Antipsychotic effects on anthropometric outcomes in anorexia nervosa: a retrospective chart review of hospitalized children and adolescents.

BACKGROUND: Off-label antipsychotic use is not uncommon in youth with anorexia nervosa (AN), aiming to enhance suboptimal weight restoration, yet its efficacy remains debated, especially in youth. METHODS: Retrospective chart review of consecutively admitted inpatients (ages 8-18 years) with restricting/binge-purge AN, comparing youth with versus without antipsychotic treatment regarding baseline factors, treatment, and anthropometric outcome characteristics including all patients and matched subgroups. Matched subsamples were also compared regarding faster versus slower weight change (median split). Furthermore, within-subject analyses compared weight gain trajectories before versus after antipsychotic use in antipsychotic-treated youth. These results were then compared in a pre-/post design with the matched control group without antipsychotic treatment, using the mean duration until antipsychotic use in the antipsychotic-treated group as the dividing timeline, controlling for a potential order effect, in that later rather than earlier antipsychotic treatment for AN may be more successful. RESULTS: Of 294 youth with AN (median age = 15.2 (interquartile range = 14.0, 16.6) years, females = 96.6%, restricting subtype = 81.0%, hospitalization duration = 98.2 ± 43.2 days), 44 (15.0%) underwent 52 antipsychotic trials (olanzapine = 63.5%). In multivariable analyses, antipsychotic use was independently associated with younger age, childhood physical abuse history, comorbid borderline personality traits, and lower pre-antipsychotic weight gain (p < 0.0001). In unmatched groups, antipsychotic-treated versus non-treated youth had significantly lower discharge anthropometric parameters, longer inpatient treatment, and lower weight change/week (p < 0.001-p = 0.005), without significant differences between olanzapine and non-olanzapine antipsychotics (p = 0.27-0.44). Non-significant antipsychotic effects on weight outcomes were confirmed in (1) matched subgroups of antipsychotic-treated versus non-treated youth (n = 43 each), (2) youth with faster versus slower weight gain (n = 21 vs. n = 22), and (3) antipsychotic-treated youth when comparing weight change before versus after antipsychotic use (n = 31). Moreover, in antipsychotic-treated youth, weight change/week remained significantly lower versus matched non-antipsychotic-treated youth (n = 31) both before (p = 0.053) and after (p = 0.006) the median time (5 weeks) until antipsychotic use. CONCLUSIONS: In this naturalistic study, clinician's antipsychotic choice, given to a more severely ill subgroup of adolescents with AN, did not significantly improve overall worse weight change trajectories during inpatient treatment, even in matched subgroups. Randomized trials in individuals reflecting real-world samples are needed to evaluate the utility of antipsychotic treatment in youth with AN.

Anorexia nervosa is one of the psychiatric diseases with the highest risk of death in adolescence. People with anorexia nervosa are often severely underweight out of fear of being too "fat". Treatment is difficult. Clinicians not infrequently use off-label antipsychotic medications to improve weight gain in anorexia nervosa. Unfortunately, currently, there is little evidence of efficacy for antipsychotics, especially in children and adolescents. We examined the files of youth (8­18 years old) who were treated as inpatients between 1992 and 2015. Altogether, 44 (15%) of the 294 youth were prescribed antipsychotics, with antipsychotic use increasing over time (1992 = 0% to 2015 = 20%). Of all antipsychotic drugs, olanzapine was given most frequently (64%). Patients who received antipsychotic medications were younger and sicker than patients without antipsychotics. Also, patients prescribed antipsychotics gained less weight per week before starting antipsychotics. They also gained less weight than patients not receiving antipsychotics. Despite being treated longer as inpatients, antipsychotic-treated youth had lower discharge body weight values. We did not find differences between olanzapine and other antipsychotics regarding weight gain. In summary, we found that antipsychotics did not help with weight gain in youth with anorexia nervosa.

Frequency and correlates of lifetime suicidal ideation and suicide attempts among consecutively hospitalized youth with anorexia nervosa and bulimia nervosa: results from a retrospective chart review.

BACKGROUND: Youth with eating disorders (EDs) face an increased risk of a premature suicide death. Precursors of completed suicide are suicidal ideation and suicide attempts, which need to be well understood to prevent suicide. However, epidemiological data on the lifetime prevalence and clinical correlates of suicidal ideation and suicide attempts (i.e., "suicidality") are lacking for the vulnerable group of inpatient ED youth. METHODS: This retrospective chart review was conducted at a psychiatric child and adolescent inpatient department, covering a 25-year period. Consecutively hospitalized youth with an ICD-10 diagnosis of anorexia nervosa (AN), restricting type (AN-R), binge-purging type (AN-BP), and bulimia nervosa (BN) were included. Data extraction and coding were standardized with trained raters extracting information from patient records according to a procedural manual and using a piloted data extraction template. The lifetime prevalence of suicidal ideation and suicide attempts was calculated for each ED subgroup, and clinical correlates of suicidality were analyzed via multivariable regression analyses. RESULTS: In the sample of 382 inpatients aged 9-18 years (median age = 15.6, females = 97.1%; AN-R: n = 242, BN: n = 84, AN-BP: n = 56), 30.6% of patients had lifetime suicidal ideation (BN:52.4% ≈ AN-BP:44.6% > AN-R:19.8%, χ2(2,382) = 37.2, p < 0.001, Φ = 0.31), and 3.4% of patients reported a history of suicide attempts (AN-BP:8.9% ≈ BN:4.8% > AN-R:1.7%, χ2(2,382) = 7.9, p = 0.019, Φ = 0.14). Independent clinical correlates of suicidality were i) for AN-R a higher number of psychiatric comorbidities (OR = 3.02 [1.90, 4.81], p < 0.001), and body weight < 1st BMI percentile at hospital admission (OR = 1.25 [1.07,1.47], p = 0.005) (r2 = 0.20); ii) for AN-BP patients a higher number of psychiatric comorbidities (OR = 3.68 [1.50, 9.04], p = 0.004) and history of childhood abuse (OR = 0.16 [0.03, 0.96], p = 0.045) (r2 = 0.36), and iii) for BN patients a higher prevalence of non-suicidal self-injury (NSSI)(OR = 3.06 [1.37, 6.83], p = 0.006) (r2 = 0.13). CONCLUSIONS: About half of youth inpatients with AN-BP and BN had lifetime suicidal ideation, and one-tenth of patients with AN-BP had attempted suicide. Treatment programs need to address specific clinical correlates of suicidality, namely, low body weight, psychiatric comorbidities, history of childhood abuse, and NSSI. TRIAL REGISTRATION: This study was not a clinical trial but a retrospective chart review based on routinely assessed clinical parameters. The study includes data from human participants; however: (1) no intervention and no prospective assignment to interventions were performed, and (2) no evaluation of intervention in participants was accomplished.

Lifetime prevalence and clinical correlates of nonsuicidal self-injury in youth inpatients with eating disorders: a retrospective chart review.

BACKGROUND: Youths with eating disorders (EDs) engaging in nonsuicidal self-injury (NSSI) are at higher suicide risk because EDs and NSSI are associated with suicidality. However, epidemiologic data on NSSI lacks in the vulnerable group of youth ED inpatients. METHODS: This retrospective chart review included patients up to 18 years of age with an ICD-10 diagnosis of anorexia nervosa, restricting type (AN-R), anorexia nervosa, binge-purge type (AN-BP), and bulimia nervosa (BN), treated at the child and adolescent inpatient department of the University Hospital in Berlin, Germany, between 1990 and 2015. Across and within ED subgroups, lifetime NSSI prevalence, methods of self-harm, and clinical correlates were evaluated. Independent correlations of demographic and clinical factors with NSSI were identified via multivariable regression models. RESULTS: Of 382 inpatients (median = 15.6 (range = 9-18) years, females = 97.1%), 21.5% reported lifetime NSSI, consisting of cutting = 86.6%, scratching = 12.2%, and hitting = 8.5%. NSSI was more frequent in BN (47.6%) and AN-BP (39.3%) than AN-R (8.3%) (Φ = 0.43). Across ED subgroups, NSSI was associated with a higher prevalence of psychiatric comorbidities (AN-R: Φ = 0.55; AN-BP: Φ = 0.69; BN: Φ = 0.78), suicidal ideation (AN-R: Φ = 0.30; AN-BP: Φ = 0.38; BN: Φ = 0.29), and psychiatric medication use (AN-R: Φ = 0.23; AN-BP: Φ = 0.64; BN: Φ = 0.60). In multivariable regression analyses, NSSI was independently associated with a higher prevalence of psychiatric comorbidities (AN-R: OR = 2.93 [1.42, 6.04]; AN-BP: OR = 2.67 [1.13, 6.31]; BN: OR = 3.75 [1.71, 8.23]). Additionally, independent correlates with NSSI in AN-R included a higher prevalence of suicidal ideation (OR = 0.21 [0.72, 0.64]) and less weekly weight gain (OR = 0.03 [0.02, 0.43]), while in BN, NSSI was correlated with longer inpatient treatment duration (OR = 1.01 [1.00, 1.02]). CONCLUSIONS: There is a high lifetime prevalence of NSSI among youth with AN and BN requiring inpatient treatment, especially those with binge-purge behaviors. Treatment programs must be tailored to address psychiatric comorbidities and suicidality to improve patient care and suicide prevention. TRIAL REGISTRATION: This study was not considered a clinical trial but a retrospective chart review based on routinely assessed clinical parameters. The study includes data from human participants, however: (1) no intervention and no prospective assignment to interventions were performed, and (2) no evaluation of an intervention on participants was accomplished.

Generic and specific recurrent neural network models: Applications for large and small scale biopharmaceutical upstream processes.

The calculation of temporally varying upstream process outcomes is a challenging task. Over the last years, several parametric, semi-parametric as well as non-parametric approaches were developed to provide reliable estimates for key process parameters. We present generic and product-specific recurrent neural network (RNN) models for the computation and study of growth and metabolite-related upstream process parameters as well as their temporal evolution. Our approach can be used for the control and study of single product-specific large-scale manufacturing runs as well as generic small-scale evaluations for combined processes and products at development stage. The computational results for the product titer as well as various major upstream outcomes in addition to relevant process parameters show a high degree of accuracy when compared to experimental data and, accordingly, a reasonable predictive capability of the RNN models. The calculated values for the root-mean squared errors of prediction are significantly smaller than the experimental standard deviation for the considered process run ensembles, which highlights the broad applicability of our approach. As a specific benefit for platform processes, the generic RNN model is also used to simulate process outcomes for different temperatures in good agreement with experimental results. The high level of accuracy and the straightforward usage of the approach without sophisticated parameterization and recalibration procedures highlight the benefits of the RNN models, which can be regarded as promising alternatives to existing parametric and semi-parametric methods.

Hydroxytyrosol is the major anti-inflammatory compound in aqueous olive extracts and impairs cytokine and chemokine production in macrophages.

Substances in olive products contribute to improved health as suggested by epidemiological data. In this study we assessed the effects of hydroxytyrosol (HT) on inflammatory mediators, cytokines and chemokines, and identified anti-inflammatory constituents of aqueous olive extracts, I.E., olive vegetation water (OVW). Murine macrophages (RAW264.7 cells) were stimulated with lipopolysaccharide (LPS) in the absence or presence of substances; inflammatory mediators [nitric oxide (NO), prostaglandin E2 (PGE2), cytokines, interleukins, chemokines] were determined by the Griess reaction, EIA, or multiplex ELISA (Luminex technology). Expression of inflammatory genes was determined by RT-PCR. Aqueous olive extracts were fractionated by preparative HPLC and the fractions investigated for their effects on NO and PGE2 production. Results were further analyzed by principal component analysis. HT inhibited production of NO and PGE2 with an IC50 of 11.4 and 19.5 µM, respectively, reflecting strong anti-inflammatory activity. HT and OVW diminished secretion of cytokines (IL-1 α, IL-1 ß, IL-6, IL-12, TNF- α), and chemokines (CXCL10/IP-10, CCL2/MCP-1). HT and OVW concentration-dependently reduced the expression of genes of inducible nitric oxide synthase (iNOS), IL-1 α, CXCL10/IP-10, MIP-1 ß, matrix metalloproteinase-9, and prostaglandin E2 synthase (PGES). The effects of HT were partly mediated VIA the NF- κB pathway, as shown by RT-PCR analysis. HT was identified as the main bioactive compound of OVW. The data provide a molecular basis for elucidating the effects of HT on inflammatory processes. The effects of HT on NO and chemokine production point to their impact on chronic inflammatory processes in endothelium or arthritis.

From the genome sequence to the proteome and back: evaluation of E. coli genome annotation with a 2-D gel-based proteomics approach.

The ambition of systems biology to understand complex biological systems at the molecular level implies that we need to have a concrete and correct understanding of each molecular entity and its function. However, even for the best-studied organism, Escherichia coli, a large number of proteins have never been identified and characterised from wild-type cells, and/or await unravelling of their biological role. Instead, the ORF models for these proteins have been predicted by suitable algorithms and/or through comparison with known, homologous proteins from other organisms, approaches which may be prone to error. In the present study, we used a combination of 2-DE, MALDI-TOF-MS and PMF to identify 1151 different proteins in E. coli K12 JM109. Comparison of the experimental with the theoretical Mr and pI values (4000 experimental values each) allowed the identification of numerous proteins with incorrect or incomplete ORF annotations in the current E. coli genome databases. Several inconsistencies in genome annotation were verified experimentally, and up to 55 candidates await further investigation. Our findings demonstrate how an up-to-date 2-D gel-based proteomics approach can be used for improving the annotation of prokaryotic genomes. They also highlight the need for harmonization among the different E. coli genome databases.

Model-based inference of gene expression dynamics from sequence information.

A dynamic model of prokaryotic gene expression is developed that makes considerable use of gene sequence information. The main contribution arises from the fact that the combined gene expression model allows us to access the impact of altering a nucleotide sequence on the dynamics of gene expression rates mechanistically. The high level of detail of the mathematical model is considered as an important step towards bringing together the tremendous amount of biological in-depth knowledge that has been accumulated at the molecular level, using a systems level analysis (in the sense of a bottom-up, inductive approach). This enables to the model to provide highly detailed insights into the various steps of the protein expression process and it allows us to access possible targets for model-based design. Taken as a whole, the mathematical gene expression model presented in this study provides a comprehensive framework for a thorough analysis of sequence-related effects on the stages of mRNA synthesis, mRNA degradation and ribosomal translation, as well as their nonlinear interconnectedness. Therefore, it may be useful in the rational design of recombinant bacterial protein synthesis systems, the modulation of enzyme activities in pathway design, in vitro protein biosynthesis, and RNA-based vaccination.

High-throughput lipophilicity measurement with immobilized artificial membranes.

We report on a new, high-throughput assay designed to measure octanol/water partition coefficients in early drug discovery. The assay is carried out in 96-well microtiterplates and measures the diffusion of compounds between two aqueous compartments separated by a thin octanol liquid layer. Octanol/water partition coefficients are derived from the apparent permeability (P(a)) values using a calibration curve. The assay can measure partition coefficients within the range -2 to + 8; thus, a dynamic range of 10 log units can be covered in one single run. Unlike chromatographic methods, the technology is not restricted to neutral and weakly basic compounds, and, as no stationary phase is involved, the data can be strictly compared with values obtained from traditional methods such as shake-flask/HPLC or dual-phase potentiometric titration.

Banning antimicrobial growth promoters in feedstuffs does not result in increased therapeutic use of antibiotics in medicated feed in pig farming.

OBJECTIVE: We analysed prescription patterns for medicated feedstuffs to find out whether the ban on nutritive antimicrobial growth promotion introduced in Switzerland in 1999 had caused an increase in the therapeutic use of antimicrobial agents given orally to piglets and fattening pigs. METHODS: From 1996 to 2001, a total of 6427 prescriptions were evaluated for medicated pig feed delivered to pig farms in the Swiss canton of St Gall. Prescribed daily doses (PDD) were derived for 14 active ingredients. The overall amount and the potency of antimicrobial agents were measured in relation to the size of the pig population (PDD/population). RESULTS: The use of antimicrobial agents decreased between 1996 (1200 kg) and 1999 (708 kg) and increased thereafter from 779 kg in 2000 to 936 kg in 2001. The PDD/population (6.1 in 1996 and 3.6 in 1999) remained low (3.3 in 2000 and 3.4 in 2001). The difference between the two parameters can be explained by changes in prescribing patterns, namely a reduction in antimicrobial therapy of respiratory diseases in fattening pigs and a shift to antimicrobial treatment of gastrointestinal-tract infections in piglets using drugs with a high PDD.