Regulation of candidalysin underlies Candida albicans persistence in intravascular catheters by modulating NETosis.

Candida albicans is a leading cause of intravascular catheter-related infections. The capacity for biofilm formation has been proposed to contribute to the persistence of this fungal pathogen on catheter surfaces. While efforts have been devoted to identifying microbial factors that modulate C. albicans biofilm formation in vitro, our understanding of the host factors that may shape C. albicans persistence in intravascular catheters is lacking. Here, we used multiphoton microscopy to characterize biofilms in intravascular catheters removed from candidiasis patients. We demonstrated that, NETosis, a type of neutrophil cell death with antimicrobial activity, was implicated in the interaction of immune cells with C. albicans in the catheters. The catheter isolates exhibited reduced filamentation and candidalysin gene expression, specifically in the total parenteral nutrition culture environment. Furthermore, we showed that the ablation of candidalysin expression in C. albicans reduced NETosis and conferred resistance to neutrophil-mediated fungal biofilm elimination. Our findings illustrate the role of neutrophil NETosis in modulating C. albicans biofilm persistence in an intravascular catheter, highlighting that C. albicans can benefit from reduced virulence expression to promote its persistence in an intravascular catheter.

A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia.

While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents.

The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade after the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for patients with R/R cHL who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011 to 2020 (N = 183) compared with those from 2001 to 2010 (N = 159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era with a trend toward lower nonrelapse mortality beyond 2 years after transplant. Among patients who progressed after AHCT, 4-year postprogression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients that underwent transplant in the modern era, age ≥45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, whereas receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS. Extranodal disease at relapse was associated with inferior OS. Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.

Management of post-autologous transplant relapse in patients with T-cell lymphomas.

Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T-cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous group of disorders. However, a significant number of patients will experience post-AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow-up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post-AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3-year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%-87%). Our report details the pattern of post-AHCT relapse and the management of relapsed disease using different therapeutic modalities.

Quantifying lower limb muscle stiffness in typically developing children and adolescents using acoustic radiation force impulse shear wave elastography (ARFI/SWE)-a pilot study.

OBJECTIVE: To investigate and quantify age-related changes in lower limb muscle stiffness in typically developing children and adolescents using acoustic radiation force impulse shear wave elastography. MATERIALS AND METHODS: Shear wave velocities of bilateral rectus femoris, tibialis anterior, and medial gastrocnemius muscles at rest were obtained in typically developing children and adolescents aged 3 to 18 years. The participants were classified into three age groups: Group 1 (children), 3 to 7 years old; Group 2, 8 to 12 (pre-adolescent); and Group 3 (adolescent), 13 to 18. The shear wave velocities of muscle were compared across the three age groups, as well as compared between right- and left-side limbs. The correlation between shear wave velocities and body weight or body mass index was assessed. RESULTS: Of the 47 participants, 21 were in Group 1, 17 in Group 2, and 9 in Group 3. There were no significant differences among the three age groups' shear wave velocities of bilateral lower limb muscles, and no significant differences between right and left sides. There was no correlation between muscle stiffness and body weight or body mass index. CONCLUSION: The present pilot study applied acoustic radiation force impulse shear wave elastography to quantify lower limb muscle stiffness in typically developing children and adolescents aged 3 to 18 years, suggesting no marked change in muscle stiffness occurs as they develop.

Translation and validation of traditional Chinese version of the pediatric eating assessment Tool-10.

BACKGROUND: /Purpose: The Pediatric Eating Assessment Tool-10 (Pedi-EAT-10) is a caregiver-administrated subjective questionnaire for evaluating swallowing and feeding disorders among children. This study translated the Pedi-EAT-10 into Traditional Chinese and tested the translated version's reliability and validity. METHODS: Pedi-EAT-10 was translated into Traditional Chinese by experts and finalized after discussion and testing. A total of 168 participants, consisting of 32 children with dysphagia from a tertiary medical center and 136 healthy controls from its Children Care Center for Employees, were recruited. All participants were assessed by an otolaryngologist and speech-language pathologist. The reliability, validity, and efficacy of the translated Pedi-EAT-10 were analyzed to ensure it could be used to identify pediatric dysphagia and feeding problems. RESULTS: The Traditional Chinese version of the Pedi-EAT-10 had significant clinical discriminative validity between the dysphagia group and the control group (total score = 9.6 vs. 2.6, P < 0.001), acceptable test-retest reliability (intraclass correlation = 0.63), and excellent internal consistency (Cronbach's α = 0.91 for the entire cohort). The overall performance of the test for distinguishing children with dysphagia from normal controls was acceptable, and the area under the curve was 74.8% (sensitivity = 71.9%; specificity = 69.9%). The optimal cutoff score was ≥3 on the Youdex index. CONCLUSIONS: The Traditional Chinese version of the Pedi-EAT-10 has fair reliability and validity and can be quickly and easily completed by caregivers. The translated Ped-EAT-10 can be used as a first-line tool for assessing the need for further referral and instrumental examination.

High incidence of cerebrovascular lesions on magnetic resonance imaging in pediatric COVID-19 during omicron outbreak - A retrospective case series.

BACKGROUND: The incidence of pediatric hospitalizations has significantly increased since the spread of the omicron variant of COVID-19. Changes of characteristics in respiratory and neurological symptoms have been reported. We performed a retrospective, cross-sectional study to characterize the MRI change in children with an emphasis on the change of cerebral vasculatures. METHODS: We retrospectively collected clinical and MRI data of 31 pediatric patients with neurological symptoms during the acute infection and abnormalities on MRI during the outbreak of omicron variant from April 2022 to June 2022 in Taiwan. The clinical manifestations and MRI abnormalities were collected and proportion of patients with vascular abnormalities was calculated. RESULTS: Among 31 pediatric patients with post-COVID-19 neurological symptoms, MRI abnormalities were observed in 15 (48.4%), predominantly encephalitis/encephalopathy (73.3%). Notable MRI findings included focal diffusion-weighted imaging (DWI) hyperintensity in cerebral cortex and thalamus, diffuse cortical T2/DWI hyperintensity, and lesions in the medulla, pons, cerebellum, and splenium of corpus callosum. Vascular abnormalities were seen in 12 (80%) patients with MRI abnormalities, mainly affecting the middle cerebral arteries. The spectrum of neurological manifestations ranged from seizures to Alice in Wonderland syndrome, underscoring the diverse impact of COVID-19 on pediatric patients. CONCLUSION: A high proportion of vascular abnormalities was observed in pediatric patients with neurological involvements, suggesting that vascular involvement is an important mechanism of neurological manifestations in omicron variant infection.

Computational fluid dynamics study in children with obstructive sleep apnea.

OBJECTIVES: This study aims to identify characteristics in image-based computational fluid dynamics (CFD) in children with obstructive sleep apnea (OSA). DESIGN: Diagnostic study. SETTING: Hospital-based cohort. PARTICIPANTS: Children with symptoms suggestive of OSA were recruited and underwent polysomnography. MAIN OUTCOME MEASURES: Three-dimensional models of computational fluid dynamics were derived from cone-beam computed tomography. RESULTS: A total of 68 children participated in the study (44 boys; mean age: 7.8 years), including 34 participants having moderate-to-severe OSA (apnea-hypopnea index [AHI] greater than 5 events/h), and 34 age, gender, and body mass index percentile matched participants having primary snoring (AHI less than 1). Children with moderate-to-severe OSA had a significantly higher total airway pressure (166.3 vs. 39.1 Pa, p = .009), total airway resistance (9851 vs. 2060 Newton-metre, p = .004) and velocity at a minimal cross-sectional area (65.7 vs. 8.8 metre per second, p = .017) than those with primary snoring. The optimal cut-off points for moderate-to-severe OSA were 46.2 Pa in the total airway pressure (area under the curve [AUC] = 73.2%), 2373 Newton-metre in the total airway resistance (AUC = 72.5%) and 12.6 metres per second in the velocity at a minimal cross-sectional area (AUC = 70.5%). The conditional logistic regression model revealed that total airway pressure, total airway resistance and velocity at minimal cross-sectional area were significantly associated with an increased risk of moderate-to-severe OSA. CONCLUSIONS: This study demonstrates that CFD could be a useful tool for evaluating upper airway patency in children with OSA.

Evaluating brain white matter hyperintensity, IQ scores, and plasma neurofilament light chain concentration in early-treated patients with infantile-onset Pompe disease.

PURPOSE: The study aimed to describe central nervous system (CNS) progression in patients with infantile-onset Pompe disease (IOPD) and explore the potential clinical impact and predictors. METHODS: Patients with IOPD treated with enzyme replacement therapy were longitudinally followed with brain magnetic resonance imaging (MRI) and evaluation for IQ scores from 2004 to 2021. Investigation of CNS involvement focused on white matter (WM) abnormalities and was quantified using a scoring system for metachromatic leukodystrophy. MRI scores were correlated with plasma neurofilament light chain (NfL) concentration and IQ scores. RESULTS: A total of 19 patients who started enzyme replacement therapy at a mean age of 26 days were analyzed; the median age at last examination was 12.1 (range = 1.7-19) years. MRI abnormalities were found in all patients, from supratentorial central WM to U-fibers, then to infratentorial WM, and eventually to gray matter. MRI scores progressed (n = 16) at variable rates (range = 0.8-2.7/y) and were positively correlated with age (n = 16) and negatively correlated with IQ scores (n = 8). Plasma NfL concentration was positively correlated with MRI scores (r2 = 0.8569; P < .001; n = 13). CONCLUSION: Our results suggest that the progression of CNS involvement in IOPD may be associated with neuroaxonal injury and decreased IQ scores. NfL could serve as a biomarker for CNS involvement in IOPD.

Should Patients with Renal Cell Carcinoma and Pathological Nodal Invasion Be Classified As Having Stage IV Disease?

BACKGROUND: Lymph node invasion is associated with poor outcome in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with RCC within a single center from 2001 to 2018 were retrospectively obtained from the Chang Gung Research Database. Patient gender, physical status, Charlson Comorbidity Index, tumor side, histology, age at diagnosis, and body mass index (BMI) were compared. The overall survival (OS) and cancer-specific survival (CSS) of each group were estimated using the Kaplan-Meier method. Log-rank tests were used to compare between the subgroups. RESULTS AND CONCLUSIONS: A total of 335 patients were enrolled, of whom 76 had pT3N0M0, 29 had pT1-3N1M0, 104 had T1-4N0M1, and 126 had T1-4N1M1 disease. Significant OS difference was noted between pT3N0M0 and pT1-3N1M0 groups with 12.08 years [95% confidence interval (CI), 8.33-15.84] versus 2.58 years (95% CI, 1.32-3.85), respectively (P < 0.005). No significant difference was observed in OS between pT1-3N1M0 and T1-4N0M1 groups with 2.58 years (95% CI, 1.32-3.85) versus 2.50 years (95% CI, 1.85-3.15, P = 0.72). The OS of N1M1 group was worse than that of N0M1 group with 1.00 year (95% CI, 0.74-1.26) versus 2.50 years (95% CI, 1.85-3.15, P < 0.05). Similar results were also observed in CSS. In summary, we claim that RCC with lymph node (LN) invasion should be reclassified as stage IV disease in terms of survival outcome.

CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma.

The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.

Radiation Therapy for Primary Cutaneous Gamma Delta Lymphoma Prior to Stem Cell Transplantation.

We present a patient with widespread PCGD-TCL of the bilateral arms and legs, who underwent radiotherapy with 34 Gy in 17 fractions using circumferential VMAT and 3-D printed bolus to the four extremities prior to planned stem cell transplant, who was then found to have progression in the liver, lung, and skin, followed by drastic regression of all in and out-of-field lesions on imaging 1.5 months later. The cause of regression may be related to a radiation-induced abscopal effect from the immunomodulatory effects of radiation, or related to immune reactivation in the setting of cessation of systemic immunosuppressive agents.

Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.

BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Five-year follow-up of a clinic-based sleep intervention for paediatric epilepsy: A randomized clinical trial.

Sleep disturbances in children with epilepsy are prevalent, and are associated with substantial adverse medical and psychosocial consequences. This study is a 5-year follow-up of a clinic-based sleep intervention study that randomized 100 toddlers and preschool-age children with epilepsy to a usual care group or a sleep intervention group. The intervention group received standard paediatric neurology care plus three education sessions during the child's routine clinic visit. The outcomes measured were: (1) child sleep by actigraphy and parental report; and (2) maternal sleep and depression. We aimed to evaluate the long-term benefits of a clinic-based sleep intervention for paediatric epilepsy. In total, 42 families (42.0%) participated. The average child's age at follow-up was 9.55 years. Thirty-eight (90.5%) children were not obtaining sufficient sleep at baseline, and 40 (95.2%) at the 5-year follow-up. The numbers of children with clinically significant sleep disturbances were 40 (95.2%) at baseline and 36 (85.7%) at the 5-year follow-up. Fourteen mothers (33.3%) had poor sleep quality and high depressive symptoms at both assessment time points. There were no differences (P > 0.05) in the child and maternal outcomes between the two trial arms. Overall, there was no evidence that a clinic-based sleep intervention that effectively improved multiple aspects of sleep in toddlers and preschool-age children with epilepsy had long-lasting beneficial effects. Our findings suggest that sleep interventions for families of children with epilepsy require ongoing reinforcement and monitoring during routine paediatric neurology care to prevent sleep problems from persisting or recurring.

Estimating the impact of drug addiction causes heart damage.

To date, few studies have investigated the toxicological effects of the combined use of amphetamine and heroin in the heart. Hence, the aim of this study was to identify indicators for clinical evaluation and prevention of cardiac injury induced by the combined use of amphetamine and heroin. Four different groups were analyzed: (1) normal group (n＝25；average age＝35 ± 6.8); (2) heart disease group (n＝25；average age＝58 ± 17.2); (3) drug abusers (n = 27; average age = 37 ± 7.7); (4) drug abstainers (previous amphetamine-heroin users who had been drug-free for more than two weeks; n = 22; average age = 35 ± 5.6). The activity of MMPs, and levels of TNF-α, IL-6, GH, IGF-I, and several serum biomarkers were examined to evaluate the impact of drug abuse on the heart. The selected plasma biomarkers and classic cardiac biomarkers were significantly increased compared to the normal group. The zymography data showed the changes in cardiac-remodeling enzymes MMP-9 and MMP-2 among combined users of amphetamine and heroin. The levels of TNF-α and IL-6 only increased in the heart disease group. Growth hormone was increased; however, IGF-I level decreased with drug abuse and the level was not restored by abstinence. We speculated that the amphetamine-heroin users might pose risk to initiate heart disease even though the users abstained for more than two weeks. The activity change of MMP-9 and MMP-2 can be a direct reason affecting heart function. The indirect reason may be related to liver damage by drug abuse reduce IGF-1 production to protect heart function.

Chain-to-Layer Dimensionality Engineering of Chiral Hybrid Perovskites to Realize Passive Highly Circular-Polarization-Sensitive Photodetection.

Chiral hybrid perovskites (CHPs), aggregating chirality and favorable semiconducting properties in one, have taken a prominent position in direct circularly polarized light detection (CPL). However, passive high circular polarization sensitivity (gres) photodetection in CHPs is still elusive and challenging. Benefitting from efficient control and turning of carrier transport of CHPs by dimensional engineering, here, we unprecedentedly proposed a chain-to-layer dimensionality engineering to realize high-gres passive photodetection. Two novel 2D layered CHPs (R/S-PPA)EAPbBr4 (2R/2S) (PPA = 1-phenylpropylamine, EA = ethylammonium) are successfully synthesized by alloying an EA cation with small steric hindrance into the chained CHPs (R/S-PPA)PbBr3 (1R/1S). Particularly, compared with the neglectable photoresponse in 1R, the obtained 2R by chain-to-layer dimensionality engineering gives rise to an excellent photoconductivity and robust polar photovoltage effect (PPE) with a giant open-circuit voltage of 2.5 V. Furthermore, such PPE promotes realizing an impressive gres in 2R up to 0.42 at zero bias because of the independent separation of photoexcited carriers, which is the highest value among the reported layered chiral perovskites. This work paves the way for the vigorous development of higher dimensional CHPs and will reveal their applications in the field of passive high-gres CPL detection.

Office Blood Pressure Monitoring in Children with Obesity and Obstructive Sleep Apnea.

OBJECTIVE: To investigate the relative contributions of obesity and obstructive sleep apnea (OSA) to unfavorable blood pressure in children. STUDY DESIGN: Children aged 3-18 years with OSA-related symptoms were recruited. All children underwent office blood pressure (BP) monitoring and full-night polysomnography. Obesity was defined as a body mass index ≥95th percentile. OSA severity was divided into primary snoring (apnea-hypopnea index [AHI] <1), mild OSA (5> AHI ≥1), and moderate to severe OSA (AHI ≥5). Age- and sex-adjusted logistic regression analysis was performed to determine the associations among OSA, obesity, and elevated BP. RESULTS: This cross-sectional study enrolled 1689 children (66% boys), with a mean age of 7.9 years. Compared with children with primary snoring, children with moderate to severe OSA had significantly higher systolic BP (108.1 mmHg vs 105.6 mmHg), diastolic BP (75.0 mmHg vs 70.4 mmHg), systolic BP percentile (75.0 vs 70.4), and diastolic BP percentile (74.0 vs 69.2). The rate of unfavorable BP (ie, elevated BP or hypertension level BP) also was significantly higher in children with more severe OSA. Children with obesity had higher BP and BP percentile. Logistic regression analysis revealed that children with obesity and moderate to severe OSA have a 3-fold greater risk of unfavorable BP compared with children without obesity and primary snoring. CONCLUSIONS: We identified a 3-fold greater risk of unfavorable BP in children with obesity and moderate to severe OSA.

Prognostic value and outcome for acute lymphocytic leukemia in children with MLL rearrangement: a case-control study.

PURPOSE: To evaluate the prognostic factors and outcome for acute lymphoblastic leukemia (ALL) in children with MLL rearrangement (MLL-r). METHODS: A total of 124 pediatric patients who were diagnosed with ALL were classified into two groups based on the MLL-r status by using a retrospective case-control study method from June 2008 to June 2020. RESULTS: The prevalence of MLL-r positive in the whole cohort was 4.9%. The complete remission (CR) rate on Day 33 in the MLL-r positive group was not statistically different from the negative group (96.8% vs 97.8%, P = 0.736). Multivariate analysis showed that T-cell, white blood cell counts (WBC) ≥ 50 × 109/L, MLL-AF4, and D15 minimal residual disease (MRD) positive were independent risk factors affecting the prognosis of MLL-r positive children. Stem cell transplantation (SCT) was a favorable independent prognostic factor affecting event-free survival (EFS) in MLL-r positive patients (P = 0.027), and there was a trend toward an independent prognostic effect on overall survival (OS) (P = 0.065). The 10-year predicted EFS for patients with MLL-AF4, MLL-PTD, MLL-ENL, other MLL partner genes, and MLL-r negative cases were 46.67 ± 28.61%, 85.71 ± 22.37%, 75 ± 32.41%, 75 ± 32.41%, and 77.33 ± 10.81%, respectively (P = 0.048). The 10-year predicted OS were 46.67 ± 28.61%, 85.71 ± 22.37%, 75 ± 32.41%, 75 ± 32.41%, and 85.2 ± 9.77%, respectively (P = 0.049). The 124 patients with ALL were followed up and eventually 5 (4%) cases relapsed, with a median relapse time of 3.9 years. CONCLUSION: Patients with MLL-r positive ALL have moderate remission rates, but are prone to relapse with low overall survival. The outcome of MLL-r positive ALL was closely related to the partner genes, and clinical attention should be paid to screening for MLL partner genes and combining them with other prognostic factors for accurate risk stratification.

Duchenne muscular dystrophy newborn screening: the first 50,000 newborns screened in Taiwan.

BACKGROUND: Duchenne muscular dystrophy (DMD/Duchenne) is a progressive X-linked muscular disease with an overall incidence of 1:5,000 live male births. Recent availability in treatment for DMD raised the need of early diagnosis, and DMD became as a selective item of newborn screening (NBS) since Feb. 2021 in our center. MATERIALS AND METHODS: Dried blood spots (DBS) muscle-type creatine kinase (CK) isoform was measured with a commercialized kit with age-adjusted cutoffs. Subjects with an elevation of CK in the first screen were requested for a re-screen 2 weeks later. A DBS whole-exome sequencing (WES) panel for dystrophin and other neuromuscular-related genes was applied to confirm the diagnosis for subjects with persistent hyperCKemia. RESULTS: During a 1-year period, 50,572 newborns (male 26,130) received DMD screening at a mean age of 2 days (SD 1 day). Among them, 632 (1.2%) had an elevated CK value. A re-screen at a mean age of 14 days (SD 8 days) revealed 14 subjects with persistent hyperCKemia, and DMD was confirmed in 3 of them. The incidence of DMD in Taiwan was 1:8,710 (95% CI 1 in 2,963 to 1 in 25,610) live birth males. Results of DMD DBS also assisted in Pompe newborn screening. CONCLUSIONS: NBS for DMD enables earlier management of the disease. The high re-screening rate could potentially be waived by moving the DBS WES assay to a second-tier test. The long-term benefit and the impact of newborn screening on the prognosis of DMD, however, remain further elucidated.

The diversity of hereditary neuromuscular diseases: Experiences from molecular diagnosis.

BACKGROUND: Hereditary neuromuscular diseases (NMDs) are a group of rare disorders, and the diagnosis of these diseases is a substantial burden for referral centers. Although next-generation sequencing (NGS) has identified a large number of genes associated with hereditary NMDs, the diagnostic rates still vary across centers. METHODS: Patients with a suspected hereditary NMD were referred to neuromuscular specialists at the National Taiwan University Hospital. Molecular diagnoses were performed by employing a capture panel containing 194 genes associated with NMDs. RESULTS: Among the 50 patients referred, 43 had a suspicion of myopathy, and seven had polyneuropathy. The overall diagnostic rate was 58%. Pathogenic variants in 19 genes were observed; the most frequent pathogenic variant found in this cohort (DYSF) was observed in only four patients, and 10 pathogenic variants were observed in one patient each. One case of motor neuron disease was clinically mistaken for myopathy. A positive family history increased the diagnostic rate (positive: 72.7% vs. negative: 56.3%). Fourteen patients with elevated plasma creatine kinase levels remained without a diagnosis. CONCLUSION: The application of NGS in this single-center study proves the great diversity of hereditary NMDs. A capture panel is essential, but high-quality clinical and laboratory evaluations of patients are also indispensable.