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.

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.

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.

The quantitative determination of neomycin sulphate by a diffusion technique on agar plates by the method of the European Pharmacopoeia, 2nd edition--evaluation of precision and reproducibility of the method.

The medium recommended by the European Pharmacopoeia (EP), 2nd edition, for the microbiological determination of neomycin by the agar diffusion method was tested and compared with the medium recommended by the EP, 1st edition. The tests were carried out in different laboratories. The medium recommended by the EP, 2nd edition, gave greater precision and reproducibility than the previous medium. The possibility of using a reference standard of almost pure neomycin B for both the determination of framycetin and neomycin was evaluated. The results demonstrated that the medium recommended by the EP, 2nd edition, gave better precision and reproducibility. Difficulty in achieving valid assays was practically the same with both media.

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.

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.

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.

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.