets by delineating the Vδ2
+
T-cell compartment into innate-like (Vγ9
+
) and adaptive (Vγ9
−
) subsets, which have distinct functions in microbial immunosurveillance.
Human Vδ2
+
γδ T cells are thought to be an innate-like T-cell population. Here the authors show the Vδ2
+
compartment contains both innate-like Vγ9
+
and an adaptive Vγ9
-
subset that undergoes clonal expansion during viral infection and can infiltrate liver tissue.
Journal Article