BALDR: A Web-based platform for informed comparison and prioritization of biomarker candidates for type 2 diabetes mellitus.

Novel biomarkers are key to addressing the ongoing pandemic of type 2 diabetes mellitus. While new technologies have improved the potential of identifying such biomarkers, at the same time there is an increasing need for informed prioritization to ensure efficient downstream verification. We have built BALDR, an automated pipeline for biomarker comparison and prioritization in the context of diabetes. BALDR includes protein, gene, and disease data from major public repositories, text-mining data, and human and mouse experimental data from the IMI2 RHAPSODY consortium. These data are provided as easy-to-read figures and tables enabling direct comparison of up to 20 biomarker candidates for diabetes through the public website https://baldr.cpr.ku.dk.

The Impact of Antenatal Corticosteroids on the Metabolome of Preterm Newborns: An Untargeted Approach.

We analyzed and compared variations in the urinary metabolome, as well as postnatal clinical outcomes among preterm infants, based on the timing of antenatal corticosteroid (ACS) administration in response to preterm labor onset in their mothers. This was a prospective observational study held in the Neonatal Intensive Care Unit, Department of Woman's and Child's Health, Padova University Hospital (Italy). A urine sample was obtained from each patient within 24 h of birth; Mass Spectrometry-based untargeted metabolomics analysis was then conducted. We searched for any significant disparities in the metabolomic profile of preterm newborns subjected to antenatal corticosteroid (ACS) treatment at varying timings; their correlation with clinical outcomes were also evaluated. The group receiving ACS within the optimal time window (1-7 days before delivery) exhibited elevated levels of cysteine, N-acetylglutamine, propionyl carnitine and 5-hydroxyindolacetic acid, coupled with a decrease in pipecolic acid. Clinically, this group demonstrated a reduced need for invasive ventilation (p = 0.04). In conclusion, metabolomics analysis identified several metabolites that discriminated preterm infants whose mothers received ACS within the recommended time window. Elevated levels of cysteine and 5-Hydroxyindoleacetic acid, metabolites characterized by antioxidant and anti-inflammatory properties, were observed in these infants. This metabolic profile correlated with improved respiratory outcomes, as evidenced by a reduced necessity for invasive ventilation at birth.

A Multi-Omics Approach Reveals Enrichment in Metabolites Involved in the Regulation of the Glutathione Pathway in LIN28B-Dependent Cancer Cells.

The RNA-binding protein LIN28B, identified as an independent risk factor in high-risk neuroblastoma patients, is implicated in adverse treatment outcomes linked to metastasis and chemoresistance. Despite its clinical significance, the impact of LIN28B on neuroblastoma cell metabolism remains unexplored. This study employs a multi-omics approach, integrating transcriptome and metabolome data, to elucidate the global metabolic program associated with varying LIN28B expression levels over time. Our findings reveal that escalating LIN28B expression induces a significant metabolic rewiring in neuroblastoma cells. Specifically, LIN28B prompts a time-dependent increase in the release rate of metabolites related to the glutathione and aminoacyl-tRNA biosynthetic pathways, concomitant with a reduction in glucose uptake. These results underscore the pivotal role of LIN28B in governing neuroblastoma cell metabolism and suggest a potential disruption in the redox balance of LIN28B-bearing cells. This study offers valuable insights into the molecular mechanisms underlying LIN28B-associated adverse outcomes in neuroblastoma, paving the way for targeted therapeutic interventions.

Investigating the causal relationships between excess adiposity and cardiometabolic health in men and women.

AIMS/HYPOTHESIS: Excess adiposity is differentially associated with increased risk of cardiometabolic disease in men and women, according to observational studies. Causal inference studies largely assume a linear relationship between BMI and cardiometabolic outcomes, which may not be the case. In this study, we investigated the shapes of the causal relationships between BMI and cardiometabolic diseases and risk factors. We further investigated sex differences within the causal framework. METHODS: To assess causal relationships between BMI and the outcomes, we used two-stage least-squares Mendelian randomisation (MR), with a polygenic risk score for BMI as the instrumental variable. To elucidate the shapes of the causal relationships, we used a non-linear MR fractional polynomial method, and used piecewise MR to investigate threshold relationships and confirm the shapes. RESULTS: BMI was associated with type 2 diabetes (OR 3.10; 95% CI 2.73, 3.53), hypertension (OR 1.53; 95% CI 1.44, 1.62) and coronary artery disease (OR 1.20; 95% CI 1.08, 1.33), but not chronic kidney disease (OR 1.08; 95% CI 0.67, 1.72) or stroke (OR 1.08; 95% CI 0.92, 1.28). The data suggest that these relationships are non-linear. For cardiometabolic risk factors, BMI was positively associated with glucose, HbA1c, triacylglycerol levels and both systolic and diastolic BP. BMI had an inverse causal relationship with total cholesterol, LDL-cholesterol and HDL-cholesterol. The data suggest a non-linear causal relationship between BMI and BP and other biomarkers (p<0.001) except lipoprotein A. The piecewise MR results were consistent with the fractional polynomial results. The causal effect of BMI on coronary artery disease, total cholesterol and LDL-cholesterol was different in men and women, but this sex difference was only significant for LDL-cholesterol after controlling for multiple testing (p<0.001). Further, the causal effect of BMI on coronary artery disease varied by menopause status in women. CONCLUSIONS/INTERPRETATION: We describe the shapes of causal effects of BMI on cardiometabolic diseases and risk factors, and report sex differences in the causal effects of BMI on LDL-cholesterol. We found evidence of non-linearity in the causal effect of BMI on diseases and risk factor biomarkers. Reducing excess adiposity is highly beneficial for health, but there is greater need to consider biological sex in the management of adiposity.

Metabolomic profiling of intrauterine growth-restricted preterm infants: a matched case-control study.

BACKGROUND: The biochemical variations occurring in intrauterine growth restriction (IUGR), when a fetus is unable to achieve its genetically determined potential, are not fully understood. The aim of this study is to compare the urinary metabolomic profile between IUGR and non-IUGR very preterm infants to investigate the biochemical adaptations of neonates affected by early-onset-restricted intrauterine growth. METHODS: Neonates born <32 weeks of gestation admitted to neonatal intensive care unit (NICU) were enrolled in this prospective matched case-control study. IUGR was diagnosed by an obstetric ultra-sonographer and all relevant clinical data during NICU stay were captured. For each subject, a urine sample was collected within 48 h of life and underwent untargeted metabolomic analysis using mass spectrometry ultra-performance liquid chromatography. Data were analyzed using multivariate and univariate statistical analyses. RESULTS: Among 83 enrolled infants, 15 IUGR neonates were matched with 19 non-IUGR controls. Untargeted metabolomic revealed evident clustering of IUGR neonates versus controls showing derangements of pathways related to tryptophan and histidine metabolism and aminoacyl-tRNA and steroid hormones biosynthesis. CONCLUSIONS: Neonates with IUGR showed a distinctive urinary metabolic profile at birth. Although results are preliminary, metabolomics is proving to be a promising tool to explore biochemical pathways involved in this disease. IMPACT: Very preterm infants with intrauterine growth restriction (IUGR) have a distinctive urinary metabolic profile at birth. Metabolism of glucocorticoids, sexual hormones biosynthesis, tryptophan-kynurenine, and methionine-cysteine pathways seem to operate differently in this sub-group of neonates. This is the first metabolomic study investigating adaptations exclusively in extremely and very preterm infants affected by early-onset IUGR. New knowledge on metabolic derangements in IUGR may pave the ways to further, more tailored research from a perspective of personalized medicine.

Transplacental permeability of heavy metals in relation to newborn sex - evidence from the neurodevelopment project.

Introduction: Gender medicine is an innovative medical approach that studies how some biological variables are influenced by the male or female sex and gender. This issue is under debate because it characterizes the impact of tailored or individual medicine. In this scenario, the aim of this study is to study the correlation between heavy metal exposure and pathologies of neurodevelopment, according to the sex of newborns. In particular, this is an observational study under the name of the Neurosviluppo Project, involving 217 mother-child couples. Material and methods: The correlation with phenotype small for gestational age and congenital malformations were studied, but above all we focused on the pattern of placental permeability to heavy metals. Results: Our results are specifically related to foetal medicine and investigate the impact of foetal sex in transplacental metal exposure. Our results did not show any significant differences related to foetal sex in terms of congenital malformations or the other variables taken into consideration. However, because these conclusions are the first related to the gender medicine in transplacental foetal medicine, they could be a marked background for further studies. Conclusions: Considering the lack of data in literature regarding foetal sexual medicine and transplacental exposure, these study results are pioneering in terms of sexual foetal medicine. Possibly in the future, studies regarding the correlation between foetal sex and obstetrics outcomes will be performed.

Liver transplantation in an infant with cerebrotendinous xanthomatosis, cholestasis, and rapid evolution of liver failure.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a disorder of bile acid (BA) metabolism due to biallelic mutations in CYP27A1. The deposition of cholesterol and cholestanol in multiple tissues results, manifesting as neurologic disease in adults or older children. Neonatal cholestasis (NC) as a presentation of CTX is rare; it may self-resolve or persist, evolving to require liver transplantation (LT). METHODS: We present in the context of similar reports an instance of CTX manifest as NC and requiring LT. RESULTS: A girl aged 4mo was evaluated for NC with normal serum gamma-glutamyl transpeptidase activity. An extensive diagnostic work-up, including liver biopsy, identified no etiology. Rapid progression to end-stage liver disease required LT aged 5mo. The explanted liver showed hepatocyte loss and micronodular cirrhosis. Bile salt export pump (BSEP), encoded by ABCB11, was not demonstrable immunohistochemically. Both severe ABCB11 disease and NR1H4 disease-NR1H4 encodes farsenoid-X receptor, necessary for ABCB11 transcription-were considered. However, selected liver disorder panel sequencing and mass-spectrometry urinary BA profiling identified CTX, with homozygosity for the predictedly pathogenic CYP27A1 variant c.646G > C p.(Ala216Pro). Variation in other genes associated with intrahepatic cholestasis was not detected. Immunohistochemical study of the liver-biopsy specimen found marked deficiency of CYP27A1 expression; BSEP expression was unremarkable. Aged 2y, the girl is free from neurologic disease. CONCLUSIONS: Bile acid synthesis disorders should be routinely included in the NC/"neonatal hepatitis" work-up. The mutually supportive triple approach of BA profiling, immunohistochemical study, and genetic analysis may optimally address diagnosis in CTX, a treatable disease with widely varying presentation.

Study of arginine metabolism in medication overuse chronic migraine: possible defect in NO synthesis.

BACKGROUND AND AIM: The pathogenesis of the pain that occurs in episodic migraine attack is due to the activation of the trigeminal system's first neuron receptors located on vessel wall. The release from the endothelium of nitric oxide, a product of arginine metabolism, causes vasodilation and stretching of the vascular trigeminal system and promotes pain. It is unknown whether this same metabolic event is involved in the pain accompanying chronic migraine. To understand the possible role of arginine in the pathogenesis of chronic migraine patients, we evaluated the metabolism of arginine in plasma of chronic migraine and control subjects. METHODS: We evaluated the metabolism of arginine in a group of patients affected by chronic migraine. Quantification of arginine, ornithine, citrulline, monomethyl arginine (NMMA), dimethylarginines (ADMA, SDMA), and tyramine was performed by ultra-performance liquid chromatography coupled with a triple quadrupole mass spectrometer. RESULTS: Chronic migraine patients showed low plasma levels of arginine, significantly elevated levels of ornithine, ADMA, and NMMA whereas the levels of citrulline and SDMA were in the range of controls. CONCLUSIONS: The elevated levels of ADMA and NMMA, inhibitors of nitric oxide synthase, suggest that the metabolism of arginine may be inhibited with a possible reduction of NO release in the circulation of chronic patients. This suggests that the origin of pain may not be related to the vasodilation of trigeminal vascular system that occurs in episodic migraine patients.

Early Biomarkers of Bronchopulmonary Dysplasia: A Quick Look to the State of the Art.

Bronchopulmonary dysplasia (BPD) is one of the most common pulmonary sequelae of extreme preterm birth, with long-lasting respiratory symptoms and reduced lung function. A reliable predictive tool of BPD development is urgent and its search remains one of the major challenges for neonatologists approaching the upcoming arrival of possible new preventive therapies. Biomarkers, identifying an ongoing pathogenetic pathway, could allow both the selection of preterm infants with an evolving disease and potentially the therapeutic targets of the indicted pathogenesis. The "omic" sciences represent well-known promising tools for this objective. In this review, we resume the current laboratoristic, metabolomic, proteomic, and microbiomic evidence in the prediction of BPD. KEY POINTS: · The early prediction of BPD development would allow the targeted implementation of new preventive therapies.. · BPD is a multifactorial disease consequently it is unlikely to find a single disease biomarker.. · "Omic" sciences offer a promising insight in BPD pathogenesis and its development's fingerprints..

Replication and cross-validation of type 2 diabetes subtypes based on clinical variables: an IMI-RHAPSODY study.

AIMS/HYPOTHESIS: Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and cross-validate these type 2 diabetes clusters in three large cohorts using variables readily measured in the clinic. METHODS: In three independent cohorts, in total 15,940 individuals were clustered based on age, BMI, HbA1c, random or fasting C-peptide, and HDL-cholesterol. Clusters were cross-validated against the original clusters based on HOMA measures. In addition, between cohorts, clusters were cross-validated by re-assigning people based on each cohort's cluster centres. Finally, we compared the time to insulin requirement for each cluster. RESULTS: Five distinct type 2 diabetes clusters were identified and mapped back to the original four All New Diabetics in Scania (ANDIS) clusters. Using C-peptide and HDL-cholesterol instead of HOMA2-B and HOMA2-IR, three of the clusters mapped with high sensitivity (80.6-90.7%) to the previously identified severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) clusters. The previously described ANDIS mild age-related diabetes (MARD) cluster could be mapped to the two milder groups in our study: one characterised by high HDL-cholesterol (mild diabetes with high HDL-cholesterol [MDH] cluster), and the other not having any extreme characteristic (mild diabetes [MD]). When these two milder groups were combined, they mapped well to the previously labelled MARD cluster (sensitivity 79.1%). In the cross-validation between cohorts, particularly the SIDD and MDH clusters cross-validated well, with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity, ranging from 36.1% to 92.3%, where individuals shifted from SIRD to MD and vice versa. People belonging to the SIDD cluster showed the fastest progression towards insulin requirement, while the MDH cluster showed the slowest progression. CONCLUSIONS/INTERPRETATION: Clusters based on C-peptide instead of HOMA2 measures resemble those based on HOMA2 measures, especially for SIDD, SIRD and MOD. By adding HDL-cholesterol, the MARD cluster based upon HOMA2 measures resulted in the current clustering into two clusters, with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA1c, HDL-cholesterol, BMI and C-peptide) results in informative clusters that are representative of the original ANDIS clusters and stable across cohorts. Adding HDL-cholesterol to the clustering resulted in the identification of a cluster with very slow glycaemic deterioration.

Correction to: The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study.

Unfortunately, 'Present address' was omitted from one of the addresses provided for Mark I. McCarthy (#26).

Endovascular management of the deep venous thrombosis: A new challenging role for the endovascular specialist in 2020.

Over the last years, the endovascular approach to the management of the acute and chronic deep vein thrombosis (DVT) has gained more and more attention from the scientific community. DVT is the third most common cardiovascular disease after coronary heart disease and stroke, with classic treatment based on anticoagulation. Recent evidences have highlighted the risk of postthrombotic syndrome as high as 30%-50% in proximal ilio-femoral lesions, with irreversible clinical symptoms and impact on the quality of life of the population. Since 2000s, the new concept of thrombus removal in the acute phase has been supported by the introduction of different techniques based on the endovascular ablation of the clot by in-situ fibrinolysis and, more recently, fragmentation and aspiration. In the chronic phase, recanalization of the thrombosed segment is recommended by stent placement to remove the obstruction and eventually reduce the congestion. Immediate technical success of these procedures is widely satisfying, whereas the long-term clinical benefits are still debated. This paper presents an overview of the modern management of the DVT by endovascular approach with regard to the clinical contexts, interventional strategies and clinical outcomes. Endovascular specialist needs to be aware of this incoming challenge, as local expertise is demanded for the modern management of these patients in multidisciplinary theaters.

Experiences matter: A longitudinal study of individual-level sources of declining social trust in the United States.

The US has experienced a substantial decline in social trust in recent decades. Surprisingly few studies analyze whether individual-level explanations can account for this decrease. We use three-wave panel data from the General Social Survey (2006-2014) to study the effects of four possible individual-level sources of changes in social trust: job loss, social ties, income, and confidence in political institutions. Findings from fixed-effects linear regression models suggest that all but social ties matter. We then use 1973-2018 GSS data to predict trust based on observed values for unemployment, confidence in institutions, and satisfaction with income, versus an alternative counterfactual scenario in which the values of those three predictors are held constant at their mean levels in the early 1970s. Predicted values from these two scenarios differ substantially, suggesting that decreasing confidence in institutions and increasing unemployment scarring may explain about half of the observed decline in US social trust.

Presumed Risk Factors and Biomarkers for Severe Respiratory Syncytial Virus Disease and Related Sequelae: Protocol for an Observational Multicenter, Case-Control Study From the Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity. CLINICAL TRIALS REGISTRATION: NCT03756766.

The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study.

AIMS/HYPOTHESIS: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). METHODS: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. RESULTS: The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. CONCLUSIONS/INTERPRETATION: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.

Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. METHODS AND FINDINGS: We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (<5% or ≥5%) available for 1,514 participants. We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and random forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operating characteristic area under the curve (ROCAUC) of 0.84 (95% CI 0.82, 0.86; p < 0.001), which compared with a ROCAUC of 0.82 (95% CI 0.81, 0.83; p < 0.001) for a model including 9 clinically accessible variables. The IMI DIRECT prediction models outperformed existing noninvasive NAFLD prediction tools. One limitation is that these analyses were performed in adults of European ancestry residing in northern Europe, and it is unknown how well these findings will translate to people of other ancestries and exposed to environmental risk factors that differ from those of the present cohort. Another key limitation of this study is that the prediction was done on a binary outcome of liver fat quantity (<5% or ≥5%) rather than a continuous one. CONCLUSIONS: In this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see: https://www.predictliverfat.org/) and made it available to the community. TRIAL REGISTRATION: ClinicalTrials.gov NCT03814915.

Volatile secondary metabolites as aposematic olfactory signals and defensive weapons in aquatic environments.

Olfaction is considered a distance sense; hence, aquatic olfaction is thought to be mediated only by molecules dissolved in water. Here, we challenge this view by showing that shrimp and fish can recognize the presence of hydrophobic olfactory cues by a "tactile" form of chemoreception. We found that odiferous furanosesquiterpenes protect both the Mediterranean octocoral Maasella edwardsi and its specialist predator, the nudibranch gastropod Tritonia striata, from potential predators. Food treated with the terpenes elicited avoidance responses in the cooccurring shrimp Palaemon elegans Rejection was also induced in the shrimp by the memory recall of postingestive aversive effects (vomiting), evoked by repeatedly touching the food with chemosensory mouthparts. Consistent with their emetic properties once ingested, the compounds were highly toxic to brine shrimp. Further experiments on the zebrafish showed that this vertebrate aquatic model also avoids food treated with one of the terpenes, after having experienced gastrointestinal malaise. The fish refused the food after repeatedly touching it with their mouths. The compounds studied thus act simultaneously as (i) toxins, (ii) avoidance-learning inducers, and (iii) aposematic odorant cues. Although they produce a characteristic smell when exposed to air, the compounds are detected by direct contact with the emitter in aquatic environments and are perceived at high doses that are not compatible with their transport in water. The mouthparts of both the shrimp and the fish have thus been shown to act as "aquatic noses," supporting a substantial revision of the current definition of the chemical senses based upon spatial criteria.

Metabolomic Profiling of Infants With Recurrent Wheezing After Bronchiolitis.

BACKGROUND: Bronchiolitis is associated with a greater risk of developing recurrent wheezing, but with currently available tools, it is impossible to know which infants with bronchiolitis will develop this condition. This preliminary prospective study aimed to assess whether urine metabolomic analysis can be used to identify children with bronchiolitis who are at risk of developing recurrent wheezing. METHODS: Fifty-two infants <1 year old treated in the emergency department at University Hospital of Padova for acute bronchiolitis were enrolled (77% tested positive for respiratory syncytial virus [RSV]). Follow-up visits were conducted for 2 years after the episode of bronchiolitis. Untargeted metabolomic analyses based on mass spectrometry were performed on urine samples collected from infants with acute bronchiolitis. Data modeling was based on univariate and multivariate data analyses. RESULTS: We distinguished children with and those without postbronchiolitis recurrent wheeze, defined as ≥3 episodes of physician-diagnosed wheezing. Pathway overrepresentation analysis pointed to a major involvement of the citric acid cycle (P < .001) and some amino acids (lysine, cysteine, and methionine; P ≤ .015) in differentiating between these 2 groups of children. CONCLUSION: This is the first study showing that metabolomic profiling of urine specimens from infants with bronchiolitis can be used to identify children at increased risk of developing recurrent wheezing.

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium.

AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. CONCLUSIONS/INTERPRETATION: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.