Effects of implementation of a care bundle on rates of necrotising enterocolitis and own mother's milk feeding in the East Midlands: protocol for a mixed methods impact and process evaluation study.

INTRODUCTION: Prevention of necrotising enterocolitis (NEC) is vital for improving neonatal outcomes. Feeding own mother's milk helps prevent NEC. Rates of own mother's milk feeding in the East Midlands are lower than the national average and the incidence of NEC is higher. The East Midlands Neonatal Operational Delivery Network (EMNODN) has created a care bundle to improve these in babies born at <32 weeks' gestation, the group at the highest risk of NEC. The bundle was introduced in September 2022 and embedded by December 2022. We will evaluate its effectiveness and conduct a process evaluation to understand barriers and facilitators to implementation. METHODS AND ANALYSIS: We will conduct a retrospective cohort study (workstream 1) using data from the National Neonatal Research Database (NNRD). We will identify infants receiving any own mother's milk on day 14 and at discharge, and cases of severe NEC. We will aggregate outcomes by birth month and use interrupted time series analysis to estimate an incidence rate ratio for changes after the care bundle was embedded, relative to pre-implementation. We will model data from all other NNRD units and assess whether there are any concurrent changes to exclude confounding due to other events.We will apply the RE-AIM framework (workstream 2), supplemented by the Consolidated Framework for Implementation Research and Framework for Implementation Fidelity, to conduct a mixed methods evaluation in EMNODN units. We will triangulate data from several sources, including questionnaires and semistructured interviews with parents and healthcare professionals, and data from patient records. ETHICS AND DISSEMINATION: The study has approval from the South East Scotland Research Ethics Committee 01 and the Health Research Authority and Health and Care Research Wales (IRAS 323099). Results will be disseminated via scientific journals and conferences, to neonatal service commissioners and through public-facing infographics. TRIAL REGISTRATION NUMBER: NCT05934123.

Association between opioid use during mechanical ventilation in preterm infants and evidence of brain injury: a propensity score-matched cohort study.

Background: Preterm infants often require mechanical ventilation (MV), which can be a painful experience. Opioids (such as morphine) are used to provide analgesia, despite conflicting evidence about their impact on the developing brain. We aimed to quantify the use of opioids during MV in infants born at <32 weeks' gestational age and to investigate the association between opioid use and evidence of brain injury. Methods: In this retrospective propensity score-matched cohort study, we used routinely recorded data from the National Neonatal Research Database to study infants born at 22-31 weeks gestational age who were admitted to neonatal units in England and Wales (between Jan 1, 2012, and Dec 31, 2020) and who were mechanically ventilated on one or more days during their hospital stay. We used propensity score matching to identify pairs of infants (one who received opioids during MV and one who did not) with similar demographic and clinical characteristics. The pre-specified primary outcome was preterm brain injury assessed in all infants who received MV for more than two days and had evidence of preterm brain injury at or before discharge from neonatal care. Adjusted analyses accounted for differences in infants' characteristics, including illness severity and painful/surgical conditions. Findings: Of 67,206 infants included, 45,193 (67%) were mechanically ventilated for one or more days and 26,201 (58% of 45,193) received an opioid whilst ventilated. Opioids were given for a median of 67% of ventilated days (IQR 43-92%) and the median exposure was 4 days (2-11). The percentage of mechanically ventilated infants who received opioids while ventilated increased from 52% in 2012 to 60% in 2020 (morphine, 51%-56%; fentanyl, 6%-18%). In the propensity score-matched cohort of 3608 pairs who were ventilated for >2 consecutive days, the odds of any preterm brain injury (adjusted odds ratio 1.22, 95% CI 1.10-1.35) were higher in those who received opioids compared with those who did not (received opioids, 990/3608 (27.4%) vs. did not receive opioids, 855/3608 (23.7%). The adjusted odds of these adverse outcomes increased with increasing number of days of opioid exposure. Interpretation: Use of opioids during mechanical ventilation of preterm infants increased during the study period (2012-2020). Although causation cannot be determined, among those ventilated for >2 consecutive days, these data suggest that opioid use is associated with an increased risk of preterm brain injury and the risk increases with longer durations of exposure. Funding: University of Nottingham Impact Fund.

Observational cohort study of use of caffeine in preterm infants and association between early caffeine use and neonatal outcomes.

OBJECTIVE: To quantify trends in caffeine use in infants born at <32 weeks' gestational age (GA), and to investigate the effects of early vs late caffeine on neonatal outcomes. STUDY DESIGN: Retrospective propensity score matched cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks' GA admitted to neonatal units in England and Wales (2012-2020). RESULTS: 89% (58 913/66 081) of infants received caffeine. In 70%, caffeine was started early (on the day of birth or the day after), increasing from 55% in 2012 to 83% in 2020. Caffeine was given for a median (IQR) of 28 (17-43) days starting on day 2 (1-3) and continued up to 34 (33-34) weeks postmenstrual age.In the propensity score matched cohort of 13 045 pairs of infants, the odds of preterm brain injury (early caffeine, 2306/13 045 (17.7%) vs late caffeine, 2528/13 045 (19.4%), OR=0.89 (95% CI 0.84 to 0.95)) and bronchopulmonary dysplasia (BPD) (early caffeine, 4020/13 045 (32.8%) vs late caffeine, 4694/13 045 (37.7%), OR=0.81 (95% CI 0.76 to 0.85)) were lower in the group that received early caffeine compared with those who received it later. CONCLUSIONS: Early use of caffeine has increased in England and Wales. This is associated with reduced risks of BPD and preterm brain injury. Randomised trials are needed to find the optimal timing of caffeine use and the groups of infants who will benefit most from early administration of caffeine.

Impact of the coronavirus disease 2019 pandemic on breastfeeding during and at discharge from neonatal care: An observational cohort study.

Importance: During the coronavirus disease 2019 (COVID-19) lockdown, changes in the visiting rules in neonatal units might have affected the initiation and continuation of breastfeeding. Objective: To investigate the effects of the implementation of the COVID-19 lockdown in the UK on mother's own milk (MOM) feeding in hospital and at the time of discharge in two UK neonatal units. Methods: Retrospective cohort study using routinely recorded data from electronic patient records. Data were retrieved from two neonatal services in the UK East Midlands region. Adjusted logistic regression was used to compare the odds of MOM feeding before, and after the implementation of the UK lockdown. Results: Among 2073 infants, after adjusting for maternal and infant characteristics and underlying trends over time, there were no differences in the odds of infants receiving any MOM during admission; any MOM at discharge or exclusive MOM at discharge before and after the imposition of the lockdown. Infants with birthweight <1000 g were three times less likely to receive any MOM at discharge compared to those with birthweight >2500 g (adjusted odds ratio [OR] 0.33, 95% confidence interval [CI]: 0.22-0.50). Younger mothers were less likely, and Black British mothers more likely, to be feeding MOM to their infants at discharge, while women in the least deprived Index of Multiple Deprivation (IMD) quintiles were 2-4 times more likely to do so, compared to those in the most deprived IMD quintile (adjusted OR 2.78, 95% CI: 1.97-3.90). Interpretation: Despite the difficulties faced during COVID-19 pandemic-induced restrictions, infants in the participating neonatal units continued to receive MOM in similar proportions as before the pandemic.

Cold Exposure Drives Weight Gain and Adiposity following Chronic Suppression of Brown Adipose Tissue.

Therapeutic activation of thermogenic brown adipose tissue (BAT) may be feasible to prevent, or treat, cardiometabolic disease. However, rodents are commonly housed below thermoneutrality (~20 °C) which can modulate their metabolism and physiology including the hyperactivation of brown (BAT) and beige white adipose tissue. We housed animals at thermoneutrality from weaning to chronically supress BAT, mimic human physiology and explore the efficacy of chronic, mild cold exposure (20 °C) and ß3-adrenoreceptor agonism (YM-178) under these conditions. Using metabolic phenotyping and exploratory proteomics we show that transfer from 28 °C to 20 °C drives weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration, thus suggesting a direct effect of a cool ambient temperature in promoting weight gain and further adiposity in obese rats. Following chronic suppression of BAT, uncoupling protein 1 mRNA was undetectable in the subcutaneous inguinal white adipose tissue (IWAT) in all groups. Using exploratory adipose tissue proteomics, we reveal novel gene ontology terms associated with cold-induced weight gain in BAT and IWAT whilst Reactome pathway analysis highlights the regulation of mitotic (i.e., G2/M transition) and metabolism of amino acids and derivatives pathways. Conversely, YM-178 had minimal metabolic-related effects but modified pathways involved in proteolysis (i.e., eukaryotic translation initiation) and RNA surveillance across both tissues. Taken together these findings are indicative of a novel mechanism whereby animals increase body weight and fat mass following chronic suppression of adaptive thermogenesis from weaning. In addition, treatment with a B3-adrenoreceptor agonist did not improve metabolic health in obese animals raised at thermoneutrality.

Observational cohort study of changing trends in non-invasive ventilation in very preterm infants and associations with clinical outcomes.

OBJECTIVE: To determine the change in non-invasive ventilation (NIV) use over time in infants born at <32 weeks' gestation and the associated clinical outcomes. STUDY DESIGN: Retrospective cohort study using routinely recorded data from the National Neonatal Research Database of infants born at <32 weeks admitted to neonatal units in England and Wales from 2010 to 2017. RESULTS: In 56 537 infants, NIV use increased significantly between 2010 and 2017 (continuous positive airway pressure (CPAP) from 68.5% to 80.2% in 2017 and high flow nasal cannula (HFNC) from 14% to 68%, respectively) (p<0.001)). Use of NIV as the initial mode of respiratory support also increased (CPAP, 21.5%-28.0%; HFNC, 1%-7% (p<0.001)).HFNC was used earlier, and for longer, in those who received CPAP or mechanical ventilation. HFNC use was associated with decreased odds of death before discharge (adjusted OR (aOR) 0.19, 95% CI 0.17 to 0.22). Infants receiving CPAP but no HFNC died at an earlier median chronological age: CPAP group, 22 (IQR 10-39) days; HFNC group 40 (20-76) days (p<0.001). Among survivors, HFNC use was associated with increased odds of bronchopulmonary dysplasia (BPD) (aOR 2.98, 95% CI 2.81 to 3.15) and other adverse outcomes. CONCLUSIONS: NIV use is increasing, particularly as initial respiratory support. HFNC use has increased significantly with a sevenfold increase soon after birth which was associated with higher rates of BPD. As more infants survive with BPD, we need robust clinical evidence, to improve outcomes with the use of NIV as initial and ongoing respiratory support.

Anti-reflux medication use in preterm infants.

BACKGROUND: Current recommendations do not support the use of anti-reflux medications to treat gastro-oesophageal reflux disease (GORD) among preterm infants. OBJECTIVE: To describe the prevalence of GORD and the use of anti-reflux medications amongst very preterm infants (<32 weeks' gestational age (GA)) in neonatal units in England and Wales. DESIGN: Retrospective cohort study using the National Neonatal Research Database. RESULTS: Among 58,108 infants [median GA (IQR) 29 (27-30) weeks], 15.8% (n = 9191) had a diagnosis of GORD and 36.9% (n = 12,446) received anti-reflux medications. Those who received anti-reflux medications were more preterm [GA, median (IQR): medications, 28 (26-30) vs. no medications, 30 (28-31); p < 0.001] and had lower birth weight [mean (SD): medications, 1124 g (354) vs. no medications, 1265 g (384); p < 0.001]. Most (57%, n = 12,224) received Gaviscon, or Histamine-2 Receptor Antagonist (H2RA) (56%, n = 11,959). Over time, prokinetic use has declined substantially, the use of H2RAs and Gaviscon has reduced although they continue to be used frequently, whilst the use of PPIs has increased. CONCLUSIONS: Anti-reflux medications are frequently prescribed in very preterm infants, despite evidence to suggest that they are not effective and may be harmful. Clear guidelines for diagnosing GORD and the use of anti-reflux medications are required to rationalise the pharmacological management of GORD in preterm infants. IMPACT: Anti-reflux medications are frequently prescribed, often without a diagnosis of gastro-oesophageal reflux disease, to very preterm infants while in the neonatal unit and at discharge. Half of the infants born at <28 weeks' gestational age receive anti-reflux medications in hospital and a quarter are discharged home on them. Although the use of prokinetics declined following alerts of adverse events, histamine2-receptor antagonists and alginates such as Gaviscon continue to be used and the use of proton-pump inhibitors has increased more than 2-fold.

Effect of Liothyronine Treatment on Dermal Temperature and Activation of Brown Adipose Tissue in Female Hypothyroid Patients: A Randomized Crossover Study.

Background: Thyroid hormones are essential for the full thermogenic response of brown adipose tissue (BAT) and have been implicated in dermal temperature regulation. Nevertheless, persistent cold-intolerance exists among a substantial proportion of hypothyroid patients on adequate levothyroxine (LT4) substitution. Materials and Methods: To assess if skin temperature and activation of BAT during treatment with liothyronine (LT3) differs from that of LT4 treatment, fifty-nine female hypothyroid patients with residual symptoms on LT4 or LT4/LT3 combination therapy were randomly assigned in a non-blinded crossover study to receive monotherapy with LT4 or LT3 for 12 weeks each. Change in supraclavicular (SCV) skin temperature overlying BAT, and sternal skin temperature not overlying BAT, during rest and cold stimulation were assessed by infrared thermography (IRT). In addition, abundance of exosomal miR-92a, a biomarker of BAT activation, was estimated as a secondary outcome. Results: Cold stimulated skin temperatures decreased less with LT3 vs. LT4 in both SCV (mean 0.009°C/min [95% CI: 0.004, 0.014]; P<0.001) and sternal areas (mean 0.014°C/min [95% CI: 0.008, 0.020]; P<0.001). No difference in serum exosomal miR-92a abundance was observed between the two treatment groups. Conclusion: LT3 may reduce dermal heat loss. Thermography data suggested increased BAT activation in hypothyroid patients with cold-intolerance. However, this finding was not corroborated by assessment of the microRNA biomarker of BAT activation. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03627611.

Semi-automated analysis of supraclavicular thermal images increases speed of brown adipose tissue analysis without increasing variation in results.

Interest in brown adipose tissue remains high a decade after it was determined to be present outside of the neonatal period. In vivo imaging, however, has remained a challenge due to the lack of a imaging modality suitable for large healthy-volunteer studies, post-prandial investigations and vulnerable groups, such as children. Infrared thermography is increasingly accepted as a valid, non-invasive and flexible alternative but there is a wide approach to analysis between different groups. Defining the region of interest with anatomical borders rather than using a simple polygon may have advantages in terms of consistency but makes image analysis slower, limiting some applications. Our novel semi-automated method, using a custom-built graphical user interface, allows an 86% improvement in speed of image analysis (54.9 (38.3-71.4) seconds/image) without increases in variation between analysers or with repeated analysis. The improved efficiency demonstrated makes feasible larger studies, longer imaging periods or increased image acquisition frequency, providing an opportunity to study novel features of brown adipose tissue function.

Nutritional practices and growth of preterm infants in two neonatal units in the UK and Malaysia: a prospective exploratory study.

Objective: To explore differences in nutritional practices and growth outcomes among preterm infants in neonatal units in Malaysia and the UK. Design: Prospective exploratory study of infants born at <34 weeks gestational age (GA). Setting: Two neonatal units, one in Malaysia and one in the UK (May 2019 to March 2020). Methods: Data collected from birth until discharge and compared between units. Results: From 100 infants included, median GA (IQR) was 31 (30-33) and mean±SD birth weight was 1549±444 g. There were more small-for-gestational age infants in Malaysian unit: 12/50 (24%) vs UK: 3/50 (6%), p=0.012 and more morbidities. More Malaysian infants received breast milk (Malaysia: 49 (98%) vs UK: 38 (76%), p=0.001), fortified breast milk (Malaysia: 43 (86%) vs UK: 13 (26%), p<0.001) and exclusive breast milk at discharge (Malaysia: 26 (52%) vs UK: 16 (32%), p=0.043). There was higher parenteral nutrition use among Malaysian infants (40/50 (80%)) vs UK (19/50 (38%)) (p<0.001) with higher protein intake (mean±SD Malaysia: 3.0±0.5 vs UK: 2.7±0.6 g/kg/d, p=0.004) in weeks 1-4 and smaller cumulative protein deficits (mean±SD Malaysia: 11.4±6.1 vs UK: 15.4±8.0 g/kg, p=0.006). There were no significant differences in short-term growth between units and more than half of the infants in both units had ≥1.28 changes in weight-for-age Z-score at discharge (p=0.841). Conclusions: An exploratory comparison of practices showed differences in patient characteristics and nutritional practices which impacted growth. Future studies with larger sample sizes and detailed analysis of maternal characteristics and infants' outcomes are needed for improving care of preterm infants in all settings.

Reduced brown adipose tissue-associated skin temperature following cold stimulation in children and adolescents with type 1 diabetes.

BACKGROUND: Brown adipose tissue (BAT) is essential to maintain body temperature. Its ability to convert chemical energy in glucose and free fatty acids to heat is conferred by a unique protein, UCP-1. BAT activity is greatest in children and adolescents, declining through adulthood. Blood glucose concentrations outside the normal nondiabetic range are common in type 1 diabetes and hyperglycaemia leads to insulin resistance in muscle and white adipose tissue, but whether this applies to BAT, is not known. METHOD: To investigate the effect of type 1 diabetes on BAT activity, we measured the supraclavicular temperature of 20 children with type 1 diabetes and compared them to 20 age-matched controls, using infrared thermography. RESULTS: The diabetes group had lower stimulated supraclavicular temperatures (diabetes group: 35.03 (34.76-35.30)°C; control group: 35.42 (35.16-35.69)°C; p = 0.037) and a reduced response in relative temperature following cold stimulation, after adjusting for BMI (diabetes group: 0.11 (0.03-0.18)°C; control group: 0.22 (0.15-0.29)°C; p = 0.034). In the diabetes group, there was no association between glycaemic measures and supraclavicular temperatures, but the method of insulin delivery may significantly affect the change in supraclavicular temperature with stimulation (injections: 0.01 (-0.07-0.09)°C; pump: 0.15 (0.04-0.26)°C; p = 0.028). CONCLUSIONS: While further work is needed to better understand the glucose-insulin-BAT relationship, one possible explanation for the reduced supraclavicular temperature is that exogenous, unlike endogenous, insulin, is not suppressed by the activity of the sympathetic nervous system, preventing lipolysis-driven activation of BAT.

Adipose tissue growth and development: the modulating role of ambient temperature.

Adipose tissue is usually laid down in small amounts in the foetus and is characterised as possessing small amounts of the brown adipose tissue-specific mitochondrial uncoupling protein (UCP)1. In adults, a primary factor determining the abundance and function of UCP1 is ambient temperature. Cold exposure causes activation and the rapid generation of heat through the free flow of protons across the mitochondria with no requirement to convert ADP to ATP. In rodents, housing at an ambient temperature below thermoneutrality promotes the appearance of beige like adipocytes. These arise as discrete regions of UCP1 containing cells in white fat depots. There is increasing evidence to show that to gain credible translational results on brown and beige fat function in rodent models that they should be housed at thermoneutrality. This not only reflects the type of environment in which humans spend a majority of their time, but is in accord with the rise of global temperature caused by industrialisation and the uncontrolled burning of fossil fuels. There is now good evidence in adult humans, that stimulating brown fat can improve glucose homeostasis which can be achieved either by nutritional or pharmacological interventions. The challenge, therefore, is to establish credible developmental models in animals maintained at thermoneutrality which will elucidate the true impact of nutrition. The primary focus should fall specifically on the components of breast milk and how these modulate long term effects on brown or beige fat development and function.

Exercise Training in Obese Rats Does Not Induce Browning at Thermoneutrality and Induces a Muscle-Like Signature in Brown Adipose Tissue.

Aim: Exercise training elicits diverse effects on brown (BAT) and white adipose tissue (WAT) physiology in rodents housed below their thermoneutral zone (i.e., 28-32°C). In these conditions, BAT is chronically hyperactive and, unlike human residence, closer to thermoneutrality. Therefore, we set out to determine the effects of exercise training in obese animals at 28°C (i.e., thermoneutrality) on BAT and WAT in its basal (i.e., inactive) state. Methods: Sprague-Dawley rats (n = 12) were housed at thermoneutrality from 3 weeks of age and fed a high-fat diet. At 12 weeks of age half these animals were randomized to 4-weeks of swim-training (1 h/day, 5 days per week). Following a metabolic assessment interscapular and perivascular BAT and inguinal (I)WAT were taken for analysis of thermogenic genes and the proteome. Results: Exercise attenuated weight gain but did not affect total fat mass or thermogenic gene expression. Proteomics revealed an impact of exercise training on 2-oxoglutarate metabolic process, mitochondrial respiratory chain complex IV, carbon metabolism, and oxidative phosphorylation. This was accompanied by an upregulation of multiple proteins involved in skeletal muscle physiology in BAT and an upregulation of muscle specific markers (i.e., Myod1, CkM, Mb, and MyoG). UCP1 mRNA was undetectable in IWAT with proteomics highlighting changes to DNA binding, the positive regulation of apoptosis, HIF-1 signaling and cytokine-cytokine receptor interaction. Conclusion: Exercise training reduced weight gain in obese animals at thermoneutrality and is accompanied by an oxidative signature in BAT which is accompanied by a muscle-like signature rather than induction of thermogenic genes. This may represent a new, UCP1-independent pathway through which BAT physiology is regulated by exercise training.

Brown Adipose Tissue Response to Cold Stimulation Is Reduced in Girls With Autoimmune Hypothyroidism.

OBJECTIVE: The interaction between thyroid status and brown adipose tissue (BAT) activation is complex. We assessed the effect of autoimmune hypothyroidism (ATD) in female children on BAT activation, measured using infrared thermography. DESIGN: Twenty-six female participants (14 with ATD and 12 healthy controls) between 5 and 17 years of age attended a single study session. Thermal images were taken of the supraclavicular region before, and after, the introduction of a cool stimulus. RESULTS: Participants with ATD had lower resting (hypothyroid, 34.9 ± 0.7°C; control, 35.4 ± 0.5°C; P = 0.03) and stimulated (hypothyroid, 35.0 ± 0.6°C; control, 35.5 ± 0.5°C; P = 0.04) supraclavicular temperatures compared with controls, but there was no difference between groups in the temperature increase with stimulation. BAT activation, calculated as the relative temperature change comparing the supraclavicular temperature to a sternal reference region, was reduced in participants with ATD (hypothyroid, 0.1 ± 0.1°C; control, 0.2 ± 0.2°C; P = 0.04). Children with ATD were frequently biochemically euthyroid due to replacement therapy, but, despite this, increased relative supraclavicular temperature was closely associated with increased TSH (r = 0.7, P = 0.01) concentrations. CONCLUSIONS: Girls with ATD had an attenuated thermogenic response to cold stimulation compared with healthy controls, but, contrary to expectation, those with suboptimal biochemical control (with higher TSH) showed increased BAT activation. This suggests that the underlying disease process may have a negative effect on BAT response, but high levels of TSH can mitigate, and even stimulate, BAT activity. In summary, thyroid status is a complex determinant of BAT activity in girls with ATD.

Caffeine exposure induces browning features in adipose tissue in vitro and in vivo.

Brown adipose tissue (BAT) is able to rapidly generate heat and metabolise macronutrients, such as glucose and lipids, through activation of mitochondrial uncoupling protein 1 (UCP1). Diet can modulate UCP1 function but the capacity of individual nutrients to promote the abundance and activity of UCP1 is not well established. Caffeine consumption has been associated with loss of body weight and increased energy expenditure, but whether it can activate UCP1 is unknown. This study examined the effect of caffeine on BAT thermogenesis in vitro and in vivo. Stem cell-derived adipocytes exposed to caffeine (1 mM) showed increased UCP1 protein abundance and cell metabolism with enhanced oxygen consumption and proton leak. These functional responses were associated with browning-like structural changes in mitochondrial and lipid droplet content. Caffeine also increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial biogenesis, together with a number of BAT selective and beige gene markers. In vivo, drinking coffee (but not water) stimulated the temperature of the supraclavicular region, which co-locates to the main region of BAT in adult humans, and is indicative of thermogenesis. Taken together, these results demonstrate that caffeine can promote BAT function at thermoneutrality and may have the potential to be used therapeutically in adult humans.

Interscapular and Perivascular Brown Adipose Tissue Respond Differently to a Short-Term High-Fat Diet.

Brown adipose tissue (BAT) function may depend on its anatomical location and developmental origin. Interscapular BAT (iBAT) regulates acute macronutrient metabolism, whilst perivascular BAT (PVAT) regulates vascular function. Although phenotypically similar, whether these depots respond differently to acute nutrient excess is unclear. Given their distinct anatomical locations and developmental origins and we hypothesised that iBAT and PVAT would respond differently to brief period of nutrient excess. Sprague-Dawley rats aged 12 weeks (n=12) were fed either a standard (10% fat, n=6) or high fat diet (HFD: 45% fat, n=6) for 72h and housed at thermoneutrality. Following an assessment of whole body physiology, fat was collected from both depots for analysis of gene expression and the proteome. HFD consumption for 72h induced rapid weight gain (c. 2.6%) and reduced serum non-esterified fatty acids (NEFA) with no change in either total adipose or depot mass. In iBAT, an upregulation of genes involved in insulin signalling and lipid metabolism was accompanied by enrichment of lipid-related processes and functions, plus glucagon and peroxisome proliferator-activated receptor (PPAR) signalling pathways. In PVAT, HFD induced a pronounced down-regulation of multiple metabolic pathways which was accompanied with increased abundance of proteins involved in apoptosis (e.g. Hdgf and Ywaq) and toll-like receptor signalling (Ube2n). There was also an enrichment of DNA-related processes and functions (e.g. nucleosome assembly and histone exchange) and RNA degradation and cell adhesion pathways. In conclusion, we show that iBAT and PVAT elicit divergent responses to short-term nutrient excess highlighting early adaptations in these depots before changes in fat mass.

Sexual Dimorphism of Brown Adipose Tissue Function.

OBJECTIVE: To determine whether brown adipose tissue (BAT) activity in school-age children differs between the sexes and to explore the impact of dietary intake, sedentary behavior, and picky/fussy eating. STUDY DESIGN: Children aged 8.5-11.8 years of age (n = 36) underwent infrared thermography to determine the temperature of the skin overlying the main superficial BAT depot in the supraclavicular region before and after 5 minutes of mild cold exposure (single-hand immersion in cool tap water at about 20°C). The relationships between the supraclavicular region temperature and parental reports of food consumption, eating behavior, and inactivity were explored. RESULTS: The supraclavicular region temperature was higher in boys (n = 16) at baseline, and after cold exposure. Boys displayed a greater thermogenic response to cold. Strong negative correlations were observed between the supraclavicular region temperature and body mass index percentile, and differences in supraclavicular region temperature between girls and boys persisted after adjustment for body mass index percentile. A negative linear relationship was observed between protein and vegetable intake and supraclavicular region temperature in girls only, but did not persist after adjustment for multiple comparisons. There was no difference in the adjusted supraclavicular region temperature between active or inactive children, or picky and nonpicky eaters. CONCLUSIONS: These findings indicate sexual dimorphism in BAT thermogenic activity and a sex-specific impact of diet. Future studies should aim to quantify the contribution of BAT to childhood energy expenditure, energy imbalance, and any role in the origins of childhood obesity.

Housing Temperature Modulates the Impact of Diet-Induced Rise in Fat Mass on Adipose Tissue Before and During Pregnancy in Rats.

Aim: To investigate whether housing temperature influences rat adiposity, and the extent it is modified by diet and/or pregnancy. Housing temperature impacts on brown adipose tissue, that possess a unique uncoupling protein (UCP) 1, which, when activated by reduced ambient temperature, enables rapid heat generation. Methods: We, therefore, examined whether the effects of dietary induced rise in fat mass on interscapular brown fat in female rats were dependent on housing temperature, and whether pregnancy further modulates the response. Four week old rats were either maintained at thermoneutrality (27°C) or at a "standard" cool temperature (20°C), and fed either a control or obesogenic (high in fat and sugar) diet until 10 weeks old. They were then either tissue sampled or mated with a male maintained under the same conditions. The remaining dams were tissue sampled at either 10 or 19 days gestation. Results: Diet had the greatest effect on fat mass at thermoneutrality although, by 19 days gestation, fat weight was similar between groups. Prior to mating, the abundance of UCP1 was higher at 20°C, but was similar between groups during pregnancy. UCP1 mRNA followed a similar pattern, with expression declining to a greater extent in the animals maintained at 20°C. Conclusion: Housing temperature has a marked influence on the effect of dietary induced rise in fat deposition that was modified through gestation. This maybe mediated by the reduction in UCP1 with housing at thermoneutrality prior to pregnancy and could subsequently impact on growth and development of the offspring.

Cognitive predictors of parent-rated inattention in very preterm children: The role of working memory and processing speed.

Inattention is one of the most common neurobehavioral problems following very preterm birth. Attention problems can persist into adulthood and are associated with negative socio-emotional and educational outcomes. This study aimed to determine whether the cognitive processes associated with inattention differ between term-born and very preterm children. Sixty-five children born very preterm (<33+0 weeks' gestation) aged 8-11 years were recruited alongside 48 term-born controls (?37 20 +0 weeks' gestation). Both groups included children with a wide spectrum of parent-rated inattention (above average attention to severe inattention) measured as a continuous dimension using the Strengths and Weaknesses of ADHD and Normal-Behavior (SWAN) scale. The children completed tests to assess basic cognitive processes and executive function. A hierarchical multiple regression analysis was implemented to assess which neurocognitive processes explained variance in parent-rated inattention and whether these differed between preterm and term-born children. In both groups, poorer verbal and visuospatial short-term memory and poorer visuospatial working memory independently explained variance in parent-rated inattention. Slower motor processing speed explained variance in inattention among very preterm children only. The cognitive mechanisms associated with parent-rated inattention were predominantly overlapping between groups, but relationships between motor processing speed and inattention were unique to very preterm children. These associations may reflect risk factors for inattention in term and very preterm children. Future research should assess the efficacy of these cognitive processes as potential targets for intervention.

Infrared Thermography.

Historically, brown adipose tissue has been elusive and not easy to detect, hence its relative obscurity in human physiology until its rediscovery in 2009. At that point, it was proven that the symmetrical artefacts frequently detected on positron emission tomography-computed tomography (PET-CT), which resolved if the environment was kept warm, were brown adipose tissue deposits. PET-CT has remained the stalwart of human brown adipose tissue research and is still considered the gold standard. However, PET-CT exposes the participant to ionising radiation, limiting studies to large, but retrospective, review of clinical imaging or a small-scale, but prospective, design. Within this context, alternative imaging modalities have been sought. Due to the heat-generating properties of brown adipose tissue, infrared thermography is a natural candidate for measuring its activity and the supraclavicular depot is relatively superficial, allowing detection of the heat signature. Infrared thermography is a non-invasive, non-contact technique for measuring temperature remotely. Recent developments in image analysis techniques have facilitated the use of infrared thermography to study brown adipose tissue activation in populations, and in ways, not previously feasible.