Model-Based ISO 14971 Risk Management of EEG-Based Medical Devices.

Risk management (RM) is a key component of the development of modern medical devices (MD) to achieve acceptable functional safety and pass the regulatory process. The emerging availability of various techniques, languages, and tools that use model-based system engineering (MBSE) promises to facilitate the development and analysis of complex MD. In this paper, we show how to integrate RM principles and activities recommended in ISO 14971 medical standard into an MBSE-driven MD development process. We propose a method and framework capable of modeling essential RM concepts and performing RM and safety analysis in the early stages of the MD development life cycle. The framework extends OMG RAAML (Object Management Group Risk Analysis and Assessment Modeling Language) to the medical domain according to ISO 14971. We illustrate our approach using a case study of the e-Glass system developed for real-time EEG-based subject monitoring with the intended use of stress monitoring.Clinical Relevance-This facilitates the MD certification process by semi-automation of RM based on ISO 14971 and obtaining safe MD by design.

Approximate zero-crossing: a new interpretable, highly discriminative and low-complexity feature for EEG and iEEG seizure detection.

Objective. Long-term monitoring of people with epilepsy based on electroencephalography (EEG) and intracranial EEG (iEEG) has the potential to deliver key clinical information for personalised epilepsy treatment. More specifically, in outpatient settings, the available solutions are not satisfactory either due to poor classification performance or high complexity to be executed in resource-constrained devices (e.g. wearable systems). Therefore, we hypothesize that obtaining high discriminative features is the main avenue to improve low-complexity seizure-detection algorithms.Approach. Inspired by how neurologists recognize ictal EEG data, and to tackle this problem by targeting resource-constrained wearable devices, we introduce a new interpretable and highly discriminative feature for EEG and iEEG, namely approximate zero-crossing (AZC). We obtain AZC by applying a polygonal approximation to mimic how our brain selects prominent patterns among noisy data and then using a zero-crossing count as a measure of the dominating frequency. By employing Kullback-Leiber divergence, leveraging CHB-MIT and SWEC-ETHZ iEEG datasets, we compare the AZC discriminative power against a set of 56 classical literature features (CLF). Moreover, we assess the performances of a low-complexity seizure detection method using only AZC features versus employing the CLF set.Main results. Three AZC features obtained with different approximation thresholds are among the five with the highest median discriminative power. Moreover, seizure classification based on only AZC features outperforms an equivalent CLF-based method. The former detects 102 and 194 seizures, against 99 and 161 for the latter (CHB-MIT and SWEC-ETHZ, respectively). Moreover, the AZC-based method keeps a similar false-alarm rate (i.e. an average of 2.1 and 1.0, against 2.0 and 0.5, per day).Significance. We propose a new feature and demonstrate its capability in seizure classification for both scalp and intracranial EEG. We envision the use of such a feature to improve outpatient monitoring with resource-constrained devices.

In vitro and in silico assessment of antitumor properties and biomolecular binding studies for two new complexes based on NiII bearing k2N,S-donor ligands.

This work deals with two new molecule-based materials, namely NiII-complexes of general formulae [Ni(L1)2] (Ni1) and [Ni(L2)2] (Ni2), where L1 = trans-cinnamaldehyde-N(4)-methyl thiosemicarbazone and L2 = trans-cinnamaldehyde-N(4)-ethyl thiosemicarbazone, as potential antitumor agents. Both compounds were characterized by elemental analysis, molar conductivity and spectroscopic techniques (FTIR and NMR). Their molecular structures were obtained by single-crystal X-ray diffraction analysis. Each one crystallizes in a monoclinic space group P 21/c, also the asymmetric unit comprises of one NiII ion located on an inversion centre and one anionic ligand, which acts as a κ2N,S-donor affording a five-membered metallaring. The compounds were screened against two selected tumour cell lines (MCF-7 and A549) and non-tumour fibroblasts cell line (MRC-5) via MTT assays. In both tumour cells, all compounds exhibited higher cytotoxicity than the control drug (cisplatin). The IC50 values ranges of 3.70 - 41.37 µM and 1.06 - 14.91 µM were found for MCF-7 and A549, respectively. Importantly, all of them were less toxicity than cisplatin in MRC-5 with SI values ranged at 11.80 - 86.60. The red blood cell (RBC) assay revealed Ni2 as non-toxic due to its reduced haemolytic effect (0--9% at 1--10 µM). The DNA binding was investigated through a combination of spectrophotometric absorption and emission titrations, electrophoresis, and circular dichroism experiments. As a result, these metal complexes were not able to strongly binding to DNA (Kb values ~104 mol L--1) but suggesting groove-binding interactions. The scavenging ability of them towards 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical was also evaluated in this work, but no important antioxidant behaviour was detected. Further, the interaction of Ni1 and Ni2 to human serum albumin (HSA) was explored by quenching of tryptophan emission, warfarin competitive assay, and molecular docking protocols. The HSA binding analyses indicated good affinity of both complexes to Sudlow site I (Kb values ⁓103 mol L-1).

Mammographic breast density and characteristics of invasive breast cancer.

INTRODUCTION: Inconclusive data exist on the association between breast density and breast cancer characteristics. MATERIALS AND METHODS: We conducted a case-only study on 667 invasive breast cancers, using data from the Piedmont Cancer Registry. We applied a multivariate logistic regression model to estimate odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of high breast density (Breast Imaging Reporting and Data System, BI-RADS 3-4) versus low (BI-RADS 1-2) in relation to histologic grade, pathological tumour size and lymph node status, histotype, estrogen and progesterone receptor, HER2 and Ki67 status. Histopathological data were assessed according to the American Joint Committee on Cancer (AJCC) Staging Manual guidelines. The model includes terms for age at diagnosis, education level, body mass index, reproductive factors, family history of breast cancer, smoking and diabetes. RESULTS: As regards histologic grade, compared to well differentiated tumours, the OR of high (versus low) breast density cases was 0.61 (95% CI 0.38-0.98) for moderately-poorly differentiated tumours. No other associations with hormonal and histopathological characteristics were observed. DISCUSSION: Our results indicate that low breast density is associated with moderately-poorly differentiated breast tumours.

To accelerate cancer prevention in Europe: Challenges for cancer registries.

The availability of population-based cancer registry (CR) data is paramount in the development of modern oncology. Major contributions consisted in accurately measuring cancer burden (incidence, survival and prevalence, beside mortality), identifying and quantifying risk factors (case control and cohort studies that, in the last two decades, included gene variant assessment) and evaluating outcomes of treatments and preventive interventions, including mass screening. Cancer registration coverage of European populations progressed slowly since 1940 and is now almost 50%. Areas lacking high-quality national population-based cancer registration still exist within large countries such as France, Italy, Romania and Spain, Germany and Poland having national plans and legislation to reach complete coverage. Depending on programme ownership, history and institutional organisation, European CRs showed huge variations in the scope (research domain), size, available resources and finally exploitation of collected data. This reflects their heterogeneous origins stemming from different professional backgrounds and healthcare systems. This review discusses not only the potential for contributing to acceleration of prevention but also the coverage expansion by and innovation of CR organizations. The latter can be attained not only by more standardisation in institutional organisation and operative methodologies but also by intensification of scientific production and risk communication. The CR's agenda should focus on cancers caused by identifiable risk factor(s) that are amenable to preventive actions, including early detection; short-term priorities usually are with tobacco, and medium-term priorities are with alcohol, occupational exposures, infection-related cancers and ultraviolet-related skin cancers, while obesity-related cancers are likely to increase gradually further in the long term.

Preliminary investigation of extracellular vesicles in mammary cancer of dogs and cats: Identification and characterization.

Extracellular vesicles (EVs) are membrane-bound vesicles produced by cells, known to play a key role in cell-to-cell communication. They exert pleiotropic biological functions via the horizontal transfer of bioactive molecules (DNA, RNAs, proteins, and lipids) within the tumour microenvironment and throughout the body. In human cancer, EVs are known to interfere with pathways that lead to tumour progression and are used as novel cancer biomarkers. In veterinary medicine, very little is known on cancer-derived EVs. In this study, we preliminarily characterized EVs in mammary gland cancer of dogs and cats. EVs were isolated by ultracentrifugation from canine (CYPp), feline (FMCp) and human (MCF7) mammary tumour cell lines. EVs were visualized by transmission electron microscopy (TEM), counted using nanoparticle tracking analysis (NTA) and characterized by immunogold (CD63 and Alix) and western blot (Alix and TSG101). Additionally, EV production by "donor" cells (palmtdTomato+ ) and uptake by "recipient" cells (GFP+ ) were assessed. EVs were successfully isolated from all 3 cell lines by ultracentrifugation. Membrane-bound structures (50-400 nm) were identified by TEM and were positive for both CD63 and Alix at immunogold. Western blot showed positivity of EVs to Alix and TSG101. NTA analysis detected EVs from cell culture media ranging from 1.67 to 2.56 × 102 as number of EVs/cell and from 80 to 600 nm in size. Confocal microscopy identified the presence of palmtdTomato+ EVs into the cytoplasm of GFP+ cells. This preliminary study identified and characterized canine and feline mammary tumour cell-derived EVs, opening in veterinary medicine a new interesting unexplored field with several applications and limitless potential.

Trends in incidence of thick, thin and in situ melanoma in Europe.

BACKGROUND: We analysed trends in incidence for in situ and invasive melanoma in some European countries during the period 1995-2012, stratifying for lesion thickness. MATERIAL AND METHODS: Individual anonymised data from population-based European cancer registries (CRs) were collected and combined in a common database, including information on age, sex, year of diagnosis, histological type, tumour location, behaviour (invasive, in situ) and lesion thickness. Mortality data were retrieved from the publicly available World Health Organization database. RESULTS: Our database covered a population of over 117 million inhabitants and included about 415,000 skin lesions, recorded by 18 European CRs (7 of them with national coverage). During the 1995-2012 period, we observed a statistically significant increase in incidence for both invasive (average annual percent change (AAPC) 4.0% men; 3.0% women) and in situ (AAPC 7.7% men; 6.2% women) cases. DISCUSSION: The increase in invasive lesions seemed mainly driven by thin melanomas (AAPC 10% men; 8.3% women). The incidence of thick melanomas also increased, although more slowly in recent years. Correction for lesions of unknown thickness enhanced the differences between thin and thick cases and flattened the trends. Incidence trends varied considerably across registries, but only Netherlands presented a marked increase above the boundaries of a funnel plot that weighted estimates by their precision. Mortality from invasive melanoma has continued to increase in Norway, Iceland (but only for elder people), the Netherlands and Slovenia.

Reparo de lesão penetrante em parede torácica de cão, ocasionada por javali (Sus scrofa scrofa), com flape unipediculado de músculo reto abdominal / Unipediculated flap of muscle rectos abdominales to repair a penetrating injury caused by javali (Sus scrofa scrofa) on the thoracic wall of a dog

Lesões penetrantes no tórax causadas por interação animal são frequentes em cães e caracterizam-se por dano extenso e desvitalização dos tecidos moles adjacentes. Quando a musculatura local é insuficiente para a reconstrução, retalhos musculares podem ser mobilizados para reparar o defeito torácico. O presente relato tem como objetivo demonstrar uma alternativa para o reparo de defeito da parede torácica em um cão, ocasionada por interação com javali (Sus scrofa scrofa), utilizando flape unipediculado de músculo reto abdominal. Com base na literatura consultada, essa técnica reconstrutiva ainda não foi descrita. O flape de músculo reto abdominal mostrou-se uma alternativa viável no reparo de lesão extensa e infectada na parede torácica em cães.(AU)

Penetrating thoracic wounds caused by animal bites are common in dogs and are characterized by extensive trauma and adjacent soft tissue devitalization. When the local musculature is insufficient for the reconstruction, muscle flaps can be taken to repair the thoracic defect. The aim of the present report is to demonstrate an alternative to the thoracic wall defect repair in a dog which was attacked by javali (Sus scrofa scrofa), using unipediculated flap of the rectus abdominis muscle. Based on the literature, this reconstructive technique has not yet been described. The rectus abdominis muscle flap proves to be a useful alternative for the repair of extensive and infected thoracic wall lesion in dogs.(AU)

Endocrine Pancreas in Cats With Diabetes Mellitus.

Pancreatic amyloidosis and loss of α and ß cells have been shown to occur in cats with diabetes mellitus, although the number of studies currently available is very limited. Furthermore, it is not known whether pancreatic islet inflammation is a common feature. The aims of the present study were to characterize islet lesions and to investigate whether diabetic cats have inflammation of the pancreatic islets. Samples of pancreas were collected postmortem from 37 diabetic and 20 control cats matched for age, sex, breed, and body weight. Histologic sections were stained with hematoxylin and eosin and Congo red; double labeled for insulin/CD3, insulin/CD20, insulin/myeloperoxidase, insulin/proliferating cell nuclear antigen, and glucagon/Ki67; and single labeled for amylin and Iba1. Mean insulin-positive cross-sectional area was approximately 65% lower in diabetic than control cats (P = .009), while that of amylin and glucagon was similar. Surprisingly, amyloid deposition was similar between groups (P = .408). Proliferation of insulin- and glucagon-positive cells and the number of neutrophils, macrophages, and T (CD3) and B (CD20) lymphocytes in the islets did not differ. The presence of T and B lymphocytes combined tended to be more frequent in diabetic cats (n = 8 of 37; 21.6%) than control cats (n = 1 of 20; 5.0%). The results confirm previous observations that loss of ß cells but not α cells occurs in diabetic cats. Islet amyloidosis was present in diabetic cats but was not greater than in controls. A subset of diabetic cats had lymphocytic infiltration of the islets, which might be associated with ß-cell loss.

Exocrine Pancreas in Cats With Diabetes Mellitus.

Pancreatitis has been described in cats with diabetes mellitus, although the number of studies currently available is very limited. In addition, ketoacidosis has been hypothesized to be associated with pancreatitis in diabetic cats. The aims of the present study were to investigate whether diabetic cats have pancreatitis and to determine if pancreatitis is more frequent with ketoacidosis. Samples of pancreas were collected postmortem from 37 diabetic cats, including 15 with ketoacidosis, and 20 control cats matched for age, sex, breed, and body weight. Sections were stained with hematoxylin and eosin, double-labeled for insulin/CD3, insulin/CD20, insulin/myeloperoxidase, insulin/PCNA, and glucagon/Ki67, and single-labeled for Iba1. A previously proposed semiquantitative score was used to characterize pancreatitis, along with counts of inflammatory cells. Scores of pancreatitis and the number of neutrophils, macrophages, and lymphocytes in the exocrine pancreas did not differ between diabetic and control cats or between diabetic cats with and without ketoacidosis. Of note, PCNA-positive acinar cells were increased (P = .002) in diabetic cats, particularly near islets (P < .001). Ki67-positive acinar cells were increased only near islets (P = .038). Ketoacidosis was not linked to proliferation. The results suggest that histopathologic evidence of pancreatitis may not be more frequent in diabetic cats and that ketoacidosis may not be associated with it at the time of death. Augmented PCNA-positive acinar cells might indicate increased proliferation due to chronic pancreatitis. The reason behind the prevalent proliferation of acinar cells surrounding pancreatic islets deserves further investigation.

Uses of cancer registries for public health and clinical research in Europe: Results of the European Network of Cancer Registries survey among 161 population-based cancer registries during 2010-2012.

AIM: To provide insight into cancer registration coverage, data access and use in Europe. This contributes to data and infrastructure harmonisation and will foster a more prominent role of cancer registries (CRs) within public health, clinical policy and cancer research, whether within or outside the European Research Area. METHODS: During 2010-12 an extensive survey of cancer registration practices and data use was conducted among 161 population-based CRs across Europe. Responding registries (66%) operated in 33 countries, including 23 with national coverage. RESULTS: Population-based oncological surveillance started during the 1940-50s in the northwest of Europe and from the 1970s to 1990s in other regions. The European Union (EU) protection regulations affected data access, especially in Germany and France, but less in the Netherlands or Belgium. Regular reports were produced by CRs on incidence rates (95%), survival (60%) and stage for selected tumours (80%). Evaluation of cancer control and quality of care remained modest except in a few dedicated CRs. Variables evaluated were support of clinical audits, monitoring adherence to clinical guidelines, improvement of cancer care and evaluation of mass cancer screening. Evaluation of diagnostic imaging tools was only occasional. CONCLUSION: Most population-based CRs are well equipped for strengthening cancer surveillance across Europe. Data quality and intensity of use depend on the role the cancer registry plays in the politico, oncomedical and public health setting within the country. Standard registration methodology could therefore not be translated to equivalent advances in cancer prevention and mass screening, quality of care, translational research of prognosis and survivorship across Europe. Further European collaboration remains essential to ensure access to data and comparability of the results.