Review of food safety hazards in circular food systems in Europe.

European food production systems have become very efficient in terms of high yield, quality and safety. However, these production systems are not sustainable since, amongst other reasons, a significant proportion of the production is wasted or lost in the supply chain. One of the strategies of the European Union is to achieve climate neutrality by moving towards a circular economy with better waste management. This includes, reducing food waste and losses, and reusing or recycling by-products of the food and feed production systems. A circular economy would greatly improve the sustainability of the European food systems, but attention must be paid to the emergence of (new) food safety hazards. New or not well-known hazards can occur because by-products are reintroduced into the system or new processing steps are used for recycling, and/or known hazards can accumulate in the food production chain due to the reuse of (by-)products. This review addresses food safety hazards in the circular biobased economy, covering the domains of plant production, animal production, aquaculture, and packaging. Instead of an exhaustive list of all potential hazards, example cases of circular food production systems are given, highlighting the known and potential emerging food safety hazards. Current literature covering emerging food safety hazards in the circular economy shows to be limited. Therefore, more research is needed to identify food safety hazards, to measure the accumulation and the distribution of such hazards in the food and feed production systems, and to develop control and mitigation strategies. We advocate a food safety by design approach.

Jekyll or Hyde? The genome (and more) of Nesidiocoris tenuis, a zoophytophagous predatory bug that is both a biological control agent and a pest.

Nesidiocoris tenuis (Reuter) is an efficient predatory biological control agent used throughout the Mediterranean Basin in tomato crops but regarded as a pest in northern European countries. From the family Miridae, it is an economically important insect yet very little is known in terms of genetic information and no genomic or transcriptomic studies have been published. Here, we use a linked-read sequencing strategy on a single female N. tenuis. From this, we assembled the 355 Mbp genome and delivered an ab initio, homology-based and evidence-based annotation. Along the way, the bacterial "contamination" was removed from the assembly. In addition, bacterial lateral gene transfer (LGT) candidates were detected in the N. tenuis genome. The complete gene set is composed of 24 688 genes; the associated proteins were compared to other hemipterans (Cimex lectularis, Halyomorpha halys and Acyrthosiphon pisum). We visualized the genome using various cytogenetic techniques, such as karyotyping, CGH and GISH, indicating a karyotype of 2n = 32. Additional analyses include the localization of 18S rDNA and unique satellite probes as well as pooled sequencing to assess nucleotide diversity and neutrality of the commercial population. This is one of the first mirid genomes to be released and the first of a mirid biological control agent.

Pemetrexed exposure predicts toxicity in advanced non-small-cell lung cancer: A prospective cohort study.

BACKGROUND: We explored whether total exposure to pemetrexed predicts effectiveness and toxicity in advanced non-small-cell lung cancer (NSCLC). Furthermore, we investigated alternative dosing schedules. METHODS: In this prospective cohort study, patients with advanced NSCLC receiving first- or second-line pemetrexed(/platinum) were enrolled. Plasma sampling was performed weekly (cyclePK) and within 24 h (24hPK) after pemetrexed administration. With population pharmacokinetic/pharmacodynamic modelling, total exposure to pemetrexed during cycle 1 (area under the curve during chemotherapy cycle 1 [AUC1]) was estimated and related to progression-free survival (PFS)/overall survival (OS). We compared mean AUC1 (mg·h/L) in patients with and without severe chemotherapy-related adverse events (AEs) during total treatment. Second, different dosing schedules were simulated to minimise the estimated variability (coefficient of variation [CV]) of AUC. RESULTS: For 106 of 165 patients, concentrations of pemetrexed were quantified (24hPK, n = 15; cyclePK, n = 106). After adjusting for prognostic factors, sex, disease stage and World Health Organisation performance score, AUC1 did not predict PFS/OS in treatment-naive patients (n = 95) (OS, hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.00-1.11; PFS, HR = 1.03, 95% CI: 0.98-1.08). Patients with severe chemotherapy-related AEs (n = 55) had significantly higher AUC1 values than patients without them (n = 51) (226 ± 53 vs 190 ± 31, p < 0.001). Compared with body surface area-based dosing (CV: 22.5%), simulation of estimated glomerular filtration rate (eGFR)-based dosing (CV 18.5%) and fixed dose of 900 mg with 25% dose reduction, if the eGFR<60 mL/min (CV: 19.1%), resulted in less interindividual variability of AUC. CONCLUSIONS: Higher exposure to pemetrexed does not increase PFS/OS but is significantly associated with increased occurrence of severe toxicity. Our findings suggest that fixed dosing reduces interpatient pharmacokinetic variability and thereby might prevent toxicity, while preserving effectiveness.

Prediction of response to pemetrexed in non-small-cell lung cancer with immunohistochemical phenotyping based on gene expression profiles.

BACKGROUND: Palliative pemetrexed-based chemotherapy remains a standard of care treatment for the majority of patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Currently, no predictive markers for pemetrexed treatment are available. METHODS: Resected tumour samples from pemetrexed-naïve NSCLC patients were collected. Gene expression profiling with respect to predicted sensitivity to pemetrexed classified predicted responders (60%) and non-responders (40%) based on differentially expressed genes encoding for pemetrexed target enzymes. Genes showing a strong correlation with these target genes were selected for measurement of corresponding protein expressions by immunohistochemical (IHC) staining. A semi-quantitative IHC scoring method was applied to construct a prediction model for response to pemetrexed. A retrospective cohort of patients with advanced NSCLC treated with first-line pemetrexed-based chemotherapy was used for external validation. RESULTS: From ninety-one patients resected tumour samples were collected. The majority of patients had early or locally advanced NSCLC (96.3%). Gene expression profiling revealed five markers, which mRNA levels strongly correlated to pemetrexed target genes mRNA levels: TPX2, CPA3, EZH2, MCM2 and TOP2A. Of 63 (69%) patients IHC staining scores of these markers were obtained, which significantly differed between predicted non-responders and responders (P < 0.05). The optimized prediction model included EZH2 (OR = 0.56, 95% CI 0.35-0.90) and TPX2 (OR = 0.55, 95% CI 0.30-1.01). The model had a sensitivity of 86.8%, specificity of 63.6% and showed a good ability to distinct between responders and non-responders (C-index 0.86). In the external study population (N = 23) the majority of patients had metastatic NSCLC (95.7%). Partial response (PR) was established in 26.1%. The sensitivity decreased drastically to 33.3%, with a specificity of 82.4% and a C-index of 0.73. CONCLUSIONS: Using external validation this prediction model with IHC staining of target enzyme correlated markers showed a good discrimination, but lacked sensitivity. The role of IHC markers as response predictors for pemetrexed in clinical practice remains questionable.

Standing and travelling waves in a spherical brain model: The Nunez model revisited.

The Nunez model for the generation of electroencephalogram (EEG) signals is naturally described as a neural field model on a sphere with space-dependent delays. For simplicity, dynamical realisations of this model either as a damped wave equation or an integro-differential equation, have typically been studied in idealised one dimensional or planar settings. Here we revisit the original Nunez model to specifically address the role of spherical topology on spatio-temporal pattern generation. We do this using a mixture of Turing instability analysis, symmetric bifurcation theory, centre manifold reduction and direct simulations with a bespoke numerical scheme. In particular we examine standing and travelling wave solutions using normal form computation of primary and secondary bifurcations from a steady state. Interestingly, we observe spatio-temporal patterns which have counterparts seen in the EEG patterns of both epileptic and schizophrenic brain conditions.

An iron-oxygen intermediate formed during the catalytic cycle of cysteine dioxygenase.

Cysteine dioxygenase is a key enzyme in the breakdown of cysteine, but its mechanism remains controversial. A combination of spectroscopic and computational studies provides the first evidence of a short-lived intermediate in the catalytic cycle. The intermediate decays within 20 ms and has absorption maxima at 500 and 640 nm.

Good Practices in Model-Informed Drug Discovery and Development: Practice, Application, and Documentation.

This document was developed to enable greater consistency in the practice, application, and documentation of Model-Informed Drug Discovery and Development (MID3) across the pharmaceutical industry. A collection of "good practice" recommendations are assembled here in order to minimize the heterogeneity in both the quality and content of MID3 implementation and documentation. The three major objectives of this white paper are to: i) inform company decision makers how the strategic integration of MID3 can benefit R&D efficiency; ii) provide MID3 analysts with sufficient material to enhance the planning, rigor, and consistency of the application of MID3; and iii) provide regulatory authorities with substrate to develop MID3 related and/or MID3 enabled guidelines.

Assessment of Interspecies Differences in Drug-Induced QTc Interval Prolongation in Cynomolgus Monkeys, Dogs and Humans.

BACKGROUND AND PURPOSE: The selection of the most suitable animal species and subsequent translation of the concentration-effect relationship to humans are critical steps for accurate assessment of the pro-arrhythmic risk of candidate molecules. The objective of this investigation was to assess quantitatively the differences in the QTc prolonging effects of moxifloxacin between cynomolgus monkeys, dogs and humans. The impact of interspecies differences is also illustrated for a new candidate molecule. EXPERIMENTAL APPROACH: Pharmacokinetic data and ECG recordings from pre-clinical protocols in monkeys and dogs and from a phase I trial in healthy subjects were identified for the purpose of this analysis. A previously established Bayesian model describing the combined effect of heart rate, circadian variation and drug effect on the QT interval was used to describe the pharmacokinetic-pharmacodynamic relationships. The probability of a ≥ 10 ms increase in QT was derived as measure of the pro-arrhythmic effect. KEY RESULTS: For moxifloxacin, the concentrations associated with a 50% probability of QT prolongation ≥ 10 ms (Cp50) varied from 20.3 to 6.4 and 2.6 µM in dogs, monkeys and humans, respectively. For NCE05, these values were 0.4 µM vs 2.0 µM for monkeys and humans, respectively. CONCLUSIONS AND IMPLICATIONS: Our findings reveal significant interspecies differences in the QT-prolonging effect of moxifloxacin. In addition to the dissimilarity in pharmacokinetics across species, it is likely that differences in pharmacodynamics also play an important role. It appears that, regardless of the animal model used, a translation function is needed to predict concentration-effect relationships in humans.

Reliability and validity of the Cancer Therapy Satisfaction Questionnaire in lung cancer.

PURPOSE: To test the reliability and validity of the Cancer Treatment Satisfaction Questionnaire (CTSQ), to assess its relation with quality of life (QoL), and to assess the interpretability of the domain scores in lung cancer patients receiving intravenous chemotherapy. METHODS: Patients with stage IIIB and IV non-squamous non-small cell lung carcinoma treated with pemetrexed were enrolled in our study. They completed the 16-item CTSQ and two other (health-related) QoL questionnaires. Information about sociodemographic characteristics, cancer stage, and the experience of adverse events was collected. Internal consistency, construct validity, and clinical interpretability were calculated. RESULTS: Fifty-five patients completed the CTSQ. Correlations of the CTSQ items with its domain were all above 0.40. A high correlation between item 8 and the expectations of therapy and satisfaction with therapy domain was observed (0.50 and 0.48, respectively). The CTSQ domains demonstrated good internal consistency and low to moderate correlations of the CTSQ with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and World Health Organization Quality of Life-BREF. No significant differences in mean domain scores were observed in relation to the number and severity of different adverse events and chemotherapy-related adverse events. CONCLUSIONS: The Dutch version of the CTSQ was found to be a reliable and valid instrument to assess satisfaction and expectations of treatment in lung cancer patients receiving intravenous chemotherapy. Furthermore, the CTSQ proved to be of additional informative value as not all of its domains correlated with the various domains of the existing HRQoL instruments.

Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis.

BACKGROUND AND PURPOSE: Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans. EXPERIMENTAL APPROACH: We derived typical ΔQTc predictions at therapeutic exposure (ΔQTcTHER ) with 95% confidence intervals (95%CI) for 3 Kv 11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2-6 studies including 10-32 dogs per compound) to derive meta-predictions of typical ΔQTcTHER . Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature. KEY RESULTS: The 95%CIs of study-predicted ΔQTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1-69%). Meta-ΔQTcTHER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline. CONCLUSIONS AND IMPLICATIONS: Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical-clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments.

A Dutch version of the Overall Anxiety Severity and Impairment Scale (OASIS): Psychometric properties and validation.

BACKGROUND: The Overall Anxiety Severity and Impairment Scale (OASIS) is a 5-item self-report measure that can be used to assess the impact of any anxiety disorder or multiple anxiety disorders. Prior US investigations have shown the OASIS to be a reliable and valid measure. To date the OASIS has not been validated for use in a Dutch sample of anxiety disordered patients. METHODS: The present study assessed the psychometric properties of a Dutch version of the OASIS in a clinical sample of anxiety patients. Latent structure, internal consistency, convergent and discriminant validity, and cutoff score analyses were conducted. Results were compared to those obtained from a clinical sample of patients with psychiatric diagnoses other than anxiety disorders. RESULTS: Principal component analysis supported a unidimensional structure. The five OASIS items loaded strongly on a single factor (eigenvalue=3.682, loadings=.80-.89) which accounted for 73.65% of the variance, and had a high degree of internal consistency (Cronbach׳s α=91). OASIS scores demonstrated robust correlations with other measures of anxiety, neuroticism and general distress. Correlations with unrelated constructs were weak. Mean score (8.46) and cutoff score of the Dutch sample of anxiety patients were lower than scores previously found in American samples. A cutoff score of 5 correctly classified 82.5% of this sample as having an anxiety disorder diagnosis or not. An improvement of 4 points is indicative of a clinically significant change. LIMITATIONS: This study mainly relied on self-report measures in order to assess validity. Other types of measures should be used in future studies. CONCLUSIONS: The Dutch version of the OASIS showed good reliability and validity. Its brevity and sound psychometric properties make it a good instrument for screening and assessment purposes in the field of anxiety disorders.

Implementation of quantitative and systems pharmacology in large pharma.

Quantitative and systems pharmacology concepts and tools are the foundation of the model-informed drug development paradigm at Merck for integrating knowledge, enabling decisions, and enhancing submissions. Rigorous prioritization of modeling and simulation activities has enabled key drug development decisions and led to a high return on investment through significant cost avoidance. Critical factors for the successful implementation, examples on impact on decision making with associated return of investment, and drivers for continued success are discussed.

A brief cognitive-behavioral intervention for treating depression and panic disorder in patients with noncardiac chest pain: a 24-week randomized controlled trial.

BACKGROUND: Most patients with noncardiac chest pain experience anxiety and depressive symptoms. Commonly they are reassured and referred back to primary care, leaving them undiagnosed and untreated. Some small studies have suggested efficacy of 12 cognitive behavioral therapy (CBT) sessions. Our aim was to examine efficacy of brief CBT in reducing anxiety and depressive symptoms in patients with noncardiac chest pain and comorbid panic and/or depressive disorders. METHODS: In this 24-week randomized controlled trial comparing CBT (n = 60) versus treatment as usual (TAU, n = 53), we included all adults who presented at the cardiac emergency unit of a university hospital with noncardiac chest pain, scored ≥8 on the hospital anxiety and depression scale (HADS) and were diagnosed with a comorbid panic and/or depressive disorder with the Mini International Neuropsychiatric Interview. CBT consisted of six individual sessions. Main outcome was disease severity assessed with the clinical global inventory (CGI) by a blinded independent rater. RESULTS: ANCOVA in the intention-to-treat and completer sample showed that CBT was superior to TAU after 24 weeks in reducing disease severity assessed with CGI (P < .001). Secondary outcomes on anxiety (HADS-anxiety, state trait anxiety inventory (STAI)-trait) and depressive symptoms (Hamilton depression rating scale) were in line with these results except for HADS-depression (P = .10), fear questionnaire (P = .13), and STAI-state (P = .11). CONCLUSIONS: Brief CBT significantly reduces anxiety and depressive symptoms in patients with noncardiac chest pain who are diagnosed with panic and/or depressive disorders. Patients presenting with noncardiac chest pain should be screened for psychopathology and if positive, CBT should be considered.

On local bifurcations in neural field models with transmission delays.

Neural field models with transmission delays may be cast as abstract delay differential equations (DDE). The theory of dual semigroups (also called sun-star calculus) provides a natural framework for the analysis of a broad class of delay equations, among which DDE. In particular, it may be used advantageously for the investigation of stability and bifurcation of steady states. After introducing the neural field model in its basic functional analytic setting and discussing its spectral properties, we elaborate extensively an example and derive a characteristic equation. Under certain conditions the associated equilibrium may destabilise in a Hopf bifurcation. Furthermore, two Hopf curves may intersect in a double Hopf point in a two-dimensional parameter space. We provide general formulas for the corresponding critical normal form coefficients, evaluate these numerically and interpret the results.

Long-term survival after ICU treatment.

BACKGROUND: The aim of this paper was to study long-term survival in patients treated in the Intensive Care Unit (ICU) and who survived to hospital discharge. METHODS: This was a single-center retrospective cohort study of patients admitted to a mixed intensivist-led 10 bed ICU in a teaching hospital between 2004 and 2009 and discharged alive from the hospital with complete follow-up until January 1, 2011. RESULTS: A total of 3477 individual patients were admitted to the ICU, 491 (14.1%) of whom died in the hospital while 2986 survived to hospital discharge. In the first year after discharge 436 out of 2986 (14.6%) patients died. Mortality after hospital discharge was highest in the first three months. For patients discharged alive from the hospital the risk of dying during the first year increased significantly with age, APACHE II score at admission and being discharged to a place other than home. Sepsis on ICU admission, mechanical ventilation, renal replacement therapy during ICU treatment or admission type had no effect on one-year mortality rate. CONCLUSION: Patients who survive ICU treatment have a high risk of dying during the next year. This risk is almost as great the risk of dying during ICU and hospital treatment and increases with age and illness severity on admission to the ICU.

Improvements in cystic fibrosis lung disease and airway inflammation associated with etanercept therapy for rheumatoid arthritis: a case report.

Cystic fibrosis (CF) lung pathology is characterized by excessive neutrophilic inflammation and high tumor necrosis factor-alpha (TNF-α) levels. A cornerstone of CF management is reduction of the inflammatory burden in the lung. We present the case of a 19-year-old CF patient who demonstrated significant clinical improvement in her lung disease associated with a reduction in sputum percent neutrophils, following commencement of etanercept (TNF-α antagonist) for rheumatoid arthritis. She has not had any infectious complications or other significant adverse effects during 2 years of treatment. It may be time to reconsider TNF-α antagonists as potential anti-inflammatory agents for CF lung disease.

Guideline for the management of chronic obstructive pulmonary disease--2011 update.

OBJECTIVE: To revise the South African Guideline for the Management of Chronic Obstructive Pulmonary Disease (COPD) based on emerging research that has informed updated recommendations. KEY POINTS: (1) Smoking is the major cause of COPD, but exposure to biomass fuels and tuberculosis are important additional factors. (2) Spirometry is essential for the diagnosis and staging of COPD. (3) COPD is either undiagnosed or diagnosed too late, so limiting the benefit of therapeutic interventions; performing spirometry in at-risk individuals will help to establish an early diagnosis. (4) Oral corticosteroids are no longer recommended for maintenance treatment of COPD. (5) A therapeutic trial of oral corticosteroids to distinguish corticosteroid responders from non-responders is no longer recommended. (6) Primary and secondary prevention are the most cost-effective strategies in COPD. Smoking cessation as well as avoidance of other forms of pollution can prevent disease in susceptible individuals and ameliorate progression. Bronchodilators are the mainstay of pharmacotherapy, relieving dyspnoea and improving quality of life. (7) Inhaled corticosteroids are recommended in patients with frequent exacerbations and have a synergistic effect with bronchodilators in improving lung function, quality of life and exacerbation frequency. (8) Acute exacerbations of COPD significantly affect morbidity, health care units and mortality. (9) Antibiotics are only indicated for purulent exacerbations of chronic bronchitis. (10) COPD patients should be encouraged to engage in an active lifestyle and participate in rehabilitation programmes. OPTIONS: Treatment recommendations are based on the following: annual updates of the Global Obstructive Lung Disease (GOLD), initiative, that provide an evidence-based comprehensive review of management; independent evaluation of the level of evidence in support of some of the new treatment trends; and consideration of factors that influence COPD management in South Africa, including lung co-morbidity and drug availability and cost. OUTCOME: Holistic management utilising pharmacological and nonpharmacological options are put in perspective. EVIDENCE: Working groups of clinicians and clinical researchers following detailed literature review, particularly of studies performed in South Africa, and the GOLD guidelines. BENEFITS, HARMS AND COSTS. The guideline pays particular attention to cost-effectiveness in South Africa, and promotes the initial use of less costly options. It promotes smoking cessation and selection of treatment based on objective evidence of benefit. It also rejects a nihilistic or punitive approach, even in those who are unable to break the smoking addiction. RECOMMENDATIONS: These include primary and secondary prevention; early diagnosis, staging of severity, use of bronchodilators and other forms of treatment, rehabilitation, and treatment of complications. Advice is provided on the management of acute exacerbations and the approach to air travel, prescribing long-term oxygen and lung surgery including lung volume reduction surgery. VALIDATION: The COPD Working Group comprised experienced pulmonologists representing all university departments in South Africa and some from private practice, and general practitioners. Most contributed to the development of the previous version of the South African guideline. GUIDELINE SPONSOR: The meeting of the Working Group of the South African Thoracic Society was sponsored by an unrestricted educational grant from Boehringer Ingelheim and Glaxo-Smith-Kline.