Exercise combined with Acceptance and Commitment Therapy for chronic pain: One-year follow-up from a randomized controlled trial.

BACKGROUND: Acceptance and Commitment Therapy (ACT) is a type of Cognitive Behavioural Therapy, which has demonstrated positive outcomes in individuals with chronic pain. The purpose of this study was to compare the effect of an 8-week programme combining Exercise with Acceptance and Commitment Therapy (ExACT) with a standalone supervised exercise programme at 1-year follow-up. METHODS: One hundred and seventy-five people with chronic pain were randomly assigned to ExACT or supervised exercise only. The primary outcome was pain interference measured with the Brief Pain Inventory-Interference Scale. Secondary and treatment process outcomes included pain severity, depression, anxiety, pain catastrophizing, pain self-efficacy, fear avoidance, pain acceptance, committed action, healthcare utilization, patient satisfaction, and global impression of change. Estimates of treatment effects at 1-year follow-up were based on intention-to-treat analyses, implemented using a linear mixed-effects model. RESULTS: Eighty-three participants (47.4%) returned the outcome measures at 1-year follow-up. No significant difference was observed between the groups for the primary outcome, pain interference. There was a statistically significant difference between the groups, in favour of ExACT for pain catastrophizing. Within group improvements that were observed within both groups at earlier timepoints were maintained at 1-year follow-up for many of the secondary and treatment process outcomes. ExACT group participants reported higher levels of satisfaction with treatment and global perceived change. CONCLUSIONS: The study results showed no significant difference between the two groups for the primary outcome pain interference at 1-year follow-up. Future research could investigate factors that may predict and optimize outcomes from these types of intervention for people living with chronic pain. SIGNIFICANCE: Few previous randomized controlled trials investigating ACT for chronic pain have included long-term follow-up. This study found that Exercise combined with ACT was not superior to supervised exercise alone for reducing pain interference at 1-year follow-up. Further research is necessary to identify key processes of therapeutic change and to explore how interventions may be modified to enhance clinical outcomes for people with chronic pain.

Genetic and environmental influences on serum oxylipins, endocannabinoids, bile acids and steroids.

Lipid bioactivity is a result of direct action and the action of lipid mediators including oxylipins, endocannabinoids, bile acids and steroids. Understanding the factors contributing to biological variation in lipid mediators may inform future approaches to understand and treat complex metabolic diseases. This research aims to determine the contribution of genetic and environmental influences on lipid mediators involved in the regulation of inflammation and energy metabolism. This study recruited 138 monozygotic (MZ) and dizygotic (DZ) twins aged 18-65 years and measured serum oxylipins, endocannabinoids, bile acids and steroids using liquid chromatography mass-spectrometry (LC-MS). In this classic twin design, the similarities and differences between MZ and DZ twins are modelled to estimate the contribution of genetic and environmental influences to variation in lipid mediators. Heritable lipid mediators included the 12-lipoxygenase products 12-hydroxyeicosatetraenoic acid [0.70 (95% CI: 0.12,0.82)], 12-hydroxyeicosatetraenoic acid [0.73 (95% CI: 0.30,0.83)] and 14­hydroxy-docosahexaenoic acid [0.51 (95% CI: 0.07,0.71)], along with the endocannabinoid docosahexaenoy-lethanolamide [0.52 (95% CI: 0.15,0.72)]. For others such as 13-hydroxyoctadecatrienoic acid and lithocholic acid the contribution of environment to variation was stronger. With increased understanding of lipid mediator functions in health, it is important to understand the factors contributing to their variance. This study provides a comprehensive analysis of lipid mediators and extends pre-existing knowledge of the genetic and environmental influences on the human lipidome.

Therapeutic Listening for Preterm Children with Sensory Dysregulation, Attention and Cognitive Problems.

Introduction Is Therapeutic Listening effective for children born preterm presenting with sensory dysregulation, attention and cognitive problems? Methods 22 children (BW<1500g) 3-4 years were enrolled in a single centre, prospective, assessor-blinded RTC. Outcome measures: Winnie-Dunn Sensory Profile; Peabody Developmental Motor Scales; Reynell Attention Scale; Preschool Language Scales - 3; RAPT; WPPSI - IV; Parent Review Questionnaires. Results The intervention group (n=9) showed better improvement in sensory processing, compared to controls (n=9) (6.4 fold improvement in sensation seeking; 5.0 in auditory processing; 4.0 in tactile processing). Six intervention children (67%) improved in vestibular processing. Attention levels improved for 9 (100%) children in the intervention group and for 7 (78%) in the control group. Higher level domains (Peabody motor skills, Auditory Comprehension, Expressive Communication, RAPT scale, and WPPSI scores) showed mixed results. Parents reported positive changes in their child's development. Conclusion Therapeutic Listening (TL) is a feasible intervention for preterm children to improve attention levels and sensory processing skills.

The association between benzodiazepine use and falls, and the impact of sleep quality on this association: data from the TILDA study.

BACKGROUND: Benzodiazepines (BZD) are associated with adverse effects, particularly in older adults. AIM: This study assesses the association between BZD use and falls, and the impact of sleep quality on this association, in community dwelling adults aged over 50. DESIGN: Cross-sectional analysis of data from wave 1 of The Irish Longitudinal Study on Ageing. METHODS: Participants were classed as BZD users or non-users and asked if they had fallen in the last year, and whether any falls were unexplained. Sleep quality was assessed via self-reported trouble falling asleep, daytime somnolence and early-rising. Logistic regression assessed for an association between BZD use and falls, and the impact of sleep quality on this association was assessed by categorizing based on BZD use and sleep quality variables. RESULTS: Of 8175 individuals, 302 (3.69%) reported taking BZDs. BZD use was associated with falls, controlling for confounders [Odds Ratio (OR) 1.40; 1.08, 1.82; P-value 0.012]. There was no significant association between BZDs and unexplained falls, controlling for confounders [OR 1.41; 95% Confidence Interval (CI) 0.95, 2.10; P-value 0.09]. Participants who use BZDs and report daytime somnolence (OR 1.93; 95% CI 1.12, 3.31; P-value 0.017), early-rising (OR 1.93; 95% CI 1.20, 3.11; P-value 0.007) or trouble falling asleep (OR 1.83; 95% CI 1.12, 2.97; P-value 0.015), have an increased odds of unexplained falls. CONCLUSION: BZD use is associated with falls, with larger effect size in those reporting poor sleep quality in community dwelling older adults. Appropriate prescription of medications such as BZDs is an important public health issue.

Childhood central adiposity at ages 5 and 9 shows consistent relationship with that of the maternal grandmother but not other grandparents.

BACKGROUND: The importance of a life course approach to childhood obesity has been emphasized; however, few studies can prospectively investigate relationships in three-generation families. OBJECTIVE: To prospectively investigate the relationship between grandparental and grandchild waist circumference (WC) at ages 5 and 9 down maternal and paternal lines. METHODS: At baseline in the Lifeways Cross-Generation Cohort, 1094 children were born to 1082 mothers; 585 were examined at age 5 and 298 at age 9. Of the total 589 children with measured WC, data were also available from 745 grandparents. Child WC was standardized for age and sex, and theory-based hierarchical linear regression was used. RESULTS: Maternal grandmother (MGM) WC was predictive of grandchild WC at both time points. At age 5, grandchild's standardized birth weight (B = 0.266, p = 0.001), mother's means tested eligibility for free medical care (B = 1.029, p = 0.001) and grandchild seeing maternal grandparents daily (B = 0.312, p = 0.048) were significant alongside MGM WC (B = 0.015, p = 0.019). At age 9, only MGM WC (B = 0.022, p = 0.033) and mother's WC (B = 0.032, p = 0.005) were significant. Mediation analysis with mother's WC showed significant direct relationship of MGM and grandchild WC. CONCLUSIONS: This prospective cross-generational cohort shows consistent patterns of association between MGM and grandchild WC, not seen in other grandparental lineages.

Predictors of adults' body mass index and the association with index child's infant birth weight, in the Lifeways Cross-Generation Cohort Study of a thousand families in the Republic of Ireland.

The Lifeways study is novel in having information on three generations of the same families. It is well established that infant birth weight (IBW) predicts individuals' risk of adult chronic disease and more recently studies report cross-generation transmission of risk patterns. The aims of this analysis were to examine whether adults' birth weights were associated with measures of own health status or social position and to relate adults' birth weights to that of the index child's IBW. Finally, we assessed whether birth weight of either adults or children was associated with adult body mass index (BMI) of parents and grandparents. We included 1075 children whose IBW was recorded at recruitment from hospital records and 2546 adult cohort members followed from 2001 until 2014. At baseline, a sub-group of 920 adults had reported own birth weight (RBW). Results showed male adults' RBW were significantly higher than females' (P=0.001). Mothers' RBW was significantly correlated with IBW (r=0.178, P<0.001). In mixed effects linear models with BMI as the outcome variable, of all adults, and in sub-groups of adults with RBW and of mothers only, the IBW was associated with adult BMI adjusting for other predictors. Adults' BMI was positively associated with age (P=0.013), index child's IBW (P=0.001), gender (P<0.001) but not own RBW, adjusting for family identification number. When mothers were removed from the adult models however, IBW ceased to be associated with BMI, a final model showed RBW being associated with adult BMI (P=0.04). There are cross-generational associations in the Lifeways cohort, the maternal association being stronger.

Total HDL cholesterol efflux capacity in healthy children - Associations with adiposity and dietary intakes of mother and child.

BACKGROUND AND AIMS: High-density lipoprotein (HDL) cholesterol efflux capacity in adults may be a measure of the atheroprotective property of HDL. Little however, is known about HDL cholesterol efflux capacity in childhood. We aimed to investigate the relationship between HDL cholesterol efflux capacity and childhood anthropometrics in a longitudinal study. METHODS AND RESULTS: Seventy-five children (mean age = 9.4 ± 0.4 years) were followed from birth until the age of 9 years. HDL cholesterol efflux capacity was determined at age 9 by incubating serum-derived HDL-supernatants with 3H-cholesterol labeled J774 macrophages and percentage efflux determined. Mothers provided dietary information by completing food frequency questionnaires in early pregnancy and then 5 years later on behalf of themselves and their children. Pearson's correlations and multiple regression analyses were conducted to confirm independent associations with HDL efflux. There was a negative correlation between HDL cholesterol efflux capacity and waist circumference at age 5 (r = -0.3, p = 0.01) and age 9 (r = -0.24, p = 0.04) and BMI at age 5 (r = -0.45, p = 0.01) and age 9 (r = -0.19, p = 0.1). Multiple regression analysis showed that BMI at age 5 remained significantly associated with reduced HDL cholesterol efflux capacity (r = -0.45, p < 0.001). HDL-C was negatively correlated with energy-adjusted fat intake (r = -0.24, p = 0.04) and positively correlated with energy-adjusted protein (r = 0.24, p = 0.04) and starch (r = 0.29, p = 0.01) intakes during pregnancy. HDL-C was not significantly correlated with children dietary intake at age 5. There were no significant correlations between maternal or children dietary intake and HDL cholesterol efflux capacity. CONCLUSIONS: This novel analysis shows that efflux capacity is negatively associated with adiposity in early childhood independent of HDL-C.

Standardised versus Individualised Parenteral Nutrition. Further Food for Thought.

Parenteral Nutrition may be prescribed as a standard PN (SPN) formulation or as an individualised PN (IPN) formulation. SPN may have advantages in terms of rapid availability, less prescription errors, decreased risk of infection and cost savings but IPN, specifically tailored to an infants needs, may achieve better outcomes in terms of nutrient intake and weight gain. The aim of our study was to determine if VLBW infants in our NICU benefited from receiving IPN over currently available SPN solutions. Our findings were that VLBW infants prescribed IPN received significantly more amino acid (28%), glucose (6%), energy (11%) and calcium (8%) from the aqueous phase of PN than had they received a similar volume of SPN. The benefits were seen over all the days for which PN was administered. In conclusion, IPN was found to offer significant benefits to our VLBW infants. Modifications to currently available SPN would result in better SPN formulations. Our study also supported the recent recommendation to reduce the calcium:phosphate ratio in PN solutions to avoid early hypophosphataemia.

A randomised controlled trial of the effect of a head-elevation pillow on intrathecal local anaesthetic spread in caesarean section.

BACKGROUND: A head-elevation pillow places a patient in a ramped posture, which maximises the view of the larynx during laryngoscopy, particularly in obese parturients. In our institution an elevation pillow is used pre-emptively for neuraxial anaesthesia. We hypothesised that head-elevation may impair cephalad spread of local anaesthetic before caesarean section resulting in a lower block or longer time to achieve a T6 level. We aimed to investigate the effect of head-elevation on spread of intrathecal local anaesthetics during anaesthesia for caesarean section. METHODS: One-hundred parturients presenting for caesarean section under combined spinal-epidural anaesthesia were randomised to either the standard supine position with lateral displacement or in the supine position with lateral displacement on an head-elevation pillow. Each patient received intrathecal hyperbaric bupivacaine 11 mg, morphine 100 µg and fentanyl 15 µg. Patients were assessed for adequacy of sensory block (T6 or higher) at 10 min. RESULTS: Sensory block to T6 was achieved within 10 min in 65.9% of parturients in the Elevation Pillow Group compared to 95.7% in the Control Group (P<0.05). Compared to the Control Group, patients in the Elevation Pillow Group had greater requirements for epidural supplementation (43.5% vs 2.1%, P<0.001) or conversion to general anaesthesia (9.3% vs 0%, P<0.04). CONCLUSIONS: Use of a ramped position with an head-elevation pillow following injection of the intrathecal component of a combined spinal-epidural anaesthetic for scheduled caesarean section was associated with a significantly lower block height at 10min.

The phenotypic manifestations of rare genic CNVs in autism spectrum disorder.

Significant evidence exists for the association between copy number variants (CNVs) and Autism Spectrum Disorder (ASD); however, most of this work has focused solely on the diagnosis of ASD. There is limited understanding of the impact of CNVs on the 'sub-phenotypes' of ASD. The objective of this paper is to evaluate associations between CNVs in differentially brain expressed (DBE) genes or genes previously implicated in ASD/intellectual disability (ASD/ID) and specific sub-phenotypes of ASD. The sample consisted of 1590 cases of European ancestry from the Autism Genome Project (AGP) with a diagnosis of an ASD and at least one rare CNV impacting any gene and a core set of phenotypic measures, including symptom severity, language impairments, seizures, gait disturbances, intelligence quotient (IQ) and adaptive function, as well as paternal and maternal age. Classification analyses using a non-parametric recursive partitioning method (random forests) were employed to define sets of phenotypic characteristics that best classify the CNV-defined groups. There was substantial variation in the classification accuracy of the two sets of genes. The best variables for classification were verbal IQ for the ASD/ID genes, paternal age at birth for the DBE genes and adaptive function for de novo CNVs. CNVs in the ASD/ID list were primarily associated with communication and language domains, whereas CNVs in DBE genes were related to broader manifestations of adaptive function. To our knowledge, this is the first study to examine the associations between sub-phenotypes and CNVs genome-wide in ASD. This work highlights the importance of examining the diverse sub-phenotypic manifestations of CNVs in ASD, including the specific features, comorbid conditions and clinical correlates of ASD that comprise underlying characteristics of the disorder.

Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.

Stage 2 of the Wellcome Trust UK-Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16-q21, 4q12-q21, 9p21, 10p14-p12 and 18q22.

Bipolar affective disorder (BPAD) is a common psychiatric disorder with complex genetic aetiology. We have undertaken a genome-wide scan in one of the largest samples of bipolar affected sibling pairs (ASPs) using a two-stage approach combining sample splitting and marker grid tightening. In this second stage analysis, we have examined 17 regions that achieved a nominally significant maximum likelihood LOD score (MLS) threshold of 0.74 (or 1.18 for the X-chromosome) in stage one. The second stage has added 135 ASP families to bring the total stage 2 sample to 395 ASPs. In total, 494 microsatellite markers have been used to screen the human genome at a density of 10 cM in the first stage sample (260 ASPs) and 5 cM in the second stage. Under the broad diagnostic model, two markers gave LOD scores exceeding 3 with two-point analysis: D4S392 (LOD=3.30) and D10S197 (LOD=3.18). Multipoint analysis demonstrated suggestive evidence of linkage between BPAD and chromosomal regions 6q16-q21 (MLS=2.61) and 4q12-q21 (MLS=2.38). 6q16-q21 is of particular interest because our data, together with those from two recent genome scans, make this the best supported linkage region in BPAD. Further, our data show evidence of a gender effect at this locus with increased sharing predominantly within the male-male pairs. Our scan also provides support for linkage (MLS> or =1.5) at several other regions that have been implicated in meta-analyses of bipolar disorder and/or schizophrenia including 9p21, 10p14-p12 and 18q22.

The Wellcome trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report.

We have completed the first stage of a two-stage genome wide screen designed to identify chromosomal regions that may harbour susceptibility genes for bipolar affective disorder. The first stage screening sample included 509 subjects from 151 nuclear families recruited within the United Kingdom and Republic of Ireland. This sample contained 154 narrowly defined affected sibling pairs (DSM-IV BPI) and 258 broadly defined affected sibling pairs (DSM-IV BPI, SABP, BPII, BPNOS or MDD(R)), approximately two thirds of all families contained at least one other additional typed individual. All individuals were genotyped using 398 highly polymorphic microsatellite markers from Applied Biosystems's Linkage Mapping Set Version 2. The average inter-marker distance was 9.6 cM and the mean heterozygosity was 0.78. Analysis of these data using non-parametric linkage methods (MAPMAKER/SIBS) found no evidence for loci of major effect and no regions reached genome-wide significance for either suggestive or significant linkage. We identified 19 points across the genome where the MLS exceeded a value set for follow up in our second stage screen (MLS > or = 0.74 (equivalent to a nominal pointwise significance of 5%) under the narrowest diagnostic model). These points were on chromosomes 2, 3, 4, 6, 7, 9, 10, 12, 17, 18 & X. Some of these points overlapped with previous linkage reports both within bipolar affective disorder and other psychiatric illnesses. Under the narrowest diagnostic model, the single most significant multipoint linkage was on chromosome 18 at marker D18S452 (MLS=1.54). Overall the highest MLS was 1.70 on chromosome 2 at marker D2S125, under the broadest diagnostic model.

Regulation of intracellular Ca2+ concentration by interleukin-1beta in rat cortical synaptosomes: an age-related study.

The pro-inflammatory cytokine interleukin-1beta (IL-1beta) is released by cells during injury and stress, and increased neuronal expression of IL-1beta is a feature of age-related neurodegeneration. We have recently reported that IL-1beta has a biphasic effect on the K+-induced rise in intracellular Ca2+ concentration ([Ca2+]i) in cortical synaptosomes, exerting an inhibitory effect on the K+-induced rise in [Ca2+]i at lower (3.5 ng/mL) concentrations and a stimulatory effect on the K+-induced rise in [Ca2+]i at higher (100 ng/mL) concentrations. In the present study, we observed that the K+-induced rise in [Ca2+]i was inhibited to a similar extent by the lower concentration of IL-1beta in cortical synaptosomes prepared from young (3-month-old), middle-aged (12-month-old) and aged (24-month-old) rats. In contrast, cortical synaptosomes prepared from the aged rats exhibited an increased susceptibility to the higher concentration of IL-1beta, resulting in a marked elevation in [Ca2+]i. We propose that the age-related increase in neuronal concentration of IL-1beta promotes a dramatic elevation in [Ca2+]i following membrane depolarization, thereby altering Ca2+ homeostasis and exacerbating neuronal vulnerability to excitotoxicity.