Investigation of Active Ingredients Within Internet-Delivered Cognitive Behavioral Therapy for Depression: A Randomized Optimization Trial.

Importance: There is limited understanding of how complex evidence-based psychological interventions such as cognitive behavioral therapy (CBT) for depression work. Identifying active ingredients may help to make therapy more potent, brief, and scalable. Objective: To test the individual main effects and interactions of 7 treatment components within internet-delivered CBT for depression to investigate its active ingredients. Design, Setting, and Participants: This randomized optimization trial using a 32-condition, balanced, fractional factorial optimization experiment (IMPROVE-2) recruited adults with depression (Patient Health Questionnaire-9 [PHQ-9] score ≥10) from internet advertising and the UK National Health Service Improving Access to Psychological Therapies service. Participants were randomized from July 7, 2015, to March 29, 2017, with follow-up for 6 months after treatment until December 29, 2017. Data were analyzed from July 2018 to April 2023. Interventions: Participants were randomized with equal probability to 7 experimental factors within the internet CBT platform, each reflecting the presence vs absence of specific treatment components (activity scheduling, functional analysis, thought challenging, relaxation, concreteness training, absorption, and self-compassion training). Main Outcomes and Measures: The primary outcome was depression symptoms (PHQ-9 score). Secondary outcomes include anxiety symptoms and work, home, and social functioning. Results: Among 767 participants (mean age [SD] age, 38.5 [11.62] years; range, 18-76 years; 635 women [82.8%]), 506 (66%) completed the 6-month posttreatment follow-up. On average, participants receiving internet-delivered CBT had reduced depression (pre-to-posttreatment difference in PHQ-9 score, -7.79 [90% CI, -8.21 to -7.37]; 6-month follow-up difference in PHQ-9 score, -8.63 [90% CI, -9.04 to -8.22]). A baseline score-adjusted analysis of covariance model using effect-coded intervention variables (-1 or +1) found no main effect on depression symptoms for the presence vs absence of activity scheduling, functional analysis, thought challenging, relaxation, concreteness training, or self-compassion training (posttreatment: largest difference in PHQ-9 score [functional analysis], -0.09 [90% CI, -0.56 to 0.39]; 6-month follow-up: largest difference in PHQ-9 score [relaxation], -0.18 [90% CI, -0.61 to 0.25]). Only absorption training had a significant main effect on depressive symptoms at 6-month follow-up (posttreatment difference in PHQ-9 score, 0.21 [90% CI, -0.27 to 0.68]; 6-month follow-up difference in PHQ-9 score, -0.54, [90% CI, -0.97 to -0.11]). Conclusions and Relevance: In this randomized optimization trial, all components of internet-delivered CBT except absorption training did not significantly reduce depression symptoms relative to their absence despite an overall average reduction in symptoms. The findings suggest that treatment benefit from internet-delivered CBT probably accrues from spontaneous remission, factors common to all CBT components (eg, structure, making active plans), and nonspecific therapy factors (eg, positive expectancy), with the possible exception of absorption focused on enhancing direct contact with positive reinforcers. Trial Registration: isrctn.org Identifier: ISRCTN24117387.

Adapted Behavioural Activation for Bipolar Depression: A Randomised Multiple Baseline Case Series.

Behavioural Activation (BA) is associated with a substantial evidence base for treatment of acute unipolar depression, and has promise as an easily disseminable psychological intervention for bipolar depression. Using a randomised multiple baseline case series design we examined the feasibility and acceptability of an adapted version of BA in a U.K. outpatient sample of 12 adults with acute bipolar depression. Participants were allocated at random to a 3-8 week wait period before being offered up to 20 sessions of BA. They completed outcome measures at intake, pre- and post-treatment and weekly symptom measures across the study period. Retention in therapy was high (11/12 participants completed the target minimum number of sessions), and all participants returning acceptability measures reported high levels of satisfaction with the intervention. No therapy-related serious adverse events were reported, nor were there exacerbations in manic symptoms that were judged to be a result of the intervention. The pattern of change on outcome measures is consistent with the potential for clinical benefit; six of the nine participants with a stable baseline showed clinically significant improvement on the primary outcome measure. The findings suggest adapted BA for bipolar depression is a feasible and acceptable approach that merits further investigation.

A randomised, double-blind study investigating the relationship between early childhood trauma and the rewarding effects of morphine.

Experiences of childhood trauma (abuse and neglect) are disproportionately higher in those with opioid use disorder (OUD). Childhood trauma may affect the reinforcing and rewarding properties of opioid drugs and responses to pain, potentially via developmental changes to the endogenous opioid system. This has been supported by preclinical research, yet this has not been investigated in non-addicted humans. Physically healthy participants with either a history of severe childhood trauma or no previous history of childhood trauma attended two sessions where they received either an intramuscular active dose of morphine (0.15 mg/kg) or a very low dose control (0.01 mg/kg) in a randomised, double-blind crossover design. Sessions were held 1 week apart. Participants' physical pain threshold and tolerance were measured pre- and post-drug administration using the cold water pressor test, alongside acute subjective and behavioural responses over 2.5 h. The trauma group reported liking the effects of morphine, feeling more euphoric and wanting more of the drug over the session, as well as feeling less nauseous, dizzy, and dislike of the effects of morphine compared to the non-trauma comparison group. Morphine increased pain threshold and tolerance, yet this did not differ between the groups. Childhood trauma may therefore sensitise individuals to the pleasurable and motivational effects of opioids and reduce sensitivity to the negative effects, providing compelling evidence for individual differences in opioid reward sensitivity. This may explain the link between childhood trauma and vulnerability to OUD, with consequent implications on interventions for OUD, the prescribing of opioids, and reducing stigmas surrounding OUD.

Per-Protocol analyses produced larger treatment effect sizes than intention to treat: a meta-epidemiological study.

OBJECTIVE: To undertake meta-analysis and compare treatment effects estimated by the intention-to-treat (ITT) method and per-protocol (PP) method in randomized controlled trials (RCTs). PP excludes trial participants who are non-adherent to trial protocol in terms of eligibility, interventions, or outcome assessment. STUDY DESIGN AND SETTING: Five high impact journals were searched for all RCTs published between July 2017 to June 2019. Primary outcome was a pooled estimate that quantified the difference between the treatment effects estimated by the two methods. Results are presented as ratio of odds ratios (ROR). Meta-regression was used to explore the association between level of trial protocol non-adherence and treatment effect. Sensitivity analyses compared results with varying within-study correlations and across various study characteristics. RESULTS: Random-effects meta-analysis (N = 156) showed that PP estimates were on average 2% greater compared to the ITT estimates (ROR: 1.02, 95% CI: 1.00-1.04, P = 0.03). The divergence further increased with higher degree of protocol non-adherence. Sensitivity analyses reassured consistent results with various within-study correlations and across various study characteristics. CONCLUSION: There was evidence of larger treatment effect with PP compared to ITT analysis. PP analysis should not be used to assess the impact of protocol non-adherence in RCTs. Instead, in addition to ITT, investigators should consider randomization based casual method such as Complier Average Causal Effect (CACE).

Working memory updating training reduces state repetitive negative thinking: Proof-of-concept for a novel cognitive control training.

Repetitive negative thinking (RNT) is a proximal risk factor implicated in the onset and maintenance of common mental health problems such as depression and anxiety. Adolescence may be a key developmental window in which to target RNT and prevent the emergence of such disorders. Impairments in updating the contents of working memory are hypothesised to causally contribute to RNT, and some theorists have suggested these difficulties may be specific to the manipulation of negative information. The present study compared the effects of computerised adaptive working memory updating training (in which the task becomes more difficult as performance improves) to a non-adaptive control task in reducing levels of RNT. 124 healthy young people were randomised to 20 sessions of (i) working memory updating training using neutral stimuli, (ii) working memory updating training using negative stimuli, or (iii) non-adaptive working memory updating training. Adaptive working memory updating training using neutral, but not negative, stimuli resulted in significant improvements to working memory updating for negative material, as assessed using an unpractised task, and significant reductions in susceptibility to state RNT. These findings demonstrate proof-of-concept that working memory updating training has the potential to reduce susceptibility to episodes of state RNT.

A comparison of the effects of sudden gains and depression spikes on short- and long-term depressive symptoms in a randomized controlled trial of behavioral activation and cognitive behavioural therapy.

OBJECTIVE: The aim of this study was to examine the effects of sudden gains and depression spikes in a randomized controlled trial of cognitive behavioral therapy (CBT) and behavioral activation (BA) for depression (COBRA trial). METHOD: This is a secondary analysis of 300 adults with major depressive disorder (MDD) who received CBT (n = 156) or BA (n = 144) (Richards et al., 2016). The Patient Health Questionnaire (PHQ-9) and Structured Clinical Interview Schedule (SCID) were used to measure depression symptoms at 6-, 12-, and 18-month follow-up. RESULTS: One-hundred and ten (37%) individuals experienced sudden gains, and 77 (26%) experienced depression spikes. There were no differences in rates of gains or spikes between treatments. Individuals with sudden gains had lower PHQ-9 scores across follow-up and were less likely to meet SCID criteria than those without a sudden gain. Generalized estimating equation (GEE) models demonstrated that individuals who had a sudden gain and were in CBT had lower PHQ-9 scores at 6 and 18 months than those in BA. Conversely, individuals who had a depression spike and were in CBT had higher PHQ-9 scores across follow-up compared to those without a depression spike and also a greater chance of meeting SCID criteria for MDD at 18 months than those who received BA. CONCLUSIONS: The short- and long-term impact of discontinuous change varied by type of treatment package. Identifying strategies within treatment packages and client processes that are associated with gains and spikes may help to inform treatment planning and clinical decision-making. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Psychological therapy for mood instability within bipolar spectrum disorder: a single-arm feasibility study of a dialectical behaviour therapy-informed approach.

BACKGROUND: We sought to evaluate the acceptability of a psychological therapy programme (Therapy for Inter-episode Mood Variability in Bipolar Disorder (ThrIVe-B)) for individuals with ongoing bipolar mood instability and the feasibility and acceptability of potential trial procedures. We also evaluated the performance of clinical and process outcome measures and the extent to which the programme potentially represents a safe and effective intervention. METHOD: We conducted an open (uncontrolled) trial in which 12 individuals with a bipolar spectrum diagnosis commenced the ThrIVe-B programme after completing baseline assessments. The programme comprised 16 group skills training sessions plus individual sessions and a supporting smartphone application. Follow-up assessments were at therapy end-point and 6 months post-treatment. RESULTS: Nine participants completed treatment. Ten provided end-of-treatment data; of these, nine were satisfied with treatment. Interviews with participants and clinicians indicated that the treatment was broadly feasible and acceptable, with suggestions for improvements to content, delivery and study procedures. Exploration of change in symptoms was consistent with the potential for the intervention to represent a safe and effective intervention. CONCLUSIONS: Conducting further evaluation of this approach in similar settings is likely to be feasible, whilst patient reports and the pattern of clinical change observed suggest this approach holds promise for this patient group. Future research should include more than one study site and a comparison arm to address additional uncertainties prior to a definitive trial. TRIAL REGISTRATION: Trial Registration: ClinicalTrials.gov NCT02637401; registered 22.12.15 (retrospectively registered).

The academic outcomes of working memory and metacognitive strategy training in children: A double-blind randomized controlled trial.

Working memory training has been shown to improve performance on untrained working memory tasks in typically developing children, at least when compared to non-adaptive training; however, there is little evidence that it improves academic outcomes. The lack of transfer to academic outcomes may be because children are only learning skills and strategies in a very narrow context, which they are unable to apply to other tasks. Metacognitive strategy interventions, which promote metacognitive awareness and teach children general strategies that can be used on a variety of tasks, may be a crucial missing link in this regard. In this double-blind randomized controlled trial, 95 typically developing children aged 9-14 years were allocated to three cognitive training programmes that were conducted daily after-school. One group received Cogmed working memory training, another group received concurrent Cogmed and metacognitive strategy training, and the control group received adaptive visual search training, which better controls for expectancy and motivation than non-adaptive training. Children were assessed on four working memory tasks, reading comprehension, and mathematical reasoning before, immediately after, and 3 months after training. Working memory training improved working memory and mathematical reasoning relative to the control group. The improvements in working memory were maintained 3 months later, and these were significantly greater for the group that received metacognitive strategy training, compared to working memory training alone. Working memory training is a potentially effective educational intervention when provided in addition to school; however, future research will need to investigate ways to maintain academic improvements long term and to optimize metacognitive strategy training to promote far-transfer. A video abstract of this article can be viewed at https://youtu.be/-7MML48ZFgw.

Reducing Stress and Preventing Depression (RESPOND): Randomized Controlled Trial of Web-Based Rumination-Focused Cognitive Behavioral Therapy for High-Ruminating University Students.

BACKGROUND: Prevention of depression is a priority to reduce its global disease burden. Targeting specific risk factors, such as rumination, may improve prevention. Rumination-focused Cognitive Behavioral Therapy (RFCBT) was developed to specifically target depressive rumination. OBJECTIVE: The primary objective of this study was to test whether guided Web-based RFCBT (i-RFCBT) would prevent the incidence of major depression relative to usual care in UK university students. The secondary objective was to test the feasibility and estimated effect sizes of unguided i-RFCBT. METHODS: To address the primary objective, a phase III randomized controlled trial was designed and powered to compare high risk university students (N=235), selected with elevated worry/rumination, recruited via an open access website in response to circulars within universities and internet advertisements, randomized to receive either guided i-RFCBT (interactive Web-based RFCBT, supported by asynchronous written Web-based support from qualified therapists) or usual care control. To address the secondary objective, participants were also randomized to an adjunct arm of unguided (self-administered) i-RFCBT. The primary outcome was the onset of a major depressive episode over 15 months, assessed with structured diagnostic interviews at 3 (postintervention), 6, and 15 months post randomization, conducted by telephone, blind to the condition. Secondary outcomes of symptoms of depression and anxiety and levels of worry and rumination were self-assessed through questionnaires at baseline and the same follow-up intervals. RESULTS: Participants were randomized to guided i-RFCBT (n=82), unguided i-RFCBT (n=76), or usual care (n=77). Guided i-RFCBT reduced the risk of depression by 34% relative to usual care (hazard ratio [HR] 0.66, 95% CI 0.35 to 1.25; P=.20). Participants with higher levels of baseline stress benefited most from the intervention (HR 0.43, 95% CI 0.21 to 0.87; P=.02). Significant improvements in rumination, worry, and depressive symptoms were found in the short-to-medium term. Of the 6 modules, guided participants completed a mean of 3.46 modules (SD 2.25), with 46% (38/82) being compliant (completing ≥4 modules). Similar effect sizes and compliance rates were found for unguided i-RFCBT. CONCLUSIONS: Guided i-RFCBT can reduce the onset of depression in high-risk young people reporting high levels of worry/rumination and stress. The feasibility study argues for formally testing unguided i-RFCBT for prevention: if the observed effect sizes are robustly replicated in a phase III trial, it has potential as a scalable prevention intervention. TRIAL REGISTRATION: ISRCTN Registry ISRCTN12683436; https://www.isrctn.com/ISRCTN12683436 (Archived by WebCite at http://www.webcitation.org/77fqycyBX). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-015-1128-9.

Prospective study of biomechanical risk factors for second and third metatarsal stress fractures in military recruits.

OBJECTIVES: This prospective study investigated anatomical and biomechanical risk factors for second and third metatarsal stress fractures in military recruits during training. DESIGN: Prospective cohort study. METHODS: Anatomical and biomechanical measures were taken for 1065 Royal Marines recruits at the start of training when injury-free. Data included passive range of ankle dorsi-flexion, dynamic peak ankle dorsi-flexion and plantar pressures during barefoot running. Separate univariate regression models were developed to identify differences between recruits who developed second (n=7) or third (n=14) metatarsal stress fracture and a cohort of recruits completing training with no injury (n=150) (p<0.05). A multinomial logistic regression model was developed to predict the risk of injury for the two sites compared with the no-injury group. Multinomial logistic regression results were back transformed from log scale and presented in Relative Risk Ratios (RRR) with 95% confidence intervals (CI). RESULTS: Lower dynamic arch index (high arch) (RRR: 0.75, CI: 0.63-0.89, p<0.01) and lower foot abduction (RRR: 0.87, CI: 0.80-0.96, p<0.01) were identified as increasing risk for second metatarsal stress fracture, while younger age (RRR: 0.78, CI: 0.61-0.99, p<0.05) and later peak pressure at the second metatarsal head area (RRR: 1.19, CI: 1.04-1.35, p<0.01) were identified as risk factors for third metatarsal stress fracture. CONCLUSIONS: For second metatarsal stress fracture, aspects of foot type have been identified as influencing injury risk. For third metatarsal stress fracture, a delayed forefoot loading increases injury risk. Identification of these different injury mechanisms can inform development of interventions for treatment and prevention.

An overview of statistical methods for handling nonadherence to intervention protocol in randomized control trials: a methodological review.

OBJECTIVE: To undertake a methodological review of statistical methods used in randomized controlled trials (RCTs) for handling intervention nonadherence. STUDY DESIGN AND SETTING: Bibliographic databases were searched using predefined search terms. RESULTS: A substantive number of identified studies (56%) were excluded as they only used naive per protocol analysis for handling nonadherence. Our review included 58 articles published between 1991 and 2015. A total of 88 methodological applications were made by these studies. The two most used methods were complier average causal effect (56%) and instrumental variable (23%) predominantly with the use of maximum likelihood (ML) estimators. These alternative applications typically produced treatment effects greater than the intention-to-treat effect but as their standard errors were larger there was no statistical difference between the methods. CONCLUSION: A substantive proportion of RCTs rely on naive per protocol for handling nonadherence. Recent years have seen an increasing number of applications of more appropriate statistical methods, in particular complier average causal effect and instrumental variable methods. However, these later methods rely on strong underlying assumptions that may be vulnerable to violation. More empirical studies are needed that directly compare the usability and performance of different statistical methods for nonadherence in RCTs.

Proinsulin is stable at room temperature for 24 hours in EDTA: A clinical laboratory analysis (adAPT 3).

AIMS: Reference laboratories advise immediate separation and freezing of samples for the assay of proinsulin, which limit its practicability for smaller centres. Following the demonstration that insulin and C-peptide are stable in EDTA at room temperature for at least 24hours, we undertook simple stability studies to establish whether the same might apply to proinsulin. METHODS: Venous blood samples were drawn from six adult women, some fasting, some not, aliquoted and assayed immediately and after storage at either 4°C or ambient temperature for periods from 2h to 24h. RESULTS: There was no significant variation or difference with storage time or storage condition in either individual or group analysis. CONCLUSION: Proinsulin appears to be stable at room temperature in EDTA for at least 24h. Immediate separation and storage on ice of samples for proinsulin assay is not necessary, which will simplify sample transport, particularly for multicentre trials.

Generational change in fasting glucose and insulin among children at ages 5-16y: Modelled on the EarlyBird study (2015) and UK growth standards (1990) (EarlyBird 69).

AIM: Pre-diabetes is a state of beta-cell stress caused by excess demand for insulin. Body mass is an important determinant of insulin demand, and BMI has risen substantially over recent time. We sought to model changes in the parameters of glucose control against rising BMI over the past 25years. METHODS: Using random coefficient mixed models, we established the correlations between HbA1C, fasting glucose, fasting insulin, HOMA2-IR and BMI in contemporary (2015) children (N=307) at ages 5-16y from the EarlyBird study, and modelled their corresponding values 25years ago according to the distribution of BMI in the UK Growth Standards (1990). RESULTS: There was little change in HbA1C or fasting glucose over the 25y period at any age or in either gender. On the other hand, the estimates for fasting insulin and HOMA2-IR were substantially higher in both genders in 2015 compared with 1990. CONCLUSION: Insofar as it is determined by body mass, there has been a substantial rise in beta cell demand among children over the past 25years. The change could be detected by fasting insulin and HOMA2-IR, but not by fasting glucose or HbA1C.

Implementing multifactorial psychotherapy research in online virtual environments (IMPROVE-2): study protocol for a phase III trial of the MOST randomized component selection method for internet cognitive-behavioural therapy for depression.

BACKGROUND: Depression is a global health challenge. Although there are effective psychological and pharmaceutical interventions, our best treatments achieve remission rates less than 1/3 and limited sustained recovery. Underpinning this efficacy gap is limited understanding of how complex psychological interventions for depression work. Recent reviews have argued that the active ingredients of therapy need to be identified so that therapy can be made briefer, more potent, and to improve scalability. This in turn requires the use of rigorous study designs that test the presence or absence of individual therapeutic elements, rather than standard comparative randomised controlled trials. One such approach is the Multiphase Optimization Strategy, which uses efficient experimentation such as factorial designs to identify active factors in complex interventions. This approach has been successfully applied to behavioural health but not yet to mental health interventions. METHODS/DESIGN: A Phase III randomised, single-blind balanced fractional factorial trial, based in England and conducted on the internet, randomized at the level of the patient, will investigate the active ingredients of internet cognitive-behavioural therapy (CBT) for depression. Adults with depression (operationalized as PHQ-9 score ≥ 10), recruited directly from the internet and from an UK National Health Service Improving Access to Psychological Therapies service, will be randomized across seven experimental factors, each reflecting the presence versus absence of specific treatment components (activity scheduling, functional analysis, thought challenging, relaxation, concreteness training, absorption, self-compassion training) using a 32-condition balanced fractional factorial design (2IV7-2). The primary outcome is symptoms of depression (PHQ-9) at 12 weeks. Secondary outcomes include symptoms of anxiety and process measures related to hypothesized mechanisms. DISCUSSION: Better understanding of the active ingredients of efficacious therapies, such as CBT, is necessary in order to improve and further disseminate these interventions. This study is the first application of a component selection experiment to psychological interventions in depression and will enable us to determine the main effect of each treatment component and its relative efficacy, and cast light on underlying mechanisms, so that we can systematically enhance internet CBT. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24117387 . Registered 26 August 2014.

Four biomechanical and anthropometric measures predict tibial stress fracture: a prospective study of 1065 Royal Marines.

BACKGROUND: Tibial stress fractures (TSFs) cause a significant burden to Royal Marines recruits. No prospective running gait analyses have previously been performed in military settings. AIM: We aimed to identify biomechanical gait factors and anthropometric variables associated with increased risk of TSF. METHODS: 1065 Royal Marines recruits were assessed in week 2 of training. Bilateral plantar pressure and three-dimensional lower limb kinematics were obtained for barefoot running at 3.6 m/s, providing dynamic arch index, peak heel pressure and lower limb joint angles. Age, bimalleolar breadth, calf girth, passive hip internal/external range of motion and body mass index (BMI) were also recorded. 10 recruits who sustained a TSF during training were compared with 120 recruits who completed training injury-free using a binary logistic regression model to identify injury risk factors. RESULTS: 4 variables significantly (p<0.05) predicted increased risk of TSF (ORs and 95% CI): smaller bimalleolar width (0.73, 0.58 to 0.93), lower BMI (0.56, 0.33 to 0.95), greater peak heel pressure (1.25, 1.07 to 1.46) and lower range of tibial rotation (0.78, 0.63 to 0.96). SUMMARY: Reduced impact attenuation and ability to withstand load were implicated in tibial stress fracture risk.

Physical activity attenuates the mid-adolescent peak in insulin resistance but by late adolescence the effect is lost: a longitudinal study with annual measures from 9-16 years (EarlyBird 66).

AIMS/HYPOTHESIS: The aim of this work was to test whether the mid-adolescent peak in insulin resistance (IR) and trends in other metabolic markers are influenced by long-term exposure to physical activity. METHODS: Physical activity (7 day ActiGraph accelerometry), HOMA-IR and other metabolic markers (glucose, fasting insulin, HbA1c, lipids and BP) were measured annually from age 9 years to 16 years in 300 children (151 boys) from the EarlyBird study in Plymouth, UK. The activity level of each child was characterised, with 95% reliability, by averaging their eight annual physical activity measures. Age-related trends in IR and metabolic health were analysed by multi-level modelling, with physical activity as the exposure measure (categorical and continuous) and body fat percentage (assessed by dual-energy X-ray absorptiometry) and pubertal status (according to age at peak height velocity and Tanner stage) as covariates. RESULTS: The peak in IR at age 12-13 years was 17% lower (p < 0.001) in the more active adolescents independently of body fat percentage and pubertal status. However, this difference diminished progressively over the next 3 years and had disappeared completely by the age of 16 years (e.g. difference was -14% at 14 years, -8% at 15 years and +1% at 16 years; 'physical activity × age(2), interaction, p < 0.01). Triacylglycerol levels in girls (-9.7%, p = 0.05) and diastolic blood pressure in boys (-1.20 mmHg, p = 0.03) tended to be lower throughout adolescence in the more active group. CONCLUSIONS/INTERPRETATION: Our finding that physical activity attenuates IR during mid-adolescence may be clinically important. It remains to be established whether the temporary attenuation in IR during this period has implications for the development of diabetes in adolescence and for future metabolic health generally.

Adiposity, chronic inflammation, and the prepubertal decline of sex hormone binding globulin in children: evidence for associations with the timing of puberty (Earlybird 58).

BACKGROUND: The regulation and role of SHBG in children are poorly defined. Here we investigated whether adiposity-related mechanisms regulate SHBG and whether SHBG levels are associated with the age of puberty. METHODS: Longitudinal modelling of annual physiological and endocrine measurements from age 5 to 15 years in a cohort of 347 Plymouth schoolchildren. RESULTS: SHBG levels were highest at age 5 years and then declined. Mean (SE) SHBG levels were higher in boys than girls at age 5 years [mean (SE) difference 7.68 (3.80) nmol/L; P = .045] but lower in boys by age 15 years [difference 12.19 (3.4) nmol/L; P < .001]. SHBG correlated inversely with adiposity [body mass index SD score (BMI SDS)], insulin, IGF-I, C-reactive protein (CRP), and leptin and positively with adiponectin but not with dehydroepiandrosterone sulphate, androstenedione, or T. In linear mixed models, five adiposity-related covariates (insulin, leptin, adiponectin, IGF-I, and CRP) all exerted significant main effects on SHBG (boys P = .04 to < .001; girls P = .007 to < .001). However, the further addition of BMI SDS rendered the effects of leptin, insulin, and adiponectin nonsignificant, whereas CRP and IGF-I remained significant. In separate models, the individual effects on SHBG of insulin, leptin, IGF-I, and adiponectin, but not CRP, were displaced by BMI SDS. Finally, in linear regression, BMI SDS little affected R(2) resulting from the five adiposity-related signals. Girls with lower SHBG levels at age 5 years reached Tanner stage 2 earlier, tended to have earlier LH secretion, and earlier age at peak height velocity and menarche. In contrast, boys with lower SHBG levels at age 5 years reached Tanner stage 2 earlier, but there were no relationships between SHBG and earlier onset of LH secretion or age at peak height velocity. CONCLUSIONS: Adiposity-related endocrine mechanisms and chronic inflammation were associated with the prepubertal decline of SHBG, and lower SHBG levels anticipated earlier puberty. These findings may be relevant to the occurrence of earlier puberty in recent decades.

A multilevel analysis of the determinants of high-risk sexual behaviour in sub-Saharan Africa.

A number of authors have identified multiple concurrent sexual partnerships by both men and women to lie at the root of the HIV/AIDS epidemic in sub-Saharan Africa. This study applies multilevel models to Demographic and Health Survey data collected during 2003-2008 in 20 sub-Saharan African countries to examine the influence of social and cultural context on involvement with multiple sexual partnerships in the region, above and beyond the effects of individual characteristics. The findings provide support for the ecological argument that health behaviours are shaped and determined by societal conditions, in addition to the effects of individual and household characteristics. Involvement with multiple sex partners is most prevalent in societies in which sexual norms are widely permissive and where polygyny is common. Individual autonomy is substantial and attitudes towards sexuality are more liberal among men and women who live in communities in which sexual norms are widely permissive. Men and women who are most likely to have multiple sex partners in the sub-Saharan region are those who initiated sexual activity earlier and those who have the individual attributes (e.g. young age, urban residence, education, media exposure and working for cash and away from home) that bring to them more rights and/or decision-making autonomy, but not necessarily more financial resources and economic security (mostly among women). On the other hand, involvement with multiple partners is determined by cultural norms (i.e. permissive sexual norms) and social change (i.e. mass education, expansion of cash employment). The findings suggest a number of opportunities for more effective policy and programmatic responses to curb the prevalence of multiple partnerships in sub-Saharan Africa.