SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.

Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-kappaB signaling. SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-kappaB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-kappaB-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-kappaB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB signaling may contribute to premature and normal aging.

Point-of-care ultrasound in pediatric anesthesiology: considerations for training and credentialing.

PURPOSE OF REVIEW: To discuss considerations surrounding the use of point-of-care ultrasound (POCUS) in pediatric anesthesiology. RECENT FINDINGS: POCUS is an indispensable tool in various medical specialties, including pediatric anesthesiology. Credentialing for POCUS should be considered to ensure that practitioners are able to acquire images, interpret them correctly, and use ultrasound to guide procedures safely and effectively. In the absence of formal guidelines for anesthesiology, current practice and oversight varies by institution. In this review, we will explore the significance of POCUS in pediatric anesthesiology, discuss credentialing, and compare the specific requirements and challenges currently associated with using POCUS in pediatric anesthesia. SUMMARY: Point-of-care ultrasound is being utilized by the pediatric anesthesiologist and has the potential to improve patient assessment, procedure guidance, and decision-making. Guidelines increase standardization and quality assurance procedures help maintain high-quality data. Credentialing standards for POCUS in pediatric anesthesiology are essential to ensure that practitioners have the necessary skills and knowledge to use this technology effectively and safely. Currently, there are no national pediatric POCUS guidelines to base credentialing processes on for pediatric anesthesia practices. Further work directed at establishing pediatric-specific curriculum goals and competency standards are needed to train current and future pediatric anesthesia providers and increase overall acceptance of POCUS use.

A Potent Recombinant Polyclonal Antibody Therapeutic for Protection Against New Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern.

Emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) possess mutations that prevent antibody therapeutics from maintaining antiviral binding and neutralizing efficacy. Monoclonal antibodies (mAbs) shown to neutralize Wuhan-Hu-1 SARS-CoV-2 (ancestral) strain have reduced potency against newer variants. Plasma-derived polyclonal hyperimmune drugs have improved neutralization breadth compared with mAbs, but lower titers against SARS-CoV-2 require higher dosages for treatment. We previously developed a highly diverse, recombinant polyclonal antibody therapeutic anti-SARS-CoV-2 immunoglobulin hyperimmune (rCIG). rCIG was compared with plasma-derived or mAb standards and showed improved neutralization of SARS-CoV-2 across World Health Organization variants; however, its potency was reduced against some variants relative to ancestral, particularly omicron. Omicron-specific antibody sequences were enriched from yeast expressing rCIG-scFv and exhibited increased binding and neutralization to omicron BA.2 while maintaining ancestral strain binding and neutralization. Polyclonal antibody libraries such as rCIG can be utilized to develop antibody therapeutics against present and future SARS-CoV-2 threats.

Sequencing the B Cell Receptor Repertoires of Antibody-Deficient Individuals With and Without Infection Susceptibility.

PURPOSE: Most individuals with antibody deficiency (hypogammaglobulinemia) need immunoglobulin replacement therapy (IgG-RT) from healthy plasma donors to stay clear of infections. However, a small subset of hypogammaglobulinemic patients do not require this substitution therapy. We set out to investigate this clinical conundrum by asking whether the peripheral B cell receptor repertoires differ between antibody-deficient patients who do and do not need IgG-RT. METHODS: We sequenced and analyzed IgG and IgM heavy chain B cell receptor repertoires from peripheral blood mononuclear cells (PBMCs) isolated from patients with low serum IgG concentrations who did or did not require IgG-RT. RESULTS: Compared to the patients who did not need IgG-RT, those who needed IgG-RT had higher numbers of IgG antibody clones, higher IgM diversity, and less oligoclonal IgG and IgM repertoires. The patient cohorts had different heavy chain variable gene usage, and the patients who needed IgG-RT had elevated frequencies of IgG clones with higher germline identity (i.e., fewer somatic hypermutations). CONCLUSION: Antibody-deficient patients with infection susceptibility who needed IgG-RT had more diverse peripheral antibody repertoires that were less diverged from germline and thus may not be as optimal for targeting pathogens, possibly contributing to infection susceptibility.

Lymphocyte Activation Gene-3 Regulates Dendritic Cell Metabolic Programing and T Cell Priming Function.

Deficiency of lymphocyte activation gene-3 (LAG3) is significantly associated with increased cardiovascular disease risk with in vitro results demonstrating increased TNF-α and decreased IL-10 secretion from LAG3-deficient human B lymphoblasts. The hypothesis tested in this study was that Lag3 deficiency in dendritic cells (DCs) would significantly affect cytokine expression, alter cellular metabolism, and prime naive T cells to greater effector differentiation. Experimental approaches used included differentiation of murine bone marrow-derived DCs (BMDCs) to measure secreted cytokines, cellular metabolism, RNA sequencing, whole cell proteomics, adoptive OT-II CD4+Lag3 +/+ donor cells into wild-type (WT) C57BL/6 and Lag3 -/- recipient mice, and ex vivo measurements of IFN-γ from cultured splenocytes. Results showed that Lag3 -/- BMDCs secreted more TNF-α, were more glycolytic, used fewer fatty acids for mitochondrial respiration, and glycolysis was significantly reduced by exogenous IL-10 treatment. Under basal conditions, RNA sequencing revealed increased expression of CD40 and CD86 and other cytokine-signaling targets as compared with WT. Whole cell proteomics identified a significant number of proteins up- and downregulated in Lag3 -/- BMDCs, with significant differences noted in exogenous IL-10 responsiveness compared with WT cells. Ex vivo, IFN-γ expression was significantly higher in Lag3 -/- mice as compared with WT. With in vivo adoptive T cell and in vitro BMDC:T coculture experiments, Lag3 -/- BMDCs showed greater T cell effector differentiation and proliferation, respectively, compared with WT BMDCs. In conclusion, Lag3 deficiency in DCs is associated with an inflammatory phenotype that provides a plausible mechanism for increased cardiovascular disease risk in humans with LAG3 deficiency.

Orthopaedic Injuries from All-Terrain Vehicles: An Epidemiological Account and Review of Legislation.

All-terrain vehicles (ATVs) are an ongoing source of orthopaedic trauma in the United States. The National Electronic Injury Surveillance System (NEISS) database was queried for ATV-related extremity trauma from 2010 to 2019. An estimated 31,979 ATV-related injuries present to emergency departments annually without significant variability between years. Patients were predominantly white (63.5%), male (72.2%), and aged 18 - 44 (49.9%). Injury sites frequently included the shoulder (24%), wrist (12.8%), and ankle (11.2%). Fractures were most common followed by strains and sprains. Only 15.5% of injuries occurred on public land. Alcohol use was rarely implicated. Orthopaedic surgeons should be aware that rates of ATV-related musculoskeletal injuries have not changed significantly over the last ten years despite legislative efforts to improve ATV safety. Additionally, safety laws are inconsistent across the US, and many apply to the use of ATVs on public land when a minority of injuries occur on non-public land. (Journal of Surgical Orthopaedic Advances 32(4):225-231, 2023).

Factors affecting need for blood transfusion in paediatric patients undergoing open surgery for hip dysplasia.

BACKGROUND AND OBJECTIVES: The management of intraoperative blood loss in the surgical treatment of paediatric hip dysplasia is resource intensive. There are numerous clinical factors that impact the need for intraoperative transfusion. Identification of patient and surgical factors associated with increased blood loss may reduce the unnecessary use of resources. This study aimed to identify factors predictive of intraoperative transfusion in children undergoing hip dysplasia surgery. MATERIALS AND METHODS: This is a single-centre retrospective review of patients undergoing surgery for hip dysplasia from 1 January 2012 to 15 April 2021. Patient demographic factors, anaesthetic, surgical and transfusion histories were reviewed. Multivariable logistic regression analysis was performed to identify factors predictive of allogeneic red blood cell transfusion requirements during the intraoperative period. RESULTS: This study includes 595 patients who underwent open surgery for hip dysplasia, including 297 (52.6%) classified as developmental dysplasia (DD) and 268 (47.3%) as neuromuscular (NM) with a mean age of 9.1 years (interquartile range 3-14). Intraoperative allogeneic transfusion was identified in 26/297 (8.8%) DD and 73/268 (27.2%) NM patients. Adjusted factors associated with increased odds of intraoperative transfusion were NM (odds ratio [OR] = 2.96, 95% confidence interval [CI] [1.76, 5.00]) and the number of osteotomies performed (OR = 1.82/osteotomy, 95% CI [1.40, 2.35]). Adjusted factors that reduced the odds of transfusion were the use of antifibrinolytics (OR = 0.35, 95% CI [0.17, 0.71]) and regional anaesthesia (OR = 0.52, 95% CI [0.29, 0.94]). CONCLUSION: For children undergoing surgery for hip dysplasia, the number of osteotomies performed is predictive of the need for allogeneic blood transfusion. Antifibrinolytics and regional anaesthesia are associated with reduced risk for allogeneic blood transfusion. Blood management initiatives, such a preoperative optimization of haemoglobin and the use of antifibrinolytics, could target patients at increased risk of intraoperative bleeding and transfusion.

Cancer Immunology and Immunotherapy: From Defining Basic Immunology to Leading the Fight Against Cancer.

The past decade has seen the advent and widespread use of several immunotherapeutic modalities that have markedly improved treatment outcomes for patients with various cancers. Nevertheless, the study of cancer immunology traces its roots back to the inception of modern immunology, and played a critical role in the of discovery of central immunological concepts and development of key technologies and methodologies and that have propelled advances in all areas of immunology.

Anesthesiology Resident Knowledge of Transfusion Medicine: Results From the Anesthesiology Transfusion Education Study.

BACKGROUND: Transfusion of blood products is a common practice in anesthesiology. Inadequate transfusion medicine knowledge may lead to inappropriate transfusion practices and patient risk. Using a validated assessment tool modified for anesthesiology, we conducted a survey of anesthesiology residents in the United States to assess transfusion medicine knowledge. METHODS: A validated transfusion medicine examination and accompanying survey were forwarded by program directors to residents for anonymous completion on May 5 and closed on June 30, 2021. The outcome of interest was the mean examination score. Secondary areas of interest were performance by year of training and previous educational experience in transfusion reported by the trainees. Rasch analysis was performed on the examination quality and individual question performance. Kruskal-Wallis H tests were used to identify differences between mean scores. Post hoc comparisons were used to assess specific pairwise differences between mean test scores by survey variable. RESULTS: Four hundred twenty-three anesthesiology residents in 37 programs completed the examination. The mean score was 45.5% ± 12.6%. There was a significant difference in mean cumulative examination scores between different resident training levels (P < 0.001). There was a significant difference in scores between clinical anesthesia (CA)-1 and CA-2 residents (P = 0.011) and CA-1 and CA-3 residents (P = 0.012). No significant difference in examination scores was observed between CA-2 and CA-3 residents (P = 0.95). All these subgroups scored below 50% on the examination. Significant differences between the residency training programs and cumulative scores were identified (P < 0.001). CONCLUSIONS: This examination highlights gaps in transfusion medicine knowledge within US anesthesiology residents. Targeted education may improve knowledge in this area and patient care.

Lung and airway ultrasound in pediatric anesthesia.

Perioperative lung ultrasound is a continuously evolving modality with numerous applications for the pediatric anesthesiologist. Lung ultrasound can be used at the bedside, including intraoperatively, to augment traditional physical examination methods of assessing cardiopulmonary structures and identifying the presence of specific and clinically significant pathology. With regard to the lungs, ultrasound has been shown to be highly sensitive at identification of pulmonary pathologies, particularly those of interest in the acute care setting (eg, pleural effusion, pneumothorax). With its relative ease of performance, lung ultrasound should be considered in the initial evaluation of intraoperative hypoxemia particularly when traditional modes of evaluation are nonexplanatory. This educational review introduces the basic concepts of lung ultrasound as they relate to pediatric anesthesia patients.

Single-cell transcriptomics reveals the effect of PD-L1/TGF-ß blockade on the tumor microenvironment.

BACKGROUND: The anti-tumor activity of anti-PD-1/PD-L1 therapies correlates with T cell infiltration in tumors. Thus, a major goal in oncology is to find strategies that enhance T cell infiltration and efficacy of anti-PD-1/PD-L1 therapy. TGF-ß has been shown to contribute to T cell exclusion, and anti-TGF-ß improves anti-PD-L1 efficacy in vivo. However, TGF-ß inhibition has frequently been shown to induce toxicity in the clinic, and the clinical efficacy of combination PD-L1 and TGF-ß blockade has not yet been proven. To identify strategies to overcome resistance to PD-L1 blockade, the transcriptional programs associated with PD-L1 and/or TGF-ß blockade in the tumor microenvironment should be further elucidated. RESULTS: We used single-cell RNA sequencing in a mouse model to characterize the transcriptomic effects of PD-L1 and/or TGF-ß blockade on nearly 30,000 single cells in the tumor and surrounding microenvironment. Combination treatment led to upregulation of immune response genes, including multiple chemokine genes such as CCL5, in macrophages, and downregulation of extracellular matrix genes in fibroblasts. Analysis of publicly available tumor transcriptome profiles showed that the chemokine CCL5 was strongly associated with immune cell infiltration in various human cancers. Further investigation with in vivo models showed that intratumorally administered CCL5 enhanced cytotoxic lymphocytes and the anti-tumor activity of anti-PD-L1. CONCLUSIONS: Taken together, our data could be leveraged translationally to complement or find alternatives to anti-PD-L1 plus anti-TGF-ß combination therapy, for example through companion biomarkers, and/or to identify novel targets that could be modulated to overcome resistance.

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth.

The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. While somatic mutations in spliceosome components have been discovered in several cancer types, the molecular bases and consequences of spliceosome aberrations in cancer are poorly understood. Here we report for the first time that PRPF6, a member of the tri-snRNP (small ribonucleoprotein) spliceosome complex, drives cancer proliferation by preferential splicing of genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP spliceosome complexes, selectively abrogated growth in cancer cells with high tri-snRNP levels. High-resolution transcriptome analyses revealed that reduced PRPF6 alters the constitutive and alternative splicing of a discrete number of genes, including an oncogenic isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 in cancer via splicing of distinct growth-related gene products.

Effect of Caudal vs. Penile Block on the Incidence of Hypospadias Complications Following Primary Repairs: A Retrospective Cohort Study.

PURPOSE: Primary repair of hypospadias is associated with risk of complications, specifically urethrocutaneous fistula and glanular dehiscence. Caudal block may potentially increase the risk of these complications. Therefore, we studied the incidence of hypospadias complications in children who underwent correction at our institution having received either penile or caudal block. MATERIALS AND METHODS: We analyzed all primary hypospadias repair cases from December 2011 through December 2018 at Texas Children's Hospital with a minimum of 1-year followup for the presence of complications: urethrocutaneous fistula and glanular dehiscence. Surgical (surgeon, operative time, block type, local anesthetic, meatal position) and patient (age at correction, prematurity) factors were additionally analyzed. RESULTS: For the primary aim, 983 patients underwent primary hypospadias correction with a minimum of 1 year of postoperative followup data. There were 897 patients (91.3%) in which no complications were identified and 86 (8.7%) with either urethrocutaneous fistula (81) or glanular dehiscence (5). Of the 86 identified complications, 45/812 (5.5%) were distal, 41/171 (24%) were proximal (p <0.001) with a complication. Rate of complications was not associated with caudal block (OR 0.67, 95% CI 0.41-1.09; p=0.11). On univariable analysis, age (OR 1.12, 95% CI 1.04-1.20; p=0.04), surgical duration (OR 1.02; 95% CI 1.01-1.02; p <0.001), prematurity <32 weeks (OR 4.38, 95% CI 1.54-4.11 p <0.001) and position of meatus as proximal (OR 5.38 95% CI 3.39-8.53; p <0.001) were associated with an increased rate of complications. However, on multivariable analysis, associations of age (OR 1.13, 95% CI 1.05-1.22; p=0.001), surgery duration (OR 1.01, 95% CI 1.01-1.02; p <0.001) and meatal position (OR 3.85, 95% CI 2.32-6.39; p <0.001) were associated with increased rate of complications. CONCLUSIONS: Our data suggest that meatal location, older age, extreme prematurity and surgical duration are associated with increased incidence of complications (urethrocutaneous fistula and glanular dehiscence) following hypospadias correction. Analgesic block was not associated with increased hypospadias complication risk.

Intermittent Hypoxia and Effects on Early Learning/Memory: Exploring the Hippocampal Cellular Effects of Pediatric Obstructive Sleep Apnea.

This review provides an update on the neurocognitive phenotype of pediatric obstructive sleep apnea (OSA). Pediatric OSA is associated with neurocognitive deficits involving memory, learning, and executive functioning. Adenotonsillectomy (AT) is presently accepted as the first-line surgical treatment for pediatric OSA, but the executive function deficits do not resolve postsurgery, and the timeline for recovery remains unknown. This finding suggests that pediatric OSA potentially causes irreversible damage to multiple areas of the brain. The focus of this review is the hippocampus, 1 of the 2 major sites of postnatal neurogenesis, where new neurons are formed and integrated into existing circuitry and the mammalian center of learning/memory functions. Here, we review the clinical phenotype of pediatric OSA, and then discuss existing studies of OSA on different cell types in the hippocampus during critical periods of development. This will set the stage for future study using preclinical models to understand the pathogenesis of persistent neurocognitive dysfunction in pediatric OSA.

The Association of Dexmedetomidine on Perioperative Opioid Consumption in Children Undergoing Adenotonsillectomy With and Without Obstructive Sleep Apnea.

BACKGROUND: Dexmedetomidine is used to reduce opioid consumption in pediatric anesthesia. However, there is conflicting evidence in pediatric adenotonsillectomy literature regarding the total perioperative opioid-sparing effects of dexmedetomidine. The aim of this study was to examine the association between dexmedetomidine and total perioperative opioid consumption in children undergoing adenotonsillectomy. METHODS: This was a retrospective cohort study of the children undergoing adenotonsillectomy surgery at Texas Children's Hospital between November 2017 and October 2018. Intraoperative dexmedetomidine was the exposure of interest. The primary outcome was total perioperative opioid consumption calculated as oral morphine equivalents (OME). Secondary outcomes of interest included opioid consumption and pain scores based on presence and absence of obstructive sleep apnea (OSA) and postanesthesia care unit (PACU) duration. We used multivariable linear regression to estimate the association of dexmedetomidine on the outcomes. RESULTS: A total of 941 patients met inclusion criteria, 697 (74.1%) received intraoperative dexmedetomidine. For every 0.1 µg/kg increase in intraoperative dexmedetomidine, the total perioperative OME (mg/kg) decreases by 0.021 mg/kg (95% CI, -0.027 to -0.015; P < .001). Pain scores did not significantly vary by OSA status. PACU duration increased by 1.14 minutes (95% CI, 0.30-1.99; P = .008) for each 0.1 µg/kg of intraoperative dexmedetomidine. CONCLUSIONS: Dexmedetomidine is associated with an overall perioperative opioid-sparing effect in children undergoing adenotonsillectomy and a small but statistically significant increase in PACU duration. Additionally, children with OSA did not have reduced perioperative opioid consumption.

Monochromic light reduces emergence delirium in children undergoing adenotonsillectomy; a double-blind randomized observational study.

BACKGROUND: Emergence delirium (ED) is common in pediatric anesthesia. This dissociative state in which the patient is confused from their surroundings and flailing can be self-injurious and traumatic for parents. Treatment is by administration of sedatives which can prolong recovery. The aim of this study was to determine if exposure to monochromatic blue light (MBL) in the immediate phase of recovery could reduce the overall incidence of emergence delirium in children following general inhalational anesthesia. METHODS: This double blinded randomized controlled study included patients ages 2-6 undergoing adenotonsillectomy. Postoperatively, 104 patients were randomization (52 in each group) for exposure to sham blue or MBL during the first phase (initial 30 min) of recovery. The primary outcome was the incidence of emergence delirium during the first phase. We also examined Pediatric Anesthesia Emergence Delirium (PAED) scores throughout the first phase. RESULTS: Emergence Delirium was reported in 5.9% of MBL patients versus 33.3% in the sham group, p = 0.001. Using logistic regression adjusting for age, weight, gender, ASA classification and PAED scores provided an adjusted relative risk ratio of 0.18; 95% CI (0.06, 0.54); p = 0.001 for patients in the MBL group. 23.5% of MBL patients versus 52.9% of sham patients had either ED or PAED scores of 12 or more throughout the first phase of recovery, p = 0.002. This produced an adjusted relative risk of 0.46, 95% CI (0.29, 0.75), p = 0.001. CONCLUSIONS: Monochromatic blue light represents a non-pharmacologic method to reduce the incidence of emergence delirium and PAED scores in children. TRIAL REGISTRATION: #NCT03285243 registered on 15/09/2017.

Incidence of Difficult Laryngoscopy in Adult Congenital Heart Disease Patients: A Retrospective Cohort Study.

OBJECTIVE: To identify the incidence of difficult intubation in patients with adult congenital heart disease (ACHD) undergoing cardiac surgery or catheterization. DESIGN: A retrospective cohort study. SETTING: A single-center academic quaternary pediatric hospital. PARTICIPANTS: All patients were >18 years of age with ACHD undergoing endotracheal intubation within the Heart Center at Texas Children's Hospital between January 2012 and December 2019. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: A retrospective chart review was performed, including patient demographics, preoperative airway assessment and intraoperative airway management characteristics. Airways were categorized as difficult using the Pediatric Difficult Intubation registry operational definitions. For patients classified as having a difficult airway, the preoperative airway examination findings were recorded in addition to factors associated with difficult airway in the adult. The study authors identified 1,029 patients with ACHD who underwent procedures with anesthesia at their institution and were analyzed for the presence of difficult airway. In total, 878 patients were intubated, with 4.3% (n = 38) identified to have difficult airway. The presence of concomitant syndromes was greater in patients with difficult intubations and those who were not intubated compared with those who were not difficult intubations (23.7% and 17.2 v 7.5; p < 0.001), respectively. Most patients did not have typical signs associated with difficult intubation. CONCLUSIONS: The study authors identified an incidence of difficult laryngoscopy in their cohort of ACHD patients to be 4.3%. Their incidences of difficult laryngoscopy were fewer than that reported in adult patients with noncongenital heart disease. Most importantly, the risk factors associated with difficult laryngoscopy in the normal adult may be different from those presenting with ACHD, necessitating further investigation.

"You can't make me!" Managing adolescent dissent to anesthesia.

When adolescents require health care, the need to obtain consent from the parent/legal guardian and assent from the patient can create the potential for an ethical dilemma when these two parties are not in agreement. Here, we describe a representative and common case scenario in which both parent and adolescent patient gave consent and assent, respectively, with a full understanding of the risks and benefits of the procedure and anesthetic. At the time of anesthetic induction, however, the patient expresses that she no longer wishes to have the procedure. We identify a number of considerations that inform the ethical analysis of such cases and offer recommendations about the most appropriate path forward for a practitioner faced with a difficult decision about how to respond.

An assessment of opioids on respiratory depression in children with and without obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea is a risk factor for respiratory depression following opioid administration as well as opioid-induced hyperalgesia. Little is known on how obstructive sleep apnea status is associated with central ventilatory depression in pediatric surgical patients given a single dose of fentanyl. METHODS: This was a single-center, prospective trial in children undergoing surgery requiring intubation and opioid administration. Sixty patients between the ages of 2-8 years presenting for surgery at Texas Children's Hospital were recruited. Twenty non-obstructive sleep apnea controls and 30 patients with moderate to severe obstructive sleep apnea met inclusion criteria. Following induction of general anesthesia and establishment of steady-state ventilation, participants received 1 mcg/kg intravenous fentanyl. Ventilatory variables (tidal volume, respiratory rate, end-tidal CO2 , and minute ventilation) were assessed each minute for 10 min. The primary outcome was the extent of opioid-induced central ventilatory depression over time by obstructive sleep apnea status when compared with baseline values. Secondary aims assessed the impact of demographics and SpO2 nadir on ventilatory depression. RESULTS: We found no significant difference in percent decrease in respiratory rate (38.1% and 37.1%; p = .950), tidal volume (6.4% and 5.4%; p = .992), and minute ventilation (35.0 L/min and 35.0 L/min; p = .890) in control and obstructive sleep apnea patients, respectively. Both groups experienced similar percent increases in end-tidal CO2 (4.0% vs. 2.2%; p = .512) in control and obstructive sleep apnea patients, respectively. CONCLUSIONS: In pediatric surgical patients, obstructive sleep apnea status was not associated with significant differences in central respiratory depression following a single dose of fentanyl (1 mcg/kg). These findings can help determine safe opioid doses in future pediatric obstructive sleep apneapatients.

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.