Methods for Multiloop Identification of Visual and Neuromuscular Pilot Responses

In this paper, identification methods are proposed to estimate the neuromuscular and visual responses of a multiloop pilot model. A conventional and widely used technique for simultaneous identification of the neuromuscular and visual systems makes use of cross-spectral density estimates. This paper shows that this technique requires a specific noninterference hypothesis, often implicitly assumed, that may be difficult to meet during actual experimental designs. A mathematical justification of the necessity of the noninterference hypothesis is given. Furthermore, two methods are proposed that do not have the same limitations. The first method is based on autoregressive models with exogenous inputs, whereas the second one combines cross-spectral estimators with interpolation in the frequency domain. The two identification methods are validated by offline simulations and contrasted to the classic method. The results reveal that the classic method fails when the noninterference hypothesis is not fulfilled; on the contrary, the two proposed techniques give reliable estimates. Finally, the three identification methods are applied to experimental data from a closed-loop control task with pilots. The two proposed techniques give comparable estimates, different from those obtained by the classic method. The differences match those found with the simulations. Thus, the two identification methods provide a good alternative to the classic method and make it possible to simultaneously estimate human's neuromuscular and visual responses in cases where the classic method fails

Environmental sustainability and gynaecological surgery:Which factors influence behaviour? An interview study

OBJECTIVE: To assess the various factors that influence environmentally sustainable behaviour in gynaecological surgery and examine the differences between gynaecologists and residents.DESIGN: An interview study.SETTING: Academic and non-academic hospitals in the Netherlands.POPULATION: Gynaecologists (n = 10) and residents (n = 6).METHODS: Thematic analysis of semi-structured interviews to determine the various factors that influence environmentally sustainable behaviour in gynaecological surgery and to examine the differences between gynaecologists and residents. By using the Desmond framework and the COM-B BCW, both organisational and individual factors related to behaviour were considered.MAIN OUTCOME MEASURES: Factors that influence environmentally sustainable behaviour.RESULTS: Awareness is increasing but practical knowledge is insufficient. It is crucial to integrate education on the environmental impact of everyday decisions for residents and gynaecologists. Gynaecologists make their own choices but residents' autonomy is limited. There is the necessity to provide environmentally sustainable surgical equipment without compromising other standards. There is a need for a societal change that encourages safe and open communication about environmental sustainability. To transition to environmentally sustainable practices, leadership, time, collaboration with the industry and supportive regulatory changes are essential.CONCLUSION: This study lays the groundwork for promoting more environmentally sustainable behaviour in gynaecological surgery. The key recommendations, addressing hospital regulations, leadership, policy revisions, collaboration with the industry, guideline development and education, offer practical steps towards a more sustainable healthcare system. Encouraging environmentally sustainable practices should be embraced to enhance the well-being of both our planet and our population, driving us closer to a more environmentally sustainable future in healthcare.</p

Deletion of IL-4 receptor alpha on dendritic cells renders BALB/c mice hypersusceptible to Leishmania major infection

In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main inducer of Th2 responses, paradoxically, it has been shown that exogenously administered IL-4 can promote dendritic cell (DC) IL-12 production and enhance Th1 development if given early during infection. To further investigate the relevance of biological quantities of IL-4 acting on DCs during in vivo infection, DC specific IL-4Rα deficient (CD11ccreIL-4Rα-/lox) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the cd11c locus. DNA, protein, and functional characterization showed abrogated IL-4Rα expression on dendritic cells and alveolar macrophages in CD11ccreIL-4Rα-/lox mice. Following infection with L. major, CD11ccreIL-4Rα-/lox mice became hypersusceptible to disease, presenting earlier and increased footpad swelling, necrosis and parasite burdens, upregulated Th2 cytokine responses and increased type 2 antibody production as well as impaired classical activation of macrophages. Hypersusceptibility in CD11ccreIL-4Rα-/lox mice was accompanied by a striking increase in parasite burdens in peripheral organs such as the spleen, liver, and even the brain. DCs showed increased parasite loads in CD11ccreIL-4Rα-/lox mice and reduced iNOS production. IL-4Rα-deficient DCs produced reduced IL-12 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and activin A, cytokines previously implicated in promoting Th2 responses. Together, these data demonstrate that abrogation of IL-4Rα signaling on DCs is severely detrimental to the host, leading to rapid disease progression, and increased survival of parasites in infected DCs due to reduced killing effector functions

An Introduction to Nuclear Supersymmetry: a Unification Scheme for Nuclei

The main ideas behind nuclear supersymmetry are presented, starting from the basic concepts of symmetry and the methods of group theory in physics. We propose new, more stringent experimental tests that probe the supersymmetry classification in nuclei and point out that specific correlations should exist for particle transfer intensities among supersymmetric partners. We also discuss possible ways to generalize these ideas to cases where no dynamical symmetries are present. The combination of these theoretical and experimental studies may play a unifying role in nuclear phenomena.Comment: 40 pages, 11 figures, lecture notes `VIII Hispalensis International Summer School: Exotic Nuclear Physics', Oromana, Sevilla, Spain, June 9-21, 200

myCopter: Enabling Technologies for Personal Air Transport Systems

This paper describes the European Commission Framework 7 funded project myCopter (2011-2014). The project is still at an early stage so the paper starts with the current transportation issues faced by developed countries and describes a means to solve them through the use of personal aerial transportation. The concept of personal air vehicles (PAV) is briefly reviewed and how this project intends to tackle the problem from a different perspective described. It is argued that the key reason that many PAV concepts have failed is because the operational infrastructure and socio-economic issues have not been properly addressed; rather, the start point has been the design of the vehicle itself. Some of the key aspects that would make a personal aerial transport system (PATS) viable include the required infrastructure and associated technologies, the skill levels and machine interfaces needed by the occupant or pilot and the views of society as a whole on the acceptability of such a proposition. The myCopter project will use these areas to explore the viability of PAVs within a PATS. The paper provides an overview of the project structure, the roles of the partners, and hence the available research resources, and some of the early thinking on each of the key project topic areas

Ideal cardiovascular health among Ghanaian populations in three European countries and rural and urban Ghana: the RODAM study.

Cardiovascular health (CVH) is a construct defined by the American Heart Association (AHA) as part of its 2020 Impact Goal definition. CVH has, until now, not been evaluated in Sub-Saharan African populations. The aim of this study was to investigate differences in the prevalence of ideal CVH and its constituent metrics among Ghanaians living in rural and urban Ghana and Ghanaian migrants living in three European countries. The AHA definition of CVH is based on 7 metrics: smoking, body mass index, diet, physical activity, blood pressure, total cholesterol, and fasting plasma glucose. These were evaluated among 3510 Ghanaian adults (aged 25-70 years) residing in rural and urban Ghana and three European cities (Amsterdam, London and Berlin) in the multi-centre RODAM study. Differences between groups were assessed using logistic regression with adjustments for gender, age, and education. Only 0.3% of all participants met all 7 metrics of the AHA's definition of ideal CVH. Compared to rural Ghana (25.7%), the proportions and adjusted odds ratio (OR) of individuals who had 6-7 CVH metrics in the ideal category were substantially lower in urban Ghana, (7.5%; OR 0.204, 95% CI 0.15-0.29), Amsterdam (4.4%; 0.13, 0.08-0.19), Berlin (2.7%; 0.06, 0.03-0.11), and London (1.7%; 0.04, 0.02-0.09), respectively. The proportion of ideal CVH for the various metrics ranged from 96% for all sites in the smoking metric to below 6% in the diet metric. The proportion of ideal CVH is extremely low in Ghanaians, especially among those living in urban Ghana and Ghanaian migrants in Europe

Desmopressin for bleeding in non-severe hemophilia A:Suboptimal use in a real-world setting

Background Desmopressin is an important treatment option in nonsevere hemophilia A because it has several benefits compared with factor (F) concentrates, including no inhibitor risk and much lower costs. Despite these advantages, data are limited on the real-world use of desmopressin in the treatment of bleeds. Objective To describe the clinical use of desmopressin in relation to other therapeutic modalities in the treatment of bleeding episodes in patients with nonsevere hemophilia A. Methods Patients with nonsevere hemophilia A aged 12-55 years were included from the DYNAMO cohort study. Data on the desmopressin test response and treated bleeding events in the period January 2009 to July 2020 were retrospectively collected from medical files. An adequate desmopressin test response was defined based on a peak FVIII level of >= 30 IU/dl. Results A total of 248 patients with a median age of 38 years (interquartile range 25-49) were included. An adequate desmopressin test response was documented in 25% and 73% of patients with moderate and mild hemophilia, respectively. In adequate responders, 51% of bleeds were exclusively treated with FVIII concentrates, 24% exclusively with desmopressin, 21% with a combination of both and 4% with other treatments. In 54% of bleeds treated with a single dose of factor concentrates, the expected FVIII level after desmopressin exceeded the level targeted. Conclusion Most bleeds in patients with an adequate response to desmopressin are treated with factor concentrates. These findings may indicate a suboptimal use of desmopressin and that barriers to the use of desmopressin should be explored.Thrombosis and Hemostasi

Dosing of factor VIII concentrate by ideal body weight is more accurate in overweight and obese haemophilia A patients

Aims Under- and, especially, overdosing of replacement therapy in haemophilia A patients may be prevented by application of other morphometric variables than body weight (BW) to dose factor VIII (FVIII) concentrates. Therefore, we aimed to investigate which morphometric variables best describe interindividual variability (IIV) of FVIII concentrate pharmacokinetic (PK) parameters. Methods PK profiling was performed by measuring 3 FVIII levels after a standardized dose of 50 IU kg(-1) FVIII concentrate. A population PK model was constructed, in which IIV for clearance (CL) and central volume of distribution (V1) was quantified. Relationships between CL, V1 and 5 morphometric variables (BW, ideal BW [IBW], lean BW, adjusted BW, and body mass index [BMI]) were evaluated in normal weight (BMI 30 kg m(-2)). Results In total, 57 haemophilia A patients (FVIII Conclusion IBW is the most suitable morphometric variable to explain interindividual FVIII PK variability and is more appropriate to dose overweight and obese patients

Bi-allelic <i>NIT1 </i>variants cause a brain small vessel disease characterized by movement disorders, massively dilated perivascular spaces, and intracerebral hemorrhage

Purpose: To describe a recessively inherited cerebral small vessel disease, caused by loss-of-function variants in Nitrilase1 (NIT1). Methods:We performed exome sequencing, brain magnetic resonance imaging, neuropathology, electron microscopy, western blotting, and transcriptomic and metabolic analyses in 7 NIT1-small vessel disease patients from 5 unrelated pedigrees. Results: The first identified patients were 3 siblings, compound heterozygous for the NIT1 c.727C&gt;T; (p.Arg243Trp) variant and the NIT1 c.198_199del; p.(Ala68∗) variant. The 4 additional patients were single cases from 4 unrelated pedigrees and were all homozygous for the NIT1 c.727C&gt;T; p.(Arg243Trp) variant. Patients presented in mid-adulthood with movement disorders. All patients had striking abnormalities on brain magnetic resonance imaging, with numerous and massively dilated basal ganglia perivascular spaces. Three patients had non-lobar intracerebral hemorrhage between age 45 and 60, which was fatal in 2 cases. Western blotting on patient fibroblasts showed absence of NIT1 protein, and metabolic analysis in urine confirmed loss of NIT1 enzymatic function. Brain autopsy revealed large electron-dense deposits in the vessel walls of small and medium sized cerebral arteries. Conclusion: NIT1-small vessel disease is a novel, autosomal recessively inherited cerebral small vessel disease characterized by a triad of movement disorders, massively dilated basal ganglia perivascular spaces, and intracerebral hemorrhage.</p

Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients

Introduction: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. Aim: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. Methods: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 μg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. Results: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C &gt; 1.00 IU/mL. Conclusion: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption.</p