Amelioration of oxygen-induced retinopathy in neonatal mice with fetal growth restriction.

Introduction: With the aim of optimizing the balance of maintaining a safe oxygen saturation and reducing the risk of retinopathy of prematurity in human neonates with fetal growth restriction (FGR), the present study investigated the distinct effects of oxygen supplementation on the retinal neovasculature using a murine premature neonatal oxygen-induced retinopathy (OIR) model with or without fetal growth restriction. Methods: For comparison with normal birth-weight neonates, maternal low-protein diet-induced FGR neonates were subjected to fluctuating oxygen levels to generate oxygen-induced retinopathy. The retinal neovasculature was histologically evaluated, and comprehensive transcriptome analysis was conducted. Results: Compared to OIR neonates with normal birth weight, significant amelioration of the neovasculature, as indicated by decreases in the number of branch junctions, vascular distribution, maximal vascular radius and microaneurysm-like tufts, was observed in OIR mice with FGR. The results of retinal RNA-sequencing revealed downregulation of angiogenic factors that trigger pathological retinal neovascularization, such as the mitogen-activated protein kinase pathway and corresponding upstream signaling pathways in OIR mice with FGR. Conclusion: Our findings demonstrated that FGR neonates have a higher capacity for retinal oxygen stress, and the risk of OIR development is attenuated compared to that in mature neonates with normal birth weight.

Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

PURPOSE: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease. METHODS: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts. RESULTS: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], P =9.5 x 10 -5 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], P =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating LMO2 activation and inactivating STAG2 inactivation ( STAG2/LMO2 ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine. CONCLUSION: γδ T-ALL in children under the age of three is extremely high-risk and enriched for STAG2/LMO2 ALL. STAG2 loss perturbs chromatin conformation and differentiation, and STAG2/LMO2 ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL. SUPPORT: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.

Complicated Acute Pericarditis and Peripheral Venous Catheter-Related Bloodstream Infection Caused by Methicillin-Resistant Staphylococcus aureus after Influenza B Virus Infection: A Case Report.

Background: In this study, we report the case of a 14-month-old female patient transferred from another hospital to our hospital with a 9-day history of fever and worsening dyspnea. Case Report. The patient tested positive for influenza type B virus 7 days before being transferred to our hospital but was never treated. The physical examination performed at presentation revealed redness and swelling of the skin at the site of the peripheral venous catheter insertion performed at the previous hospital. Her electrocardiogram revealed ST segment elevations in leads II, III, aVF, and V2-V6. An emergent transthoracic echocardiogram revealed pericardial effusion. As ventricular dysfunction due to pericardial effusion was not present, pericardiocentesis was not performed. Furthermore, blood culture revealed methicillin-resistant Staphylococcus aureus (MRSA). Thus, a diagnosis of acute pericarditis complicated with sepsis and peripheral venous catheter-related bloodstream infection (PVC-BSI) due to MRSA was made. Frequent bedside ultrasound examinations were performed to evaluate the outcomes of the treatment. After administering vancomycin, aspirin, and colchicine, the patient's general condition stabilized. Conclusions: In children, it is crucial to identify the causative organism and provide appropriate targeted therapy to prevent worsening of the condition and mortality due to acute pericarditis. Moreover, it is important to carefully monitor the clinical course for the progression of acute pericarditis to cardiac tamponade and evaluate the treatment outcomes.

The Inhibition of Glycolysis in T Cells by a Jak Inhibitor Ameliorates the Pathogenesis of Allergic Contact Dermatitis in Mice.

Allergic contact dermatitis (ACD) and atopic dermatitis develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory drugs, such as Jak inhibitors, would be useful for the long-term management of these diseases owing to their profile of favorable adverse effects. However, the efficacy of Jak inhibitors for ACD treatment has not been fully determined under a variety of settings. Therefore, we evaluated the effects of ruxolitinib, a Jak inhibitor for Jak1 and Jak2, using a mouse ACD model. As a result, the lower numbers of immune cells, including CD4+ T cells, CD8+ T cells, neutrophils, and possibly macrophages, as well as milder pathophysiological aspects have been observed in the inflamed skin of ACD with the administration of ruxolitinib. In addition, the treatment of differentiating T cells with ruxolitinib downregulated the level of IL-2-mediated glycolysis in vitro. Furthermore, symptoms of ACD did not develop in T-cell-specific Pgam1-deficient mice whose T cells had no glycolytic capacity. Taken together, our data suggest that the downregulation of glycolysis in T cells by ruxolitinib could be an important factor in the suppression of ACD development in mice.

Rearing in an Enriched Environment Ameliorates the ADHD-like Behaviors of Lister Hooded Rats While Suppressing Neuronal Activities in the Medial Prefrontal Cortex.

In addition to genetic factors, environmental factors play a role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). This study used Lister hooded rats (LHRs) as ADHD model animals to evaluate the effects of environmental factors. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in an enriched environment [EE]) until 9 weeks of age. EE rearing but not rearing in a large flat cage decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. RNA sequencing revealed that the immediate-early gene expression in the medial prefrontal cortex of LHRs reared in an EE was reduced. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC.

Changes in the Incidence of Infantile Spinal Muscular Atrophy in Shikoku, Japan between 2011 and 2020.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Al-though there was no cure for SMA, newly developed therapeutic drugs (nusinersen, onasemnogene abeparvovec, and risdiplam) have been proven effective for the improvement of motor function and prevention of respiratory insufficiency of infants with SMA. Nusinersen was introduced in Japan in 2017 and onasemnogene abeparvovec in 2020. We hypothesized that the introduction of these drugs might influence the incidence of SMA (more precisely, increase the diagnosis rate of SMA) in Japan. To test this hypothesis, we conducted a second epidemiological study of infantile SMA using questionnaires in Shikoku, Japan between October 2021 and February 2022. The incidence of infantile SMA during the period 2016-2020 was 7.08 (95% confidence interval [CI] 2.45-11.71) per 100,000 live births. According to our previous epidemiological study, the incidence of infantile SMA during 2011-2015 was 2.70 (95% CI 0.05-5.35) per 100,000 live births. The increased incidence of infantile SMA suggests that the widespread news in Japan regarding the introduction of therapeutic agents, nusinersen and onasemnogene abeparvovec, raised clinicians' awareness about SMA, leading to increased and earlier diagnosis of SMA in Shikoku.

Acetaminophen-induced Stevens-Johnson syndrome with lethal lung injury: A case report.

Stevens-Johnson syndrome (SJS) with respiratory distress can lead to fatal outcomes. However, there are a few reports of drug-induced lung injury with diffuse alveolar damage caused by acetaminophen, the most severe type. Here, we describe a fatal case of acetaminophen-induced SJS in a child with irreversible lung lesions.

Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia.

KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.

Postchemotherapy immune status in infants with acute lymphoblastic leukemia: A report from the JPLSG MLL-10 trial.

The MLL-10 trial (UMIN000004801) modified a Children's Oncology Group (COG) AALL0631 therapy for infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL). In 2016, one registered case developed secondary immunodeficiency during maintenance therapy and eventually died due to cytomegalovirus infection. Around the same time, fatal secondary immunodeficiencies were reported in five infants with ALL in North America who had received COG-based chemotherapy between 1996 and 2015. Given these cases, we decided to conduct a retrospective study on the postchemotherapy immune status of infants with ALL. A questionnaire collected data on posttreatment immune function, frequency of infections, and supportive care for the 34 infants in the MLL-10 trial. Patients receiving allogeneic hematopoietic stem cell transplantation in first remission were excluded. Responses to the survey were obtained in 28 cases (85%). Most patients were immunocompetent after the completion of chemotherapy (median follow-up duration from the day of chemotherapy completion was 431 days), except for the aforementioned case. There were seven patients with nonsevere viral infection, all of whom recovered. In conclusion, severe chemotherapy-induced immunodeficiency in infants with ALL appears to be rare, but prospective data collection of immune function is necessary to clarify this finding.

Transvenous pacing approach for atrioventricular block in fontan - Possibility of transvenous approach by electrophysiological assessment.

In extracardiac Fontan, an epicardial pacemaker implantation has many limitations, especially given that it is highly invasive and a high-risk procedure due to repeat thoracotomy. Herein we illustrate a case with the possibility of transvenous pacing in extracardiac Fontan being less invasive and lower risk transvenous dual-chamber pacemaker implantation by electrophysiological assessment. .

Discrepancy between subjective and objective sleepiness in adolescents.

BACKGROUND: Lack of correlation between subjective and objective measurements of daytime sleepiness is common. Here, the frequency of discrepancy between subjective and objective sleepiness, as well as possible predictors, were examined for an adolescent cohort. METHODS: This study included pediatric patients (aged 10-18 years, n = 211) with various sleep disorder symptoms were evaluated between August 2011 and February 2021. Subjective and objective sleepiness were assessed based on eleven or more scores of the Japanese version of Epworth Sleepiness Scale and a mean sleep latency of 8.0 min or less on the Multiple Sleep Latency Test, respectively. Patients were then classified as both subjectively and objectively sleepy, objectively sleepy, subjectively sleepy, and non-sleepy. Discrepancy-related factors were identified with multivariable logistic regression analysis. RESULTS: The frequency of discrepancy between subjective and objective sleepiness was 46.4%, with 35.5% (75/211) of the patients exhibiting subjective sleepiness without objective sleepiness and 10.9% (23/211) of the patients exhibiting objective sleepiness without subjective sleepiness. Co-existence of neurodevelopmental disorders was associated more often with subjective sleepiness compared to non-sleepiness (odds ratio (OR), 4.12; 95% confidence interval (CI), 1.30 to 12.99) or concordant sleepiness (OR, 7.54; 95% CI, 2.43 to 23.38). CONCLUSIONS: Nearly half of the patients exhibited discrepancy between subjective and objective sleepiness, and it more often involved subjective sleepiness. Furthermore, age, bedtime, and neurodevelopmental disorders were identified as significant factors related to subjective sleepiness without objective sleepiness.

Machine learning for rhabdomyosarcoma histopathology.

Correctly diagnosing a rare childhood cancer such as sarcoma can be critical to assigning the correct treatment regimen. With a finite number of pathologists worldwide specializing in pediatric/young adult sarcoma histopathology, access to expert differential diagnosis early in case assessment is limited for many global regions. The lack of highly-trained sarcoma pathologists is especially pronounced in low to middle-income countries, where pathology expertise may be limited despite a similar rate of sarcoma incidence. To address this issue in part, we developed a deep learning convolutional neural network (CNN)-based differential diagnosis system to act as a pre-pathologist screening tool that quantifies diagnosis likelihood amongst trained soft-tissue sarcoma subtypes based on whole histopathology tissue slides. The CNN model is trained on a cohort of 424 centrally-reviewed histopathology tissue slides of alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and clear-cell sarcoma tumors, all initially diagnosed at the originating institution and subsequently validated by central review. This CNN model was able to accurately classify the withheld testing cohort with resulting receiver operating characteristic (ROC) area under curve (AUC) values above 0.889 for all tested sarcoma subtypes. We subsequently used the CNN model to classify an externally-sourced cohort of human alveolar and embryonal rhabdomyosarcoma samples and a cohort of 318 histopathology tissue sections from genetically engineered mouse models of rhabdomyosarcoma. Finally, we investigated the overall robustness of the trained CNN model with respect to histopathological variations such as anaplasia, and classification outcomes on histopathology slides from untrained disease models. Overall positive results from our validation studies coupled with the limited worldwide availability of sarcoma pathology expertise suggests the potential of machine learning to assist local pathologists in quickly narrowing the differential diagnosis of sarcoma subtype in children, adolescents, and young adults.

Activation of fibroblast growth factor-inducible 14 in the early phase of childhood IgA nephropathy.

IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Pediatric patients in Japan are diagnosed with IgAN at an early stage of the disease through annual urinary examinations. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) have various roles, including proinflammatory effects, and modulation of several kidney diseases; however, no reports have described their roles in pediatric IgAN. In this study, we performed pathological and immunohistochemical analyses of samples from 14 pediatric IgAN patients. Additionally, gene expression arrays of glomeruli by laser-captured microdissection were performed in hemi-nephrectomized high serum IgA (HIGA) mice, a model of IgA nephropathy, to determine the role of Fn14. Glomeruli with intense Fn14 deposition were observed in 80% of mild IgAN cases; however, most severe cases showed glomeruli with little or no Fn14 deposition. Fn14 deposition was not observed in obvious mesangial proliferation or the crescent region of glomeruli, but was detected strongly in the glomerular tuft, with an intact appearance. In HIGA mice, Fn14 deposition was observed mildly beginning at 11 weeks of age, and stronger Fn14 deposition was detected at 14 weeks of age. Expression array analysis indicated that Fn14 expression was higher in HIGA mice at 6 weeks of age, increased slightly at 11 weeks, and then decreased at 26 weeks when compared with controls at equivalent ages. These findings suggest that Fn14 signaling affects early lesions but not advanced lesions in patients with IgAN. Further study of the TWEAK/Fn14 pathway will contribute to our understanding of the progression of IgAN.

Properties of Staphylococcus lugdunensis in Children.

Background. Staphylococcus lugdunensis is one of the clinically important coagulase-negative staphylococci. The purpose of this study was to elucidate the microbiological features of S. lugdunensis in hospitalized children. Methods. From January 2012 to December 2019, all isolates were retrospectively screened for S. lugdunensis. Results. Twenty-five children were eligible for study. Nineteen and six children were classified into a critical care unit group (Group A) and a general medical ward group (Group B), respectively. The prevalence of methicillin-resistant S. lugdunensis was significantly higher in Group A than in Group B (68.4% vs 0%; P < .01). Eleven children (44%) had S. lugdunensis infections, while the remaining children were colonized. Six of the 11 infected children (55%) had healthcare-associated infections. Moreover, 3 isolates exhibited the methicillin resistance. Conclusions. The bacteriological characteristics of S. lugdunensis differ depending on patient background. Selection of antibiotic treatment should in part rely on patient background data.

[Acute leukemia of infants and neonates].

Leukemias diagnosed in <1-year-old infants generally have an aggressive clinical nature and unique biological characteristics. Acute lymphoblastic leukemia (ALL) in infants is still intractable and difficult to treat as compared with other pediatric ALLs, for which considerable progress in treatment outcomes has been recently achieved. Infant leukemia cells frequently carry chromosome translocations involving the 11q23 locus, resulting in the rearrangement and fusion of the KMT2A (MLL) gene. Among several KMT2A fusion genes, KMT2A-AFF1 (MLL-AF4) fusion is characteristically observed in neonatal and infant ALL, representing a hallmark of poor prognosis. The cytogenetic/molecular abnormalities t (1;22)(p13.3;q13.1)/RBM15-MKL1 and t (8;16)(p11.2;p13.3)/KAT6A-CREBBP (MOZ-CBP) are also well-known in acute myeloblastic leukemia in this population. Although many neonatal leukemias occurring within the first 28 days of birth are refractory, spontaneous remissions are occasionally observed, especially in the case of t (8;16). Therefore, international collaborative studies are necessary to improve understanding and facilitate the development of better treatment for this rare disease. Thus, this study summarizes the recently reported clinical, cytogenetic, and molecular biology aspects of neonatal and infant leukemias.