Systemic proteome adaptions to 7-day complete caloric restriction in humans.

Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for religious purposes, used to treat diseases such as epilepsy, and recently gained popularity as weight loss intervention, but we still have a very limited understanding of the systemic adaptions in humans to extreme caloric restriction of different durations. Here we show that a 7-day water-only fast leads to an average weight loss of 5.7 kg (±0.8 kg) among 12 volunteers (5 women, 7 men). We demonstrate nine distinct proteomic response profiles, with systemic changes evident only after 3 days of complete calorie restriction based on in-depth characterization of the temporal trajectories of ~3,000 plasma proteins measured before, daily during, and after fasting. The multi-organ response to complete caloric restriction shows distinct effects of fasting duration and weight loss and is remarkably conserved across volunteers with >1,000 significantly responding proteins. The fasting signature is strongly enriched for extracellular matrix proteins from various body sites, demonstrating profound non-metabolic adaptions, including extreme changes in the brain-specific extracellular matrix protein tenascin-R. Using proteogenomic approaches, we estimate the health consequences for 212 proteins that change during fasting across ~500 outcomes and identified putative beneficial (SWAP70 and rheumatoid arthritis or HYOU1 and heart disease), as well as adverse effects. Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation.

The Effect of Alginate Encapsulated Plant-Based Carbohydrate and Protein Supplementation on Recovery and Subsequent Performance in Athletes.

The main purpose of this study was to investigate the effect of a novel alginate-encapsulated carbohydrate-protein (CHO-PRO ratio 2:1) supplement (ALG) on cycling performance. The ALG, designed to control the release of nutrients, was compared to an isocaloric carbohydrate-only control (CON). Alginate encapsulation of CHOs has the potential to reduce the risk of carious lesions. METHODS: In a randomised cross-over clinical trial, 14 men completed a preliminary test over 2 experimental days separated by ~6 days. An experimental day consisted of an exercise bout (EX1) of cycling until exhaustion at W~73%, followed by 5 h of recovery and a subsequent time-to-exhaustion (TTE) performance test at W~65%. Subjects ingested either ALG (0.8 g CHO/kg/hr + 0.4 g PRO/kg/hr) or CON (1.2 g CHO/kg/hr) during the first 2 h of recovery. RESULTS: Participants cycled on average 75.2 ± 5.9 min during EX1. Levels of plasma branched-chain amino acids decreased significantly after EX1, and increased significantly with the intake of ALG during the recovery period. During recovery, a significantly higher plasma insulin and glucose response was observed after intake of CON compared to ALG. Intake of ALG increased plasma glucagon, free fatty acids, and glycerol significantly. No differences were found in the TTE between the supplements (p = 0.13) nor in the pH of the subjects' saliva. CONCLUSIONS: During the ALG supplement, plasma amino acids remained elevated during the recovery. Despite the 1/3 less CHO intake with ALG compared to CON, the TTE performance was similar after intake of either supplement.

Introducing FRED: Software for Generating Feedback Reports for Ecological Momentary Assessment Data.

Ecological Momentary Assessment (EMA) is a data collection approach utilizing smartphone applications or wearable devices to gather insights into daily life. EMA has advantages over traditional surveys, such as increasing ecological validity. However, especially prolonged data collection can burden participants by disrupting their everyday activities. Consequently, EMA studies can have comparably high rates of missing data and face problems of compliance. Giving participants access to their data via accessible feedback reports, as seen in citizen science initiatives, may increase participant motivation. Existing frameworks to generate such reports focus on single individuals in clinical settings and do not scale well to large datasets. Here, we introduce FRED (Feedback Reports on EMA Data) to tackle the challenge of providing personalized reports to many participants. FRED is an interactive online tool in which participants can explore their own personalized data reports. We showcase FRED using data from the WARN-D study, where 867 participants were queried for 85 consecutive days with four daily and one weekly survey, resulting in up to 352 observations per participant. FRED includes descriptive statistics, time-series visualizations, and network analyses on selected EMA variables. Participants can access the reports online as part of a Shiny app, developed via the R programming language. We make the code and infrastructure of FRED available in the hope that it will be useful for both research and clinical settings, given that it can be flexibly adapted to the needs of other projects with the goal of generating personalized data reports.

Impact of Pandemic SARS COVID-19 on Different Construction Project Management: Problems and Solutions.

This study discusses risk management strategies caused by pandemic-related (Covid-19) suspensions in thirty-six engineering projects of different types and sizes selected from countries in the middle east and especially Iraq. The primary data collection method was a survey and questionnaire completed by selected project crew and laborers. Data were processed using Microsoft Excel to construct models to help decision-makers find solutions to the scheduling problems that may be expected to occur during a pandemic. A theoretical and practical concept for project risk management that addresses a range of global and local issues that affect schedule and cost is presented and results indicate that the most significant delays are due to a lack of good project risk management skills and remote project management capability which is exacerbated by shortfalls in technical development and information technology.

Similar performance after intake of carbohydrate plus whey protein and carbohydrate only in the early phase after non-exhaustive cycling.

AIM: The aim of the present study was to compare performance 5 h after a 90-min endurance training session when either carbohydrate only or carbohydrate with added whey hydrolysate or whey isolate was ingested during the first 2 h of the recovery period. METHODS: Thirteen highly trained competitive male cyclists completed three exercise and diet interventions (double-blinded, randomized, crossover design) separated by 1 week. The 90-min morning session (EX1) included a 60 min time-trial (TT60 ). Immediately and 1 h after exercise, participants ingested either (1) 1.2 g carbohydrate∙kg-1 ∙h-1 (CHO), (2) 0.8 g carbohydrate∙kg-1 ∙h-1 + 0.4 g isolate whey protein∙kg-1 ∙h-1 (ISO) or (3) 0.8 g carbohydrate∙kg-1 ∙h-1 + 0.4 g hydrolysate whey protein∙kg-1 ∙h-1 (HYD). Additional intakes were identical between interventions. After 5 h of recovery, participants completed a time-trial performance (TTP ) during which a specific amount of work was performed. Blood and urine were collected throughout the day. RESULTS: TTP did not differ significantly between dietary interventions (CHO: 43:54 ± 1:36, ISO: 46:55 ± 2:32, HYD: 44:31 ± 2:01 min). Nitrogen balance during CHO was lower than ISO (p < 0.0001) and HYD (p < 0.0001), with no difference between ISO and HYD (p = 0.317). In recovery, the area under the curve for blood glucose was higher in CHO compared to ISO and HYD. HR, VO2 , RER, glucose, and lactate during EX2 were similar between interventions. CONCLUSION: Performance did not differ after 5 h of recovery whether carbohydrate only or isocaloric carbohydrate plus protein was ingested during the first 2 h. Correspondingly, participants were not in negative nitrogen balance in any dietary intervention.

Reduction in omission events after implementing a Rapid Response System: a mortality review in a department of gastrointestinal surgery.

BACKGROUND: Hospitals worldwide have implemented Rapid Response Systems (RRS) to facilitate early recognition and prompt response by trained personnel to deteriorating patients. A key concept of this system is that it should prevent 'events of omission', including failure to monitor patients' vital signs, delayed detection, and treatment of deterioration and delayed transfer to an intensive care unit. Time matters when a patient deteriorates, and several in-hospital challenges may prevent the RRS from functioning adequately. Therefore, we must understand and address barriers for timely and adequate responses in cases of patient deterioration. Thus, this study aimed to investigate whether implementing (2012) and developing (2016) an RRS was associated with an overall temporal improvement and to identify needs for further improvement by studying; patient monitoring, omission event occurrences, documentation of limitation of medical treatment, unexpected death, and in-hospital- and 30-day mortality rates. METHODS: We performed an interprofessional mortality review to study the trajectory of the last hospital stay of patients dying in the study wards in three time periods (P1, P2, P3) from 2010 to 2019. We used non-parametric tests to test for differences between the periods. We also studied overall temporal trends in in-hospital- and 30-day mortality rates. RESULTS: Fewer patients experienced omission events (P1: 40%, P2: 20%, P3: 11%, P = 0.01). The number of documented complete vital sign sets, median (Q1,Q3) P1: 0 (0,0), P2: 2 (1,2), P3: 4 (3,5), P = 0.01) and intensive care consultations in the wards ( P1: 12%, P2: 30%, P3: 33%, P = 0.007) increased. Limitations of medical treatment were documented earlier (median days from admission were P1: 8, P2: 8, P3: 3, P = 0.01). In-hospital and 30-day mortality rates decreased during this decade (rate ratios 0.95 (95% CI: 0.92-0.98) and 0.97 (95% CI: 0.95-0.99)). CONCLUSION: The RRS implementation and development during the last decade was associated with reduced omission events, earlier documentation of limitation of medical treatments, and a temporal reduction in the in-hospital- and 30-day mortality rates in the study wards. The mortality review is a suitable method to evaluate an RRS and provide a foundation for further improvement. TRIAL REGISTRATION: Retrospectively registered.

Large Interferometer for Exoplanets: VIII. Where Is the Phosphine? Observing Exoplanetary PH3 with a Space-Based Mid-Infrared Nulling Interferometer.

Phosphine could be a key molecule in the understanding of exotic chemistry that occurs in (exo)planetary atmospheres. While phosphine has been detected in the Solar System's giant planets, it has not been observed in exoplanets to date. In the exoplanetary context, however, it has been theorized to be a potential biosignature molecule. The goal of our study was to identify which illustrative science cases for PH3 chemistry are observable with a space-based mid-infrared nulling interferometric observatory like the Large Interferometer for Exoplanets (LIFE) concept. We identified a representative set of scenarios for PH3 detections in exoplanetary atmospheres that vary over the whole dynamic range of the LIFE mission. We used chemical kinetics and radiative transfer calculations to produce forward models of these informative, prototypical observational cases for LIFEsim, our observation simulator software for LIFE. In a detailed, yet first order approximation, it takes a mission like LIFE: (i) about 1 h to find phosphine in a warm giant around a G star at 10 pc, (ii) about 10 h in H2 or CO2 dominated temperate super-Earths around M star hosts at 5 pc, (iii) and even in 100 h it seems very unlikely that phosphine would be detectable in a Venus-Twin with extreme PH3 concentrations at 5 pc. Phosphine in concentrations previously discussed in the literature is detectable in 2 out of the 3 cases, and it is detected about an order of magnitude faster than in comparable cases with James Webb Space Telescope. We show that there is a significant number of objects accessible for these classes of observations. These results will be used to prioritize the parameter range for the next steps with more detailed retrieval simulations. They will also inform timely questions in the early design phase of a mission like LIFE and guide the community by providing easy-to-scale first estimates for a large part of detection space of such a mission.

Risk and survival in colorectal cancer with increasing body mass index: A nationwide population-based cohort study.

AIM: The aim was to explore potential associations between the body mass index (BMI) and the risk of colorectal cancer (CRC), including subsites of the colon, and cancer-specific death. METHODS: A registry-based cohort study was conducted with baseline data gathered from the Norwegian Tuberculosis Screening Programme, collected between 1963 and 1975, and linked to follow-up data from the Cancer Registry of Norway and the Norwegian Cause of Death Registry. Cox regression models were used to explore associations between BMI and CRC risk and cancer-specific death. RESULTS: Of 1 723 692 included individuals, 76 616 developed CRC during 55 370 707 person-years of follow-up. In men, a 5 kg/m2 increase in BMI was associated with an increased risk of colon cancer, including both right and left subsites, and rectal cancer. Allowing for nonlinearities, we found a U-shaped association for the right colon and an inverse U-shape for the left colon and rectum cancer. In women, a 5 kg/m2 increase in BMI in early adulthood was associated with increased risk of colon cancer, including both subsites. In women, an increased risk of CRC death with increasing BMI was found for colon cancer. CONCLUSIONS: Men of all ages have an increased risk of CRC with increasing BMI, with the highest risk for right-sided colon cancer. An increased risk for colon cancer was also found in women with high BMI in early adulthood. Furthermore, women of all age groups appeared to have an increased risk of CRC death with higher BMI.

Body mass index and pancreatic adenocarcinoma: A nationwide registry-based cohort study.

BACKGROUND AND OBJECTIVE: An association between body mass index (BMI) and pancreatic cancer is suggested in observational studies. However, further studies are required to substantiate available evidence. The aim of this study was to explore the association between BMI and pancreatic ductal adenocarcinoma (PDAC) risk, treatment, and mortality. METHODS: A registry-based cohort study was performed by combining data from four registries in Norway. Baseline data were collected between 1963 and 1975 with follow-up data collected until 2018. Kaplan-Meier curves and multivariable Cox regressions were estimated. Chi-square tests were used to analyze differences between groups. RESULTS: The study cohort consisted of 1,723,692 individuals. A total of 8973 PDAC cases were identified during 55,744,749 person-years of follow-up. A 5 kg/m2 increase in BMI was associated with an increased risk of PDAC if high BMI at young age (16-29 years) (hazard ratio (HR): 1.21, 95% confidence interval (CI): 1.13-1.31), both for men (HR: 1.30, 95% CI: 1.15-1.46) and women (HR: 1.16, 95% CI: 1.05-1.28). In men, there was a 52% increase in risk of early-onset PDAC (

Endogenous glutamine is rate-limiting for anti-CD3 and anti-CD28 induced CD4+ T-cell proliferation and glycolytic activity under hypoxia and normoxia.

To meet the demand for energy and biomass, T lymphocytes (T cells) activated to proliferation and clonal expansion, require uptake and metabolism of glucose (Gluc) and the amino acid (AA) glutamine (Gln). Whereas exogenous Gln is converted to glutamate (Glu) by glutaminase (GLS), Gln is also synthesized from the endogenous pool of AA through Glu and activity of glutamine synthase (GS). Most of this knowledge comes from studies on cell cultures under ambient oxygen conditions (normoxia, 21% O2). However, in vivo, antigen induced T-cell activation often occurs under moderately hypoxic (1-4% O2) conditions and at various levels of exogenous nutrients. Here, CD4+ T cells were stimulated for 72 h with antibodies targeting the CD3 and CD28 markers at normoxia and hypoxia (1% O2). This was done in the presence and absence of the GLS and GS inhibitors, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and methionine sulfoximine (MSO) and at various combinations of exogenous Gluc, Gln and pyruvate (Pyr) for the last 12 h of stimulation. We found that T-cell proliferation, viability and levels of endogenous AA were significantly influenced by the availability of exogenous Gln, Gluc and Pyr as well as inhibition of GLS and GS. Moreover, inhibition of GLS and GS and levels of oxygen differentially influenced oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Finally, BPTES-dependent down-regulation of ECAR was associated with reduced hexokinase (HK) activity at both normoxia and hypoxia. Our results demonstrate that Gln availability and metabolism is rate-limiting for CD4+ T-cell activity.

Proteome Analysis of Pancreatic Tumors Implicates Extracellular Matrix in Patient Outcome.

Pancreatic cancer remains a disease with unmet clinical needs and inadequate diagnostic, prognostic, and predictive biomarkers. In-depth characterization of the disease proteome is limited. This study thus aims to define and describe protein networks underlying pancreatic cancer and identify protein centric subtypes with clinical relevance. Mass spectrometry-based proteomics was used to identify and quantify the proteome in tumor tissue, tumor-adjacent tissue, and patient-derived xenografts (PDX)-derived cell lines from patients with pancreatic cancer, and tissues from patients with chronic pancreatitis. We identified, quantified, and characterized 11,634 proteins from 72 pancreatic tissue samples. Network focused analysis of the proteomics data led to identification of a tumor epithelium-specific module and an extracellular matrix (ECM)-associated module that discriminated pancreatic tumor tissue from both tumor adjacent tissue and pancreatitis tissue. On the basis of the ECM module, we defined an ECM-high and an ECM-low subgroup, where the ECM-high subgroup was associated with poor prognosis (median survival months: 15.3 vs. 22.9 months; log-rank test, P = 0.02). The ECM-high tumors were characterized by elevated epithelial-mesenchymal transition and glycolytic activities, and low oxidative phosphorylation, E2F, and DNA repair pathway activities. This study offers novel insights into the protein network underlying pancreatic cancer opening up for proteome precision medicine development. Significance: Pancreatic cancer lacks reliable biomarkers for prognostication and treatment of patients. We analyzed the proteome of pancreatic tumors, nonmalignant tissues of the pancreas and PDX-derived cell lines, and identified proteins that discriminate between patients with good and poor survival. The proteomics data also unraveled potential novel drug targets.

cAMP-Mediated Autophagy Promotes Cell Survival via ROS-Induced Activation of PARP1: Implications for Treatment of Acute Lymphoblastic Leukemia.

DNA-damaging therapy is the basis for treatment of most cancers, including B-cell precursor acute lymphoblastic leukemia (BCP-ALL, hereafter ALL). We have previously shown that cAMP-activating factors present in the bone marrow render ALL cells less sensitive to DNA damage-induced apoptosis, by enhancing autophagy and suppressing p53. To sensitize ALL cells to DNA-damaging therapy, we have searched for novel targets that may counteract the effects induced by cAMP signaling. In the current study, we have identified PARP1 as a potential target. We show that the PARP1 inhibitors olaparib or PJ34 inhibit cAMP-mediated autophagy and thereby potentiate the DNA-damaging treatment. Furthermore, we reveal that cAMP-mediated PARP1 activation is preceded by induction of reactive oxygen species (ROS) and results in depletion of nicotinamide adenine dinucleotide (NAD), both of which are autophagy-promoting events. Accordingly, we demonstrate that scavenging ROS by N-acetylcysteine and repleting NAD independently reduce DNA damage-induced autophagy. In addition, olaparib augmented the effect of DNA-damaging treatment in a human xenograft model of ALL in NOD-scidIL2Rgammanull mice. On the basis of the current findings, we suggest that PARP1 inhibitors may enhance the efficiency of conventional genotoxic therapies and thereby provide a novel treatment strategy for pediatric patients with ALL. IMPLICATIONS: PARP1 inhibitors augment the DNA damage-induced killing of ALL cells by limiting the opposing effects of cAMP-mediated autophagy, which involves ROS-induced PARP1 activation and depletion of cellular NAD levels.

Diagnostic accuracy of routine liver function tests to identify patients with significant and advanced alcohol-related liver fibrosis.

AIMS: Alcohol is the leading cause of cirrhosis, but most patients go undetected until decompensation occurs despite frequent contacts with the healthcare system. We aimed to evaluate the diagnostic accuracy of routine liver function tests compared with indirect and direct fibrosis markers and to assess doctors' abilities to diagnose significant and advanced alcohol-related liver fibrosis. METHODS: This study was a retrospective evaluation of liver function tests for diagnosing alcohol-related liver disease compared to indirect fibrosis tests, the ELF test, and transient elastography. We also surveyed nine doctors who were presented with 225 patient cases from a cross-sectional, biopsy-controlled, single-centre study that evaluated diagnostic tools for alcohol-related liver fibrosis. The doctors assessed each case for significant (≥F2) or advanced (≥F3) fibrosis. We assessed inter-rater variability with Fleiss' kappa. RESULTS: Routine liver function tests had poor diagnostic accuracy (highest area under the ROC curve for platelet count = 0.752) and poor sensitivities (10%-67%) when using the upper or lower normal limits as cut-offs. Indirect fibrosis indices performed significantly better but were still inferior to the ELF test and transient elastography. The nine doctors disagreed substantially in their predictions, with Fleiss' kappa of 0.24 (95% CI0.22-0.26) and 0.51 (0.44-0.55) for significant and advanced fibrosis. All nine doctors exhibited poor case-finding abilities with sensitivities of 22-93%. CONCLUSIONS: When using routine liver function tests, doctors may fail to diagnose more than half of all alcohol-overusing patients with advanced fibrosis, probably because they rely on upper and lower normal limits of routine liver function tests.

PRO-C3 and ADAPT algorithm accurately identify patients with advanced fibrosis due to alcohol-related liver disease.

BACKGROUND: Alcohol is a main cause of preventable deaths and frequently leads to the development of alcohol-related liver disease. Due to the lack of diagnostics, patients are commonly diagnosed after developing clinical manifestations. Recently, the biomarker PRO-C3 was shown to accurately identify fibrosis due to non-alcoholic fatty liver disease. AIM: To assess the diagnostic accuracy of PRO-C3, the ADAPT score and best-performing non-patented serological test to detect advanced alcohol-related liver fibrosis. METHODS: We enrolled 426 patients with alcohol overuse in a prospective biopsy-controlled study. We evaluated the accuracy of PRO-C3 and the PRO-C3-based algorithm ADAPT to detect advanced liver fibrosis. RESULTS: The accuracy of PRO-C3 was good with an AUROC of 0.85 (95% CI 0.79-0.90). The best-performing non-patented test was the Forns index with an AUROC of 0.83 (95% CI 0.78-0.89). The ADAPT algorithm performed better as compared to both the Forns index and PRO-C3 alone with an AUROC = 0.88 (95% CI 0.83-0.93). CONCLUSION: PRO-C3 is a new marker with high accuracy to detect advanced alcohol-related liver fibrosis. The diagnostic accuracy of PRO-C3 can be further improved by using the ADAPT algorithm in which the test outperforms currently available non-patented serological fibrosis markers. The study is registered in the Odense Patient Data Exploratory Network (OPEN) under study identification numbers OP_040 (https://open.rsyd.dk/OpenProjects/da/openProject.jsp?openNo=40) and OP_239 (https://open.rsyd.dk/OpenProjects/openProject.jsp?openNo=239&lang=da).

PKA Cß: a forgotten catalytic subunit of cAMP-dependent protein kinase opens new windows for PKA signaling and disease pathologies.

3',5'-cyclic adenosine monophosphate (cAMP) dependent protein kinase or protein kinase A (PKA) has served as a prototype for the large family of protein kinases that are crucially important for signal transduction in eukaryotic cells. The PKA catalytic subunits are encoded by the two major genes PRKACA and PRKACB, respectively. The PRKACA gene encodes two known splice variants, the ubiquitously expressed Cα1 and the sperm-specifically expressed Cα2. In contrast, the PRKACB gene encodes several splice variants expressed in a highly cell and tissue-specific manner. The Cß proteins are called Cß1, Cß2, Cß3, Cß4 and so-called abc variants of Cß3 and Cß4. Whereas Cß1 is ubiquitously expressed, Cß2 is enriched in immune cells and the Cß3, Cß4 and their abc variants are solely expressed in neuronal cells. All Cα and Cß splice variants share a kinase-conserved catalytic core and a C-terminal tail encoded by exons 2 through 10 in the PRKACA and PRKACB genes, respectively. All Cα and Cß splice variants with the exception of Cα1 and Cß1 are hyper-variable at the N-terminus. Here, we will discuss how the PRKACA and PRKACB genes have developed as paralogs that encode distinct and functionally non-redundant proteins. The fact that Cα and Cß splice variant mutations are associated with numerous diseases further opens new windows for PKA-induced disease pathologies.

Cellular metabolism dictates T cell effector function in health and disease.

In a healthy person, metabolically quiescent T lymphocytes (T cells) circulate between lymph nodes and peripheral tissues in search of antigens. Upon infection, some T cells will encounter cognate antigens followed by proliferation and clonal expansion in a context-dependent manner, to become effector T cells. These events are accompanied by changes in cellular metabolism, known as metabolic reprogramming. The magnitude and variation of metabolic reprogramming are, in addition to antigens, dependent on factors such as nutrients and oxygen to ensure host survival during various diseases. Herein, we describe how metabolic programmes define T cell subset identity and effector functions. In addition, we will discuss how metabolic programs can be modulated and affect T cell activity in health and disease using cancer and autoimmunity as examples.

Prediction of liver fibrosis severity in alcoholic liver disease by human microfibrillar-associated protein 4.

BACKGROUND: Alcoholic liver disease (ALD) is a public health concern that is the cause of half of all cirrhosis-related deaths. Early detection of fibrosis, ideally in the precirrhotic stage, is a key strategy for improving ALD outcomes and for preventing progression to cirrhosis. Previous studies identified the blood-borne marker human microfibrillar-associated protein 4 (MFAP4) as a biomarker for detection of hepatitis C virus (HCV)-related fibrosis. AIM: To evaluate the diagnostic accuracy of MFAP4 to detect ALD-induced fibrosis. METHOD: We performed a prospective, liver biopsy-controlled study involving 266 patients with prior or current alcohol overuse. Patients were split into a training and a validation cohort. RESULTS: MFAP4 was present in fibrotic hepatic tissue and serum MFAP4 levels increased with fibrosis grade. The area under the receiver operating characteristic curve (AUROC) for detection of cirrhosis was 0.91 (95% CI 0.85-0.96) in the training cohort and 0.91 (95% CI 0.79-1.00) in the validation cohort. For detection of advanced fibrosis, the AUROC was 0.88 (95% CI 0.81-0.94) in the training cohort and 0.92 (95% CI 0.83-1.00) in the validation cohort. The diagnostic accuracy did not differ between MFAP4 and the enhanced liver fibrosis (ELF) test or transient elastography (TE) in an intention-to-diagnose analysis. MFAP4 did not predict hepatic decompensation in a time-to-decompensation analysis in a subgroup of patients with cirrhosis. CONCLUSION: MFAP4 is a novel biomarker that can detect ALD-related fibrosis with high accuracy.

Bleeding signs due to acquired von Willebrand syndrome at diagnosis of chronic myeloid leukaemia in children.

A considerable proportion of patients with chronic myeloid leukaemia (CML) may present at diagnosis with high platelet counts. This may result in thrombosis or bleeding complications due to binding of von Willebrand factor (VWF) multimers to platelets. Paediatric CML is very rare and no systematic investigation on clinical complications of elevated platelets has been reported. Data on platelet count and associated haemostaseological complications were retrospectively analysed in a cohort of 156 children with CML. Fifty-one percent (81/156) patients presented with thrombocytosis (platelet count> 500 × 109 /l), and were extreme (>1 000 × 109 /l) in 23/156 (16%). There were no cases of thrombosis but mild bleeding signs were present in 12% (n = 9) children with thrombocytosis. Bleeding occurred without correlation to elevated platelet counts and was associated with reduced large VWF multimers, indicating a diagnosis of acquired von Willebrand syndrome (AVWS), which resolved after initiation of CML treatment. Patients with paediatric CML frequently exhibit high platelet counts not resulting in thrombosis. In patients with thrombocytosis mild bleeding signs due to a low percentage of large VWF multimers can be demonstrated. AVWS may be underdiagnosed in paediatric CML (Clinical-Trials.gov NCT00445822, 9 March 2007).

Protein intake in the early recovery period after exhaustive exercise improves performance the following day.

The aim of the present study was to investigate the effect of protein and carbohydrate ingestion during early recovery from exhaustive exercise on performance after 18-h recovery. Eight elite cyclists (V̇o2max: 74.0 ± 1.6 ml·kg-1·min-1) completed two exercise and diet interventions in a double-blinded, randomized, crossover design. Participants cycled first at 73% of V̇o2max (W73%) followed by 1-min intervals at 90% of V̇o2max until exhaustion. During the first 2 h of recovery, participants ingested either 1.2 g carbohydrate·kg-1·h-1 (CHO) or 0.8 g carbohydrate + 0.4 g protein·kg-1·h-1 (CHO + PROT). The diet during the remaining recovery period was similar for both interventions and adjusted to body weight. After an 18-h recovery, cycling performance was assessed with a 10-s sprint test, 30 min of cycling at W73%, and a cycling time trial (TT). The TT was 8.5% faster (41:53 ± 1:51 vs. 45:26 ± 1:32 min; P < 0.03) after CHO + PROT compared with CHO. Mean power output during the sprints was 3.7% higher in CHO + PROT compared with CHO (1,063 ± 54 vs. 1,026 ± 53 W; P = 0.01). Nitrogen balance in the recovery period was negative in CHO and neutral in CHO + PROT (-82.4 ± 11.5 vs. 7.0 ± 15.4 mg/kg; P < 0.01). In conclusion, TT and sprint performances were improved 18 h after exhaustive cycling by CHO + PROT supplementation during the first 2 h of recovery compared with isoenergetic CHO supplementation. Our results indicate that intake of carbohydrate plus protein after exhaustive endurance exercise more rapidly converts the body from a catabolic to an anabolic state than carbohydrate alone, thus speeding recovery and improving subsequent cycling performance.NEW & NOTEWORTHY Prolonged high intensity endurance exercise depends on glycogen utilization and high oxidative capacity. Still, exhaustion develops and effective recovery strategies are required to compete in multiday stage races. We show that coingestion of protein and carbohydrate during the first 2 h of recovery is superior to isoenergetic intake of carbohydrate to stimulate recovery, and improves both endurance time-trial and 10-s sprint performance the following day in elite cyclists.