78 research outputs found

    Visualizing Kinetically Robust (Co4L6)-L-III Assemblies in Vivo: SPECT Imaging of the Encapsulated [Tc-99m]TcO4- Anion

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    © 2018 American Chemical Society. Noncovalent encapsulation is an attractive approach for modifying the efficacy and physiochemical properties of both therapeutic and diagnostic species. Abiotic self-assembled constructs have shown promise, yet many hurdles between in vitro and (pre)clinical studies remain, not least the challenges associated with maintaining the macromolecular, hollow structure under nonequilibrium conditions. Using a kinetically robust CoIII4L6 tetrahedron we now show the feasibility of encapsulating the most widely used precursor in clinical nuclear diagnostic imaging, the I-emitting [99mTc]TcO4- anion, under conditions compatible with in vivo administration. Subsequent single-photon emission computed tomography imaging of the caged-anion reveals a marked change in the biodistribution compared to the thyroid-accumulating free oxo-anion, thus moving clinical applications of (metallo)supramolecular species a step closer

    Effectiveness of a structured educational intervention using psychological delivery methods in children and adolescents with poorly controlled type 1 diabetes: a cluster-randomized controlled trial of the CASCADE intervention.

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    INTRODUCTION: Type 1 diabetes (T1D) in children and adolescents is increasing worldwide with a particular increase in children <5 years. Fewer than 1 in 6 children and adolescents achieve recommended glycated hemoglobin (HbA1c) values. METHODS: A pragmatic, cluster-randomized controlled trial assessed the efficacy of a clinic-based structured educational group incorporating psychological approaches to improve long-term glycemic control, quality of life and psychosocial functioning in children and adolescents with T1D. 28 pediatric diabetes services were randomized to deliver the intervention or standard care. 362 children (8-16 years) with HbA1c≥8.5% were recruited. Outcomes were HbA1c at 12 and 24 months, hypoglycemia, admissions, self-management skills, intervention compliance, emotional and behavioral adjustment, and quality of life. A process evaluation collected data from key stakeholder groups in order to evaluate the feasibility of delivering the intervention. RESULTS: 298/362 patients (82.3%) provided HbA1c at 12 months and 284/362 (78.5%) at 24 months. The intervention did not improve HbA1c at 12 months (intervention effect 0.11, 95% CI -0.28 to 0.50, p=0.584), or 24 months (intervention effect 0.03, 95% CI -0.36 to 0.41, p=0.891). There were no significant changes in remaining outcomes. 96/180 (53%) families in the intervention arm attended at least 1 module. The number of modules attended did not affect outcome. Reasons for low uptake included difficulties organizing groups and work and school commitments. Those with highest HbA1cs were less likely to attend. Mean cost of the intervention was £683 per child. CONCLUSIONS: Significant challenges in the delivery of a structured education intervention using psychological techniques to enhance engagement and behavior change delivered by diabetes nurses and dietitians in routine clinical practice were found. The intervention did not improve HbA1c in children and adolescents with poor control. TRIAL REGISTRATION NUMBER: ISRCTN52537669, results

    Identifying the science and technology dimensions of emerging public policy issues through horizon scanning

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    Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security.Public policy requires public support, which in turn implies a need to enable the public not just to understand policy but also to be engaged in its development. Where complex science and technology issues are involved in policy making, this takes time, so it is important to identify emerging issues of this type and prepare engagement plans. In our horizon scanning exercise, we used a modified Delphi technique [1]. A wide group of people with interests in the science and policy interface (drawn from policy makers, policy adviser, practitioners, the private sector and academics) elicited a long list of emergent policy issues in which science and technology would feature strongly and which would also necessitate public engagement as policies are developed. This was then refined to a short list of top priorities for policy makers. Thirty issues were identified within broad areas of business and technology; energy and environment; government, politics and education; health, healthcare, population and aging; information, communication, infrastructure and transport; and public safety and national security

    Comparison of empirically derived and model-based estimates of key population HIV incidence and the distribution of new infections by population group in sub-Saharan Africa

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    Background: The distribution of new HIV infections among key populations, including female sex workers (FSWs), gay men and other men who have sex with men (MSM), and people who inject drugs (PWID) are essential information to guide an HIV response, but data are limited in sub-Saharan Africa (SSA). We analyzed empirically derived and mathematical model-based estimates of HIV incidence among key populations and compared with the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates.Methods: We estimated HIV incidence among FSW and MSM in SSA by combining meta-analyses of empirical key population HIV incidence relative to the total population incidence with key population size estimates (KPSE) and HIV prevalence. Dynamic HIV transmission model estimates of HIV incidence and percentage of new infections among key populations were extracted from 94 country applications of 9 mathematical models. We compared these with UNAIDS-reported distribution of new infections, implied key population HIV incidence and incidence-to-prevalence ratios.Results: Across SSA, empirical FSW HIV incidence was 8.6-fold (95% confidence interval: 5.7 to 12.9) higher than total population female 15–39 year incidence, and MSM HIV incidence was 41.8-fold (95% confidence interval: 21.9 to 79.6) male 15–29 year incidence. Combined with KPSE, these implied 12% of new HIV infections in 2021 were among FSW and MSM (5% and 7% respectively). In sensitivity analysis varying KPSE proportions within 95% uncertainty range, the proportion of new infections among FSW and MSM was between 9% and 19%. Insufficient data were available to estimate PWID incidence rate ratios. Across 94 models, median proportion of new infections among FSW, MSM, and PWID was 6.4% (interquartile range 3.2%–11.7%), both much lower than the 25% reported by UNAIDS.Conclusion: Empirically derived and model-based estimates of HIV incidence confirm dramatically higher HIV risk among key populations in SSA. Estimated proportions of new infections among key populations in 2021 were sensitive to population size assumptions and were substantially lower than estimates reported by UNAIDS.</div

    Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours

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    Background: This phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulin-liposomal formulation (eribulin-LF) in patients with advanced solid tumours. Methods:\ud Eligible patients with ECOG PS 0–1 were treated with eribulin-LF either on day 1 every 21 days (Schedule 1), or on days 1 and 15 every 28 days (Schedule 2). Doses ranged from 1.0 to 3.5 mg/m2, with dose escalation in a 3 + 3 design. The dose-expansion phase evaluated eribulin-LF in select tumour types. Primary objectives: maximum tolerated dose (MTD) and the recommended dose/schedule of eribulin-LF. Results: Totally, 58 patients were enroled (median age = 62 years). The MTD was 1.4 mg/m2 (Schedule 1) or 1.5 mg/m2 (Schedule 2), the latter dose selected for the dose-expansion phase. Dose-limiting toxicity (DLTs) in Schedule 1: hypophosphatemia and increased transaminase levels. DLTs in Schedule 2: stomatitis, increased alanine aminotransferase, neutropenia and febrile neutropenia. The pharmacokinetic profile of eribulin-LF showed a similar half-life to that of eribulin (~30 h), but with a 5-fold greater maximum serum concentration and a 40-fold greater area-under-the-curve. Eribulin-LF demonstrated clinical activity with approximately 10% of patients in both schedules achieving partial responses. Conclusions: Eribulin-LF was well tolerated with a favourable pharmacokinetic profile. Preliminary evidence of clinical activity in solid tumours was observed

    Pain and depression are associated with both physical and mental fatigue independently of comorbidities and medications in primary Sjögren's syndrome

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    Objectives To report on fatigue in patients from the United Kingdom primary Sjögren’s syndrome (pSS) registry identifying factors associated with fatigue and robust to assignable causes such as comorbidities and medications associated with drowsiness. Methods From our cohort (n = 608), we identified those with comorbidities associated with fatigue, and those taking medications associated with drowsiness. We constructed dummy variables, permitting the contribution of these potentially assignable causes of fatigue to be assessed. Using multiple regression analysis, we modelled the relationship between Profile of Fatigue and Discomfort physical and mental fatigue scores and potentially related variables. Results Pain, depression and daytime sleepiness scores were closely associated with both physical and mental fatigue (all p ≤ 0.0001). In addition, dryness was strongly associated with physical fatigue (p ≤ 0.0001). These effects were observed even after adjustment for comorbidities associated with fatigue or medications associated with drowsiness. Conclusions These findings support further research and clinical interventions targeting pain, dryness, depression and sleep to improve fatigue in patients with pSS. This finding is robust to both the effect of other comorbidities associated with fatigue and medications associated with drowsiness
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