Association of Advanced Airway Insertion Timing and Outcomes After Out-of-Hospital Cardiac Arrest.

STUDY OBJECTIVE: While often prioritized in the resuscitation of patients with out-of-hospital cardiac arrest, the optimal timing of advanced airway insertion is unknown. We evaluated the association between the timing of advanced airway (laryngeal tube and endotracheal intubation) insertion attempt and survival to hospital discharge in adult out-of-hospital cardiac arrest. METHODS: We performed a secondary analysis of the Pragmatic Airway Resuscitation Trial (PART), a clinical trial comparing the effects of laryngeal tube and endotracheal intubation on outcomes after adult out-of-hospital cardiac arrest. We stratified the cohort by randomized airway strategy (laryngeal tube or endotracheal intubation). Within each subset, we defined a time-dependent propensity score using patients, arrest, and emergency medical services systems characteristics. Using the propensity score, we matched each patient receiving an initial attempt of laryngeal tube or endotracheal intubation with a patient at risk of receiving laryngeal tube or endotracheal intubation attempt within the same minute. RESULTS: Of 2,146 eligible patients, 1,091 (50.8%) and 1,055 (49.2%) were assigned to initial laryngeal tube and endotracheal intubation strategies, respectively. In the propensity score-matched cohort, timing of laryngeal tube insertion attempt was not associated with survival to hospital discharge: 0 to lesser than 5 minutes (risk ratio [RR]=1.35, 95% confidence interval [CI] 0.53 to 3.44); 5 to lesser than10 minutes (RR=1.07, 95% CI 0.66 to 1.73); 10 to lesser than 15 minutes (RR=1.17, 95% CI 0.60 to 2.31); or 15 to lesser than 20 minutes (RR=2.09, 95% CI 0.35 to 12.47) after advanced life support arrival. Timing of endotracheal intubation attempt was also not associated with survival: 0 to lesser than 5 minutes (RR=0.50, 95% CI 0.05 to 4.87); 5 to lesser than10 minutes (RR=1.20, 95% CI 0.51 to 2.81); 10 to lesser than15 minutes (RR=1.03, 95% CI 0.49 to 2.14); 15 to lesser than 20 minutes (RR=0.85, 95% CI 0.30 to 2.42); or more than/equal to 20 minutes (RR=0.71, 95% CI 0.07 to 7.14). CONCLUSION: In the PART, timing of advanced airway insertion attempt was not associated with survival to hospital discharge.

The Association Between the Number of Prehospital Providers On-Scene and Out-of-Hospital Cardiac Arrest Outcomes.

Objective: The ideal number of emergency medical services (EMS) providers needed on-scene during an out-of-hospital cardiac arrest (OHCA) resuscitation is unknown. Our objective was to evaluate the association between the number of providers on-scene and OHCA outcomes. Methods: This was a secondary analysis of adults (≥18 years old) with non-traumatic OHCA from a 10-site North American prospective cardiac arrest registry (Resuscitation Outcomes Consortium) including a 2005-2011 cohort and a 2011-2015 cohort. The primary outcome was survival to hospital discharge. We calculated the median number of EMS providers on-scene during the first 10 minutes of the resuscitation and used multivariable logistic regression adjusting for age, sex, witness status, bystander CPR, arrest location, initial rhythm, and dispatch to EMS arrival time. Results: There were 30,613 and 41,946 patients with necessary variables in the 2005-2011 and 2011-2015 cohorts, respectively. Survival to hospital discharge (95% CI) was higher with 9 or more providers on-scene (17.2% [15.8-18.5] and 14.0% [12.6-15.4]) compared to 7-8 (14.1% [13.4-14.8] and 10.5% [9.9-11.1]), 5-6 (10.0% [9.5-10.5] and 8.5% [8.1-8.9]), 3-4 (10.5% [9.3-11.6] and 9.3% [8.5-10.1]), and 1-2 (8.6% [7.2-10.0] and 8.0% [7.1-9.0]) providers for the 2005-2011 and 2011-2015 cohorts, respectively. In multivariable logistic regressions, compared to 5-6 providers, there were no significant differences in survival to hospital discharge for 1-2 or 3-4 providers, while having 7-8 (adjusted odds ratios (aORs) 1.53 [1.39-1.67] and 1.31 [1.20-1.44]) and 9 or more (aORs 1.76 [1.56-1.98] and 1.63 [1.41-1.89]) providers were associated with improved survival in both the 2005-2011 and 2011-2015 cohorts, respectively. Conclusions: The presence of seven or more prehospital providers on-scene was associated with significantly greater adjusted odds of survival to hospital discharge after OHCA compared to fewer on-scene providers.

Cluster cross-over randomised trial of paediatric airway management devices in the simulation lab and operating room among paramedic students.

OBJECTIVES: The objective of this study was to compare paediatric emergency airway management strategies in the simulation lab and operating room environments. METHODS: This was a two-part cluster cross-over randomised trial including simulation lab and operating room environments conducted between January 2017 and June 2018 in Portland, Oregon, USA. In simulated infant cardiac arrests, paramedic students placed an endotracheal tube, an i-gel or a laryngeal mask airway in random order. In the operating room, paramedic students placed a laryngeal mask airway or i-gel device in random order in sequential patients. The primary outcome for both portions of the study was time to ventilation. In the operating room portion, we also evaluated leak pressures and average initial tidal volumes. RESULTS: There were 58 paramedic students who participated in the simulation lab and 22 who participated in the operating room study. The mean time to airway placement in the simulation lab was 48.5 s for the i-gel, 68.9 s for the laryngeal mask and 129.5 s for the endotracheal tube. In the operating room, mean time to i-gel placement was 34.3 s with 45.2 s for the laryngeal mask. In multivariable analysis of the simulation study, the laryngeal mask and i-gel were significantly faster than the endotracheal tube, and the i-gel was faster than the laryngeal mask. In the operating room, there was no significant difference in time to placement, leak pressure and average volume of the first five breaths between the i-gel and laryngeal mask. CONCLUSIONS: We found that paramedic students were able to place supraglottic devices rapidly with high success rates in simulation lab and operating room environments. Supraglottic devices, particularly the i-gel, were rated as easy to use. The i-gel may be easiest to use since it lacks an inflable cuff and requires fewer steps to place.

Association of Intra-arrest Transport vs Continued On-Scene Resuscitation With Survival to Hospital Discharge Among Patients With Out-of-Hospital Cardiac Arrest.

Importance: There is wide variability among emergency medical systems (EMS) with respect to transport to hospital during out-of-hospital cardiac arrest (OHCA) resuscitative efforts. The benefit of intra-arrest transport during resuscitation compared with continued on-scene resuscitation is unclear. Objective: To determine whether intra-arrest transport compared with continued on-scene resuscitation is associated with survival to hospital discharge among patients experiencing OHCA. Design, Setting, and Participants: Cohort study of prospectively collected consecutive nontraumatic adult EMS-treated OHCA data from the Resuscitation Outcomes Consortium (ROC) Cardiac Epidemiologic Registry (enrollment, April 2011-June 2015 from 10 North American sites; follow-up until the date of hospital discharge or death [regardless of when either event occurred]). Patients treated with intra-arrest transport (exposed) were matched with patients in refractory arrest (at risk of intra-arrest transport) at that same time (unexposed), using a time-dependent propensity score. Subgroups categorized by initial cardiac rhythm and EMS-witnessed cardiac arrests were analyzed. Exposures: Intra-arrest transport (transport initiated prior to return of spontaneous circulation), compared with continued on-scene resuscitation. Main Outcomes and Measures: The primary outcome was survival to hospital discharge, and the secondary outcome was survival with favorable neurological outcome (modified Rankin scale <3) at hospital discharge. Results: The full cohort included 43 969 patients with a median age of 67 years (interquartile range, 55-80), 37% were women, 86% of cardiac arrests occurred in a private location, 49% were bystander- or EMS-witnessed, 22% had initial shockable rhythms, 97% were treated by out-of-hospital advanced life support, and 26% underwent intra-arrest transport. Survival to hospital discharge was 3.8% for patients who underwent intra-arrest transport and 12.6% for those who received on-scene resuscitation. In the propensity-matched cohort, which included 27 705 patients, survival to hospital discharge occurred in 4.0% of patients who underwent intra-arrest transport vs 8.5% who received on-scene resuscitation (risk difference, 4.6% [95% CI, 4.0%- 5.1%]). Favorable neurological outcome occurred in 2.9% of patients who underwent intra-arrest transport vs 7.1% who received on-scene resuscitation (risk difference, 4.2% [95% CI, 3.5%-4.9%]). Subgroups of initial shockable and nonshockable rhythms as well as EMS-witnessed and unwitnessed cardiac arrests all had a significant association between intra-arrest transport and lower probability of survival to hospital discharge. Conclusions and Relevance: Among patients experiencing out-of-hospital cardiac arrest, intra-arrest transport to hospital compared with continued on-scene resuscitation was associated with lower probability of survival to hospital discharge. Study findings are limited by potential confounding due to observational design.

Theophylline and Caffeine as Alternatives During an Aminophylline Shortage.

The latest aminophylline shortage has prompted a need for alternative reversal agents for pharmacological stress testing. Cardiac stress testing is common for diagnosis and prognosis in patients with coronary heart disease. Options for pharmacological stress test agents include adenosine, regadenoson, dipyridamole, and dobutamine, whereas aminophylline is the recommended reversal agent. Adenosine and dobutamine can be used as alternatives to regadenoson and dipyridamole to decrease or eliminate the use of aminophylline. Alternatives to aminophylline include theophylline and caffeine. It is important to efficiently identify alternatives during a drug shortage to maintain optimal patient outcomes.

FAK is required for c-Met/ß-catenin-driven hepatocarcinogenesis.

UNLABELLED: Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide and most patients with HCC have limited treatment options. Focal adhesion kinase (FAK) is overexpressed in many HCC specimens, offering a potential target for HCC treatment. However, the role of FAK in hepatocarcinogenesis remains elusive. Establishing whether FAK expression plays a role in HCC development is necessary to determine whether it is a viable therapeutic target. In this study, we generated mice with hepatocyte-specific deletion of Fak and investigated the role of Fak in an oncogenic (c-MET/ß-catenin, MET/CAT)-driven HCC model. We found that deletion of Fak in hepatocytes did not affect morphology, proliferation, or apoptosis. However, Fak deficiency significantly repressed MET/CAT-induced tumor development and prolonged survival of animals with MET/CAT-induced HCC. In mouse livers and HCC cell lines, Fak was activated by MET, which induced the activation of Akt/Erk and up-regulated cyclin D1 and tumor cell proliferation. CAT enhanced MET-stimulated FAK activation and synergistically induced the activation of the AKT/ERK-cyclin D1 signaling pathway in a FAK kinase-dependent manner. In addition, FAK was required for CAT-induced cyclin D1 expression in a kinase-independent fashion. CONCLUSION: Fak is required for c-Met/ß-catenin-driven hepatocarcinogenesis. Inhibition of FAK provides a potential strategy to treat HCC.

Functional specificity of CpG DNA-binding CXXC domains in mixed lineage leukemia.

The MLL CXXC domain binds nonmethylated CpG-containing DNA and is essential for the oncogenic properties of MLL fusion proteins. To determine potential functional promiscuity of similar DNA binding domains, we replaced the MLL CXXC domain in the context of the leukemogenic MLL-AF9 fusion with CXXC domains from DNMT1, CGBP (CFP1), and MBD1, or with a methyl-CpG-binding domain (MBD) from MBD1. MLL(DNMT1 CXXC)-AF9 shows robust in vitro colony forming activity and in vivo leukemogenesis, similar to MLL-AF9. However, colony forming ability and leukemogenicity are abrogated in MLL-AF9 containing either the CGBP or MBD1 CXXC domains or the MBD1 MBD domain. Direct comparison of in vitro DNA binding affinity of the isolated CXXC or MBD domains demonstrated that MLL, DNMT1, and CGBP CXXC domains could each bind to unmethylated DNA but with differing affinity. In contrast, the isolated MBD1 CXXC and MBD1 MBD domains were unable to bind to the same DNA. However, all substituted domains still allowed targeting of the MLL fusions to the functionally important Hoxa9 locus in primary bone marrow progenitor cells. In addition to DNA binding activity, it was critical that specific CpG residues in the Hoxa9 locus were protected from methylation for leukemia development. This ultimately prevented histone 3 lysine 9 trimethylation (H3K9me3) of the locus and enabled Hoxa9 expression. These were properties shared by MLL and DNMT1 CXXC domains but not by CGBP CXXC or the other swapped fusions tested. We demonstrate that similar CXXC domains can be mechanistically distinguished by specificity of CpG nucleotides preferentially protected from DNA methylation.

Overexpression of Foxn1 attenuates age-associated thymic involution and prevents the expansion of peripheral CD4 memory T cells.

The forkhead box n1 (Foxn1) transcription factor is essential for thymic organogenesis during embryonic development; however, a functional role of Foxn1 in the postnatal thymus is less well understood. We developed Foxn1 transgenic mice (Foxn1Tg), in which overexpression of Foxn1 is driven by the human keratin-14 promoter. Expression of the Foxn1 transgene increased the endogenous Foxn1 levels. In aged mice, overexpression of Foxn1 in the thymus attenuated the decline in thymocyte numbers, prevented the decline in frequency of early thymic progenitors, and generated a higher number of signal joint TCR excised circle. Histologic studies revealed that structural alterations associated with thymic involution were diminished in aged Foxn1 Tg. Total numbers of EpCAM+ MHC II+ and MHC II(hi) thymic epithelial cells were higher in young and old Foxn1Tg and more EpCAM+ MHC II(hi) TEC expressed Ki-67 in aged Foxn1Tg compared with WT. Furthermore, Foxn1Tg displayed a significant reduction in the expansion of splenic CD4+ memory compartments and attenuated the decline in CD4+ and CD8+ naive compartments. Our data indicate that manipulation of Foxn1 expression in the thymus ameliorates thymopoiesis in aged mice and offer a strategy to combat the age-associated decline in naive T-cell production and CD4 naive/memory ratios in the elderly.

Aberrant overexpression and function of the miR-17-92 cluster in MLL-rearranged acute leukemia.

MicroRNA (miRNA)-17-92 cluster (miR-17-92), containing seven individual miRNAs, is frequently amplified and overexpressed in lymphomas and various solid tumors. We have found that it is also frequently amplified and the miRNAs are aberrantly overexpressed in mixed lineage leukemia (MLL)-rearranged acute leukemias. Furthermore, we show that MLL fusions exhibit a much stronger direct binding to the locus of this miRNA cluster than does wild-type MLL; these changes are associated with elevated levels of histone H3 acetylation and H3K4 trimethylation and an up-regulation of these miRNAs. We further observe that forced expression of this miRNA cluster increases proliferation and inhibits apoptosis of human cells. More importantly, we show that this miRNA cluster can significantly increase colony-forming capacity of normal mouse bone marrow progenitor cells alone and, particularly, in cooperation with MLL fusions. Finally, through combinatorial analysis of miRNA and mRNA arrays of mouse bone marrow progenitor cells transfected with this miRNA cluster and/or MLL fusion gene, we identified 363 potential miR-17-92 target genes that exhibited a significant inverse correlation of expression with the miRNAs. Remarkably, these potential target genes are significantly enriched (P < 0.01; >2-fold) in cell differentiation, hematopoiesis, cell cycle, and apoptosis. Taken together, our studies suggest that overexpression of miR-17-92 cluster in MLL-rearranged leukemias is likely attributed to both DNA copy number amplification and direct up-regulation by MLL fusions, and that the miRNAs in this cluster may play an essential role in the development of MLL-associated leukemias through inhibiting cell differentiation and apoptosis, while promoting cell proliferation, by regulating relevant target genes.

A Rare Case of Varicella-Zoster Virus Encephalitis Presenting With Lost Ability to Play the Piano in an Immunocompetent Pediatric Patient.

Varicella-zoster virus (VZV) is a member of the alpha-herpesvirus family, which can occasionally cause severe neurological complications such as encephalitis. In this case report, we discuss a rare finding of VZV encephalitis in which an immunocompetent pediatric patient, vaccinated against varicella, presented with altered mental status and no vesicular rash. A 15-year-old male presented to the Emergency Department with progressively worsening altered mental status over the past three days. The patient's mother stated that he was exhibiting frequent memory lapses as well as the sudden loss of the ability to play the piano. After admission to the pediatric general floor, lumbar puncture was performed and cerebrospinal fluid analysis returned positive for VZV, confirmed by polymerase chain reaction. The patient was then started on intravenous (IV) acyclovir at a dose of 650 mg every 8 hours to treat VZV-induced encephalitis. While the patient continued to have intermittent episodes of confusion and headaches, his overall condition improved, and by day 4, he was able to resume playing the piano and ukulele. The patient was discharged on day 8 with no home medications, and a follow-up with this primary care physician was scheduled. This patient is one of only four recorded cases of VZV encephalitis in immunocompetent children. It is extremely rare to encounter pediatric patients with this diagnosis and, as such, can elude physicians when developing differential diagnoses. If VZV is suspected, a lumbar puncture should be performed promptly, and, if confirmed, IV acyclovir should be started. Furthermore, this case highlights the need for future research with regard to VZV and potential predisposing factors in immunocompetent patients.

Culture-Negative Fibrinous Peritonitis in a Postpartum Female.

Peritonitis is inflammation of the peritoneum that can arise from a number of complications affecting the lining of the abdominal wall and organs. Acute abdomen and peritonitis is a rare complication in a previously healthy woman following a seemingly uncomplicated normal full-term vaginal delivery. We report such a case in a 20-year-old gravida 2 para 2 (G2P2) woman of Guatemalan descent, who presented nine days postpartum following an uncomplicated delivery, to the emergency room with acute abdomen and associated systemic inflammatory reaction. Interventional radiology paracentesis was performed, yielding a milky, purulent peritoneal fluid with no visible organisms and negative cultures. Antibiotics and paracentesis were insufficient in managing her condition, which continued to worsen over the course of several days. Given her continued deterioration despite clinical intervention, she underwent an exploratory laparotomy and peritoneal lavage along with continued broad-spectrum antibiotics. Cultures continued to be negative but operative findings included diffuse fibrinous peritonitis with no obvious abscess or perforated abdominal viscus. Following surgical laparotomy, she recovered fully without any complications. We review the available literature regarding peritonitis, discuss its management, and speculate as to its cause in this case.

Hydropneumothorax as a Presentation of Birt-Hogg-Dubé Syndrome.

Birt-Hogg-Dubé syndrome (BHDS) is a rare genetic disorder characterized by cutaneous, pulmonary, and renal manifestations. We present a unique case in which a combination of multiple chronic illnesses, genetic testing, and significant family history led to a diagnosis of BHDS. A 72-year-old male patient presented to their primary care physician with a persistent cough of four months and was admitted to the emergency department after the discovery of a left hydropneumothorax. The patient's medical history was significant for recurrent spontaneous bilateral pneumothoraces diagnosed over 20 years ago, chronic obstructive pulmonary disease (COPD), and many other systemic illnesses. A combination of the patient's significant past medical and family history led to a diagnosis of BHDS. Genetic testing was also done to confirm the diagnosis. Despite benign skin lesions being the most common finding, they are not always present, as seen in our case, which can result in missed diagnosis. Due to the autosomal dominant nature of BHDS, it is vital to make an accurate diagnosis to allow for proper genetic counseling, as the development of renal cancer is the leading cause of mortality.

Metabolic and quality of life effects of growth hormone replacement in patients with TBI and AGHD: A pilot study.

OBJECTIVE: Traumatic brain injury (TBI), a common cause of adult growth hormone deficiency (AGHD), affects 20% of Veterans returning from Iraq and Afghanistan (OEF/OIF/OND). Growth hormone replacement therapy (GHRT) improves quality of life (QoL) in AGHD but remains unexplored in this population. This pilot, observational study investigates the feasibility and efficacy of GHRT in AGHD following TBI. DESIGN: In this 6-month study of combat Veterans with AGHD and TBI starting GHRT (N = 7), feasibility (completion rate and rhGH adherence) and efficacy (improvements in self-reported QoL) of GHRT were measured (primary outcomes). Secondary outcomes included body composition, physical and cognitive function, psychological and somatic symptoms, physical activity, IGF-1 levels and safety parameters. It was hypothesized that participants would adhere to GHRT and that QoL would significantly improve after six months. RESULTS: Five subjects (71%) completed all study visits. All patients administered daily rhGH injections, 6 (86%) of whom consistently administered the clinically-prescribed dose. While QoL demonstrated numeric improvement, this change did not reach statistical significance (p = 0.17). Significant improvements were observed in total lean mass (p = 0.02), latissimus dorsi strength (p = 0.05), verbal learning (Trial 1, p = 0.02; Trial 5, p = 0.03), attention (p = 0.02), short-term memory (p = 0.04), and post-traumatic stress disorder (PTSD) symptoms (p = 0.03). Body weight (p = 0.02) and total fat mass (p = 0.03) increased significantly. CONCLUSION: GHRT is a feasible and well-tolerated intervention for U.S. Veterans with TBI-related AGHD. It improved key areas impacted by AGHD and symptoms of PTSD. Larger, placebo-controlled studies testing the efficacy and safety of this intervention in this population are warranted.

Mindfulness based stress reduction in post-treatment breast cancer patients: an examination of symptoms and symptom clusters.

To investigate prevalence and severity of symptoms and symptom clustering in breast cancer survivors who attended MBSR(BC). Women were randomly assigned into MBSR(BC) or Usual Care (UC). Eligible women were ≥ 21 years, had been diagnosed with breast cancer and completed treatment within 18 months of enrollment. Symptoms and interference with daily living were measured pre- and post-MBSR(BC) using the M.D. Anderson Symptom Inventory. Symptoms were reported as highly prevalent but severity was low. Fatigue was the most frequently reported and severe symptom among groups. Symptoms clustered into 3 groups and improved in both groups. At baseline, both MBSR(BC) and the control groups showed similar mean symptom severity and interference; however, after the 6-week post-intervention, the MBSR(BC) group showed statistically-significant reduction for fatigue and disturbed sleep (P < 0.01) and improved symptom interference items, compared to the control group. For the between-group comparisons, 11 of 13 symptoms and 5 of 6 interference items had lower means in the MBSR(BC) condition than the control condition. These results suggest that MBSR(BC) modestly decreases fatigue and sleep disturbances, but has a greater effect on the degree to which symptoms interfere with many facets of life. Although these results are preliminary, MBSR intervention post-treatment may effectively reduce fatigue and related interference in QOL of breast cancer survivors.

State of the Evidence for Proximal Junctional Kyphosis Prevention in Adult Spinal Deformity Surgery: A Systematic Review of Current Literature.

OBJECTIVE: Proximal junctional kyphosis (PJK) is a widely recognized complication of adult spinal deformity surgery, and various PJK prevention strategies have been reported in recent years. The goal of the present study was to perform a systematic review of the PJK prevention strategies, report on their effectiveness, and delineate future directions for investigation regarding PJK prevention. METHODS: A systematic review was conducted using PubMed, Embase, and Scopus to identify studies examining PJK prevention techniques. The titles and abstracts were screened, and those studies progressing to the full text review were screened using prespecified inclusion and exclusion criteria. The studies were organized thematically for analysis. RESULTS: The search identified a total of 382 studies, 23 of which were included. The overall quality of evidence was level III. The reported PJK prevention strategies included optimization of postoperative sagittal alignment by avoiding over- or undercorrection, prophylactic vertebral cement augmentation, the use of a transverse process hook at upper instrumented vertebra, the use of more flexible rod constructs, novel pedicle screw insertion techniques, the use of junctional tethers, and teriparatide therapy, which seemed to reduce the PJK rates. CONCLUSIONS: The reports of PJK prevention strategies were heterogeneous, and high-level evidence regarding any particular technique remains limited. Further development of additional PJK prevention techniques and validation of their efficacy in clinical practice are needed to optimize the outcomes of adult spinal deformity surgery.

Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization.

Chromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene produce chimeric proteins that cause abnormal expression of a subset of HOX genes and leukemia development. Here, we show that MLL normally regulates expression of mir-196b, a hematopoietic microRNA located within the HoxA cluster, in a pattern similar to that of the surrounding 5' Hox genes, Hoxa9 and Hoxa10, during embryonic stem (ES) cell differentiation. Within the hematopoietic lineage, mir-196b is most abundant in short-term hematopoietic stem cells and is down-regulated in more differentiated hematopoietic cells. Leukemogenic MLL fusion proteins cause overexpression of mir-196b, while treatment of MLL-AF9 transformed bone marrow cells with mir-196-specific antagomir abrogates their replating potential in methylcellulose. This demonstrates that mir-196b function is necessary for MLL fusion-mediated immortalization. Furthermore, overexpression of mir-196b was found specifically in patients with MLL associated leukemias as determined from analysis of 55 primary leukemia samples. Overexpression of mir-196b in bone marrow progenitor cells leads to increased proliferative capacity and survival, as well as a partial block in differentiation. Our results suggest a mechanism whereby increased expression of mir-196b by MLL fusion proteins significantly contributes to leukemia development.

MLL protects CpG clusters from methylation within the Hoxa9 gene, maintaining transcript expression.

Homeobox (HOX) genes play a definitive role in determination of cell fate during embryogenesis and hematopoiesis. MLL-related leukemia is coincident with increased expression of a subset of HOX genes, including HOXA9. MLL functions to maintain, rather than initiate, expression of its target genes. However, the mechanism of MLL maintenance of target gene expression is not understood. Here, we demonstrate that Mll binds to specific clusters of CpG residues within the Hoxa9 locus and regulates expression of multiple transcripts. The presence of Mll at these clusters provides protection from DNA methylation. shRNA knock-down of Mll reverses the methylation protection status at the previously protected CpG clusters; methylation at these CpG residues is similar to that observed in Mll null cells. Furthermore, reconstituting MLL expression in Mll null cells can reverse DNA methylation of the same CpG residues, demonstrating a dominant effect of MLL in protecting this specific region from DNA methylation. Intriguingly, an oncogenic MLL-AF4 fusion can also reverse DNA methylation, but only for a subset of these CpGs. This method of transcriptional regulation suggests a mechanism that explains the role of Mll in transcriptional maintenance, but it may extend to other CpG DNA binding proteins. Protection from methylation may be an important mechanism of epigenetic inheritance by regulating the function of both de novo and maintenance DNA methyltransferases.

Heart Rate Variability and Its Ability to Detect Worsening Suicidality in Adolescents: A Pilot Trial of Wearable Technology.

OBJECTIVE: Suicide is the 2nd leading cause of death in adolescence, and acute pediatric mental health emergency department (ED) visits have doubled in the past decade. The objective of this study was to evaluate physiologic parameters relationship to suicide severity. METHODS: This was a prospective, observational study from April 2018 thru November 2019 in a tertiary care pediatric emergency department (ED) and inpatient pediatric psychiatric unit enrolling acutely suicidal adolescent patients. Patients wore a wrist device that used photoplethysmography for 7 days during their acute hospitalization to measure heart rate variability (HRV). During that time, Columbia Suicide Severity Scores (CSSRS) were assessed at 3 time points. RESULTS: There was complete device data and follow-up for 51 patients. There was an increase in the high frequency (HF) component of HRV in patients that had a 25% or greater decrease in their CSSRS (mean difference 11.89 ms/ Hz ; p-value 0.005). Patients with a CSSRS≥15 on day of enrollment had a lower, although not statistically significant, HF component (mean difference -8.34 ms/ Hz; p-value 0.071). CONCLUSION: We found an inverse correlation between parasympathetic activity measured through the HF component and suicidality in an acutely suicidal population of adolescents. Wearable technology may have the ability to improve outpatient monitoring for earlier detection and intervention.

Capturing the Experiences and Challenges of Emerging Adults in College During the COVID-19 Pandemic.

Emerging adulthood (ages 18-30 years) coincides with "aging out" of pediatric care. As a result, combined internal medicine and pediatrics (Med-Peds) providers are tasked with promoting the health and well-being of this population during and post-coronavirus disease 2019 (COVID-19). In order to inform the response efforts, we aimed to capture emerging adults' COVID-19 experiences and challenges during a two-week period of the pandemic in June 2020. We administered items from the California Health Interview Survey and an open-ended qualitative item via Qualtrics to 242 diverse emerging adults enrolled in a large US public university (mean age = 20.10, SD = 1.26). More than 90% of all students reported that they or their families or close friends experienced difficulties coping with the stressors and challenges presented by COVID-19. Almost half experienced financial difficulties and more than three-fourths experienced household disruptions during the pandemic. Qualitative findings underscored that these challenges were compounded by mental health and broader social issues. Recommendations for Med-Peds providers are provided to promote emerging adulthood health during and post-pandemic.

Prospective evaluation of airway management in pediatric out-of-hospital cardiac arrest.

OBJECTIVE: The objective of the study was to identify the association between airway management modality and time to the initial dose of epinephrine in pediatric out-of-hospital cardiac arrest (OHCA). METHODS: This was a prospective observational study conducted between April 2016 to April 2018. Ten Emergency Medical Services (EMS) agencies in 2 US metropolitan areas, which were part of the Resuscitation Outcomes Consortium research network, participated in the study. We included all EMS-treated OHCA patients less than 18 years of age during the study period. Study outcomes included time to the initial dose of epinephrine, airway management success rates, rescue techniques, and complications (e.g. pneumothorax, pneumonia). RESULTS: The study included a total of 155 patients, 67% were male, and 55% were less than age one. The airway management modality (TI, SGA, BMV) was not associated with the time to the intial dose of epinephrine in the adjusted analysis. Tracheal intubation (TI) was the most common airway management modality (47.1%) followed by bag-mask-ventilation (BMV) (40.7%), and supraglottic airways (SGA) (12.3%). Success was 65.7% for TI and 94.7% for SGA. We found a significant difference in the proportion of initial survivors diagnosed with pneumonia on chest X-ray between those with BMV (1/19) versus TI (13/21) p < 0.001. CONCLUSIONS: In this prospective study, the airway management modality was not associated with the time to the initial dose of epinephrine. Unexpectedly, pneumonia was significantly more common among children treated with TI compared to BMV. SGAs had high first-attempt success rates, while intubation success rates were low.