Does celecoxib prescription for pain management impact post-tonsillectomy hemorrhage requiring surgery? A retrospective observational cohort study.

BACKGROUND: Adenotonsillectomy and tonsillectomy (now referred to as tonsillectomy thereafter) are common pediatric surgeries. Postoperative complications include hemorrhage requiring surgery (2-3% of cases) and pain. While non-steroidal anti-inflammatory drugs are commonly administered for post-surgical pain, controversy exists regarding bleeding risk with cyclo-oxygenase-1 inhibition and associated platelet dysfunction. Preliminary evidence suggests selective cyclo-oxygenase-2 inhibitors, for example celecoxib, effectively manage pain without adverse events including bleeding. Given the paucity of data for routine celecoxib use after tonsillectomy, we investigated the association between post-operative celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery using chart-review data from the Children's Hospital of Eastern Ontario, Canada. METHODS: After ethics approval we performed a retrospective single-center observational cohort study in children <18 yrs undergoing tonsillectomy from January 2007 to December 2017. Cases of adenoidectomy alone were excluded due to low bleed rates. The primary outcome was the proportion of patients with post-tonsillectomy hemorrhage requiring surgery. The association between a celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery was estimated using inverse probability of treatment weighting based on propensity scores and using generalized estimating equations to accommodate clustering by surgeon. RESULTS: An initial patient cohort of 6468 was identified and 5846 children with complete data were included in analyses. Median (interquartile range) age was 6.10 (4.40, 9.00) years and 46% were female. In our cohort, 28.1% (n=1644) were prescribed celecoxib. Among the 4996 tonsillectomy patients, 1.7% (n=86) experienced post-tonsillectomy hemorrhage requiring surgery. The proportion with post-tonsillectomy hemorrhage requiring surgery among patients who had a tonsillectomy and were or were not prescribed celecoxib was 1.94% (30/1548; 95% CI: 1.36-2.75) and 1.62% (56/3448; 95% CI: 1.25-2.10), respectively. Modelling did not identify an association between celecoxib prescription and increased odds of post-tonsillectomy hemorrhage requiring surgery (OR=1.4, 95% CI: 0.85-2.31, p=0.20). CONCLUSIONS: Celecoxib does not significantly increase the odds of post-tonsillectomy hemorrhage requiring surgery, after adjusting for covariates. This large pediatric cohort study of celecoxib administered after tonsillectomy provides compelling evidence for safety but requires confirmation with a multi-site randomized controlled trial.

Treatment practices and implementation of guidelines for hyperbilirubinemia and rebound hyperbilirubinemia.

BACKGROUND: Hyperbilirubinemia (HB), defined as elevated total serum bilirubin (TSB) levels, commonly affects neonates and requires prompt treatment to prevent neurological complications. Up to 10%of neonates experience rebound hyperbilirubinemia (RHB), requiring re-initiation of treatment. Unfortunately, treatment guidelines lack practical recommendations surrounding subthreshold phototherapy, treatment termination, and RHB investigations. We examined local management practices for HB and RHB treatment in a well newborn nursery. As a secondary aim, we investigated the association between treatment practices and RHB rates. METHODS: Retrospective chart review identified neonates treated for hyperbilirubinemia between January 2015 and December 2019 during their birth hospitalization at a tertiary care centre. Standardized data collection sheets were used to record treatment parameters. RESULTS: Over the 5-year period, there were 9683 births and 305 (3.15%) neonates received phototherapy. Of the treated cases, 20-25%were subthreshold to practice guideline values. Upon treatment termination 25-55%of cases had TSB levels within 3 mg/dL, which may increase the risk of RHB. In our cohort, 20.3%of treated cases experienced one episode of RHB and 3.9%experienced two episodes of RHB. Although clinicians evaluated neonates for RHB 0-12 hours following treatment termination prior to discharge, many cases were identified in outpatient settings and required re-admission for phototherapy. CONCLUSION: When managing HB and RHB, treatment practices such as when to terminate treatment in relation to threshold values, and timing of RHB investigations, are largely inconsistent amongst clinicians. Future studies are required to better understand the landscape of hyperbilirubinemia treatment beyond initiation of phototherapy.

Validation of published rebound hyperbilirubinemia risk prediction scores during birth hospitalization after initial phototherapy: a retrospective chart review.

BACKGROUND: Hyperbilirubinemia commonly affects newborns and may lead to neurotoxicity if untreated. Neonates can experience rebound hyperbilirubinemia (RHB), defined as elevated bilirubin levels requiring re-initiation of treatment. Although studies have formulated risk prediction scores, they lack external validation. In this study, we examine the discrimination and calibration performance of risk prediction scores for RHB, to provide external validation. METHODS: We reviewed charts of neonates born ≥35 weeks of gestation between January 2015 and December 2019 receiving phototherapy at birth hospitalization. We plotted predicted probabilities against observed outcome proportions to assess model calibration and evaluated discrimination using area under the receiver operating characteristic (AUROC) curves. Odds ratios (ORs) were estimated to evaluate variables associated with RHB. RESULTS: Of the 271 infants identified, 24% developed RHB. Two- and three-variable prediction scores had lower discrimination in our cohort with AUROC of 0.662 (95% CI 0.590-0.735) and 0.691 (95% CI, 0.619-0.763) compared to 0.876 (95% CI 0.854-0.899) and 0.881 (95% CI 0.859-0.903), respectively, in the published studies. Estimated ORs confirm associations between RHB and variables included in prediction scores. CONCLUSIONS: Current prediction models for RHB have unclear clinical utility in our patient population. Additional studies are required to further validate these scores. IMPACT: Describes performance characteristics of two- and three-variable risk prediction scores that lack external validation beyond the initial study cohort. Our findings suggest unclear clinical utility in our clinical population of neonates during birth hospitalization, with lower performance of these prediction scores than observed in the derivation cohort. Odds ratios estimated by logistic regression in our study cohort provide further evidence that variables in published risk prediction scores are associated with rebound hyperbilirubinemia. Further studies are required to externally validate these risk prediction scores and to assess their generalizability.

WDR45, one gene associated with multiple neurodevelopmental disorders.

The WDR45 gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ß-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat ß-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in WDR45 can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders.Abbreviations: ATG/Atg: autophagy related; BPAN: ß-propeller protein associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; EEG: electroencephalograph; ENO2/neuron-specific enolase, enolase 2; EOEE: early-onset epileptic encephalopathy; ER: endoplasmic reticulum; ID: intellectual disability; IDR: intrinsically disordered region; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NCOA4: nuclear receptor coactivator 4; PtdIns3P: phosphatidylinositol-3-phosphate; RLS: Rett-like syndrome; WDR45: WD repeat domain 45; WIPI: WD repeat domain, phosphoinositide interacting.

Association between postsurgical pain and heart rate variability: protocol for a scoping review.

INTRODUCTION: Surgical interventions can elicit neuroendocrine responses and sympathovagal imbalance, ultimately affecting cardiac autonomic function. Cardiac complications account for 30% of postoperative complications and are the leading cause of morbidity and mortality following non-cardiac surgery. One cardiovascular parameter, heart rate variability (HRV), has been found to be predictive of postoperative morbidity and mortality. HRV is defined as variation in time intervals between heartbeats and is affected by cardiac autonomic balance. Furthermore, altered HRV has been shown to predict cardiovascular events in non-surgical settings. In multiple studies, experimentally induced pain in healthy humans leads to reduced HRV suggesting a causal relationship. In a different studies, chronic pain has been associated with altered HRV, however, in the setting of clinical pain conditions, it remains unclear how much HRV impairment is due to pain itself versus autonomic changes related to analgesia. We aim to review the available evidence describing the association between postsurgical pain and HRV alterations in the early postoperative period. METHODS AND ANALYSIS: We will conduct a scoping review of relevant studies using detailed searches of MEDLINE and EMBASE, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. Included studies will involve participants undergoing non-cardiac surgery and investigate outcomes of (1) measures of pain intensity; (2) measures of HRV and (3) statistical assessment of association between #1 and #2. As secondary review outcomes included studies will also be examined for other cardiovascular events and for their attempts to control for analgesic treatment and presurgical HRV differences among treatment groups in the analysis. This work aims to synthesise available evidence to inform future research questions related to postsurgical pain and cardiac complications. ETHICS AND DISSEMINATION: Ethics review and approval is not required for this review. The results will be submitted for publication in peer-reviewed journals.

Scoping review of the association between postsurgical pain and heart rate variability parameters.

Surgical interventions can elicit neuroendocrine and sympathovagal responses, leading to cardiac autonomic imbalance. Cardiac complications account for approximately 30% of postoperative complications. Altered heart rate variability (HRV) was initially described in the 1970s as a predictor of acute coronary syndromes and has more recently been shown to be an independent predictor of postoperative morbidity and mortality after noncardiac surgery. In general, HRV reflects autonomic balance, and altered HRV measures have been associated with anesthetic use, chronic pain conditions, and experimental pain. Despite the well-documented relationship between altered HRV and postsurgical outcomes and various pain conditions, there has not been a review of available evidence describing the association between postsurgical pain and HRV. We examined the relationship between postsurgical pain and HRV. MEDLINE and EMBASE databases were searched until December 2020 and included all studies with primary data. Two reviewers independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Review of Interventions. A total of 8 studies and 1002 participants were included. Studies examined the association of postsurgical pain and HRV or analgesia nociception index derived from HRV. There was a statistically significant association between HRV measures and postsurgical pain in 6 of 8 studies. Heterogeneity of studies precluded meta-analyses. No studies reported cardiovascular outcomes. There is a potential association between postsurgical pain and HRV or analgesia nociception index, although results are likely impacted by confounding variables. Future studies are required to better delineate the relationship between postsurgical pain and HRV and impacts on cardiovascular outcomes.

Development of the Social Motor Function Classification System for Children with Autism Spectrum Disorders: A Psychometric Study.

To examine reliability and validity of the new Social Motor Function Classification System for Children with Autism Spectrum Disorders (SMFCS-ASD). The SMFCS-ASD reliability was examined on 25 children (62.4 months SD 7.8) with ASD among six physical therapists. The validity study involved 1001 children (57.0 months, SD 9.9) with ASD using the gross motor scale (GMS) of the Peabody Developmental Motor Scales (PDMS-2). The indices of agreement and reliability across six examiners were moderate to substantial (Cohen's κ ≤ 0.65 and ICC > 0.90, all p < 0.001). The SMFCS-ASD was significantly correlated with the GMS of PDMS-2 (all rho from 0.61 to 0.76, p < 0.001). The SMFCS-ASD was reliable and significantly correlated with the GMS of the PDMS-2.

Impact of the COVID-19 pandemic on anaesthesia trainees and their training.

Coronavirus disease 2019 (COVID-19; severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] has dislocated clinical services and postgraduate training. To better understand and to document these impacts, we contacted anaesthesia trainees and trainers across six continents and collated their experiences during the pandemic. All aspects of training programmes have been affected. Trainees report that reduced caseload, sub-specialty experience, and supervised procedures are impairing learning. Cancelled educational activities, postponed examinations, and altered rotations threaten progression through training. Job prospects and international opportunities are downgraded. Work-related anxieties about provision of personal protective equipment, and risks to self and to colleagues are superimposed on concerns for family and friends and domestic disruption. These seismic changes have had consequences for well-being and mental health. In response, anaesthetists have developed innovations in teaching and trainee support. New technologies support trainer-trainee interactions, with a focus on e-learning. National training bodies and medical regulators that specify training and oversee assessment of trainees and their progression have provided flexibility in their requirements. Within anaesthesia departments, support transcends grades and job titles with lessons for the future. Attention to wellness, awareness of mental health issues and multimodal support can attenuate but not eliminate trainee distress.

Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes.

Transcriptional enhancers are critical for maintaining cell-type-specific gene expression and driving cell fate changes during development. Highly transcribed genes are often associated with a cluster of individual enhancers such as those found in locus control regions. Recently, these have been termed stretch enhancers or super-enhancers, which have been predicted to regulate critical cell identity genes. We employed a CRISPR/Cas9-mediated deletion approach to study the function of several enhancer clusters (ECs) and isolated enhancers in mouse embryonic stem (ES) cells. Our results reveal that the effect of deleting ECs, also classified as ES cell super-enhancers, is highly variable, resulting in target gene expression reductions ranging from 12% to as much as 92%. Partial deletions of these ECs which removed only one enhancer or a subcluster of enhancers revealed partially redundant control of the regulated gene by multiple enhancers within the larger cluster. Many highly transcribed genes in ES cells are not associated with a super-enhancer; furthermore, super-enhancer predictions ignore 81% of the potentially active regulatory elements predicted by cobinding of five or more pluripotency-associated transcription factors. Deletion of these additional enhancer regions revealed their robust regulatory role in gene transcription. In addition, select super-enhancers and enhancers were identified that regulated clusters of paralogous genes. We conclude that, whereas robust transcriptional output can be achieved by an isolated enhancer, clusters of enhancers acting on a common target gene act in a partially redundant manner to fine tune transcriptional output of their target genes.

Diacylglycerol Kinase-ε: Properties and Biological Roles.

In mammals there are at least 10 isoforms of diacylglycerol kinases (DGK). All catalyze the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA). Among DGK isoforms, DGKε has several unique features. It is the only DGK isoform with specificity for a particular species of DAG, i.e., 1-stearoyl-2-arachidonoyl glycerol. The smallest of all known DGK isoforms, DGKε, is also the only DGK devoid of a regulatory domain. DGKε is the only DGK isoform that has a hydrophobic segment that is predicted to form a transmembrane helix. As the only membrane-bound, constitutively active DGK isoform with exquisite specificity for particular molecular species of DAG, the functional overlap between DGKε and other DGKs is predicted to be minimal. DGKε exhibits specificity for DAG containing the same acyl chains as those found in the lipid intermediates of the phosphatidylinositol-cycle. It has also been shown that DGKε affects the acyl chain composition of phosphatidylinositol in whole cells. It is thus likely that DGKε is responsible for catalyzing one step in the phosphatidylinositol-cycle. Steps of this cycle take place in both the plasma membrane and the endoplasmic reticulum membrane. DGKε is likely present in both of these membranes. DGKε is the only DGK isoform that is associated with a human disease. Indeed, recessive loss-of-function mutations in DGKε cause atypical hemolytic-uremic syndrome (aHUS). This condition is characterized by thrombosis in the small vessels of the kidney. It causes acute renal insufficiency in infancy and most patients develop end-stage renal failure before adulthood. Disease pathophysiology is poorly understood and there is no therapy. There are also data suggesting that DGKε may play a role in epilepsy and Huntington disease. Thus, DGKε has many unique molecular and biochemical properties when compared to all other DGK isoforms. DGKε homologs also contain a number of conserved sequence features that are distinctive characteristics of either the rodents or specific groups of primate homologs. How cells, tissues and organisms harness DGKε's catalytic prowess remains unclear. The discovery of DGKε's role in causing aHUS will hopefully boost efforts to unravel the mechanisms by which DGKε dysfunction causes disease.

Diacylglycerol kinase epsilon suppresses expression of p53 and glycerol kinase in mouse embryo fibroblasts.

The incorporation of glycerol into lipid was measured using SV40 transformed mouse embryo fibroblasts (MEFs) from either wild-type (WT) mice or from mice in which the epsilon isoform of diacylglycerol kinase (DGKε) was knocked out (DGKε-/-). We present an explanation for our finding that DGKε-/- MEFs exhibited greater uptake of 3H-glycerol into the cell and a greater incorporation into lipids compared with their WT counterparts, with no change in the relative amounts of various lipids between the DGKε-/- and WT MEFs. Glycerol kinase is more highly expressed in the DGKε-/- cells than in their WT counterparts. In addition, the activity of glycerol kinase is greater in the DGKε-/- cells than in their WT counterparts. Other substrates that enter the cell independent of glycerol kinase, such as pyruvate or acetate, are incorporated into lipid to the same extent between DGKε-/- and WT cell lines. We also show that expression of p53, a transcription factor that increases the synthesis of glycerol kinase, is increased in DGKε-/- MEFs in comparison to WT cells. We conclude that the increased incorporation of glycerol into lipids in DGKε-/- cells is a consequence of up-regulation of glycerol kinase and not a result of an increase in the rate of lipid synthesis. Furthermore, increased expression of the pro-survival gene, p53, in cells knocked out for DGKε suggests that cells over-expressing DGKε would have a greater propensity to become tumorigenic.

Transient monoplegia and paraesthesia after an epidural blood patch for a spinal cerebrospinal fluid leak.

We describe the very rare complication of new onset complete paralysis and numbness of one limb after an epidural blood patch in a 36-year-old woman. Intracranial hypotension resulting from a spinal cerebrospinal fluid fistula may be treated by epidural injection of autologous blood that is, a blood patch. This is usually a safe and effective procedure. The woman's muscle strength of hip flexion, extension, ankle dorsiflexion and plantarflexion decreased from 5/5 to 0/5 following the procedure. After symptom onset, an MRI of her spine showed no compressive or ischaemic lesions amenable to urgent intervention. The cause of neurological deficit was at that time unknown and steroids were administered. Her symptoms persisted for about 2 days and gradually improved. In this paper, the management plan and the course of this rare and alarming complication is reported.