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Relating the mass eruption rate (MER) of explosive eruptions to column height in the atmosphere is key to reconstructing past eruptions and forecasting volcanic hazards. Using 134 eruptive events from the Independent Volcanic Eruption Source Parameter Archive (IVESPA v1.0), we explore the canonical MER-height relationship for four measures of column height: spreading level, sulfur dioxide height, and top height from both directly observed plumes and those reconstructed from deposits. These relationships show significant differences and should be chosen carefully for operational and research applications. The roles of atmospheric stratification, wind, and humidity remain challenging to assess across the large range of eruptive conditions in this database, ultimately resulting in empirical relationships outperforming analytical models that account for atmospheric conditions. This finding reveals the complexity of the height-MER relation that is difficult to constrain based on available heterogeneous observations, which reinforces the need for improved datasets to develop eruptive column models.

In 2014, the decision in Richardson v Oracle significantly increased compensation awards for victims of discrimination and sexual harassment. Commentators referred to the decision as ‘ground-breaking’ and hypothesised that the floodgates would open for sexual harassment and discrimination cases. This article reviews these claims seven years on and asks: did the floodgates open? Case law review and analysis concludes that, while the ground did not break open for victims of discrimination and sexual harassment, it has certainly cracked – although unevenly. As such, more is required to create truly just outcomes for victims in discrimination law.

Background: The question of how best to support children who are refugees to resettle and thrive in a new country is important and complex. One of the many challenges experienced by such children is disrupted education. It is widely recognised that a sense of belonging and integration within a new school and community are key to enhancing children’s chances of achieving their potential. Tutoring programmes, where tutors work one-to-one with tutees, can offer a form of support in this regard. Purpose: Set within the context of the COVID-19 pandemic, this study sought to explore experiences of tutors involved in a pilot project in Scotland for primary schoolchildren from a refugee community. The home-based, online tutoring project focused on building confidence and a sense of belonging in order to support achievement in school. Methods: Participants were 18 tutors who had taken part in the pilot project. Semi-structured questionnaires were used to gather rich data about the tutors’ experiences of working with the children from the refugee community. Data were analysed qualitatively, using a reflexive thematic analytical approach. Findings: Tutors believed that relationships between tutor and child were essential to success. Personalisation appeared key to building confidence and helping children progress. Tutors spent time getting to know their tutee and took care to let their tutee get to know them as a person, as a way of bringing down barriers and helping the child connect. Tutors reported that they needed knowledge of the local curriculum, liaison with class teachers and understanding of the refugee community. They described the peer support network as invaluable for sharing knowledge. Although each worked with a different child, tutors learned from and assisted each other through their support network, sharing resources and ideas. Conclusion: The study highlights the value of a professional learning community, particularly when tutors are working in isolation. It also draws attention to the importance of training for tutors taking on such roles, including support with the pastoral aspects of working with a child, such as the personalisation and relationship-building that was of such significance in this study.

Hematopoietic stem and progenitor cells develop from the hemogenic endothelium located in various sites during development, including the dorsal aorta from where Hematopoietic Stem Cells (HSCs) emerge. This process has proven especially challenging to recapitulate in vitro from pluripotent stem cells and further studies are needed to pinpoint the missing stimuli in vitro. Here, we compared iPSC-derived endothelial cells and in vivo HSC-primed hemogenic endothelium and identified 9 transcription factors expressed at significantly lower levels in cells generated in vitro. Using a novel DOX-inducible CRISPR activation system we induced the expression of those genes during in vitro differentiation. To study the phenotypical changes induced by the activation of target genes, we employed single cell RNA sequencing in combination with engineered gRNA that are detectable within the sequencing pipeline. Our data showed a significant expansion of arterial-fated endothelial cells associated with a higher in vitro progenitor activity. The expanded arterial cluster was marked by high expression of IGFBP2 and it was distinct from the hemogenic cluster that showed increased cell cycle progression. We demonstrated that the addition of IGFBP2 to differentiating PSCs resulted in a higher number of functional progenitors, identifying the supporting role of arterial cells play to the emergence of blood progenitors via IGFBP2 paracrine signalling.

Inflammatory bowel disease (IBD) can affect young and reproductively active patients. Our aim was to analyze pregnancy outcomes in a large cohort of women with IBD.All women with at least one pregnancy were given a questionnaire regarding the outcome of their pregnancy. They were divided into IBD pregnancies and controls depending on whether pregnancy occurred within or over 10 years prior to the diagnosis of IBD.Three hundred questionnaires were analyzed for a total of 478 pregnancies that led to live-born babies. Age at conception was older in IBD women than in the controls. Active smoking was more frequent in the control group. The risk of intrauterine growth restriction (IUGR) was higher in IBD pregnancies (odds ratio [OR] 3.028, 95% confidence interval [CI] 1.245-7.370, P = 0.013). The week of gestation at delivery was lower in the IBD population. And the risk of cesarean section was higher in IBD pregnancies (OR 1.963, 95% CI 1.274-3.028, P = 0.002). Among women with IBD pregnancy, the risk of preterm birth was higher in patients with active disease at the time of conception (OR 4.088, 95% CI 1.112-15.025, P = 0.030), but lower in patients who continued regular therapy during pregnancy. Similarly, the risk of urgent cesarean section was reduced in the case of disease remission, while the risk of a planned cesarean delivery was higher in patients with perianal disease (OR 11.314, 95% CI 3.550-36.058, P 0.01).Our study shows a higher risk of IUGR, cesarean section, and poor blood pressure control in IBD pregnancies. We emphasize the importance of achieving disease remission before considering pregnancy.

Traditional rationales for discrimination law often focus on the immutability of characteristics. Pursuant to these rationales, discrimination should be prohibited where it relates to a characteris...

Acute ischemic stroke (IS) and transient ischemic attack (TIA) are associated with raised von Willebrand factor (VWF) and decreased ADAMTS13 activity (ADAMTS13Ac). Their impact on mortality and morbidity is unclear. We conducted a prospective investigation of the VWF-ADAMTS13 axis in 292 adults (acute IS, n = 103; TIA, n = 80; controls, n = 109) serially from presentation until >6 weeks. The National Institutes of Health Stroke Score (NIHSS) and modified Rankin scale (mRS) were used to assess stroke severity. Presenting median VWF antigen (VWF:Ag)/ADAMTS13Ac ratios were: IS, 2.42 (range, 0.78-9.53); TIA, 1.89 (range, 0.41-8.14); and controls, 1.69 (range, 0.25-15.63). Longitudinally, the median VWF:Ag/ADAMTS13Ac ratio decreased (IS, 2.42 to 1.66; P = .0008; TIA, 1.89 to 0.65; P < .0001). The VWF:Ag/ADAMTS13Ac ratio was higher at presentation in IS patients who died (3.683 vs 2.014; P < .0001). A presenting VWF:Ag/ADAMTS13Ac ratio >2.6 predicted mortality (odds ratio, 6.33; range, 2.22-18.1). Those with a VWF:Ag/ADAMTS13Ac ratio in the highest quartile (>3.091) had 31% increased risk mortality. VWF:Ag/ADAMTS13Ac ratio at presentation of ischemic brain injury was associated with higher mRS (P = .021) and NIHSS scores (P = .029) at follow-up. Thrombolysis resulted in prompt reduction of the VWF:Ag/ADAMTS13Ac ratio and significant improvement in mRS on follow-up. A raised VWF:Ag/ADAMTS13Ac ratio at presentation of acute IS or TIA is associated with increased mortality and poorer functional outcome. A ratio of 2.6 seems to differentiate outcome. Prompt reduction in the ratio in thrombolysed patients was associated with decreased mortality and morbidity. The VWF:Ag/ADAMTS13Ac ratio is a biomarker for the acute impact of an ischemic event and longer-term outcome.

This article describes the use of a case formulation approach, integrating evidence-based treatment in the context of individual clinical traits. It focuses on the supplementation of cognitive behavioural therapy (CBT) with eye movement desensitization and reprocessing (EMDR) in the treatment of a young person, presenting with an initial diagnosis of obsessive-compulsive disorder (OCD). A case formulation suggested the possibility of a differential diagnosis of Adjustment Disorder, indicating the usefulness of the addition of EMDR sessions to process memories of severe bullying. Previous studies promote the idea of using EMDR in cases that do not meet the threshold for Post-Traumatic Stress Disorder (PTSD), in order to reduce the presentation of anxiety. Earlier research suggests that each of these models has specific strengths and attributes in the treatment of mental health difficulties and, whilst based within the context of a well-established case conceptualisation, can be effectively integrated.

Considerable evidence shows that adolescent intimate relationships influence the course of adult relationships, that is, whether relationship experiences are characterized by abuse or violence, or healthy, equitable dynamics. Controlling behaviors (CBs)—a phenomenon related to intimate partner violence (IPV)—are pervasive in adolescent intimate relationships, yet there is a lack of consensus on how to conceptualize them and subsequently, limited research which explores the role of CBs, including their role as warning signs for other forms of harm and abuse. As such, there are gaps in integrating CBs in policy and program interventions that could prevent IPV from the earliest stages. This article presents findings from in-depth qualitative research on adolescent relationship violence conducted in under studied settings of Brazil and Honduras. Adolescents described using or experiencing CBs in at least one form in 147 interviews with girls/young women and boys/young men aged 14–24 in rural and urban sites. Drawing from these empirical findings and conceptual and theoretical aspects from the literature, this article analyzes CBs in adolescent relationships and how they relate to IPV. By doing so, it seeks to offer a conceptual framework on CBs that could better inform policies and programs by being reflective of adolescent experiences, and ultimately more nuanced in promoting healthy adolescent relationships.

Purpose Child marriages and unions can infringe upon adolescent and youth sexual and reproductive health (AYSRH). Interventions increasingly promote strategies to transform social norms or foster the agency of adolescent girls. Recent empirical studies call for further understanding of how social norms and agency interact in ways that influence these practices, especially in contexts where girls' agency is central. Methods A secondary cross-case analysis of three qualitative studies (in Brazil, Guatemala, Honduras) was conducted to inform the investigation of how norms and agency may relate in sustaining or mitigating child marriage. Results Social norms dictating how girls/young women and how men should act indirectly led to child marriages and unions. The data showed that (1) social norms regulated girls' acceptable actions and contributed to their exercise of “oppositional” agency; (2) social norms promoted girls' “accommodating” agency; and (3) girls exercised “transformative” agency to resist harmful social norms. Conclusions Research should advance frameworks to conceptualize how social norms interact with agency in nuanced and context-specific ways. Practitioners should encourage equitable decision-making; offer confidential, adolescent-friendly AYSRH services; and address the social norms of parents, men and boys, and community members.

Concerning approaches and communications to the Royal Family and other British public figures are relatively numerous. This paper examines over 2000 such cases logged over a three-year period in the United Kingdom. Using police and health data, the paper conducts a series of bivariate and multivariate analyses to demonstrate the predictors of what types of risk are posed by an individual case (e.g., communicate only, approach, security breach). The results showed that (a) the rates of serious mental disorders are higher among this sample than the general population base rate, (b) approachers were significantly more likely than communicators to suffer from serious mental disorders, (c) approachers were significantly more likely than communicators to have a history of substance use and abuse problems, (d) approachers were significantly more likely than communicators to have a history of violent behavior against property and persons, and (e) the motivations of approachers and communicators significantly differ. The paper concludes with a consideration of the implications for threat assessment and management.

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti–von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

Essentials Congenital thrombotic thrombocytopenic purpura (TTP) is primarily treated with plasma infusion. We present a pharmacokinetic analysis of ADAMTS-13 in six patients following plasma infusion. A median half-life of 130 h was demonstrated, ranging between 82.6 and 189.5 h. Investigation of interindividual clearance of ADAMTS-13 is necessary to optimize treatment. SUMMARY: Background Congenital thrombotic thrombocytopenic purpura (TTP) is defined by persistent severe deficiency of ADAMTS-13 in the absence of anti-ADAMTS-13 inhibitory antibodies, confirmed by mutational analysis. Replacement of the missing protease prevents disease relapse, primarily using plasma infusion (PI). Objectives, patients and methods There is scant evidence regarding optimal dose and frequency of treatment, which tends to be empirically guided. We present a pharmacokinetic analysis of ADAMTS-13 in six patients with congenital TTP on established regimes following PI. Results We found a median clearance of 25.41 mL h-1 and half-life of 130 h, ranging between 82.6 and 189.5 h (3.4-7.9 days, respectively). All patients reached baseline ADAMTS-13 level within 7-10 days post-plasma. Median ADAMTS-13 activity peak post-PI was 24.05 IU dL-1 . Variation was related to elimination rate, which, in turn, was affected by weight and metabolism, but not to von Willebrand factor antigen or activity levels. Using the pharmacokinetic parameters, we simulated individualized protocols based on PI dose or frequency to target hypothetical optimal plasma levels of ADAMTS-13 of 10 and 50 IU dL-1 , respectively. Results suggest a target trough ADAMTS-13 of 10 IU dL-1 is feasible but 50 IU dL-1 would not be achievable taking into account volume required. Conclusions Further work is needed to compare treatment of congenital TTP with PI vs. recombinant ADAMTS-13. PI may provide longer duration of ADAMTS-13 effect, but is limited by plasma volume required, whereas recombinant therapy can provide a higher ADAMTS-13 peak. We propose that investigation of interindividual clearance of ADAMTS-13 is necessary to optimize treatment and provide the rationale for dose and frequency of prophylaxis.

Our understanding of the development of secular institutional governments in Europe during the central Middle Ages has long been shaped by an implicit or explicit opposition between royal and lay aristocratic power. That is to say, the growth of public, institutional and/or bureaucratic central authorities involved the decline and/or exclusion of noble aristocratic power, which thus necessarily operated in a zero-sum game. While much research has shown that this conflict-driven narrative is problematic, it remains in our understanding as a rather shadowy but still powerful causal force of governmental development during this period. This paper compares the changing conceptualisation of the relationship between royal and aristocratic power in the French and Scottish kingdoms to demonstrate, first, how narratives built at the periphery of Europe have important contributions and challenges to make to those formed from the core areas of Europe and, second, that state formation did not involve a decline in aristocratic power. Instead, the evidence from royalactain both kingdoms shows that aristocratic power was formalised at a central level, and then built into the forms of government which were emerging in very different ways in both kingdoms in the late twelfth and early thirteenth centuries. Set in broader perspective, this suggests that governmental development involved an intensification of existing structures of elite power, not a diminution.

Background Almost half of ischemic strokes in young individuals are cryptogenic. Thrombophilia testing is routinely sent despite limited evidence linking to arterial cerebrovascular events. A full blood count may identify underlying hematological disorder. Methods We retrospectively reviewed all patients younger than 60 years with stroke and transient ischemic attack (TIA) presenting to a regional hyperacute stroke unit and daily TIA clinic from January 2015 to August 2016. We examined hematocrit level and platelet count, and whether abnormalities were further investigated. We examined if primary hematological disorders associated with stroke were considered, specifically myeloproliferative diseases (MPDs) and thrombotic thrombocytopenic purpura (TTP). Results Of 609 patients who presented with stroke or TIA, there were 161 abnormalities in hematocrit level or platelet count in 153 patients (25.1%). One hundred sixteen patients had high hematocrit levels (19%), 19 had thrombocytosis (3.1%), 26 had thrombocytopenia (4.3%), and 8 had abnormalities in both lineages (1.3%). A total of 119 patients had repeat testing (74%). Molecular investigations for MPD were warranted in 19 patients (3.1%), performed in 3 patients (.5%) with 2 patients subsequently diagnosed. ADAMTS13 analysis was indicated in 10 patients with thrombocytopenia, performed in 2 patients with 1 diagnosed with TTP thereafter. Conclusions One quarter of our cohort (n = 153) had abnormalities in hematocrit and/or platelets. MPD or TTP was present in 3 of the 5 patients specifically investigated. At least 22 patients (14%) merited further investigation. Although primary hematological disorders are rare in stroke aetiology, the full blood count is important to exclude known causes of arterial cerebrovascular events in young patients.

IntroductionApproximately 40% of strokes in young adults are cryptogenic. The diagnostic yield of thrombophilia screening remains controversial. We aimed to determine utility of current thrombophilia testing for young patients with stroke and transient ischaemic attack (TIA).MethodsWe present a retrospective review of all patients with stroke and TIA ≤60 years presenting to University College London Hospital stroke unit and daily TIA clinic from 1 January 2015 to 1 August 2016. Consecutive clinical records and thrombophilia tests, including factor V Leiden (FVL), prothrombin G20210A mutation (PGM), antiphospholipid antibody (APA), and protein S, C and antithrombin (AT) levels, were reviewed.ResultsThe mean age of 628 patients with stroke and TIA was 49.1 years (SD 9.2). Thrombophilia testing was performed in 360 (57%) patients, including 171 with stroke and 189 with TIA. Positive tests were found in 50 (14%) patients, of whom 24 patients were ConclusionThrombophilia testing was positive in only 14% of cases overall. Thrombophilia mutations and protein C, S or AT abnormalities were found rarely and were very uncommon in patients with TIA. Follow-up of abnormal results was generally poor for all groups, which further limited the impact of the thrombophilia testing policy.

SUMMARYProminent figures are frequently subjected to unwanted and intrusive attentions. Such stalking behaviour is often driven by psychotic illness, angrily blaming the public figure for delusional persecution (resentful motivation), or based on erotomanic delusions (intimacy seeking motivation), for example. This behaviour can cause psychological harm to both perpetrator and victim, and is unlawful. In the rare instances where a public figure has been attacked, the perpetrator has usually had a history of such stalking behaviour and of severe mental illness. For these reasons, early identification and diversion into appropriate care and treatment will be for the benefit of both parties and will prevent more serious violence in a minority of cases. The importance of the provision of education to improve both reporting rates by victims and an appropriate response from the criminal justice system is highlighted. A multi-agency approach involving the criminal justice system and mental health services is the most effective means of achieving these aims.DECLARATION OF INTERESTNone.LEARNING OBJECTIVES•Learn that severe mental illness, particularly psychosis, is often an important driver of stalking behaviour•Learn that delusional disorder is a treatable mental illness•Appreciate that prevention rather than prediction is the approach to managing the risks of high-harm low-probability outcomes.