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Summary Precision nutrition based on metabolic phenotype may increase the effectiveness of interventions. In this proof-of-concept study, we investigated the effect of modulating dietary macronutrient composition according to muscle insulin-resistant (MIR) or liver insulin-resistant (LIR) phenotypes on cardiometabolic health. Women and men with MIR or LIR (n = 242, body mass index [BMI] 25–40 kg/m2, 40–75 years) were randomized to phenotype diet (PhenoDiet) group A or B and followed a 12-week high-monounsaturated fatty acid (HMUFA) diet or low-fat, high-protein, and high-fiber diet (LFHP) (PhenoDiet group A, MIR/HMUFA and LIR/LFHP; PhenoDiet group B, MIR/LFHP and LIR/HMUFA). PhenoDiet group B showed no significant improvements in the primary outcome disposition index, but greater improvements in insulin sensitivity, glucose homeostasis, serum triacylglycerol, and C-reactive protein compared with PhenoDiet group A were observed. We demonstrate that modulating macronutrient composition within the dietary guidelines based on tissue-specific insulin resistance (IR) phenotype enhances cardiometabolic health improvements. Clinicaltrials.gov registration: NCT03708419, CCMO registration NL63768.068.17.

ScopeWestern type of diets are characterized by high animal protein intake and are associated with various chronic inflammatory diseases. With a higher protein consumption, excess undigested protein will reach the colon and be subsequently metabolized by gut microbiota. Depending on the type of protein, fermentation in the colon generates different metabolites with varying biological effects. This study aims to compare the impact of protein fermentation products from different sources on gut health. Methods and resultsThree high protein diets (vital wheat gluten [VWG], lentil, or casein) are submitted to the in vitro model of colon. Fermentation of excess lentil protein for 72 h results in highest production of short-chain fatty acids and lowest production of branched-chain fatty acids. Exposure of Caco-2 monolayers or Caco-2 monolayers co-cultured with THP-1 macrophages to luminal extracts of fermented lentil protein results in less cytotoxicity of Caco-2 monolayers and less damage to barrier integrity, when compared to VWG and casein. Lowest induction of interleukin-6 is observed in THP-1 macrophages after treatment with lentil luminal extracts, which is identified to be regulated by aryl hydrocarbon receptor signaling. ConclusionThe findings indicate that protein sources affect the health effects of high protein diet in the gut.

For most elite athletes winning an Olympic gold medal is the ultimatedream. To make this dream come true, in the first place one needs sufficienttalent. However next to this talent, several years of training with largeamounts of strenuous work is necessary. It is therefore not remarkable thatthe time required for adequate recovery may easily be compromised.Doing so, an athlete is often challenging the optimal balance betweenexercise and recovery.The general purpose of this study was to get more understanding in thephysiological adaptation processes of highly trained elite enduranceathletes during periods of strenuous training.This thesis is divided into three parts. The first part (chapter 2, 3 and 4)describes the results of a three-year longitudinal study in professionalOlympic distance (OD) triathletes in preparation for Sydney 2000 Olympicgames. Chapter 2 gives a description of some measured performancerelated physiological- and anthropometric variables in OD triathletesduring the different phases of a year. Despite a clear difference in theamount of training between the several phases during the year, nosignificant differences were found between the measured performancerelated variables during submaximal and maximal exercise intensities.In spite of large amounts of training elite OD triathletes have still a lowermaximal oxygen uptake (VO2max) compared to elite distance runners andelite cyclists. Chapter 3 describes the changes in the hematological bloodprofile, as a result of endurance- and altitude training. As red blood cellsplay an important role in the transport of oxygen to the working muscles,it is important to get insight into the dynamics of the red blood profileand its possible changes in athletes, for instance with very intensivetraining and altitude training. Over a three-year period, in a group of elitemale and female OD triathletes' blood samples were collected duringseveral moments throughout the year. It was found that intensiveendurance training had not much influence on the red blood cell profile inmale and female OD triathletes. However, it was found that most of theathletes examined (female even more than male athletes), hadhematological values (particularly hemoglobin and ferritin) close to or insome cases below the lower limit of the normal range. Altitude trainingdid alter the red blood profile significantly only when altitude training wasperformed above 2000 meters above sea level. In chapter 4, the effects ofendurance training on the endocrine system throughout a year in ODtriathletes are described. Changes in hormonal plasma values are oftenmentioned as good indicators for the balance between training andrecovery. Despite the significant differences in the amount of trainingbetween the different phases of a competitive season, no significantchanges were found in the measured hormones throughout the year inelite male and female triathletes.In the second part (chapter 5 and 6) some exercise protocols that aregenerally used to evaluate training and performance are addressed. Inchapter 5 (cycling) and chapter 6 (running), the effect of stage durationon physiological variables in an incremental exercise test was studied.For measuring reliable lactate values during an incremental cyclingexercise tests a stage duration of at least 5 minutes has to be taken intoaccount. In a running protocol, the stage duration for obtaining bloodlactate values that match exercise intensity, should be at least 6 minutes.When measuring maximal values such as peak VO2, peak heart rates ormaximal workload incremental protocols with increments every minuteare sufficient.In the third part (chapter 7 to 9) training intervention studies are described.The purpose of these studies was to get more insight into the physiologicalchanges of the human body during periods of imbalance between trainingload and recovery. Chapter 7 describes the effects of a 50% reduction intraining load over a period of 21 days on some performance-relatedvariables. Many trainers and athletes are afraid to reduce the training asthey think this will cause a loss in performance. However, the resultsdescribed in this chapter show that this fear is not supported by evidence.Furthermore, it was found that an intermittent training program had nobenefit above a long slow distance training program. In chapter 8, theresults of a training intervention study (overreaching) are described.The main purpose of this study was to investigate whether the generallyaccepted overtraining markers are useful, and can be used as early markersfor overreaching. The main outcome of this study was that simple psychologicalquestionnaires appear to be a more indicative and sensitive markersfor detecting overreaching/overtraining in an early stage compared to themeasured biochemical- endocrinological- and physiological variables.Furthermore, it was found that overreaching is associated with earlychanges in cognitive performance, which can be detected by simplecognitive performance tests. In chapter 9, possible differences in bloodchemical, neuro-endocrine and psychological parameters in response to anintensified training period in runners and cyclists were investigated. Theresults of this study indicate that runners experienced a period ofstrenuous training as heavier compared to the cyclists. This difference ofsubjective feeling was not reflected in the measured blood chemical andneuro-endocrine variables.In conclusion, the most important findings in this thesis are:'' OD triathletes show hardly any variation in generally in sport measuredbiochemical-, hormonal-, or performance related variables.'' Regular control of the red blood profile is useful in well-trained enduranceathletes as many of these athletes have blood values close to or below thelower limit of the normal range'' The results of this study indicate that there exists an 'altitude threshold'above which hematological alterations occur.'' The endocrine system is (with the exception of cortisol) not a good toolto prevent overtraining.'' Cognitive performance tests appear to be useful to detect overreaching inits earliest stage.'' Endurance athletes are able to maintain their performance level for someweeks in spite of reducing the training volume.'' The subjective perception of very intense training is different betweencyclist and runners'' To ensure a reliable lactate level in incremental exercise tests, a stageduration of at least 5 minutes is required.

Background & aims: Carbohydrates (CHO) and leucine (LEU) both have insulinotropic properties, and could therefore enhance the protein anabolic capacity of dietary proteins, which are important nutrients in preventing muscle loss in patients with Chronic Obstructive Pulmonary Disease (COPD). LEU is also known to activate protein anabolic signaling pathways independent of insulin. Based on our previous findings in COPD, we hypothesized that whole body protein anabolism is enhanced to a comparable extent by the separate and combined co-ingestion of CHO and LEU with protein.Methods: To disentangle the protein anabolic effects of CHO and/or free LEU when co-ingested with a high-quality protein, we studied 10 patients with moderate to very severe COPD and dyspnea (GOLD: II-IV, mMRC dyspnea scale >= 2), at risk for muscle loss, and 10 healthy age- and gender-matched controls. On four occasions, in a single-blind randomized crossover design, each subject ingested a drink containing 0.6 g/kg fat-free mass (ffm) hydrolyzed casein protein with, a) no add-ons (protein), b) 0.3 g/kg ffm CHO (protein + CHO), c) 0.095 g/kg ffm leucine (protein + LEU), d) both add-ons (protein + CHO + LEU). Whole body protein breakdown (PB), protein synthesis (PS), and net protein balance (= PS - PB) were measured by IV primed and continuous infusion of L-[ring-H-2(5)]-phenylalanine and L-[C-13(9),N-15]-tyrosine. L-[N-15]-phenylalanine was added to the protein drinks to measure splanchnic extraction.Results: In both groups, whole body PS, PB and net protein balance responses were comparable between the four protein drinks, despite higher postprandial plasma LEU concentrations for the LEU supplemented drinks (P Conclusions: Adding CHO and/or LEU to a serving of high-quality protein does not further augment whole body protein anabolism in dyspneic COPD patients at risk for muscle loss or healthy older adults. Trial registry: ClinicalTrials.gov; No. NCT01734473; URL: www.clinicaltrials.gov. (C) 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Skeletal muscle plasticity is reflected by a dynamic balance between protein synthesis and breakdown, with basal muscle tissue protein synthesis rates ranging between 0.02 and 0.09%/h. Though it is evident that other musculoskeletal tissues should also express some level of plasticity, data on protein synthesis rates of most of these tissues in vivo in humans is limited. Six otherwise healthy patients (62±3 y), scheduled to undergo unilateral total knee arthroplasty, were subjected to primed continuous intravenous infusions with L-[ring-13C6]-Phenylalanine throughout the surgical procedure. Tissue samples obtained during surgery included muscle, tendon, cruciate ligaments, cartilage, bone, menisci, fat, and synovium. Tissue-specific fractional protein synthesis rates (%/h) were assessed by measuring the incorporation of L-[ring-13C6]-Phenylalanine in tissue protein and were compared with muscle tissue protein synthesis rates using a paired t test. Tendon, bone, cartilage, Hoffa's fat pad, anterior and posterior cruciate ligament, and menisci tissue protein synthesis rates averaged 0.06±0.01, 0.03±0.01, 0.04±0.01, 0.11±0.03, 0.07±0.02, 0.04±0.01, and 0.04±0.01%/h, respectively, and did not significantly differ from skeletal muscle protein synthesis rates (0.04±0.01%/h; P>0.05). Synovium derived protein (0.13±0.03%/h) and intercondylar notch bone tissue protein synthesis rates (0.03±0.01%/h) were respectively higher and lower compared to skeletal muscle protein synthesis rates (P

Background A small percentage of neonates with sacrococcygeal teratoma die shortly after birth from hemorrhagic complications. The incidence of and risk factors associated with hemorrhagic mortality are unknown. In this multicenter study we determined the incidence of early death in neonates born with SCT and evaluated potential risk factors for hemorrhagic mortality. Methods 235 children with SCT treated from 1970 to 2010 in the Netherlands were retrospectively included. The following candidate risk factors for hemorrhagic mortality were examined: sex, prematurity, Altman type, tumor volume, tumor histology, necessity of emergency operation and time of diagnosis. Results Eighteen patients (7.7%) died at a median age of 163.5days (range 1.7–973days). Nine patients died of a malignancy. Nine others (3.8%) died postnatally (age 1–27days), six even within two days after birth. In seven of these nine patients death was related to tumor–hemorrhage and/or circulatory failure. Risk factors for hemorrhagic mortality were prematurity, tumor volume>1000cm 3 and performance of an emergency operation. Conclusions Hemorrhagic mortality of neonates with SCT is relatively high (3.8%) representing almost 70% of the overall mortality in the neonatal period. High-output cardiac failure, internal tumor hemorrhage and perioperative bleeding were the most common causes of early death and were all strongly associated with larger tumor sizes. Level-of-evidence rating II (Retrospective study).

Karin JC Sanders,1 Juliette HRJ Degens,1 Anne-Marie C Dingemans,2 Annemie MWJ Schols1 1Department of Respiratory Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands; 2Department of Respiratory Medicine, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands Background: Computed tomography (CT) is increasingly used in clinical research for single-slice assessment of muscle mass to correlate with clinical outcome and evaluate treatment efficacy. The third lumbar level (L3) is considered as reference for muscle, but chest scans generally do not reach beyond the first lumbar level (L1). This study investigates if pectoralis muscle and L1 are appropriate alternatives for L3. Methods: CT scans of 115 stage IV non-small cell lung cancer patients were analyzed before and during tumor therapy. Skeletal muscle assessed at pectoralis and L1 muscle was compared to L3 at baseline. Furthermore, the prognostic significance of changes in muscle mass determined at different locations was investigated. Results: Pearson’s correlation coefficient between skeletal muscle at L3 and L1 was stronger (r=0.90, P

Background: Global DNA methylation has been reported to be associated with urothelial cell carcinoma (UCC) by studies using blood samples collected at diagnosis. Using the Illumina HumanMethylation450 assay, we derived genome-wide measures of blood DNA methylation and assessed them for their prospective association with UCC risk. Methods: We used 439 case–control pairs from the Melbourne Collaborative Cohort Study matched on age, sex, country of birth, DNA sample type, and collection period. Conditional logistic regression was used to compute odds ratios (OR) of UCC risk per s.d. of each genome-wide measure of DNA methylation and 95% confidence intervals (CIs), adjusted for potential confounders. We also investigated associations by disease subtype, sex, smoking, and time since blood collection. Results: The risk of superficial UCC was decreased for individuals with higher levels of our genome-wide DNA methylation measure (OR=0.71, 95% CI: 0.54–0.94; P=0.02). This association was particularly strong for current smokers at sample collection (OR=0.47, 95% CI: 0.27–0.83). Intermediate levels of our genome-wide measure were associated with decreased risk of invasive UCC. Some variation was observed between UCC subtypes and the location and regulatory function of the CpGs included in the genome-wide measures of methylation. Conclusions: Higher levels of our genome-wide DNA methylation measure were associated with decreased risk of superficial UCC and intermediate levels were associated with reduced risk of invasive disease. These findings require replication by other prospective studies.

Purpose: Outcomes of patients with an ARM-type rectovesical fistula are scarcely reported in medical literature. This study evaluates associated congenital anomalies and long-term colorectal and urological outcome in this group of ARM-patients.Methods: A retrospective Dutch cohort study on patients treated between 1983 and 2014 was performed. Associated congenital anomalies were documented, and colorectal and urological outcome recorded at five and ten years of follow-up.Results: Eighteen patients were included, with a mean follow-up of 10.8 years. Associated congenital anomalies were observed in 89% of the patients, 61% considered a VACTERL-association. Total sacral agenesis was present in 17% of our patients. At five and ten years follow-up voluntary bowel movements were described in 80% and 50%, constipation in 80% and 87%, and soiling in 42% and 63% of the patients, respectively. Bowel management was needed in 90% and one patient had a definitive colostomy. PSARP was the surgical reconstructive procedure in 83%. Urological outcome showed 14 patients (81%) to be continent. No kidney transplantations were needed.Conclusion: In our national cohort of ARM-patients type rectovesical fistula that included a significant proportion of patients with major sacral anomalies, the vast majority remained reliant on bowel management to be clean after ten years follow-up, despite "modern" PSARP-repair. Continence for urine is achieved in the majority of patients, and end-stage kidney failure is rare. (C) 2016 Elsevier Inc. All rights reserved.