A proof-of-concept study applying machine learning methods to putative risk factors for eating disorders: results from the multi-centre European project on healthy eating.

BACKGROUND: Despite a wide range of proposed risk factors and theoretical models, prediction of eating disorder (ED) onset remains poor. This study undertook the first comparison of two machine learning (ML) approaches [penalised logistic regression (LASSO), and prediction rule ensembles (PREs)] to conventional logistic regression (LR) models to enhance prediction of ED onset and differential ED diagnoses from a range of putative risk factors. METHOD: Data were part of a European Project and comprised 1402 participants, 642 ED patients [52% with anorexia nervosa (AN) and 40% with bulimia nervosa (BN)] and 760 controls. The Cross-Cultural Risk Factor Questionnaire, which assesses retrospectively a range of sociocultural and psychological ED risk factors occurring before the age of 12 years (46 predictors in total), was used. RESULTS: All three statistical approaches had satisfactory model accuracy, with an average area under the curve (AUC) of 86% for predicting ED onset and 70% for predicting AN v. BN. Predictive performance was greatest for the two regression methods (LR and LASSO), although the PRE technique relied on fewer predictors with comparable accuracy. The individual risk factors differed depending on the outcome classification (EDs v. non-EDs and AN v. BN). CONCLUSIONS: Even though the conventional LR performed comparably to the ML approaches in terms of predictive accuracy, the ML methods produced more parsimonious predictive models. ML approaches offer a viable way to modify screening practices for ED risk that balance accuracy against participant burden.

Application of fragment based virtual screening towards inhibition of bacterial N-acetyglucosaminidase$.

A structure-based approach is applied for the development of inhibitors of bacterial N-acetyglucosaminidase (autolysin). Autolysins are enzymes involved in the degradation of peptidoglycan and therefore participate in bacterial cell growth and different lysis phenomena. Several studies indicate that by the inhibition of autolysins, and consequently of bacterial cell division, antibacterial activity can be obtained, thus paving the road to a novel group of therapeutics against human pathogens. As crystal structures of the autolysin E (AtlE)-ligand complexes were obtained in our laboratories, fragment-based virtual screening was the method of choice for the initial studies. Fragment libraries from various databases were merged to increase the number of compounds for the virtual screening. Twenty-four commercially available virtual hits were selected and subjected to quantitative analysis of binding interactions using the surface plasmon resonance technique. Twelve fragments showed fragment-AtlE interactions. For F1, the top hit of the virtual screening, a KD of 228 µM was determined, while other fragments displayed non-stoichiometric binding. Blind docking of potential binders uncovers three possible allosteric sites. Ligands of N-acetyglucosaminidase identified in our study represent valuable information for the further development of AtlE inhibitors, which could in future represent antibacterial agents acting by a novel mode of action.

DC-SIGN antagonists, a potential new class of anti-infectives.

DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a type II C-type lectin that functions as an adhesion molecule located on dendritic cells (DCs). It enables some of the functions of DCs, including migration, pathogen recognition, internalisation and processing, and their binding to T cells. HIV-1 has been reported to enter DCs by being bound to DC-SIGN, escaping the normal lytic pathway in DCs' endosomes and avoiding the immune system defence system. A very similar mechanism of survival has been observed for some other pathogens. This makes DC-SIGN a receptor of interest in the design of distinctive anti-infectives that would inhibit DC-SIGN-pathogen interaction by blocking the very first step in pathogen infection. In this review we outline the development of DC-SIGN antagonists, focusing mainly on a glycomimetic approach. Based on the fact that DCSIGN binds mannose- and fucose-based oligo- and polysaccharides, their structural mimics have been designed and proved to inhibit pathogen-DC-SIGN interaction. Furthermore, recent in vitro studies have demonstrated that DC-SIGN antagonists block effectively the transmission of pathogens like HIV-1 and Ebola to CD4+ T cells. Although DC-SIGN has not been validated in vivo as a druggable target yet, we await future DC-SIGN antagonists as a new and highly promising group of novel anti-infectives.

Lifetime course of eating disorders: design and validity testing of a new strategy to define the eating disorders phenotype.

BACKGROUND: Aetiological studies of eating disorders would benefit from a solution to the problem of instability of eating disorder symptoms. We present an approach to defining an eating disorders phenotype based on the retrospective assessment of lifetime eating disorders symptoms to define a lifetime pattern of illness. We further validate this approach by testing the most common lifetime categories for differences in the prevalence of specific childhood personality traits. METHOD: Ninety-seven females participated in this study, 35 with a current diagnosis of restricting anorexia nervosa, 32 with binge/purging subtype of anorexia nervosa and 30 with bulimia nervosa. Subjects were interviewed by a newly developed EATATE Lifetime Diagnostic Interview for a retrospective assessment of the lifetime course of eating disorders symptoms and childhood traits reflecting obsessive-compulsive personality. RESULTS: The data illustrate the extensive instability of the eating disorders diagnosis. Four most common lifetime diagnostic categories were identified that significantly differ in the prevalence of childhood traits. Perfectionism and rigidity were more common in groups with a longer duration of underweight status, longer episodes of severe food restriction, excessive exercising, and shorter duration of binge eating. CONCLUSIONS: The assessment of lifetime symptoms may produce a more accurate definition of the eating disorders phenotype. Obsessive-compulsive traits in childhood may moderate the course producing longer periods of underweight status. These findings may have important implications for nosology, treatment and future aetiological studies of eating disorders.

Childhood eating and weight in eating disorders: a multi-centre European study of affected women and their unaffected sisters.

BACKGROUND: Previous studies have suggested that childhood eating and weight problems may be risk factors for eating disorders. Robust evidence is still lacking. AIMS: To investigate whether childhood eating and weight problems increase the risk of eating disorders in affected women compared to their unaffected sisters. METHODS: Women (150) with anorexia (AN) or bulimia nervosa (BN) recruited from clinical and community samples were compared to their unaffected sister closest in age on maternal reports of childhood eating and weight. RESULTS: Women with BN were significantly more overweight at the ages of 5 and 10 (both OR = 2.8, p < 0.01), ate a lot (OR = 1.3, p < 0.01), were less picky (OR = 0.6, p < 0.05) and ate quickly (OR = 2.3, p < 0.05) between the ages of 6 and 10 compared to their healthy sisters. Significantly more women with AN were described as having a higher weight at 6 months (OR = 0.8, p < 0.01) and 1 year (OR = 0.6, p < 0.01) compared to their healthy sisters. Childhood eating was comparable in the women with AN and their unaffected sisters. CONCLUSIONS: Traits of childhood overeating were more common in bulimic women compared to their unaffected siblings. Subjects with AN did not differ from their sisters on eating variables. The increased risk of BN due to childhood overweight suggests that prevention strategies for childhood obesity and overweight may therefore be applicable in BN.

Set shifting in anorexia nervosa: an examination before and after weight gain, in full recovery and relationship to childhood and adult OCPD traits.

Deficits in set shifting tasks are present in anorexia nervosa (AN), but it is not known whether these deficits are traits independent of current disease or nutritional status or merely a temporary consequence of starvation or psychopathology. The aims of the present study were to determine if set-shifting sub-optimal performance are state or trait-related by examining set shifting in patients with current or past AN, and the extent of association of these deficits with obsessive compulsive traits and behaviours. To achieve this we examined set shifting abilities in three groups of subjects: (a) AN patients with current illness, prior to receiving treatment (AN); (b) people with past AN currently in long term recovery (ANRec) and a healthy comparison group (HC). We also longitudinally followed up a subset for the AN group who showed weight recovery in response to in patient treatment (ANWR). We administered a group of set shifting tests, which included cognitive, perceptual and motor shifting tasks. A semi-structured interview was obtained to ascertain obsessive compulsive personality disorder (OCPD) traits as a child and adult. Set-shifting difficulties were observed in the AN group, but to a lesser extent in the ANRec group. In the AN group these difficulties did not show any improvement follow re-testing after weight recovery. Performance on set shifting tasks was associated with childhood rigidity and inflexibility. Some aspects of set shifting sub-optimal performance in AN appear to be a trait rather than a state marker.

Combined family trio and case-control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa.

The high activity Val158 (H) allele of the dopamine-metabolizing enzyme catechol-O-methyltransferase (COMT) was associated with anorexia nervosa (AN) in a recent family trio-based study of patients from Israel. In an attempt to replicate this finding, we performed a combined family trio and case-control study in an European population from seven centers in six different countries (Austria, Germany, Great Britain, Italy [Milan], Italy [Florence], Slovenia, and Spain), together contributing a total of 372 family trios, 684 controls and 266 cases. TDT analyses of high (H) and low (L) alleles in family trios showed that H allele and L allele were each transmitted 101 times (chi(2) = 0, ns). Allele-wise case-control analysis using separate samples simply combined from the centers was also not significant, with the frequencies of the H allele 50% in cases and same in controls. Stratified analysis of data from all centers gave an odds ratio of 0.98 (Cornfield 95% confidence limits 0.78-1.24). Analysis by genotype was likewise not significant (overall chi(2) = 0.42). Because we were not able to support the primary hypothesis that Val158Met is a risk factor for AN, we did not perform secondary analysis of minimum body mass index (mBMI), age at onset or illness subtype (restricting or binge purging anorexia). Overall we found no support for the hypothesis that the Val158 allele of COMT gene is associated with AN in our combined European sample.

Thrombin receptor antagonists; recent advances in PAR-1 antagonist development.

The receptor for the serine protease thrombin, the protease-activated receptor-1 (PAR-1), has been recently characterized. Its key roles in thrombin-stimulated human platelet activation, vascular endothelial and smooth muscle proliferation, inflammatory responses and neurodegeneration suggest receptor involvement in various disorders such as arterial thrombosis, atherosclerosis, restenosis, inflammation and myocardial infarction. It has been established that thrombin elicits the majority of its effects via PAR-1. PAR-1 has a novel mechanism of activation. The receptor, a member of the seven-transmembrane domain receptor family, is cleaved by thrombin at a specific site on the N-terminal extension, and a newly exposed N-terminus acts as a tethered ligand to activate the receptor itself. The need for development of a PAR-1 antagonist that may be valuable as a therapeutic agent has been recognized. An intriguing challenge is the necessity of the antagonist to compete with an intramolecular ligand while showing no intrinsic activity. The lead compounds were found to be synthetic peptides containing N-terminal hexapeptide or pentapeptide (Ser-Phe-Leu-Leu-Arg-Asn, Ser-Phe-Leu-Leu-Arg) or modified sequences (TRAPs; thrombin receptor-activating peptides), which exhibit full PAR-1 agonist activity. Selective PAR-1 antagonists have already been synthesized. Though their potency is still not enough to justify therapeutic use, it is clear that future progress will bring a novel class of drugs-thrombin receptor antagonists. The emphasis of this review, therefore, will be placed on advances in the discovery of potent and selective PAR-1 antagonists.