Interstitial IgG antibody pharmacokinetics assessed by combined in vivo- and physiologically-based pharmacokinetic modelling approaches

Abstract

For most therapeutic antibodies, the interstitium is the target space. Although experimental methods for measuring antibody pharmacokinetics (PK) in this space are not well established, making quantitative assessment difficult, the interstitial antibody concentration is assumed to be low. Here, we combined direct quantification of antibodies in the interstitial fluid with a physiologically-based PK (PBPK) modelling approach with the goal of better describing the PK of monoclonal antibodies in the interstitial space of different tissues. We isolated interstitial fluid by tissue centrifugation, and conducted an antibody biodistribution study in mice, measuring total tissue- and interstitial concentrations in selected tissues. Residual plasma, interstitial volumes and lymph flows, which are important PBPK model parameters, were assessed in vivo. We could thereby refine PBPK modelling of monoclonal antibodies, better interpret antibody biodistribution data and more accurately predict their PK in the different tissue spaces. Our results indicate that in tissues with discontinuous capillaries (liver and spleen), interstitial concentrations are reflected by plasma concentration. In tissues with continuous capillaries (e.g. skin and muscle), ∼50-60% of plasma concentration is found in the interstitial space. In brain and kidney, on the other hand, antibodies are restricted to the vascular space. Our data may significantly impact the interpretation of biodistribution data of monoclonal antibodies and might be important when relating measured concentrations to a therapeutic effect. Opposing the view that antibodies distribution to the interstitial space is limited, we show by direct measurements and model-based data interpretation that high antibody interstitial concentrations are reached in most tissues.

This article is protected by copyright. All rights reserved

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Intrapartum assessment of fetal well-being

1A012A043J02

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Brain functional connectivity differentiates dexmedetomidine from propofol and natural sleep

Abstract

Background.

We used functional connectivity measures from brain resting state functional magnetic resonance imaging to identify human neural correlates of sedation with dexmedetomidine or propofol and their similarities with natural sleep.

Methods.

Connectivity within the resting state networks that are proposed to sustain consciousness generation was compared between deep non-rapid-eye-movement (N3) sleep, dexmedetomidine sedation, and propofol sedation in volunteers who became unresponsive to verbal command. A newly acquired dexmedetomidine dataset was compared with our previously published propofol and N3 sleep datasets.

Results.

In all three unresponsive states (dexmedetomidine sedation, propofol sedation, and N3 sleep), within-network functional connectivity, including thalamic functional connectivity in the higher-order (default mode, executive control, and salience) networks, was significantly reduced as compared with the wake state. Thalamic functional connectivity was not reduced for unresponsive states within lower-order (auditory, sensorimotor, and visual) networks. Voxel-wise statistical comparisons between the different unresponsive states revealed that thalamic functional connectivity with the medial prefrontal/anterior cingulate cortex and with the mesopontine area was reduced least during dexmedetomidine-induced unresponsiveness and most during propofol-induced unresponsiveness. The reduction seen during N3 sleep was intermediate between those of dexmedetomidine and propofol.

Conclusions.

Thalamic connectivity with key nodes of arousal and saliency detection networks was relatively preserved during N3 sleep and dexmedetomidine-induced unresponsiveness as compared to propofol. These network effects may explain the rapid recovery of oriented responsiveness to external stimulation seen under dexmedetomidine sedation.

Trial registry number.

Committee number: 'Comité d'Ethique Hospitalo-Facultaire Universitaire de Liège' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

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Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant

Germline mosaicism for a novel missense variant p.Thr645Met located in the SNF2-related ATP dependent helicase domain of CHD2 in 2 affected siblings with autism spectrum disorder.

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Development: Epigenome dynamics from seed to seedling

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Demographic history, selection and functional diversity of the canine genome

Despite being a single species, dogs represent nearly 400 breeds with substantial genetic, morphological and behavioural diversity. In this Review, Ostrander et al. discuss how genomics studies of dogs have enhanced our understanding of dog and human population history, the desired and unintended consequences of trait-based selective breeding, and potentially human-applicable insights into cancer, ageing, behaviour and neurological diseases.

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Procaine and Local Anesthetic Toxicity: A Collaboration Between the Clinical and Basic Sciences.

In 1924, the Therapeutic Research Committee of the American Medical Association appointed a special committee to investigate deaths following the administration of local anesthetics. The Committee for the Study of Toxic Effects of Local Anesthetics found procaine, although a safer clinical alternative to cocaine, was capable of causing death when large doses were injected into tissues and advised that it should be used with caution. This article describes a collaboration beginning in 1928 between Dr John Lundy of the Mayo Clinic and Dr Robert Isenberger of the University of Kansas, which arose from a controversy surrounding systemic adverse reactions to procaine. Isenberger then traveled to the Mayo Clinic to conduct research on various procaine local and spinal anesthesia doses and sodium amytal's protective effect against procaine-induced toxicity. Lundy and Isenberger's work would add to the ongoing discovery of systemic reactions to local anesthetics. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Impact of Regional Anesthesia on Recurrence, Metastasis, and Immune Response in Breast Cancer Surgery: A Systematic Review of the Literature.

Background and Objectives: The perioperative period is critical in the long-term prognosis of breast cancer patients. The use of regional anesthesia, such as paravertebral block (PVB), could be associated with improvements in long-term survival after breast cancer surgery by modulating the inflammatory and immune response associated with the surgical trauma, reducing opioid and general anesthetic consumption, and promoting cancer cells death by a direct effect of local anesthetics. Methods: A systematic literature search was conducted for studies of patients who received PVB for breast cancer surgery. The Jadad score and Ottawa-Newcastle scale were used to assess the methodological quality of randomized controlled trial and observational retrospective studies, respectively. Only high-quality studies were considered for meta-analysis. The selected studies were divided into 3 groups to determine the impact of PVB on (a) recurrence and survival, (b) humoral response, and (c) cellular immune response. Results: We identified 467 relevant studies; 121 of them underwent title and abstract review, 107 were excluded, and 15 studies were selected for full text reading and quality assessment. A meta-analysis was not conducted because of low-quality studies and lack of uniform definition among primary outcomes. Thus, a systematic review of the current evidence was performed. Conclusions: Our study indicates that there are no data to support or refute the use of PVB for reduction of cancer recurrence or improvement in cancer-related survival. However, PVB use is associated with lower levels of inflammation and a better immune response in comparison with general anesthesia and opioid-based analgesia. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Gliotransmission and adenosinergic modulation: insights from mammalian spinal motor networks

Astrocytes are proposed to converse with neurons at tripartite synapses, detecting neurotransmitter release and responding with release of gliotransmitters, which in turn modulate synaptic strength and neuronal excitability. However, a paucity of evidence from behavioral studies calls into question the importance of gliotransmission for the operation of the nervous system in healthy animals. Central pattern generator (CPG) networks in the spinal cord and brainstem coordinate the activation of muscles during stereotyped activities such as locomotion, inspiration and mastication, and may therefore provide tractable models in which to assess the contribution of gliotransmission to behaviorally relevant neural activity. Here, we review evidence for gliotransmission within spinal locomotor networks, including studies indicating that adenosine derived from astrocytes regulates the speed of locomotor activity via metamodulation of dopamine signaling.

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Breathing above the brainstem: Volitional control and attentional modulation in humans.

While the neurophysiology of respiration has traditionally focused on automatic brainstem processes, higher brain mechanisms underlying the cognitive aspects of breathing are gaining increasing interest. Therapeutic techniques have used conscious control and awareness of breathing for millennia with little understanding of the mechanisms underlying their efficacy. Using direct intracranial recordings in humans, we correlated cortical and limbic neuronal activity as measured by the intracranial electroencephalogram (iEEG) with the breathing cycle. We show this to be the direct result of neuronal activity, as demonstrated both by the specificity of the finding to the cortical grey matter and the tracking of breath by the gamma band (40-150 Hz) envelope in these structures. We extend prior observations by showing the iEEG signal to track the breathing cycle across a widespread network of cortical and limbic structures. We further demonstrate a sensitivity of this tracking to cognitive factors using tasks adapted from cognitive behavioral therapy and meditative practice. Specifically, volitional control and awareness of breathing engage distinct but overlapping brain circuits. During volitionally-paced breathing, iEEG-breath coherence increases in a fronto-temporal-insular network, and during attention to breathing, we demonstrate increased coherence in the anterior cingulate, premotor, insular and hippocampal cortices. Our findings suggest that breathing can act as an organizing hierarchical principle for neuronal oscillations throughout the brain, and detail mechanisms of how cognitive factors impact otherwise-automatic neuronal processes during interoceptive attention.

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Low-threshold mechanoreceptors play a frequency-dependent, dual role in subjective ratings of mechanical allodynia.

In the setting of injury, myelinated primary afferent fibers that normally signal light touch, are thought to switch modality and instead signal pain. In the absence of injury, touch is perceived as more intense when firing rates of Aβ afferents increase. However, it is not known if varying the firing rates of Aβ afferents have any consequence to perception of dynamic mechanical allodynia (DMA). We hypothesized that, in the setting of injury, the unpleasantness of DMA would be intensified as the firing rates of Aβ afferents increase. Using a stimulus-response protocol established in normal skin, where increased brush velocity results in an increase of Aβ afferent firing rates, we tested if brush velocity modulated the unpleasantness of capsaicin-induced DMA. We analyzed how changes in estimated mechanoreceptor firing activity influenced perception and brain activity (fMRI) of DMA. Brushing on normal skin was perceived as pleasant, but brushing on sensitized skin produced both painful and pleasant sensations. Surprisingly, there was an inverse relationship between Aβ firing rates and unpleasantness, such that brush stimuli that produced low firing rates were most painful and those that elicited high firing rates were rated as pleasant. Concurrently, we found increased cortical activity in response to low Aβ firing rates in regions previously implicated in pain processing while brushing sensitized skin. We suggest that Aβ signals do not merely switch modality to signal pain during injury. Instead, they exert a high and low frequency-dependent dual role in the injured state, with respectively both pleasant and unpleasant consequences.

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Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike and wave-like electrographic events in vitro.

Acute In vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike and wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalised and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden and apparent anatomical origin (thalamic, neocortical or both), but any relationship between this heterogeneity and underlying pathology remains elusive. Here we demonstrate that physiological delta frequency rhythms act as an effective substrate to permit modelling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modelled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies.

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Memory-guided saccades show effect of perceptual illusion whereas visually-guided saccades do not

The double-drift stimulus (a drifting Gabor with orthogonal internal motion) generates a large discrepancy between its physical and perceived path. Surprisingly, saccades directed to the double-drift stimulus land along the physical, and not perceived, path (Lisi & Cavanagh, 2015). Here we asked whether memory-guided saccades exhibited the same dissociation from perception. Participants were asked to keep their gaze centered on a fixation dot while the double-drift stimulus moved back and forth on a linear path in the periphery. The offset of the fixation was the go-signal to make a saccade to the target. In the visually-guided saccade condition, the Gabor kept moving on its trajectory after the go-signal but was removed once the saccade began. In the memory conditions, the Gabor disappeared before or at the same time as the go-signal (0 to 1000 ms delay) and participants made a saccade to its remembered location. The results showed that visually-guided saccades again targeted the physical rather than the perceived location. However, memory saccades, even with 0 ms delay, had landing positions shifted toward the perceived location. Our result shows that memory- and visually-guided saccades are based on different spatial information.

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High variability impairs motor learning regardless of whether it affects task performance

Motor variability plays an important role in motor learning, although the exact mechanisms of how variability affects learning is not well understood. Recent evidence suggests that motor variability may have different effects on learning in redundant tasks, depending on whether it is present in the task space (where it affects task performance), or in the null space (where it has no effect on task performance). Here we examined the effect of directly introducing null and task space variability using a manipulandum during the learning of a motor task. Participants learned a bimanual shuffleboard task for 2 days, where their goal was to slide a virtual puck as close as possible towards a target. Critically, the distance traveled by the puck was determined by the sum of the left and right hand velocities, which meant that there was redundancy in the task. Participants were divided into five groups - based on both the dimension in which the variability was introduced and the amount of variability that was introduced during training. Results showed that although all groups were able to reduce error with practice, learning was affected more by the amount of variability introduced rather than the dimension in which variability was introduced. Specifically, groups with higher movement variability during practice showed larger errors at the end of practice compared to groups that had low variability during learning. These results suggest that although introducing variability can increase exploration of new solutions, this may adversely affect the ability to retain the learned solution.

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Iron Status in Pediatric Celiac Disease: A Retrospective Chart Review.

This study assessed the role of serum ferritin as a non-invasive biomarker in the diagnosis and monitoring of pediatric celiac disease. A retrospective chart review was performed on patients

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Nutrition Practices and Predictors of Postnatal Growth in Preterm Infants During Hospitalization: A Longitudinal Study.

Premature infants are at high risk of undernutrition and extrauterine growth restriction (EUGR). Aim: To evaluate the relation between nutrition practices and growth rate in preterm infants from birth to 36 weeks postmenstrual age (PMA). Methods: Longitudinal data were collected retrospectively in 103 infants born

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The Pediatric Eating Assessment Tool (PediEAT): Factor structure and psychometric properties.

Objectives: The Pediatric Eating Assessment Tool (PediEAT) is a parent-report instrument developed to assess symptoms of feeding problems in children aged 6 months to 7 years. The purpose of this study was to identify the factor structure of the PediEAT and test its psychometric properties, including internal consistency reliability, temporal stability, and construct validity. Methods: Participants included 567 parents of children aged 6 months to 7 years. Fifty-four percent of the sample had parent report of a diagnosed feeding problem or feeding concerns. Exploratory factor-analysis techniques were used to remove redundant or non-endorsed items and identify the factor structure of the instrument. Construct validity was examined with 466 parents completing the Mealtime Behavior Questionnaire (MBQ) as a criterion standard. Known-groups validation was used to compare PediEAT scores between children with and without diagnosed feeding problems. Temporal stability of the PediEAT was examined with 97 parents repeating the PediEAT after 2 weeks. Results: Principal components factor analysis with varimax rotation supported a 4-factor model accounting for 39.4% of the total variance. The four subscales (Physiologic Symptoms, Problematic Mealtime Behaviors, Selective/Restrictive Eating, Oral Processing) demonstrated acceptable internal consistencies (coefficient alphas: .92, .91, .83, .83; respectively). Construct validity was supported in two ways. The PediEAT correlated with the MBQ (r = .77, p

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Growth Trajectory in Children With Short Bowel Syndrome During the First Two Years of Life.

Objectives: Infants with short bowel syndrome (SBS) require diligent nutritional support for adequate growth. Enteral independence is a primary goal, but must be balanced with ensuring sufficient nutrition. We aimed to describe growth trajectory in infants with SBS as function of nutritional intake during first two years of life. Methods: Infants with SBS were reviewed (2008-2016). Z-scores for weight, height, and head circumference (HC), were recorded at birth, 3, 6, 12, 18, and 24 months. Nutritional intake, serum liver enzyme, and bilirubin levels were assessed at all time points. Pearson correlation coefficients were used to measure association with p 0 at birth, but

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Parental Distress and Quality of Life in Pediatric Inflammatory Bowel Disease: Implications for the Outpatient Clinic.

Objectives: The interrelation between the course of Inflammatory Bowel Disease (IBD) in children and parent's distress, and the subsequent impact this may have on Health-Related Quality Of Life (HRQOL) of the child is unclear. Therefore, we investigated (I) patient's HRQOL and parental distress, and (II) the association between the course of IBD, parental distress, and HRQOL of pediatric IBD patients. Methods: Pediatric IBD patients (8-18 years) and parents were invited. Patients completed the Pediatric Quality of Life Inventory, and parents the Distress Thermometer for Parents, simultaneously. Disease course was expressed as current clinical disease activity or months since last IBD flare. Patient's HRQOL and parental distress were compared to healthy controls. Results: In total, 87 patients (71% response rate, 59% male, median age 15.2 years) and parents were included. Patients had an impaired total HRQOL ([beta] = 0.125, p = 0.010), driven by lower physical ( = 0.196, p = 0.001) and school ([beta] = 0.232, p

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Anti-TNF[alpha] Treatment in Children and Adolescents With Combined Inflammatory Bowel Disease and Autoimmune Liver Disease.

Objectives: Inflammatory bowel disease (IBD) and autoimmune liver disease (AILD) are closely associated, the former often dictating progression of the latter. Antibodies to tumor necrosis factor alpha (anti- TNF[alpha]) are effective in the management of IBD, but may cause liver injury. Methods: Retrospective review of medical records of patients with juvenile AILD who received anti-TNF[alpha] for IBD to evaluate the safety and efficacy of anti-TNF[alpha]. Results: Eleven patients (6 males), aged 9-15y (median 13y) were identified. 10 had ulcerative colitis (UC) and 1 Crohn's disease; 2 had autoimmune hepatitis type 1 (AIH-1) and 9 autoimmune hepatitis-sclerosing cholangitis variant. All patients were started on infliximab (5 mg/kg) and 2 required dose increase (10 mg/kg); 3/11 switched to adalimumab due to allergic reaction or non-response. 3 received adalimumab after losing response or developing antibodies to IFX. Liver function tests (LFTs) improved in 5, 1 continued to have stably abnormal LFTs and 2 maintained normal LFTs. Patients on adalimumab showed stable or improved liver function compared to pre-treatment status. 6/8 treated with a full course of infliximab maintained clinical remission of IBD for 6m-2.5y; of the 6 patients treated with adalimumab, one sustained IBD clinical remission for 24 months, 2 achieved remission only after tacrolimus addition and 3 did not respond. Conclusions: IBD in patients with AILD can be aggressive, requiring escalation to anti-TNF[alpha] or switching to other biologics. In this series, anti-TNF[alpha] did not impair liver function and improved gut disease in most of the patients, indicating that it can be beneficial and safe. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Cecal Volvulus in Children: Is There Place for Colonoscopic Decompression?.

No abstract available

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Association of Heparin-binding EGF-like Growth Factor Polymorphisms with Necrotizing Enterocolitis in Preterm Infants.

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) protects the intestines from injury in experimental necrotizing enterocolitis (NEC). We hypothesized that polymorphisms in the HB-EGF gene lead to low HB-EGF production in peripheral blood and increased risk of NEC in the Chinese Han population. To test this hypothesis, thirty NEC patients and eighty control subjects were selected. Five HB-EGF single-nucleotide polymorphisms (SNPs) and its plasma levels were measured by genotyping and ELISA, respectively. Only one out of the five SNPs showed a notable result. The notable SNP (rs4912711) was associated with NEC in its minor allele frequency (MAF) and its 'G/T' genotype distribution. Additionally, plasma HB-EGF levels were reduced especially the 'G/T' genotype in NEC patients. Our data suggest that if validated in larger studies screening for HB-EGF SNPs/genotypes and plasma levels might be useful as a risk factor for NEC in the future. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Can Basic Characteristics Estimate Body Composition in Early Infancy?.

Objectives: Increasing evidence demonstrates that body composition in early life contributes to the programming of health later in life in both full-term and preterm infants. Given the important role of body composition, the increased availability of easy, non-invasive and accurate techniques for its assessment has been recommended. The aim of the present study was to identify basic characteristics and anthropometric measurements that best correlate with body composition in infants. Methods: Anthropometric measurements and body composition assessed by air-displacement plethysmography were assessed either at birth or at term-corrected age in 1239 infants (654 full-term, 585 preterm). The associations of gender, GA (gestational age) and weight with FFM (fat-free mass) and FM (fat mass) adjusted by length (g/cm) were investigated by multiple linear regression models. Bland-Altman tests were performed, and an equation for calculating FFM was determined. Results: Preterm infants exhibited increased FM and reduced FFM compared with full-term infants (477.6 +/- 204 g vs. 259.7 +/- 147 g and 2583 +/- 494 g vs. 2770 +/- 364 g, respectively). GA, male gender and weight were positively associated with FFM (R2 = 0.806, p

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Letter to the editor: Oral Cholic Acid in Zellweger Spectrum Disorders: A Word of Caution.

No abstract available

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Neonatal Exposure to Hepatitis C Virus Antigens in Uninfected Children Born to Infected Mothers.

Objectives: Vertical transmission of hepatitis C virus (HCV) infection is uncommon and occurs in around 5% of births from HCV infected mothers. The reason for the low transmission rate is unclear. We aimed to investigate if there is evidence of HCV exposure also in the non-infected children born to HCV infected mothers by the presence of a detectable immune response. Methods: Serum and peripheral blood mononuclear cells from 9 HCV vertically infected children, 32 uninfected children born to HCV infected mothers, and 15 HCV chronically infected mothers, were analyzed. HCV-RNA negative adults and children were used as controls. HCV specific T cell responses were analyzed by interferon gamma (IFN-[gamma]) using an enzyme-linked immunospot (ELISpot) assay and 3H-thymidine incorporation assay. HCV antibodies were also analyzed. Results: An HCV specific T cell response was detected in 73% (11/15) of the HCV infected mothers, 67% (6/9) of the vertically infected children, 56% (18/32) of the exposed but uninfected children and in 10% and 20% of the control groups, respectively. The two groups of HCV exposed children both had a significantly higher proportion of HCV specific T cell responders compared to pediatric controls (p = 0.01 and p = 0.02). Conclusion: HCV specific immune responses were more common in children born to HCV infected mothers, regardless of the presence of HCV RNA. We conclude that non-infected children born to HCV infected mothers may have been exposed to HCV antigens. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Comparison of Transperianal Ultrasound With Colonoscopy and Magnetic Resonance Imaging in Perianal Crohn's Disease.

Objectives: Perianal fistulae and/or abscesses are common complications of Crohn's disease (CD), especially in children. Magnetic resonance imaging (MRI) and gross examination under anesthesia are accurate diagnostic modalities for evaluating perianal lesions. However, both methods are expensive and have some limitations for use in children. This study aims to assess the accuracy of transperianal ultrasound (TPUS) and colonoscopic examination, compared with MRI, in pediatric patients with perianal CD (PACD). Methods: Thirty-eight children and adolescents with PACD who underwent MRI, TPUS, and gross colonoscopic examination under sedation were included. Fistulae were classified according to Parks' and St. James's University Hospital classifications. Abscesses were identified by their presence and location on each modality. Results: Fifty-nine fistulae (26 superficial, 23 intersphincteric, 10 transsphincteric) and 16 abscesses were detected using MRI. Fifty-nine fistulae and 10 abscesses were detected using TPUS. Forty-five fistulae [sensitivity 76.3%, positive predictive value (PPV) 84.2%, and kappa value 0.296] and nine abscesses (sensitivity 56.3%, PPV 90.0%, and kappa value 0.624) on TPUS corresponded with MRI findings. Forty-six fistulae and fifteen abscesses were detected using colonoscopy. Forty fistulae (sensitivity 67.8%, PPV 89.9%, and kappa value 0.369) and seven abscesses (sensitivity 43.8%, PPV 48.8%, and kappa value 0.304) on colonoscopy corresponded with MRI findings. With respect to abscess, agreement between TPUS and MRI was superior to that between colonoscopy and MRI (Spearman's rho 0.651 vs. 0.304, P = 0.007). Conclusions: TPUS is an appropriate, simple, and real-time method for detecting perianal fistula and/or abscess, in children with PACD. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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P 25 Reference values for the cross-sectional area of the vagus nerve in healthy subjects – a high-resolution ultrasound study

Examination of peripheral nerves with high-resolution ultrasound (HRUS) now routinely complements electrophysiological studies in various diseases. Prerequisite for nerve HRUS are well-defined reference values. Notably, reference values of the vagus nerve (VN) are varying (Cartwright, 2008; López-Hernández, 2014) and, overall, poorly studied. Aim of this study was to assess reference values for the VN as well as to examine inter-rater and intra-rater reliability and inter-ultrasound system agreement.

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P 23 fMRI-mapping of somatosensory finger representation in complex regional pain syndrome

Somatosensory deficits are often reported in patients with complex regional pain syndrome (CRPS). In particular reduced spatial tactile resolution is a typical clinical finding in CRPS patients. The detailed underlying mechanism for development and preservation of these deficits is not yet fully understood.However, a systematic review of studies on pain representation and cerebral representation showed a smaller representation of the hand in the primary somatosensory cortex (S1) contralateral to the affected upper limb (Di Pietro et al., 2013).

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P 24 Electrophysiological connectivity during oscillatory cycles of alpha activity and the BOLD-signal correlate in major depression

Major depressive disorder (MDD) belongs to the leading causes of disability worldwide. From an electrophysiological point of view, EEG-alpha activity and alpha phase synchronization seem to be possible biomarkers with diagnostic and prognostic value. In parallel, functional magnetic resonance imaging (fMRI) studies suggest altered blood oxygen-level dependent (BOLD) signals in e.g. frontal and prefrontal brain areas (Lemogne et al., 2012). However, the association between electrophysiological alterations and differences of fMRI activity in MDD remains vague.

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The Effect of Prophylactic Phenylephrine and Ephedrine Infusions on Umbilical Artery Blood pH in Women With Preeclampsia Undergoing Cesarean Delivery With Spinal Anesthesia: A Randomized, Double-Blind Trial.

BACKGROUND: Spinal anesthesia for cesarean delivery is associated with a high incidence of hypotension. Phenylephrine results in higher umbilical artery pH than ephedrine when used to prevent or treat hypotension in healthy women. We hypothesized that phenylephrine compared to ephedrine would result in higher umbilical artery pH in women with preeclampsia undergoing cesarean delivery with spinal anesthesia. METHODS: This study was a randomized double-blind clinical trial. Nonlaboring women with preeclampsia scheduled for cesarean delivery with spinal anesthesia at Prentice Women's Hospital of Northwestern Medicine were randomized to receive prophylactic infusions of phenylephrine or ephedrine titrated to maintain systolic blood pressure >80% of baseline. Spinal anesthesia consisted of hyperbaric 0.75% bupivacaine 12 mg, fentanyl 15 [micro]g, and morphine 150 [micro]g. The primary outcome was umbilical arterial blood pH and the secondary outcome was umbilical artery base excess. RESULTS: One hundred ten women were enrolled in the study and 54 per group were included in the analysis. There were 74 and 72 infants delivered in the ephedrine and phenylephrine groups, respectively. The phenylephrine:ephedrine ratio for umbilical artery pH was 1.002 (95% confidence interval [CI], 0.997-1.007). Mean [standard deviation] umbilical artery pH was not different between the ephedrine 7.20 [0.10] and phenylephrine 7.22 [0.07] groups (mean difference -0.02, 95% CI of the difference -0.06 to 0.07; P = .38). Median (first, third quartiles) umbilical artery base excess was -3.4 mEq/L (-5.7 to -2.0 mEq/L) in the ephedrine group and -2.8 mEq/L (-4.6 to -2.2mEq/L) in the phenylephrine group (difference -0.6 mEq/L, 95% CI of the difference -1.6 to 0.3 mEq/L; P = .10). When adjusted for gestational age and infant gender, umbilical artery pH did not differ between groups. There were also no differences in the umbilical artery pH stratified by magnesium therapy or by the severity of preeclampsia. CONCLUSIONS: We were unable to demonstrate a beneficial effect of phenylephrine on umbilical artery pH compared with ephedrine. Our findings suggest that phenylephrine may not have a clinically important advantage compared with ephedrine with regard to improved neonatal acid-base status when used to prevent spinal anesthesia-induced hypotension in women with preeclampsia undergoing cesarean delivery. (C) 2017 International Anesthesia Research Society

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In Response.

No abstract available

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Understanding the Significance of Aerosolized Vasodilator Use in Pulmonary Hypertension: What Is Numerically, Statistically, and Clinically Meaningful?.

No abstract available

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Mechanisms Supporting Astrocyte-Mediated Neuroprotection.

No abstract available

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The Effect of Zinc Lozenge on Postoperative Sore Throat: A Prospective Randomized, Double-Blinded, Placebo-Controlled Study.

BACKGROUND: Postoperative sore throat (POST) is commonly seen after endotracheal intubation, and oral zinc prevents oral mucositis associated with chemotherapy. This study is designed to evaluate the effects of administration of zinc lozenges on POST. METHODS: Seventy-nine patients undergoing low- or moderate-risk surgery with endotracheal intubation were randomly assigned into 2 groups: Control group received placebo and zinc group received 40-mg zinc lozenges 30 minutes preoperatively. Patients were assessed for incidence and severity (4-point scale, 0-3) of POST at 0, 2, 4, and 24 hours postoperatively. The primary outcome was incidence of POST at 4 hours after surgery. The secondary outcomes were the incidence of POST at 0, 2, and 24 hours and the severity of POST. RESULTS: At 4 hours, there was a significantly lower incidence of POST in the zinc group, 7%, than the control group, 29% (P = .046). The incidence of POST at 0 hour was 0% in zinc group and 24% in control group (P = .004). The highest incidence of POST occurred at the second hour after surgery, with the rate of 10% in the zinc group and 34% in the control group (P = .0495). The incidence of POST at 24 hours was 13% in zinc group and 24% in control group (not significant). The severity of POST was significantly lower in the zinc group for mild (P = .003) and moderate (P = .004) POST. CONCLUSIONS: The administration of a single dose of 40-mg zinc lozenge 30 minutes preoperatively is effective to reduce both incidence of POST in the first 4 hours and severity of mild and moderate POST in the immediate postoperative period. (C) 2017 International Anesthesia Research Society

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Spine kinematics exhibited during the stop-jump by physically-active individuals with adolescent idiopathic scoliosis and spinal fusion

After spinal fusion, adolescent idiopathic scoliosis individuals (SF-AIS) often return to exercise and sport. However, the movements SF-AIS use to compensate for the loss of spinal flexibility during high-effort tasks are not known.Purpose: To compare, between SF-AIS and healthy controls (CON) groups, the spinal kinematics of the trunk segments displayed during the stop-jump, a maximal effort task.Study Design: Case Controlled design

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BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

We report the case of a 7-year-old male of Western European origin presenting with moderate intellectual disability, severe childhood apraxia of speech in the presence of oral and manual dyspraxia, and hypotonia across motor systems including the oral and speech motor systems. Exome sequencing revealed a de novo frameshift protein truncating mutation in the fourth exon of BCL11A, a gene recently demonstrated as being involved in cognition and language development. Making parallels with a previously described patient with a 200 kb 2p15p16.1 deletion encompassing the entire BCL11A gene and displaying a similar phenotype, we characterize in depth how BCL11A is involved in clinical aspects of language development and oral praxis.

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Real-world experience with neuromuscular blockade reversal

Neuromuscular blocking agents are used in many surgical procedures and have enabled new surgical advances. The expanded landscape of neuromuscular blockade (NMB) reversal drugs allows for fast and complete NMB reversal and the reduction of postoperative complications from residual block. In the United States, neostigmine/glycopyrrolate and sugammadex are the primary agents for pharmacologic antagonism of neuromuscular blocking agents. Whereas neostigmine and an anticholinergic have been available for decades, sugammadex has only recently become available.

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Neurofibromatosis type 1 and right mandibular hypoplasia: unusual diagnosis of occlusion of the left common carotid artery

Neurofibromatosis type 1 also known as Von Recklinghausen's disease is an autosomal dominant neurocutaneous disease, with a disturbance of the NF1 gene localized in the 17th chromosome. Its incidence is 1 of 2500–3300 newborns. It is characterized by the formation of tumours in ectoderm and mesoderm tissues; consequently, its clinical manifestations are widely varied. Most frequent clinical manifestations are café-au-lait spots, axillary and groin freckling, Lisch nodules and neurofibromas. Other manifestations include hyperpigmentation, tumours and skeletal, neurological and cardiovascular disturbances [1].

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Airway management: Utilizing radiologist expertise and neuroimaging with head and neck masses

Securing the airway in a patient with a head and neck mass is often challenging [1,2]. The location, size, and character of the mass can impede the anesthesiologist from safely extending the neck, opening the mouth, or placing airway devices such as an oral airway, LMA, or laryngoscope blade. Masses involving the larynx present an additional challenge of potential airway obstruction [2,3]. These cases can present with workup limited to labs and radiology imaging. In the absence of fiberoptic endoscopy or indirect laryngoscopy, imaging may be the only available map of the patient's airway.

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Ultrasound guided continuous transmuscular quadratus lumborum analgesia for open renal surgery: A case series

Enhanced recovery following open renal surgery benefits from optimal dynamic analgesia allowing early mobilisation and patient comfort. Although, thoracic epidural analgesia (TEA) is considered as the gold standard, recent trends have revealed a move towards multimodal analgesia involving less invasive techniques that have a superior risk profile [1]. Wound infusion analgesia (WIA) has been described following open nephrectomy through a flank incision [2]. However, they fail to provide adequate pre-emptive and intraoperative analgesia.

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Ventricular fibrillation caused by electrocautery for pericardium hemostasis during thoracotomy

Ventricular fibrillation (VF) is a serious perioperative cardiac event. Electrocautery devices are widely used in modern surgical procedures. Although these devices are safe and effective if used appropriately, there are also potential risks to the patients. This report presented a rare case of electrocautery-induced VF in a 52-year-old patient undergoing elective thoracotomy. The patient had no other underlying systemic diseases and no significant findings on physical examination. Upon entering the operating room, the monitors including ECG, pulse oximeter, and invasive arterial blood pressure monitor were applied.

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Laparoscopic guided continuous type 1 quadratus lumborum block — “Sindwani technique with case series”

Quadratus lumborum block (QLB) is a new abdominal wall block which has shown promising results in the post-operative pain management of patients undergoing abdominal surgeries [1]. Using ultrasound it can be given in four different ways [2]. QLB is a deep muscle plane block making it difficult even for an experienced anesthesiologist to perform it accurately using ultrasound. Presence of excess fat in obese patients adds to this challenge [3]. We would thus like to present a unique technique wherein, laparoscopic guided continuous type 1 QLB was successfully performed to manage the post-operative pain in a series of five patients undergoing laparoscopic nephrectomy.

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At most hospitals in the state of Iowa, most surgeons' daily lists of elective cases include only 1 or 2 cases: Individual surgeons' percentage operating room utilization is a consistently unreliable metric

Percentage utilization of operating room (OR) time is not an appropriate endpoint for planning additional OR time for surgeons with high caseloads, and cannot be measured accurately for surgeons with low caseloads. Nonetheless, many OR directors claim that their hospitals make decisions based on individual surgeons' OR utilizations. This incongruity could be explained by the OR managers considering the earlier mathematical studies, performed using data from a few large teaching hospitals, as irrelevant to their hospitals.

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Argon embolus from argon beam coagulator

Argon beam coagulators (ABCs) have enhanced the ability of surgeons to perform procedures on highly vascular organs where bleeding is difficult to control with occlusion techniques alone. These coagulators work by using argon gas to create a path for electrical current to reach tissue. Although generally considered safe, there is the potential for argon gas embolism to occur with fatal or near fatal complications [1–9]. We recently cared for a patient that developed intra-operative symptoms consistent with argon embolism.

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A pragmatic trial to improve adherence with scheduled appointments in an inner-city pain clinic by human phone calls in the patient's preferred language

We investigated if human reminder phone calls in the patient's preferred language increase adherence with scheduled appointments in an inner-city chronic pain clinic. We hypothesized that language and cultural incongruence is the underlying mechanism to explain poor attendance at clinic appointments in underserved Hispanic populations.

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Epidural labor analgesia: Whence come our patients' misconceptions?

The effect of epidural analgesia on labor outcomes has historically generated tremendous debate among obstetricians, anesthesiologists, midwives and labor nurses. Data from initial observational studies showed that women who chose epidural analgesia had an increased risk of prolonged labor and cesarean delivery compared with women who chose other types of analgesia or no analgesia. And women who received epidural analgesia early in labor, rather than later, had an increased risk of cesarean delivery.

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Programmed intermittent peripheral nerve local anesthetic bolus compared with continuous infusions for postoperative analgesia: A systematic review and meta-analysis

The role of the programmed intermittent bolus (PIB) technique for infusion of local anesthetics in continuous peripheral nerve blockade (CPNB) remains to be elucidated. Randomized controlled trials (RCTs) on PIB versus continuous infusion for CPNB have demonstrated conflicting results and no systematic review or meta-analysis currently exists. We aimed to delineate via systematic review with meta-analysis if there is any analgesic benefit to performing PIB versus continuous infusion for CPNB.

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Validity of using a work habits scale for the daily evaluation of nurse anesthetists' clinical performance while controlling for the leniencies of the rating anesthesiologists

Anesthesiologists can provide psychometrically reliable daily evaluations of certified registered nurse anesthetist (CRNA) work habits for purposes of the mandatory ongoing professional practice evaluation (OPPE). Our goal was to evaluate the validity of assessing CRNA work habits.

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Paravertebral block restore diaphragmatic motility measured by ultrasonography in patients with multiple rib fractures

Multiple rib fractures are associated with severe pain, leading to alteration of pulmonary function. Paravertebral block (PVB) rather than systemic opioids have been recommended for prevention of critical pneumonia due to sufficient pain relief to facilitate coughing up [1]. Sonographic evaluation of the diaphragm is an accepted qualitative method of assessing the diaphragmatic motion in normal and pathological situations [2]. The norm of mean diaphragmatic excursion is 18±3mm during quiet breathing and 66±13mm during deep breathing [2].

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With directed study before a 4-day operating room management course, trust in the content did not change progressively during the classroom time

A 4-day course in operating room (OR) management is sufficient to provide anesthesiologists with the knowledge and problem solving skills needed to participate in projects of the systems-based-practice competency. Anesthesiologists may need to learn fewer topics when the objective is, instead, limited to comprehension of decision-making on the day of surgery, We tested the hypothesis that trust in course content would not increase further after completion of topics related to OR decision-making on the day of surgery.

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The Murphy eye as guidance for topical airway anesthesia during awake tracheal intubation with a channeled blade videolaryngoscope

Several publications have been published proposing awake videolaryngoscope-assisted intubation with a channeled videolaryngoscope [1,2]. We absolutely agree with this approach of awake videolaryngoscope-assisted tracheal intubation with maintained spontaneous respiration. We think that this approach is still significantly underused and could prevent a relevant part of airway problems in anesthesia. To become a more common and widespread approach, it should be as simple and efficient as possible.

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Should we withhold angiotensin converting enzyme inhibitors before anaesthesia? An updated debate on the pros and cons

We read with interest the article by Vaquero Roncero et al. [1]. Indeed, over the last three decades, several investigators have endeavoured to identify risk factors associated to systemic hypotension following the assumption of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). In the 90s, administration of general anaesthetics in patients on chronic ACEi/ARBs was believed to be invariably associated to catastrophic hypotension occurring soon after induction, as described in some reports [2].

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Selection of anesthesia technique: Not always the right reasons or the right outcomes…

Anesthesiologists often strive to achieve the perfect anesthetic technique for a given surgical procedure. Unfortunately, the reality is that we do not have a perfect anesthetic even for common and simple surgeries (e.g., laparoscopic cholecystectomy) [1,2]. General anesthesia, even for minor surgeries, often results in significant discomfort to patients due to postoperative nausea, vomiting and sore throat [3–5]. Neuraxial anesthesia frequently causes hypotension, pruritus and urinary retention [6–8].

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Sildenafil related cerebral venous thrombosis following spinal anesthesia

Various factors have been demonstrated in the etiology of cerebral venous thrombosis (CVT), including hypotension, dehydration, hormonal states (pregnancy, obesity), systemic diseases, malignancy and drugs. We report the case of a man who developed CVT following spinal anesthesia that was related to a long-term usage of sildenafil. Written informed consent was obtained from the patient to publish this report.

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Influence of depth of neuromuscular blockade on surgical conditions during low-pressure pneumoperitoneum laparoscopic cholecystectomy: A randomized blinded study

To evaluate the influence of neuromuscular blockade (NMB) on surgical conditions during low-pressure pneumoperitoneum (8mmHg) laparoscopic cholecystectomy (LC), while comparing moderate and deep NMB. Secondary objective was to evaluate if surgical conditions during low-pressure pneumoperitoneum LC performed with deep NMB could be comparable to those provided during standard-pressure pneumoperitoneum (12mmHg) LC.

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Ultrasound-guided pectoral nerves (PECS) block: Complications observed in 498 consecutive cases

To the Editor

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