Stress and suicide risk among adolescents: the role of problematic internet use, gaming disorder and emotional regulation.

BACKGROUND: Previous studies have associated videogame playing and social media use with suicidal behaviors together with lower stress coping or poor emotion regulation strategies. Due to the inconclusive evidence regarding the factors associated with suicidal behavior, the present study aimed to overcome the limitations of previous research and explored the relationship between adolescent stress, problematic internet use (PIU), gaming disorder (GD), and emotional regulation (ER) in a cross-section design. It was hypothesized that stress would have a direct effect on suicide risk (SR) as well as being mediated by PIU, GD, and ER. METHODS: The participants comprised 430 adolescents (58.4% male) aged between 16 and 19 years. They completed an online survey including the Mobile-Related Experiences Questionnaire, Internet Gaming Disorder Scale-Short Form, Meta-Mood Trait Repair Scale, and Spanish version of the Suicidal Behaviors Questionnaire. RESULTS: A total of 34.2% of the adolescents (N = 147) were at risk for SR. Results also indicated that 30,7% had experienced suicidal ideation at some point in their life, 12.1% had at least one plan to die by suicide, and 5.1% had attempted suicide. Results of path analysis confirmed that stress appeared to be a risk factor for suicide, but that its effects were not mediated by PIU. However, ER and GD mediated the effect of stress on SR. The results suggest that stress is a main risk factor for suicide, especially among adolescents with poor emotional regulation or problematic gaming. CONCLUSIONS: Considering the prevalence of suicide among adolescents, the results of the present study suggest that suicide prevention programs should include emotional regulation strategies, stress coping, and videogaming management skills in the early stages of high school. Providing these protective resources to adolescents will help them face the stressful and changing situations typical of adolescence and will help them to attain greater well-being and satisfaction with life.

The relationship between suicidal behavior and perceived stress: The role of cognitive emotional regulation and problematic alcohol use in Spanish adolescents.

Suicidal behavior has become an important public health problem, correlating with stress and emotional deficits in recent research. This study examined the relationship between perceived stress and suicidal behavior risk, testing the mediating roles of cognitive emotion regulation and impulsivity, and the moderating role of problematic alcohol use in stress-suicidal behavior association in a sample of 121 Spanish adolescents surveyed online. Results showed positive and significant associations between perceived stress and suicidal behavior risk, as well a mediation role of adaptive cognitive emotion regulation strategies and a moderation role of problematic alcohol use between perceived stress and suicidal behavior risk, supporting stress as an influential factor in suicidal behavior. Our findings emphasize adaptive emotional regulation strategies in stressful situations, as well as the importance of promoting responsible alcohol consumption to decrease suicide risk in adolescents. Additionally, they contribute to effective educational suicide prevention programs for young people.

Autonomy of Nursing Students: Methodological Study of Validation of the PALOP Scale Portuguese Short Version.

The cultivation of critical thinking and decision-making skills promotes student autonomy. Only a few instruments measure nursing students' autonomy, and the PALOP® Scale is one of them. This study aimed to semantically and culturally adapt the PALOP® Scale to European Portuguese and assess the psychometric properties of a short version. A methodological study was conducted with 530 second and fourth-year undergraduate nursing students. Content validity was assessed using exploratory and discriminant factor analysis, and reliability was determined through analyses of internal consistency, temporal stability, and floor and ceiling effects. The analysis of the psychometric properties of a short version of the PALOP®-PT Scale revealed complete agreement (100%) among panel members for content validity. The scale also showed discriminative capacity among second- and fourth-year students (t (528) = -7.907, p < 0.001) with a five-factor structure, with a total explained variance of 57.2%. Reliability analysis showed excellent internal consistency (α = 0.935) and moderate temporal stability (95% ICC (3.1) = 0.520 [0.290-0.693], p < 0.01). The short version of the PALOP®-PT Scale is a promising tool to assess nursing students' perceived autonomy and identify necessary adjustments to their professional identity.

Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer.

BACKGROUND AND AIMS: The gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes. METHODS: A multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months. RESULTS: Thirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 × 10-11); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR = 1.30 × 10-12), but metabolite clusters were not associated with disease-free survival (p = 0.358). An association was identified between Met 1 and DNA mismatch-repair deficiency (p = 0.005). FBXW7 mutations were only found in cancers predominant in microbiota cluster 7. CONCLUSIONS: Networks of pathobionts in the tumour mucosal niche are associated with tumour mutation and metabolic subtypes and predict favourable outcome following CRC resection. Video Abstract.

Family caregiver emotional distress in advanced cancer: the DME-C scale psychometric properties.

BACKGROUND: Family caregivers of patients with advanced illness at end of life often report high levels of emotional distress. To address this emotional distress is necessary to have adequate and reliable screening tools. AIM: This study analyses the psychometric properties and clinical utility of the Family Caregiver Emotional Detection Scale for caregivers of patients with end-stage cancer (DME-C, Spanish acronym) who are receiving palliative care (PC). DESIGN: Multicentre, cross-sectional study. SETTINGS/PARTICIPANTS: Family caregivers of patients with advanced cancer at end of life receiving palliative treatment were interviewed to explore their emotional distress through the DME-C scale and other instruments measuring anxiety and depression (Hospital Anxiety and Depression Scale (HADS)), distress thermometer (DT) and overload (B), as well as a clinical psychological assessment (CPA). RESULTS: 138 family caregivers, 85 (61.6%) female and 53 (38.4%) male, with an average age of 59.69±13.3 participated in the study. The reliability of the scale, as measured by Cronbach's alpha, was 0.76, and its stability over time was 0.734. Positive, significant correlations were found between the DME-C and the scores for anxiety and depression registered on the HADS scale, as well as with the total result of this latter scale and the results for B, the DT and the CPA. A statistical analysis of the receiver-operating characteristic curves showed that the scale has a sensitivity and specificity of 75%, and that the cut-off point for the detection of emotional distress was a score ≥11. Fifty-four per cent of the caregivers displayed emotional distress according to this scale. CONCLUSIONS: The DME-C displays good psychometric properties. It is simple, short, reliable and easy to administer. We believe that the instrument is useful for the detection of emotional distress in the family caregivers of hospitalised patients suffering from end-stage illnesses and receiving PC.

Spanish Version of the Bedtime Procrastination Scale: Cross-Cultural Adaptation and Psychometric Evaluation in a Sample of Nursing Students.

A recent line of research concerns bedtime procrastination, its effects on sleep quality and duration, and the associated repercussions for health and wellbeing. The Bedtime Procrastination Scale is a brief, self-report instrument developed by Kroese et al. with the aim of evaluating this behavior and exploring its association with insufficient sleep, and hence with health. The aim was to develop and validate a Spanish version of the Bedtime Procrastination Scale (BPS-Sp) and to examine the relationship between bedtime procrastination and both general procrastination and self-control. The original BPS was translated from English into Spanish in accordance with international guidelines on the cross-cultural adaptation of measurement instruments. The sample for the validation study comprised 177 nursing students who completed a questionnaire requesting demographic data and which included the following instruments: the newly developed BPS-Sp, the Tuckman Procrastination Scale, and the Brief Self-Control Scale. Statistical analysis involved tests of normality (Kolmogorov-Smirnov), reliability (Cronbach's alpha, test-retest), construct validity, and confirmatory factor analysis. Scores on the BPS-Sp showed excellent internal consistency (α = .83) and temporal stability (test-retest r = .84), as well as significant correlations with general procrastination (r = .26; p < .01) and self-control (r = -.17; p < .05). Confirmatory factor analysis showed an adequate fit for the single-factor solution proposed by Kroese et al. The results suggest that the BPS-Sp is a valid and reliable instrument for assessing bedtime procrastination in the Spanish-speaking population.

Caregiver emotional distress: external open-behaviour signs.

OBJECTIVES: To determine whether specific external signs of emotional distress (ESED) can be an indirect measure of emotional distress in caregivers. METHODS: A cross-sectional multicentre design was used. 148 primary caregivers of advanced cancer patients attended in four Spanish palliative care units participated in this study. The emotional distress of caregivers was measured using both the Emotional Distress of Caregivers Scale and a psychological interview. Health professionals collected data using a standard clinical interview process after a brief training period. RESULTS: More than half the caregivers (60%) presented with emotional distress. A positive correlation (r=0.566) was found between the intensity of ESED and emotional distress per se. Caregivers who presented emotional distress showed more ESED than those that did not (p<0.01). The study found significant differences for the categories 'visible signs of sadness, fear, crying, feeling overwhelmed' (p<0.001), 'difficulty in separating from the patient: family refuses to let the patient make decisions and insists on care' (p<0.001) and 'visible signs of anger, irritability or frequent disagreement with therapeutic measures' (p<0.001). No significant differences were found with respect to gender. The set of items to measure these external signs presented an adequate reliability assessed using Cronbach's alpha (α=0.773). CONCLUSIONS: The assessment of ESED in caregivers could serve as a useful method to assess their emotional distress. Incorporating the systematic assessment of these external signs as part of the assessment of the emotional distress of primary caregivers could improve the overall assessment and treatment provided to these caregivers.

Exercise Addiction and Muscle Dysmorphia: The Role of Emotional Dependence and Attachment.

Background: Both exercise addiction (EA) and muscle dysmorphia (MD) primarily involve the compulsive practice of physical exercise and are classified as behavioral addictions in different lines of research. These types of addictions are frequently comorbid with other addictive pathologies, such as emotional dependence (ED), which is closely related to childhood attachment. This study is presented to address the scarcity of research relating EA and MD with other behavioral addictions. The aims are to analyze the sex differences found in emotional dependence, attachment dimensions, EA and MD; to analyze the association between EA and MD and other behavioral addictions, such as emotional dependence and attachment dimensions; and to analyze the possible role that childhood attachment plays in mediating the interaction between emotional dependence and EA and MD. Method: The sample comprised 366 participants (54.6% women) aged 17-31 (M = 23.53; SD = 6.48). Results: There are sex differences, with men scoring higher in EA, MD, and ED. The positive relationship between EA and ED (values between 0.16 and 0.28), MD (presenting values between 0.42 and 0.70), and attachment styles based on preoccupation, interference, permissiveness, and value of parental authority (values between 0.11 and 0.14) is highlighted. On the other hand, MD was positively related to ED (values ranging from 0.24 to 0.36) and attachment styles based on the value of parental authority, self-sufficiency, and resentment toward parents (between 0.17 and 0.18), and negatively related to secure attachment (values between -0.13 and -0.18). Likewise, the predictive role of ED and attachment styles in EA and MD was tested. And it was observed how attachment styles mediated the relationship between EA and ED, as well as the relationship between MD and ED. Thus, it has been shown that people with EA and MD present attachment styles that may influence negatively the decision-making process when choosing inappropriate strategies to achieve adequate emotional regulation, even selecting inappropriate goals for physical exercise with negative consequences. Conclusions: The dissemination of the findings among mental health and sports science professionals is necessary to develop prevention and intervention strategies for people affected by EA and MD.

Perceived Stress in Relation to Quality of Life and Resilience in Patients with Advanced Chronic Kidney Disease Undergoing Hemodialysis.

Background: Patients with chronic kidney disease undergo various stages of therapeutic adaptation which involve lifestyle modifications, physical changes, and adjustment to renal replacement therapy. This process produces adaptive stress. Objective: To identify how resilience, health- related quality of life, and sociodemographic, clinical, and hemodialysis routine-related variables are related to perceived stress in patients with chronic kidney disease receiving hemodialysis for more than six months. Methods: This was a multicenter and cross-sectional study involving 144 patients from the Valencian Community (Spain). The assessment scales used for the study were the Perceived Stress Scale 10, the Kidney Disease Quality of Life 36, and the Connors-Davidson Resilience Scale. To identify variables with predictive power over Perceived Stress Scale 10 scores, multiple regression analyses were performed. Results: Employment status (p = 0.003), resilience (p < 0.001), and quality of life (p < 0.001) were shown to be significantly related to perceived stress. The regression models determined that health-related quality of life and resilience explained up to 27.1% of the variance of total PSS10 scores. Conclusions: Resilience was identified as one of the most important predictors of Perceived Stress Scale 10 scores. Thus, the development of interventions to promote resilience may have a positive impact on perceived stress in patients with chronic kidney disease.

Representing the Metabolome with High Fidelity: Range and Response as Quality Control Factors in LC-MS-Based Global Profiling.

Liquid chromatography-mass spectrometry (LC-MS) is a powerful and widely used technique for measuring the abundance of chemical species in living systems. Its sensitivity, analytical specificity, and direct applicability to biofluids and tissue extracts impart great promise for the discovery and mechanistic characterization of biomarker panels for disease detection, health monitoring, patient stratification, and treatment personalization. Global metabolic profiling applications yield complex data sets consisting of multiple feature measurements for each chemical species observed. While this multiplicity can be useful in deriving enhanced analytical specificity and chemical identities from LC-MS data, data set inflation and quantitative imprecision among related features is problematic for statistical analyses and interpretation. This Perspective provides a critical evaluation of global profiling data fidelity with respect to measurement linearity and the quantitative response variation observed among components of the spectra. These elements of data quality are widely overlooked in untargeted metabolomics yet essential for the generation of data that accurately reflect the metabolome. Advanced feature filtering informed by linear range estimation and analyte response factor assessment is advocated as an attainable means of controlling LC-MS data quality in global profiling studies and exemplified herein at both the feature and data set level.

The suicidal behaviors questionnaire-revised. Spanish form.

This study consists of a translation, intercultural adaptation and analysis of the psychometric properties of the Spanish version of Suicide Behavior Questionnaire Revised using a sample of 325 undergraduates. Internal consistency, reliability and temporal stability, calculated through Cronbach's alpha (α =.81) and test-retest correlations (ICC =. 88), respectively, were excellent. The criterion-related validity of the SBQ-R was established by correlating SBQ-R with other psychological constructs. A confirmatory factor analysis demonstrated adequate fit of the measurement model. This SBQ-R Spanish adaptation is a reliable and valid tool that might be useful to researchers and clinicians wishing to identify young people at a high risk of suicide.

Urinary metabolic phenotyping for Alzheimer's disease.

Finding early disease markers using non-invasive and widely available methods is essential to develop a successful therapy for Alzheimer's Disease. Few studies to date have examined urine, the most readily available biofluid. Here we report the largest study to date using comprehensive metabolic phenotyping platforms (NMR spectroscopy and UHPLC-MS) to probe the urinary metabolome in-depth in people with Alzheimer's Disease and Mild Cognitive Impairment. Feature reduction was performed using metabolomic Quantitative Trait Loci, resulting in the list of metabolites associated with the genetic variants. This approach helps accuracy in identification of disease states and provides a route to a plausible mechanistic link to pathological processes. Using these mQTLs we built a Random Forests model, which not only correctly discriminates between people with Alzheimer's Disease and age-matched controls, but also between individuals with Mild Cognitive Impairment who were later diagnosed with Alzheimer's Disease and those who were not. Further annotation of top-ranking metabolic features nominated by the trained model revealed the involvement of cholesterol-derived metabolites and small-molecules that were linked to Alzheimer's pathology in previous studies.

Performance of metabonomic serum analysis for diagnostics in paediatric tuberculosis.

We applied a metabonomic strategy to identify host biomarkers in serum to diagnose paediatric tuberculosis (TB) disease. 112 symptomatic children with presumptive TB were recruited in The Gambia and classified as bacteriologically-confirmed TB, clinically diagnosed TB, or other diseases. Sera were analysed using 1H nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Multivariate data analysis was used to distinguish patients with TB from other diseases. Diagnostic accuracy was evaluated using Receiver Operating Characteristic (ROC) curves. Model performance was tested in a validation cohort of 36 children from the UK. Data acquired using 1H NMR demonstrated a sensitivity, specificity and Area Under the Curve (AUC) of 69% (95% confidence interval [CI], 56-73%), 83% (95% CI, 73-93%), and 0.78 respectively, and correctly classified 20% of the validation cohort from the UK. The most discriminatory MS data showed a sensitivity of 67% (95% CI, 60-71%), specificity of 86% (95% CI, 75-93%) and an AUC of 0.78, correctly classifying 83% of the validation cohort. Amongst children with presumptive TB, metabolic profiling of sera distinguished bacteriologically-confirmed and clinical TB from other diseases. This novel approach yielded a diagnostic performance for paediatric TB comparable to that of Xpert MTB/RIF and interferon gamma release assays.

Academic procrastination in nursing students. Spanish adaptation of the Academic Procrastination Scale-Short Form (APS-SF). / Procrastinación académica en estudiantes de enfermería. Adaptación española de la Academic Procrastination Scale-Short Form (APS-SF).

AIM: The aim of this paper was the translation and adaptation to Spanish of the Academic Procrastination Scale-Short Form of McClosky / Yockey, and to determine its preliminary psychometric properties of validity and reliability in a sample of nursing students. METHOD: 178 nursing students, 143 female and 35 male, participated in the study. They answered an anonymous and self-administered questionnaire, which contained demographic data, the Academic Procrastination Scale-Short Form (APS-SF) and the Tuckman Procrastination Scale (TPS). RESULTS: A Cronbach's alpha coefficient of 0.87 and a two-week test-retest coefficient of 0.89 was obtained. The correlation between the 2administered scales was 0.70. The confirmatory factor analysis shows a suitable fit to the unifactorial model proposed for the original version of the scale. No significant floor or ceiling effects were observed in the APS-SF scores. DISCUSSION: The results of the study seem to confirm that the Spanish version of the Brief Scale of Academic Procrastination is a valid and reliable instrument, which, due to its characteristics, can be useful to quickly evaluate procrastinating behaviours related to the academic activities of Spanish-speaking students.

Resilience in Caregivers: A Systematic Review.

BACKGROUND: Resilience is a multidimensional construct that explains why people facing the consequences of adversity and stress can have a positive outcome, emphasizing adjustment to experiences that are perceived as threatening. OBJECTIVE: The aim of this study is to review the construct of resilience and associated variables in caregivers of patients with chronic, advanced illness and at the end of life. METHODS: The review included studies published between January 2009 and January 2019, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guide reporting. The Medline, ScienceDirect, HINARI, PsychINFO, and SciELO databases were used for bibliographic exploration to identify research studies that examined the impact of resilience on adaptation and overall well-being in caregivers of patients with chronic and advanced illness. RESULTS: A total of 23 quantitative and qualitative studies were identified whose aim was to describe the role of resilience in adaptation and coping in caregivers. In these studies, resilience was associated with a positive impact on the quality of life and emotional distress. Communication and social support increase resilient coping strategies. In most selected articles, the sampling strategy used was convenience sampling. Data collection used evaluation scales related to resilience and associated variables for quantitative studies, and semistructured interviews were used for qualitative studies. CONCLUSION: Promoting a resilient coping style in caregivers reduces the distress that normally results from illness-related changes in the biopsychosocial and spiritual dimensions. A resilient coping style can diminish the risk of stress and burden, and promote adaptation in the caregiver.

Relationship of academic procrastination with perceived competence, coping, self-esteem and self-efficacy in nursing students. / Relación de la procrastinación académica con la competencia percibida, el afrontamiento, la autoestima y la autoeficacia en estudiantes de enfermería.

OBJECTIVE: The aim of this study was to study the role that perceived competence, resilient coping, self-esteem and self-efficacy can have as protective factors of the academic procrastination of nursing students. METHOD: Participants were 237 nursing students, 202 women and 35 men. The participants answered a questionnaire that contained the Spanish forms of the following instruments: Tuckman Procrastination Scale (TPS), Perceived Personal Competence Scale (PPC), Brief Resilient Coping Scale (BRCS), Rosenberg Self-Esteem Scale (RSES) and General Self-Efficacy Scale (GSE). RESULTS: Significant and negative correlation coefficients (p<.01) were obtained between the procrastination scale and the rest of the measures used. The linear regression analysis identified Perceived Competence (PPC) as the only predictive variable of procrastinating behaviour, explaining 21.5% (R2aj) of the variance. DISCUSSION: The results of the study show the important protective role that the variables associated with 'positive' psychology have on procrastination. Of special relevance for the theory and practice of teaching is the result that indicates the predictive role of Perceived Competence on the academic procrastination of students.

Breaking the cycle: Reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate.

Objective: To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in patients with relapsing-remitting MS (RRMS) using untargeted plasma metabolomics. Methods: Plasma from 27 patients with RRMS was collected at baseline and 6 weeks after initiating DMF. Patients were separated into discovery (n = 15) and validation cohorts (n = 12). Ten healthy controls were also recruited. Metabolomic profiling using ultra-high-performance liquid chromatography mass spectrometry (UPLC-MS) was performed on the discovery cohort and healthy controls at Metabolon Inc (Durham, NC). UPLC-MS was performed on the validation cohort at the National Phenome Centre (London, UK). Plasma neurofilament concentration (pNfL) was assayed using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events. Results: In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate, and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine increased 6 weeks following treatment (q < 0.05). Methyl succinyl-carnitine increased in the validation cohort (q < 0.05). These changes were not observed in the control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing and abdominal symptoms). pNfL concentration was higher in patients with RRMS than in controls and reduced over 15 months of treatment. Conclusion: TCA cycle intermediates and metabolites are increased in patients with RRMS treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxycarboxylic acid receptor 2 to both therapeutic effects and adverse events requires investigation.

Enhanced Microbial Bile Acid Deconjugation and Impaired Ileal Uptake in Pregnancy Repress Intestinal Regulation of Bile Acid Synthesis.

Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia.

Ultra-Performance Liquid Chromatography-High-Resolution Mass Spectrometry and Direct Infusion-High-Resolution Mass Spectrometry for Combined Exploratory and Targeted Metabolic Profiling of Human Urine.

The application of metabolic phenotyping to epidemiological studies involving thousands of biofluid samples presents a challenge for the selection of analytical platforms that meet the requirements of high-throughput precision analysis and cost-effectiveness. Here direct infusion-nanoelectrospray (DI-nESI) was compared with an ultra-performance liquid chromatography (UPLC)-high-resolution mass spectrometry (HRMS) method for metabolic profiling of an exemplary set of 132 human urine samples from a large epidemiological cohort. Both methods were developed and optimized to allow the simultaneous collection of high-resolution urinary metabolic profiles and quantitative data for a selected panel of 35 metabolites. The total run time for measuring the sample set in both polarities by UPLC-HRMS was 5 days compared with 9 h by DI-nESI-HRMS. To compare the classification ability of the two MS methods, we performed exploratory analysis of the full-scan HRMS profiles to detect sex-related differences in biochemical composition. Although metabolite identification is less specific in DI-nESI-HRMS, the significant features responsible for discrimination between sexes were mostly the same in both MS-based platforms. Using the quantitative data, we showed that 10 metabolites have strong correlation (Pearson's r > 0.9 and Passing-Bablok regression slope of 0.8-1.3) and good agreement assessed by Bland-Altman plots between UPLC-HRMS and DI-nESI-HRMS and thus can be measured using a cheaper and less sample- and time-consuming method. A further twenty metabolites showed acceptable correlation between the two methods with only five metabolites showing weak correlation (Pearson's  r < 0.4) and poor agreement due to the overestimation of the results by DI-nESI-HRMS.

XCMS-MRM and METLIN-MRM: a cloud library and public resource for targeted analysis of small molecules.

We report XCMS-MRM and METLIN-MRM ( http://xcmsonline-mrm.scripps.edu/ and http://metlin.scripps.edu/ ), a cloud-based data-analysis platform and a public multiple-reaction monitoring (MRM) transition repository for small-molecule quantitative tandem mass spectrometry. This platform provides MRM transitions for more than 15,500 molecules and facilitates data sharing across different instruments and laboratories.