The state of integrated disease surveillance in seven countries: a synthesis report.

OBJECTIVES: Integrated disease surveillance (IDS) offers the potential for better use of surveillance data to guide responses to public health threats. However, the extent of IDS implementation worldwide is unknown. This study sought to understand how IDS is operationalized, identify implementation challenges and barriers, and identify opportunities for development. STUDY DESIGN: Synthesis of qualitative studies undertaken in seven countries. METHODS: Thirty-four focus group discussions and 48 key informant interviews were undertaken in Pakistan, Mozambique, Malawi, Uganda, Sweden, Canada, and England, with data collection led by the respective national public health institutes. Data were thematically analysed using a conceptual framework that covered governance, system and structure, core functions, finance and resourcing requirements. Emerging themes were then synthesised across countries for comparisons. RESULTS: None of the countries studied had fully integrated surveillance systems. Surveillance was often fragmented, and the conceptualization of integration varied. Barriers and facilitators identified included: 1) the need for clarity of purpose to guide integration activities; 2) challenges arising from unclear or shared ownership; 3) incompatibility of existing IT systems and surveillance infrastructure; 4) workforce and skills requirements; 5) legal environment to facilitate data sharing between agencies; and 6) resourcing to drive integration. In countries dependent on external funding, the focus on single diseases limited integration and created parallel systems. CONCLUSIONS: A plurality of surveillance systems exists globally with varying levels of maturity. While development of an international framework and standards are urgently needed to guide integration efforts, these must be tailored to country contexts and guided by their overarching purpose.

Integration of disease surveillance in the English context: a qualitative study.

OBJECTIVES: The world is experiencing increasing threats from infectious diseases and environmental hazards. Integration of disease surveillance systems has been put forth as one way to ensure more timely analysis of data and response. This study sought to explore the current context and state of integration of disease surveillance in England, including the barriers and facilitators to integration, as well as opportunities for improvement. STUDY DESIGN: Qualitative study with focus groups and key informant interviews. METHODS: Focus group discussions (FGDs) and key informant interviews (KIIs) were conducted with key national, regional, and local stakeholders involved in surveillance activities in August and September 2022. These discussions and interviews were recorded, transcribed, and coded using a within-case content and thematic analysis. RESULTS: In total, five FGDs and 10 KIIs were conducted with 27 participants. Participants had different views on what integration is, though mostly agreed that surveillance systems in England are not integrated. Lack of standardisation, governance and oversight, and structural and financial barriers were hindering the current system from being more integrated. The additional benefits of integration above and beyond the 'status quo' during response activities were questioned by some. CONCLUSION: England does not have a single integrated disease surveillance system but has a range of disease-specific surveillance systems that have evolved largely independently to meet operational needs. Greater integration may be desired and to a certain extent is important, but it is essential that it is understood as a means to an end and the overall purpose of surveillance is kept in mind.

Inpatient target discharge weight for early-onset anorexia nervosa: Restoring premorbid BMI percentile to improve height prognosis.

OBJECTIVE: Early-onset anorexia nervosa (EO-AN) is characterized by restricted food intake leading to low body weight, emerging before 14 years old. Most patients reaching a target body mass index (BMI) around the 25th percentile at hospitalization discharge display an incomplete prospective height catch-up. A better understanding of height prognosis determinants is required. METHODS: In 74 children with an EO-AN, we collected height and weight premorbidly, at hospitalization, and at discharge, 6 months, 12 months, and at longer-term follow-up of 36 months. We defined a height prognosis parameter (HPP) as the difference between the height percentile at follow-up times and the premorbid height percentile. We explored the relationship between weight parameters and height catch-up at follow-up with linear regression analyses. RESULTS: A higher weight suppression (WS) - i.e., difference between premorbid and current BMI - at admission and discharge was associated with lower HPP - i.e., a greater loss of height - at 12 months and 36 months follow-up. Similarly, a higher premorbid BMI percentile was associated with a lower HPP at 12 and 36 months. CONCLUSION: Target discharge weight for EO-AN patients should be tailored and based on premorbid BMI trajectory to improve height prognosis.

The attitude-behaviour gap in biosecurity: Applying social theories to understand the relationships between commercial chicken farmers' attitudes and behaviours.

Introduction: Traditionally, it is believed that people's behaviours align with their attitudes; however, during COVID-19 pandemic, an attitude-behaviour gap in relation to preventive measures has been observed in recent studies. As such, the mixed-methods research was used to examine the relationships between farmers' biosecurity attitudes and behaviours in Taiwan's chicken industry based on the cognitive consistency theory. Methods: Content analysis of face-to-face interviews with 15 commercial chicken farmers identified their biosecurity responses to infectious disease threats. Results: The results indicated the mismatch of farmers' attitudes and behaviours towards specific biosecurity measures, in that they act differently than they think. The findings of the qualitative research allowed the research team to conduct the subsequent quantitative, confirmatory assessment to investigate the mismatch of farmers' attitudes and behaviours in 303 commercial broiler farmers. Survey data were analyzed to discover the relationships between farmers' attitudes and behaviours in relation to 29 biosecurity measures. The results show a mixed picture. The percentage of the farmers who had the attitude-behaviour gap towards 29 biosecurity measures ranged from 13.9 to 58.7%. Additionally, at the 5% significant level, there is an association between farmers' attitudes and behaviours for 12 biosecurity measures. In contrast, a significant association does not exist for the other 17 biosecurity measures. Specifically, out of the 17 biosecurity measures, the disconnection of farmers' attitudes and behaviours was observed in three specific biosecurity measures such as using a carcass storage area. Discussion: Based on a fairly large sample of farmers in Taiwan, this study confirms the existence of an attitude-behaviour gap in context and applies social theories to provide an in-depth understanding of how infectious diseases are managed in the animal health context. As the results demonstrate the necessity of tailoring biosecurity strategies to address the gap, it is time to reconsider the current approach by understanding farmers' real attitudes and behaviours in relation to biosecurity for the success of animal disease prevention and control at the farm level.

Determinants of farmers' biosecurity mindset: A social-ecological model using systems thinking.

Commercial poultry is often farmed in high-density facilities, therefore, predisposing exposure to threats of infectious diseases. Studies suggest that it is likely that farmers have little motivation to practise on-farm biosecurity. In Taiwan, where high-density intensive poultry production is commonplace, unfortunately, several avian influenza outbreaks have occurred over the past decade despite the establishment of biosecurity procedures. To develop effective interventions, it is essential to understand the determinants of farmers' biosecurity mindset through systems thinking. In this qualitative study, we directly explored the opinions of Taiwan's chicken farmers, and a grounded theory analysis was performed. The study revealed that farmers allocate resources based on their justification for the optimisation of resource utilisation, and biosecurity is the most concerning challenge. Farmers focus on the economic aspects of their production systems, particularly when the implementation of biosecurity increases production costs, and there are multifaceted, complex barriers to implementing on-farm biosecurity. Although the participant farmers accepted to take major responsibility for disease management, paradoxically, some farmers blamed the practicality of government regulations and government employees' attitudes. Additionally, the farmers rejected the government's intentions to ask farmers to take major responsibility for the outbreaks of avian influenza while some of them intended to ignore the perceived risks. Government interventions that were considered not directly related to biosecurity also negatively influenced farmers' willingness to improve biosecurity. Using the interview results together with information in the scientific literature, we constructed a modified six-level social-ecological model to explain the complex influences of macro socio-economic conditions on farmers' biosecurity mindset. The novelty of this research lies in its wider relevance to Taiwan's chicken production industry in that it provides first-hand evidence-based knowledge to demonstrate a wide number of determinants of farmers' biosecurity mindset. This social-ecological model highlights the importance of systems thinking for the development of behavioural interventions and allows adaptation to the local context. The findings of this study have relevance to Taiwan's chicken production industry and potentially to similar systems in other countries in the wider region and should result in more effective animal health management at the farm level.

An Approach to Surgery for Cubital Tunnel Syndrome A Pilot Series.

BACKGROUND: Cubital tunnel syndrome and the resulting loss of hand dexterity and strength may necessitate surgical management. Studies have demonstrated no difference in outcome between surgical techniques. In an attempt to leave more ulnar nerves in situ while providing for stability within the cubital tunnel, we suggest a surgical treatment approach. METHODS: The approach addresses individual anatomy methodically, eliminating muscular obstruction first and providing further decompression and stability as required. A retrospective review of 27 adult patients with ulnar neu- ropathy treated according to this method was performed. RESULTS: The mean duration of symptoms prior to surgery was 2.75 years (SD = 2.4). The mean follow-up was 17.1 months (SD = 16.9). All patients improved following surgery. Two revision surgeries were performed 4 years following the original surgery. CONCLUSIONS: We believe the nerve recovers best when left in situ, provided it is stable and not compressed within the cubital tunnel. A further comparison study is necessary to substantiate the advantage of this "personalized" approach over other surgical techniques for cubital tunnel release.

Follow-up after emergency laparotomy suggests high one- and five-year mortality with risk stratified by ASA.

INTRODUCTION: We investigated all-cause mortality following emergency laparotomy at 1 and 5 years. We aimed to establish a basis from which to advise patients and relatives on long-term mortality. METHODS: Local data from a historical audit of emergency laparotomies from 2010 to 2012 were combined with National Emergency Laparotomy Audit (NELA) data from 2017 to 2020. Covariates collected included deprivation status, preoperative blood work, baseline renal function, age, American Society of Anesthesiologists (ASA) grade, operative time, anaesthetic time and gender. Associations between covariates and survival were determined using multivariate logistic regression and Kaplan-Meier analysis. We used patients undergoing laparoscopic cholecystectomy between 2015 and 2020 as controls. RESULTS: ASA grade was the best discriminator of long-term outcome following laparotomy (n=894) but was not a predictor of survival following cholecystectomy (n=1,834), with mortality being significantly greater in the laparotomy group. Following cholecystectomy, 95% confidence intervals for survival at 5 years were 98-99%. Following laparotomy these intervals were: ASA grade 1, 79-96%; ASA grade 2, 69-82%; ASA grade 3, 44-58%; ASA grade 4, 33-48%; and ASA grade 5, 4-51%. The majority of deaths occurred after 30 days. CONCLUSIONS: Emergency laparotomy is associated with a significantly increased risk of death in the following 5 years. The risk is strongly correlated to ASA grade. Thirty-day mortality estimation is not a good basis on which to advise patients and carers on long-term outcomes. ASA grade can be used to predict long-term outcomes and to guide patient counsel.

Clinicians' experiences of using and implementing a medical mobile phone app (QUiPP V2) designed to predict the risk of preterm birth and aid clinical decision making.

BACKGROUND: As the vast majority of women who present in threatened preterm labour (TPTL) will not deliver early, clinicians need to balance the risks of over-medicalising the majority of women, against the potential risk of preterm delivery for those discharged home. The QUiPP app is a free, validated app which can support clinical decision-making as it produces individualised risks of delivery within relevant timeframes. Recent evidence has highlighted that clinicians would welcome a decision-support tool that accurately predicts preterm birth. METHODS: Qualitative interviews were undertaken as part of the EQUIPTT study (The Evaluation of the QUiPP app for Triage and Transfer) (REC: 17/LO/1802) which aimed to evaluate the impact of the QUiPP app on management of TPTL. Individual semi-structured telephone interviews were used to explore clinicians' (obstetricians' and midwives') experiences of using the QUiPP app and how it was implemented at their hospital sites. Thematic analysis was chosen to explore the meaning of the data, through a framework approach. RESULTS: Nineteen participants from 10 hospital sites in England took part. Data analysis revealed three overarching themes which were: 'experience of using the app', 'how QUiPP risk changes practice' and 'successfully adopting QUiPP: context is everything'. With these final themes we appeared to have achieved our aim of exploring the clinicians' experiences of using and implementing the QUiPP app. CONCLUSION: This study explored different clinician's experiences of implementing the app. The organizational and cultural context at different sites appeared to have a large impact on how well the QUiPP app was implemented. Future work needs to be undertaken to understand how best to embed the intervention within different settings. This will inform scale up of QUiPP app use across the UK and ensure that clinicians have access to this free, easy-to-use tool which can positively aid clinical decision making when caring for women in TPTL. CLINICAL TRIAL REGISTRY AND REGISTRATION NUMBER: ISRCTN 17846337, registered 08th January 2018, https://doi.org/10.1186/ISRCTN17846337 .

Ten women's decision-making experiences in threatened preterm labour: Qualitative findings from the EQUIPTT trial.

BACKGROUND: Clinical triage of women in threatened preterm labour (TPTL) could be improved through utilising the QUiPP App, as symptoms alone are poor predictors of early delivery. As most women in TPTL ultimately deliver at term, they must weigh this likelihood with their own personal considerations, and responsibilities. The importance of personal considerations was highlighted by the 2015 Montgomery ruling, and the significance of shared decision-making. AIMS: Through qualitative interviews, the primary aim was to explore women's decision-making experiences in TPTL through onset of symptoms, triage, clinical assessment, and discharge. METHODS: Qualitative interviews were undertaken as part of the EQUIPTT study (REC: 17/LO/1802) using a semi-structured interview schedule. Descriptive labels of the coding scheme were applied to the raw transcript data. This coding scheme was then increasingly refined into key themes and allowed parallels to be made within and between cases. RESULTS: Ten ethnically diverse women who presented at six different London hospitals sites in TPTL were interviewed. Three final themes emerged from the data incorporating 10 sub-themes, 'Seeking help', 'Being "assessed" vs making clinical decisions together', and 'End result.' CONCLUSION: Women described their busy lives and the need to juggle their commitments. Participants drew comparisons between their TPTL symptoms and 'period pain,' contrasting to typical medical terminology. Shared decision-making and the clinician-patient relationship could be improved through clinicians utilizing terminology women understand and relate to. Women used language that highlighted the clinician-patient power balance. While not fully involved in shared decision-making, women were overall satisfied with their care.

LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency.

BACKGROUND: A poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tumors is vasculopathic and whether its inhibition has therapeutic utility. METHODS: Tumor growth and vascular structure were analyzed in subcutaneous and genetically engineered mouse models in wild-type and Lrg1 knockout mice. The effects of LRG1 antibody blockade as monotherapy, or in combination with co-therapies, on vascular function, tumor growth, and infiltrated lymphocytes were investigated. FINDINGS: In mouse models of cancer, Lrg1 expression was induced in tumor endothelial cells, consistent with an increase in protein expression in human cancers. The expression of LRG1 affected tumor progression as Lrg1 gene deletion, or treatment with a LRG1 function-blocking antibody, inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function, resulting in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy, and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent to immune active. CONCLUSIONS: LRG1 drives vascular abnormalization, and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics. FUNDING: Wellcome Trust (206413/B/17/Z), UKRI/MRC (G1000466, MR/N006410/1, MC/PC/14118, and MR/L008742/1), BHF (PG/16/50/32182), Health and Care Research Wales (CA05), CRUK (C42412/A24416 and A17196), ERC (ColonCan 311301 and AngioMature 787181), and DFG (CRC1366).

Impact of a medical mobile phone app (QUiPP) for predicting preterm birth on the anxiety and decisional conflicts faced by women in threatened preterm labour.

BACKGROUND: The QUiPP app is a free, validated mobile phone application (app) that supports clinical decision-making for women in threatened preterm labour by providing an individualised risk of delivery within clinically important time points. Alongside generating a percentage risk score, the QUiPP app also provides the risk score in an infographic donut chart, allowing the clinician to communicate with the woman in an easy to understand format. Informing women of their risk status using the QUIPP app may help to reduce anxiety in women and decrease decisional conflict. METHOD: A subset of participants from the EQUIPTT study [REC Ref. 17/LO/1802] were asked to complete a questionnaire booklet which was used to evaluate decisional conflict and anxiety. Seven sites were randomised to the QUiPP app intervention (to use as a decision and communication tool) and six sites were randomised to the control (continued their normal practice). The first section of the questionnaire booklet was completed by the woman before her assessment, and the second section after. The pre and postassessment anxiety scores utilised the Visual Analogue Scale for Anxiety (Hornblow and Kidson, 1976). The Decisional Conflict Scale (O'Connor, 1995) measured decisional conflict post assessment. The data were then analysed to determine the impact of the QUiPP App on the anxiety and decisional conflicts faced by women in threatened preterm labour. RESULTS: Questionnaires were completed by 221 women from 12 of the potential 13 sites. After exclusions 202 questionnaires were included in the analysis. There was a significant reduction in difference between anxiety scores before and after clinical assessment. While there were reductions in anxiety and decisional conflict for women who were aware of the QUiPP app use, this failed to reach statistical significance. CONCLUSIONS: The QUiPP app has potential to reduce anxiety and decisional conflict in women who are aware that it is being used in their care. Additional work is required to ensure clinicians are aware of the QUiPP app and optimise using it as a communication tool when counselling women.

An observational study to compare the utilisation of computed tomography colonography with optical colonoscopy as the first diagnostic imaging tool in patients with suspected colorectal cancer.

AIM: To evaluate the clinical and cost implications of using computed tomography colonography (CTC) compared to optical colonoscopy (OC) as the initial colonic investigation in patients with low-to-intermediate risk of colorectal cancer (CRC). MATERIALS AND METHODS: A non-randomised, prospective single-centre study recruited 180 participants to compare the cost implications of two clinical pathways used in the diagnosis of low-to-intermediate risk of CRC that differ in the initial diagnostic test, either CTC or OC. Costs were compared using generalised linear models (GLM) and combined with quality-adjusted life years (QALYs, based on the EQ-5D-5L) to estimate cost-effectiveness at 6 months post-recruitment. Secondary outcomes assessed access to care and patient satisfaction. RESULTS: Mean (SD, n) cost at 6 months post-recruitment per participant was £991 (£316, n=105) for the OC group and £645 (£607, n=68) for the CTC group, leading to an estimated cost difference of -£370 (95% CI: -£554, -£185, p<0.001). Assuming a £20,000 willingness-to-pay per QALY threshold, there was a 91.4% probability of CTC being cost-effective at month 6. The utilisation of CTC led to improved access to care, with a shorter mean time from referral from primary care to results (6.3 days difference, p=0.005). No differences in patient satisfaction were detected between both groups. CONCLUSION: The utilisation of CTC as the first-line investigation for patients with low-to-intermediate risk of CRC has the potential to release OC capacity, of pivotal importance for patients more likely to benefit from an invasive diagnostic approach.

Development and validation of predictive models for QUiPP App v.2: tool for predicting preterm birth in women with symptoms of threatened preterm labor.

OBJECTIVE: To develop enhanced prediction models to update the QUiPP App prototype, a tool providing individualized risk of spontaneous preterm birth (sPTB), for use in women with symptoms of threatened preterm labor (TPTL), incorporating risk factors, transvaginal ultrasound assessment of cervical length (CL) and cervicovaginal fluid quantitative fetal fibronectin (qfFN) test results. METHODS: Participants were pregnant women between 23 + 0 and 34 + 6 weeks' gestation with symptoms of TPTL, recruited as part of four prospective cohort studies carried out at 16 UK hospitals between October 2010 and October 2017. The training set comprised all women whose outcomes were known in May 2017 (n = 1032). The validation set comprised women whose outcomes were gathered between June 2017 and March 2018 (n = 506). Parametric survival models were developed for three combinations of predictors: risk factors plus qfFN test results alone, risk factors plus CL alone, and risk factors plus both qfFN and CL. The best models were selected using the Akaike and Bayesian information criteria. The estimated probability of sPTB < 30, < 34 or < 37 weeks' gestation and within 1 or 2 weeks of testing was calculated and receiver-operating-characteristics (ROC) curves were created to demonstrate the diagnostic ability of the prediction models. RESULTS: Predictive statistics were similar between the training and the validation sets at most outcome time points and for each combination of predictors. Areas under the ROC curves (AUC) demonstrated that all three algorithms had good accuracy for the prediction of sPTB at < 30, < 34 and < 37 weeks' gestation and within 1 and 2 weeks' post-testing in the validation set, particularly the model combining risk factors plus qfFN alone (AUC: 0.96 at < 30 weeks; 0.85 at < 34 weeks; 0.77 at < 37 weeks; 0.91 at < 1 week from testing; and 0.92 at < 2 weeks from testing). CONCLUSIONS: Validation of the new prediction models suggests that the QUiPP App v.2 can reliably calculate risk of sPTB in women with TPTL. Use of the QUiPP App in practice could lead to better targeting of intervention, while providing reassurance and avoiding unnecessary intervention in women at low risk. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Desarrollo y validación de modelos predictivos para la Aplicación QUiPP v.2: herramienta para predecir el parto pretérmino en mujeres con síntomas de amenaza de parto prematuro OBJETIVO: Desarrollar modelos de predicción mejorados para actualizar el prototipo de la Aplicación QUiPP, una herramienta que proporciona el riesgo individualizado de parto pretérmino espontáneo (PPTE), para su uso en mujeres con síntomas de amenaza de parto pretérmino (APPT), mediante la incorporación de los factores de riesgo, la evaluación de la longitud cervical (LC) mediante ecografía transvaginal y los resultados de la prueba de fibronectina fetal cuantitativa (qfFN, por sus siglas en inglés) del líquido cérvico-vaginal. MÉTODOS: Las participantes fueron mujeres embarazadas entre 23 + 0 y 34 + 6 semanas de gestación con síntomas de APPT, reclutadas como parte de cuatro estudios de cohorte prospectivos llevados a cabo en 16 hospitales del Reino Unido entre octubre de 2010 y octubre de 2017. El grupo de entrenamiento comprendía a todas las mujeres cuyos resultados se conocían en mayo de 2017 (n = 1032). El grupo de validación estaba compuesto por mujeres cuyos resultados se recogieron entre junio de 2017 y marzo de 2018 (n = 506). Se desarrollaron modelos paramétricos de supervivencia para tres combinaciones de predictores: factores de riesgo más resultados de pruebas de qfFN solamente, factores de riesgo más LC solamente, y factores de riesgo más tanto qfFN como LC. Los mejores modelos fueron seleccionados utilizando los criterios de información de Akaike y Bayesiano. Se calculó la probabilidad estimada de PPTE a <30, <34 o <37 semanas de gestación y dentro de 1 o 2 semanas de la prueba y se crearon curvas de la característica operativa del receptor (ROC, por sus siglas en inglés) para demostrar la capacidad de diagnóstico de los modelos de predicción. RESULTADOS: Las estadísticas de predicción fueron similares entre los grupos de entrenamiento y de validación en la mayoría de los puntos de tiempo de los resultados y para cada combinación de predictores. Las áreas bajo las curvas (ABC) ROC demostraron que los tres algoritmos tuvieron una buena precisión para la predicción del PPTE a <30, <34 y <37 semanas de gestación y dentro de 1 a 2 semanas después de la prueba en el grupo de validación, en particular el modelo que combina los factores de riesgo más qfFN por si solo (ABC: 0,96 a <30 semanas; 0,85 at <34 semanas; 0,77 at <37 semanas; 0,91 at <1 semana de la prueba; y 0,92 a <2 semanas de la prueba CONCLUSIONES: La validación de los nuevos modelos de predicción sugiere que la Aplicación QUiPP v.2 puede calcular de manera fiable el riesgo de PPTE en mujeres con APPT. El uso de la Aplicación QUiPP en la práctica podría llevar a un mejor cribado para la intervención, a la vez que daría seguridad y evitaría intervenciones innecesarias en mujeres con bajo riesgo.

Development and validation of predictive models for QUiPP App v.2: tool for predicting preterm birth in asymptomatic high-risk women.

OBJECTIVES: Accurate mid-pregnancy prediction of spontaneous preterm birth (sPTB) is essential to ensure appropriate surveillance of high-risk women. Advancing the QUiPP App prototype, QUiPP App v.2 aimed to provide individualized risk of delivery based on cervical length (CL), quantitative fetal fibronectin (qfFN) or both tests combined, taking into account further risk factors, such as multiple pregnancy. Here we report development of the QUiPP App v.2 predictive models for use in asymptomatic high-risk women, and validation using a distinct dataset in order to confirm the accuracy and transportability of the QUiPP App, overall and within specific clinically relevant time frames. METHODS: This was a prospective secondary analysis of data of asymptomatic women at high risk of sPTB recruited in 13 UK preterm birth clinics. Women were offered longitudinal qfFN testing every 2-4 weeks and/or transvaginal ultrasound CL measurement between 18 + 0 and 36 + 6 weeks' gestation. A total of 1803 women (3878 visits) were included in the training set and 904 women (1400 visits) in the validation set. Prediction models were created based on the training set for use in three groups: patients with risk factors for sPTB and CL measurement alone, with risk factors for sPTB and qfFN measurement alone, and those with risk factors for sPTB and both CL and qfFN measurements. Survival analysis was used to identify the significant predictors of sPTB, and parametric structures for survival models were compared and the best selected. The estimated overall probability of delivery before six clinically important time points (< 30, < 34 and < 37 weeks' gestation and within 1, 2 and 4 weeks after testing) was calculated for each woman and analyzed as a predictive test for the actual occurrence of each event. This allowed receiver-operating-characteristics curves to be plotted, and areas under the curve (AUC) to be calculated. Calibration was performed to measure the agreement between expected and observed outcomes. RESULTS: All three algorithms demonstrated high accuracy for the prediction of sPTB at < 30, < 34 and < 37 weeks' gestation and within 1, 2 and 4 weeks of testing, with AUCs between 0.75 and 0.90 for the use of qfFN and CL combined, between 0.68 and 0.90 for qfFN alone, and between 0.71 and 0.87 for CL alone. The differences between the three algorithms were not statistically significant. Calibration confirmed no significant differences between expected and observed rates of sPTB within 4 weeks and a slight overestimation of risk with the use of CL measurement between 22 + 0 and 25 + 6 weeks' gestation. CONCLUSIONS: The QUiPP App v.2 is a highly accurate prediction tool for sPTB that is based on a unique combination of biomarkers, symptoms and statistical algorithms. It can be used reliably in the context of communicating to patients the risk of sPTB. Whilst further work is required to determine its role in identifying women requiring prophylactic interventions, it is a reliable and convenient screening tool for planning follow-up or hospitalization for high-risk women. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

L-Selectin Enhanced T Cells Improve the Efficacy of Cancer Immunotherapy.

The homing molecule, L-selectin (CD62L), is commonly used as a T cell activation marker, since expression is downregulated following engagement of the T cell receptor. Studies in mice have shown that CD62L+ central memory T cells are better at controlling tumor growth than CD62L- effector memory T cells, while L-selectin knockout T cells are poor at controlling tumor growth. Here, we test the hypothesis that T cells expressing genetically modified forms of L-selectin that are maintained following T cell activation (L-selectin enhanced T cells) are better at controlling tumor growth than wild type T cells. Using mouse models of adoptive cell therapy, we show that L-selectin enhancement improves the efficacy of CD8+ T cells in controlling solid and disseminated tumor growth. L-selectin knockout T cells had no effect. Checkpoint blockade inhibitors synergized with wild type and L-selectin enhanced T cells but had no effect in the absence of T cell transfers. Reduced tumor growth by L-selectin enhanced T cells correlated with increased frequency of CD8+ tumor infiltrating T cells 21 days after commencing therapy. Longitudinal tracking of Zirconium-89 (89Zr) labeled T cells using PET-CT showed that transferred T cells localize to tumors within 1 h and accumulate over the following 7 days. L-selectin did not promote T cell homing to tumors within 18 h of transfer, however the early activation marker CD69 was upregulated on L-selectin positive but not L-selectin knockout T cells. L-selectin positive and L-selectin knockout T cells homed equally well to tumor-draining lymph nodes and spleens. CD69 expression was upregulated on both L-selectin positive and L-selectin knockout T cells but was significantly higher on L-selectin expressing T cells, particularly in the spleen. Clonal expansion of isolated L-selectin enhanced T cells was slower, and L-selectin was linked to expression of proliferation marker Ki67. Together these findings demonstrate that maintaining L-selectin expression on tumor-specific T cells offers an advantage in mouse models of cancer immunotherapy. The beneficial role of L-selectin is unrelated to its' well-known role in T cell homing and, instead, linked to activation of therapeutic T cells inside tumors. These findings suggest that L-selectin may benefit clinical applications in T cell selection for cancer therapy and for modifying CAR-T cells to broaden their clinical scope.

ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells.

L-selectin on T-cells is best known as an adhesion molecule that supports recruitment of blood-borne naïve and central memory cells into lymph nodes. Proteolytic shedding of the ectodomain is thought to redirect activated T-cells from lymph nodes to sites of infection. However, we have shown that activated T-cells re-express L-selectin before lymph node egress and use L-selectin to locate to virus-infected tissues. Therefore, we considered other roles for L-selectin proteolysis during T cell activation. In this study, we used T cells expressing cleavable or non-cleavable L-selectin and determined the impact of L-selectin proteolysis on T cell activation in virus-infected mice. We confirm an essential and non-redundant role for ADAM17 in TCR-induced proteolysis of L-selectin in mouse and human T cells and show that L-selectin cleavage does not regulate T cell activation measured by CD69 or TCR internalisation. Following virus infection of mice, L-selectin proteolysis promoted early clonal expansion of cytotoxic T cells resulting in an 8-fold increase over T cells unable to cleave L-selectin. T cells unable to cleave L-selectin showed delayed proliferation in vitro which correlated with lower CD25 expression. Based on these results, we propose that ADAM17-dependent proteolysis of L-selectin should be considered a regulator of T-cell activation at sites of immune activity.

Characterization and treatment of congenital thrombotic thrombocytopenic purpura.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.

Translating the Intention to Seek Treatment into Action: Does Symptom Monitoring Make a Difference? Results from a Randomized Controlled Trial.

BACKGROUND: Most people with common mental health problems do not seek evidence-based psychological interventions. AIMS: The aim of this study was to investigate whether monitoring symptoms of depression and anxiety using an app increased treatment-seeking. METHOD: Three hundred and six people with significant levels of anxiety and depression, none of whom were currently receiving treatment, were randomly allocated to receive either (a) information about local psychological services only, (b) information plus regular symptom monitoring (every 6 days), or (c) information plus open symptom monitoring (monitoring when they felt like it). An app was used to provide information and monitor mood. RESULTS: The proportion of participants who reported receiving treatment after starting the study was 7.2% (10/138) in the information only group, 8.1% (9/111) in the information plus regular monitoring group and 15.8% (9/57) in the information plus open monitoring group. There was a trend for participants who were able to monitor whenever they wished to be more likely to report receiving treatment than people who were only given information about their local treatment services. The impact of the intervention was greatest among participants who intended to seek treatment before taking part. Limitations were that only a small minority of those who downloaded the app completed the study and that the study relied on self-reported measures of treatment-seeking. CONCLUSIONS: Symptom monitoring can increase actual treatment-seeking in those with an intention to seek treatment.

Measurement of rivaroxaban concentrations demonstrates lack of clinical utility of a PT, dPT and APTT test in estimating levels.

INTRODUCTION: Rivaroxaban concentrations were measured in 127 inpatient samples using an HPLC-MS/MS assay. METHODS: We compared this measurement with a calibrated anti-Xa assay and performed PT, aPTT and dilute PT tests to assess the value of clot-based assays in clinical decision-making. RESULTS: The correlation between the anti-Xa assay and the HPLC-MS/MS at therapeutic concentrations was strong (R2  = 0.98). The PT, RecombiPlasTin 2G, and aPTT, Actin FS, showed a linear dose-response but poor correlation (R2  = 0.32 and 0.44, respectively) and at dilutions of 1 in 150 to 1 in 750 the dilute PT assay also showed poor correlation with rivaroxaban concentrations measured by specific assays. A normal PT or aPTT alone did not identify a likely safe rivaroxaban concentration to allow surgery or invasive procedures, but the combination of normal PT and aPTT identified a group of patients with rivaroxaban levels less than 90 ng/mL. Combined normal PT and aPTT had specificity and sensitivity of 0.97 (95% CI 0.92-0.99) and 0.37 (95% CI 0.1-0.74) for a rivaroxaban concentration < 32 ng/mL. CONCLUSIONS: The PT and aPTT show poor correlation with rivaroxaban levels measured by calibrated anti-Xa and HPLC-MS/MS assays. A normal combined PT and APTT identified low rivaroxaban levels with high specificity but lacked sensitivity. The dPT assay at several dilutions could not be used to quantify rivaroxaban in clinical samples. The utility of these PT, aPTT and dilute PT assays in a clinical setting is very limited, and results generated must be interpreted with caution.