Critical comparison of methods for fault diagnosis in metabolomics data.

Platforms like metabolomics provide an unprecedented view on the chemical versatility in biomedical samples. Many diseases reflect themselves as perturbations in specific metabolite combinations. Multivariate analyses are essential to detect such combinations and associate them to specific diseases. For this, usually targeted discriminations of samples associated to a specific disease from non-diseased control samples are used. Such targeted data interpretation may not respect the heterogeneity of metabolic responses, both between diseases and within diseases. Here we show that multivariate methods that find any set of perturbed metabolites in a single patient, may be employed in combination with data collected with a single metabolomics technology to simultaneously investigate a large array of diseases. Several such untargeted data analysis approaches have been already proposed in other fields to find both expected and unexpected perturbations, e.g. in Statistical Process Control. We have critically compared several of these approaches for their sensitivity and their correct identification of the specifically perturbed metabolites. Also a new approach is introduced for this purpose. The newly introduced Sparse Mean approach, which we find here as most sensitive and best able to identify the specifically perturbed metabolites, turns metabolomics into an untargeted diagnostic platform. Aside from metabolomics, the proposed approach may greatly benefit fault diagnosis with untargeted analyses in many other fields, such as Industrial Process Control, food Adulteration Detection, and Intrusion Detection.

The association between vascular complications during pregnancy in women with Type 1 diabetes and congenital malformations.

AIMS: To assess the association between vascular complications of diabetes and the risk of congenital malformations in pregnant women with Type 1 diabetes. METHODS: We conducted an observational retrospective cohort study in women with Type 1 diabetes who received care consecutively from three tertiary care diabetes-in-pregnancy clinics in Calgary, Alberta, Canada. Multivariable logistic regression was used to assess the association between vascular complications (retinopathy, nephropathy and pre-existing hypertension) and congenital malformations in offspring of women with Type 1 diabetes. RESULTS: Of 232 women with Type 1 diabetes, 49 (21%) had at least one vascular complication and there were 52 babies with congenital malformations. Maternal age (31.8 ± 5.0 vs. 29.4 ± 4.7 years, P < 0.01), diabetes duration (20.9 ± 6.7 vs. 11.2 ± 7.4 years, P < 0.01) and pre-eclampsia rate (12.5% vs. 1.3%, P < 0.01) were higher in mothers with vascular complications than in those without. Multivariable analyses showed that vascular complications were not associated with an increased risk of congenital malformations (odds ratio 1.16, 95% confidence interval 0.46 to 2.88). CONCLUSIONS: Vascular complications are common, occurring in one-fifth of pregnant women with Type 1 diabetes, and in this study do not appear to be associated with an increased risk of congenital malformations in children.

Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial.

Importance: Results of studies on use of prophylactic haloperidol in critically ill adults are inconclusive, especially in patients at high risk of delirium. Objective: To determine whether prophylactic use of haloperidol improves survival among critically ill adults at high risk of delirium, which was defined as an anticipated intensive care unit (ICU) stay of at least 2 days. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled investigator-driven study involving 1789 critically ill adults treated at 21 ICUs, at which nonpharmacological interventions for delirium prevention are routinely used in the Netherlands. Patients without delirium whose expected ICU stay was at least a day were included. Recruitment was from July 2013 to December 2016 and follow-up was conducted at 90 days with the final follow-up on March 1, 2017. Interventions: Patients received prophylactic treatment 3 times daily intravenously either 1 mg (n = 350) or 2 mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride. Main Outcome and Measures: The primary outcome was the number of days that patients survived in 28 days. There were 15 secondary outcomes, including delirium incidence, 28-day delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay. Results: All 1789 randomized patients (mean, age 66.6 years [SD, 12.6]; 1099 men [61.4%]) completed the study. The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0-0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78-1.30, P=.82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, -3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0-0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0-0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 [0.3%] for the 2-mg haloperidol group vs 1 [0.1%] for the placebo group). Conclusions and Relevance: Among critically ill adults at high risk of delirium, the use of prophylactic haloperidol compared with placebo did not improve survival at 28 days. These findings do not support the use of prophylactic haloperidol for reducing mortality in critically ill adults. Trial Registration: clinicaltrials.gov Identifier: NCT01785290.

[Less ventilator-associated pneumonia after oral decontamination with chlorhexidine; a randomised trial]. / Minder beademingspneumonieën door orale decontaminatie met chloorhexidine; gerandomiseerde trial.

OBJECTIVE: To determine the effect of oral decontamination with either chlorhexidine (CHX, 2%) or the combination chlorhexidine-colistin (CHX-COL, 2%-2%) on the frequency and the time to onset of ventilator-associated pneumonia in Intensive Care patients. DESIGN: Double blind, placebo-controlled, multicentre, randomised trial. METHODS: Consecutive ICU patients needing at least 48 h of mechanical ventilation were enrolled in a randomized trial with 3 arms: CHX, CHX-COL, and placebo (PLAC). The trial medication was administered in the oral cavity every 6 h. Oropharyngeal swabs were obtained daily and analysed quantitatively for Gram-positive and Gram-negative microorganisms. Endotracheal colonisation was monitored twice weekly. Ventilator-associated pneumonia was diagnosed on the basis of a combination of clinical, radiological and microbiological criteria. RESULTS: Of 385 patients included, 130 received PLAC, 127 CHX and 128 CHX-COL. Baseline characteristics in the three groups were comparable. The daily risk of ventilator-associated pneumonia was reduced in both treatment groups compared to PLAC: 65% (HR= 0.352; 95% CI: 0.160-0.791; p = 0.012) for CHX and 55% (HR= 0.454; 95%/ CI: 0.224-0.925; p = 0.030) for CHX-COL. CHX-COL provided a significant reduction in oropharyngeal colonisation with both Gram-negative and Gram-positive microorganisms, whereas CHX significantly affected only colonisation with Gram-positive microorganisms. There were no differences in the duration of mechanical ventilation, ICU-stay or ICU-survival. CONCLUSION: Oral decontamination of the oropharyngeal cavity with chlorhexidine or the combination chlorhexidine-colistin reduced the incidence and the time to onset ofventilator-associated pneumonia.

Orgasm after radical prostatectomy.

OBJECTIVE: To evaluate the ability to obtain and the quality of orgasm after radical prostatectomy. PATIENTS AND METHODS: The orgasms experienced after undergoing radical prostatectomy were evaluated in 20 men (median age 65 years, range 56-76) using a semi-structured interview and a self-administered questionnaire. In addition, the patients were asked to write a brief statement about their experiences and sensations during orgasm before and after the operation. RESULTS: Eighteen patients returned the questionnaire and 17 completed a statement indicating what their orgasm was like before and after radical prostatectomy. After the operation, no patient was able to maintain a completely rigid erection, but for five patients the erection was sufficient for sexual intercourse. Nine patients used a vacuum device or intracavernosal self-injection. Half the patients reported diminished sexual desire (libido) and arousal after the operation and reported the same to occur in their partners. During their "dry' orgasm post-operatively, none of the patients experienced the exquisite sensation of inevitability, the so-called "point of no return'. Seven of the 14 patients experiencing orgasm complained that their orgasmic sensation was weakened. Four patients reported normal pleasure and sensation compared to that experienced pre-operatively. Surprisingly, nine of the 14 patients had involuntary loss of urine at orgasm; for five of them this was sufficient reason to avoid any sexual contact with their partner. CONCLUSION: Radical prostatectomy may have serious consequences on libido and erectile function but sometimes other important factors, such as the absence of prostate and seminal vesicle contractions, the loss of ejaculation and involuntary loss of urine, may also compromise the orgasm.