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Accelerating progress towards the 2030 neglected tropical diseases targets : how can quantitative modeling support programmatic decisions?
Get PDFOver the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021–2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets
Rapid expansion and international spread of M1 UK in the post-pandemic UK upsurge of Streptococcus pyogenes
Get PDFThe UK observed a marked increase in scarlet fever and invasive group A streptococcal infection in 2022 with severe outcomes in children and similar trends worldwide. Here we report lineage M1UK to be the dominant source of invasive infections in this upsurge. Compared with ancestral M1global strains, invasive M1UK strains exhibit reduced genomic diversity and fewer mutations in two-component regulator genes covRS. The emergence of M1UK is dated to 2008. Following a bottleneck coinciding with the COVID-19 pandemic, three emergent M1UK clades underwent rapid nationwide expansion, despite lack of detection in previous years. All M1UK isolates thus-far sequenced globally have a phylogenetic origin in the UK, with dispersal of the new clades in Europe. While waning immunity may promote streptococcal epidemics, the genetic features of M1UK point to a fitness advantage in pathogenicity, and a striking ability to persist through population bottlenecks
The Juncker Commission : internal perceptions of a Spitzenkandidaten presidency
No full textThis chapter examines how Jean-Claude Juncker interpreted the mandate delivered by the Spitzenkandidaten procedure to lead a ‘political Commission’ and to introduce ‘new ways of working’, with a tier of vice presidents coordinating the implementation of the Commission President’s programme. It looks at how Commission staff viewed the Spitzenkandidaten process as well as these two features that characterised the Juncker model, across the organisation. The chapter also argues that the Juncker model of presidential leadership has proved to be enduring. Although Juncker is so far the only Commission President to have been appointed via the Spitzenkandidaten procedure, his Presidency extended the process of presidentialisation initiated by his predecessor, José Manuel Barroso, and has created a new model of presidentialism, that persisted under his successor, Ursula von der Leyen, even though she was not a Spitzenkandidat
Astrocyte ryanodine receptors facilitate gliotransmission and astroglial modulation of synaptic plasticity
Get PDFIntracellular Ca2+-signaling in astrocytes is instrumental for their brain “housekeeping” role and astroglial control of synaptic plasticity. An important source for elevating the cytosolic Ca2+ level in astrocytes is a release from endoplasmic reticulum which can be triggered via two fundamental pathways: IP3 receptors and calcium-induced calcium release (CICR) mediated by Ca2+-sensitive ryanodine receptors (RyRs). While the physiological role for glial IP3 became a focus of intensive research and debate, ryanodine receptors received much less attention. We explored the role for ryanodine receptors in the modulation of cytosolic Ca2+-signaling in the cortical and hippocampal astrocytes, astrocyte-neuron communication and astroglia modulation of synaptic plasticity. Our data show that RyR-mediated Ca2+-induced Ca2+-release from ER brings substantial contribution into signaling in the functional microdomains hippocampal and neocortical astrocytes. Furthermore, RyR-mediated CICR activated the release of ATP and glutamate from hippocampal and neocortical astrocytes which, in turn, elicited transient purinergic and tonic glutamatergic currents in the neighboring pyramidal neurons. The CICR-facilitated release of ATP and glutamate was inhibited after intracellular perfusion of astrocytes with ryanodine and BAPTA and in the transgenic dnSNARE mice with impaired astroglial exocytosis. We also found out that RyR-mediated amplification of astrocytic Ca2+-signaling enhanced the long-term synaptic potentiation in the hippocampus and neocortex of aged mice. Combined, our data demonstrate that ryanodine receptors are essential for astrocytic Ca2+-signaling and efficient astrocyte-neuron communications. The RyR-mediated CICR contributes to astrocytic control of synaptic plasticity and can underlie, at least partially, neuroprotective and cognitive effects of caffein
Inter- and intra-observer reliability and agreement of O2Pulse inflection during cardiopulmonary exercise testing : a comparison of subjective and novel objective methodology
Get PDFCardiopulmonary exercise testing (CPET) is the ‘gold standard’ method for evaluating functional capacity, with oxygen pulse (O2Pulse) inflections serving as a potential indicator of myocardial ischaemia. However, the reliability and agreement of identifying these inflections have not been thoroughly investigated. This study aimed to assess the inter- and intra-observer reliability and agreement of a subjective quantification method for identifying O2Pulse inflections during CPET, and to propose a more robust and objective novel algorithm as an alternative methodology. A retrospective analysis was conducted using baseline data from the HIIT or MISS UK trial. The O2Pulse curves were visually inspected by two independent examiners, and compared against an objective algorithm. Fleiss’ Kappa was used to determine the reliability of agreement between the three groups of observations. The results showed almost perfect agreement between the algorithm and both examiners, with a Fleiss’ Kappa statistic of 0.89. The algorithm also demonstrated excellent inter-rater reliability (ICC) when compared to both examiners (0.92–0.98). However, a significant level (P ≤0.05) of systematic bias was observed in Bland-Altman analysis for comparisons involving the novice examiner. In conclusion, this study provides evidence for the reliability of both subjective and novel objective methods for identifying inflections in O2Pulse during CPET. These findings suggest that further research into the clinical significance of O2Pulse inflections is warranted, and that the adoption of a novel objective means of quantification may be preferable to ensure equality of outcome for patients
SAFE-RL: Saliency-Aware Counterfactual Explainer for Deep Reinforcement Learning Policies
Get PDFWhile Deep Reinforcement Learning (DRL) has emerged as a promising solution for intricate control tasks, the lack of explainability of the learned policies impedes its uptake in safety-critical applications, such as automated driving systems (ADS). Counterfactual (CF) explanations have recently gained prominence for their ability to interpret black-box Deep Learning (DL) models. CF examples are associated with minimal changes in the input, resulting in a complementary output by the DL model. Finding such alternations, particularly for high-dimensional visual inputs, poses significant challenges. Besides, the temporal dependency introduced by the reliance of the DRL agent action on a history of past state observations further complicates the generation of CF examples. To address these challenges, we propose using a saliency map to identify the most influential input pixels across the sequence of past observed states by the agent. Then, we feed this map to a deep generative model, enabling the generation of plausible CFs with constrained modifications centred on the salient regions. We evaluate the effectiveness of our framework in diverse domains, including ADS, Atari Pong, Pacman and Space-invaders games, using traditional performance metrics such as validity, proximity and sparsity. Experimental results demonstrate that this framework generates more informative and plausible CFs than the state-of-the-art for a wide range of environments and DRL agents. In order to foster research in this area, we have made our datasets and codes publicly available at https://github.com/Amir-Samadi/SAFE-RL
Motherhood and domestic authority in British and colonial Quakerism
Get PDFThis article explores how women, as mothers, acquired international influence within British and North American Quakerism between 1650 and 1775. It has been well established that Quakerism disrupted traditional domestic hierarchies, but less is known about the ways in which maternity provided agency for female Quakers in their everyday lives. This article focuses on the labors and experiences of women who did not undertake transatlantic travel, whose lives were primarily centered around raising their children and supporting the Quaker community. It shows how the evolving Religious Society of Friends enhanced the status of mothers in important ways, enabling women’s “reproductive labor” to be the subject of veneration and recognition. Using the journals and writings of traveling ministers, as well as correspondence exchanged between ministers, their hosts, and other members of the Society of Friends, it shows how women’s domestic roles provided a vital function for the transatlantic Quaker community.
Using the journals and writings of travelling ministers, as well as correspondence exchanged between ministers, their hosts, and other members of the Society of Friends, it shows how women’s domestic roles, provided a vital function for the transatlantic Quaker community
Parenting knowledge and parenting self-efficacy of mothers with borderline personality disorder and depression : “I know what to do but think I am not doing it”
Get PDFBorderline personality disorder (BPD) is a complex mental health condition often associated with previous childhood adversity including maladaptive parenting. When becoming a parent themselves, mothers with BPD have difficulties with various parenting cognitions and practices, but unknown is whether they have appropriate knowledge of sensitive parenting. This study explored whether differences in parenting knowledge or self-efficacy are specific to BPD or also found in mothers with depression, and whether symptom severity or specific diagnosis better explain parenting perceptions. Mothers with BPD (n = 26), depression (n = 25) or HCs (n = 25) completed a Q-sort parenting knowledge task and a parenting self-efficacy questionnaire. Results showed mothers with BPD had the same knowledge of sensitive parenting behaviors as mothers with depression and healthy mothers. Self-reported parenting self-efficacy was lower in mothers with BPD and depression compared with healthy mothers, with symptom severity most strongly associated. A significant but low correlation was found between parenting self-efficacy and knowledge. Findings suggest that mothers with BPD and depression know what good parenting is but think they are not parenting well. Mental health difficulties are not associated with parenting knowledge, but symptom severity appears to be a common pathway to lower parenting self-efficacy. Future interventions should test whether reduction of symptom severity or positive parenting feedback could improve parenting self-efficacy
Computing points on bielliptic modular curves over fixed quadratic fields
Get PDFWe present a Mordell–Weil sieve that can be used to compute points on certain bielliptic modular curves X0(N) over fixed quadratic fields. We study X0(N)(Q(d−−√)) for N∈{53,61,65,79,83,89,101,131} and |d|<100
Disclosing a random walk
Get PDFWe examine a dynamic disclosure model in which the value of a firm follows a random walk. Every period, with some probability, the manager learns the firm's value and decides whether to disclose it. The manager maximizes the market perception of the firm's value, which is based on disclosed information. In equilibrium, the manager follows a threshold strategy with thresholds below current prices. He sometimes reveals pessimistic information that reduces the market perception of the firm's value. He does so to reduce future market uncertainty, which is valuable even under risk-neutrality