Novel autoantibodies help diagnose anti-SSA antibody negative Sjögren disease and predict abnormal labial salivary gland pathology.

OBJECTIVES: Sjögren disease (SjD) diagnosis often requires either positive anti-SSA antibodies or a labial salivary gland biopsy with a positive focus score (FS). One-third of patients with SjD lack anti-SSA antibodies (SSA-), requiring a positive FS for diagnosis. Our objective was to identify novel autoantibodies to diagnose 'seronegative' SjD. METHODS: IgG binding to a high-density whole human peptidome array was quantified using sera from SSA- SjD cases and matched non-autoimmune controls. We identified the highest bound peptides using empirical Bayesian statistical filters, which we confirmed in an independent cohort comprising SSA- SjD (n=76), sicca-controls without autoimmunity (n=75) and autoimmune-feature controls (SjD features but not meeting SjD criteria; n=41). In this external validation, we used non-parametric methods for binding abundance and controlled false discovery rate in group comparisons. For predictive modelling, we used logistic regression, model selection methods and cross-validation to identify clinical and peptide variables that predict SSA- SjD and FS positivity. RESULTS: IgG against a peptide from D-aminoacyl-tRNA deacylase (DTD2) bound more in SSA- SjD than sicca-controls (p=0.004) and combined controls (sicca-controls and autoimmune-feature controls combined; p=0.003). IgG against peptides from retroelement silencing factor-1 and DTD2 were bound more in FS-positive than FS-negative participants (p=0.010; p=0.012). A predictive model incorporating clinical variables showed good discrimination between SjD versus control (area under the curve (AUC) 74%) and between FS-positive versus FS-negative (AUC 72%). CONCLUSION: We present novel autoantibodies in SSA- SjD that have good predictive value for SSA- SjD and FS positivity.

Respiratory Severity Score and Oxygen Saturation Index during the First 2 Hours of Life as Predictors for Noninvasive Respiratory Support Failure in Respiratory Distress Syndrome.

OBJECTIVE: Noninvasive respiratory support (NRS) failure is common in preterm infants with respiratory distress syndrome (RDS). We evaluated the utility of respiratory severity score (RSS) and oxygen saturation index (OSI) during the first 2 hours of life (HOL) as predictors for NRS failure in moderate preterm infants. STUDY DESIGN: We conducted a retrospective cohort study of infants born between 280/7 and 336/7 weeks with RDS. Univariate and multivariable logistic regression analyses were used to assess whether the RSS and OSI summary measures were associated with NRS failure. RESULTS: A total of 282 infants were included in the study. Median gestational age and birth weights were 32 weeks and 1.7 kg, respectively. Fifty-eight infants (21%) developed NRS failure at the median age of 10.5 hours. RSS and OSI summary measures in the first 2 HOL were associated with NRS failure within 72 HOL. CONCLUSION: RSS and OSI during the first 2 HOL can predict NRS failure. Optimal RSS and OSI cutoffs for the prediction of NRS failure need to be determined in large cohort studies. KEY POINTS: · Nearly one in five moderate preterm infants on NRS at 2 hours of life developed NRS failure.. · RSS and OSI during the first 2 HOL can predict NRS failure.. · Optimal RSS and OSI cutoffs for the prediction of NRS failure need to be determined..

Risk of Hypovitaminosis and Vitamin C Deficiency in Pediatric Patients Undergoing Cardiopulmonary Bypass.

Vitamin C levels are known rapidly decrease in adult critical illness. Vitamin C scavenges free radicals, provides critical protection of the endothelial barrier, and improves endothelial responsiveness to catecholamines. Children with congenital heart disease and undergoing cardiac surgery might be at increased risk for low circulating vitamin C levels. A prospective single-center observational study investigated perioperative changes in vitamin C levels in critically ill Children who underwent congenital heart surgery using CPB. Vitamin C serum levels were collected preoperatively and postoperatively (upon admission to the ICU, 24 and 72 h). Linear mixed-effect model was used to estimate mean circulating concentration of vitamin C and to estimate changes in concentration over time. Primary outcome was change in circulating levels of vitamin C before and after CPB. Secondary outcomes were hospital length of stay (LOS), acute kidney injury (AKI), and illness severity. Forty-one patients with a median age of 4.5 [interquartile range (IQR) 2.6-65.6] months at the time of surgery were consented and enrolled. Median CPB duration was 130 [90-175] minutes, and hospital LOS was 9.1 [5.2-19] days. Mean vitamin C levels (µmol/L) before CPB, at PICU admission, 24 h, and 72 h were 82.0 (95% CI 73.4-90.7), 53.4 (95% CI 44.6,62.0), 55.1 (95% CI 46.3,63.8), and 59.2 (95% CI 50.3,68.1), respectively. Upon postoperative admission to the PICU, vitamin C levels decreased by 28.7 (95% CI 20.6-36.8; p < 0.001) µmol/L, whereas levels at 24 and 72 h recovered and did not differ substantially from concentrations reported upon PICU admission (p > 0.15). Changes in vitamin C concentration were not associated with CPB time, STAT mortality category, age, or PIM3. Three patients had post-CPB hypovitaminosis C or vitamin C deficiency. Reduction in vitamin C levels was not associated with hospital LOS (p = 0.673). A 25 µmol/L decrease in vitamin C levels upon PICU admission was associated with developing AKI (aOR = 3.65; 95% CI 1.01-18.0, p = 0.049). Pediatric patients undergoing cardiac surgery with CPB showed decreased vitamin C levels during the immediate postoperative period. Effects of hypovitaminosis C and vitamin C deficiency in this population remain unclear.

Respiratory Severity Score during the First 3 Hours of Life as a Predictor for Failure of Noninvasive Respiratory Support and Need for Late Rescue Surfactant Administration.

OBJECTIVE: Preterm infants often develop failure of noninvasive respiratory support. These infants miss the advantages of early rescue surfactant therapy. In this study, we evaluate the utility of respiratory severity score (RSS) during the first 3 hours of life (HOL) as a predictor for failure of noninvasive respiratory support. STUDY DESIGN: We conducted a post hoc analysis of infants between 23 and 40 weeks' gestational age who received usual care in the AERO-02 clinical trial. Univariate and multivariable logistic regression analysis were used to assess whether the RSS summary measures were associated with the odds of surfactant administration. RESULTS: Study involved 146 infants. Sixty-four infants (45%) received surfactant within the first 72 hours. Administration of surfactant was associated with the mean RSS (p < 0.01) and the linear trend (p < 0.01). CONCLUSION: We demonstrated that RSS during the first 3 HOL can predict failure of noninvasive respiratory support and need for late rescue surfactant administration. Optimal RSS cutoffs for early rescue surfactant therapy need to be determined in large cohort studies. KEY POINTS: · Early recognition of infants at risk of failure of noninvasive ventilation is important to prevent complications.. · It is desirable to identify patients who would benefit from early rescue surfactant treatment.. · RSS in first 3 hours can be used as a predictor of failure of noninvasive respiratory support..

Retrospective investigation of perioperative risk factors for immediate postoperative corneal erosions in dogs undergoing phacoemulsification.

OBJECTIVE: To characterize the incidence, contributing risk factors, and healing characteristics of immediate postoperative corneal erosions (IPCE) in dogs undergoing routine phacoemulsification. ANIMALS STUDIED: Medical records of 313 canine eyes (159 dogs) undergoing routine phacoemulsification surgery. PROCEDURES: Medical records of dogs undergoing planned cataract surgery at UW Veterinary Care were retrospectively reviewed. Patient-related variables including age, skull conformation, diabetes status, and cataract stage at the time of surgery were recorded. Intraoperative variables per eye were also recorded including surgical technique, surgeon expertise level, average phacoemulsification power, and phacoemulsification time. Diagnosis of IPCE ≤ 24 h after completion of surgery and time to IPCE healing were recorded where follow-up data were available. RESULTS: Immediate postoperative corneal erosions were observed in 48/313 (15.3%) operated eyes. The presence of diabetes mellitus or brachycephalic skull conformation, preoperative Schirmer tear test (STT) value, surgical technique and surgeon experience level, phacoemulsification time, and absolute phacoemulsification time were not statistically significant risk factors for IPCE. Average phacoemulsification power was associated with IPCE (RR 1.52, p = .001). Time to IPCE healing was similar in diabetic and non-diabetic dogs (median [IQR] 8 [6-11] days and 8 [6-15] days, respectively). Diabetes mellitus, brachycephaly, and phacoemulsification parameters were not associated with IPCE healing at 7 or 14 days postoperatively. CONCLUSIONS: Higher average phacoemulsification power may be associated with the development of IPCE in canine eyes. The presence of diabetes mellitus or brachycephaly are not risk factors for the development of IPCE, nor are they factors that influence IPCE healing.

21-Deoxycortisol is a Key Screening Marker for 21-Hydroxylase Deficiency.

OBJECTIVES: To assess whether 21-deoxycortisol (21deoxy) can be used to predict 21-hydroxylase deficiency (21OHD) in newborns and to evaluate the influence of gestational age and the timing of collection on 21deoxy concentrations. STUDY DESIGN: 17-hydroxyprogesterone (17OHP) and 21deoxy levels were measured in 906 newborn screening specimens (851 unaffected newborns, 55 confirmed cases of 21OHD) to compare their ability to identify babies with 21OHD. In addition, these 2 steroids were assessed in the unaffected cohort to determine the influence of gestational age (ranging from 23 to 42 weeks) and the timing of specimen collection on the measured concentrations. RESULTS: The gestational age of the newborn impacted both 17OHP and 21deoxy concentrations, but the degree of influence was more substantial for 17OHP. Timing of collection did not affect 21deoxy concentration. Moreover, 21deoxy was a better predictor of 21OHD status compared with 17OHP, with little overlap in concentrations between the unaffected population and confirmed cases of 21OHD. A streamlined decision tree using solely 21deoxy (cutoff value, 0.85 ng/mL) yielded a 91.7% positive predictive value for 21OHD screening. CONCLUSIONS: Our findings demonstrate that 21deoxy is a key disease marker of 21OHD and can be used to improve the accuracy of newborn screening for this disorder.

Renal oxygenation measured by near-infrared spectroscopy in preterm neonates in the first week.

OBJECTIVE: To describe renal regional saturation of oxygen (RrSO2) values during the first week of life for preterm neonates born at <32 weeks gestational age (GA). METHODS: RrSO2 values recorded over the first week of life using near-infrared spectroscopy were retrospectively analyzed in this two-center cohort study of preterm infants without known congenital anomalies of the kidney. RESULTS: A cohort of 109 neonates with a median GA of 26.9 weeks and a median of 120 (IQR: 87-141) hours of continuous RrSO2 monitoring were included. Separately fitted trends in RrSO2 did not differ (p = 0.52) between sites and demonstrated a consistent decrease in RrSO2 by 20 points (95% CI: 9.6-30.1) during the first 60 h of life, followed by a stabilization of RrSO2 thereafter. RrSO2 baseline trends increased by 2.1 (95% CI: 0.8-3.3) percentage points for each additional week GA between 24 and 32 weeks GA. CONCLUSIONS: Despite differences in adjusted RrSO2 values between sites, profiles over time are consistent, allowing for the determination of RrSO2 trajectories in preterm infants. This expected pattern of RrSO2 changes in the first week may help guide future investigations and interventions to identify and reduce kidney injury in the preterm neonate. IMPACT: Renal regional saturation of oxygen (RrSO2) slowly decreases during the first 60 h of age in <32-week preterm neonates. While site differences were identified with respect to absolute values, RrSO2 trends from two different centers were not different. Lower gestational age neonates have lower RrSO2 levels during the first week.

Rapid Infliximab Biosimilar Infusion in Children With Inflammatory Bowel Disease.

OBJECTIVES: Compare prevalence of infusion reaction (IR) between infliximab (IFX) and infliximab biosimilar (IFX-abda) at standard and rapid rates and measure the impact on health care cost in children with inflammatory bowel disease (IBD). METHODS: Records of subjects receiving IFX and IFX-abda were reviewed over a 21-month period. Demographics and IRs were recorded. Cost analysis utilized average wholesale pricing, infusion duration, nursing time, and infusion center throughput. RESULTS: Fifty-six subjects received 498 infusions. Sixteen subjects received both IFX and IFX-abda. Thirteen IRs occurred for an overall prevalence of 2.6%. One outlier subject accounted for 8 of 13 (62%) of IRs. Data were analyzed with and without the outlier. Standard rate infusion of both IFX and IFX-abda was associated with increased risk of IR compared with rapid rate but only reached significance for IFX when calculated with the outlier removed. Risk of IR was not statistically significant between IFX and IFX-abda for both standard and rapid rates. IFX-abda saved an average of $2,611 per infusion. Rapid infusion saved 70 minutes of infusion time, 20 minutes of estimated nursing time per infusion, and decreased infusion center appointment length by as much as 2 hours per infusion. CONCLUSIONS: Rapid IFX-abda appears safe without increased IRs and decreases cost.

The Inter-Rater Reliability of Pediatric Point-of-Care Lung Ultrasound Interpretation in Children With Acute Respiratory Failure.

OBJECTIVES: Use of point-of-care lung ultrasound (POC-LUS) has increased significantly in pediatrics yet it remains under-studied in the pediatric intensive care unit (PICU). No studies explicitly evaluate the reliability of POC-LUS artifact interpretation among critically ill children with acute respiratory failure (ARF) in the PICU. We thus designed this study to determine the inter-rater reliability of POC-LUS interpretation in pediatric ARF among pediatric intensivists trained in POC-LUS and an expert intensivist. METHODS: We compared the interpretation of lung sliding, pleural line characteristics, ultrasound artifacts, and POC-LUS diagnoses among pediatric intensivists and an expert intensivist in a cohort of children admitted to the PICU for ARF. Kappa statistics (k) adjusted for maximum attainable agreement (k/kmax ) were used to quantify chance-correct agreement between the pediatric intensivist and expert physician. RESULTS: We enrolled 88 patients, evaluating 3 zones per hemithorax (anterior, lateral, and posterior) for lung sliding, pleural line characteristics, ultrasound artifacts, and diagnosis. There was moderate agreement between the PICU intensivist and expert-derived diagnoses with 56% observed agreement (k/kmax  = 0.46, 95% confidence interval [CI] 0.31-0.65). Agreement in identification of lung sliding (k = 0.19, 95% CI -0.17 to 0.56) and pleural line characteristics (k = 0.24, 95% CI 0.08-0.40) was slight and fair, respectively, while agreement in the interpretation of ultrasound artifacts ranged from moderate to substantial. CONCLUSIONS: Evidence supporting the evaluation of neonatal and adult patients with POC-LUS should not be extrapolated to critically ill pediatric patients. This study adds to the evidence supporting use of POC-LUS in the PICU by demonstrating moderate agreement between PICU intensivist and expert-derived POC-LUS diagnoses.

Anticholinergics and serious adverse events in pediatric procedural sedation: A report of the pediatric sedation research consortiums.

BACKGROUND: Pediatric sedation is a clinical activity with potential for serious but rare airway adverse events, particularly laryngospasm. Anticholinergic drugs, atropine and glycopyrrolate, are frequently used with the intention to improve sedation safety by virtue of their antisialagogue effects. AIMS: The objective of this study is to describe the current practice of anticholinergic use in pediatric sedation and to compare the frequency of serious sedation-related adverse events in patients who received anticholinergics to those who did not. METHODS: We examined prospectively collected data from the Pediatric Sedation Research Consortium database. Patient characteristics, procedure type, sedation provider, sedatives, location of sedation, anticholinergic administered, adverse events, and airway interventions were reported. Propensity score matching and multivariable logistic regression were used to test whether any association exists between anticholinergic use and serious sedation-related adverse events. RESULTS: Anticholinergics were administered in 7.1% (n = 18 707) of all cases (n = 263 883) reported between November 2011 and October 2017. When anticholinergics were used, atropine was used in 22% (n = 4111) and glycopyrrolate in 78.1% (n = 14 601) of sedations. Use of anticholinergics was more common in patients with well-described risk factors for airway adverse events: active/history of upper respiratory infection, history of reactive airway disease/asthma, and exposure to smoke. However, infants and ASA 3 patients were not associated with higher rate of anticholinergic use. Anticholinergic use was independently associated with an increase in the odds of serious adverse events, OR 1.8 (95% CI 1.6-2.1), especially airway adverse events. CONCLUSIONS: In this large Pediatric Sedation Research Consortium study, we found the use of anticholinergic adjuvants independently associated with greater odds of serious adverse events, especially airway adverse events, after adjusting for well-known sedation risk factors using propensity score matching and multivariate analysis.

Clinical Outcomes of Neonatal Intensive Care Unit Graduates with Bridled Nasogastric Feeding Tubes.

OBJECTIVE: The aim of this study was to describe clinical outcomes of bridled nasogastric tube (NGT) program implementation for infants requiring assisted home feeding (AHF) to discharge from the neonatal intensive care unit (NICU). STUDY DESIGN: This was a descriptive prospective analysis of a pilot cohort of infants after implementation of a bridled NGT AHF program to facilitate discharge from level III and IV NICUs from March 2019 to October 2020. RESULTS: Of 29 attempts in infants, 22 infants were discharged with bridled NGTs over 18 months. Bridle placement was unsuccessful in three patients, and four bridles were removed before discharge. Bridle use ranged from 7 to 125 days, with a median duration of 37 days. Dislodgement rate was 0.69 per 100 days. Seventeen infants (77%) achieved full oral feeds, while five (23%) discharged with bridled NGTs later converted to gastrostomy tubes. CONCLUSION: Implementation of a bridled NGT program is feasible for level III and IV NICUs to facilitate discharging infants who require feeding support to transition home. KEY POINTS: · Bridled NGT use after NICU is typically 1 month.. · Infants have low bridle NGT dislodgement.. · Most bridled NGT NICU grads attain full oral feeds..

Oxygen Saturation Profiles in Healthy Term Infants in Early Postnatal Life.

OBJECTIVE: Oxygen saturation profiles generated by pulse oximetry are used as a clinical tool in the neonatal intensive care unit (NICU). There is limited evidence on normal oxygen saturation profile values in term infants. This study aimed to determine oxygen saturation profiles over an 8-hour monitoring period among healthy term neonates between 24 and 48 hours after birth. STUDY DESIGN: A prospective cohort study of healthy term neonates born at 37 to 41 weeks of gestation. Preductal oxygen saturations were continuously monitored for an 8-hour period between 24 and 48 hours of life using pulse oximetry. Oxygen profile histograms were recorded for analysis. The average percent oxygen saturation (SpO2) was measured over the entire study duration for each neonate and was characterized as the fraction of time of their SpO2 reading was in each of five intervals: ≤80, 81 to 84, 85 to 89, 90 to 94, and 95 to 100%. RESULTS: Seventy-five neonates were included in the study. Median SpO2 was 95.4%. Percentage time spent in each of the five SpO2 intervals was as follows: 0.07 (≤80), 0.15 (81-84), 0.88 (85-89), 26.9 (90-94), and 67.3% (95-100%). Eighteen infants (24%) spent the highest percentage of time in SpO2 of 90 to 94%. CONCLUSION: This study provides reference ranges for oxygen profiles in healthy term neonates during 24 to 48 hours of life. Nearly one-quarter of newborns spent the highest percentage of time in SpO2 of 90 to 94%. This data is important when interpreting oxygen saturation profiles of term neonates admitted to the NICU. KEY POINTS: · This study provide reference ranges for oxygen profiles in healthy term neonates during 24 to 48 hours.. · Median SpO2 was 95.4%.. · Nearly one quarter of newborns spent the highest percentage of time in SpO2 of 90 to 94%..

Point-of-Care Lung Ultrasound to Diagnose the Etiology of Acute Respiratory Failure at Admission to the PICU.

OBJECTIVES: Determine the sensitivity and specificity of point-of-care lung ultrasound in identifying the etiology of acute respiratory failure at admission to the PICU. DESIGN: Prospective observational study. SETTING: Tertiary PICU. PATIENTS: Children older than 37 weeks gestational age and less than or equal to 18 years old admitted to the PICU with acute respiratory failure from December 2018 to February 2020. INTERVENTION: Point-of-care lung ultrasound performed within 14 hours of admission to the PICU by physicians blinded to patient history and clinical course. Two physicians, blinded to all clinical information, independently interpreted the point-of-care lung ultrasound and then established a consensus diagnosis (ultrasound diagnosis). The ultrasound diagnosis was compared with an independent, standardized review of the medical record following hospital discharge (final diagnosis). MEASUREMENTS AND RESULTS: Eighty-eight patients were enrolled in the study. Forty-eight patients had a final diagnosis of bronchiolitis/viral pneumonitis (55%), 29 had pneumonia (33%), 10 had status asthmaticus (11%), and one was excluded because of an inability to differentiate the final diagnosis. Point-of-care lung ultrasound correctly identified the etiology of acute respiratory failure in 56% of patients (49/87; 95% CI, 46-66%). It identified bronchiolitis/viral pneumonitis with 44% sensitivity (95% CI, 0.31-0.58) and 74% specificity (95% CI, 0.59-0.85), pneumonia with 76% sensitivity (95% CI, 0.58-0.88) and 67% specificity (95% CI 0.54-0.78), and status asthmaticus with 60% sensitivity (95% CI, 0.31-0.83) and 88% specificity (95% CI, 0.79-0.94). CONCLUSIONS: In contrast to literature demonstrating high utility differentiating the cause of acute respiratory failure in adults, blinded point-of-care lung ultrasound demonstrates moderate sensitivity and specificity in identifying the etiology of pediatric acute respiratory failure at admission to the PICU among children with bronchiolitis, pneumonia, and status asthmaticus.

Hypothyroxinemia Detected at 4 Weeks of Life in Preterm Infants Born at Less than 30 Weeks of Gestation.

OBJECTIVE: Data on free thyroxine (FT4) concentrations beyond first 2 weeks of preterm infants are limited. This study was aimed to describe the association between perinatal characteristics and FT4 concentrations and the incidence of hypothyroxinemia at 4 weeks. STUDY DESIGN: Retrospective analysis of serum thyroid function tests at 4 weeks in preterm infants <30 weeks of gestation. Association between FT4 at 4 weeks of life and perinatal characteristics were determined by bivariate analysis and multivariable regression. Incidence of hypothyroxinemia was determined using a gestational age adjusted definition based on in utero levels at the equivalent postmenstrual age. RESULTS: The study cohort consisted of 280 infants. FT4 concentrations at 4 weeks of life were significantly associated with gestational age, birth weight, gender, and maternal history of thyroid disease. Hypothyroxinemia was found in 32.8% of the study cohort. CONCLUSION: Perinatal characteristics are associated with FT4 concentrations at 4 weeks of life. Nearly one-third of infants born <30 weeks had hypothyroxinemia at 4 weeks of life when compared with in utero levels at the equivalent postmenstrual age.

Patterns of farm exposure are associated with reduced incidence of atopic dermatitis in early life.

BACKGROUND: Farm exposures may reduce the risk of atopic dermatitis (AD) in children, but this is controversial and US data are limited. OBJECTIVE: This study was conducted to identify patterns of farm exposure in Wisconsin family farms that modify AD incidence and prevalence in early childhood. METHODS: Environmental exposures, health history, and clinical outcomes were prospectively recorded for 111 farm families and 129 non-farm families enrolled in the Wisconsin Infant Study Cohort birth cohort study. Exposures from the prenatal and early postnatal (2-month) visits were evaluated together with parental report of AD diagnosis by a health care provider through age 24 months. Latent class analysis was performed with prenatal and early postnatal farm-exposure variables to assign farm children to 3 classes. RESULTS: Overall, children of farm families had reduced AD incidence (P = .03). Within farm families, exposures including poultry (3% vs 28%; P = .003), pig (4% vs 25%; P = .04), feed grain (13% vs 34%; P = .02), and number of animal species were inversely associated with AD incidence. Among the latent class groups, children in families with diverse or more intense farm exposures (classes A and B) had reduced AD incidence, whereas low-exposure (class C) infants had AD incidence similar to that in nonfarm children. CONCLUSIONS: Infants in Wisconsin farm families had reduced AD incidence, and patterns of farm exposures further defined AD risk. These findings suggest that exposure to diverse farm animals, feed, and bedding during the prenatal period and in early infancy reduce the risk of early-onset AD, a phenotype associated with multiple other atopic diseases.

Ageing and genetic background influence anaesthetic effects in a D. melanogaster model of blunt trauma with brain injury†.

BACKGROUND: General anaesthetics interact with the pathophysiological mechanisms of traumatic brain injury (TBI). We used a Drosophila melanogaster (fruit fly) model to test the hypothesis that ageing and genetic background modulate the effect of anaesthetics and hyperoxia on TBI-induced mortality in the context of blunt trauma. METHODS: We exposed flies to isoflurane or sevoflurane under normoxic or hyperoxic conditions and TBI, and subsequently quantified the effect on mortality 24 h after injury. To determine the effect of age on anaesthetic-induced mortality, we analysed flies at 1-8 and 43-50 days old. To determine the effect of genetic background, we performed a genome-wide association study (GWAS) analysis on a collection of young inbred, fully sequenced lines. RESULTS: Exposure to anaesthetics and hyperoxia differentially affected mortality in young and old flies. Pre-exposure of young but not old flies to anaesthetics reduced mortality. Post-exposure selectively increased mortality. For old but not young flies, hyperoxia enhanced the effect on mortality of post-exposure to isoflurane but not to sevoflurane. Post-exposure to isoflurane in hyperoxia increased the mortality of young fly lines in the Drosophila Genetic Reference Panel collection to different extents. GWAS analysis of these data identified single nucleotide polymorphisms in genes involved in cell water regulation and oxygen sensing as being associated with the post-exposure effect on mortality. CONCLUSIONS: Ageing and genetic background influence the effects of volatile general anaesthetics and hyperoxia on mortality in the context of traumatic brain injury. Polymorphisms in specific genes are identified as potential causes of ageing and genetic effects.

NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice.

Global distribution of hepatocellular carcinomas (HCCs) is dominated by its incidence in developing countries, accounting for >700,000 estimated deaths per year, with dietary exposures to aflatoxin (AFB1) and subsequent DNA adduct formation being a significant driver. Genetic variants that increase individual susceptibility to AFB1-induced HCCs are poorly understood. Herein, it is shown that the DNA base excision repair (BER) enzyme, DNA glycosylase NEIL1, efficiently recognizes and excises the highly mutagenic imidazole ring-opened AFB1-deoxyguanosine adduct (AFB1-Fapy-dG). Consistent with this in vitro result, newborn mice injected with AFB1 show significant increases in the levels of AFB1-Fapy-dG in Neil1-/- vs. wild-type liver DNA. Further, Neil1-/- mice are highly susceptible to AFB1-induced HCCs relative to WT controls, with both the frequency and average size of hepatocellular carcinomas being elevated in Neil1-/- The magnitude of this effect in Neil1-/- mice is greater than that previously measured in Xeroderma pigmentosum complementation group A (XPA) mice that are deficient in nucleotide excision repair (NER). Given that several human polymorphic variants of NEIL1 are catalytically inactive for their DNA glycosylase activity, these deficiencies may increase susceptibility to AFB1-associated HCCs.

Retrospective analysis of complications associated with retrobulbar bupivacaine in dogs undergoing enucleation surgery.

OBJECTIVE: To investigate complications associated with, and without, bupivacaine retrobulbar local anesthesia in dogs undergoing unilateral enucleation surgery. STUDY DESIGN: Retrospective, observational study. ANIMALS: A total of 167 dogs underwent unilateral enucleation surgery via a transpalpebral approach. METHODS: Records from 167 dogs that underwent unilateral enucleation surgery that did (RB) or did not (NB) include retrobulbar bupivacaine anesthesia were reviewed, including anesthetic record, daily physical examination records, surgery report, patient discharge report and patient notes within 14 days of the surgery. Specific complications and severity were compared between RB and NB using the Wilcoxon rank-sum test. A 'complication burden' (0-5) comprising five prespecified complications was assigned and tested using rank-sum procedures. Statistical significance was set to 0.05. RESULTS: Group RB included 97 dogs and group NB 70 dogs. Dogs in NB had a 17.0 percentage points (points) greater risk for a postoperative recovery complication (38.6% versus 21.6%; 95% confidence interval: 3.0-30.6 points; p = 0.017). There was inconclusive evidence that dogs in group RB had a lower risk of requiring perioperative anticholinergic administration (12.4% versus 22.9%; 10.5 points; p = 0.073). Other complications were similar between groups RB and NB with risks that differed by <10 points. The risk of hemorrhage was similar between groups RB (22.7%) and NB (20.0%) with no significant difference in the level of severity (p = 0.664). CONCLUSIONS AND CLINICAL RELEVANCE: In this retrospective study, the use of retrobulbar bupivacaine for enucleation surgery in dogs was not associated with an increased risk of major or minor complications.

Separate and interacting effects of the endogenous circadian system and behaviors on plasma aldosterone in humans.

Measurements of aldosterone for diagnosis of primary aldosteronism are usually made from blood sampled in the morning when aldosterone typically peaks. We tested the relative contributions and interacting influences of the circadian system, ongoing behaviors, and prior sleep to this morning peak in aldosterone. To determine circadian rhythmicity and separate effects of behaviors on aldosterone, 16 healthy participants completed a 5-day protocol in dim light while all behaviors ranging from sleep to exercise were standardized and scheduled evenly across the 24-h circadian period. In another experiment, to test the separate effects of prior nocturnal sleep or the inactivity that accompanies sleep on aldosterone, 10 healthy participants were studied across 2 nights: 1 with sleep and 1 with maintained wakefulness (randomized order). Plasma aldosterone was measured repeatedly in each experiment. Aldosterone had a significant endogenous rhythm ( P < 0.001), rising across the circadian night and peaking in the morning (~8 AM). Activity, including exercise, increased aldosterone, and different behaviors modulated aldosterone differently across the circadian cycle (circadian phase × behavior interaction; P < 0.001). In the second experiment, prior nocturnal sleep and prior rested wakefulness both increased plasma aldosterone ( P < 0.001) in the morning, to the same extent as the change in circadian phases between evening and morning. The morning increase in aldosterone is due to effects of the circadian system plus increased morning activities and not prior sleep or the inactivity accompanying sleep. These findings have implications for the time of and behaviors preceding measurement of aldosterone, especially under conditions of shift work and jet lag.

Morning impairment in vascular function is unrelated to overnight sleep or the inactivity that accompanies sleep.

Adverse cardiovascular events, such as myocardial infarction and sudden cardiac death, occur more frequently in the morning. Prior studies have shown that vascular endothelial function (VEF), a marker of cardiovascular disease, is attenuated during physical inactivity and declines across the night. We sought to determine whether a morning attenuation in VEF is a result of prior sleep or the inactivity that inevitably accompanies sleep. After 1 wk of a rigorously controlled sleep-wake schedule and behaviors, 10 healthy participants completed a randomized crossover protocol in dim light and constant conditions, incorporating a night of 6 h of sleep opportunity and a night of immobility while they were supine and awake. VEF was measured in the dominant brachial artery as flow mediated dilation (FMD) before and after each 6-h trial. To avoid disturbing sleep and posture of the participants, blood was drawn using a 12-ft catheter from an adjoining laboratory room before, during, and after each 6-h trial, and plasma was analyzed for markers of oxidative stress [malondialdehyde adducts (MDA)], and endothelin-1. Contrary to expectation, both nocturnal sleep and nocturnal inactivity significantly increased FMD ( P < 0.05). There was no significant change in MDA or endothelin-1 within and between trials. Contrary to expectations based on prior studies, we found that overnight sleep or the inactivity that accompanies sleep did not result in attenuation in VEF in the morning hours in healthy people. Thus, it is plausible that the endogenous circadian system, a remaining factor not studied here, is responsible for the commonly observed decline in VEF across the night.