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Lipin-alpha and -beta are the alternatively spliced gene products of the Lpin1 gene, whose product lipin is required for adipocyte differentiation. Lipin deficiency causes lipodystrophy, fatty liver, and insulin resistance in mice, whereas adipose tissue lipin overexpression results in increased adiposity but improved insulin sensitivity. To assess lipin expression and its relation to insulin resistance in humans, we examined lipin-alpha and -beta mRNA levels in subjects with normal or impaired glucose tolerance. We found higher expression levels of both lipin isoforms in lean, insulin-sensitive subjects. When compared with normal glucose-tolerant subjects, individuals with impaired glucose tolerance were more insulin resistant, demonstrated higher levels of intramyocellular lipids (IMCLs), and expressed approximately 50% lower levels of lipin-alpha and -beta. In addition, there was a strong inverse correlation between adipose tissue lipin expression and muscle IMCLs but no evidence for an increase in muscle lipid oxidation. After treatment of the impaired glucose-tolerant subjects with insulin sensitizers for 10 weeks, pioglitazone (but not metformin) resulted in a 60% increase in the insulin sensitivity index (Si) and a 32% decrease in IMCLs (both P < 0.01), along with an increase in lipin-beta (but not lipin-alpha) expression by 200% (P < 0.005). Lipin expression in skeletal muscle, however, was not related to obesity or insulin resistance. Hence, high adipose tissue lipin expression is found in insulin-sensitive subjects, and lipin-beta expression increases following treatment with pioglitazone. These results suggest that increased adipogenesis and/or lipogenesis in subcutaneous fat, mediated by the LPIN1 gene, may prevent lipotoxicity in muscle, leading to improved insulin sensitivity. [ABSTRACT FROM AUTHOR]

To examine the role of adipose-resident macrophages in insulin resistance, we examined the gene expression of CD68, a macrophage marker, along with macrophage chemoattractant protein-1 (MCP-1) in human subcutaneous adipose tissue using real-time RT-PCR. Both CD68 and MCP-1 mRNAs were expressed in human adipose tissue, primarily in the stromal vascular fraction. When measured in the adipose tissue from subjects with normal glucose tolerance, covering a wide range of BMI (21-51 kg/m2) and insulin sensitivity (S(I)) (0.6-8.0 x 10(-4)min(-1).microU(-1).ml(-1)), CD68 mRNA abundance, which correlated with the number of CD68-positive cells by immunohistochemistry, tended to increase with BMI but was not statistically significant. However, there was a significant inverse relation between CD68 mRNA and S(I) (r=-0.55, P=0.02). In addition, there was a strong positive relationship among adipose tissue CD68 mRNA, tumor necrosis factor-alpha (TNF-alpha) secretion in vitro (r=0.79, P<0.005), and plasma interleukin-6 (r=0.67, P < 0.005). To determine whether improving S(I) in subjects with impaired glucose tolerance (IGT) was associated with decreased CD68 expression, IGT subjects were treated for 10 weeks with pioglitazone or metformin. Pioglitazone increased S(I) by 60% and in the same subjects reduced both CD68 and MCP-1 mRNAs by >50%. Furthermore, pioglitazone resulted in a reduction in the number of CD68-positive cells in adipose tissue and reduced plasma TNF-alpha. Metformin had no effect on any of these measures. Thus, treatment with pioglitazone reduces expression of CD68 and MCP-1 in adipose tissue, apparently by reducing macrophage numbers, resulting in reduced inflammatory cytokine production and improvement in S(I). [ABSTRACT FROM AUTHOR]

The 1997 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) report, Food, Nutrition and the Prevention of Cancer: a global perspective, has become the most authoritative statement on the topic. Since then, new evidence has emerged, and more sophisticated methods of reviewing and assessing the literature have been developed. As a result, WCRF/AICR has invited a new expert panel of scientists, with observers from the United Nations and other international agencies, to work on the production of a second report, due to be published in 2006. In addition, a special methodology task force, commissioned by WCRF, has established a methodology to systematically review the evidence. No such methodology has, up to now, been used for assessing mainly observational data on causation of disease. A portfolio approach to the evidence is used, in which all types of study, with their advantages and disadvantages, contribute to the inference of causation. Seven academic centres from the UK, the USA and continental Europe are using this new methodology to comprehensively review evidence in systematic literature reviews. In a separate process, an expert panel will make conclusions from the systematic literature reviews. Together with other relevant evidence, the panel will use these conclusions as the basis for formulating recommendations. Set against this backdrop, the new report will act as the most authoritative global report ever to be published on the subject of food, nutrition, physical activity and the prevention of cancer. It will form the basis for coherent strategies for cancer prevention and control and will set the scientific agenda for years to come. [ABSTRACT FROM AUTHOR]

Objectives: The National Health Service Digital Diabetes Prevention Programme is a nine-month behavioural intervention for adults in England at risk of type 2 diabetes. This qualitative study aimed to explore how service users engaged with the group support available within the programme., Methods: The majority of participants ( n = 33), all service users, were interviewed twice via telephone, at 2-4 months into the programme, and at the end of the programme at 8-10 months. Semi-structured interviews covered participants' experiences of online group support functions and how such groups served as a route of support to aid participants' behavioural changes. Data were analysed using manifest thematic analysis., Results: The majority of participants valued the format of closed group chats, which provided an interactive platform to offer and receive support during their behaviour change journey. However, engagement with group chats reduced over time, and some participants did not find them useful when there was a lack of common interests within the group. Health coaches helped to promote engagement and build rapport among participants within the group chats. Participants reported mixed experiences of discussion forums., Conclusions: Programme developers should consider how to optimise online group support to help service users make behavioural changes, in terms of format, participant composition and use of health coach moderators. Further research is required to better understand who might benefit most from 'group chat' or 'discussion forum' support. Health coach moderation of online support groups is likely to facilitate engagement., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The Healthier You National Health Service Digital Diabetes Prevention Programme (NHS-digital-DPP) is a 9-month digital behavior change intervention delivered by 4 independent providers that is implemented nationally across England. No studies have explored the design features included by service providers of digital diabetes prevention programs to promote engagement, and little is known about how participants of nationally implemented digital diabetes prevention programs such as this one make use of them., Objective: This study aimed to understand engagement with the NHS-digital-DPP. The specific objectives were to describe how engagement with the NHS-digital-DPP is promoted via design features and strategies and describe participants' early engagement with the NHS-digital-DPP apps., Methods: Mixed methods were used. The qualitative study was a secondary analysis of documents detailing the NHS-digital-DPP intervention design and interviews with program developers (n=6). Data were deductively coded according to an established framework of engagement with digital health interventions. For the quantitative study, anonymous use data collected over 9 months for each provider representing participants' first 30 days of use of the apps were obtained for participants enrolled in the NHS-digital-DPP. Use data fields were categorized into 4 intervention features (Track, Learn, Coach Interactions, and Peer Support). The amount of engagement with the intervention features was calculated for the entire cohort, and the differences between providers were explored statistically., Results: Data were available for 12,857 participants who enrolled in the NHS-digital-DPP during the data collection phase. Overall, 94.37% (12,133/12,857) of those enrolled engaged with the apps in the first 30 days. The median (IQR) number of days of use was 11 (2-25). Track features were engaged with the most (number of tracking events: median 46, IQR 3-22), and Peer Support features were the least engaged with, a median value of 0 (IQR 0-0). Differences in engagement with features were observed across providers. Qualitative findings offer explanations for the variations, including suggesting the importance of health coaches, reminders, and regular content updates to facilitate early engagement., Conclusions: Almost all participants in the NHS-digital-DPP started using the apps. Differences across providers identified by the mixed methods analysis provide the opportunity to identify features that are important for engagement with digital health interventions and could inform the design of other digital behavior change interventions., (©Jamie Ross, Rhiannon E Hawkes, Lisa M Miles, Sarah Cotterill, Peter Bower, Elizabeth Murray. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 17.08.2023.)

Background: Digital behaviour change interventions may offer a scalable way to promote weight loss by increasing physical activity and improving diet. However, user engagement is necessary for such benefits to be achieved. There is a dearth of research that assesses engagement with nationally implemented digital programmes offered in routine practice. The National Health Service Digital Diabetes Prevention Programme (NHS-DDPP) is a nine-month digital behaviour change intervention delivered by independent providers for adults in England who are at high risk of developing type 2 diabetes. This study reports engagement with the NHS-DDPP for users enrolled onto the programme over the nine-month duration., Methods: Anonymous usage data was obtained for a cohort of service users ( n  = 1826) enrolled on the NHS-DDPP with three independent providers, between December 2020 and June 2021. Usage data were obtained for time spent in app, and frequency of use of NHS-DDPP intervention features in the apps including self-monitoring, goal setting, receiving educational content (via articles) and social support (via health coaches and group forums), to allow patterns of usage of these key features to be quantified across the nine-month intervention. Median usage was calculated within nine 30-day engagement periods to allow a longitudinal analysis of the dose of usage for each feature., Results: App usage declined from a median of 32 min (IQR 191) in month one to 0 min (IQR 14) in month nine. Users self-monitored their behaviours (e.g., physical activity and diet) a median of 117 times (IQR 451) in the apps over the nine-month programme. The open group discussion forums were utilised less regularly (accessed a median of 0 times at all time-points). There was higher engagement with some intervention features (e.g., goal setting) when support from a health coach was linked to those features., Conclusions: App usage decreased over the nine-month programme, although the rate at which the decrease occurred varied substantially between individuals and providers. Health coach support may promote engagement with specific intervention features. Future research should assess whether engagement with particular features of digital diabetes prevention programmes is associated with outcomes such as reduced bodyweight and HbA1c levels., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

Background: The National Health Service (NHS) Digital Diabetes Prevention Programme (DDPP) is a behaviour change programme for adults in England who are at high risk of developing type 2 diabetes. Four independent providers deliver the NHS-DDPP following a competitive tendering process. Although providers work to a single service specification, there is potential for some variation in the service across providers. This study (1) assesses fidelity of the structural features of the design of the NHS-DDPP compared to the service specification, (2) describes the structural features of delivery of the NHS-DDPP as implemented (3) reports developers' views on how the structural components of the NHS-DDPP were developed and why changes were made following implementation., Methods: Using mixed methods, we conducted a document review of providers' NHS-DDPP design and delivery documentation, and extracted information using the Template for Intervention Description and Replication checklist, which was adapted to capture features of digital delivery. Documentation was supplemented by content analysis of interviews with 12 health coaches involved in delivering the NHS-DDPP. Semi-structured interviews were also conducted with 6 programme developers employed by the digital providers., Results: Provider plans for the NHS-DDPP show relatively high fidelity to the NHS service specification. Despite this, there was wide variation in structural features of delivery of the NHS-DDPP across providers, particularly for delivery of 'support' (e.g. use, dose and scheduling of health coaching and/or group support). Interviews with developers of the programmes showed that much of this variation is likely to be attributable to the origin of each provider's programme, which was usually a pre-existing programme that was adapted to conform to the NHS-DDPP service specification. The NHS-DDPP is continually improved and developed based on user experience feedback and research conducted by the providers., Conclusion: Indirect evidence suggests that variation in delivery of support could affect effectiveness of the NHS-DDPP. A priority for future research is ascertaining whether the variation in delivery of the NHS-DDPP across providers is related to any differences in health outcomes. It is recommended that future rounds of commissioning the NHS-DDPP pre-specify the type of support participants should receive, including expected dose and scheduling., (© 2023. The Author(s).)

The National Health Service Digital Diabetes Prevention Programme (NHS-DDPP) is a behavioural intervention for adults in England at risk of developing Type 2 diabetes, rolled out nationally via independent providers and their digital partners. The NHS England programme specification indicated 19 behaviour change techniques (BCTs) which should be present in the intervention, including BCTs to support self-regulation. A previous evaluation of the face-to-face service found an under-delivery of some self-regulatory BCTs. This study assessed whether those 19 BCTs were offered in the different interventions delivered by four digital providers. A cross-sectional analysis of BCT content in the NHS-DDPP was elicited from the following sources: (a) online platforms (e.g. apps), (b) educational materials, and (c) health coaching (assessed via interviews with health coaches and audio-recorded telephone consultations). All materials were coded using the Behaviour Change Technique Taxonomy v1. A total of 17, 15, 15 and 14 of the 19 specified BCTs were identified across the four digital provider programmes. A mean proportion of 43% of specified BCTs were present via providers' apps, 74% via educational materials, and 62% via health coaching. An additional 41 BCTs were included in at least one of the four providers' programmes. Fidelity of BCT content in the NHS-DDPP was better than previously identified for the face-to-face DPP service. However, BCTs were offered via multiple modalities, thus the degree to which users engage with the modalities will impact on their exposure to BCTs and likely effectiveness of the digital programme., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: The National Health Service Digital Diabetes Prevention Programme (NHS-DDPP) is a program for adults in England at risk of developing type 2 diabetes mellitus (T2DM). It is based on NHS England specifications that stipulate specific behavior change techniques (BCTs), that is, active ingredients to produce behavior change to target diet and physical activity. Now rolled out nationally, the NHS-DDPP is being delivered by 4 independent providers as a 9-month intervention via apps, educational material, and remote health coaching. To optimize effectiveness, participants need to be able to understand and use behavior change content (eg, goal setting and problem solving) of an intervention delivered to them digitally. Previous research has shown that people benefit from support to aid the understanding and use of BCTs., Objective: The objectives of this qualitative study were to evaluate how participants in the NHS-DDPP understand and use BCT content, investigate how participants describe the role of health coaches in supporting their behavior change, and examine how the understanding and use of behavior change content of the NHS-DDPP varies across providers., Methods: In total, 45 service users were interviewed twice by telephone at 2 to 4 months into, and at the end of, the program. Topics included participants' understanding and use of key BCTs to support self-regulation (eg, goal setting) and the support they received via the program. Transcripts were analyzed thematically, informed by the framework method., Results: Participants described their understanding and use of some behavior change content of the program as straightforward: use of BCTs (eg, self-monitoring of behavior) delivered digitally via provider apps. Participants valued the role of health coaches in supporting their behavior change through the emotional support they offered and their direct role in delivery and application of some BCTs (eg, problem solving) to their specific circumstances. Participants expressed frustration over the lack of monitoring or feedback regarding their T2DM risk within the program. Variations in the understanding and use of behavior change content of the NHS-DDPP were present across provider programs., Conclusions: Health coaches' support in delivery of key components of the program seems to be pivotal. To improve the understanding and use of BCTs in digital interventions, it is important to consider routes of delivery that offer additional interactive human support. Understanding of some self-regulatory BCTs may benefit from this support more than others; thus, identifying the optimal mode of delivery for behavior change content is a priority for future research. The NHS-DDPP could be improved by explicitly setting out the need for health coaches to support understanding of some self-regulatory BCT content such as problem solving in the service specification and amending the discharge process so that knowledge of any change in T2DM risk is available to participants., (©Lisa M Miles, Rhiannon E Hawkes, David P French. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 11.01.2023.)

Background: "Healthy Living for People with type 2 Diabetes (HeLP-Diabetes)" was a theory-based digital self-management intervention for people with type 2 diabetes mellitus that encouraged behavior change using behavior change techniques (BCTs) and promoted self-management. HeLP-Diabetes was effective in reducing HbA1c levels in a randomized controlled trial (RCT). National Health Service (NHS) England commissioned a national rollout of HeLP-Diabetes in routine care (now called "Healthy Living"). Healthy Living presents a unique opportunity to examine the fidelity of the national rollout of an intervention originally tested in an RCT., Objective: This research aimed to describe the Healthy Living BCT and self-management content and features of intervention delivery, compare the fidelity of Healthy Living with the original HeLP-Diabetes intervention, and explain the reasons for any fidelity drift during national rollout through qualitative interviews., Methods: Content analysis of Healthy Living was conducted using 3 coding frameworks (objective 1): the BCT Taxonomy v1, a new coding framework for assessing self-management tasks, and the Template for Intervention Description and Replication. The extent to which BCTs and self-management tasks were included in Healthy Living was compared with published descriptions of HeLP-Diabetes (objective 2). Semistructured interviews were conducted with 9 stakeholders involved in the development of HeLP-Diabetes or Healthy Living to understand the reasons for any changes during national rollout (objective 3). Qualitative data were thematically analyzed using a modified framework approach., Results: The content analysis identified 43 BCTs in Healthy Living. Healthy Living included all but one of the self-regulatory BCTs ("commitment") in the original HeLP-Diabetes intervention. Healthy Living was found to address all areas of self-management (medical, emotional, and role) in line with the original HeLP-Diabetes intervention. However, 2 important changes were identified. First, facilitated access by a health care professional was not implemented; interviews revealed this was because general practices had fewer resources in comparison with the RCT. Second, Healthy Living included an additional structured web-based learning curriculum that was developed by the HeLP-Diabetes team but was not included in the original RCT; interviews revealed that this was because of changes in NHS policy that encouraged referral to structured education. Interviewees described how the service provider had to reformat the content of the original HeLP-Diabetes website to make it more usable and accessible to meet the multiple digital standards required for implementation in the NHS., Conclusions: The national rollout of Healthy Living had good fidelity to the BCT and self-management content of HeLP-Diabetes. Important changes were attributable to the challenges of scaling up a digital intervention from an RCT to a nationally implemented intervention, mainly because of fewer resources available in practice and the length of time since the RCT. This study highlights the importance of considering implementation throughout all phases of intervention development., (©Jack S Benton, Sarah Cotterill, Rhiannon E Hawkes, Lisa M Miles, David P French. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 07.12.2022.)

Background: New oscillometry devices allowing quantification of respiratory function using tidal breathing are commercially available, but reference equations are lacking for the multiethnic Canadian pediatric population., Methods: We conducted a prospective cross-sectional study of healthy children carefully selected for absence of asthma, atopy, tobacco smoke, obesity, prematurity, and recent respiratory infection. Triplicate measures were obtained of respiratory system resistance (Rrs) and reactance (Xrs), area under the reactance curve (AX) and resonant frequency (Fres) on four signals, whose testing order was randomized: two signals on the Resmon Pro Full (8 Hz and 5-11-19 Hz) and two signals on the tremoflo C-100 (5-37 Hz and 7-41 Hz). Feasibility was defined as the ability to obtain valid reproducible results. Prediction equations and 95% confidence intervals were derived for whole- and within-breath Rrs and Xrs and for AX and Fres, using linear regression or Generalized Additive Models for Location, Scale and Shape., Results: Of 306 children randomized, valid and reproducible results on ≥1 signal were obtained in 299 (98%) multiethnic (69% Caucasians: 8% Black: 23% Others) children aged 3-17 years, 91-189 cm tall. Standing height was the strongest predictor with no significant effect of sex, age, body mass index or ethnicity. Significant within-patient differences were observed between Resmon Pro and tremoflo C-100 measurements, justifying the derivation of device-specific reference equations., Conclusion: Valid reproducible oscillometry measurements are highly feasible in children aged 3 years and older. Device-specific reference equations, valid for our multiethnic population, are derived., (© 2022 Wiley Periodicals LLC.)

Background: The National Health Service (NHS) Diabetes Prevention Program (DPP) is a nationally implemented behavioral intervention for adults at high risk of developing Type 2 diabetes in England, based on a program specification that stipulates inclusion of 19 specific behavior change techniques (BCTs). Previous work has identified drift in fidelity from these NHS England specifications through providers' program manuals, training, and delivery, especially in relation to BCTs targeting self-regulatory processes., Purpose: This qualitative study investigates intervention receipt, i.e., how the self-regulatory BCT content of the NHS-DPP is understood by participants., Methods: Twenty participants from eight NHS-DPP locations were interviewed; topics included participants' understanding of self-monitoring of behavior, goal setting, feedback, problem solving, and action planning. Transcripts were analyzed thematically using the framework method., Results: There was a wide variation in understanding among participants for some BCTs, as well as between BCTs. Participants described their understanding of "self-monitoring of behaviors" with ease and valued BCTs focused on outcomes (weight loss). Some participants learned how to set appropriate behavioral goals. Participants struggled to recall "action planning" or "problem solving" or found these techniques challenging to understand, unless additional support was provided (e.g., through group discussion)., Conclusions: Participants' lack of understanding of some self-regulatory BCTs is consistent with the drift across fidelity domains previously identified from NHS design specifications. Behavioral interventions should build-in necessary support for participants to help them understand some BCTs such as action planning and problem solving. Alternatively, these self-regulatory BCTs may be intrinsically difficult to use for this population., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

Introduction: Asthma guided self-management enhances patients' control of their condition under the guidance of the treating physician. The aim of the present study was to understand how physicians perceive, endorse, uptake, and support asthma guided self-management., Methods: We conducted a secondary supplementary analysis of data originally collected as part of a multicenter collective case study in which physicians treating patients with asthma were interviewed. Using reflective thematic analysis, we aimed to explore physicians' understanding of guided asthma self-management as related to four ideas, namely: (a) understanding of the disease management and treatment goals; (b) defining medical frame and guidance; (c) describing the importance of patient-physician relationship; and (d) implementing asthma guided self-management., Results: Evidence indicates that physicians perceived optimal guided self-management as related to patients' adherence to physician's instructions and recommendations, supported by the adjustment of prescribed pharmaceutical therapy contingent upon patient's symptoms. Some physicians also perceived behavior change and environmental control along with the medical recommendations. While physicians' perception of asthma and its treatment were aligned with the recommended guidelines-i.e., patient-centered care approach based on guided self-management, the actual guidance offered to patients remained primarily directive and paternalistic. Non-pharmacological approaches, such as exercise, smoking cessation, patient self-monitoring, and self-management supported by education and written self-management plans, were given little consideration in the context of the recommended treatment plan.

Background: Health services interventions are typically more effective in randomised controlled trials than in routine healthcare. One explanation for this 'voltage drop', i.e. reduction in effectiveness, is a reduction in intervention fidelity, i.e. the extent to which a programme is implemented as intended. This article discusses how to optimise intervention fidelity in nationally implemented behaviour change programmes, using as an exemplar the National Health Service Diabetes Prevention Programme (NHS-DPP); a behaviour change intervention for adults in England at increased risk of developing Type 2 diabetes, delivered by four independent provider organisations. We summarise key findings from a thorough fidelity evaluation of the NHS-DPP assessing design (whether programme plans were in accordance with the evidence base), training (of staff to deliver key intervention components), delivery (of key intervention components), receipt (participant understanding of intervention content), and highlight lessons learned for the implementation of other large-scale programmes., Results: NHS-DPP providers delivered the majority of behaviour change content specified in their programme designs. However, a drift in fidelity was apparent at multiple points: from the evidence base, during programme commissioning, and on to providers' programme designs. A lack of clear theoretical rationale for the intervention contents was apparent in design, training, and delivery. Our evaluation suggests that many fidelity issues may have been less prevalent if there was a clear underpinning theory from the outset., Conclusion: We provide recommendations to enhance fidelity of nationally implemented behaviour change programmes. The involvement of a behaviour change specialist in clarifying the theory of change would minimise drift of key intervention content. Further, as loss of fidelity appears notable at the design stage, this should be given particular attention. Based on these recommendations, we describe examples of how we have worked with commissioners of the NHS-DPP to enhance fidelity of the next roll-out of the programme., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

AbstractThe scarcity of asexual reproduction in vertebrates alludes to an inherent cost. Several groups of asexual vertebrates exhibit lower endurance capacity (a trait predominantly sourced by mitochondrial respiration) compared with congeneric sexual species. Here we measure endurance capacity in five species of Aspidoscelis lizards and examine mitochondrial respiration between sexual and asexual species using mitochondrial respirometry. Our results show reduced endurance capacity, reduced mitochondrial respiration, and reduced phenotypic variability in asexual species compared with parental sexual species, along with a positive relationship between endurance capacity and mitochondrial respiration. Results of lower endurance capacity and lower mitochondrial respiration in asexual Aspidoscelis are consistent with hypotheses involving mitonuclear incompatibility.

Background: The National Health Service (NHS) Diabetes Prevention Program is a behavior change intervention for adults in England who are identified as being at high risk of developing type 2 diabetes. The face-to-face service was launched in 2016, followed by a digital service (NHS Digital Diabetes Prevention Program [NHS-DDPP]) in 2019. A total of 4 service providers were commissioned to deliver the NHS-DDPP and were required to deliver the digital service in line with a program specification detailing the key intervention content. The fidelity of the behavior change content in the digital service (ie, the extent to which the program is delivered as intended) is currently unknown. Digital interventions may allow higher fidelity as staff do not have to be trained to deliver all intervention content. Assessing fidelity of the intervention design is particularly important to establish the planned behavior change content in the NHS-DDPP and the extent to which this adheres to the program specification. This is the first known independent assessment of design fidelity in a large-scale digital behavior change intervention., Objective: This study aims to assess the fidelity of the behavior change content in each of the 4 NHS-DDPP providers' intervention designs to the full program specification., Methods: We conducted a document review of each provider's NHS-DDPP intervention design, along with interviews with program developers employed by the 4 digital providers (n=6). Providers' intervention design documents and interview transcripts were coded for behavior change techniques (BCTs; ie, the active ingredients of the intervention) using the Behavior Change Technique Taxonomy version 1 and underpinning theory using the Theory Coding Scheme framework. The BCTs identified in each digital provider's intervention design were compared with the 19 BCTs included in the program specification., Results: Of the 19 BCTs specified in the program specification, the 4 providers planned to deliver 16 (84%), 17 (89%), 16 (84%), and 16 (84%) BCTs, respectively. An additional 41 unspecified BCTs were included in at least one of the 4 digital providers' intervention designs. By contrast, inconsistent use of the underpinning theory was apparent across providers, and none of the providers had produced a logic model to explain how their programs were expected to work. All providers linked some of their planned BCTs to theoretical constructs; however, justification for the inclusion of other BCTs was not described., Conclusions: The fidelity of BCT content in the NHS-DDPP was higher than that previously documented for the face-to-face service. Thus, if service users engage with the NHS-DDPP, this should increase the effectiveness of the program. However, given that a clear theoretical underpinning supports the translation of BCTs in intervention designs to intervention delivery, the absence of a logic model describing the constructs to be targeted by specific BCTs is potentially problematic., (©Rhiannon E Hawkes, Lisa M Miles, David P French. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 27.04.2022.)

Background: COVID-19-associated invasive pulmonary aspergillosis (CAPA) is associated with increased mortality. Cases of CAPA caused by azole-resistant Aspergillus fumigatus strains have been reported., Objectives: To analyse the twelve-month CAPA prevalence in a German tertiary care hospital and to characterise clinical A. fumigatus isolates from two German hospitals by antifungal susceptibility testing and microsatellite genotyping., Patients/methods: Retrospective observational study in critically ill adults from intensive care units with COVID-19 from 17 February 2020 until 16 February 2021 and collection of A. fumigatus isolates from two German centres. EUCAST broth microdilution for four azole compounds and microsatellite PCR with nine markers were performed for each collected isolate (N = 27) and additional for three non-COVID A. fumigatus isolates., Results: welve-month CAPA prevalence was 7.2% (30/414), and the rate of azole-resistant A. fumigatus isolates from patients with CAPA was 3.7% with detection of one TR34/L98H mutation. The microsatellite analysis revealed no major clustering of the isolates. Sequential isolates mainly showed the same genotype over time., Conclusions: Our findings demonstrate similar CAPA prevalence to other reports and a low azole-resistance rate. Genotyping of A. fumigatus showed polyclonal distribution except for sequential isolates., (© 2022 The Authors. Mycoses published by Wiley-VCH GmbH.)

Background: Cold urticaria (coldU) is associated with substantial morbidity and risk of fatality. Data on coldU in children are sparse. We aimed to evaluate the clinical characteristics, management, risk of associated anaphylaxis, and resolution rate of coldU in a pediatric cohort. Additionally, we sought to compare these metrics to children with chronic spontaneous urticaria (CSU)., Methods: We prospectively enrolled children with coldU from 2013-2021 in a cohort study at the Montreal Children's Hospital and an affiliated allergy clinic. Data for comparison with participants with solely CSU were extracted from a previous study. Data on demographics, comorbidities, severity of presentation, management, and laboratory values were collected at study entry. Patients were contacted yearly to assess for resolution., Results: Fifty-two children with cold urticaria were recruited, 51.9% were female and the median age of symptom onset was 9.5 years. Most patients were managed with second-generation H1-antihistamines (sgAHs). Well-controlled disease on sgAHs was negatively associated with concomitant CSU (adjusted odds ratio (aOR) = 0.69 [95%CI: 0.53, 0.92]). Elevated eosinophils were associated with cold-induced anaphylaxis (coldA; aOR = 1.38 [95%CI: 1.04, 1.83]), which occurred in 17.3% of patients. The resolution rate of coldU was 4.8 per 100 patient-years, which was lower than that of CSU (adjusted hazard ratio = 0.43 [95%CI: 0.21, 0.89], p < 10 -2 )., Conclusion: Pediatric coldU bears a substantial risk of anaphylaxis and a low-resolution rate. Absolute eosinophil count and co-existing CSU may be useful predictive factors., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: The National Health Service Diabetes Prevention Programme (NHS-DPP) is a behavioural intervention for people identified as high risk for developing type 2 diabetes that has been rolled out across England. The present study evaluates whether the four commercial providers of the NHS-DPP train staff to deliver behaviour change technique (BCT) content with fidelity to intervention plans., Method: One set of mandatory training courses across the four NHS-DPP providers (seven courses across 13 days) was audio-recorded, and all additional training materials used were collected. Recordings and training materials were coded for BCT content using the BCT Taxonomy v1. BCTs and depth of training (e.g. instruction, demonstration, practice) of BCT content was checked against providers' intervention plans., Results: Ten trainers and 78 trainees were observed, and 12 documents examined. The number of unique BCTs in audio recordings and associated training materials ranged from 19 to 44 across providers, and staff were trained in 53 unique BCTs across the whole NHS-DPP. Staff were trained in 66% of BCTs that were in intervention plans, though two providers trained staff in approximately half of BCTs to be delivered. The most common way that staff were trained in BCT delivery was through instruction. Training delivery style (e.g. experiential versus educational) varied between providers., Conclusion: Observed training evidences dilution from providers' intervention plans. NHS-DPP providers should review their training to ensure staff are trained in all key intervention components, ensuring thorough training of BCTs (e.g. demonstrating and practicing how to deliver) to enhance BCT delivery., (© 2021. The Author(s).)

Objective: This study (MEasurement Reactions In Trials) aimed to produce recommendations on how best to minimize bias from measurement reactivity (MR) in randomized controlled trials of interventions to improve health., Study Design and Setting: The MERIT study consisted of: (1) an updated systematic review that examined whether measuring participants had effects on participants' health-related behaviors, relative to no-measurement controls, and three rapid reviews to identify: (i) existing guidance on MR; (ii) existing systematic reviews of studies that have quantified the effects of measurement on behavioral or affective outcomes; and (iii) studies that have investigated the effects of objective measurements of behavior on health-related behavior; (2) a Delphi study to identify the scope of the recommendations; and (3) an expert workshop in October 2018 to discuss potential recommendations in groups., Results: Fourteen recommendations were produced by the expert group to: (1) identify whether bias is likely to be a problem for a trial; (2) decide whether to collect data about whether bias is likely to be a problem; (3) design trials to minimize the likelihood of this bias., Conclusion: These recommendations raise awareness of how and where taking measurements can produce bias in trials, and are thus helpful for trial design., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Measurement can affect the people being measured; for example, asking people to complete a questionnaire can result in changes in behaviour (the 'question-behaviour effect'). The usual methods of conduct and analysis of randomised controlled trials implicitly assume that the taking of measurements has no effect on research participants. Changes in measured behaviour and other outcomes due to measurement reactivity may therefore introduce bias in otherwise well-conducted randomised controlled trials, yielding incorrect estimates of intervention effects, including underestimates., Objectives: The main objectives were (1) to promote awareness of how and where taking measurements can lead to bias and (2) to provide recommendations on how best to avoid or minimise bias due to measurement reactivity in randomised controlled trials of interventions to improve health., Methods: We conducted (1) a series of systematic and rapid reviews, (2) a Delphi study and (3) an expert workshop. A protocol paper was published [Miles LM, Elbourne D, Farmer A, Gulliford M, Locock L, McCambridge J, et al. Bias due to MEasurement Reactions In Trials to improve health (MERIT): protocol for research to develop MRC guidance. Trials 2018; 19 :653]. An updated systematic review examined whether or not measuring participants had an effect on participants' health-related behaviours relative to no-measurement controls. Three new rapid systematic reviews were conducted to identify (1) existing guidance on measurement reactivity, (2) existing systematic reviews of studies that have quantified the effects of measurement on outcomes relating to behaviour and affective outcomes and (3) experimental studies that have investigated the effects of exposure to objective measurements of behaviour on health-related behaviour. The views of 40 experts defined the scope of the recommendations in two waves of data collection during the Delphi procedure. A workshop aimed to produce a set of recommendations that were formed in discussion in groups., Results: Systematic reviews - we identified a total of 43 studies that compared interview or questionnaire measurement with no measurement and these had an overall small effect (standardised mean difference 0.06, 95% confidence interval 0.02 to 0.09; n  = 104,096, I 2  = 54%). The three rapid systematic reviews identified no existing guidance on measurement reactivity, but we did identify five systematic reviews that quantified the effects of measurement on outcomes (all focused on the question-behaviour effect, with all standardised mean differences in the range of 0.09-0.28) and 16 studies that examined reactive effects of objective measurement of behaviour, with most evidence of reactivity of small effect and short duration. Delphi procedure - substantial agreement was reached on the scope of the present recommendations. Workshop - 14 recommendations and three main aims were produced. The aims were to identify whether or not bias is likely to be a problem for a trial, to decide whether or not to collect further quantitative or qualitative data to inform decisions about if bias is likely to be a problem, and to identify how to design trials to minimise the likelihood of this bias., Limitation: The main limitation was the shortage of high-quality evidence regarding the extent of measurement reactivity, with some notable exceptions, and the circumstances that are likely to bring it about., Conclusion: We hope that these recommendations will be used to develop new trials that are less likely to be at risk of bias., Future Work: The greatest need is to increase the number of high-quality primary studies regarding the extent of measurement reactivity., Study Registration: The first systematic review in this study is registered as PROSPERO CRD42018102511., Funding: Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council-National Institute for Health Research Methodology Research Programme.

Background: Acceptability is recognised as a key concept in the development of health interventions, but there has been a lack of consensus about how acceptability should be conceptualised. The theoretical framework of acceptability (TFA) provides a potential tool for understanding acceptability. It has been proposed that acceptability measured before use of an intervention (anticipated acceptability) may differ from measures taken during and after use (experienced acceptability), but thus far this distinction has not been tested for a specific intervention. This paper 1) directly compares ratings of anticipated and experienced acceptability of a text message-based intervention, 2) explores the applicability of the TFA in a technology-based intervention, and 3) uses these findings to inform suggestions for measuring acceptability over the lifespan of technology-based health interventions., Methods: Data were obtained from a quantitative online survey assessing anticipated acceptability of the proposed text messages (n = 59) and a 12-week proof-of-concept mixed methods study assessing experienced acceptability while receiving the text messages (n = 48). Both quantitative ratings by return text message, and qualitative data from participant interviews were collected during the proof-of-concept study., Results: The quantitative analysis showed anticipated and experienced acceptability were significantly positively correlated (r s  > .4). The qualitative analysis identified four of the seven constructs of the TFA as themes (burden, intervention coherence, affective attitude and perceived effectiveness). An additional two themes were identified as having an important impact on the TFA constructs (perceptions of appropriateness and participants' role). Three suggestions are given related to the importance of appropriateness, what may affect ratings of acceptability and what to consider when measuring acceptability., Conclusions: The high correlation between anticipated and experienced acceptability was a surprising finding and could indicate that, in some cases, acceptability of an intervention can be gauged adequately from an anticipated acceptability study, prior to an expensive pilot or feasibility study. Directly exploring perceptions of appropriateness and understanding whether the acceptability described by participants is related to the intervention or the research - and is for themselves or others - is important in interpreting the results and using them to further develop interventions and predict future use.

Background: Community use of epinephrine for the treatment of anaphylaxis is low. Knowledge of rates of epinephrine use in the pre-hospital setting along with identification of barriers to its use will contribute to the development of policies and guidelines., Objectives: A search was conducted on PubMed and Embase in April 2020. Our systematic review focused on 4 domains: (1) epinephrine use in the pre-hospital setting; (2) barriers to epinephrine use in the pre-hospital setting; (3) cost evaluation and cost-effectiveness of epinephrine use; and (4) programs and strategies to improve epinephrine use during anaphylaxis., Methods: Two meta-analyses with logit transformation were conducted to: (1) calculate the pooled estimate of the rate of epinephrine use in the pre-hospital setting among cases of anaphylaxis and (2) calculate the pooled estimate of the rate of biphasic reactions among all cases of anaphylaxis., Results: Epinephrine use in the pre-hospital setting was significantly higher for children compared with adults (20.98% [95% confidence interval (CI): 16.38%, 26.46%] vs 7.17% [95% CI: 2.71%, 17.63%], respectively, P = .0027). The pooled estimate of biphasic reactions among all anaphylaxis cases was 3.92% (95% CI: 2.88%, 5.32%). Our main findings indicate that pre-hospital use of epinephrine in anaphylaxis remains suboptimal. Major barriers to the use of epinephrine were identified as low prescription rates of epinephrine autoinjectors and lack of stock epinephrine in schools, which was determined to be cost-effective. Finally, in reviewing programs and strategies, numerous studies have engineered effective methods to promote adequate and timely use of epinephrine., Conclusion: The main findings of our study demonstrated that across the globe, prompt epinephrine use in cases of anaphylaxis remains suboptimal. For practical recommendations, we would suggest considering stock epinephrine in schools and food courts to increase the use of epinephrine in the community. We recommend use of pamphlets in public areas (ie, malls, food courts, etc.) to assist in recognizing anaphylaxis and after that with prompt epinephrine administration, to avoid the rare risk of fatality in anaphylaxis cases., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: It is considered best practice to provide clear theoretical descriptions of how behaviour change interventions should produce changes in behaviour. Commissioners of the National Health Service Diabetes Prevention Programme (NHS-DPP) specified that the four independent provider organisations must explicitly describe the behaviour change theory underpinning their interventions. The nationally implemented programme, launched in 2016, aims to prevent progression to Type 2 diabetes in high-risk adults through changing diet and physical activity behaviours. This study aimed to: (a) develop a logic model describing how the NHS-DPP is expected to work, and (b) document the behaviour change theories underpinning providers' NHS-DPP interventions., Methods: A logic model detailing how the programme should work in changing diet and activity behaviours was extracted from information in three specification documents underpinning the NHS-DPP. To establish how each of the four providers expected their interventions to produce behavioural changes, information was extracted from their programme plans, staff training materials, and audio-recorded observations of mandatory staff training courses attended in 2018. All materials were coded using Michie and Prestwich's Theory Coding Scheme., Results: The NHS-DPP logic model included information provision to lead to behaviour change intentions, followed by a self-regulatory cycle including action planning and monitoring behaviour. None of the providers described an explicit logic model of how their programme will produce behavioural changes. Two providers stated their programmes were informed by the COM-B (Capability Opportunity Motivation - Behaviour) framework, the other two described targeting factors from multiple theories such as Self-Regulation Theory and Self-Determination Theory. All providers cited examples of proposed links between some theoretical constructs and behaviour change techniques (BCTs), but none linked all BCTs to specified constructs. Some discrepancies were noted between the theory described in providers' programme plans and theory described in staff training., Conclusions: A variety of behaviour change theories were used by each provider. This may explain the variation between providers in BCTs selected in intervention design, and the mismatch between theory described in providers' programme plans and staff training. Without a logic model describing how they expect their interventions to work, justification for intervention contents in providers' programmes is not clear.

Background: Some forms of chronic urticaria (CU) can be specifically attributed to a response to a definite trigger, referred to as chronic inducible urticaria (CIndU). We aimed to assess the demographics, clinical characteristics, comorbidities, natural history, and management of pediatric patients with CIndU., Methods: Over a 6-year period, children presenting to the allergy clinic at the Montreal Children's Hospital (MCH) with CIndU were prospectively recruited. CU was defined as the presence of wheals and/or angioedema, occurring for at least 6 weeks. A standardized diagnostic test was used to establish the presence of a specific form of urticaria. Resolution was defined as the absence of hives for 1 year without treatment., Results: Sixty-four patients presented with CIndU, of which 51.6% were male, with a median age of 12.5 (interquartile range 7.3, 15.9) years. Cold CU and cholinergic CU were the most common subtypes (60.3 and 41.3%, respectively). Basophil counts were undetectable in 48.4% of the cases, and C-reactive protein levels were elevated in 7.8% of patients. Of all cases, 71.4% were controlled with second-generation antihistamines. The resolution rate was of 45.3% (95% confidence interval 33.1-57.5%), based on per-protocol population within the 6-year course of the study. Resolution was more likely in patients who presented with well-controlled urticaria control test scores and elevated CD63 counts and in those suffering from thyroid comorbidity., Conclusion: The natural history of CIndU resolution in pediatric patients was relatively low and was associated with elevated CD63 levels, as well as thyroid comorbidity., (© 2021 S. Karger AG, Basel.)

There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type., Competing Interests: Declaration of Interests D.L., A.H., H.S.K., and L.B. have filed a U.S. patent application related to this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The question-behavior effect (QBE) refers to whether asking people questions can result in changes in behavior. Such changes in behavior can lead to bias in trials. This study aims to update a systematic review of randomized controlled trials investigating the QBE, in light of several large preregistered studies being published., Study Design and Setting: A systematic search for newly published trials covered 2012 to July 2018. Eligible trials randomly allocated participants to measurement vs. non-measurement control conditions or to different forms of measurement. Studies that reported health-related behavior as outcomes were included., Results: Forty-three studies (33 studies from the original systematic review and 10 new studies) compared measurement vs. no measurement. An overall small effect was found using a random effect model: standardized mean difference = 0.06 (95% CI: 0.02-0.09), n = 104,388. Statistical heterogeneity was substantial (I 2  = 54%). In an analysis restricted to studies with a low risk of bias, the QBE remained small but significant. There was positive evidence of publication bias., Conclusion: This update shows a small but significant QBE in trials with health-related outcomes but with considerable unexplained heterogeneity. Future trials with lower risk of bias are needed, with preregistered protocols and greater attention to blinding., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is now clear systematic review evidence that measurement can affect the people being measured; much of this evidence focusses on how asking people to complete a questionnaire can result in changes in behaviour. Changes in measured behaviour and other outcomes due to this reactivity may introduce bias in otherwise well-conducted randomised controlled trials (RCTs), yielding incorrect estimates of intervention effects. Despite this, measurement reactivity is not currently adequately considered in risk of bias frameworks. The present research aims to produce a set of guidance statements on how best to avoid or minimise bias due to measurement reactivity in studies of interventions to improve health, with a particular focus on bias in RCTs., Methods: The MERIT study consists of a series of systematic and rapid reviews, a Delphi study and an expert workshop to develop guidance on how to minimise bias in trials due to measurement reactivity. An existing systematic review on question-behaviour effects on health-related behaviours will be updated and three new rapid reviews will be conducted to identify (1) existing guidance on measurement reactivity; (2) systematic reviews of studies that have quantified the effects of measurement on outcomes relating to behaviour and affective outcomes in health and non-health contexts and (3) trials that have investigated the effects of objective measurements of behaviour on concurrent or subsequent behaviour itself. A Delphi procedure will be used to combine the views of experts with a view to reaching agreement on the scope of the guidance statements. Finally, a workshop will be held in autumn 2018, with the aim of producing a set of guidance statements that will form the central part of new MRC guidance on how best to avoid bias due to measurement reactivity in studies of interventions to improve health., Discussion: Our ambition is to produce MRC guidance on measurement reactions in trials which will be used by future trial researchers, leading to the development of trials that are less likely to be at risk of bias.

Background/objectives: The available evidence from randomised controlled trials suggests that vitamin B12 supplementation does not improve neurologic function in older people with marginal but not deficient Vitamin B12 status. This secondary analysis used data from the Older People and Enhanced Neurological function (OPEN) randomised controlled trial to assess whether baseline vitamin B12 status or change in vitamin B12 status over 12 months altered the effectiveness of dietary vitamin B12 supplementation on neurologic function in asymptomatic older people with depleted vitamin B12 status at study entry., Subjects/methods: Vitamin B12 status was measured as serum concentrations of vitamin B12, holotranscobalamin, homocysteine and via a composite indicator (cB12). Neurological function outcomes included eleven electrophysiological measures of sensory and motor components of peripheral and central nerve function. Linear regression analyses were restricted to participants randomised into the intervention arm of the OPEN trial (n=91)., Results: Analyses revealed an inconsistent pattern of moderate associations between some measures of baseline vitamin B12 status and some neurological responses to supplementation. The directions of effect varied and heterogeneity in effect across outcomes could not be explained according to type of neurological outcome. There was no evidence of differences in the neurological response to vitamin B12 supplementation according to change from baseline over 12 months in any indicator of B12 status., Conclusions: This secondary analysis of high-quality data from the OPEN trial provides no evidence that baseline (or change from baseline) vitamin B12 status modifies the effect of vitamin B12 supplementation on peripheral or central nerve conduction among older people with marginal vitamin B12 status. There is currently insufficient evidence of efficacy for neurological function to support population-wide recommendations for vitamin B12 supplementation in healthy asymptomatic older people with marginal vitamin B12 status.

Background: Aging is associated with a progressive decline in vitamin B-12 status. Overt vitamin B-12 deficiency causes neurologic disturbances in peripheral and central motor and sensory systems, but the public health impact for neurologic disease of moderately low vitamin B-12 status in older people is unclear. Evidence from observational studies is limited by heterogeneity in the definition of vitamin B-12 status and imprecise measures of nerve function., Objective: We aimed to determine whether vitamin B-12 status is associated with electrophysiologic indexes of peripheral or central neurologic function in asymptomatic older people with moderately low vitamin B-12 status., Design: We used a cross-sectional analysis of baseline data from the Older People and Enhanced Neurological Function study conducted in Southeast England. This trial investigated the effectiveness of vitamin B-12 supplementation on electrophysiologic indexes of neurologic function in asymptomatic older people (mean age: 80 y) with moderately low vitamin B-12 status (serum vitamin B-12 concentrations ≥107 and <210 pmol/L without anemia, n = 201). Vitamin B-12 status was assessed with the use of total vitamin B-12, holotranscobalamin, and a composite indicator of vitamin B-12 status (cB-12). Electrophysiologic measures of sensory and motor components of peripheral and central nerve function were assessed in all participants by a single observer., Results: In multivariate models, there was no evidence of an association of vitamin B-12, holotranscobalamin, or cB-12 with any nerve conduction outcome. There was also no evidence of an association of vitamin B-12 status with clinical markers of neurologic function., Conclusion: This secondary analysis of high-quality trial data did not show any association of any measure of vitamin B-12 status with either peripheral or central neurologic function or any clinical markers of neurologic function in older people with moderately low vitamin B-12 status. The results of this study are unlikely to be generalizable to a less healthy older population with more severe vitamin B-12 deficiency. This trial was registered at www.controlled-trials.com as ISRCTN54195799., (© 2016 American Society for Nutrition.)

Low vitamin B12 status is common in older people; however, its public health significance in terms of neurological manifestations remains unclear. The present systematic review evaluated the association of vitamin B12 status with neurological function and clinically relevant neurological outcomes in adults aged 50+ years. A systematic search of nine bibliographic databases (up to March 2013) identified twelve published articles describing two longitudinal and ten cross-sectional analyses. The included study populations ranged in size (n 28-2287) and mean/median age (range 65-81 years). Studies reported various neurological outcomes: nerve function; clinically measured signs and symptoms of nerve function; self-reported neurological symptoms. Studies were assessed for risk of bias, and results were synthesised qualitatively. Among the general population groups of older people, one longitudinal study reported no association, and four of seven cross-sectional studies reported limited evidence of an association of vitamin B12 status with some, but not all, neurological outcomes. Among groups with clinical and/or biochemical evidence of low vitamin B12 status, one longitudinal study reported an association of vitamin B12 status with some, but not all, neurological outcomes and three cross-sectional analyses reported no association. Overall, there is limited evidence from observational studies to suggest an association of vitamin B12 status with neurological function in older people. The heterogeneity and quality of the evidence base preclude more definitive conclusions, and further high-quality research is needed to better inform understanding of public health significance in terms of neurological function of vitamin B12 status in older people.

Microstructural white matter deficits in Autism Spectrum Disorders (ASD) have been suggested by both histological findings and Diffusion Tensor Imaging (DTI) studies, which show reduced fractional anisotropy (FA) and increased mean diffusivity (MD). However, imaging reports are generally not consistent across studies and the underlying physiological causes of the reported differences in FA and MD remain poorly understood. In this study, we sought to further characterize white matter deficits in ASD by employing an advanced diffusion imaging method, the Diffusional Kurtosis Imaging (DKI), and a two-compartment diffusion model of white matter. This model differentially describes intra- and extra-axonal white matter compartments using Axonal Water Fraction (faxon ) a measure reflecting axonal caliber and density, and compartment-specific diffusivity measures. Diagnostic utility of these measures and associations with processing speed performance were also examined. Comparative studies were conducted in 16 young male adults with High Functioning Autism (HFA) and 17 typically developing control participants (TDC). Significantly decreased faxon was observed in HFA compared to the control group in most of the major white matter tracts, including the corpus callosum, cortico-spinal tracts, and superior longitudinal, inferior longitudinal and inferior fronto-occipital fasciculi. Intra-axonal diffusivity (Daxon ) was also found to be reduced in some of these regions. Decreased axial extra-axonal diffusivity (ADextra ) was noted in the genu of the corpus callosum. Reduced processing speed significantly correlated with decreased faxon and Daxon in several tracts. faxon of the left cortico-spinal tract and superior longitudinal fasciculi showed good accuracy in discriminating the HFA and TDC groups. In conclusion, these findings suggest altered axonal microstructure in young adults with HFA which is associated with reduced processing speed. Compartment-specific diffusion metrics appear to improve specificity and sensitivity to white matter deficits in this population.

The aim of the present systematic review was to evaluate the influence of early life exposure (maternal and childhood) to peanuts and the subsequent development of sensitisation or allergy to peanuts during childhood. Studies were identified using electronic databases and bibliography searches. Studies that assessed the impact of non-avoidance compared with avoidance or reduced quantities of peanuts or peanut products on either sensitisation or allergy to peanuts, or both outcomes, were eligible. Six human studies were identified: two randomised controlled trials, two case-control studies and two cross-sectional studies. In addition, published animal and mechanistic studies, relevant to the question of whether early life exposure to peanuts affects the subsequent development of peanut sensitisation, were reviewed narratively. Overall, the evidence reviewed was heterogeneous, and was limited in quality, for example, through lack of adjustment for potentially confounding factors. The nature of the evidence has therefore hindered the development of definitive conclusions. The systematic review of human studies and narrative expert-led reviews of animal studies do not provide clear evidence to suggest that either maternal exposure, or early or delayed introduction of peanuts in the diets of children, has an impact upon subsequent development of sensitisation or allergy to peanuts. Results from some animal studies (and limited evidence from human subjects) suggest that the dose of peanuts is an important mediator of peanut sensitisation and tolerance; low doses tend to lead to sensitisation and higher doses tend to lead to tolerance.

Plasma levels of adiponectin are lower in obese and insulin-resistant subjects compared with lean and insulin-sensitive ones. Thiazolidinediones increase plasma adiponectin levels in diabetic subjects, although the mechanism of this increased plasma adiponectin has not been well studied. In the present study, we compared the plasma levels and adipose tissue expression of adiponectin in subjects with normal (NGT) and impaired glucose tolerance (IGT) and also studied the effects of metformin and pioglitazone on plasma and adipose tissue mRNA level of adiponectin in IGT subjects. IGT subjects had lower plasma adiponectin levels compared with NGT subjects, and similarly IGT subjects had lower adiponectin mRNA levels. In contrast, the increased plasma levels of adiponectin in response to pioglitazone were not associated with increased adiponectin expression in adipose tissue. Metformin did not cause any change in plasma or expression levels of adiponectin. Other adipokines were examined, and both pioglitazone and metformin decreased plasma levels of resistin in IGT subjects, and pioglitazone (but not metformin) decreased plasma levels of leptin. These data suggest that pioglitazone increases plasma adiponectin levels by posttranscriptional regulation in contrast to transcriptional regulation of adiponectin in relation to insulin sensitivity in NGT vs. IGT subjects.

Patients with insulin resistance often manifest increased intramyocellular lipid (IMCL) along with increased visceral adipose tissue. This study was designed to determine whether the insulin sensitizer drugs pioglitazone and metformin would improve glucose intolerance and insulin sensitivity by decreasing IMCL. In this study, 23 generally healthy subjects with impaired glucose tolerance were randomized to receive either pioglitazone 45 mg/day or metformin 2,000 mg/day for 10 wk. Before and after treatment, we measured insulin sensitivity and abdominal subcutaneous and visceral adipose tissue with CT scanning. In addition, muscle biopsies were performed for measurement of IMCL and muscle oxidative enzymes. After treatment with pioglitazone, 2-h glucose fell from 9.6 mmol/l (172 mg/dl) to 6.1 mmol/l (119 mg/dl), whereas there was no change in 2-h glucose with metformin. With pioglitazone treatment, there was a 65% increase in insulin sensitivity along with a 34% decrease in IMCL (both P < or = 0.002). This decrease in IMCL was not due to increased muscle lipid oxidation, as there were no changes in muscle lipid oxidative enzymes. However, pioglitazone resulted in a 2.6-kg weight gain along with a significant decrease in the visceral-to-subcutaneous adipose tissue ratio. In contrast, metformin treatment resulted in no change in insulin sensitivity, IMCL, oxidative enzymes, or adipose tissue volumes. Pioglitazone improved glucose tolerance and insulin sensitivity by reducing IMCL. This reduction in IMCL was not due to an increase in muscle lipid oxidation but to a diversion of lipid from ectopic sites into subcutaneous adipose tissue.

The 1997 World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR) report, Food, Nutrition and the Prevention of Cancer: a global perspective, has become the most authoritative statement on the topic. WCRF International has begun the process of producing its second global report on food, nutrition, physical activity, and the prevention of cancer. The process is in three stages. The first begins with the development of a suitable methodology as advised by a task force of experts. The second stage will involve the systematic collection and display of the evidence by independent review teams. The final stage will be the assessment and judgment of that evidence by an independent panel of experts responsible for the content of the report, including its conclusions and recommendations. Two major differences between this report and previous reports on the prevention of chronic diseases are that a portfolio approach to the evidence is being used in which all types of study are weighed and the process of collecting and displaying the evidence is being clearly separated from assessment and judgment. This paper outlines the methodological procedures and their development that will be applied for the second WCRF International report.

Cyclophilins (Cyps) constitute a highly conserved family of proteins present in a wide variety of organisms. Historically, Cyps were first identified by their ability to bind the immunosuppressive agent cyclosporin A (CsA) with high affinity; they later were found to have peptidyl-prolyl cis-trans isomerase (PPIase) activity, which catalyzes the folding of oligopeptides at proline-peptide bonds in vitro and may be important for protein folding in vivo. Cells of Saccharomyces cerevisiae contain at least two distinct Cyp-related PPIases encoded by the genes CYP1 and CYP2. A yeast strain (GL81) containing genomic disruptions of three known yeast PPIase-encoding genes [CYP1, CYP2 and RBP1 (for rapamycin-binding protein); Koltin et al., Mol. Cell. Biol. 11 (1991) 1718-1723] was previously constructed and found to be viable. Soluble fractions of these cells possess residual CsA-sensitive PPIase activity (2-5% of that present in wild-type cells as assayed in vitro). We have purified an approx. 18-kDa protein exhibiting PPIase activity from a soluble fraction of GL81 cells and determined that its N-terminal amino acid (aa) sequence exhibits significant homology (but nonidentity) to the Cyp1 and Cyp2 proteins. We designate the gene for this new protein, CYP3. Using a degenerate oligodeoxyribonucleotide (oligo) based on the N-terminal aa sequence, plus an internal oligo homologous to a conserved region within the portion of CYP1 and CYP2 that had been deleted in the genome, a CYP3-specific DNA fragment was generated by the polymerase chain reaction (PCR) using GL81 genomic DNA as a substrate. This PCR fragment was used as a probe to isolate CYP3 genomic and cDNA clones.(ABSTRACT TRUNCATED AT 250 WORDS)

Human interleukin-1 beta (IL-1 beta) is expressed in activated monocytes as a 31-kDa precursor protein which is processed and secreted as a mature, unglycosylated 17-kDa carboxyl-terminal fragment, despite the fact that it contains a potential N-linked glycosylation site near the NH2 terminus (-Asn7-Cys8-Thr9-). cDNA coding for authentic mature IL-1 beta was fused to the signal sequence from the Candida albicans glucoamylase gene, two amino acids downstream from the signal processing site. Upon expression in Saccharomyces cerevisiae, approximately equimolar amounts of N-glycosylated (22 kDa) and unglycosylated (17 kDa) IL-1 beta protein were secreted. The N-glycosylated yeast recombinant IL-1 beta exhibited a 5-7-fold lower specific activity compared to the unglycosylated species. The mechanism responsible for inefficient glycosylation was also studied. We found no differences in secretion kinetics or processing between the two extracellular forms of IL-1 beta. The 17-kDa protein, which was found to lack core sugars, does not result from deglycosylation of the 22-kDa protein in vivo and does not result from saturation of the glycosylation enzymatic machinery through overexpression. Alteration of the uncommon Cys8 residue in the -Asn-X-Ser/Thr-glycosylation site to Ser also had no effect. However, increasing the distance between Asn7 and the signal processing site increased the extent of core N-linked glycosylation, suggesting a reduction in glycosylation efficiency near the NH2 terminus.

A human interleukin-1 (IL-1) beta cDNA was cloned, and the region coding for the mature protein was expressed in Escherichia coli. The 17-kDa biologically active product was purified in 40% yield to apparent homogeneity, without chaotropes, from the soluble fraction of sonicated cell lysates. The recombinant IL-1 beta was characterized by amino acid analysis, NH2- and COOH-terminal sequence analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, spectroscopy, and biological assay. Specific biological activity was 4.6 X 10(8) units/mg in a co-mitogenic IL-2 induction assay using cultured EL-4 T-lymphocytes. The molar extinction coefficient was determined to be 10,300 cm-1 M-1 at 280 nm. NH2-terminal sequence analysis revealed that 70% of the product begins with the Ala corresponding to the NH2 terminus of the natural protein, while 30% begins with the following Pro. No initiator Met was observed. Both of the sulfhydryl groups are reactive to Ellman's reagent and to iodoacetamide under nonreducing conditions, indicating that the Cys residues do not form disulfide bonds. S-Carboxamidomethyl-Cys-rIL-1 beta retained biological activity in the IL-2 induction assay. Circular dichroism suggested an extensive beta sheet structure for rIL-1 beta.

The functionality of the Streptomyces lividans beta-galactosidase signal peptide to direct heterologous protein export was examined. The signal peptide plus eight amino acids of mature protein were sufficient to export not only a naturally exported protein, interleukin-1 beta, but also a naturally occurring cytoplasmic protein, Escherichia coli galactokinase. Interestingly, cells which expressed yet exported galactokinase were phenotypically Gal-. The potential use of the exported galactokinase system for the isolation and characterization of mutations within signal peptides and the export machinery of the host is discussed.

Recombinant HIV-1 reverse transcriptase (RT) was stably overproduced as a soluble protein in Escherichia coli using a double-plasmid expression system in which an RT precursor protein was expressed and processed in vivo by HIV-1 protease produced in trans. The RT thus produced consisted of an equimolar mixture of two polypeptides, p66 and p51, which were copurified to greater than 90% homogeneity and were found to share a common NH2 terminus as judged by sequence analysis of the polypeptide mixture. The observed sequence confirmed correct in vivo cleavage by protease at the protease-RT polyprotein junction to yield an NH2 terminus identical to that of genuine viral RT (M. M. Lightfoote et al. (1986) J. Virol. 60, 771-775; F. diMarzo Veronese et al. (1986) Science 231, 1289-1291). The bacterially expressed RT had a specific activity similar to that of viral RT and inhibition studies with phosphonoformate confirmed that it was indistinguishable from the viral enzyme with respect to sensitivity to this inhibitor. Polymerase activated gel analysis of the mixture indicated that p66 was associated with a higher level of RT activity than p51. RNase H activated gel analysis suggested that the purified preparation of recombinant RT was free of endogenous E. coli RNase H, and that the RNase H activity of RT was exclusively associated with the p66 polypeptide, supporting the hypothesis that the RNase H domain is located in the COOH-terminal region of the molecule.