Surgical injury in the neonatal rat alters the adult pattern of descending modulation from the rostroventral medulla

Background: Neonatal pain and injury can alter long-term sensory thresholds. Descending rostroventral medulla (RVM) pathways can inhibit or facilitate spinal nociceptive processing in adulthood. As these pathways undergo significant postnatal maturation, the authors evaluated long-term effects of neonatal surgical injury on RVM descending modulation. Methods: Plantar hind paw or forepaw incisions were performed in anesthetized postnatal day (P)3 Sprague-Dawley rats. Controls received anesthesia only. Hind limb mechanical and thermal withdrawal thresholds were measured to 6 weeks of age (adult). Additional groups received pre- and post-incision sciatic nerve levobupivacaine or saline. Hind paw nociceptive reflex sensitivity was quantified in anesthetized adult rats using biceps femoris electromyography, and the effect of RVM electrical stimulation (5–200 μA) measured as percentage change from baseline. Results: In adult rats with previous neonatal incision (n = 9), all intensities of RVM stimulation decreased hind limb reflex sensitivity, in contrast to the typical bimodal pattern of facilitation and inhibition with increasing RVM stimulus intensity in controls (n = 5) (uninjured vs. neonatally incised, P < 0.001). Neonatal incision of the contralateral hind paw or forepaw also resulted in RVM inhibition of hind paw nociceptive reflexes at all stimulation intensities. Behavioral mechanical threshold (mean ± SEM, 28.1 ± 8 vs. 21.3 ± 1.2 g, P < 0.001) and thermal latency (7.1 ± 0.4 vs. 5.3 ± 0.3 s, P < 0.05) were increased in both hind paws after unilateral neonatal incision. Neonatal perioperative sciatic nerve blockade prevented injury-induced alterations in RVM descending control. Conclusions: Neonatal surgical injury alters the postnatal development of RVM descending control, resulting in a predominance of descending inhibition and generalized reduction in baseline reflex sensitivity. Prevention by local anesthetic blockade highlights the importance of neonatal perioperative analgesia

Sensitivity and specificity of a neuropathic screening tool (Self-report Leeds Assessment of Neuropathic Symptoms and Signs, S-LANSS) in adolescents with moderate-severe chronic pain

Neuropathic screening tools improve recognition of neuropathic pain in adults. Although utilized in pediatric populations, the sensitivity, specificity and methodology of screening tool delivery have not been compared in children. We evaluated the Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) in adolescents (10-18 years) referred to a tertiary pediatric pain clinic. History and examination by specialist clinicians and multidisciplinary assessment informed classification of the primary pain type. In a prospective cohort, scores were obtained at interview (S-LANSS interview; n=161, 70% female), and following substitution of self-reported signs with examination findings in the primary pain region (LANSS-examination). Secondly, we retrospectively retrieved questionnaires self-completed by adolescents at their initial clinic appointment (S-LANSS self-completed; n=456, 73% female). Thirdly, we explored relationships between patient-reported outcomes and S-LANSS scores. S-LANSS interview scores varied with pain classification, and S-LANSS self-completed scores were similarly highest with neuropathic pain (median[IQR]: 18[11,21]) and complex regional pain syndrome (21[14,24]), variable with musculoskeletal pain (13[7,19]) and lowest with visceral pain (6.5[2,11.5]) and headache (8.5[4,14]). As in adults, the cutpoint score of 12/24 was optimal. Sensitivity was highest with inclusion of examination findings and lowest with self-completion (LANSS-examination vs interview vs self-completed: 86.3% vs 80.8% vs 74.7%), but specificity was relatively low (37.8% vs 36.7% vs 48%). High S-LANSS scores in non-neuropathic groups were associated with female sex and high pain catastrophizing. The S-LANSS is a sensitive screening tool for pain with neuropathic features in adolescents, but needs to be interpreted in the context of clinical evaluation. (clinicaltrials.gov NCT03312881

Amygdalar Functional Connectivity Differences Associated With Reduced Pain Intensity in Pediatric Peripheral Neuropathic Pain

Background: There is evidence of altered corticolimbic circuitry in adults with chronic pain, but relatively little is known of functional brain mechanisms in adolescents with neuropathic pain (NeuP). Pediatric NeuP is etiologically and phenotypically different from NeuP in adults, highlighting the need for pediatric-focused research. The amygdala is a key limbic region with important roles in the emotional-affective dimension of pain and in pain modulation. Objective: To investigate amygdalar resting state functional connectivity (rsFC) in adolescents with NeuP. Methods This cross-sectional observational cohort study compared resting state functional MRI scans in adolescents aged 11–18 years with clinical features of chronic peripheral NeuP (n = 17), recruited from a tertiary clinic, relative to healthy adolescents (n = 17). We performed seed-to-voxel whole-brain rsFC analysis of the bilateral amygdalae. Next, we performed post hoc exploratory correlations with clinical variables to further explain rsFC differences. Results: Adolescents with NeuP had stronger negative rsFC between right amygdala and right dorsolateral prefrontal cortex (dlPFC) and stronger positive rsFC between right amygdala and left angular gyrus (AG), compared to controls (PFDR&amp;lt;0.025). Furthermore, lower pain intensity correlated with stronger negative amygdala-dlPFC rsFC in males (r = 0.67, P = 0.034, n = 10), and with stronger positive amygdala-AG rsFC in females (r = −0.90, P = 0.006, n = 7). These amygdalar rsFC differences may thus be pain inhibitory. Conclusions: Consistent with the considerable affective and cognitive factors reported in a larger cohort, there are rsFC differences in limbic pain modulatory circuits in adolescents with NeuP. Findings also highlight the need for assessing sex-dependent brain mechanisms in future studies, where possible

Delivering transformative action in paediatric pain: a <i>Lancet Child &amp; Adolescent Health</i> Commission

Every infant, child, and adolescent will experience pain at times throughout their life. Childhood pain ranges from acute to chronic, and includes procedural, disease-related, breakthrough, and other types of pain. Despite its ubiquity, pain is a major challenge for individuals, families, health-care professionals, and societies. As a private mental experience, pain is often hidden and can go undiscussed or ignored. Undertreated, unrecognised, or poorly managed pain in childhood leads to important and long-lasting negative consequences that continue into adulthood, including continued chronic pain, disability, and distress. This undertreatment of pain should not continue, as there are available tools, expertise, and evidence to provide better treatment for childhood pain

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

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Validation of a Preclinical Spinal Safety Model Effects of Intrathecal Morphine in the Neonatal Rat

The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model