An Evaluation Schema for the Ethical Use of Autonomous Robotic Systems in Security Applications

We propose a multi-step evaluation schema designed to help procurement agencies and others to examine the ethical dimensions of autonomous systems to be applied in the security sector, including autonomous weapons systems

Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs

BACKGROUND: A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip. RESULTS: We analysed epigenome-wide DNA methylation profiles in 41 cancer discordant MZ twin-pairs with affected individuals diagnosed with tumours at different single primary sites: the breast, cervix, colon, endometrium, thyroid gland, skin (melanoma), ovary, and pancreas. No significant global differences in whole blood DNA methylation profiles were observed. Epigenome-wide analyses identified one novel pan-cancer differentially methylated position at false discovery rate (FDR) threshold of 10 % (cg02444695, P = 1.8 × 10(-7)) in an intergenic region 70 kb upstream of the SASH1 tumour suppressor gene, and three suggestive signals in COL11A2, AXL, and LINC00340. Replication of the four top-ranked signals in an independent sample of nine cancer-discordant MZ twin-pairs showed a similar direction of association at COL11A2, AXL, and LINC00340, and significantly greater methylation discordance at AXL compared to 480 healthy concordant MZ twin-pairs. The effects at cg02444695 (near SASH1), COL11A2, and LINC00340 were the most promising in biomarker potential because the DNA methylation differences were found to pre-exist in samples obtained prior to diagnosis and were limited to a 5-year period before diagnosis. Gene expression follow-up at the top-ranked signals in 283 healthy individuals showed correlation between blood methylation and gene expression in lymphoblastoid cell lines at PRL, and in the skin tissue at AXL. A significant enrichment of differential DNA methylation was observed in enhancer regions (P = 0.03). CONCLUSIONS: We identified DNA methylation signatures in blood associated with pan-cancer, at or near SASH1, COL11A2, AXL, and LINC00340. Three of these signals were present up to 5 years prior to cancer diagnosis, highlighting the potential clinical utility of whole blood DNA methylation analysis in cancer surveillance

Fexinidazole for human African trypanosomiasis, the fruit of a successful public-private partnership

After 100 years of chemotherapy with impractical and toxic drugs, an oral cure for human African trypanosomiasis (HAT) is available: Fexinidazole. In this case, we review the history of drug discovery for HAT with special emphasis on the discovery, pre-clinical development, and operational challenges of the clinical trials of fexinidazole. The screening of the Drugs for Neglected Diseases initiative (DNDi) HAT-library by the Swiss TPH had singled out fexinidazole, originally developed by Hoechst (now Sanofi), as the most promising of a series of over 800 nitroimidazoles and related molecules. In cell culture, fexinidazole has an IC50 of around 1 microM against Trypanosoma brucei and is more than 100-fold less toxic to mammalian cells. In the mouse model, fexinidazole cures both the first, haemolymphatic, and the second, meningoencephalitic stage of the infection, the latter at 100 mg/kg twice daily for 5 days. In patients, the clinical trials managed by DNDi and supported by Swiss TPH mainly conducted in the Democratic Republic of the Congo demonstrated that oral fexinidazole is safe and effective for use against first- and early second-stage sleeping sickness. Based on the positive opinion issued by the European Medicines Agency in 2018, the WHO has released new interim guidelines for the treatment of HAT including fexinidazole as the new therapy for first-stage and non-severe second-stage sleeping sickness caused by Trypanosoma brucei gambiense (gHAT). This greatly facilitates the diagnosis and treatment algorithm for gHAT, increasing the attainable coverage and paving the way towards the envisaged goal of zero transmission by 2030

Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (IMPAMEL II).

BACKGROUND: Treatment of late-stage human African trypanosomiasis (HAT) with melarsoprol can be improved by shortening the regimen. A previous trial demonstrated the safety and efficacy of a 10-day treatment schedule. We demonstrate the effectiveness of this schedule in a noncontrolled, multinational drug-utilization study. METHODS: A total of 2020 patients with late-stage HAT were treated with the 10-day melarsoprol schedule in 16 centers in 7 African countries. We assessed outcome on the basis of major adverse events and the cure rate after treatment and during 2 years of follow-up. RESULTS: The cure rate 24 h after treatment was 93.9%; 2 years later, it was 86.2%. However, 49.3% of patients were lost to follow-up. The overall fatality rate was 5.9%. Of treated patients, 8.7% had an encephalopathic syndrome that was fatal 45.5% of the time. The rate of severe bullous and maculopapular eruptions was 0.8% and 6.8%, respectively. CONCLUSIONS: The 10-day treatment schedule was well implemented in the field and was effective. It reduces treatment duration, drug amount, and hospitalization costs per patient, and it increases treatment-center capacity. The shorter protocol has been recommended by the International Scientific Council for Trypanosomiasis Research and Control for the treatment of late-stage HAT caused by Trypanosoma brucei gambiense

28-jähriger Patient mit erfolgreich behandelter dilatativer Kardiomyopathie

Zusammenfassung: Ein 28-jähriger Patient wurde mit dekompensierter Herzinsuffizienz notfallmäßig zugewiesen. In der Vorgeschichte bestand ein hypogonadotroper Hypogonadismus. Echokardiographisch fand sich eine dilatative Kardiomyopathie. Ein erhöhtes Serumferritin und eine Eisenüberladung in der Leberbiopsie ließen eine hereditäre Hämochromatose vermuten. Die kardiale Beteiligung konnte mittels Magnetresonanztomographie nachgewiesen werden. Genetische Abklärungen ergaben eine homozygote Mutation für G320V und bewiesen eine juvenile Hämochromatose. Eine Aderlasstherapie führte innerhalb eines Jahres zur Normalisierung des Eisenstatus und der kardialen Pumpfunktio

Self-Calibration of Cameras with Euclidean Image Plane in Case of Two Views and Known Relative Rotation Angle

The internal calibration of a pinhole camera is given by five parameters that are combined into an upper-triangular $3\times 3$ calibration matrix. If the skew parameter is zero and the aspect ratio is equal to one, then the camera is said to have Euclidean image plane. In this paper, we propose a non-iterative self-calibration algorithm for a camera with Euclidean image plane in case the remaining three internal parameters --- the focal length and the principal point coordinates --- are fixed but unknown. The algorithm requires a set of $N \geq 7$ point correspondences in two views and also the measured relative rotation angle between the views. We show that the problem generically has six solutions (including complex ones). The algorithm has been implemented and tested both on synthetic data and on publicly available real dataset. The experiments demonstrate that the method is correct, numerically stable and robust.Comment: 13 pages, 7 eps-figure

Evolution of Biological Bandages as First Cover for Burn Patients.

Significance: Cutaneous wound regeneration is vital to keep skin functions and for large wounds, to maintain human survival. In a deep burn, the ability of the skin to heal is compromised due to the damage of vasculature and resident cells, hindering a coordinated response in the regeneration process. Temporal skin substitutes used as first cover can play a major role in skin regeneration as they allow a rapid wound covering that, in turn, can significantly reduce infection risk, rate of secondary corrective surgeries, and indirectly hospitalization time and costs. Recent Advances: Skin was one of the first tissues to be bioengineered providing thus a skin equivalent; however, what is the current status subsequent to 40 years of tissue engineering? We review the classic paradigms of biological skin substitutes used as first cover and evaluate recent discoveries and clinical approaches adapted for burn injuries cover, with an emphasis on innovative cell-based approaches. Critical Issues: Cell-based first covers offer promising perspectives as they can have an active function in wound healing, such as faster healing minimizing scar formation and prepared wound bed for subsequent grafting. However, cell-based therapies encounter some limitations due to regulatory hurdles, as they are considered as "Advanced Therapy Medicinal Products," which imposes the same industry-destined good manufacturing practices as for pharmaceutical products and biological drug development. Future Directions: Further improvements in clinical outcome can be expected principally with the use of cell-based therapies; however, hospital exemptions are necessary to assure accessibility to the patient and safety without hindering advances in therapies

Burn patient care lost in good manufacturing practices?

Application of cell therapies in burn care started in the early 80s in specialized hospital centers world-wide. Since 2007, cell therapies have been considered as "Advanced Therapy Medicinal Products" (ATMP), so classified by European Directives along with associated Regulations by the European Parliament. Consequently, regulatory changes have transformed the standard linear clinical care pathway into a more complex one. It is important to ensure the safety of cellular therapies used for burn patients and to standardize as much as possible the cell sources and products developed using cell culture procedures. However, we can definitely affirm that concentrating the bulk of energy and resources on the implementation of Good Manufacturing Practice (GMP) alone will have a major negative impact on the care of severely burned patients world-wide. Developing fully accredited infrastructures and training personnel (required by the new directives), along with obtaining approval for clinical trials to go ahead, can be a lengthy process.We discuss whether or not these patients could benefit from cell therapies provided by standard in-hospital laboratories, thus avoiding having to meet rigid regulations concerning the use of industrial pharmaceutical products. "Hospital Exemption" could be a preferred means to offer burn patients a customized and safe product, as many adaptations may be required throughout their treatment pathway. Patients who are in need of rapid treatment will be the ones to suffer the most from regulations intended to help them