Gene expression prognostic of early relapse risk in low-risk B-cell acute lymphoblastic leukaemia in children.

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukaemia (ALL) and is associated with favorable outcomes, especially in low-risk children. However, as many as 10% of children relapse within 3 years, and such early relapses have poor survival. Identifying children at risk for early relapse is an important challenge. We interrogated data from 87 children with low-risk ETV6::RUNX1-positive B-cell ALL and with available preserved bone marrow samples (discovery cohort). We profiled somatic point mutations in a panel of 559 genes and genome-wide transcriptome and single-nucleotide variants. We found high TIMD4 expression (> 85th-percentile value) at diagnosis was the most important independent prognostic factor of early relapse (hazard ratio [HR] = 5.07 [1.76, 14.62]; p = 0.03). In an independent validation cohort of low-risk ETV6::RUNX1-positive B-cell ALL (N = 68) high TIMD4 expression at diagnosis had an HR = 4.78 [1.07, 21.36] (p = 0.04) for early relapse. In another validation cohort including 78 children with low-risk ETV6::RUNX1-negative B-cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 [1.31, 11.79] (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low-risk B-cell ALL in children might be associated with high risk for early relapse.

Refining eligibility criteria of unit selection for myeloablative cord blood transplantation in acute leukemia: Real-world experience of a referral center.

The algorithm for cord blood (CB) unit selection is still somewhat ambiguous. We retrospectively analyzed 620 cases of acute leukemia between 2015 and 2020, who were treated with myeloablative single-unit umbilical CB transplantation (UCBT). We found that, when human leukocyte antigen (HLA) mismatch was ≤3/10, CD34+ cell dosage <0.83 × 105/kg-considerably lower than prevalent guidelines-was permissible without affecting survival. Moreover, synergy between donor killer-cell immunoglobulin-like receptors (KIR) haplotypes-B and donor-recipient HLA-C mismatch protected against relapse-related mortality. We submit that minimum required CD34+ cell dosage can possibly be relaxed to broaden access to UCBT, and donor KIR genotyping should be considered during unit selection.

The Composite Immune Risk Score predicts overall survival after allogeneic hematopoietic stem cell transplantation: A retrospective analysis of 1838 cases.

There has been little consensus on how to quantitatively assess immune reconstitution after hematopoietic stem cell transplantation (HSCT) as part of the standard of care. We retrospectively analyzed 11 150 post-transplant immune profiles of 1945 patients who underwent HSCT between 2012 and 2020. 1838 (94.5%) of the cases were allogeneic HSCT. Using the training set of patients (n = 729), we identified a composite immune signature (integrating neutrophil, total lymphocyte, natural killer, total T, CD4+ T, and B cell counts in the peripheral blood) during days 91-180 after allogeneic HSCT that was predictive of early mortality and moreover simplified it into a formula for a Composite Immune Risk Score. When we verified the Composite Immune Risk Score in the validation (n = 284) and test (n = 391) sets of patients, a high score value was found to be associated with hazard ratios (HR) of 3.64 (95% C.I. 1.55-8.51; p = .0014) and 2.44 (95% C.I., 1.22-4.87; p = .0087), respectively, for early mortality. In multivariate analysis, a high Composite Immune Risk Score during days 91-180 remained an independent risk factor for early mortality after allogeneic HSCT (HR, 1.80; 95% C.I., 1.28-2.55; p = .00085). In conclusion, the Composite Immune Risk Score is easy to compute and could identify the high-risk patients of allogeneic HSCT who require targeted effort for prevention and control of infection.

'Dynamic zero-COVID' policy and viral clearance during an omicron wave in Tianjin, China: a city-wide retrospective observational study.

OBJECTIVE: To report how the Chinese mainland battled its first omicron wave, which happened in Tianjin, a metropolis with 14 million residents. We also sought to better understand how clinical features affected the timing of viral clearance. DESIGN: A retrospective study of the omicron wave in Tianjin between 8 January 2022 and 3 March 2022. SETTING: Except for the first cases on 8 January, all the omicron cases were identified through PCR mass testing in the residential communities. Residential quarantine and serial PCR mass testing were dynamically adjusted according to the trends of new cases. PARTICIPANTS: All the 417 consecutive PCR-positive cases identified through mass screening of the entire city's 14 million residents. 45.3% of the cases were male, and the median age was 37 (range 0.3-90). 389 (93%) cases had complete data for analysing the correlation between clinical features and the timing of viral clearance. MAIN OUTCOME AND MEASURE: Time to viral clearance. RESULTS: Tianjin initiated the 'dynamic zero-COVID' policy very early, that is, when daily new case number was ≈0.4 cases per 1 000 000 residents. Daily new cases dropped to <5 after 3 February, and the number of affected residential subdivisions dropped to ≤2 after 13 February. 64% (267/417) of the cases had no or mild symptoms. The median interval from hospital admission to viral clearance was 10 days (range 3-28). An exploratory analysis identified a feature cluster associated with earlier viral clearance, with HRs of 3.56 (95% CI 1.66 to 7.63) and 3.15 (95% CI 1.68 to 5.91) in the training and validation sets, respectively. CONCLUSIONS: The 'dynamic zero-COVID' policy can suppress an omicron wave within a month. It might be possible to predict in advance which cases will require shorter periods of isolation based on their clinical features.

[Prevalence and risk factors of obesity in children with Diamond-Blackfan anemia]. / å ˆå¤©æ€§çº¯çº¢ç»†èƒžå†ç”Ÿéšœç¢æ€§è´«è¡€æ‚£å„¿è‚¥èƒ–å‘ç”Ÿæƒ å†µåŠå½±å“å› ç´ åˆ†æž.

OBJECTIVES: To investigate the distribution of body mass index (BMI) and risk factors for obesity in children with Diamond-Blackfan Anemia (DBA). METHODS: The children with DBA who attended National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, from January 2003 to December 2020 were enrolled as subjects. The related clinical data and treatment regimens were recorded. The height and weight data measured within 1 week before or after follow-up time points were collected to calculate BMI. The risk factors for obesity were determined by multivariate regression analysis in children with DBA. RESULTS: A total of 129 children with DBA were enrolled, among whom there were 80 boys (62.0%) and 49 girls (38.0%), with a median age of 49 months (range 3-189 months). The prevalence rate of obesity was 14.7% (19/129). The multivariate logistic regression analysis showed that the absence of ribosomal protein gene mutation was closely associated with obesity in children with DBA (adjusted OR=3.63, 95%CI: 1.16-11.38, adjusted P=0.027). In children with glucocorticoid-dependent DBA, obesity was not associated with age of initiation of glucocorticoid therapy, duration of glucocorticoid therapy, and maintenance dose of glucocorticoids (P>0.05). CONCLUSIONS: There is a high prevalence rate of obesity in children with DBA, and the absence of ribosomal protein gene mutation is closely associated with obesity in children with DBA.

Development and validation of a prognostic scoring model to risk stratify childhood acute myeloid leukaemia.

To create a personal prognostic model and modify the risk stratification of paediatric acute myeloid leukaemia, we downloaded the clinical data of 597 patients from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database as a training set and included 189 patients from our centre as a validation set. In the training set, age at diagnosis, -7/del(7q) or -5/del(5q), core binding factor fusion genes, FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)/nucleophosmin 1 (NPM1) status, Wilms tumour 1 (WT1) mutation, biallelic CCAAT enhancer binding protein alpha (CEBPA) mutation were strongly correlated with overall survival and included to construct the model. The prognostic model demonstrated excellent discriminative ability with the Harrell's concordance index of 0.68, 3- and 5-year area under the receiver operating characteristic curve of 0.71 and 0.72 respectively. The model was validated in the validation set and outperformed existing prognostic systems. Additionally, patients were stratified into three risk groups (low, intermediate and high risk) with significantly distinct prognosis, and the model successfully identified candidates for haematopoietic stem cell transplantation. The newly developed prognostic model showed robust ability and utility in survival prediction and risk stratification, which could be helpful in modifying treatment selection in clinical routine.

Significance of paroxysmal nocturnal hemoglobinuria clone in immunosuppressive therapy for children with severe aplastic anemia. / é˜µå‘æ€§ç¡çœ æ€§è¡€çº¢è›‹ç™½å°¿å ‹éš†åœ¨å„¿ç«¥é‡åž‹å†ç”Ÿéšœç¢æ€§è´«è¡€å ç–«æŠ‘åˆ¶æ²»ç–—ä¸­çš„æ„ä¹‰.

OBJECTIVES: To study the association between paroxysmal nocturnal hemoglobinuria (PNH) clone and immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA). METHODS: A retrospective analysis was performed on the medical data of 151 children with SAA who were admitted and received IST from January 2012 to May 2020. According to the status of PNH clone, these children were divided into a negative PNH clone group (n=135) and a positive PNH clone group (n=16). Propensity score matching was used to balance the confounding factors, and the impact of PNH clone on the therapeutic effect of IST was analyzed. RESULTS: The children with positive PNH clone accounted for 10.6% (16/151), and the median granulocyte clone size was 1.8%. The children with positive PNH clone had an older age and a higher reticulocyte count at diagnosis (P<0.05). After propensity score matching, there were no significant differences in baseline features between the negative PNH clone and positive PNH clone groups (P>0.05). The positive PNH clone group had a significantly lower overall response rate than the negative PNH clone group at 6, 12, and 24 months after IST (P<0.05). The evolution of PNH clone was heterogeneous after IST, and the children with PNH clone showed an increase in the 3-year cumulative incidence rate of aplastic anemia-PNH syndrome (P<0.05). CONCLUSIONS: SAA children with positive PNH clone at diagnosis tend to have poor response to IST and are more likely to develop aplastic anemia-PNH syndrome.

Short Stature in Patients with Diamond-Blackfan Anemia: A Cross-Sectional Study.

OBJECTIVE: To systematically describe the short stature of patients with Diamond-Blackfan anemia and to explore factors affecting the height development of patients with Diamond-Blackfan anemia. STUDY DESIGN: This cross-sectional study was conducted at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and the height, weight, and clinical data of 129 patients with Diamond-Blackfan anemia were collected from June 2020 to September 2020. RESULTS: The median height-age-z score (HAZ) of children affected by Diamond-Blackfan anemia was -1.54 (-6.36-1.96). Short stature was found in 37.98% of the patients. Specific Diamond-Blackfan anemia growth curves were developed for weight, height, and body mass index, separately for male and female patients. Multivariable logistic regression models showed that female sex (aOR 4.92; 95% CI 1.29-18.71; P = .0195), underweight (aOR 10.41, 95% CI 1.41-76.98, P = .0217), cardiovascular malformations (aOR 216.65; 95% CI 3.29-14279.79; P = .0118), and RPL11(aOR 29.14; 95% CI 1.18-719.10; P = .0392) or RPS26 (aOR 53.49; 95% CI 1.40-2044.30; P = .0323) mutations were independent risk factors for short stature. In the subgroup of patients who were steroid-dependent, patients with a duration of steroid therapy over 2 years (OR 2.95; 95% CI 1.00-8.66; P = .0494) or maintenance dose of prednisone >0.1 mg/kg per day (OR 3.30; 95% CI 1.02-10.72; P = .0470) had a higher incidence of short stature. CONCLUSIONS: Patients with Diamond-Blackfan anemia had a high prevalence of short stature. The risk of short stature increased with age and was associated with sex, underweight, congenital malformations, and RPL11 or RPS26 mutations. The duration of steroid therapy and maintenance dose of steroid was significantly associated with the incidence of short stature in steroid-dependent patients with Diamond-Blackfan anemia.

A Phenogenetic Axis that Modulates Clinical Manifestation and Predicts Treatment Outcome in Primary Myeloid Neoplasms.

Although the concept of "myeloid neoplasm continuum" has long been proposed, few comparative genomics studies directly tested this hypothesis. Here we report a multi-modal data analysis of 730 consecutive newly diagnosed patients with primary myeloid neoplasm, along with 462 lymphoid neoplasm cases serving as the outgroup. Our study identified a "Pan-Myeloid Axis" along which patients, genes, and phenotypic features were all aligned in sequential order. Utilizing relational information of gene mutations along the Pan-Myeloid Axis improved prognostic accuracy for complete remission and overall survival in adult patients of de novo acute myeloid leukemia and for complete remission in adult patients of myelodysplastic syndromes with excess blasts. We submit that better understanding of the myeloid neoplasm continuum might shed light on how treatment should be tailored to individual diseases. Significance: The current criteria for disease diagnosis treat myeloid neoplasms as a group of distinct, separate diseases. This work provides genomics evidence for a "myeloid neoplasm continuum" and suggests that boundaries between myeloid neoplastic diseases are much more blurred than previously thought.

Dynamic forecasting of severe acute graft-versus-host disease after transplantation.

Forecasting of severe acute graft-versus-host disease (aGVHD) after transplantation is a challenging 'large p, small n' problem that suffers from nonuniform data sampling. We propose a dynamic probabilistic algorithm, daGOAT, that accommodates sampling heterogeneity, integrates multidimensional clinical data and continuously updates the daily risk score for severe aGVHD onset within a two-week moving window. In the studied cohorts, the cross-validated area under the receiver operator characteristic curve (AUROC) of daGOAT rose steadily after transplantation and peaked at ≥0.78 in both the adult and pediatric cohorts, outperforming the two-biomarker MAGIC score, three-biomarker Ann Arbor score, peri-transplantation features-based models and XGBoost. Simulation experiments indicated that the daGOAT algorithm is well suited for short time-series scenarios where the underlying process for event generation is smooth, multidimensional and where there are frequent and irregular data missing. daGOAT's broader utility was demonstrated by performance testing on a remotely different task, that is, prediction of imminent human postural change based on smartphone inertial sensor time-series data.

Fluctuations in waist circumference increase diabetes risk: a 4-year cohort study in 61,587 older adults.

PURPOSE: To evaluate the effect of fluctuations in waist circumference (WC), weight, and body mass index (BMI) on the incidence of diabetes in older adults. PATIENTS AND METHODS: A prospective cohort of 61,587 older adults (age, 60-96 years) who did not have diabetes at study initiation was examined. Data on weight, BMI, and WC were collected, and participants were followed up until 31 December 2018. The main end point was new-onset diabetes. A Cox regression model was used to estimate the risk of diabetes (hazard ratios [HRs] and confidence intervals [CI]) in these participants. RESULTS: During a mean follow-up of 3.6 years, being overweight (HR [95% CI] 1.87 [1.62-2.17]), obesity (1.41 [1.26-1.59]), abdominal obesity (1.42 [1.28-1.58]), and obesity plus abdominal obesity at baseline (1.93 [1.66-2.25]) increased the risk of diabetes onset. Compared with older adults who "maintained normal WC", those who "remained abdominally obese" (HR = 1.66), "became abdominally obese" (HR = 1.58), or "achieved normal WC" (HR = 1.36) were at a higher risk of diabetes onset, as well as those with an increase in WC > 3 cm or > 5% compared with the baseline level. Weight gain or loss > 6 kg or weight gain > 5%, increase or decrease in BMI > 2 kg/m2, or an increase in BMI > 10% were associated with a higher diabetes risk. The diabetes risk was reduced by 19% in overweight older adults who exercised daily. CONCLUSION: For older adults, WC, BMI, and healthy weight maintenance reduce the diabetes risk. The findings may provide evidence for developing guidelines of proper weight and WC control for older adults.

RNA-Seq Analysis of the Effect of Zinc Deficiency on Microsporum canis, ZafA Gene Is Important for Growth and Pathogenicity.

Microsporum canis, a common pathogenic skin fungus, can cause dermatophytosis in humans and animals. Zinc is an important trace element and plays an important role in the growth and metabolism of fungi. Currently, the effects of zinc deficiency on growth, gene expression, and metabolic pathway have not been clarified in M. canis. Therefore, M. canis was cultured under zinc restriction, and RNA-Seq was conducted in this study. The growth of M. canis was severely inhibited, and many genes showed significant upregulation and downregulation in M. canis with zinc deficiency. Zinc deficiency could negatively affect the gene expression and biological metabolic pathway in M. canis. The zinc-responsiveness transcriptional activator (ZafA) gene was significantly upregulated and shared homology with Zap1. Thus, the ZafA gene might be the main transcription factor regulating M. canis zinc homeostasis. The ZafA gene knockout strain, ZafA-hph, was constructed via Agrobacterium tumefaciens-mediated transformation (ATMT) in M. canis for the first time to assess its function. In vitro growth ability, hair biodegradation ability, virulence test, and zinc absorption capacity in ZafA-hph and wild-type M. canis strains were compared. Results showed that the ZafA gene plays an important role in zinc absorption, expression of zinc transporter genes, and growth and pathogenicity in M. canis and can be used as a new drug target. Cutting off the zinc absorption pathway can be used as a way to prevent and control infection in M. canis.

The Use of a Three-in-One Practice-Management-Innovation Training Model in the Construction of an Infection Control Team.

OBJECTIVE: This study aims to explore the role of a three-in-one practice, management, and innovation training model (also called as three-in-one practice-management-innovation training model) in the construction of an infection control team. METHODS: This study retrospectively analyzed the position structure, mastery of professional knowledge, and working methods of the full-time and part-time personnel of the Changzhou Cancer Hospital, compared the training content of Jiangsu Hospital Infection Control Center with the actual situation of the hospital, and formulated and implemented a three-in-one practice-management-innovation training model. First, the team members were selected for the construction and management of the Hospital Infection Management Department according to the relevant responsibility and management requirements, and their learning and mastery of the basic knowledge and skills concerning infection control were completed based on their professional roles. In line with the regulations of the hospital and department, full-time personnel were ensured of having the opportunity to participate in provincial- and municipal-level academic exchanges and then learn from each other, through collaboration between doctors and nurses, how to exercise basic management skills. At the same time, a fair competitive incentive mechanism was established through the three-level network of the hospital infection committee, the hospital infection management department, and nosocomial infection management department to implement innovative project-based management and cultivate an awareness of hospital infection control in all employees. RESULTS: The professional structure of the full-time infection control personnel has been optimized, the awareness of the infection control team concerning active participation in practice has gradually increased, and infection control management and innovation has been significantly improved. CONCLUSION: After the selection of an infection control management team and the delivery of well-planned training, the quality of infection control management has improved.

Dual Covalent Cross-Linking Networks in Polynorbornene: Comparison of Shape Memory Performance.

In this work, tetrakis(dimethyllamino)ethylene (TDAE) plasticized polynorbornene (PNB) was used as the matrix, sulfur (S) and dicumyl peroxide (DCP) were simultaneously used as crosslinking agents to construct dual covalent cross-linking networks in PNB. The effects of different amounts of cross-linkers on the crosslinking degree, mechanical property, glass transition temperature, and PNB shape memory performance were investigated. Two crosslinking mechanisms were examined by Fourier transform infrared spectrometer and Raman spectrometer. The results showed that sulfur-rich cross-linked PNB exhibited a higher crosslinking degree, tensile strength, and slightly higher glass transition temperature than the DCP-rich system. Cross-linked PNB presented better shape memory performance than the uncross-linked one. Sulfur-rich cross-linked PNB showed even better shape memory behavior than the DCP-rich system, both with a shape fixation ratio of over 99% and a shape recovery ratio of over 90%. The reaction mechanism of sulfur and DCP in cross-linking PNB was different. Sulfur reacted with the α-H in PNB to form monosulfide bonds, disulfide bonds, and polysulfide bonds in PNB and the number of polysulfide bonds increased with increased amounts of sulfur. DCP reacted with the double bonds in PNB to form C-C covalent bond crosslinking networks. The crosslinking mechanism revealed that the sulfur-containing cross-linked bonds, especially polysulfide bonds, were more flexible and bore large deformation, which gave the PNB excellent mechanical properties and ensured a higher shape entropy elastic recovery ratio.

Direct-acting antiviral treatments display excellent outcomes even in older HCV-infected patients at increased risk of fibrosis.

BACKGROUND: This study compared the efficacy and tolerability of available direct-acting antiviral (DAA) regimens between individuals aged 60 years and older and younger patients in a real-life setting. Specifically, we aimed to provide evidence of the efficacy and safety of DAAs in the treatment of older adults in Tianjin, China. METHODS: In this retrospective observational cohort study, patients with chronic hepatitis C virus (HCV) were enrolled between April 2018 and December 2019 at 2 tertiary hospitals in Tianjin, China. We assessed the sustained virologic response (SVR) 12 weeks (SVR12) after DAA treatment, and adverse events in two groups using age stratification by comparing older adults (≥60 years) and younger adults (<60 years). Logistic regression analyses were performed to explore the risk factors associated with the SVR12. RESULTS: Of 1,106 patients, 440 (39.8%) were ≥60 years of age. The overall SVR12 rate was 97.8% in the entire cohort. In the older adult group, the SVR12 rate was 98.0% (431/440) compared to 97.7% (651/666) in the younger adult group. A multivariate analysis showed that (I) age was not predictive of SVR; and (II) the variables of treatment-experience [adjusted odds ratio (aOR) =27.53; 95% confidence interval (CI) =3.35-226.08; P=0.002] and aspartate aminotransferase (AST) (aOR =1.02; 95% CI =1.01-1.04; P=0.027) were independently associated with the SVR12 in the older adult group. All of the available DAA regimens were well-tolerated in older adult group. CONCLUSIONS: Chinese older adults with chronic HCV infection showed a significantly higher percentage of fibrosis; however, the available different DAA regimens were safe, well-tolerated, and achieved high rates of SVR in all age subgroups. Our observations suggest that DAA treatment should not be withheld even from older patients suffering from chronic HCV.

Association between N-terminal pro-BNP and 12 months major adverse cardiac events among patients admitted with NSTEMI.

BACKGROUND: In recent years, the hospital admission rate of non-ST-elevation myocardial infarction (NSTEMI) patients has exhibited an increasing trend, and a forthcoming transition from ST-elevation myocardial infarction (STEMI) to NSTEMI has been observed in China. The association between serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and major adverse cardiac events (MACEs) within 12 months after discharge among patients with NSTEMI remains unclear. METHODS: A total of 1,357 consecutively admitted NSTEMI patients were from the TAMI cohort. The patients' baseline demographic and clinical information were collected, and follow-up was carried out for 12 months. The primary outcome was composite MACEs consisting of all-cause death, hospital admission for unstable angina, hospital admission for heart failure, non fatal recurrent myocardial infarction, and target lesion revascularization (TLR). We adopted a Cox proportional hazard model to analyze the effect of NT-proBNP on MACEs and quantified the added prognostic value of NT-proBNP on the Global Registry of Acute CoronaryEvents (GRACE) risk score using the Harrell C-index, NRI, and IDI. RESULTS: The overall average follow-up period was 313 days. In total, 211 (15.55%) patients suffered from at least one MACE, and 97 patients were lost to follow-up, with a median follow-up time of 147 days. As the NT-proBNP level increased, a significant uptrend in the incidence of composite MACEs, all-cause death, and heart failure was observed. The multivariable Cox model revealed that NT-proBNP was an independent risk factor for composite MACEs [medium- vs. low-, HR: 2.19 (1.45-3.32), P=0.0002]; [high- vs. low-, HR: 3.07 (1.78-5.29), P<0.0001], as well as for all-cause death and heart failure. Subgroup analysis indicated that NT-proBNP was a robust prognostic biomarker, and the prognostic value was more evident for patients older than 60 years and whose LVEF was less than 40%. NT-proBNP (log-scale) was moderately correlated with the GRACE score (r=0.58, P<0.0001). The Harrell C-index of NT-proBNP combined with the GRACE score was 0.7715, which was higher than that of the GRACE score alone (0.7149) for predicting composite MACEs, and this improvement was verified by significant IDI (0.064, 95% CI: 0.027-0.106). CONCLUSIONS: NT-proBNP is a robust long-term prognostic biomarker for patients diagnosed with NSTEMI, especially for older patients and those with impaired cardiac ejection function. Combined usage of NT-proBNP levels with the GRACE score might help identify a subset of NSTEMI patients at a particularly high risk of MACEs 12 months after discharge.