The dual weighted residuals approach to optimal control of ordinary differential equations

The methodology of dual weighted residuals is applied to an optimal control problem for ordinary differential equations. The differential equations are discretized by finite element methods. An a posteriori error estimate is derived and an adaptive algorithm is formulated. The algorithm is implemented in Matlab and tested on a simple model problem from vehicle dynamics

Valerian: No Evidence for Clinically Relevant Interactions

In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients

Safety and Effectiveness of Vibration Massage by Deep Oscillations: A Prospective Observational Study

The objective of this study is to assess the safety of treatment with vibration massage using a deep oscillation device and the effects on symptom severity and quality of life in patients with primary fibromyalgia syndrome (FMS). Outpatients with FMS performed an observational prospective study with visits 2–4 weeks after the last treatment (control) and after further 2 months (follow-up). Patients were treated with 10 sessions of 45 min deep oscillation massage, 2/week. Primary outcome parameters were safety and tolerability (5-level Likert scale (1 = very good)) (after each treatment session and at control visit). Secondary outcome parameters were symptom severity (Fibromyalgia Impact Questionnaire (FIQ), pain) and quality of life (SF-36). Seventy patients (97.1% females) were included. At control visit, 41 patients (58.6%) reported 63 mild and short-lasting adverse events, mainly worsening of prevalent symptoms such as pain and fatigue. Tolerability was rated as 1.8 (95% confidence interval: 1.53; 2.07). Symptoms and quality of life were significantly improved at both control and follow-up visits (at least P<0.01). In conclusion, deep oscillation massage is safe and well tolerated in patients with FMS and might improve symptoms and quality of life rather sustained

Investigating Alkylated Prodigiosenes and Their Cu(II)-Dependent Biological Activity: Interactions with DNA, Antimicrobial and Photoinduced Anticancer Activity

Prodigiosenes are a family of red pigments with versatile biological activity. Their tripyrrolic core structure has been modified many times in order to manipulate the spectrum of activity. We have been looking systematically at prodigiosenes substituted at the C ring with alkyl chains of different lengths, in order to assess the relevance of this substituent in a context that has not been investigated before for these derivatives: Cu(II) complexation, DNA binding, self-activated DNA cleavage, photoinduced cytotoxicity and antimicrobial activity. Our results indicate that the hydrophobic substituent has a clear influence on the different aspects of their biological activity. The cytotoxicity study of the Cu(II) complexes of these prodigiosenes shows that they exhibit a strong cytotoxic effect towards the tested tumor cell lines. The Cu(II) complex of a prodigiosene lacking any alkyl chain excelled in its photoinduced anticancer activity, thus demonstrating the potential of prodigiosenes and their metal complexes for an application in photodynamic therapy (PDT). Two derivatives along with their Cu(II) complexes showed also antimicrobial activity against Staphylococcus aureus strains

Towards Phytoplankton Parasite Detection Using Autoencoders

Phytoplankton parasites are largely understudied microbial components with a potentially significant ecological impact on phytoplankton bloom dynamics. To better understand their impact, we need improved detection methods to integrate phytoplankton parasite interactions in monitoring aquatic ecosystems. Automated imaging devices usually produce high amount of phytoplankton image data, while the occurrence of anomalous phytoplankton data is rare. Thus, we propose an unsupervised anomaly detection system based on the similarity of the original and autoencoder-reconstructed samples. With this approach, we were able to reach an overall F1 score of 0.75 in nine phytoplankton species, which could be further improved by species-specific fine-tuning. The proposed unsupervised approach was further compared with the supervised Faster R-CNN based object detector. With this supervised approach and the model trained on plankton species and anomalies, we were able to reach the highest F1 score of 0.86. However, the unsupervised approach is expected to be more universal as it can detect also unknown anomalies and it does not require any annotated anomalous data that may not be always available in sufficient quantities. Although other studies have dealt with plankton anomaly detection in terms of non-plankton particles, or air bubble detection, our paper is according to our best knowledge the first one which focuses on automated anomaly detection considering putative phytoplankton parasites or infections

Living Long and Well: Prospects for a Personalized Approach to the Medicine of Ageing.

Research into ageing and its underlying molecular basis enables us to develop and implement targeted interventions to ameliorate or cure its consequences. However, the efficacy of interventions often differs widely between individuals, suggesting that populations should be stratified or even individualized. Large-scale cohort studies in humans, similar systematic 56 studies in model organisms, and detailed investigations into the biology of ageing can provide individual validated biomarkers and mechanisms, leading to recommendations for targeted interventions. Human cohort studies are already ongoing, and can be supplemented by in silico simulations. Systematic studies in animal models are made possible by the use of inbred strains, or genetic reference populations of mice. Combining both, the comprehensive picture of the various determinants of ageing and healthspan can be studied in detail, and an appreciation of the relevance of results from model organisms to humans emerges. The interactions between genotype and environment, particularly the psychosocial environment, are poorly studied in both humans and model organisms, presenting serious challenges to any approach to a personalized medicine of ageing. To increase success of preventive interventions, we argue that there is a pressing need for an individualized evaluation of interventions such as physical exercise, nutrition, nutraceuticals and calorie restriction mimetics as well as psychosocial and environmental factors, separately and in combination. The expected extension of healthspan enables us to refocus healthcare spending on individual prevention starting in late adulthood, and on the brief period of morbidity at very old age

An Evidence Review of Gender-Integrated Interventions in Reproductive and Maternal-Child Health

Evidence-based behavior change interventions addressing gender dynamics must be identified and disseminated to improve child health outcomes. Interventions were identified from systematic searches of the published literature and a web-based search (Google and implementer's websites). Studies were eligible if an intervention addressed gender dynamics (i.e., norms, unequal access to resources), measured relevant behavioral outcomes (e.g., family planning, antenatal care, nutrition), used at least a moderate evaluation design, and were implemented in low- or middle-income countries. Of the 23 interventions identified, 22 addressed reproductive and maternal-child health behaviors (e.g., birth spacing, antenatal care, breastfeeding) that improve child health. Eight interventions were accommodating (i.e., acknowledged, but did not seek to change gender dynamics), and 15 were transformative (i.e., sought to change gender dynamics). The majority of evaluations (n=12), including interventions that engaged men and women to modify gender norms, had mixed effects. Evidence was most compelling for empowerment approaches (i.e., participatory action for maternal-child health; increase educational and economic resources, and modify norms to reduce child marriage). Two empowerment approaches had sufficient evidence to warrant scaling-up. Research is needed to assess promising approaches, particularly those that engage men and women to modify gender norms around communication and decision making between spouses

In vivo safety profile and biodistribution of GMP-manufactured human skin-derived ABCB5-positive mesenchymal stromal cells for use in clinical trials

Background aims Human dermal ABCB5-expressing mesenchymal stromal cells (ABCB5+ MSCs) represent a promising candidate for stem cell–based therapy of various currently uncurable diseases in several fields of regenerative medicine. We have developed and validated a method to isolate, from human skin samples, and expand ABCB5+ MSCs that meet the guideline criteria of the International Society for Cellular Therapy. We are able to process these cells into a Good Manufacturing Practice–conforming, MSC-based advanced-therapy medicinal product. Methods To support the development of ABCB5+ MSCs for potential therapeutic topical, intramuscular and intravenous administration, we have tested our product in a series of Good Laboratory Practice–compliant nonclinical in-vivo studies addressing all relevant aspects of biosafety, including potential long-term persistence and proliferation, distribution to nontarget tissues, differentiation into undesired cell types, ectopic tissue formation, tumor formation and local tissue reaction. Results (i) Subcutaneous application of 1 × 107 ABCB5+ MSCs/animal and intravenous application of 2 × 106 ABCB5+ MSCs/animal, respectively, to immunocompromised mice did not result in safety-relevant biodistribution, persistence or proliferation of the cells; (ii) three monthly subcutaneous injections of ABCB5+ MSCs at doses ranging from 1 × 105 to 1 × 107 cells/animal and three biweekly intravenous injections of 2 × 106 ABCB5+ MSCs/animal, respectively, to immunocompromised mice were nontoxic and revealed no tumorigenic potential; and (iii) intramuscular injection of 5 × 106 ABCB5+ MSCs/animal to immunocompromised mice was locally well tolerated. Discussion The present preclinical in vivo data demonstrate the local and systemic safety and tolerability of a novel advanced-therapy medicinal product based on human skin-derived ABCB5+ MSCs

Towards Phytoplankton Parasite Detection Using Autoencoders

Phytoplankton parasites are largely understudied microbial components with a potentially significant ecological influence on phytoplankton bloom dynamics. To better understand the impact of phytoplankton parasites, improved detection methods are needed to integrate phytoplankton parasite interactions into monitoring of aquatic ecosystems. Automated imaging devices commonly produce vast amounts of phytoplankton image data, but the occurrence of anomalous phytoplankton data in such datasets is rare. Thus, we propose an unsupervised anomaly detection system based on the similarity between the original and autoencoder-reconstructed samples. With this approach, we were able to reach an overall F1 score of 0.75 in nine phytoplankton species, which could be further improved by species-specific fine-tuning. The proposed unsupervised approach was further compared with the supervised Faster R-CNN-based object detector. Using this supervised approach and the model trained on plankton species and anomalies, we were able to reach a highest F1 score of 0.86. However, the unsupervised approach is expected to be more universal as it can also detect unknown anomalies and it does not require any annotated anomalous data that may not always be available in sufficient quantities. Although other studies have dealt with plankton anomaly detection in terms of non-plankton particles or air bubble detection, our paper is, according to our best knowledge, the first that focuses on automated anomaly detection considering putative phytoplankton parasites or infections

Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration

Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox4(-/-)) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox4(-/-) mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy