Family-Based Model Checking with mCRL2

\u3cp\u3eFamily-based model checking targets the simultaneous verfication of multiple system variants, a technique to handle feature-based variability that is intrinsic to software product lines (SPLs). We present an approach for family-based verification based on the feature μ-calculus μL\u3csub\u3ef\u3c/sub\u3e, which combines modalities with feature expressions. This logic is interpreted over featured transition systems, a well-accepted model of SPLs, which allows one to reason over the collective behavior of a number of variants (a family of products). Via an embedding into the modal μ-calculus with data, underpinned by the general-purpose mCRL2 toolset, off-the-shelf tool support for μLf becomes readily available. We illustrate the feasibility of our approach on an SPL benchmark model and show the runtime improvement that family-based model checking with mCRL2 offers with respect to model checking the benchmark product-by-product.\u3c/p\u3

Associations of Infant Subcutaneous Fat Mass with Total and Abdominal Fat Mass at School-Age: The Generation R Study

BACKGROUND:Skinfold thickness enables the measurement of overall and regional subcutaneous fatness in infancy and may be associated with total and abdominal body fat in later childhood. We examined the associations of subcutaneous fat in infancy with total and abdominal fat at school-age. METHODS:In a population-based prospective cohort study among 821 children, we calculated total subcutaneous fat (sum of biceps, triceps, suprailiacal, and subscapular skinfold thicknesses) and central-to-total subcutaneous fat ratio (sum of suprailiacal and subscapular skinfold thicknesses/total subcutaneous fat) at 1.5 and 24 months. At 6 years, we measured fat mass index (total fat/height(3) ), central-to-total fat ratio (trunk fat/total fat), and android-to-gynoid fat ratio (android fat/gynoid fat) by dual-energy X-ray absorptiometry and preperitoneal fat mass area by abdominal ultrasound. RESULTS:Central-to-total subcutaneous fat ratio at 1.5 months was positively associated with fat mass index and central-to-total fat ratio at 6 years, whereas both total and central-to-total subcutaneous fat ratio at 24 months were positively associated with all childhood adiposity measures. A 1-standard-deviation scores higher total subcutaneous fat at 24 months was associated with an increased risk of childhood overweight (odds ratio 1.70, 95% confidence interval 1.36, 2.12). These associations were weaker than those for body mass index and stronger among girls than boys. CONCLUSIONS:Subcutaneous fat in infancy is positively associated with total and abdominal fat at school-age. Our results also suggest that skinfold thicknesses add little value to estimate later body fat, as compared with body mass index

Tau PET and relative cerebral blood flow in Dementia with Lewy bodies: A PET study

Purpose: Alpha-synuclein often co-occurs with Alzheimer’s disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. / Methods: Eighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology(DLB-AD+). Receptor parametric mapping(cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests. / Results: Regional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p>0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p<0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p<0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stβ=0.72) and category fluency (stβ=0.69) tests. Lower parietal R1 was related to lower delayed (stβ=0.50) and immediate (stβ=0.48) recall, VOSP number location (stβ=0.70) and fragmented letters (stβ=0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stβ=0.61), all p<0.05. / Conclusion: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET

The 2020 Expert Survey on Formal Methods

International audienc

The cost-effectiveness of the RSI QuickScan intervention programme for computer workers: Results of an economic evaluation alongside a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The costs of arm, shoulder and neck symptoms are high. In order to decrease these costs employers implement interventions aimed at reducing these symptoms. One frequently used intervention is the RSI QuickScan intervention programme. It establishes a risk profile of the target population and subsequently advises interventions following a decision tree based on that risk profile. The purpose of this study was to perform an economic evaluation, from both the societal and companies' perspective, of the RSI QuickScan intervention programme for computer workers. In this study, effectiveness was defined at three levels: exposure to risk factors, prevalence of arm, shoulder and neck symptoms, and days of sick leave.</p> <p>Methods</p> <p>The economic evaluation was conducted alongside a randomised controlled trial (RCT). Participating computer workers from 7 companies (N = 638) were assigned to either the intervention group (N = 320) or the usual care group (N = 318) by means of cluster randomisation (N = 50). The intervention consisted of a tailor-made programme, based on a previously established risk profile. At baseline, 6 and 12 month follow-up, the participants completed the RSI QuickScan questionnaire. Analyses to estimate the effect of the intervention were done according to the intention-to-treat principle. To compare costs between groups, confidence intervals for cost differences were computed by bias-corrected and accelerated bootstrapping.</p> <p>Results</p> <p>The mean intervention costs, paid by the employer, were 59 euro per participant in the intervention and 28 euro in the usual care group. Mean total health care and non-health care costs per participant were 108 euro in both groups. As to the cost-effectiveness, improvement in received information on healthy computer use as well as in their work posture and movement was observed at higher costs. With regard to the other risk factors, symptoms and sick leave, only small and non-significant effects were found.</p> <p>Conclusions</p> <p>In this study, the RSI QuickScan intervention programme did not prove to be cost-effective from the both the societal and companies' perspective and, therefore, this study does not provide a financial reason for implementing this intervention. However, with a relatively small investment, the programme did increase the number of workers who received information on healthy computer use and improved their work posture and movement.</p> <p>Trial registration</p> <p>Trial registration number: NTR1117</p

Naturally Occurring Lipid A Mutants in Neisseria meningitidis from Patients with Invasive Meningococcal Disease Are Associated with Reduced Coagulopathy

Neisseria meningitidis is a major cause of bacterial meningitis and sepsis worldwide. Lipopolysaccharide (LPS), a major component of the Gram-negative bacterial outer membrane, is sensed by mammalian cells through Toll-like receptor 4 (TLR4), resulting in activation of proinflammatory cytokine pathways. TLR4 recognizes the lipid A moiety of the LPS molecule, and the chemical composition of the lipid A determines how well it is recognized by TLR4. N. meningitidis has been reported to produce lipid A with six acyl chains, the optimal number for TLR4 recognition. Indeed, meningococcal sepsis is generally seen as the prototypical endotoxin-mediated disease. In the present study, we screened meningococcal disease isolates from 464 patients for their ability to induce cytokine production in vitro. We found that around 9% of them were dramatically less potent than wild-type strains. Analysis of the lipid A of several of the low-activity strains by mass spectrometry revealed they were penta-acylated, suggesting a mutation in the lpxL1 or lpxL2 genes required for addition of secondary acyl chains. Sequencing of these genes showed that all the low activity strains had mutations that inactivated the lpxL1 gene. In order to see whether lpxL1 mutants might give a different clinical picture, we investigated the clinical correlate of these mutations in a prospective nationwide observational cohort study of adults with meningococcal meningitis. Patients infected with an lpxL1 mutant presented significantly less frequently with rash and had higher thrombocyte counts, consistent with reduced cytokine induction and less activation of tissue-factor mediated coagulopathy. In conclusion, here we report for the first time that a surprisingly large fraction of meningococcal clinical isolates have LPS with underacylated lipid A due to mutations in the lpxL1 gene. The resulting low-activity LPS may have an important role in virulence by aiding the bacteria to evade the innate immune system. Our results provide the first example of a specific mutation in N. meningitidis that can be correlated with the clinical course of meningococcal disease

The role and scope of practice of midwives in humanitarian settings:a systematic review and content analysis

Abstract Background Midwives have an essential role to play in preparing for and providing sexual and reproductive health (SRH) services in humanitarian settings due to their unique knowledge and skills, position as frontline providers and geographic and social proximity to the communities they serve. There are considerable gaps in the international guidance that defines the scope of practice of midwives in crises, particularly for the mitigation and preparedness, and recovery phases. We undertook a systematic review to provide further clarification of this scope of practice and insights to optimise midwifery performance. The review aimed to determine what SRH services midwives are involved in delivering across the emergency management cycle in humanitarian contexts, and how they are working with other professionals to deliver health care. Methods Four electronic databases and the websites of 33 organisations were searched between January and March 2017. Papers were eligible for inclusion if they were published in English between 2007 and 2017 and reported primary research pertaining to the role of midwives in delivering and performing any component of sexual and/or reproductive health in humanitarian settings. Content analysis was used to map the study findings to the Minimum Initial Service Package (MISP) for SRH across the three phases of the disaster management cycle and identify how midwives work with other members of the health care team. Results Fourteen studies from ten countries were included. Twelve studies were undertaken in conflict settings, and two were conducted in the context of the aftermath of natural disasters. We found a paucity of evidence from the research literature that examines the activities and roles undertaken by midwives across the disaster management cycle. This lack of evidence was more apparent during the mitigation and preparedness, and recovery phases than the response phase of the disaster management cycle. Conclusion Research-informed guidelines and strategies are required to better align the scope of practice of midwives with the objectives of multi-agency guidelines and agreements, as well as the activities of the MISP, to ensure that the potential of midwives can be acknowledged and optimised across the disaster management cycle

The bisphosphonate zoledronic acid impairs membrane localisation and induces cytochrome c release in breast cancer cells

Bisphosphonates are well established in the management of cancer-induced bone disease. Recent studies have indicated that these compounds have direct inhibitory effects on cultured human breast cancer cells. Nitrogen-containing bisphosphonates including zoledronic acid have been shown to induce apoptosis associated with PARP cleavage and DNA fragmentation. The aim of this study was to identify the signalling pathways involved. Forced expression of the anti-apoptotic protein bcl-2 attenuated bisphosphonate-induced loss of cell viability and induction of DNA fragmentation in MDA-MB-231 cells. Zoledronic acid-mediated apoptosis was associated with a time and dose-related release of mitochondrial cytochrome c into the cytosol in two cell lines. Rescue of cells by preincubation with a caspase-3 selective inhibitor and demonstration of pro-caspase-3 cleavage products by immunoblotting suggests that at least one of the caspases activated in response to zoledronic acid treatment is caspase-3. In both MDA-MB-231 and MCF-7 breast cancer cells, zoledronic acid impaired membrane localisation of Ras indicating reduced prenylation of this protein. These observations demonstrate that zoledronic acid-mediated apoptosis is associated with cytochrome c release and consequent caspase activation. This process may be initiated by inhibition of the enzymes in the mevalonate pathway leading to impaired prenylation of key intracellular proteins including Ras