Protocol for a Gamification Tool Targeting Microelimination

Baptista-Leite, R., Lopes, H., Vandewalle, B., Félix, J., Franco, D., Clemens, T., & Brand, H. (2023). Epidemiological Modeling of the Impact of Public Health Policies on Hepatitis C: Protocol for a Gamification Tool Targeting Microelimination. JMIR Research Protocols, 12, [e38521]. https://doi.org/10.2196/38521---Gilead Sciences Europe Ltd is providing financial support for data collection, web design, and IT-related processes in the Let’s End HepC project. Manuscript authorship, the national advisory boards that contributed to this study, and scientific and academic work are not sponsored.Background: Hepatitis C is a disease with a strong social component, as its main transmission route is via blood, making it associated with lifestyle. Therefore, it is suitable to be worked on from the perspective of public health policy, which still has a lot of room to explore and improve, contrary to diagnoses and treatments, which are already very refined and effective. Objective: An interactive gamified policy tool, designated as Let’s End HepC (LEHC), was created to understand the impact of policies related to hepatitis C on the disease’s epidemiology on a yearly basis until 2030. Methods: To this end, an innovative epidemiological model was developed, integrating Markov chains to model the natural history of the disease and adaptive conjoint analysis to reflect the degree of application of each of the 24 public health policies included in the model. This double imputation model makes it possible to assess a set of indicators such as liver transplant, incidence, and deaths year by year until 2030 in different risk groups. Populations at a higher risk were integrated into the model to understand the specific epidemiological dynamics within the total population of each country and within segments that comprise people who have received blood products, prisoners, people who inject drugs, people infected through vertical transmission, and the remaining population. Results: The model has already been applied to a group of countries, and studies in 5 of these countries have already been concluded, showing results very close to those obtained through other forms of evaluation. Conclusions: The LEHC model allows the simulation of different degrees of implementation of each policy and thus the verification of its epidemiological impact on each studied population. The gamification feature allows assessing the adequate fulfillment of the World Health Organization goals for the elimination of hepatitis C by 2030. LEHC supports health decision makers and people who practice patient advocacy in making decisions based on science, and because LEHC is democratically shared, it ends up contributing to the increase of citizenship in health.publishersversionpublishe

In-line measurement of the surface texture of rolls using long slender piezoresistive microprobes

Long slender piezoresistive silicon microprobes are a new type of sensor for measurement of surface roughness. Their advantage is the ability to measure at speeds of up to 15 mm/s, which is much faster than conventional stylus probes. The drawbacks are their small measurement range and tendency to break easily when deflected by more than the allowed range of 1 mm. In this article, previously developed microprobes were tested in the laboratory to evaluate their metrological properties, then tested under industrial conditions. There are several industrial measurement applications in which microprobes are useful. Measurement of the roughness of paper machine rolls was selected for testing in this study. The integration of a microprobe into an existing roll measurement device is presented together with the measurement results. The results are promising, indicating that measurements using a microprobe can give useful data on the grinding process

Critical behavior of the dimerized Si(001) surface: A continuous order-disorder phase transition in the 2D Ising universality class

The critical behavior of the order-disorder phase transition in the buckled dimer structure of the Si(001) surface is investigated both theoretically by means of first-principles calculations and experimentally by spot profile analysis low-energy electron diffraction (SPA-LEED). We use density functional theory (DFT) with three different functionals commonly used for Si to determine the coupling constants of an effective lattice Hamiltonian describing the dimer interactions. Experimentally, the phase transition from the low-temperature $c(4 {\times} 2)$- to the high-temperature $p(2 {\times} 1)$-reconstructed surface is followed through the intensity and width of the superstructure spots within the temperature range of 78-400 K. Near the critical temperature $T_\mathrm{c} = 190.6$ K, we observe universal critical behavior of spot intensities and correlation lengths which falls into the universality class of the two-dimensional (2D) Ising model. From the ratio of correlation lengths along and across the dimer rows we determine effective nearest-neighbor couplings of an anisotropic 2D Ising model, $J_\parallel = (-24.9 \pm 0.9_\mathrm{stat} \pm 1.3_\mathrm{sys})$ meV and $J_\perp = (-0.8 \pm 0.1_\mathrm{stat})$ meV. We find that the experimentally determined coupling constants of the Ising model can be reconciled with those of the more complex lattice Hamiltonian from DFT when the critical behavior is of primary interest. The anisotropy of the interactions derived from the experimental data via the 2D Ising model is best matched by DFT calculations using the PBEsol functional. The trends in the calculated anisotropy are consistent with the surface stress anisotropy predicted by the DFT functionals, pointing towards the role of surface stress reduction as a driving force for establishing the $c(4 {\times} 2)$-reconstructed ground state

Sequential Kibble-Zurek dynamics in the anisotropic Ising model of the Si(001) surface

As a simplified description of the non-equilibrium dynamics of buckled dimers on the Si(001) surface, we consider the anisotropic 2D Ising model and study the freezing of spatial correlations during a cooling quench across the critical point. The dependence of the frozen correlation lengths $\xi_\|$ and $\xi_\perp$ on the cooling rate obtained numerically matches the Kibble-Zurek scaling quite well. However, we also find that the ratio $\xi_\|/\xi_\perp$ of their frozen values deviates significantly from the ratio in equilibrium. Supported by analytical arguments, we explain this difference by the fact that the deviation from equilibrium in the weakly coupled direction occurs earlier than in the strongly coupled direction.Comment: 4+2+1 pages, 3 figure

Complement activation and cellular inflammation in Fabry disease patients despite enzyme replacement therapy

Defective α-galactosidase A (AGAL/GLA) due to missense or nonsense mutations in the GLA gene results in accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and its deacylated derivate globotriaosylsphingosine (lyso-Gb3) in cells and body fluids. The aberrant glycosphingolipid metabolism leads to a progressive lysosomal storage disorder, i. e. Fabry disease (FD), characterized by chronic inflammation leading to multiorgan damage. Enzyme replacement therapy (ERT) with agalsidase-alfa or -beta is one of the main treatment options facilitating cellular Gb3 clearance. Proteome studies have shown changes in complement proteins during ERT. However, the direct activation of the complement system during FD has not been explored. Here, we demonstrate strong activation of the complement system in 17 classical male FD patients with either missense or nonsense mutations before and after ERT as evidenced by high C3a and C5a serum levels. In contrast to the strong reduction of lyso-Gb3 under ERT, C3a and C5a markedly increased in FD patients with nonsense mutations, most of whom developed anti-drug antibodies (ADA), whereas FD patients with missense mutations, which were ADA-negative, showed heterogenous C3a and C5a serum levels under treatment. In addition to the complement activation, we found increased IL-6, IL-10 and TGF-ß1 serum levels in FD patients. This increase was most prominent in patients with missense mutations under ERT, most of whom developed mild nephropathy with decreased estimated glomerular filtration rate. Together, our findings demonstrate strong complement activation in FD independent of ERT therapy, especially in males with nonsense mutations and the development of ADAs. In addition, our data suggest kidney cell-associated production of cytokines, which have a strong potential to drive renal damage. Thus, chronic inflammation as a driver of organ damage in FD seems to proceed despite ERT and may prove useful as a target to cope with progressive organ damage

Urban Air Mobility Vehicle and Fleet-level Life-Cycle Assessment Using a System-of-Systems Approach

Can Urban Air Mobility (UAM) systems constitute viable and sustainable mobility solutions? This question has increasingly been concerning scientists, companies, policy makers, and authorities as more and more UAM vehicle concepts are seeing the light of day. In order to come closer to answering this question and to demonstrate the dependencies and impacts of the numerous parameters used to describe a highly complex system of a fleet of UAM vehicles operating in an urban environment, this paper employs a System of Systems (SoS) approach. A collaborative SoS framework with an agent-based simulation is introduced, which connects the UAM vehicle design, fleet performance, vertiport network, and re-energizing infrastructure with a Life-Cycle Assessment (LCA). The framework is used to simulate four exemplary UAM fleet-operation scenarios based on two cities and two operational modes, namely urban and suburban operations. Different vehicle design configurations, e.g. multirotor and lift + cruise vehicles, are evaluated in each scenario based on respectively realistic Concepts of Operations (CONOPS). Additionally, two different points in time, namely 2025 and 2050, are considered and assessed for powering the vehicles by taking into account the characteristics of batteries as well as the underlying electricity mix for their operation. Lithium nickel manganese cobalt oxide battery and lithium-sulfur (Li-S) batteries are considered. The SoS framework helps to asses various UAM metrics such as the average wait time for a passenger, the ideal number of aircraft needed for transporting all passengers within given time, the energy required on a vehicle and fleet level, sustainability metrics, e.g. the global warming potential associated with the energy carriers and many more. The capability to explore a wide design space and to visualize the dependencies between the system parameters and their impacts on different SoS metrics provides stakeholders with a helpful tool for their decision making

Soziologie der Nachhaltigkeit

Das in der Soziologie neu auflebende Interesse an Nachhaltigkeitsforschung lässt sich als ‚zweite Welle‘ einer Soziologie der Nachhaltigkeit deuten. Dass dabei andere Perspektiven als zu Beginn der soziologischen Befassung mit Nachhaltigkeit in den Vordergrund rücken, scheint sich angesichts des veränderten gesellschaftlichen Kontextes von selbst zu verstehen. Jedoch: Wie lassen sich die Besonderheiten einer solchen ‚zweiten Welle‘ näher bestimmen? Wie lassen sie sich von der ‚ersten Welle‘ soziologischer Nachhaltigkeitsforschung in den späten neunziger und frühen zweitausender Jahren abgrenzen? Darüber hat sich in der Onlinezeitschrift Soziologie und Nachhaltigkeit (SuN) sowie auf der Sektionssitzung des Göttinger Soziologiekongresses eine Diskussion zwischen Karl-Werner Brand, Vertreter*innen des DFG-Netzwerks Soziologie der Nachhaltigkeit sowie einer soziologischen Öffentlichkeit mit Schwerpunkten vor allem in der Umwelt-, Wissens- und Wissenschaftssoziologie entwickelt. Diese Debatte soll in zusammenfassend-resümierender Weise hier für eine breitere Fachöffentlichkeit wiedergegeben werden.&nbsp

Phenotypic and molecular insights into CASK-related disorders in males

Background: Heterozygous loss-of-function mutations in the X-linked CASK gene cause progressive microcephaly with pontine and cerebellar hypoplasia (MICPCH) and severe intellectual disability (ID) in females. Different CASK mutations have also been reported in males. The associated phenotypes range from nonsyndromic ID to Ohtahara syndrome with cerebellar hypoplasia. However, the phenotypic spectrum in males has not been systematically evaluated to date. Methods: We identified a CASK alteration in 8 novel unrelated male patients by targeted Sanger sequencing, copy number analysis (MLPA and/or FISH) and array CGH. CASK transcripts were investigated by RT-PCR followed by sequencing. Immunoblotting was used to detect CASK protein in patient-derived cells. The clinical phenotype and natural history of the 8 patients and 28 CASK-mutation positive males reported previously were reviewed and correlated with available molecular data. Results: CASK alterations include one nonsense mutation, one 5-bp deletion, one mutation of the start codon, and five partial gene deletions and duplications; seven were de novo, including three somatic mosaicisms, and one was familial. In three subjects, specific mRNA junction fragments indicated in tandem duplication of CASK exons disrupting the integrity of the gene. The 5-bp deletion resulted in multiple aberrant CASK mRNAs. In fibroblasts from patients with a CASK loss-of-function mutation, no CASK protein could be detected. Individuals who are mosaic for a severe CASK mutation or carry a hypomorphic mutation still showed detectable amount of protein. Conclusions: Based on eight novel patients and all CASK-mutation positive males reported previously three phenotypic groups can be distinguished that represent a clinical continuum: (i) MICPCH with severe epileptic encephalopathy caused by hemizygous loss-of-function mutations, (ii) MICPCH associated with inactivating alterations in the mosaic state or a partly penetrant mutation, and (iii) syndromic/nonsyndromic mild to severe ID with or without nystagmus caused by CASK missense and splice mutations that leave the CASK protein intact but likely alter its function or reduce the amount of normal protein. Our findings facilitate focused testing of the CASK gene and interpreting sequence variants identified by next-generation sequencing in cases with a phenotype resembling either of the three groups

Optical Dissection of Neural Circuits Responsible for Drosophila Larval Locomotion with Halorhodopsin

Halorhodopsin (NpHR), a light-driven microbial chloride pump, enables silencing of neuronal function with superb temporal and spatial resolution. Here, we generated a transgenic line of Drosophila that drives expression of NpHR under control of the Gal4/UAS system. Then, we used it to dissect the functional properties of neural circuits that regulate larval peristalsis, a continuous wave of muscular contraction from posterior to anterior segments. We first demonstrate the effectiveness of NpHR by showing that global and continuous NpHR-mediated optical inhibition of motor neurons or sensory feedback neurons induce the same behavioral responses in crawling larvae to those elicited when the function of these neurons are inhibited by Shibirets, namely complete paralyses or slowed locomotion, respectively. We then applied transient and/or focused light stimuli to inhibit the activity of motor neurons in a more temporally and spatially restricted manner and studied the effects of the optical inhibition on peristalsis. When a brief light stimulus (1–10 sec) was applied to a crawling larva, the wave of muscular contraction stopped transiently but resumed from the halted position when the light was turned off. Similarly, when a focused light stimulus was applied to inhibit motor neurons in one or a few segments which were about to be activated in a dissected larva undergoing fictive locomotion, the propagation of muscular constriction paused during the light stimulus but resumed from the halted position when the inhibition (>5 sec) was removed. These results suggest that (1) Firing of motor neurons at the forefront of the wave is required for the wave to proceed to more anterior segments, and (2) The information about the phase of the wave, namely which segment is active at a given time, can be memorized in the neural circuits for several seconds