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.

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.

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.

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 .

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.

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.

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.

Presenting ADAMTS13 antibody and antigen levels predict prognosis in immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by antibodies against ADAMTS13. From the United Kingdom TTP registry, we undertook a prospective study investigating the impact of the presenting anti-ADAMTS13 IgG antibody and ADAMTS13 antigen on mortality. A total of 312 episodes involving 292 patients over 87 months were included; 68% were female, median age 46 (range, 11-88 years), and median presenting ADAMTS13 of <5% (range, <5%-18%). The mortality rate was 10.3% (n = 32); 68% of patients had a raised troponin at presentation conferring a sixfold increase in mortality compared with those with normal troponin levels (12.1% vs 2.0%, P = .04). Twenty-four percent had a reduced Glasgow Coma Score (GCS) at presentation with a ninefold increase in mortality (20% vs 2.2% for normal GCS at presentation, P < .0001). Mortality increased with higher anti-ADAMTS13 antibody levels and lower ADAMTS13 antigen levels. Those with antibody levels in the upper quartile (antibody >77%) had a mortality of 16.9% compared with 5.0% for the lowest quartile (antibody <20%) (P = .004). Those with an antigen level in the lowest quartile (antigen <1.5%) had a mortality of 18% compared with 3.8% for the highest quartile (antigen >11%) (P = .005). The synergistic effect of anti-ADAMTS13 IgG antibody in the upper quartile and ADAMTS13 antigen in the lowest quartile had the highest mortality of 27.3%. We conclude that both anti-ADAMTS13 IgG antibody and ADAMTS13 antigen levels correlate with outcome in TTP with increased cardiac and neurological involvement and increased mortality.

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.

A transfusion prescription template and other human factor interventions to improve balanced transfusion delivery in major haemorrhage due to trauma.

OBJECTIVES: The aim of this study is to improve practice in the management of major haemorrhage, particularly in red cell to plasma transfusion ratios. BACKGROUND: A review of the management of major haemorrhage in trauma in Newcastle Hospitals Trust in 2012-2013 showed good mortality outcomes but found that red cell : plasma transfusion ratios could be improved. Human factors techniques transferable from industry and the military were identified, and a package of interventions was implemented, including an intensive multidisciplinary team training programme and a new major haemorrhage prescription template. METHODS/MATERIALS: We reviewed the management of all 243 adult trauma patients admitted with major haemorrhage to the Emergency Department in the Newcastle Hospitals Trust in the 4-year period from April 2012. We analysed clinical details, blood components transfused and patient outcomes and used Trauma Audit and Research Network data to correlate with injury severity and predicted survival. RESULTS: Mean transfusion ratios of red cells to plasma improved from 1·5 : 1 and 1·6 : 1 in the first 2 years to 1·1 : 1 in the 2 years following implementation of the new measures. There was a statistically significant improvement in the delivery of a balanced transfusion, defined as a red cell : plasma ratio of <1·3 : 1 following the changes. CONCLUSION: Simple changes to procedures, specifically implementation of a new major haemorrhage prescription template and multidisciplinary team training, have resulted in marked improvement in the ratio of red cells to plasma transfused to trauma patients with major haemorrhage or requiring emergency blood. The package of changes could be easily replicated in other health-care settings.

The QUiPP App: a safe alternative to a treat-all strategy for threatened preterm labor.

OBJECTIVE: To evaluate the impact of triaging women at risk of spontaneous preterm birth (sPTB) using the QUiPP App, which incorporates a predictive model combining history of sPTB, gestational age and quantitative measurements of fetal fibronectin, compared with a treat-all policy (advocated by the UK National Institute for Health and Care Excellence) among women with threatened preterm labor before 30 weeks' gestation. METHODS: Prospectively collected data of pregnant women presenting with symptoms of preterm labor (abdominal pain or tightening) at 24-34 weeks' gestation were retrieved from the research databases of the EQUIPP and PETRA studies for subanalysis. Each episode of threatened preterm labor was retrospectively assigned a risk for sPTB within 7 days using the QUiPP App. A primary outcome of delivery within 7 days was used to model the performance accuracy of the QUiPP App compared with a treat-all policy. RESULTS: Using a 5% risk of delivery within 7 days according to the QUiPP App as the threshold for intervention, 9/9 women who presented with threatened preterm labor < 34 weeks would have been treated correctly, giving a sensitivity of 100% (one-sided 97.5% CI, 66.4%) and a negative predictive value of 100% (97.5% CI, 98.9-100%). The positive predictive value for delivery within 7 days was 30.0% (95% CI, 11.9-54.3%) for women presenting before 30 weeks and 20.0% (95% CI, 12.7-30.1%) for women presenting between 30 + 0 and 34 + 0 weeks. If this 5% threshold had been used to triage women presenting between 24 + 0 and 29 + 6 weeks, 89.4% (n = 168) of admissions could have been safely avoided, compared with 0% for a treat-all strategy. No true case of preterm labor would have been missed, as no woman who was assigned a risk of < 10% delivered within 7 days. CONCLUSION: For women with threatened preterm labor, the QUiPP App can accurately guide management at risk thresholds for sPTB of 1%, 5% and 10%, allowing outpatient management in the vast majority of cases. A treat-all approach would not have avoided admission for any woman, and would have exposed 188 mothers and their babies to unnecessary hospitalization and steroid administration and increased the burden on network and transport services owing to unnecessary in-utero transfers. Prediction of sPTB should be performed before 30 weeks to determine management until there is evidence that such a high level of unnecessary intervention, as suggested by the treat-all strategy, does less harm than the occurrence of rare false negatives. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Purity of transferred CD8(+) T cells is crucial for safety and efficacy of combinatorial tumor immunotherapy in the absence of SHP-1.

Adoptive transfer of tumor-specific cytotoxic T cells is a promising advance in cancer therapy. Similarly, checkpoint inhibition has shown striking clinical results in some patients. Here we combine adoptive cell transfer with ablation of the checkpoint protein Src homology 2-domain-containing phosphatase 1 (SHP-1, Ptpn6). Naturally occurring motheaten mice lack SHP-1 and do not survive weaning due to extensive immunopathology. To circumvent this limitation, we created a novel SHP-1(null) mouse that is viable up to 12 weeks of age by knocking out IL1r1. Using this model, we demonstrate that the absence of SHP-1 augments the ability of adoptively transferred CD8(+) T cells to control tumor growth. This therapeutic effect was only observed in situations where T-cell numbers were limited, analogous to clinical settings. However, adoptive transfer of non-CD8(+) SHP-1(null) hematopoietic cells resulted in lethal motheaten-like pathology, indicating that systemic inhibition of SHP-1 could have serious adverse effects. Despite this caveat, our findings support the development of SHP-1 inhibition strategies in human T cells to complement adoptive transfer therapies in the clinic.

SHP-1: the next checkpoint target for cancer immunotherapy?

The immense power of the immune system is harnessed in healthy individuals by a range of negative regulatory signals and checkpoints. Manipulating these checkpoints through inhibition has resulted in striking immune-mediated clearance of otherwise untreatable tumours and metastases; unfortunately, not all patients respond to treatment with the currently available inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Combinatorial studies using both anti-CTLA-4 and anti-PD-1 demonstrate synergistic effects of targeting multiple checkpoints, paving the way for other immune checkpoints to be targeted. Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a widely expressed inhibitory protein tyrosine phosphatase (PTP). In T-cells, it is a negative regulator of antigen-dependent activation and proliferation. It is a cytosolic protein, and therefore not amenable to antibody-mediated therapies, but its role in activation and proliferation makes it an attractive target for genetic manipulation in adoptive transfer strategies, such as chimeric antigen receptor (CAR) T-cells. This review will discuss the potential value of SHP-1 inhibition in future tumour immunotherapy.

Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells.

The success of adoptive T-cell therapies for the treatment of cancer patients depends on transferred T-lymphocytes finding and infiltrating cancerous tissues. For intravenously transferred T-cells, this means leaving the bloodstream (extravasation) from tumour blood vessels. In inflamed tissues, a key event in extravasation is the capture, rolling and arrest of T-cells inside blood vessels which precedes transmigration across the vessel wall and entry into tissues. This depends on co-ordinated signalling of selectins, integrins and chemokine receptors on T-cells by their respective ligands which are up-regulated on inflamed blood vessels. Clinical data and experimental studies in mice suggest that tumour blood vessels are anergic to inflammatory stimuli and the recruitment of cytotoxic CD8(+)T-lymphocytes is not very efficient. Interestingly, and somewhat counter-intuitively, anti-angiogenic therapy can promote CD8(+)T-cell infiltration of tumours and increase the efficacy of adoptive CD8(+)T-cell therapy. Rather than inhibit tumour angiogenesis, anti-angiogenic therapy 'normalizes' (matures) tumour blood vessels by promoting pericyte recruitment, increasing tumour blood vessel perfusion and sensitizing tumour blood vessels to inflammatory stimuli. A number of different approaches are currently being explored to increase recruitment by manipulating the expression of homing-associated molecules on T-cells and tumour blood vessels. Future studies should address whether these approaches improve the efficacy of adoptive T-cell therapies for solid, vascularized cancers in patients.

Enhancement of T cell responses as a result of synergy between lower doses of radiation and T cell stimulation.

As a side effect of cancer radiotherapy, immune cells receive varying doses of radiation. Whereas high doses of radiation (>10 Gy) can lead to lymphopenia, lower radiation doses (2-4 Gy) represent a valid treatment option in some hematological cancers, triggering clinically relevant immunological changes. Based on our earlier observations, we hypothesized that lower radiation doses have a direct positive effect on T cells. In this study, we show that 0.6-2.4 Gy radiation enhances proliferation and IFN-γ production of PBMC or purified T cells induced by stimulation via the TCR. Radiation with 1.2 Gy also lowered T cell activation threshold and broadened the Th1 cytokine profile. Although radiation alone did not activate T cells, when followed by TCR stimulation, ERK1/2 and Akt phosphorylation increased above that induced by stimulation alone. These changes were followed by an early increase in glucose uptake. Naive (CD45RA(+)) or memory (CD45RA(-)) T cell responses to stimulation were boosted at similar rates by radiation. Whereas increased Ag-specific cytotoxic activity of a CD8(+) T cell line manifested in a 4-h assay (10-20% increase), highly significant (5- to 10-fold) differences in cytokine production were detected in 6-d Ag-stimulation assays of PBMC, probably as a net outcome of death of nonstimulated and enhanced response of Ag-stimulated T cells. T cells from patients receiving pelvic radiation (2.2-2.75 Gy) also displayed increased cytokine production when stimulated in vitro. We report in this study enhanced T cell function induced by synergistic radiation treatment, with potential physiological significance in a wide range of T cell responses.

Ability of a preterm surveillance clinic to triage risk of preterm birth: a prospective cohort study.

OBJECTIVE: To identify whether preterm surveillance clinics (PSCs) risk-stratify high-risk women accurately by comparing outcomes of those admitted to hospital on the basis of asymptomatic testing with those not admitted. METHODS: We performed a subanalysis from a larger prospective cohort study on sonographic cervical length, quantitative fetal fibronectin (qfFN) and risk of spontaneous preterm birth. We identified 1130 asymptomatic singleton pregnancies at high risk of preterm birth, screened between 23 and 28 weeks of gestation at a PSC in a tertiary hospital in London, UK. Gestational age at delivery, the proportion of preterm births that delivered < 30 weeks and neonatal outcomes were compared between women admitted electively when asymptomatic as a consequence of screening-test results and those who were not routinely admitted. RESULTS: In total, 66 (6%) women attending the PSC were admitted to hospital following asymptomatic screening (inpatient group). The mean gestational age at delivery for those not admitted electively (outpatient group) was at term and was significantly higher than that of those admitted from PSC (38.4 vs 31.2 weeks; P < 0.0001). Preterm birth < 30 weeks' gestation was rare in the outpatient group relative to those admitted (1.32% vs 36.4%; P < 0.0001). Neonatal mortality was 0.188% in the outpatient group compared with 4.55% in those admitted electively (P < 0.0001). The incidence of other complications such as neonatal death, 5-min Apgar score < 7, special care baby unit/neonatal intensive care unit admission, respiratory distress syndrome, intraventricular hemorrhage and low birth weight were significantly lower in those managed as outpatients than in those admitted electively. CONCLUSION: PSCs measuring cervical length and qfFN accurately triage asymptomatic high-risk pregnant women, enabling those at highest risk of adverse outcome to be identified for elective admission to hospital and appropriate management. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Heparan sulfate inhibits hematopoietic stem and progenitor cell migration and engraftment in mucopolysaccharidosis I.

Mucopolysaccharidosis I Hurler (MPSI-H) is a pediatric lysosomal storage disease caused by genetic deficiencies in IDUA, coding for α-l-iduronidase. Idua(-/-) mice share similar clinical pathology with patients, including the accumulation of the undegraded glycosaminoglycans (GAGs) heparan sulfate (HS), and dermatan sulfate (DS), progressive neurodegeneration, and dysostosis multiplex. Hematopoietic stem cell transplantation (HSCT) is the most effective treatment for Hurler patients, but reduced intensity conditioning is a risk factor in transplantation, suggesting an underlying defect in hematopoietic cell engraftment. HS is a co-receptor in the CXCL12/CXCR4 axis of hematopoietic stem and progenitor cell (HSPC) migration to the bone marrow (BM), but the effect of HS alterations on HSPC migration, or the functional role of HS in MPSI-H are unknown. We demonstrate defective WT HSPC engraftment and migration in Idua(-/-) recipient BM, particularly under reduced intensity conditioning. Both intra- but especially extracellular Idua(-/-) BM HS was significantly increased and abnormally sulfated. Soluble heparinase-sensitive GAGs from Idua(-/-) BM and specifically 2-O-sulfated HS, elevated in Idua(-/-) BM, both inhibited CXCL12-mediated WT HSPC transwell migration, while DS had no effect. Thus we have shown that excess overly sulfated extracellular HS binds, and sequesters CXCL12, limiting hematopoietic migration and providing a potential mechanism for the limited scope of HSCT in Hurler disease.

The compliance of healthcare workers with universal precautions in the emergency room at the university hospital of the west indies.

OBJECTIVES: The study assessed compliance among health workers in the Emergency Room at the University Hospital of the West Indies with universal precautions. This was done by determining the knowledge, practices and perceptions of staff of universal precautions and by assessing compliance. Reported adherence with universal precautions was compared with observed practice. METHODS: This was a cross-sectional study conducted over a one-year period. It was approved by the University Hospital of the West Indies/University of the West Indies/Faculty of Medical Sciences Ethics Committee. Data were analysed using Stata version 11.1. RESULTS: During the study period, 67 persons gave consent for the study, data were obtained for 62 of these participants and 52 of the respondents were observed. All of the participants were aware that universal precautions related to blood. Eighty-six per cent erroneously thought that universal precautions apply to urine. Seventy-nine per cent of the participants reported always washing their hands after performing a procedure and 43.5% reported always washing their hands before a procedure. Just over half of the participants reported always wearing gloves while doing procedures (56.5%). Only 9% reported always using a gown with a trauma patient. However, 31% and 43.3% reported wearing a gown when placing a chest tube and when anticipating splashes, respectively. Of those participants who reported washing their hands often after a procedure, over 30% did not perform hand-washing when observed. Fifty per cent of persons that reported never recapping needles were observed to recap needles by hand. CONCLUSION: The study revealed that compliance among staff in the Emergency Room with universal precautions was unsatisfactory. The need for education in this area was recognized.

Survivorship care plans: a work in progress.

BACKGROUND: Health agencies across the world have echoed the recommendation of the U.S. Institute of Medicine (iom) that survivorship care plans (scps) should be provided to patients upon completion of treatment. To date, reviews of scps have been limited to the United States. The present review offers an expanded scope and describes how scps are being designed, delivered, and evaluated in various countries. METHODS: We collected scps from Canada, the United States, Europe, the United Kingdom, Australia, and New Zealand. We selected for analysis the scps for which we could obtain the actual scp, information about the delivery approach, and evaluation data. We conducted a content analysis and compared the scps with the iom guidelines. RESULTS: Of 47 scps initially identified, 16 were analyzed. The scps incorporated several of the iom's guidelines, but many did not include psychosocial services, identification of a key point of contact, genetic testing, and financial concerns. The model of delivery instituted by the U.K. National Cancer Survivorship Initiative stands out because of its unique approach that initiates care planning at diagnosis and stratifies patients into a follow-up program based on self-management capacities. SUMMARY: There is considerable variation in the approach to delivery and the extent to which scps follow the original recommendations from the iom. We discuss the implications of this review for future care-planning programs and prospective research. A holistic approach to care that goes beyond the iom recommendations and that incorporates care planning from the point of diagnosis to beyond completion of treatment might improve people's experience of cancer care.

Clustering broiler farmers based on their behavioural differences towards biosecurity to prevent highly pathogenic avian influenza.

Highly pathogenic avian influenza (HPAI) is an important zoonotic disease. The study aims to identify farmer behaviour types to inform the design of behaviour change programmes for mitigating the transmission of HPAI. Therefore, the study utilised multivariate statistical analysis for gaining a better understanding of the relationships among farmers' 30 biosecurity behaviours, the risk of HPAI infection, and distinct features of commercial broiler farmers, which is different from using simple and few binary biosecurity measures. Convenience sampling was used to collect data from 303 Taiwan's farmers among which 40 farmers (13.2%) self-reported having had a HPAI outbreak in the study year while 16 farmers (5.3%) self-reported having had a HPAI outbreak in the past two years. Using categorical principal components analysis and a two-stage cluster analysis, four farmer clusters were identified with distinct features: 1)'Reserved' (4.6%) tended to choose 'No idea' for answering specific questions about HPAI; 2)'Secure' (76.3%) had a higher biosecurity status than the other farms; 3) 'Jeopardised' (16.8%) had a lower biosecurity status than the other farms; 4) 'No-response' (2.3%) tended to skip specific questions about HPAI. The biosecurity status of the 'Reserved' and 'No-response' clusters was undetermined, placing these farms at risk of HPAI infection. Compared to the 'Secure' cluster, the 'Jeopardised' cluster exhibited higher odds of self-reported HPAI in the study year (OR: 2.61, 95% CI: 1.22-5.58) and in the past two years (OR: 4.28, 95% CI: 1.39-13.19). Additionally, the 'Jeopardised' cluster showed increased odds of HPAI recurrence (OR: 4.01, 95% CI: 1.41-11.43). Our study demonstrates that inadequate biosecurity practices can elevate the occurrence or recurrence of HPAI outbreaks. The findings underscore the importance of distinguishing between these clusters to accurately assess the risk of HPAI infection across farms. Furthermore, understanding farmers' behaviours can inform the development of strategies aimed at behaviour change among farmers.