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Purpose: The purpose of this study was to determine factors significantly associated with mortality and length of stay (LOS) in admissions to the pediatric intensive care unit (PICU) for traumatic brain injury (TBI)., Methods: A cross-sectional, retrospective cohort study that identified PICU admissions with TBI from forty-nine hospitals in the USA using the Pediatric Health Information System database from 2016 to 2021. Univariable analyses comparing those who did and did not experience mortality were performed. The following regression analyses were conducted: logistic regression with mortality as dependent variable; linear regression with LOS as the dependent variable; logistic regression with mortality as the dependent variable but only included patients with cerebral edema; and linear regression with LOS as the dependent variable but only included patients who survived. From the regression analysis for mortality in all TBI patients was utilized to develop a mortality risk score., Results: A total of 3041 admissions were included. Those with inpatient mortality (18.5%) tended to be significantly younger (54 vs. 92 months, p < 0.01), have < 9 pediatric Glasgow Coma Scale on admission (100% vs. 52.9%, p < 0.01) and more likely to experience acute renal, hepatic and respiratory failure, acidosis, central diabetes insipidus, hyperkalemia, and hypocalcemia. Regression analysis identified that pediatric Glasgow Coma Scale, alkalosis and cardiac arrest significantly increased risks of mortality. The TBI mortality risk score had an area under the curve of 0.89 to identify those with mortality; a score of 6 ≤ was associated with 88% mortality., Conclusion: Patients admitted to the PICU with TBI have 18.5% risk of inpatient mortality with most occurring the first 48 h and these are characterized with greater multisystem organ dysfunction, received medical and mechanical support. TBI mortality risk score suggested is a practical tool to identify patients with an increase likelihood to die., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background The oral condition known as recurrent aphthous ulceration (RAU) or recurrent aphthous stomatitis (RAS) is very prevalent. Its etiopathogenesis is unknown; hence, symptomatic therapy is all that can be offered if it manifests clinically. Lesion care aims to minimize discomfort and the frequency of relapses by bringing active illness under local control in the affected area. The current treatment options that may have negative side effects include the use of topical and systemic steroids, antibiotics, cauterization, and laser therapy. Objectives and Importance This study aimed to compare the efficiency of HiOra SG gel with triamcinolone acetonide gel in the management of RAS. Materials and Methods Fifty individuals with RAS were recruited for the trial and randomly assigned to either group I (HiOra SG gel) or group II (0.1% triamcinolone acetonide ointment; Oraways). After each meal for a total of 10 days, those with mouth ulcers were instructed to topically administer the drugs. The clinical data were analyzed by comparing the ulcer severity scores from the first, fifth, and 10th days. Results There was a statistically significant (p = 0.001) reduction in reported pain, pain duration, and overall ulcer severity across all groups. After therapy, however, neither the HiOra gel group nor the triamcinolone group showed any discernible improvement over the other. Conclusion The present study's findings corroborate the efficacy of HiOra SG gel in the treatment of RAS when compared to triamcinolone acetonide gel (0.1%). In this trial, no patients had any negative reactions to HiOra SG gel. In the future, further studies are needed with larger samples to prove its benefits., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Nayak et al.)

Type I interferon (IFN-1) regulates gene expression and hematopoiesis both during development and in response to inflammatory stress. We previously showed that during development in mice, hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) induce IFN-1 target genes shortly before birth. This coincides with the onset of a transition to adult hematopoiesis, and it drives the expression of genes associated with antigen presentation. However, it is not clear whether perinatal IFN-1 modulates hematopoietic output, as has been observed in contexts of inflammation. We have characterized hematopoiesis at several different stages of blood formation, from HSCs to mature blood cells, and found that loss of the IFN-1 receptor (IFNAR1) leads to depletion of several phenotypic HSC and MPP subpopulations in neonatal and juvenile mice. Committed lymphoid and myeloid progenitor populations expand simultaneously. These changes had a surprisingly little effect on the production of more differentiated blood cells. Cellular indexing of transcriptomes and epitopes by sequencing resolved the discrepancy between the extensive changes in progenitor numbers and modest changes in hematopoiesis, revealing stability in most MPP populations in Ifnar1-deficient neonates when the populations were identified based on gene expression rather than surface marker phenotype. Thus, basal IFN-1 signaling has only modest effects on hematopoiesis. Discordance between transcriptionally and phenotypically defined MPP populations may affect interpretations of how IFN-1 shapes hematopoiesis in other contexts, such as aging or inflammation., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: The primary objective of this study was to determine whether Altmetric score, number of reads, and citations for paediatric cardiology manuscripts correlate with one another. A secondary objective was to determine the extent to which factors mediated citation number for paediatric cardiology manuscripts., Methods: Data for this study came from manuscripts published in Cardiology in the Young (2010-2021). Data were extracted by using data shared on the journal website. Spearman's correlation analyses were conducted between manuscript reads, citations, and Altmetric score. Regression analyses were conducted with number of citations as the dependent variable and year of publication, publication type, number of reads, and Altmetric score as independent variables., Results: A total of 2642 manuscripts were included in the final analyses. Reads and citations had poor correlation (r-value 0.32); reads and Altmetric score had negligible correlation (r-value 0.26); and Altmetric score and citations had negligible correlation (r-value 0.07). Year of publication was independently associated with number of citations (β -0.95, p-value <0.01). Manuscript type was independently associated with number of citations (β 1.04, p-value <0.01). Number of reads was independently associated with citations (β 0.01, p-value <0.01). Altmetric score was independently associated with number of citations (β 0.05, p-value <0.01)., Conclusion: This study describes the correlation of reads, citations, and Altmetric score in manuscripts published in Cardiology in the Young , demonstrating poor correlation, at best, between these metrics. Each bibliometric index seems to represent a different phenomenon of manuscript consumption. No single bibliometric index in isolation offers ample representation of manuscript consumption.

Introduction: Persistent coronary microcirculatory dysfunction (CMD) and elevated trimethylamine N-oxide (TMAO) levels after ST-elevation myocardial infarction (STEMI) may drive negative structural and electrical cardiac remodeling, resulting in new-onset atrial fibrillation (AF) and a decrease in left ventricular ejection fraction (LVEF)., Aims: TMAO and CMD are investigated as potential predictors of new-onset AF and left ventricular remodeling following STEMI., Methods: This prospective study included STEMI patients who had primary percutaneous coronary intervention (PCI) followed by staged PCI three months later. Cardiac ultrasound images were obtained at baseline and after 12 months to assess LVEF. Coronary flow reserve (CFR), and index of microvascular resistance (IMR) were assessed using the coronary pressure wire during the staged PCI. Microcirculatory dysfunction was defined as having an IMR value ≥25 U and CFR value <2.5 U., Results: A total of 200 patients were included in the study. Patients were categorized according to whether or not they had CMD. Neither group differed from the other with regards to known risk factors. Despite making up only 40.5% of the study population, females represented 67.4% of the CMD group p < 0.001. Similarly, CMD patients had a much higher prevalence of diabetes than those without CMD (45.7% vs. 18.2%; p < 0.001). At the one-year follow-up, the LVEF in the CMD group had decreased to significantly lower levels than those in the non-CMD group (40% vs. 50%; p < 0.001), whereas it had been higher in the CMD group at baseline (45% vs. 40%; p = 0.019). Similarly, during the follow-up, the CMD group had a greater incidence of AF (32.6% vs. 4.5%; p < 0.001). In the adjusted multivariable analysis, the IMR and TMAO were associated with increased odds of AF development (OR: 1.066, 95% CI: 1.018-1.117, p = 0.007), and (OR: 1.290, 95% CI: 1.002-1.660, p = 0.048), respectively. Similarly, elevated levels of IMR and TMAO were linked with decreased odds of LVEF improvement, while higher CFR values are related to a greater likelihood of LVEF improvement., Conclusions: CMD and elevated TMAO levels were highly prevalent three months after STEMI. Patients with CMD had an increased incidence of AF and a lower LVEF 12 months after STEMI.

Acute myeloid leukemia (AML) initiation requires multiple rate-limiting mutations to cooperatively reprogram progenitor cell identity. For example, FLT3 internal tandem duplication (FLT3ITD) mutations cooperate with a variety of different initiating mutations to reprogram myeloid progenitor fate. These initiating mutations often skew toward either pediatric or adult AML patient populations, though FLT3ITD itself occurs at similar frequencies in both age groups. This raises the question of whether FLT3ITD might induce distinct transcriptional programs and unmask distinct therapeutic vulnerabilities when paired with pediatric, as opposed to adult AML-initiating mutations. To explore this possibility, we compared AML evolution in mice that carried Flt3ITD/NUP98-HOXD13 (NHD13) or Flt3ITD/Runx1DEL mutation pairs, which are respectively most common in pediatric and adult AML. Single-cell analyses and epigenome profiling revealed distinct interactions between Flt3ITD and its cooperating mutations. Whereas Flt3ITD and Flt3ITD/Runx1DEL caused aberrant expansion of myeloid progenitors, Flt3ITD/NHD13 drove the emergence of a pre-AML population that did not resemble normal hematopoietic progenitors. Differences between Flt3ITD/Runx1DEL and Flt3ITD/NHD13 cooperative target gene expression extended to fully transformed AML as well. Flt3ITD/NHD13 cooperative target genes were enriched in human NUP98-translocated AML. Flt3ITD/NHD13 selectively hijacked type I interferon signaling to drive expansion of the pre-AML population. Blocking interferon signaling delayed AML initiation and extended survival. Thus, common AML driver mutations, such as FLT3ITD, can coopt different mechanisms of transformation in different genetic contexts. Furthermore, pediatric-biased NUP98 fusions convey actionable interferon dependence., (© 2023 by The American Society of Hematology.)

Sample size and statistical power are often limited in pediatric cardiology studies due to the relative infrequency of specific congenital malformations of the heart and specific circulatory physiologies. The primary aim of this study was to determine what proportion of pediatric cardiology randomized controlled trials achieve an 80% statistical power. Secondary aims included characterizing reporting habits in these studies. A systematic review was performed to identify pertinent pediatric cardiology randomized controlled trials. The following data were collected: publication year, journal, if "power" or "sample size" were mentioned if a discrete, primary endpoint was identified. Power analyses were conducted to assess if the sample size was adequate to demonstrate results at 80% power with a p-value of less than 0.05. A total of 83 pediatric cardiology randomized controlled trials were included. Of these studies, 48% mentioned "power" or "sample size" in the methods, 49% mentioned either in the results, 12% mentioned either in the discussion, and 66% mentioned either at any point in the manuscript. 63% defined a discrete, primary endpoint. 38 studies (45%) had an adequate sample size to demonstrate differences with 80% power at a p-value of less than 0.05. A majority of these are not powered to reach the conventionally accepted 80% power target. Adequately powered studies were found to be more likely to report "power" or "sample size" and have a discrete, primary endpoint., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To compare the predictive value of the IAP and WHO criteria in identifying obesity complications in Indian children and adolescents., Methods: Blood pressure and body mass index was measured in 4434 children and adolescents [2539 boys; mean age 11.9 (3.0), 5.1-18 y] from affluent schools. The predictive accuracy of IAP 2015 and WHO BMI criteria in identifying hypertension was assessed., Results: IAP 2015 BMI criteria labelled 203 more children obese than the WHO reference (649 as against 446). Hypertension was present in 75 (37%) of these. The difference in the prevalence of hypertension in subjects obese as per IAP 2015 criteria and their nonobese counterparts (50.2% as against 10.8%, p < 0.0001) was greater than that between subjects obese only by IAP 2015 or by both the criteria (36.9% as against 56.3%, p < 0.0001). The difference in the proportion of subjects with hypertension between two consecutive IAP 2015 BMI SDS category was highest for + 1.5 in boys (32.3% as against 49.8%, p < 0.0001) and + 2 in girls (25.9% as against 59.3%, p < 0.00012)., Conclusion: IAP BMI criteria better predict hypertension in Indian children than WHO cutoffs and should be used in clinical practice to predict obesity complications., (© 2022. Dr. K C Chaudhuri Foundation.)

Objective: To develop and validate a mobile application-based tool for the management guidance of children and adolescents with diabetic ketoacidosis (DKA)., Methods: The study involved the development of a mobile application-based tool for DKA management in accordance with the International Society of Pediatric and Adolescent Diabetes (ISAPD) guidelines, 2018. The impact of the mobile application in preventing protocol deviation and resultant complications was assessed. Case records of 70 children and adolescents [39 boys, 8.9 (4.1) y of age] with severe DKA managed in the authors' intensive care unit were examined. The application guidance and real-time management were compared to the standard protocol., Results: Protocol deviations were observed in 58 (82.9%), with two or more errors in 28 (40%). These included lack of initial fluid bolus (4, 5.7%), excessive fluid supplementation (8, 11.4%), inadequate initial fluid (25, 35.7%) and potassium supplementation (13, 18.6%), delayed response to fall in potassium (15, 21.4%) and glucose levels (24, 34.3%), and erroneous insulin administration (19, 27.1%). These errors contributed to 42.1% of severe hypokalemia and 56% of significant hypoglycemia episodes. The mobile application guidance was in accordance with the protocol in all the case scenario., Conclusion: Deviation from the management protocol is common in DKA and associated with adverse outcomes. Mobile application guidance is expected to reduce the protocol deviation with a potential of improving outcomes., (© 2022. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Objectives: This study aimed to describe the process of adapting an evidence-based patient engagement intervention, enhanced medical rehabilitation (E-MR), for inpatient spinal cord injury/disease (SCI/D) rehabilitation using an implementation science framework., Design: We applied the collaborative intervention planning framework and included a community advisory board (CAB) in an intervention mapping process., Setting: A rehabilitation hospital., Participants: Stakeholders from inpatient SCI/D rehabilitation (N=7) serving as a CAB and working with the research team (N=7) to co-adapt E-MR., Interventions: E-MR., Main Outcome Measures: Logic model and matrices of change used in CAB meetings to identify areas of intervention adaptation., Results: The CAB and research team implemented adaptations to E-MR, including (1) identifying factors influencing patient engagement in SCI/D rehabilitation (eg, therapist training); (2) revising intervention materials to meet SCI/D rehabilitation needs (eg, modified personal goals interview and therapy trackers to match SCI needs); (3) incorporating E-MR into the rehabilitation hospital's operations (eg, research team coordinated with CAB to store therapy trackers in the hospital system); and (4) retaining fidelity to the original intervention while best meeting the needs of SCI/D rehabilitation (eg, maintained core E-MR principles while adapting)., Conclusions: This study demonstrated that structured processes guided by an implementation science framework can help researchers and clinicians identify adaptation targets and modify the E-MR program for inpatient SCI/D rehabilitation., (Copyright © 2022 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To study determinants and predictors of body fat in Indian children and adolescents., Methods: In this cross-sectional study, 5175 children and adolescents [3014 boys, age 12.8 (3) y, 5-18 y] participated. Determinants and predictors of body fat were assessed using partial correlation (corrected for age, and gender) and linear regression., Results: Fat percentage correlated negatively with the duration of physical activity (r = -0.091, p < 0.01) and sleep (r = -0.044, p = 0.01) and positively with parental body mass index (BMI) (r = 0.202, p < 0.01 for father and r = 0.235, p < 0.01 for mother), and birth weight (r = 0.050, p < 0.01). On linear regression, fat percentage was positively associated with parental BMI and birth weight, and negatively with physical activity and sleep duration. All adiposity markers [BMI standard deviation score (SDS) (r = 0.863, p < 0.01), weight SDS (r = 0.827, p < 0.01) waist to height ratio (r = 0.819, p < 0.01), waist circumference SDS (r = 0.765, p < 0.01) wrist circumference (r = 0.21, p < 0.01), and neck circumference (r = 0.19, p < 0.01)] correlated significantly with fat percentage, showing highest correlation with BMI SDS., Conclusion: Reduced sleep and physical activity are the key modifiable risk factors for adiposity. BMI SDS is the best clinical surrogate of body fat in Indian children and adolescents. There is a need to explore the impact of lifestyle interventions targeting sleep and physical activity on adiposity., (© 2021. Dr. K C Chaudhuri Foundation.)

Packed red blood cell (PRBC) transfusions are commonly administered in pediatric patients following the Norwood operation. This study was conducted to determine the effect of PRBC transfusions on hemodynamic parameters in pediatric patients with single-ventricle physiology and parallel circulation. A single-center, retrospective chart review was conducted. Pediatric patients admitted to the cardiac intensive care unit after Norwood operation between 2017 and 2018 were identified. Hemodynamic parameters were collected within a four-hour period before and after a PRBC transfusion. Univariate analyses using paired t tests were conducted to compare blood gas values before and after PRBC transfusion. Next, multivariate regression analyses were conducted to model the impact of transfusion volume, change in hemoglobin levels, and change in FiO2 on the change in PaO2 and PaCO2. These analyses included data from 33 eligible patients who received a PRBC transfusion following a Norwood operation. The hemoglobin levels (p < 0.01) and the PaO2/FiO2 ratio (p = 0.04) were significantly increased, while arterial lactate levels (p = 0.03) were significantly decreased following the transfusion. Transfusion for a pre-transfusion hemoglobin of 12.4 g/dL appears to provide greatest reduction in lactate, used as a surrogate marker for systemic oxygen delivery. No significant changes were found in arterial pH, PaO2, and PaCO2. PRBC transfusions following the Norwood operation may be a useful intervention to increase systemic oxygen delivery, improving PaO2/FiO2 ratio and improving serum lactate. The benefits of PRBC transfusions must be weighed against previously identified risks on a patient-specific basis. Further studies are warranted to further delineate the effects of such transfusions in this population., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Short stature is a common presentation to pediatricians with a significant overlap between physiology and pathology. Thus, while most short children have a physiological cause, growth failure may be the only manifestation of severe underlying disease. Growth failure evaluation aims to avoid unnecessary investigations in children with a physiological cause without missing pathology. Guidelines for the evaluation of short stature allow stepwise evaluation but are limited by their resource-intense nature. An objective application of anthropometric indices and careful clinical evaluation allows rational growth failure workup. The use of height standard deviation score (SDS) for determining the need for evaluation (no evaluation above -2, follow-up between -2 to -3, and immediate workup with height below -3), corrected height SDS to identify familial short stature (above -1.5), height SDS for bone age for constitutional delay of puberty and growth (above -2), and BMI SDS for nutritional pattern growth failure (below -1) helps reduce the burden of investigations. The present review provides a framework for comprehensive growth evaluation across resource levels and settings., (© 2021. Dr. K C Chaudhuri Foundation.)

Objective: Subclinical hypothyroidism is common in children and adolescents with obesity and has been considered to be its effect with no need for treatment. Its metabolic impact has not been evaluated. Therefore the present study was conducted to determine the metabolic impact of obesity related subclinical hypothyroidism., Methods: Retrospective record review of obese children and adolescents between 5 and 18 y of age presenting to pediatric endocrine clinic was done. Four hundred four obese children and adolescents [251 boys, 11.8 (3.2); 5.1-18 y, BMI SDS 2.4 (0.7); 1.4-6.6] were assessed regarding thyroid functions, adiposity (clinical and DXA derived) and metabolic complications., Results: Subclinical hypothyroidism was observed in 122 (30.2%) and was associated with higher fat percentage [49.2 (5.8) vs. 47.2 (6.4) p = 0.009], android to gynoid ratio [1.1 (0.1) vs. 1.0 (0.1), p = 0.007] and alanine aminotransferase (ALT) levels [49.3 (31.5) vs. 40.8 (38.1), p = 0.04]. Subjects with subclinical hypothyroidism had 1.9 times greater odds of having non-alcoholic steatohepatitis (47.3% vs. 31.8%, p = 0.005) with no difference in the prevalence of dyslipidemia, dysglycemia or hypertension. Subclinical hypothyroidism was the only determinant of non-alcoholic steatohepatitis on binomial logistic regression (WALD = 11.04, p = 0.001) with no impact of BMI SDS, waist circumference SDS, fat percentage or android to gynoid ratio. Thyroid stimulating hormone (TSH) was the most important determinant of ALT on linear regression (B = 3.027, p < 0.005)., Conclusions: Obesity related subclinical hypothyroidism predisposes to increased ALT and non-alcoholic steatohepatitis independent of severity adiposity. The impact of thyroid supplementation in this setting needs to be explored.

The myeloid tumor suppressor KMT2C is recurrently deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly therapy-related MDS/AML (t-MDS/t-AML), as part of larger chromosome 7 deletions. Here, we show that KMT2C deletions convey a selective advantage to hematopoietic stem cells (HSCs) after chemotherapy treatment that may precipitate t-MDS/t-AML. Kmt2c deletions markedly enhance murine HSC self-renewal capacity without altering proliferation rates. Haploid Kmt2c deletions convey a selective advantage only when HSCs are driven into cycle by a strong proliferative stimulus, such as chemotherapy. Cycling Kmt2c-deficient HSCs fail to differentiate appropriately, particularly in response to interleukin-1. Kmt2c deletions mitigate histone methylation/acetylation changes that accrue as HSCs cycle after chemotherapy, and they impair enhancer recruitment during HSC differentiation. These findings help explain why Kmt2c deletions are more common in t-MDS/t-AML than in de novo AML or clonal hematopoiesis: they selectively protect cycling HSCs from differentiation without inducing HSC proliferation themselves., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To compare the diagnostic accuracy of IAP 2015, WHO and IAP 2007 growth charts in identifying pathological short stature in Indian children., Methodology: The predictive value of the growth charts for pathological short stature was assessed in 500 (266 boys) short subjects (age 5-17.9 years) presenting to our pediatric endocrine clinic., Results: WHO, IAP 2015, IAP 2007 criteria classified 500, 410 (82%) and 331 (66.2%) subjects short respectively. A total of 218 (43.6%) subjects had a pathological cause. Two out of 90 subjects short by WHO criteria but normal as per IAP 2015 had a pathological cause (2.2%) whereas 38 out of 79 subjects short as per WHO and IAP 2015 criteria but normal by IAP 2007 had pathological short stature. The diagnostic measures of IAP 2015 and IAP 2007 charts in identifying pathological short stature showed a sensitivity 99.1% and 81.7%, negative predictive value 97.8% as against 76.3%, positive predictive value 52.7% and 53.8%, and specificity of 31.2% and 45.7%, respectively., Conclusion: IAP 2015 growth charts are superior in identifying pathological growth failure compared to WHO and IAP 2007.

Purpose: This study aimed to evaluate the risk of various substances in young acute myocardial infarction (AMI) inpatients and analyze patient demographics and hospital outcomes for significant substance use risk factors., Methods: We conducted a retrospective analysis of the Nationwide Inpatient Sample data (2010-2014). Patients (aged 15-22 years) with a primary diagnosis for AMI (N = 1,694) were compared with non-AMI (N = 9,465,255) inpatients for odds ratio (OR) of substance use by logistic regression model, adjusted for demographics, medical risk factors, and comorbid substance use., Results: Tobacco (28.4%) and cannabis (14.9%) use were most prevalent in AMI inpatients. Cocaine (OR = 3.9), amphetamine (OR = 2.3), and cannabis (OR = 1.3) users were at higher risk of AMI hospitalizations. Higher proportion of cannabis users (14.7%) had major severity of illness at admission and higher mean total charge ($53,608) compared with that seen in cocaine and amphetamine users. Angioplasty was used more in cannabis users (19.4%) than others. The in-hospital mortalities were 2.7% and 2% in overall AMI cohort and cannabis users, respectively, and none in cocaine and amphetamine users., Conclusions: Our study demonstrates a higher prevalence and significant odds of AMI inpatients with cannabis use, along with the potential cost burdens because of severe morbidity and higher use of treatment modalities. Physicians need to familiarize themselves with rising use of cannabis and other substances in adolescent and younger population and the typical presentations of cannabis-induced myocardial infarction., (Copyright © 2019 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

MLL rearrangements are translocation mutations that cause both acute lymphoblastic leukemia and acute myeloid leukemia (AML). These translocations can occur as sole clonal driver mutations in infant leukemias, suggesting that fetal or neonatal hematopoietic progenitors may be exquisitely sensitive to transformation by MLL fusion proteins. To test this possibility, we used transgenic mice to induce one translocation product, MLL-ENL , during fetal, neonatal, juvenile and adult stages of life. When MLL-ENL was induced in fetal or neonatal mice, almost all died of AML. In contrast, when MLL-ENL was induced in adult mice, most survived for >1 year despite sustained transgene expression. AML initiation was most efficient when MLL-ENL was induced in neonates, and even transient suppression of MLL-ENL in neonates could prevent AML in most mice. MLL-ENL target genes were induced more efficiently in neonatal progenitors than in adult progenitors, consistent with the distinct AML initiation efficiencies. Interestingly, transplantation stress mitigated the developmental barrier to leukemogenesis. Since fetal/neonatal progenitors were highly competent to initiate MLL-ENL -driven AML, we tested whether Lin28b , a fetal master regulator, could accelerate leukemogenesis. Surprisingly, Lin28b suppressed AML initiation rather than accelerating it. This may explain why MLL rearrangements often occur before birth in human infant leukemia patients, but transformation usually does not occur until after birth, when Lin28b levels decline. Our findings show that the efficiency of MLL-ENL -driven AML initiation changes through the course of pre- and postnatal development, and developmental programs can be manipulated to impede transformation., (© 2019 by The American Society of Hematology.)

Purpose: Sickle cell anemia is the most commonly inherited blood disorder in the United States. Despite its prevalence, clinicians know little about the extent of its impact on orofacial manifestations., Materials and Methods: All patients with diagnoses of mandible fracture and sickle cell anemia admitted from 2004 through 2014 were identified using the National Inpatient Sample. Patient demographics, fracture regions, and complications were characterized by descriptive statistics., Results: Fifty-one of 48,464 patients admitted for mandible fracture had sickle cell anemia. The mean age of the identified patients was 25 years (range, 4 to 58 yr). Of all admitted patients, mandible angle fracture was the most common (19%), followed by fracture of the body of the mandible. Seventy-five percent of cases reviewed were treated with open reduction and internal fixation., Conclusions: Most mandible fractures in patients with sickle cell anemia were located in the angle of the mandible. Complications were minimal and outcomes were satisfactory. Aseptic necrosis of the jaw was a frequent complication of mandible fracture in patients with sickle cell anemia. These results provide clinicians with a better understanding of the distribution and hospital course of patients with sickle cell anemia and facial fractures., (Copyright © 2019 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Aims: ERCP is a complex procedure often performed in patients at high risk for sedation-related adverse events (SRAEs). However, there is no current standard of care with regard to mode of sedation and airway management during ERCP. The aim of this study was to assess the safety of general endotracheal anesthesia (GEA) versus propofol-based monitored anesthesia care (MAC) without endotracheal intubation in patients undergoing ERCP at high risk for SRAEs., Methods: Consecutive patients undergoing ERCP at high risk for SRAEs at a single center were invited to participate in this randomized controlled trial comparing GEA and MAC. Inclusion criteria were STOP-BANG score ≥3, abdominal ascites, body mass index ≥35, chronic lung disease, American Society of Anesthesiologists class >3, Mallampati class 4 airway, and moderate to heavy alcohol use. Exclusion criteria were preceding EUS, emergent ERCP, tracheostomy, unstable airway, gastric outlet obstruction or delayed gastric emptying, and altered foregut anatomy. The primary endpoint was composite incidence of SRAEs: hypoxemia, use of airway maneuvers, hypotension requiring vasopressors, sedation-related procedure interruption, cardiac arrhythmia, and respiratory failure. Secondary outcomes included procedure duration, cannulation success, in-room time, and immediate adverse events., Results: Two hundred patients (mean age, 61.1 ± 13.6 years; 36.5% women) were randomly assigned to GEA (n = 101) or MAC (n = 99) groups. Composite SRAEs were significantly higher in the MAC group compared with the GEA group (51.5% vs 9.9%, P < .001). This was primarily driven by the frequent need for airway maneuvers in the MAC group. Additionally, ERCP was interrupted in 10.1% of patients in the MAC group to convert to GEA because of respiratory instability refractory to airway maneuvers (n = 8) or significant retained gastric contents (n = 2). There were no statistically significant differences in cannulation, in-room, procedure, or fluoroscopy times between the 2 groups. All patients undergoing GEA were successfully extubated in the procedure room at completion of ERCP, and Aldrete scores in recovery did not differ between the 2 groups. There were no immediate adverse events., Conclusion: In patients at high risk for SRAEs undergoing ERCP, sedation with GEA is associated with a significantly lower incidence of SRAEs, without impacting procedure duration, success, recovery, or in-room time. These data suggest that GEA should be used for ERCP in patients at high risk for SRAEs (Clinical trial registration number: NCT02850887.)., (Copyright © 2019. Published by Elsevier Inc.)

Nodal-related protein (ndr2) is amember of the transforming growth factor type β superfamily of factors and is required for ventral midline patterning of the embryonic central nervous system in zebrafish. In humans, mutations in the gene encoding nodal cause holoprosencephaly and heterotaxy. Mutations in the ndr2 gene in the zebrafish ( Danio rerio ) lead to similar phenotypes, including loss of the medial floor plate, severe deficits in ventral forebrain development and cyclopia. Alleles of the ndr2 gene have been useful in studying patterning of ventral structures of the central nervous system. Fifteen different ndr2 alleles have been reported in zebrafish, of which eight were generated using chemical mutagenesis, four were radiation-induced and the remaining alleles were obtained via random insertion, gene targeting (TALEN) or unknown methods. Therefore, most mutation sites were random and could not be predicted a priori. Using the CRISPR-Cas9 system from Streptococcus pyogenes, we targeted distinct regions in all three exons of zebrafish ndr2 and observed cyclopia in the injected (G 0 ) embryos.We show that the use of sgRNA-Cas9 ribonucleoprotein (RNP) complexes can cause penetrant cyclopic phenotypes in injected (G 0 ) embryos. Targeted polymerase chain reaction amplicon analysis using Sanger sequencing showed that most of the alleles had small indels resulting in frameshifts. The sequence information correlates with the loss of ndr2 activity. In this study, we validate multiple CRISPR targets using an in vitro nuclease assay and in vivo analysis using embryos. We describe one specific mutant allele resulting in the loss of conserved terminal cysteine-coding sequences. This study is another demonstration of the utility of the CRISPR-Cas9 system in generating domain-specific mutations and provides further insights into the structure-function of the ndr2 gene.

The role of Y chromosome in prostate cancer progression and incidence is not well known. Among the 46 chromosomes, Y chromosome determines the male gender. The Y chromosome is smaller than the X chromosome and contains only 458 genes compared to over 2000 genes found in the X chromosome. The Y chromosome is prone to high mutation rates, created exclusively in sperm cells due to the highly oxidative environment of the testis. Y chromosome harbors epigenetic information, which affects the expression of genes associated with the incidence and progression of prostate cancer. In this review, we focus on Y chromosome related genetic abnormalities, likely to be involved in the development and progression of prostate cancer.