Caplacizumab in paediatric immune thrombotic thrombocytopenic purpura (iTTP): the UK TTP Registry experience.

Paediatric thrombotic thrombocytopenic purpura (TTP) is an ultra-rare disease. Immune TTP (iTTP) is driven by anti-ADAMTS13 autoantibodies causing an imbalanced VWF:ADAMTS13 axis, and rarer still in children, but potentially life-threatening. Caplacizumab is licensed for iTTP treatment in adults and adolescents aged 12 years and older who weigh 40kg plus. There is a need to clarify whether caplacizumab can be used in younger children. We retrospectively describe caplacizumab use in 16 patients under 18 years of age from the UK TTP Registry, including 4 children aged less than 12 years. For patients weighing less than 40kg (n=3), caplacizumab was dosed at 5mg od. The youngest patient was 33 months old at diagnosis. Plasma exchange (PEX) was used in 15 patients, with a median of 5 exchanges required before platelet count normalisation (range 2-9). One patient was managed without plasma exchange. All patients achieved normalisation of platelet count (median 5.5 days, range 3-28) and ADAMTS13 activity (median 35 days, range 8 to 149), with a median hospital admission of 11 days (range 5 to 26). There were no refractory patients. One patient relapsed at 9 months post presentation. Bleeding requiring VWF supplementation and reduction of caplacizumab use occurred in one patient with severe epistaxis, with no significant intracranial or gastrointestinal bleeding. We demonstrate the efficacy and safety of caplacizumab in the paediatric population, synonymous with the adult trial data: primarily, reduction of PEX compared with the pre-caplacizumab era. This has implications for intensification and duration of admission, particularly relevant in paediatric care.

Identifying Opportunities for Early Detection of Cerebral Palsy.

This study aimed to evaluate assessment and referral practices for the early detection and diagnosis of children at risk for or with cerebral palsy (CP) by health care and education providers in Maryland and Delaware. A secondary aim was to identify barriers for using early detection tools and identify opportunities for change to support early diagnosis and improve care. Seventy-two participants answered ≥ 50% of the survey questions. Most were occupational or physical therapists (86%) working in early intervention (61%). Eighty-eight percent indicated awareness that CP can be diagnosed by 12 months. Though 86% stated they typically suspect a diagnosis of CP between 0 and 12 months, only 19% reported that their patients received a CP diagnosis < 12 months. The Developmental Assessment of Young Children (73%) and the Peabody Developmental Motor Scales-2 (59%) were used most. Many respondents indicated never using magnetic resonance imaging (70%), the General Movements Assessment (87%), or the Hammersmith Infant Neurological Exam (69%). Participants identified clinical signs and symptoms prompting a referral for the diagnostic assessment of CP, most commonly stiffness in legs (95%), excessive head lag (93%), and persistent fisting (92%). Policy and organizational change, clinician education, and training are needed to support the implementation of CP early detection guidelines.

Measles Vaccine Coverage and Disease Outbreaks: A Systematic Review of the Early Impact of COVID-19 in Low and Lower-Middle Income Countries.

Objectives: We aimed to evaluate changes to measles-containing vaccine (MCV) provision and subsequent measles disease cases in low- and lower-middle income countries (LICs, LMICs) in relation to the COVID-19 pandemic. Methods: A systematic search was conducted of MEDLINE, OVID EMBASE and PubMed records. Primary quantitative and qualitative research studies published from January 2020 were included if they reported on COVID-19 impact on MCV provision and/or measles outbreak rates within LICs and LMICs. Results: 45 studies were included. The change in MCV1 vaccination coverage in national and international regions ranged -13% to +44.4% from pre-COVID time periods. In local regions, the median MCV1 and overall EPI rate changed by -23.3% and -28.5% respectively. Median MCV2 rate was disproportionally impacted in local areas during COVID-interruption time-periods (-48.2%) with ongoing disruption in early-recovery time-periods (-17.7%). 8.9% of studies reported on vaccination status of confirmed measles cases; from these, 71%-91% had received no MCV dose. Conclusion: MCV vaccination coverage experienced ongoing disruption during the recovery periods after initial COVID-19 disruption. Vaccination in local area datasets notably experienced longer-term disruption compared to nationally reported figures.

An evaluation of a trauma-informed educational intervention to enhance therapeutic engagement and reduce coercive practices in a child and adolescent inpatient mental health unit.

High-risk behaviours are sometimes encountered in Child and Adolescent inpatient mental health units and can prompt the use of coercive practices to maintain safety. Coercive practices may lead to re-traumatisation of young people and deteriorating therapeutic relationships. Trauma-informed practice (TIP) has successfully reduced coercive practices. While education is identified as foundational to implementation, evaluations of programmes remain minimal. The aim of this study was to explore mental health professionals' views and experiences of a trauma-informed education programme and its likely impact on their approach to practice. Five mental health professionals agreed to participate, four contributed in a focus group and one in an individual interview. Data were analysed thematically using the Braun and Clarke Framework. Three main themes were identified. Firstly, shifting attitudes and perceptions of trauma-informed practice. Participants believed they had developed more compassion towards clients and these attitudes were reflected in their clinical practice. Secondly, challenges associated with trauma-informed practice educational intervention. Staffing issues and shift work made it difficult for participants to attend education sessions regularly. Participants identified barriers to practicing in a trauma-informed manner in the current clinical environment. Finally, the need for interdisciplinary communication and support was identified. Participants saw the need for all professionals, not only nurses, to take responsibility for changing practice, and for stronger support at the organisational level. Trauma-informed practice is crucial to recovery-focused mental health nursing practice. These findings highlight the importance of TIP education and suggest areas for further improvement to enhance positive mental health outcomes for young people.

Review: Cultural adaptations to psychosocial interventions for families with refugee/asylum-seeker status in the United Kingdom - a systematic review.

BACKGROUND: Young people with refugee or asylum-seeker status (R/AS) often present with complex mental health needs, in the context of traumatic life experiences. Generic mental health services in the United Kingdom (UK) may be ill-equipped to manage the unique experiences of these young people. Culturally adapted interventions (CAI) could provide a culturally sensitive approach to mental health support for refugee children experiencing difficult symptoms. A systematic review was conducted to determine the different types of cultural adaptation in the included studies, and to determine the efficacy of CAIs in comparison to generic treatment. METHODS: Systematic searches of eleven databases were completed in December 2020. Any psychosocial interventions conducted in the United Kingdom aimed at providing mental health support for refugee young people and families were included. This was to ensure the potential inclusion of all studies regardless of their adherence to the traditional framework of assessment and intervention in high-income countries, for example randomised control trials. RESULTS: Eleven studies of varying methodology, participant group, intervention type and outcome measures were included in this review. Studies used a variety of cultural adaptations including surface-level and deep-level adaptations. Studies showed some support for the use of CAIs with young people with R/AS, with varying degrees of symptom reduction. It was not possible to compare the effectiveness of CAIs against 'treatment-as-usual', nor to determine the effectiveness of different CAI components. CONCLUSIONS: Whilst there is evidence for the use of CAIs with R/AS young people, the heterogeneity between studies limits the generalisability of these results. The available research is not sufficient to provide conclusive evidence of the use of CAIs over 'treatment-as-usual'. Research and clinical implications are highlighted. Future research could examine the most effective components of CAIs and aim to increase the evidence base of interventions for young people and families with R/AS.

Pregnancy outcomes in inflammatory bowel disease: Data from a large cohort survey.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Predictors of varying levels of risks posed by fixated individuals to British public figures.

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.

Assessing thrombogenesis and treatment response in congenital thrombotic thrombocytopenic purpura.

Despite clinical remission and normal platelet counts, congenital TTP (cTTP) is associated with non-overt symptoms. Prophylactic ADAMTS13 replacement therapy such as plasma infusion (PI) prevents acute episodes and improves symptomatology. There is no current method to investigate disease severity or monitor the impact of treatment. We utilize a dynamic high shear flow assay to further understand disease pathophysiology and determine the impact of cTTP on symptomatology and therapy, despite normal platelet counts. Whole blood, under high shear, was run over collagen-coated channels, causing platelet adhesion to von Willebrand factor (VWF) multimers. The resulting surface coverage by platelet-VWF thrombus was assessed. The normal range was 6-39% in 50 controls. Twenty-two cTTP patients with normal platelet counts were evaluated. Median pre-treatment surface coverage was 89%, and PI reduced coverage to a median of 44% (p = 0.0005). Patients taking antiplatelets had further reduced coverage when combined with PI and improved non-overt symptoms such as headache, lethargy, and abdominal pain in 100% of patients compared to 74% with PI alone (p = 0.046). We use a dynamic assay to report increased in vitro platelet adhesion and aggregation and additionally demonstrate significantly decreased thrombi following PI, with levels in the normal range levels achieved in patients taking additional antiplatelet therapy.

Real-world experience with caplacizumab in the management of acute TTP.

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.

von Willebrand factor/ADAMTS13 ratio at presentation of acute ischemic brain injury is predictive of outcome.

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.

Child Marriages and Unions in Latin America: Understanding the Roles of Agency and Social Norms.

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.

Spontaneous Differentiation of Human Neural Stem Cells on Nanodiamonds.

The potential use of stem cells in regenerative medicine requires the ability to be able to control stem cell fate as cellular networks are developed. Here, nanodiamonds (≈10 nm) are supported on glass and shown to be an excellent host for the attachment and proliferation of human neural stem cells. Moreover, it is shown that spontaneous differentiation into neurons occurs on nanodiamonds. The use of variously oxygen terminated and hydrogen terminated nanodiamonds has been explored. It is shown that O-ND monolayers promote the differentiation of human neural stem cells into neurons with increased total neurite length, degree of branching, and density of neurites when compared with H-NDs or the glass control. The total number of neurites and total neurite length expressing MAP2, a protein enriched in dendrites, is over five times higher for spontaneously differentiated neurones on the O-NDs compared to the control. The fact that inexpensive nanodiamonds can be attached through simple sonication from water on 2D and 3D shapes indicates significant promise for their potential as biomaterials in which neuro-regenerative diseases can be studied.

Treating a 16 Year Old with a History of Severe Bullying: Supplementing Cognitive Behavioural Therapy with EMDR within the Context of a Case Formulation Approach.

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.

Assessment of the Impact of Deformable Registration of Diagnostic MRI to Planning CT on GTV Delineation for Radiotherapy for Oropharyngeal Carcinoma in Routine Clinical Practice.

BACKGROUND: Aim of study was to assess impact of deformable registration of diagnostic MRI to planning CT upon gross tumour volume (GTV) delineation of oropharyngeal carcinoma in routine practice. METHODS: 22 consecutive patients with oropharyngeal squamous cell carcinoma treated with definitive (chemo)radiotherapy between 2015 and 2016, for whom primary GTV delineation had been performed by a single radiation oncologist using deformable registration of diagnostic MRI to planning CT, were identified. Separate GTVs were delineated as part of routine clinical practice (all diagnostic imaging available side-by-side for each delineation) using: CT (GTVCT), MRI (GTVMR), and CT and MRI (GTVCTMR). Volumetric and positional metric analyses were undertaken using contour comparison metrics (Dice conformity index, centre of gravity distance, mean distance to conformity). RESULTS: Median GTV volumes were 13.7 cm³ (range 3.5⁻41.7), 15.9 cm³ (range 1.6⁻38.3), 19.9 cm³ (range 5.5⁻44.5) for GTVCT, GTVMR and GTVCTMR respectively. There was no significant difference in GTVCT and GTVMR volumes; GTVCTMR was found to be significantly larger than both GTVMR and GTVCT. Based on positional metrics, GTVCT and GTVMR were the least similar (mean Dice similarity coefficient (DSC) 0.71, 0.84, 0.82 for GTVCT⁻GTVMR, GTVCTMR⁻GTVCT and GTVCTMR⁻GTVMR respectively). CONCLUSIONS: These data suggest a complementary role of MRI to CT to reduce the risk of geographical misses, although they highlight the potential for larger target volumes and hence toxicity.

The Importance of the Full Blood Count in Cerebral Ischemia: A Review of 609 Consecutive Young Patients with Stroke and Transient Ischemic Attacks.

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.

Utility of current thrombophilia screening in young patients with stroke and TIA.

INTRODUCTION: Approximately 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). METHODS: We 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. RESULTS: The 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 <50 years. Positive results were found in 36 (10%) with acute ischaemic stroke, 4 (1%) with haemorrhagic stroke and 10 (3%) with TIA. Thirteen patients (4%) had homozygous/heterozygous FVL or PGM, and 27 (7.5%) had positive APA (anticardiolipin antibody, anti-ß2 glycoprotein antibody or lupus anticoagulant). Of 27 (7.5%) patients with protein C, S or AT deficiency, 10 (2.8%) had primary deficiency, presumed hereditary with other secondary causes excluded. 9% of patients with protein C, S or AT and 27% with APA were followed by confirmatory testing. CONCLUSION: Thrombophilia 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.