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Hybrid trials are a new trend in dermatological research that leverage mobile health technologies to decentralize a subset of clinical trial elements and thereby reduce the number of in-clinic visits. In a Phase I/IIa randomized controlled hybrid trial, the safety and efficacy of an anti-proliferative and anti-inflammatory drug inhibiting cytosolic phospholipase A2 (AVX001) was tested using 1%, 3% or vehicle gel in 60 patients with actinic keratosis (AK) and assessed in-clinic as well as remotely. Over the course of 12 weeks, patients were assessed in-clinic at baseline, end of treatment (EOT) and end of study (EOS), as well as 9 times remotely on a weekly to biweekly basis. Safety outcomes comprising local skin reactions (LSR; 0–5), adverse events (AE) and cosmesis, were graded in-clinic and remotely using patient-obtained smartphone photographs (PSPs) and questionnaires; efficacy was assessed in-clinic based on clinically visible clearance of AK target area of >50%. A total of 55 participants (91.7%) completed the treatment course. The average submission rate of PSPs was high (≥85%), of which 93% were of sufficient quality. No serious AE were reported and only two experienced temporary LSR >2 (scale 0–4) and cosmesis remained stable throughout the study. Based on the mild AE and LSR profile, daily application of AVX001 gel for 1 month appears safe, tolerable, and cosmetically acceptable for use in patients with AK. At EOT, AVX001 achieved a subtle treatment response with clearance of AK target area of >50% in 18% of patients. Remote and in-clinic assessments of LSRs were in high agreement, suggesting that the use of mobile health technologies in early-phase hybrid studies of AK does not compromise patient safety., Hybrid trials are a new trend in dermatological research that leverage mobile health technologies to decentralize a subset of clinical trial elements and thereby reduce the number of in-clinic visits. In a Phase I/IIa randomized controlled hybrid trial, the safety and efficacy of an anti-proliferative and anti-inflammatory drug inhibiting cytosolic phospholipase A2 (AVX001) was tested using 1%, 3% or vehicle gel in 60 patients with actinic keratosis (AK) and assessed in-clinic as well as remotely. Over the course of 12 weeks, patients were assessed in-clinic at baseline, end of treatment (EOT) and end of study (EOS), as well as 9 times remotely on a weekly to biweekly basis. Safety outcomes comprising local skin reactions (LSR; 0–5), adverse events (AE) and cosmesis, were graded in-clinic and remotely using patient-obtained smartphone photographs (PSPs) and questionnaires; efficacy was assessed in-clinic based on clinically visible clearance of AK target area of >50%. A total of 55 participants (91.7%) completed the treatment course. The average submission rate of PSPs was high (≥85%), of which 93% were of sufficient quality. No serious AE were reported and only two experienced temporary LSR >2 (scale 0–4) and cosmesis remained stable throughout the study. Based on the mild AE and LSR profile, daily application of AVX001 gel for 1 month appears safe, tolerable, and cosmetically acceptable for use in patients with AK. At EOT, AVX001 achieved a subtle treatment response with clearance of AK target area of >50% in 18% of patients. Remote and in-clinic assessments of LSRs were in high agreement, suggesting that the use of mobile health technologies in early-phase hybrid studies of AK does not compromise patient safety.

Background: Remote monitoring was used to assess and manage skin diseases. Objective: To investigate to what extent smartphone photographs along with a self-reported body region (BR) score can be used to evaluate psoriasis severity. Methods: Psoriasis severity was assessed in the clinic using the psoriasis area and severity index and the physician's global assessment. On the same day, the patients took a photograph of a representative lesion from 4 BR (head/neck, upper limbs, trunk, and lower limbs) and completed a questionnaire about BR score. The photographs were rated by 5 dermatologists. Intraclass correlation coefficients with 95% CIs were calculated. Results: Overall, 32 were included, of which 6% had almost clear, 69% had mild, and 25% had moderate psoriasis. Perfect agreement between the self-reported and the doctors’ BR score was observed for 59%, and near-perfect agreement (deviation of maximum 1 score) was 92%. The intraclass correlation coefficient between clinical and photographic psoriasis area and severity index was 0.78 (95% CI, 0.55-0.90), and for physician's global assessment, perfect agreement was 53%. Conclusions: The agreement between psoriasis severity assessed clinically and by photographs was good in a study setting. This gives the opportunity to remotely assess psoriasis severity by combining photographs with self-reported BR scores.

Background: Clinical trials often suffer from recruitment barriers and poor adherence, which increases costs and affects trial outcomes. Objective: To investigate the feasibility of Decentralized Clinical Trial (DCT) design elements to recruit, enroll, and engage patients with type 2 diabetes mellitus (T2DM). Methods: Patients with T2DM were recruited through a pharmacy and online recruitment using advert on Facebook, to 3 weeks monitoring of glucose and behaviometric parameters. Subjects recruited online could either complete an informed consent conversation in the pharmacy or through live video call managed by the study app. A continuous glucose monitoring (CGM) device to collect glucose data, and a hybrid smartwatch to monitor heart rate, track activity and sleep pattern were delivered by postal service to the participants’ home address. The devices were connected to a study specific app on the participant’s smartphone also capturing GPS data and questionnaire answers. Results: Twenty-six subjects (3 pharmacy, 23 online) with T2DM were recruited, 85% preferred online informed consent conversation. All participants were able to self-apply the CGM device, use the smartwatch, and download the app. GPS location was captured more than 100 times for each participant, and more than 90% completed all 3 questionnaires. All the participants felt safe with the informed consent process and they felt confident in participating from home. Three participants dropped-out during the study period leaving a retention rate at 87%. Conclusions: Use of DCT design elements to conduct a T2DM study is feasible regarding recruitment, data collection from various electronic devices, and participant engagement.

Background Increasing costs and complexity in clinical trials requires recruitment of more narrowly defined patient populations. However, recruitment for clinical trials remains a considerable challenge. Aim Our overall aim was to quantify recruitment performance in industry-sponsored phase III clinical trials conducted globally during 2008-2019 with primary aim to examine development of overall clinical trial measures (number of trials completed, number of participants enrolled, trial duration in months) and key recruitment metrics (recruitment rate, number of sites, number of patients enrolled per site). Methods The publicly available AACT database containing data on all trials registered at Clinical-Trials.gov since 2008 was used. The analysis was completed during three time periods from 2008-2019 of 4 years each. Results and conclusion Recruitment duration for industry-sponsored phase III clinical trials have increased significantly during the last 12 years from an average recruitment period of 13 months (IQR 7-23) in 2008-2011 to 18 months (IQR 11-28) in 2016-2019 (p = 0.0068). Further, phase III clinical trials have increased the number of registered sites per clinical trial by more than 30% during the last 12 years from a median number 43 sites (IQR 17-84) in 2012-2015 to 64 sites (IQR 30-118) in 2016-2019 (p = 0.025), and concurrently, the number of participants enrolled in clinical research has decreased significantly from 2012-2015 and 2016-2019 (p = 0.046). We believe that these findings indicate that recruitment for phase III clinical trials is less effective today compared to 12 years ago.

Background: The use of photographs to diagnose and monitor skin diseases is gaining ground. Objectives: To investigate the validity and reliability of photographic assessments of atopic dermatitis (AD) severity. Methods: AD severity was evaluated in the clinic by two assessors using the Eczema Area and Severity Index (EASI), SCOring Atopic Dermatitis (SCORAD), and Investigator's Global Assessment (IGA). Participants photographed the lesions with their own smartphone and completed a questionnaire about the extent of eczema the same day from home. The photographs were assessed twice with an 8 weeks interval by five dermatologists experienced in photographic evaluations. Intraclass correlation coefficients (ICC) with 95% confidence interval (CI) were applied. Results: Seventy-nine participants were enrolled. The ICC between clinical EASI and photographic EASI was 0.88 (95% CI 0.81–0.93), and 0.86 (0.70–0.93) between clinical SCORAD and photographic SCORAD. Perfect agreement between clinical IGA and photograph IGA was observed for 62%, with the difference between the two never deviating with more than 1 score. The inter-rater ICC for photographic EASI and photographic SCORAD, respectively, was 0.90 (0.85–0.94), and 0.96 (0.91–0.98). The intra-rater agreements between the first and second assessments varied from 0.95 to 0.98 for photographic EASI, and from 0.86 to 0.94 for photographic SCORAD. Conclusion: There was high agreement between mild to moderate AD severity assessed clinically and based on smartphone photographs. Further, the photographic assessments can be reproduced with high reliability.

Background: Digital imaging of dermatological patients is a novel approach to remote assessment and has recently become more relevant since telehealth and remote decentralized clinical trials are gaining ground. Objective: We aimed to investigate whether photographs taken by a smartphone are of adequate quality to allow severity assessments to be made and to explore the usefulness of an established atopic dermatitis severity assessment instrument on photograph evaluation. Methods: During scheduled visits in a previously published study, the investigating doctor evaluated the severity of atopic dermatitis using the Scoring AD (SCORAD) index and took photographs of the most representative lesions (target lesions) with both a smartphone and a digital single-lens reflex camera (DSLR). The photographs were then assessed by 5 dermatologists using the intensity items of the SCORAD (iSCORAD), which consists of erythema, oedema/papulation, excoriations, lichenification, oozing/crusts, and dryness (scale 0-3, maximum score 18). The mean iSCORAD of the photographs was calculated and compared with in-person assessments using Pearson correlation and Bland-Altman plots. Intraclass correlation coefficients were used for interrater reliability. Results: A total of 942 photographs from 95 patients were assessed. The iSCORAD based on smartphone photographs correlated strongly with the evaluations performed in person (iSCORAD: r=0.78, P<.001; objective SCORAD: r=0.81, P<.001; and total SCORAD: r=0.78, P<.001). For iSCORAD specifically, a Bland-Altman plot showed a difference in mean score of 1.31 for in-person and remote iSCORAD. In addition, the interrater agreement between the 5 rating dermatologists was 0.93 (95% CI 0.911-0.939). A total of 170 lesions were photographed, and the difference in mean scores was 1.32, 1.13, and 1.43 between in-person and remote evaluations based on photographs taken by a DSLR camera, a smartphone without flash, and a smartphone with flash

Background: Recruitment for clinical trials continues to be a challenge, as patient recruitment is the single biggest cause of trial delays. Around 80% of trials fail to meet the initial enrollment target and timeline, and these delays can result in lost revenue of as much as US $8 million per day for drug developing companies.Objective: This study aimed to conduct a systematic review and meta-analysis examining the effectiveness of online recruitment of participants for clinical trials compared with traditional in-clinic/offline recruitment methods.Methods: Data on recruitment rates (the average number of patients enrolled in the study per month and per day of active recruitment) and conversion rates (the percentage of participants screened who proceed to enroll into the clinical trial), as well as study characteristics and patient demographics were collected from the included studies. Differences in online and offline recruitment rates and conversion rates were examined using random effects models. Further, a nonparametric paired Wilcoxon test was used for additional analysis on the cost-effectiveness of online patient recruitment. All data analyses were conducted in R language, and PResults: In total, 3861 articles were screened for inclusion. Of these, 61 studies were included in the review, and 23 of these were further included in the meta-analysis. We found online recruitment to be significantly more effective with respect to the recruitment rate for active days of recruitment, where 100% (7/7) of the studies included had a better online recruitment rate compared with offline recruitment (incidence rate ratio [IRR] 4.17, P=.04). When examining the entire recruitment period in months we found that 52% (12/23) of the studies had a better online recruitment rate compared with the offline recruitment rate (IRR 1.11, P=.71). For cost-effectiveness, we found that online recruitment had a significantly lower cost per enrollee compared with off

Introduction: Clinical trials often suffer from significant recruitment barriers, poor adherence, and dropouts, which increase costs and negatively affect trial outcomes. The aim of this study was to examine whether making it virtual and reward-based would enable nationwide recruitment, identify patients with variable disease severity, achieve high adherence, and reduce dropouts. Methods: In a siteless, virtual feasibility study, individuals with atopic dermatitis (AD) were recruited online. During the 8-week study, subjects used their smartphones weekly to photograph target AD lesions, and completed patient-oriented eczema measure (POEM) and treatment use questionnaires. In return, subjects were rewarded every week with personalized lifestyle reports based on their DNA. Results: Over the course of the 11 day recruitment period, 164 (82% women and 18% men) filled in the form to participate, of which 65 fulfilled the inclusion criteria and signed the informed consent. Ten were excluded as they did not complete the mandatory study task of returning the DNA sample. 55 (91% women, 9% men) subjects returned the DNA sample and were enrolled throughout Denmark, the majority outside the Copenhagen capital region in rural areas with relatively low physician coverage. The mean age was 28.5 (SD ±9.5 years, range 18-52 years). The baseline POEM score was 14.5±5.6 (range 6-28). Based on the POEM, 7 individuals had mild, 28 had moderate, 17 had severe, and 3 had very severe eczema. The retention rate was 96% as 53 out of 55 enrolled completed the study. The adherence was very high, and more than 90% of all study tasks were completed. Follow up of 41 subjects showed that 90% would take part again or continue if the study had been longer. Conclusion: A virtual trial design enables recruitment with broad geographic reach and throughout the full spectrum of disease severity. Providing personalized genetic reports as a reward seems to contribute to high adherence and retention.

Infectious diarrhoea is a worldwide problem in newborns. Optimal bacterial colonisation may enhance gut maturation and protect against pathogenic bacteria after birth. We hypothesised that lactic acid bacteria (LAB) administration prevents pathogen-induced diarrhoea in formula-fed newborns. Newborn caesarean-delivered, colostrum-deprived term piglets on parenteral nutrition for the first 15 h, were used as models for sensitive newborn infants. A commercially available probiotic strain, Lactobacillus paracasei F19 (LAP, 2·6x108 colony-forming units (CFU)/kg per d) and a novel LAB isolate, Pediococcus pentosaceus (PEP, 1·3x1010 CFU/kg per d), were administered for 5 d with or without inoculation of the porcine pathogen, Escherichia coli F18 (F18, 1010 CFU/d). This resulted in six treatment groups: Controls (n 9), LAP (n 10), PEP (n 10), F18 (n 10), F18-LAP (n 10) and F18-PEP (n 10). The pathogen challenge increased diarrhoea and density of F18 in the intestinal mucosa (P<0·05). LAB supplementation further increased the diarrhoea score, relative to F18 alone (P<0·01). Intestinal structure and permeability were similar among groups, whereas brush border enzymes were affected in variable intestinal regions with decreased activities in most cases after F18 and LAB inoculation. Bacterial density in colon mucosa increased after F18 inoculation (P<0·05) but was unaffected by LAB supplementation. In colon contents, acetic and butyric acids were increased by PEP (P<0·05). The LAB used in this study failed to reduce E. coli-induced diarrhoea in sensitive newborn pigs. In vulnerable newborns there may be a delicate balance among bacterial composition and load, diet and the host. Caution may be required when administering LAB to compromised newborns suffering from enteric infections.

Preterm pigs show many signs of immaturity that are characteristic of preterm infants. In preterm infants, the cerebellum grows particularly rapid and hypoplasia and cellular lesions are associated with motor dysfunction and cognitive deficits. We hypothesized that functional brain delays observed in preterm pigs would be paralleled by both structural and molecular differences in the cerebellum relative to term born piglets. Cerebella were collected from term (n = 56) and preterm (90% gestation, n = 112) pigs at 0, 5, and 26 days after birth for stereological volume estimations, large‐scale qPCR gene expression analyses (selected neurodevelopmental genes) and western blot protein expression analysis (Sonic Hedgehog pathway). Memory and learning was tested using a T‐maze, documenting that preterm pigs showed delayed learning. Preterm pigs also showed reduced volume of both white and gray matter at all three ages but the proportion of white matter increased postnatally, relative to term pigs. Early initiation of enteral nutrition had limited structural or molecular effects. The Sonic Hedgehog pathway was unaffected by preterm birth. Few differences in expression of the selected genes were found, except consistently higher mRNA levels of Midkine, p75, and Neurotrophic factor 3 in the preterm cerebellum postnatally, probably reflecting an adaptive response to preterm birth. Pig cerebellar development appears more affected by postconceptional age than by environmental factors at birth or postnatally. Compensatory mechanisms following preterm birth may include faster white matter growth and increased expression of selected genes for neurotrophic factors and regulation of angiogenesis. While the pig cerebellum is immature in 90% gestation preterm pigs, it appears relatively mature and resilient toward environmental factors., Preterm pigs show many signs of immaturity that are characteristic of preterm infants. In preterm infants, the cerebellum grows particularly rapid and hypoplasia and cellular lesions are associated with motor dysfunction and cognitive deficits. We hypothesized that functional brain delays observed in preterm pigs would be paralleled by both structural and molecular differences in the cerebellum relative to term born piglets. Cerebella were collected from term (n = 56) and preterm (90% gestation, n = 112) pigs at 0, 5, and 26 days after birth for stereological volume estimations, large-scale qPCR gene expression analyses (selected neurodevelopmental genes) and western blot protein expression analysis (Sonic Hedgehog pathway). Memory and learning was tested using a T-maze, documenting that preterm pigs showed delayed learning. Preterm pigs also showed reduced volume of both white and gray matter at all three ages but the proportion of white matter increased postnatally, relative to term pigs. Early initiation of enteral nutrition had limited structural or molecular effects. The Sonic Hedgehog pathway was unaffected by preterm birth. Few differences in expression of the selected genes were found, except consistently higher mRNA levels of Midkine, p75, and Neurotrophic factor 3 in the preterm cerebellum postnatally, probably reflecting an adaptive response to preterm birth. Pig cerebellar development appears more affected by postconceptional age than by environmental factors at birth or postnatally. Compensatory mechanisms following preterm birth may include faster white matter growth and increased expression of selected genes for neurotrophic factors and regulation of angiogenesis. While the pig cerebellum is immature in 90% gestation preterm pigs, it appears relatively mature and resilient toward environmental factors.

Background: Necrotizing enterocolitis (NEC) is a serious feeding-related inflammatory gut disease with high mortality. Early clinical markers of NEC are of great importance for optimizing preventive interventions. Objective: Using preterm pigs as models, we hypothesized that an early postnatal onset of NEC can be predicted by decreased physical activity during the first few days after birth. Methods: Cesarean-delivered preterm pigs were fed parenteral nutrition and increasing amounts of formula for 5 days after birth (n = 120). Their physical activity was quantified by a continuous camera surveillance system and they were evaluated twice daily for clinical signs of apathy, discoloration, respiratory distress, abdominal distension and diarrhea. The volume of gastric residuals and the presence of macroscopic NEC-like lesions in the stomach, intestine and colon were recorded at euthanasia on day 5. Results: Half of the pigs (48%) showed clear NEC-like lesions on day 5, and these individuals had more adverse clinical symptoms from day 3 but decreased physical activity already from day 2 relative to the unaffected pigs (both p < 0.05). Only animals with NEC lesions in the small intestine had lower physical activity on days 2 and 3, and the increased volume of gastric residuals was specifically related to colon lesions (both p < 0.05). Conclusions: Decreased physical activity precedes the clinical symptoms of NEC in the small intestine of preterm pigs, and increased gastric residuals predict NEC lesions in the colon. Physical activity and gastric residuals may function as clinical biomarkers for region-specific NEC lesions in preterm neonates.

BACKGROUND: Preterm infants often tolerate full enteral nutrition few weeks after birth but it is not known how this is related to gut maturation. Using pigs as models, we hypothesized that intestinal structure and digestive function are similar in preterm and term individuals at 3-4 weeks after birth and that early enteral nutrition promotes maturation.METHODS: Preterm or term cesarean-delivered pigs were fed total parenteral nutrition (TPN), or partial enteral nutrition (ENT, 16-64 mL/kg/d of bovine colostrum) for 5 d, followed by full enteral milk feeding until d 26. The intestine was collected for histological and biochemical analyses at d 0, 5 and 26 (n = 8-12 in each of ten treatment groups).RESULTS: Intestinal weight (relative to body weight) was reduced in preterm pigs at 0-5 d but ENT feeding stimulated the mucosal volume and peptidase activities. Relative to term pigs, mucosal volume remained reduced in preterm pigs until 26 d although plasma glucagon-like peptide 2 (GLP-2) and glucose-dependent insulin-trophic peptide (GIP) levels were increased. Preterm pigs also showed reduced hexose absorptive capacity and brush-border enzyme (sucrase, maltase) activities at 26 d, relative to term pigs.CONCLUSION: Intestinal structure shows a remarkable growth adaptation in the first week after preterm birth, especially with enteral nutrition, while some digestive functions remain immature until at least 3-4 weeks. It is important to identify feeding regimens that stimulate intestinal maturation in the postnatal period of preterm infants because some intestinal functions may show long-term developmental delay.

Several studies have investigated the effects of fish oil (FO) on infant growth, but little is known about the effects of FO and sex on insulin-like growth factor-1 (IGF-1), the main regulator of growth in childhood. We explored whether FO v. sunflower oil (SO) supplementation from 9 to 18 months of age affected IGF-1 and its binding protein-3 (IGFBP-3) and whether the potential effects were sex specific. Danish infants (n 115) were randomly allocated to 5 ml/d FO (1·2 g/d n-3 long-chain PUFA (n-3 LCPUFA)) or SO. We measured growth, IGF-1, IGFBP-3 and erythrocyte EPA, a biomarker of n-3 LCPUFA intake and status, at 9 and 18 months. Erythrocyte EPA increased strongly with FO compared with SO (P<0·001). There were no effects of FO compared with SO on IGF-1 in the total population, but a sex×group interaction (P=0·02). Baseline-adjusted IGF-1 at 18 months was 11·1 µg/l (95 % CI 0·4, 21·8; P=0·04) higher after FO compared with SO supplementation among boys only. The sex×group interaction was borderline significant in the model of IGFBP-3 (P=0·09), with lower IGFBP-3 with FO compared with SO among girls only (P=0·03). The results were supported by sex-specific dose-response associations between changes in erythrocyte EPA and changes in IGF-1 and IGFBP-3 (both P<0·03). Moreover, IGF-1 was sex specifically associated with BMI and length. In conclusion, FO compared with SO resulted in higher IGF-1 among boys and lower IGFBP-3 among girls. The potential long-term implications for growth and body composition should be investigated further.

BACKGROUND: Preterm infants show delayed development of motor function after birth. This may relate to functional immaturity of many organs, including the gut and brain. Using pigs as model for preterm infants, we hypothesized that early initiation of enteral feeding stimulates both gut growth and neonatal physical activity.METHODS: In experiment 1, preterm and term pigs were fed parenteral nutrition (PN) or PN plus bovine colostrum (BC, 16-64 ml/kg/d enterally) for 5 d. In experiment 2, preterm pigs were fed PN+BC or PN+formula for 5 d. In experiment 3, preterm pigs were fed BC, formula, or human milk (HM) for 10 d. Incubator home cage activity (HCA) was quantified by continuous camera recordings.RESULTS: Preterm birth was associated with reduced intestinal weight and HCA (experiment 1), and BC or formula supplementation increased intestinal weights and HCA (experiments 1+2). Enteral BC and HM feeding increased HCA, intestinal weights, and necrotizing enteritis resistance, relative to formula (experiment 3).CONCLUSION: Preterm pigs show decreased physical activity, and the first enteral feeds diet dependently stimulate both gut growth and physical activity. The effects may arise from maturation of digestive, metabolic, and neurological functions, including gut serotonin production, by the first enteral feeds and milk bioactive factors.Pediatric Research (2015); doi:10.1038/pr.2015.73.

Long-chain n-3 fatty acids (n-3 LCPUFA) improve blood pressure (BP) and lipid profile in adults and improve insulin sensitivity in rodents. We have previously shown that n-3 LCPUFA reduces BP and plasma triacylglycerol (TAG) in infants. Few studies have found effects on glucose homeostasis in humans. We explored possible effect modification by FADS, PPARG2, and COX2 genotypes to support potential effects of n-3 LCPUFA on metabolic markers in infants. Danish infants (133) were randomly allocated to daily supplementation with a teaspoon (~5 mL/day) of fish oil (FO) or sunflower oil (SO) from 9 to 18 months of age. Before and after the intervention, we assessed BP, erythrocyte n-3 LCPUFA, plasma lipid profile, insulin, and glucose in addition to functional single nucleotide polymorphisms in FADS, PPARG2, and COX2. At 18 months, plasma TAG was lower in the FO compared with SO group (p = 0.014). This effect was modified by PPARG2-Pro12Ala, as TAG only decreased among heterozygotes. FO supplemented PPARG2 Pro12Ala heterozygotes also had decreased plasma glucose compared with the SO group (p = 0.043). The effect of FO on mean arterial BP at 18 months was gender dependent (p = 0.020) and reduced in boys only (p = 0.028). Diastolic BP was, however, lower among all FO supplemented homozygous COX2-T8473C variant allele carriers compared with the SO group (p = 0.001). In conclusion, our results confirm that FO supplementation in late infancy reduces TAG and BP and indicates that the effects are mediated via peroxisome proliferator-activated receptor-γ and cyclooxygenase-2. Furthermore, FO reduced plasma glucose only in PPARG2 heterozygotes.

PROBLEMSTILLING: Præmature spædbørn har en øget risiko for udviklingsproblemer, fx forsinket fysisk udvikling og nedsat kognition, sammenlignet med terminsfødte spædbørn. Formålet med dette studie er, at undersøge, om anvendelsen af præmature spædgrise kan efterligne problematikker relateret til præmaturitet, og derved bidrage til at give en bedre forståelse af udviklingen af de basalmotoriske funktioner, indlæring og hukommelse i præmature spædbørn. METODE: Syv kuld (n=116 grise) blev forløst ved kejsersnit over en periode på seks måneder; 105 præmature (gestations alder (GA) 106 dage) og 56 terminsfødte (GA 118 dage) grise, blev fordelt på to grupper i forbindelse med forskellige fodringsregimer de første 5 dage efter fødslen: total parenteral ernæring (TPE) og parenteral ernæring med minimal enteral ernæring (MEE); pattegrisene blev aflivet på dag 1 (n=41), 5 (n=59) og 26 (n=39) efter fødslen. Gennem de første 5 dage efter fødslen blev tiden for de basalmotoriske funktioner registreret ved, hvornår grisene stod, gik og åbnede øjnene for første gang; ligeledes i sammenhæng med de basalmotoriske funktioner, blev grisene filmet i en open field på dag 4, 9, 16 og 23 efter fødslen for at undersøge udviklingen i balance og koordinaion. Yderligere fik grise, som levede til dag 26, undersøgt deres indlæringsevne samt hukommelse ved først konditionering af associationen for "klik" med en belønning i deres bure i 12 +/- 5 dage og efterfølgende ved test i sessioner af 5 minutter i et specialdesignet testbur i op til 8 gange. RESULTATER: Præmature grise havde en forsinkelse på op til 60 timer til at stå, gå og åbne øjnene for første gang i forhold til de terminsfødte grise. Terminsfødte grise havde signifikant bedre balance og koordination gennem hele perioden, når de blev sammenlignet med de præmature grise. Det var ikke muligt at vise en forskel mellem MEE og TPE grise på de kortsigtede endpoints, men MEE grisene havde en bedre balance og koordinering på dag 9 og 1, PROBLEM: Preterm Infants have an increased risk of neurodevelopmental problems such as delays in physical development and cognitive deficits when compared with term infants. The aim of this study was to investigate the suitablility of using the preterm piglet ot mimic sequelae associated with preterm birth, and in this way contribute with a better understanding of the development in basic motor function, learning and memory in preterm infants. METHOD: Seven litters (n=116 piglets) were delivered by caesarean section throughout a period of six months; 105 premature (gestational age (GA) 106 days) and 56 mature (GA 118 days) piglets were divided into two groups according to feeding regimes the first five days: total parenteral nutrition (TPN) and parenteral nutrition with minimal enteral nutrition (MEN); piglets were sacrificed at postnatal day 1 (n=41), 5 (n=59) or 26 (n=39). During the 5 first postnatal days, basic motor skill functions were recorded of the piglets' time to first stand, time to first walk and time to first eye lid opening; also, in the context of basic motor function, piglets were recorded in an open field on postnatal day 4, 9, 16 and 23 for the assessment of balance and coordination. To assess learning capacity and memory, piglets that lived until postnatal day 26 were condicitioned to associate a click with a reward in their home cages for 12 +/- 5 days and subsequently tested in sessions of five minutes in a specially designed test cage for up to eight trials. RESULTS: Preterm piglets had up to 60 hours delay in, time to first stand, first walk and time to open eyes when compared with term piglets. Term piglets had a significnatly better balance and coordination throughout the period when compared with preterm piglets. It was not possible to show a difference between the nutritional intervention groups at short-term endpoints, but MEN piglets had better balance and coordination at postnatal day 9 and 16 than TPN piglets. CONC

Long-chain n-3 PUFA (LCPUFA) and palmitate (16:0) positioning in the triacylglycerol (TAG) of infant formula may affect calcium-uptake which could affect bone health. We investigated if a human milk fat substitute (HMFS) with a modified TAG structure holding 16:0 predominantly in the sn-2-position compared with a control (CONT) and if increasing n-3LCPUFA intake giving fish oil (FO) compared with sunflower oil (SO) would affect bone parameters in piglets in two sets of controlled 14d-interventions (n=12/group). We assessed this by dual-energy x-ray absorptiometry, and ex vivo peripheral quantitative computed tomography and mechanical strength. Bone mineral content (BMC) was higher in the FO compared to the SO-group (p=0.03). Despite similar weight gain in HMFS- and CONT-groups, body fat accumulation was higher with HMFS (p

Background Obesity induced by a high-caloric diet has previously been associated with changes in the gut microbiota in mice and in humans. In this study, pigs were cloned to minimize genetic and biological variation among the animals with the aim of developing a controlled metabolomic model suitable for a diet-intervention study. Cloning of pigs may be an attractive way to reduce genetic influences when investigating the effect of diet and obesity on different physiological sites. The aim of this study was to assess and compare the changes in the composition of the gut microbiota of cloned vs. non-cloned pigs during development of obesity by a high-fat/high-caloric diet. Furthermore, we investigated the association between diet-induced obesity and the relative abundance of the phyla Firmicutes and Bacteroidetes in the fecal-microbiota. The fecal microbiota from obese cloned (n = 5) and non-cloned control pigs (n= 6) was investigated biweekly over a period of 136 days, by terminal restriction fragment length polymorphism (T-RFLP) and quantitative real time PCR (qPCR). Results A positive correlation was observed between body-weight at endpoint and percent body-fat in cloned (r=0.9, P<0.0001) and in non-cloned control pigs (r=0.9, P<0.0001). Shannon Weaver and principal component analysis (PCA) of the terminal restriction fragments (T-RFs) revealed no differences in the bacterial composition or variability of the fecal microbiota between the cloned pigs or between cloned and non-cloned control pigs. Body-weight correlated positively with the relative abundance of Firmicutes in both cloned (r=0.37; P<0.02) and non cloned-control pigs (r=0.45; P<0.006), and negatively with the abundance of Bacteroidetes in cloned pigs (r=-0.33, P<0.04), but not in the non-cloned control pigs. Conclusion The cloned pigs did not have reduced inter-individual variation as compared to non-cloned pigs in regard to their gut microbiota in neither th