Correlation between the Human Development Index and the Incidence and Mortality of Non-Hodgkin Lymphoma.

OBJECTIVE: This study was to examine the relationship between socioeconomic status and the incidence and mortality of non-Hodgkin lymphoma (NHL). METHODS: We compared the age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and the ASMR to ASIR ratio (MIR) at national and regional levels and studied the correlation between the MIR and the human development index (HDI) in 2012 and 2018. RESULTS: The highest ASIR was in North America in 2012 and in Australia in 2018, and the lowest ASIR was in Central and South Asia in both 2012 and 2018. The highest ASMR was in North Africa in both 2012 and 2018, and the lowest ASMR was in Eastern Asia and South-Central Asia in 2012 and in South-Central Asia in 2018. The lowest MIR was in Australia in both 2012 and 2018, and the highest MIR was in Western Africa in both 2012 and 2018. HDI was strongly negatively correlated with MIR (r: -0.8810, P<0.0001, 2012; r: -0.8895, P<0.0001, 2018). Compared to the 2012 data, the MIR in the intermediate HDI countries significantly deceased and the HDI in low and high HDI countries significantly increased in 2018. CONCLUSION: The MIR is negatively correlated with HDI. Increasing the HDI in low and intermediate HDI countries may reduce the MIR and increase the survival of patients with NHL.

Power mapping-based stability analysis and order adjustment control for fractional-order multiple delayed systems.

This article investigates the asymptotic stability of a general class of fractional-order multiple delayed systems to evaluate the delay robustness. We establish a one-to-one spectral connection between the original fractional-order system and the transformed one under the power mapping. The applicability of the Cluster Treatment of Characteristic Roots paradigm to the transformed dynamics is proved by this connection. Then, we utilize the Dixon resultant-based frequency sweeping framework to create the complete stability map. The results demonstrate that the order adjustment control significantly enhances the control flexibility and brings unlimited possibilities for the improvement of the delay robustness. Finally, we inspect the stability preservation problem when using the integer-order approximations for practical implementation.

Multiple assessments of non-inferiority trials with ordinal endpoints.

Non-inferiority (NI) trials are implemented when there is a practical demand to search for alternatives to standard therapies, such as to reduce side effects. An experimental treatment is considered non-inferior to the standard treatment when it exhibits clinically non-significant loss of efficacy. Ordinal categorical responses are frequently observed in clinical trials. It has been reported that responses measured using an ordinal scale produce more informative analysis than when responses collapse into binary outcomes. We study the NI trials using ordinal endpoints. We propose a latent variable model for ordinal categorical responses. Based on the proposed latent variable model, the mean efficacy of the different treatments is denoted by the corresponding mean parameter of the underlying continuous distributions. A two-step procedure is proposed for model identification and parameter estimation. A non-inferiority analysis can then be conducted based on the latent variable model and the corresponding estimation procedure. We also develop a method and an algorithm to produce an optimal sample size configuration based on the proposed testing procedure. Two clinical examples are provided for demonstrative purposes.

Modified Dynamic Movement Primitives: Robot Trajectory Planning and Force Control Under Curved Surface Constraints.

Dynamic movement primitives (DMPs) have been widely applied in robot motion planning and control. However, in some special cases, original discrete DMP fails to generalize proper trajectories. Moreover, it is difficult to produce trajectories on the curved surface. To solve the above problems, a modified DMP method is proposed for robot control by adding the scaling factor and force coupling term. First, the adjusted cosine similarity is defined to assess the similarity of the generalized trajectory with respect to the demonstrated trajectory. By optimizing the similarity, the trajectories can be generated in all situations. Next, by adding the force coupling term derived from adaptive admittance control to the transformation system of the original DMP, the controller achieves the force control ability. Then, the modified DMP-based robot control system is developed. The stability and convergence of the system are proved. Finally, the high precisions of the proposed method are verified by simulations and experiments. The method is significant for trajectory learning and generalization on the curved surface.

Dose-individualization Efficiently Maintains Sufficient Exposure to Methotrexate without Additional Toxicity in High-dose Methotrexate Regimens for Pediatric Acute Lymphoblastic Leukemia.

OBJECTIVE: Methotrexate (MTX) can be safely administered to most patients but may cause severe toxicity in others. This study aimed to summarize the characteristics of high-dose methotrexate (HD-MTX) chemotherapy and to evaluate whether the modified dose-adjustment program was able to improve the maintenance of sufficient MTX exposure levels while minimizing toxicities. METHODS: We evaluated 1172 cycles of high-dose MTX chemotherapy from 294 patients who were treated according to the CCCG-ALL-2015 protocol (clinical trial number: ChiCTR-IPR-14005706) and analyzed the data of actual MTX dosage, MTX concentration, toxicity, and prognosis. We compared data between the dose-adjustment Program 1 (fixed 20% reduction in dose) and the dose-adjustment Program 2 (dose-individualization based on reassessment of the creatine clearance rate and the MTX concentration-monitoring point at 16 h), which were applied if the MTX clearance was delayed in the previous cycle. RESULTS: The patients who used Program 2 had higher actual MTX infusion doses and infusion rates and were able to better maintain the MTX concentration at 44 h at the established target value than those on Program 1 (P<0.001). No significant differences in toxicities were found between these two programs except that abnormal serum potassium levels and prolonged myelosuppression in intermediate-risk/high-risk patients were more frequently observed in patients using Program 2 (P<0.001). No significant correlations were observed between the MTX dose, dose-adjustment programs, or MTX concentrations and relapse-free survival. CONCLUSION: Adjusting the MTX dose using Program 2 is more efficient for maintaining sufficient MTX exposure without significantly increasing the toxicity.

A De Novo Mutation in MYH9 in a Child With Severe and Prolonged Macrothrombocytopenia.

Congenital macrothrombocytopenia is a diverse group of hereditary disorders caused by mutations in the MYH9 gene, which encodes the nonmuscle myosin heavy chain-A, an important motor protein in hemopoietic cells. Thus, the term MYH9-related disease has been proposed, but the clinicopathologic basis of MYH9 mutations has been poorly investigated. Here, we report a sporadic case of Epstein syndrome, an MYH9 disorder, in a 4-year-old Chinese boy who presented with macrothrombocytopenia. He had no family history of thrombocytopenia, hearing loss, or renal failure. A de novo heterozygous MYH9 mutation, c.287C>T; p. (Ser96Leu), was found in this patient. Genotype-phenotype analysis of all reported mutations suggested a domain-specific relationship between the location of the MYH9 mutation and the penetrance of the nonhematologic characteristics of MYH9-related disorders. Our study highlights the importance of suspecting MYH9-related disease even in cases of chronic macrothrombocytopenia without a family history or extrahematologic symptoms.

CSF-1R inhibition disrupts the dialog between leukaemia cells and macrophages and delays leukaemia progression.

Research in the last few years has revealed that leukaemic cells can remodel the bone marrow niche into a permissive environment favouring leukaemic stem cell expansion. Tumour-associated macrophages (TAMs) are prominent components of the tumour microenvironment and play an important role in the onset and progression of solid tumours. However, little is known about their role in the development of acute lymphoblastic leukaemia (ALL). Using a unique mouse model of T-ALL induced by injection of EL4 T-cell lymphoma cells to syngeneic C57BL/6 mice, we report herein that ALL leads to the invasion of leukaemia-associated monocyte-derived cells (LAMs) into the bone marrow and spleen of T-ALL mice. Furthermore, we found that leukaemia cells could polarize bone marrow-derived macrophages (BMDMs) into LAMs. In turn, LAMs were able to protect leukaemia cells from drug-induced apoptosis in vitro. Therapies targeted against the TAMs by inhibiting colony stimulating factor-1 receptor (CSF-1R) have emerged as a promising approach for cancer treatment. In this study, we demonstrate that CSF-1R inhibition inhibits the viability of BMDMs, blocks LAMs polarization and reduces the abundance of LAMs in T-ALL mice. In vivo, combination treatment of CSF-1R inhibitor and vincristine (VCR) dramatically increased the survival of T-ALL mice and delayed leukaemia progression compared with VCR monotherapy. Finally, these data reinforce the role of microenvironments in leukaemia and suggest that macrophages are a potential target for the development of novel therapeutic strategies in T-ALL.

Huai Qi Huang-induced Apoptosis via Down-regulating PRKCH and Inhibiting RAF/MEK/ERK Pathway in Ph+ Leukemia Cells.

Imatinib mesylate (IM) is the first-line treatment for Philadelphia (Ph) chromosomal positive leukemia by inhibiting phosphorylation of substrates via binding to the ABL kinase domain. Because of the drug resistance, side effects and the high cost of IM, it is necessary to find anti-cancer drugs with relatively low toxicity and cost, and enhanced efficacy, such as traditional Chinese medicines (TCMs). As one of TCMs, Huai Qi Huang (HQH) was chosen to treat BV173 and K562 cells. Various concentrations of HQH were added to cells for 24-72 h. Co-treatment of HQH and trametinib, an MEK inhibitor, was used to verify the synergistic effects on cell viability and apoptosis. Knockdown and overexpression of mitogen-activated protein kinase kinase 4 (MEK4) were implemented to demonstrate the role of MEK in cell apoptosis. Cell viability and apoptosis were measured by cell counting kit-8 assay (CCK8) and flow cytometry, respectively. Western blotting and real-time quantitative PCR (RT-qPCR) were used to assess protein and mRNA expression levels, respectively. The results showed that HQH inhibited survival and promoted apoptosis of BV173 and K562 cells in a dose-dependent manner, accompanied with down-regulation of PRKCH mRNA as well as CRAF, MEK4, phospho-ERK (pERK) and BCL2 proteins, and up-regulation of cleaved caspase3 protein. Co-treatment of HQH and trametinib had a synergistic effect on inhibiting survival and promoting apoptosis. MEK4 knockdown increased apoptosis, and had a synergistic effect with HQH. In contrast, MEK4 overexpression decreased apoptosis, and had the opposite effect with HQH. Collectively, the results of this study may identify a therapeutic mechanism of HQH on promoting apoptosis, and provide a potential option for treatment of Ph+ leukemia.

Huai Qi Huang Potentiates Dexamethasone-Mediated Lethality in Acute Lymphoblastic Leukemia Cells by Upregulating Glucocorticoid Receptor α.

BACKGROUND Glucocorticoids are important components of a number of chemotherapeutic regimens used to treat pediatric acute lymphoblastic leukemia (ALL). A primary cause of treatment failure of ALL is acquired resistance to glucocorticoids. Recently, traditional Chinese medicines were effectively used to treat solid tumors. Thus, the aim of this study was to investigate whether Huai Qi Huang (HQH), a traditional Chinese medicine, increased the efficacy of glucocorticoids in the treatment of ALL, and if so, to determine the underlying mechanism. MATERIAL AND METHODS Various concentrations of HQH were used to treat Jurkat and Nalm-6 cells for 24 to 72 hours. Subsequently, cells were co-treated with HQH and the glucocorticoid receptor agonist, dexamethasone (DEX), or a MEK inhibitor (PD98059) to verify the synergistic effects on apoptosis in Jurkat and Nalm-6 cells for 24 hours. Cell Counting Kit-8 assay and flow cytometry were used to measure cell viability and apoptosis, respectively. Protein and mRNA expression levels were assessed using western blotting and quantitative polymerase chain reaction. RESULTS The results revealed that cell survival was reduced and apoptosis was increased as the HQH concentration was increased, and this was accompanied with increases in the levels of BAX, cleaved-caspase-3 and glucocorticoid receptor alpha (GRalpha) and decreases in the levels of Bcl-2 and phospho-ERK (pERK). Glucocorticoid receptor ß (GRß) and total ERK (t-ERK) had no significant changes. Combined treatment with HQH and DEX or PD98059 increased apoptosis in Jurkat and Nalm-6 cells, and concurrently increased BAX, cleaved-caspase-3, GILZ, NFKBIA, and GRalpha and decreased Bcl-2 and pERK. CONCLUSIONS HQH enhanced the sensitivity of ALL cells to glucocorticoids by increasing the expression of GRalpha and inhibiting the MEK/ERK pathway, thus providing a rational foundation for the treatment of ALL with HQH.

Adaptive Designs for Non-inferiority Trials with Multiple Experimental Treatments.

The increase in the popularity of non-inferiority clinical trials represents the increasing need to search for substitutes for some reference (standard) treatments. A new treatment would be preferred to the standard treatment if the benefits of adopting it outweigh a possible clinically insignificant reduction in treatment efficacy (non-inferiority margin). Statistical procedures have recently been developed for treatment comparisons in non-inferiority clinical trials that have multiple experimental (new) treatments. An ethical concern for non-inferiority trials is that some patients undergo the less effective treatments; this problem is more serious when multiple experimental treatments are included in a balanced trial in which the sample sizes are the same for all experimental treatments. With the aim of giving fewer patients the inferior treatments, we propose a response-adaptive treatment allocation scheme that is based on the doubly adaptive biased coin design. The proposed adaptive design is also shown to be superior to the balanced design in terms of testing power.

Kinematic analysis and fault-tolerant trajectory planning of space manipulator under a single joint failure.

A space manipulator plays an important role in spacecraft capturing, repairing, maintenance, and so on. However, the harsh space environment will cause its joints fail to work. For a non-redundant manipulator, single joint locked failure will cause it to lose one degree of freedom (DOF), hence reducing its movement ability. In this paper, the key problems related to the fault-tolerant including kinematics, workspace, and trajectory planning of a non-redundant space manipulator under single joint failure are handled. First, the analytical inverse kinematics equations are derived for the 5-DOF manipulator formed by locking the failure joint of the original 6-DOF manipulator. Then, the reachable end-effector pose (position and orientation) is determined. Further, we define the missions can be completed by the 5-DOF manipulator. According to the constraints of the on-orbital mission, we determine the grasp envelope required for the end-effector. Combining the manipulability of the manipulator and the performance of its end-effector, a fault tolerance parameter is defined and a planning method is proposed to generate the reasonable trajectory, based on which the 5-DOF manipulator can complete the desired tasks. Finally, typical cases are simulated and the simulation results verify the proposed method.

[Clinical safety studies based on 30 026 post-marketing cases of Shenqi Fuzheng injection by intensive hospital monitoring nested NCCS].

This study adopted a large sample, multicenter, registered hospital centralized monitoring nested prospective case-control study design. From the real world clinical application of Shenqi Fuzheng injection, monitored 30 026 cases of patients with the use of Shenqi Fuzheng injection. A total of 51 adverse drug reaction (ADR) cases was monitored, including 1 case of severe adverse reactions. ADR incidence rate was 1.7 per 1,000. Blood samples were collected from patients with allergic reactions and their matched controls. Related biological indicators of allergic reactions were unified detected and analysed in order to explore the mechanism of allergic reaction and promote the clinical safety.