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Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-Cre ERT2 knock-in mouse. When crossed to CAG-LSL-Myc T58A mice, Msi2-Cre ERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2 + pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2 + cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer., Competing Interests: Declaration of interests T.R. is a founder and member of the Board of Directors, and holds executive roles at Tiger Hill Therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pancreatic cancer is characterized by extensive resistance to conventional therapies, making clinical management a challenge. Here we map the epigenetic dependencies of cancer stem cells, cells that preferentially evade therapy and drive progression, and identify SWI/SNF complex member SMARCD3 as a regulator of pancreatic cancer cells. Although SWI/SNF subunits often act as tumor suppressors, we show that SMARCD3 is amplified in cancer, enriched in pancreatic cancer stem cells and upregulated in the human disease. Diverse genetic mouse models of pancreatic cancer and stage-specific Smarcd3 deletion reveal that Smarcd3 loss preferentially impacts established tumors, improving survival especially in context of chemotherapy. Mechanistically, SMARCD3 acts with FOXA1 to control lipid and fatty acid metabolism, programs associated with therapy resistance and poor prognosis in cancer. These data identify SMARCD3 as an epigenetic modulator responsible for establishing the metabolic landscape in aggressive pancreatic cancer cells and a potential target for new therapies., (© 2023. The Author(s).)

Despite gains in knowledge of the intrinsic signals governing cancer progression, effective clinical management of cancer remains a challenge. Drug resistance and relapse, pose the greatest barriers to cancer care, and are often driven by the co-option of stem cell programs by subpopulations of aggressive cancer cells. Here, we focus on the role of the microenvironment in the acquisition and/or maintenance of stem cell states in cancer in the context of resistance and metastasis. We further discuss the role of cancer stem cells in immune evasion through the course of metastasis, dormancy, and relapse. Understanding the niche in which cancer stem cells live and the signals that sustain them may lead to new strategies that target them by disrupting microenvironmental support., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Three patients ranging from 49 to 61 years-old presented to our pain clinic after failing multiple treatment attempts for debilitating, chronic post-traumatic headaches, neck pain and involuntary muscle spasm following gunshot wounds to the head, neck and face. Concurrent cervical dystonia was noted in each patient on presentation. All patients were treated with onabotulinumtoxin A (ONA) injections in the head and neck. Each patient reported between 70% and 100% improvement of their headache pain, neck pain and spasm with a significant reduction in the frequency, duration and intensity of their headaches. This level of improvement has been successfully maintained in all three patients with regular ONA injections at 90-day intervals. Two patients experienced a single relapse in symptoms when scheduling conflicts caused them to miss their regularly scheduled ONA injections by several weeks. These symptoms resolved when their ONA injections resumed, suggesting that ONA is the causative agent alleviating their symptoms., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To evaluate the effectiveness of a quality-improvement initiative in reducing cardiac arrests in infants and children in the cardiac ICU., Design: Prospective observational before-after cohort study., Setting: Single pediatric cardiac ICU in the United Kingdom., Patients: All patients less than 18 years old admitted to the ICU., Intervention: Initial interdisciplinary training in cardiac arrest prevention followed by clinical practice change whereby patients with high-risk myocardium were identified on daily rounds. High-risk patients had bolus epinephrine preordered and prepared for immediate administration in the event of acute hypotension., Measurements and Main Results: Interrupted time series analysis was used to compare the cardiac arrest rate in the 18 months before and 4.5 years after implementation. Mean monthly cardiac arrest rate was 17.2 per 1,000 patient days before and 7.6 per 1,000 patient days after the initiative (56% decrease). Patient characteristics and ICU interventions were similar in the control and intervention periods. In the time series analysis, monthly cardiac arrest rate in the ICU decreased by 12.4 per 1,000 patient days (95% CI, -1.5 to -23.3; p = 0.03) immediately following the intervention, followed by a nonsignificant downward trend of 0.36 per 1,000 patient days per month (95% CI, -1.3 to 0.6; p = 0.44). Bolus epinephrine was administered during 110 hypotension events in 77 patients (eight administrations per 1,000 ICU days); responder rate was 77%. There were no significant changes in ICU and hospital mortality., Conclusions: Implementation of the initiative led to a significant, sustained reduction in ICU cardiac arrest rate.

In our daily lives, we consume foods that have been transported, stored, prepared, cooked, or otherwise processed by ourselves or others. Food storage and preparation have drastic effects on the chemical composition of foods. Untargeted mass spectrometry analysis of food samples has the potential to increase our chemical understanding of these processes by detecting a broad spectrum of chemicals. We performed a time-based analysis of the chemical changes in foods during common preparations, such as fermentation, brewing, and ripening, using untargeted mass spectrometry and molecular networking. The data analysis workflow presented implements an approach to study changes in food chemistry that can reveal global alterations in chemical profiles, identify changes in abundance, as well as identify specific chemicals and their transformation products. The data generated in this study are publicly available, enabling the replication and re-analysis of these data in isolation, and serve as a baseline dataset for future investigations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The optimal method for monitoring antiplatelet therapy in children supported with ventricular assist devices (VADs) is unknown. We conducted a retrospective study to compare Thromboelastography Platelet Mapping (TEG/PM) with multiple electrode platelet aggregometry (MEA) on a Multiplate analyzer (Roche Diagnostics, Mannheim, Germany). We analyzed data from 66 paired blood samples from 9 patients <16 years of age on VAD where platelet function was simultaneously measured with TEG/PM and MEA. Antiplatelet dose-response relationships and intraindividual variability during steady state therapy were determined. Agreement in determination of therapeutic antiplatelet therapy was poor (arachidonic acid, κ 0.23; adenosine diphosphate [ADP], κ 0.13). Rate of aspirin and clopidogrel resistance was much higher when determined using TEG/PM than MEA. In patients receiving ≥5 mg/kg/day aspirin, 72% of TEG/PM measurements showed subtherapeutic response compared with 11% of MEA measurements. There was evidence of a dose-response relationship with clopidogrel and MEA ADP-induced aggregation (R2 = 0.56; p < 0.0001); however, there was no association between dose and TEG/PM% ADP inhibition (p = 0.15). Intraindividual variability in platelet reactivity was far greater when measured by TEG/PM during steady state therapy. Multiple electrode platelet aggregometry appears to be more reliable than TEG/PM for monitoring antiplatelet therapy in children supported with VAD.

Aim: Data on arrhythmia outcome following device closure of atrial septal defect (ASD) are lacking. This study provides medium-term follow-up data on atrial arrhythmias in patients who were ≥40 years of age at the time of transcatheter ASD closure., Methods and Results: It is a retrospective review. Mean age of the 159 patients was 57 years. Median follow-up was 3.6 years (range 6 months-10.9 years). Patients were classified, according to arrhythmia status prior to ASD closure, into Group I, no history of atrial arrhythmia (n = 119, mean age 55.5 years); Group II, paroxysmal atrial arrhythmia (n = 18, mean age 55.7 years); and Group III, persistent atrial fibrillation (n = 22, mean age 65.7 years). Group III patients were significantly older, had larger left atrial size, and had higher mean pulmonary arterial pressure than Group I and II patients (P < 0.001). Prior to closure, radiofrequency ablation was carried out in 12/18 (66%) of Group II and 3/22 (14%) of Group III. After device closure, 7 patients (6%) of Group I developed new atrial fibrillation. Fifty per cent (9/18) of Group II but only 9% (2/22) of Group III were in sinus rhythm on follow-up., Conclusion: Device closure alone in patients with persistent atrial arrhythmia is not likely to restore sinus rhythm in the medium term. New atrial arrhythmia occurred in 6% of patients who were in sinus rhythm prior to device closure. At least 50% of the patients with paroxysmal atrial arrhythmia continue to have significant atrial arrhythmia following device closure, and the role of ablation prior to closure in patients with a history of arrhythmia requires refinement., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Daptomycin is excreted primarily unchanged by the kidney. Dosage regimens in children with renal failure remain to be determined. We report the case of an 8-year-old child with multiorgan failure undergoing continuous peritoneal dialysis, successfully treated with intravenous daptomycin for methicillin-resistant Staphylococcus epidermidis bacteremia. A dosage of 8 mg/kg every 48 hour was used. Plasma peak and trough concentrations of daptomycin were 68 mg/L and 14.6 mg/L, respectively, on day 6 of treatment. The dosage regimen achieved daptomycin exposure comparable to that reported in adults undergoing continuous ambulatory peritoneal dialysis and receiving recommended dosages., Competing Interests: Disclosure The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Background/purpose: The gastrointestinal system is prone to complications following heart surgery. We sought to determine the incidence and factors associated with gastrointestinal complication after cardiac surgery in children., Methods: A retrospective review of patients aged <16years that underwent cardiac surgery between 2009 and 2013. Primary outcome was occurrence of gastrointestinal complication within 30days. Multivariable logistic regression was performed to identify variables related to occurrence of gastrointestinal complication. Patients with gastrointestinal complication were matched with controls and postoperative lengths of stay compared., Results: Eight hundred eighty-one children underwent 1120 cardiac surgical procedures. At time of operation, 18% were neonates and 39% were infants. Cardiopulmonary bypass was used in 79%. Of 1120 procedures, 31 (2.8% [95% CI 2.0-3.9%]) had gastrointestinal complication. Necrotizing enterocolitis accounted for 61% of complications. Of patients with gastrointestinal complication, 87% survived to hospital discharge. Gastrointestinal complication was associated with preoperative co-morbidity (OR 2.2 [95% CI 1.02-4.8]) and univentricular disease (OR 2.5 [95% CI 1.1-5.5]). Neonates had the highest risk of gastrointestinal complication. Patients with gastrointestinal complications had longer hospital stays than controls (median difference, 13days [95% CI 3-43])., Conclusions: Serious gastrointestinal complications are uncommon but associated with longer hospital stay. Neonates with univentricular disease and preoperative comorbidity are at highest risk., Type of Study: Prognosis study., Level of Evidence: II., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Background: Observational studies in adults have shown a worse outcome associated with hyperoxia after resuscitation from cardiac arrest. Extrapolating from adult data, current pediatric resuscitation guidelines recommend avoiding hyperoxia. We investigated the relationship between arterial partial oxygen pressure and survival in patients admitted to the pediatric intensive care unit (PICU) after cardiac arrest., Methods and Results: We conducted a retrospective cohort study using the Pediatric Intensive Care Audit Network (PICANet) database between 2003 and 2010 (n=122,521). Patients aged <16 years with documented cardiac arrest preceding PICU admission and arterial blood gas analysis taken within 1 hour of PICU admission were included. The primary outcome measure was death within the PICU. The relationship between postarrest oxygen status and outcome was modeled with logistic regression, with nonlinearities explored via multivariable fractional polynomials. Covariates included age, sex, ethnicity, congenital heart disease, out-of-hospital arrest, year, Pediatric Index of Mortality-2 (PIM2) mortality risk, and organ supportive therapies. Of 1875 patients, 735 (39%) died in PICU. Based on the first arterial gas, 207 patients (11%) had hyperoxia (Pa(O)(2) ≥300 mm Hg) and 448 (24%) had hypoxia (Pa(O)(2) <60 mm Hg). We found a significant nonlinear relationship between Pa(O)(2) and PICU mortality. After covariate adjustment, risk of death increased sharply with increasing hypoxia (odds ratio, 1.92; 95% confidence interval, 1.80-2.21 at Pa(O)(2) of 23 mm Hg). There was also an association with increasing hyperoxia, although not as dramatic as that for hypoxia (odds ratio, 1.25; 95% confidence interval, 1.17-1.37 at 600 mm Hg). We observed an increasing mortality risk with advancing age, which was more pronounced in the presence of congenital heart disease., Conclusions: Both severe hypoxia and, to a lesser extent, hyperoxia are associated with an increased risk of death after PICU admission after cardiac arrest.

Objective: To evaluate the performance of an extubation readiness test based on a spontaneous breathing trial using pressure support., Design: Retrospective chart review., Setting: Pediatric intensive care unit., Patients: All infants and children admitted to the pediatric intensive care unit requiring intubation from July 2007 to December 2008 were eligible for this study., Interventions: Routine use of an extubation readiness test using pressure support set according to endotracheal tube size to determine completion of weaning and readiness for extubation., Measurements and Main Results: A total of 755 extubation readiness tests were performed in 538 patients with a pass rate of 83%. Of 500 children who passed the extubation readiness test and were extubated without planned noninvasive ventilation use, the extubation failure rate was 11.2% (5.8% required reintubation). Extubation failure was defined as need for noninvasive ventilation or reintubation within 24 hrs of planned extubation. Logistic regression analysis revealed a significant association between duration of mechanical ventilation and extubation failure. Children ventilated for over 48 hrs had an 18.5% failure rate despite passing an extubation readiness test before extubation and the extubation readiness test was not a significant predictor of extubation success. Most extubation failures were the result of inadequate gas exchange attributable to lower respiratory tract dysfunction., Conclusions: A spontaneous breathing trial using pressure support set at higher levels for smaller endotracheal tubes overestimates readiness for extubation in children and contributes to a higher failed extubation rate. The objective data obtained during an extubation readiness test may help to identify patients who will benefit from extubation to noninvasive ventilation.

Objective: Cerebral oedema is a potentially devastating complication of diabetic ketoacidosis (DKA). The relationship between osmolar changes, acid-base changes and development of cerebral oedema during therapy is unclear., Design: Retrospective cohort study on 53 children with severe DKA (mean pH at presentation 6.92±0.08). Cerebral oedema was diagnosed using neurological status, response to osmotherapy, and neuroimaging, and classified as: early (occurring ≤1 h after presentation, n=15), late (1-48 h, n=17) or absent (controls, n=21). The temporal profiles for various osmolar and acid-base profiles were examined using a random coefficients fractional polynomial mixed model, adjusted for known risk factors., Results: The three groups could not be differentiated by demographic, osmolar or acid-base variables at presentation. All osmolar and acid-base variables showed non-linear temporal trajectories. Children who developed late onset oedema showed dramatically different temporal profiles for effective osmolality and glucose-corrected serum sodium (both p<0.001). Glucose-corrected sodium provided better qualitative discrimination, in that it typically fell in children who developed late oedema and rose in controls. The maximum between-group difference for both variables approximated the median time of clinical cerebral oedema onset. Blood glucose and acid-base temporal profiles did not differ between the groups. Late onset oedema patients received more fluid in the first 4 h, but this did not influence the osmolar or glucose-corrected sodium trajectories in a predictable fashion., Conclusions: Glucose-corrected serum sodium may prove a useful early warning for the development of cerebral oedema in DKA.

We describe an 11-year-old girl with a seizure disorder who developed fever, rash, rhabdomyolysis, and multiorgan failure 2 weeks after commencing a transition from sodium valproate to lamotrigine therapy. To our knowledge, this patient represents the most severe life-threatening hypersensitivity lamotrigine reaction described in the pediatric literature. We recommend caution when prescribing lamotrigine to children on concomitant sodium valproate, and immediate discontinuation of lamotrigine and the provision of aggressive supportive care in patients with features of lamotrigine hypersensitivity.

The objective of this study was to assess analgesic use and the use of a pain scoring system on those children presenting to a paediatric accident and emergency (A&E) department with a history of injury due to trauma. A random sample of patients who presented to a paediatric A&E department over a 6-week period with a history of limb trauma were prospectively studied. Pain severity scores were assessed on arrival and at 10, 30 and 60 minutes using the Douhit Faces Scale and any analgesia given or plaster application was noted. One hundred and seventy-two patients were studied. The median age was 10 years (range 3-13 years) and the majority, 56%, were male. The mean initial pain scores were 2.7 (range 1-4) for boys and 3.0 (range 1-4) for girls. The presenting injuries were 103 upper or lower limb fractures and 69 'soft tissue' injuries. Only 84 (49%) patients received analgesic medication in the department (30% morphine; 70% paracetamol); analgesia was not given to the remaining 88 (51%). Of these, 7 declined analgesia, and 5 had already taken analgesia on arrival to A&E. Despite prompt triage (median time 2 minutes, range 0-10 minutes), the median time from arrival to paracetamol administration was 20 minutes (range 4-105 minutes) and for morphine was 14 minutes (range 2-57 minutes). Pain is a common symptom in patients presenting to A&E. Because children's pain can be particularly difficult to assess, a pain scoring system such as the Douhit Faces Scale can be a useful means of pain assessment in the A&E setting. Despite increased awareness, pain is still under treated in the A&E department.

Dissimilatory nitrate reductase was purified to homogeneity from anaerobic cultures of the denitrifying bacterium Pseudomonas aeruginosa. The following procedures were used in the rapid isolation of this unstable enzyme: induction by nitrate in semianaerobic cell suspension, heat-stimulated activation and solubilization from the membrane fraction, and purification by hydrophobic interaction chromatography. The molecular weight of the purified enzyme was estimated by nondenaturing polyacrylamide gel electrophoresis, sucrose density gradient sedimentation, and gel filtration chromatography. Subunit molecular weights were estimated by electrophoresis in sodium dodecyl sulfate-polyacrylamide gels. The active enzyme monomer, with a molecular weight of 176,000 to 260,000 (depending upon the method of determination), was composed of subunits with molecular weights of approximately 64,000 and 118,000. The monomer aggregated to form an inactive tetramer of about 800,000 molecular weight. Purified enzyme exhibited a broad pH optimum, between 6.5 and 7.5. Kinetic studies showed that the apparent Km was 0.30 mM for nitrate, and 2.2 to 2.9 microM for dithionite-reduced benzyl viologen. Azide was an effective inhibitor: the concentration required for half-maximal inhibition was 21 to 24 microM. Azide inhibition was competitive with nitrate (Ki = 2.0 microM) but uncompetitive with reduced benzyl viologen (Ki = 25 microM). Based upon spectral evidence, the purified molybdo-enzyme had no associated cytochromes but did contain nonhaem iron that responded to dithionite reduction and nitrate oxidation. The enzyme that was purified after being heat solubilized from membranes had properties essentially identical to those of the enzyme that was purified after deoxycholate solubilization.