MiMIR: R-shiny application to infer risk factors and endpoints from Nightingale Health's 1H-NMR metabolomics data.

MOTIVATION: 1H-NMR metabolomics is rapidly becoming a standard resource in large epidemiological studies to acquire metabolic profiles in large numbers of samples in a relatively low-priced and standardized manner. Concomitantly, metabolomics-based models are increasingly developed that capture disease risk or clinical risk factors. These developments raise the need for user-friendly toolbox to inspect new 1H-NMR metabolomics data and project a wide array of previously established risk models. RESULTS: We present MiMIR (Metabolomics-based Models for Imputing Risk), a graphical user interface that provides an intuitive framework for ad hoc statistical analysis of Nightingale Health's 1H-NMR metabolomics data and allows for the projection and calibration of 24 pre-trained metabolomics-based models, without any pre-required programming knowledge. AVAILABILITY AND IMPLEMENTATION: The R-shiny package is available in CRAN or downloadable at https://github.com/DanieleBizzarri/MiMIR, together with an extensive user manual (also available as Supplementary Documents to the article). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Lifestyle factors and metabolomic aging biomarkers: Meta-analysis of cross-sectional and longitudinal associations in three prospective cohorts.

Biological age uses biophysiological information to capture a person's age-related risk of adverse outcomes. MetaboAge and MetaboHealth are metabolomics-based biomarkers of biological age trained on chronological age and mortality risk, respectively. Lifestyle factors contribute to the extent chronological and biological age differ. The association of lifestyle factors with MetaboAge and MetaboHealth, potential sex differences in these associations, and MetaboAge's and MetaboHealth's sensitivity to lifestyle changes have not been studied yet. Linear regression analyses and mixed-effect models were used to examine the cross-sectional and longitudinal associations of scaled lifestyle factors with scaled MetaboAge and MetaboHealth in 24,332 middle-aged participants from the Doetinchem Cohort Study, Rotterdam Study, and UK Biobank. Random-effect meta-analyses were performed across cohorts. Repeated metabolomics measurements had a ten-year interval in the Doetinchem Cohort Study and a five-year interval in the UK Biobank. In the first study incorporating longitudinal information on MetaboAge and MetaboHealth, we demonstrate associations between current smoking, sleeping ≥8 hours/day, higher BMI, and larger waist circumference were associated with higher MetaboHealth, the latter two also with higher MetaboAge. Furthermore, adhering to the dietary and physical activity guidelines were inversely associated with MetaboHealth. Lastly, we observed sex differences in the associations between alcohol use and MetaboHealth.

1H-NMR metabolomics-based surrogates to impute common clinical risk factors and endpoints.

BACKGROUND: Missing or incomplete phenotypic information can severely deteriorate the statistical power in epidemiological studies. High-throughput quantification of small-molecules in bio-samples, i.e. 'metabolomics', is steadily gaining popularity, as it is highly informative for various phenotypical characteristics. Here we aim to leverage metabolomics to impute missing data in clinical variables routinely assessed in large epidemiological and clinical studies. METHODS: To this end, we have employed ∼26,000 1H-NMR metabolomics samples from 28 Dutch cohorts collected within the BBMRI-NL consortium, to create 19 metabolomics-based predictors for clinical variables, including diabetes status (AUC5-Fold CV = 0·94) and lipid medication usage (AUC5-Fold CV = 0·90). FINDINGS: Subsequent application in independent cohorts confirmed that our metabolomics-based predictors can indeed be used to impute a wide array of missing clinical variables from a single metabolomics data resource. In addition, application highlighted the potential use of our predictors to explore the effects of totally unobserved confounders in omics association studies. Finally, we show that our predictors can be used to explore risk factor profiles contributing to mortality in older participants. INTERPRETATION: To conclude, we provide 1H-NMR metabolomics-based models to impute clinical variables routinely assessed in epidemiological studies and illustrate their merit in scenarios when phenotypic variables are partially incomplete or totally unobserved. FUNDING: BBMRI-NL, X-omics, VOILA, Medical Delta and the Dutch Research Council (NWO-VENI).

Melatonin treatment and male replacement every week on the reproductive performance in Sarda sheep breed.

The aim of this study was to highlight whether the combination of melatonin treatment and weekly male replacement could influence reproductive performances in Sarda sheep breed. In a preselected farm, on 5th March 2016, 400 lactating ewes were identified, aged 3-5 years, with body condition score (BCS) 2.5-4.0, who lambed between 20th October and 1st December 2015. The 400 chosen animals were subsequently divided into 4 groups with 100 animals in each group (M, MR, C and CR). On 20th March 2016 the animals of Group M and MR (consisting of 100 ewes each) were treated with melatonin implants and on 24th April 2016 five entire rams were introduced into each group. In groups MR and CR, males were replaced each week with other males whereas in groups M and C the introduced males were not replaced. The MR group showed the highest fertility (number of lambed ewes) compared to the other three groups (P < 0.01). Both the melatonin treated groups (M and MR) exhibited an increase in fertility greater than the controls groups C and CR (P < 0.01). However, when the two groups treated with melatonin were compared, the MR group showed a higher fertility than the M group (P < 0.01). The same can be said for the two control groups, of which the CR group showed a greater increase in fertility than the C group (P < 0.01). The mean interval of days from male introduction to lambing was lower in the treated than in the control groups (P < 0.05). The MR group presented the lowest mean interval of days from male introduction to lambing amongst all of the groups (P < 0.05). A similar trend was recorded for group CR when compared to group C (P < 0.05). In the MR and M groups the lambing peak was recorded close to 170 days after the males introduction, whereas the CR group and the C group were reported to be around 180 days and 190 days, respectively. At the 170th day from the male introduction the number of ewes lambed in the MR group was greater than that of the M group (P < 0.05) (60 vs. 42), and more than double of that of the C and CR groups (P < 0.01). In conclusion, weekly male replacement improved the reproductive activity and strengthened the effect of the pineal hormone on reproductive efficiency. Therefore male replacement either in untreated animals or in association with the melatonin implants, can be straightforwardly applied to guarantee a more efficient reproduction in sheep breeding.

Prediction of thiopental induction dose based on caffeine volume of distribution.

Similarities in the physicochemical properties of caffeine and thiopental would suggest that the apparent volume of distribution of caffeine (aVd) may be comparable to the initial volume of distribution of thiopental. It is the initial volume of distribution of thiopental that is critical in the early minutes of anesthetic induction. A comparison of the aVd of caffeine and thiopental induction dose was made in 21 male New Zealand white rabbits. The aVd of caffeine was determined from serial saliva determinations following intravenous injection of caffeine (7.5 mg/kg). The loss of the pupillary light reflex was used as the end point for induction with thiopental. A statistically significant correlation (r = .722, P less than .0001) was found between the aVd of caffeine and thiopental induction dose. Also, both thiopental induction dose and caffeine aVd decreased significantly with age in these animals. These findings provide a basis for development of an uninvasive test for predicting thiopental dose in humans.

Correlation between thiopental induction dose and the volume of distribution of caffeine in human subjects.

The correlation between the apparent volume of distribution (aVd) of caffeine and the induction dose of thiopental was studied in 23 patients. Caffeine, which has an effective partition coefficient that approaches that of thiopental, was used as an indicator substance to estimate the immediate volume of distribution of thiopental. The immediate volume of distribution is critical in determining thiopental induction dose. The aVd of caffeine was determined noninvasively from serial saliva samples after consumption of caffeine, which was given to the patients as coffee. A strong correlation (r = .69; P less than .01) was found between the aVd of caffeine and the anesthetic induction dose of thiopental when the loss of eyelid reflex was used as the end point. The correlation between thiopental induction dose and body weight for the same individuals (r = .188) was not statistically significant.

Effects of antigastrin drugs on the interaction of 125I-human gastrin with rat gastric mucosa membranes.

A method for studying the interaction of 125I-human gastrin with a rat gastric mucosal membrane fraction is described, and the saturability, high affinity and reversibility of the preparations, as well as the correlation of pharmacological responses to antigastrin-drugs with the observed binding are discussed. Proglumide and other antigastrin drugs inhibit gastrin binding in a dose-dependent way, and their activities in such a system are well correlated with the "in vivo" antisecretory activities of these drugs.

Hemodynamic changes in critically ill patients during induction of anesthesia.

Hemodynamic changes resulting from anesthesia and endotracheal intubation were studied in 32 critically ill patients. Cardiac preload, afterload, and output were measured utilizing Swan-Ganz catheter, arterial catheter, and thermodilution technique. Group I: 15 patients with known cardiac disease. Group II: 10 patients with no known cardiac disease, but with non-specific ECG findings and/or mild cardiomegaly shown by x-ray. Group III: seven patients with no known cardiac disease and without the ECG and x-ray findings of group II. Anesthesia and endotracheal intubation caused an increase in heart rate, systemic arterial pressure, central venous pressure, and pulmonary artery wedge pressure, and a decrease in cardiac output and left ventricular function. Left ventricular function curves showed: group I - severe depression with no recovery; group II - moderate depression with only partial recovery; group III - moderate depression with full recovery. The severity of cardiovascular changes seen varied with the degree of pre-existing cardiac disease. It is concluded that patients with non-specific ECG findings and/or cardiomegaly indicated by x-ray have an increased risk of cardiac dysfunction during anesthesia and require similar preoperative and intraoperative management as do patients with cardiac disease.

Flammable surgical drapes--a patient and personnel hazard.

After a surgical drape fire, the New York State Society of Anesthesiologists, Operating Room Safety Committee, investigated the factors contributing to it. Subsequently, eight detailed cases were collected. It found that no voluntary standards or government regulations exist to oversee the flammability of surgical drapes; no agency or bureau collects reports of operating room fires; most professionals are not aware of the hazard because no labelling requirements regarding flammability exist and because most episodes are minor in nature or settled out of court and thus not reported. This relatively new hazard has developed with the more frequent use of high-energy devices designed to provide better therapeutic results.

Studies on the safety of a new non-steroidal anti-inflammatory drug: protacine (CR 604).

The effects of 3'-(4-[2-(1-p-chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazinyl-1-yl)propyl-4-benzamido-N,N-dipropyl-glutaramate(+/-)dimaleate(protacine, CR 604) on gastrointestinal physiology and tolerance were investigated. The anti-inflammatory activities and the effects on the gastrointestinal tract showed a very good separation. Protacine showed a smaller influence on gastric prostaglandins and did not stimulate both basal and cAMP enhanced gastric acid output as did other antiinflammatory drugs. This may explain, at least in part, its gastrointestinal safety. Articular cartilage metabolism showed to remain practically unchanged by protacine both in in vitro and ex vivo experiments. All these results show that protacine has very good gastrointestinal safety indexes, that effects on articular cartilage metabolism are very low and that, from these points of view, it is superior to other non-steroidal anti-inflammatory drugs of similar potency.

Critical level of oxygen delivery in anesthetized man.

Fifty-eight patients studied were anesthetized with diazepam, pancuronium, and a moderate dose of fentanyl; 99 sets of multiple hemodynamic variables were measured after sternotomy and before cardiopulmonary bypass. The relationship between oxygen consumption (VO2) and oxygen delivery (DO2) was studied. The critical value of DO2 was identified to be 330 ml/min X M2 or 8.2 ml/min X kg by an analysis of the regression lines. When DO2 was less than 330 ml/min X M2, the value of VO2 decreased in proportion to a decrease in DO2 and VO2 was expressed as: VO2 = 0.36 X DO2 - 11.20 (n = 30, r = 0.77, p less than 10(-6). At DO2 greater than 330 ml/min X M2, VO2 values plateaued at 109 +/- 16 (SD): n = 69; r = -0.02, p greater than 0.05; while mixed venous oxygen tension (PVO2) decreased in proportion to the decrease in DO2, suggesting compensatory increase of oxygen extraction. A decrease of VO2 at DO2 less than 330 ml/min X M2 suggests tissue oxygen deprivation occurred.

Studies on the mechanism of action of protacine (CR 604), a new non-steroidal anti-inflammatory agent.

3'-(4-[2-(1-P-Chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazin-1-yl)propyl-4-benzamido-N,N-dipropyl-glutaramate(+/-)dimaleate (protacine, CR 604), a new non-steroidal compound active on experimental inflammation, in vitro inhibits prostaglandin synthesis from arachidonic acid and platelet aggregation. When administered p.o., it prevents ex vivo platelet aggregation and in vivo arachidonate-induced thrombosis in rabbits. The cAMP levels of rat leucocytes are significantly reduced after treatment in vivo with protacine, even under maximum PGE-mediated stimulation. These effects, the inhibition of the proteolytic activity of trypsin and the fibrinolytic properties evidenced on recalcified plasma clots, contribute to explain the anti-inflammatory activity of protacine.

Pharmacological study of a new non-steroidal anti-inflammatory drug: protacine (CR 604).

The pharmacological activities of 3'-(4-[2-(1-p-chlorobenzoyl-5-methoxy-2-methyl-indol-3-yl-acetoxy)-ethyl]-piperazin-1-yl)propyl-4-benzamido-N,N-dipropylglutaramate(+/-)dimaleate (protacine, CR 604), a new indolyl derivative with strong anti-inflammatory, analgesic and antipyretic activities, are described. The dose-dependent activity of protacine on inflammation has been shown both in short-term experiments, like the hind paw edema induced by carrageenin and several other irritants, and long-term tests, like the aminoacetonitrile-induced osteolathyrism, the adjuvant-induced arthritis and the cotton pellet-induced granuloma. The analgesic activity of the drug has been evidenced in the phenylquinone-induced writhing and the Randall-Selitto tests, and the antipyretic effects in the yeast-induced hyperthermia in rats. Other general pharmacological effects have been studied, too. Contrarily to several other anti-inflammatory drugs, including indometacin, showing advers effects at doses which are in the same range of those active on experimental inflammation, protacine shows these effects to a minor degree and at doses which are much larger than those pharmacologically active. The therapeutic index of protacine therefore is superior to that of other anti-inflammatory drugs.