Quality-adjusted time without symptoms or toxicity analysis of haploidentical-related donor vs.identical sibling donor hematopoietic stem cell transplantation in acute myeloid leukemia

Objective:We aimed to compare the quality-adjusted time without symptoms or toxicity(Q-TWiST)in acute myeloid leukemia(AML)patients who received haploidentical-related donor(HID)and identical sibling donor(ISD)hematopoietic stem cell transplantation(HSCT).Methods:Five clinical health states were defined:toxicity(TOX),acute graft-versus-host disease(GVHD),chronic GVHD(cGVHD),time without symptoms and toxicity(TWiST)and relapse(REL).The equation used in this study was as follows:Q-TWiST=UTOX×TOX+UTWiST×TWiST+UREL×REL+UaGVHD×aGVHD+UcGVHD×cGVHD.Results:A total of 239 AML patients were enrolled.We established a mathematical model,i.e.,Q-TWiST HID HSCT>Q-TWiST ISD HSCT,to explore the range of utility coefficients satisfying the inequality.Based on the raw data,the utility coefficient is equivalent to the following inequality:10.57067UTOX-46.27733UREL+105.9374+3.388078UaGVHD-210.8198UcGVHD>0.The model showed that when UTOX,UREL,and UaGVHD were within the range of 0-1,as well as when UcGVHD was within the range of 0-0.569,the inequality Q-TWiST HID HSCT>Q-TWiST ISD HSCT was valid.According to the results of the ChiCTR1800016972 study,the median coefficients of TOX,acute GVHD(aGVHD),and cGVHD were 0.56(0.41-0.76),0.56(0.47-0.72),and 0.54(0.37-0.79),respectively.We selected a series of specific examples of the coefficients,i.e.,UTOX=0.5,UREL=0.05,UaGVHD-0.5,and UcGVHD-0.5.The Q-TWiST values of ISD and HID HSCT were 896 and 900 d,respectively(P=0.470).Conclusions:We first observed that Q-TWiST was comparable between AML patients receiving HID HSCT and those receiving ISD HSCT.

An empirical model of the global distribution of plasmaspheric hiss based on Van Allen Probes EMFISIS measurements

Using wave measurements from the EMFISIS instrument onboard Van Allen Probes,we investigate statistically the spatial distributions of the intensity of plasmaspheric hiss waves.To reproduce these empirical results,we establish a fitting model that is a thirdorder polynomial function of L-shell,magnetic local time(MLT),magnetic latitude(MLAT),and AE*.Quantitative comparisons indicate that the model’s fitting functions can reflect favorably the major empirical features of the global distribution of hiss wave intensity,including substorm dependence and the MLT asymmetry.Our results therefore provide a useful analytic model that can be readily employed in future simulations of global radiation belt electron dynamics under the impact of plasmaspheric hiss waves in geospace.

A Morphological Classification Method of ECG ST-Segment Based on Curvature Scale Space

Aomalous changes in the ST segment, including ST level deviation and ST shape change, are the major parameters in clinical electrocardiogram (ECG) diagnosis of myocardial ischemia. Automatic detection of ST segment morphology can provide a more accurate evidence for clinical diagnosis of myocardial ischemia. In this paper, we proposed a method for classifying the shape of the ST-segment based on the curvature scale space (CSS) technique. First, we established a reference ST set and preprocessed the ECG signal by using the CSS technique. Then, the corner points in the ST-segment were detected at a high scale of the CSS and tracked through multiple lower scales, in order to improve its localization. Finally, the current beat of ST morphology can be distinguished by the corner points. We applied the developed algorithm to the ECG recordings in European ST-T database and QT database to validate the accuracy of the algorithm. The experimental results showed that the average detection accuracy of our algorithm was 91.60%. We could conclude that the proposed method is able to provide a new way for the automatic detection of myocardial ischemia.

Interferon-α salvage treatment is effective for patients with acute leukemia/myelodysplastic syndrome with unsatisfactory response to minimal residual disease-directed donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation

The efficacy of salvage interferon-α(IFN-α) treatment was investigated in patients with unsatisfactory response to minimal residual disease (MRD)-directed donor lymphocyte infusion (DLI)(n=24). Patients who did not become MRD-negative at 1 month after DLI were those with unsatisfactory response and were eligible to receive salvage IFN-α treatment within 3 months of DLI. Recombinant human IFN-α-2b injections were subcutaneously administered 2–3 times a week for 6 months. Nine (37.5%), 6 (25.0%), and 3 (12.5%) patients became MRD-negative at 1, 2, and>2 months after the salvage IFN-α treatment, respectively. Two-year cumulative incidences of relapse and non-relapse mortality were 35.9% and 8.3%, respectively. Two-year probabilities of event-free survival, disease-free survival, and overall survival were 51.6%, 54.3%, and 68.0%, respectively. Outcomes of patients subjected to salvage IFN-α treatment after DLI were significantly better than those with persistent MRD without IFN-α treatment. Moreover, clinical outcomes were comparable between the salvage DLI and IFN-α treatment groups. Thus, salvage IFN-α treatment may help improve the outcome of patients with unsatisfactory responses to MRD-directed DLI and could be a potential salvage treatment for these patients after allogeneic hematopoietic stem cell transplantation.

Reduced β2-GPI is associated with increased platelet aggregation and activation in patients with prolonged isolated thrombocytopenia after allo-HSCT

We aimed to measure platelet function and its relationship with β2-GPI in prolonged isolated thrombocytopenia(PT) after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Fifty-six patients with PT and 60 allo-HSCT recipients without PT(non-PT controls) were enrolled.Platelet aggregation and activation,β2-GPI and anti-β2-GPI antibody levels,vWF antigen,and vWF activity were analyzed.The effect of β2-GPI on platelet aggregation was also measured ex vivo.Results showed that ADP-induced platelet aggregation significantly increased(39%±7.5% vs.23%±8.5%,P=0.032),and the platelet expression of both CD62 p(33.6%±11.6% vs.8.5%±3.5%,P<0.001) and PAC-1(42.4%±7.6% vs.6.8%±2.2%,P<0.001) was significantly higher in patients with PT than in those without PT.Significantly lower β2-GPI levels(164.2±12 μg m L^-1 vs.234.2±16 μg mL^-1,P<0.001),higher anti-β2-GPI IgG levels(1.78±0.46 U mL^-1 vs.0.94±0.39 U mL^-1,P<0.001),and increased vWF activity(133.06%±30.50% vs.102.17%±25.90%,P<0.001) were observed in patients with PT than in those without PT.Both ADPinduced platelet aggregation(n=116,r^2=-0.5042,P<0.001) and vWF activity(n=116,r^2=-0.2872,P<0.001) were negatively correlated with β2-GPI levels.In summary,our data suggested that platelet aggregation and activation were significantly higher in patients with PT than in those without PT,which might be associated with reduced β2-GPI levels.The reduced β2-GPI levels might be due to the existence of anti-β2-GPI IgG.

Minimal residual disease-directed immunotherapy for high-risk myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation

The efficacy of minimal residual disease (MRD)-directed immunotherapy,including interferon-α (IFN-α) treatment and chemotherapy plus granulocyte colony-stimulating factor-primed donor leukocyte infusion (chemo-DLI),was investigated in patients with high-risk myelodysplastic syndrome (MDS) who were MRD-positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT).High-risk MDS patients who received non-T-cell-depleted allo-HSCT at the Peking University Institute of Hematology and were MRD-positive after ailo-HSCT were studied (n =47).The MRD-positive status was considered if leukemia-associated aberrant immune phenotypes or Wilms' tumor gene 1 expression is present in a single bone marrow sample.The cumulative incidence of the relapse and non-relapse mortality 2 years after immunotherapy were 14.5% and 21.4% (P=0.377)and 9.1% and 0.0% (P=0.985) for patients in the IFN-α and chemo-DLI groups,respectively.The probability of disease-free and overall survival 2 years after immunotherapy were 76.4% and 78.6% (P =0.891) and 84.3% and 84.6% (P=0.972) for patients in the IFN-α and chemo-DLI groups,respectively.Persistent MRD after immunotherapy was associated with poor survival.Thus,the MRD-directed immunotherapy was effective for patients with high-risk MDS who were MRD-positive after alIo-HSCT,and the efficacy was comparable between chemo-DLI and IFN-α treatment.

Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia

Chronic graft-versus-host disease(cGVHD)is a major complication following unmanipulated haploidentical hematopoietic stem cell transplantation(haplo-HSCT).We aimed to identify the risk factors for cGVHD in patients who underwent anti-thymocyte globulin-based haplo-HSCT for acute myeloid leukemia(n=280).The diagnosis of cGVHD was in accordance with the National Institutes of Health consensus criteria.A total of 169 patients suffered from cGVHD.The patients who had 3 loci mismatched had a higher 8-year incidence of cGVHD(total,66.0%vs.53.7%,P=0.031;moderate to severe,42.4%vs.30.1%,P=0.036)than the patients who had 1 to 2 loci mismatched.The patients who had maternal donors had a higher 8-year incidence of moderate to severe cGVHD(49.2%vs.32.9%,P=0.024)compared with the patients who had other donors.The patients who had grades III to IV acute GVHD(aGVHD)had higher 8-year incidence of cGVHD(total,88.0%vs.50.4%,P<0.001;moderate to severe,68.0%vs.27.0%,P<0.001)compared with the patients without aGVHD.In multivariate analysis,grades III to IV aGVHD was the only independent risk factor for cGVHD.Thus,further interventions should be considered in patients with severe aGVHD to prevent cGVHD.

Dynamics of the SARS-CoV-2 antibody response up to 10 months after infection

COVID-19 caused by SARS-CoV-2 infection has caused substantial morbidity and mortality worldwide and paralyzed the international economy.Understanding the magnitude and duration of the antibody response to SARS-CoV-2 is important to achieve a balance between curbing the pandemic and minimizing adverse effects on society.1 Although the antibody response to SARS-CoV-2 within 9 months has been extensively studied,2,3,4,5,6 little is known about the magnitude and kinetics of antibody responses for over 9 months.Moreover,with limited observations over 9 months(n<100),2,7,8 several studies have produced inconsistent conclusions about antibody dynamics,suggesting different rates of antiviral antibody positivity at the last follow-up.2,7,8 These studies have been limited by a lack of measurement of neutralizing antibodies(NAbs),7 of inclusion of mild or asymptomatic cases,2,8 and of further exploration of potential predisposing factors for antibody dynamics.2,7 Considering the individual heterogeneity(such as disease severity)8 and time-dependent nature1 of the immune response,in-depth characterization of SARS-CoV-2 antibody kinetics across disease severity groups over a long period is urgently needed.Therefore,we repeatedly tested IgM,IgG,viral spike protein receptor-binding dom(anti-RBD)IgG,and NAb titers in COVID-19 patients during a follow-up period of up to 10 months and explored potential predisposing factors of antibody titers during follow-up.

Neutralization against SARS-CoV-2 Delta/Omicron variants and B cell response after inactivated vaccination among COVID-19 convalescents

Emerging SARS-CoV-2 variants have made COVID-19 convalescents susceptible to re-infection and have raised concern about the efficacy of inactivated vaccination in neutralization against emerging variants and antigen-specific B cell response.To this end,a study on a long-term cohort of 208 participants who have recovered from COVID-19 was conducted,and the participants were followed up at 3.3(Visit 1),9.2(Visit 2),and 18.5(Visit 3)months after SARS-CoV-2 infection.They were classified into three groups(no-vaccination(n=54),one-dose(n=62),and two-dose(n=92)groups)on the basis of the administration of inactivated vaccination.The neutralizing antibody(NAb)titers against the wild-type virus continued to decrease in the no-vaccination group,but they rose significantly in the one-dose and two-dose groups,with the highest NAb titers being observed in the two-dose group at Visit 3.The NAb titers against the Delta variant for the no-vaccination,one-dose,and two-dose groups decreased by 3.3,1.9,and 2.3 folds relative to the wild-type virus,respectively,and those against the Omicron variant decreased by 7.0,4.0,and 3.8 folds,respectively.Similarly,the responses of SARS-CoV-2 RBD-specific B cells and memory B cells were boosted by the second vaccine dose.Results showed that the convalescents benefited from the administration of the inactivated vaccine(one or two doses),which enhanced neutralization against highly mutated SARS-CoV-2 variants and memory B cell responses.Two doses of inactivated vaccine among COVID-19 convalescents are therefore recommended for the prevention of the COVID-19 pandemic,and vaccination guidelines and policies need to be updated.

Risk stratification system for skin and soft tissue infections after allogeneic hematopoietic stem cell transplantation:PAH risk score

Skin and soft tissue infections(SSTIs)refer to infections involving the skin,subcutaneous tissue,fascia,and muscle.In transplant populations with hematological malignancies,an immunocompromised status and the routine use of immunosuppressants increase the risk of SSTIs greatly.However,to date,the profiles and clinical outcomes of SSTIs in hematopoietic stem cell transplantation(HSCT)patients remain unclear.This study included 228 patients(3.67%)who developed SSTIs within 180 days after allogeneic HSCT from January 2004 to December 2019 in Peking University People’s Hospital.The overall annual survival rate was 71.5%.We compared the differences between survivors and non-survivors a year after transplant and found that primary platelet graft failure(PPGF),comorbidities of acute kidney injury(AKI),and hospital-acquired pneumonia(HAP)were independent risk factors for death in the study population.A PPGF-AKI-HAP risk stratification system was established with a mortality risk score of 1×PPGF+1×AKI+1×HAP.The areas under the curves of internal and external validation were 0.833(95%CI 0.760–0.906)and 0.826(95%CI 0.715–0.937),respectively.The calibration plot revealed the high consistency of the estimated risks,and decision curve analysis showed considerable net benefits for patients.

Influence of the degree of donor bone marrow hyperplasia on patient clinical outcomes after allogeneic hematopoietic stem cell transplantation

This study evaluated the influence of the degree of donor bone marrow(BM)hyperplasia on patient clinical outcomes after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Twelve patients received allo-HSCT from hypoplastic BM donors between January 2010 and December 2017.Forty-eight patients whose donors demonstrated BM hyperplasia were selected using a propensity score matching method(1:4).Primary graft failure including poor graft function and graft rejection did not occur in two groups.In BM hypoplasia and hyperplasia groups,the cumulative incidence(CI)of neutrophil engraftment at day 28(91.7%vs.93.8%,P=0.75),platelet engraftment at day 150(83.3%vs.93.8%,P=0.48),the median time to myeloid engraftment(14 days vs.14 days,P=0.85)and platelet engraftment(14 days vs.14 days,P=0.85)were comparable.The 3-year progression-free survival,overall survival,CI of non-relapse mortality and relapse were 67.8%vs.71.7%(P=0.98),69.8%vs.77.8%(P=0.69),18.5%vs.13.6%(P=0.66),and 10.2%vs.10.4%(P=0.82),respectively.In multivariate analysis,donor BM hypoplasia did not affect patient clinical outcomes after allo-HSCT.If patients have no other suitable donor,a donor with BM hypoplasia can be used for patients receiving allo-HSCT if the donor Complete Blood Count and other examinations are normal.