Between-study Differences Research Articles

Technical and vocational education and training (TVET) for young people in low- and middle-income countries: a systematic review and meta-analysis

The world is facing a worsening youth employment crisis. In response, technical and vocational education and training (TVET) is back on the development agenda after years of neglect. This systematic review examined the evidence from studies evaluating the impacts of TVET interventions for young people in low- and middle-income countries (LMICs). The 26 included studies evaluated 20 different interventions, predominantly from Latin America. Meta-analyses of the effectiveness of TVET on five outcome measure categories were conducted. The overall mean effects on overall paid employment, formal employment, and monthly earnings were small, positive, and significant; however, significant heterogeneity was observed. Moderator analysis was performed in an attempt to explain between-study differences in effects. The overall paucity of research in this area, together with specific gaps and methodological limitations, affirm the need for strengthening the evidence base. Implications for policy, practice and research are discussed.

Value of Preoperative Ultrasound-Guided Axillary Lymph Node Biopsy for Preventing Completion Axillary Lymph Node Dissection in Breast Cancer: A Systematic Review and Meta-Analysis

This meta-analysis was designed to evaluate the utility of preoperative axillary ultrasound combined with US-guided lymph node biopsy if indicated (AUS ± biopsy), in terms of staging the axilla and preventing two-step axillary surgery in the form of sentinel node biopsy (SNB) followed by completion axillary lymph node (ALN) dissection. We systematically searched electronic databases for studies that addressed preoperative assessment of ALN status by AUS ± biopsy. A pooled estimate was calculated for the false-negative rate (FNR) of AUS ± biopsy (defined as the proportion of women with a negative AUS ± biopsy result subsequently proven to have a positive axilla) and sensitivity (defined as the proportion of women with a positive AUS ± biopsy result among all women with a tumor positive axilla). The pooled FNR was 25 % (95 % confidence interval [CI] = 24-27) and the pooled sensitivity was 50 % (95 % CI = 43-57). There was substantial heterogeneity across studies for both FNR (I (2) = 69.42) and sensitivity (I (2) = 93.25), which was not explained by between-study differences in biopsy technique, mean/median tumor size, biopsy indication, or study design. Sensitivity was increased in studies with a high prevalence of ALN metastases. Preoperative axillary ultrasound-guided biopsy is a useful step in the process of axillary staging. Approximately 50 % of women with axillary involvement can be identified preoperatively. Still, one in four women with an ultrasound-guided biopsy-"proven" negative axilla has a positive SNB.

Carbohydrate Supplementation and Prolonged Intermittent High-Intensity Exercise in Adolescents

In the last decade, research has begun to investigate the efficacy of carbohydrate supplementation for improving aspects of physical capacity and skill performance during sport-specific exercise in adolescent team games players. This research remains in its infancy, and further study would be beneficial considering the large youth population actively involved in team games. Literature on the influence of carbohydrate supplementation on skill performance is scarce, limited to shooting accuracy in adolescent basketball players and conflicting in its findings. Between-study differences in the exercise protocol, volume of fluid and carbohydrate consumed, use of prior fatiguing exercise and timing of skill tests may contribute to the different findings. Conversely, initial data supports carbohydrate supplementation in solution and gel form for improving intermittent endurance running capacity following soccer-specific shuttle running. These studies produced reliable data, but were subject to limitations including lack of quantification of the metabolic response of participants, limited generalization of data due to narrow participant age and maturation ranges, use of males and females within the same sample and non-standardized pre-exercise nutritional status between participants. There is a lack of consensus regarding the influence of frequently consuming carbohydrate-containing products on tooth enamel erosion and the development of obesity or being overweight in adolescent athletes and non-athletes. These discrepancies mean that the initiation or exacerbation of health issues due to frequent consumption of carbohydrate-containing products by adolescents cannot be conclusively refuted. Coupled with the knowledge that consuming a natural, high-carbohydrate diet -3-8 hours before exercise can significantly alter substrate use and improve exercise performance in adults, a moral and ethical concern is raised regarding the direction of future research in order to further knowledge while safeguarding the health and well-being of young participants. It could be deemed unethical to continue study into carbohydrate supplementation while ignoring the potential health concerns and the possibility of generating similar performance enhancements using natural dietary interventions. Therefore, future work should investigate the influence of pre-exercise dietary intake on the prolonged intermittent, high-intensity exercise performance of adolescents. This would enable quantification of whether pre-exercise nutrition can modulate exercise performance and, if so, the optimum dietary composition to achieve this. Research could then combine this knowledge with ingestion of carbohydrate-containing products during exercise to facilitate ethical and healthy nutritional guidelines for enhancing the exercise performance of adolescents. This article addresses the available evidence regarding carbohydrate supplementation and prolonged intermittent, high-intensity exercise in adolescent team games players. It discusses the potential health concerns associated with the frequent use of carbohydrate-containing products by adolescents and how this affects the research ethics of the field, and considers directions for future work.

COST-EFFECTIVENESS OF COMPUTED TOMOGRAPHY COLONOGRAPHY IN COLORECTAL CANCER SCREENING: A SYSTEMATIC REVIEW

The European Code Against Cancer recommends individuals aged ≥ 50 should participate in colorectal cancer screening. CT-colonography (CTC) is one of several screening tests available. We systematically reviewed evidence on, and identified key factors influencing, cost-effectiveness of CTC screening. PubMed, Medline, and the Cochrane library were searched for cost-effectiveness or cost-utility analyses of CTC-based screening, published in English, January 1999 to July 2010. Data was abstracted on setting, model type and horizon, screening scenario(s), comparator(s), participants, uptake, CTC performance and cost, effectiveness, ICERs, and whether extra-colonic findings and medical complications were considered. Sixteen studies were identified from the United States (n = 11), Canada (n = 2), and France, Italy, and the United Kingdom (1 each). Markov state-transition (n = 14) or microsimulation (n = 2) models were used. Eleven considered direct medical costs only; five included indirect costs. Fourteen compared CTC with no screening; fourteen compared CTC with colonoscopy-based screening; fewer compared CTC with sigmoidoscopy (8) or fecal tests (4). Outcomes assessed were life-years gained/saved (13), QALYs (2), or both (1). Three considered extra-colonic findings; seven considered complications. CTC appeared cost-effective versus no screening and, in general, flexible sigmoidoscopy and fecal occult blood testing. Results were mixed comparing CTC to colonoscopy. Parameters most influencing cost-effectiveness included: CTC costs, screening uptake, threshold for polyp referral, and extra-colonic findings. Evidence on cost-effectiveness of CTC screening is heterogeneous, due largely to between-study differences in comparators and parameter values. Future studies should: compare CTC with currently favored tests, especially fecal immunochemical tests; consider extra-colonic findings; and conduct comprehensive sensitivity analyses.

474P - Phase 1 Study of the Selective Akt Inhibitor MK-2206 in Japanese Patients with Advanced Solid Tumors

ABSTRACT Background The AKT pathway, which mediates cell proliferation, survival, and angiogenesis, is commonly dysregulated in cancer. MK-2206 is an orally active, allosteric AKT 1/2 inhibitor with wide preclinical activity. This open-label, nonrandomized study investigated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of MK-2206 in Japanese patients with solid tumors who were refractory to standard therapy. Methods Patients received once every other day (qod) or once-weekly (qw) doses of MK-2206 in 28-day treatment cycles, with a 1-week drug holiday following Cycle 1. Dose-limiting toxicities (DLTs) were evaluated during Cycle 1, with cohorts of 3, 6, or 9 patients, depending on the dose studied and adverse events (AEs) experienced by patients. Overall antitumor activity was assessed at designated time points every other treatment cycle after initial screening, following RECIST guidelines. Results Treated patients (N = 24; male/female: 10/14; median age: 57 yrs; ECOG PS 0/1: 16/8) received MK-2206 45 mg or 60 mg qod (n = 12) and 135 mg or 200 mg qw (n = 12). Grade 3 rash was the DLT at both 60 mg qod (1 of 9 patients) and 200 mg qw (3 of 9 patients). Common reversible drug-related toxicities included rash (83.3%), stomatitis (58.3%), pyrexia (58.3%), and hyperglycemia (54.2%). MK-2206 terminal half-life did not differ from non-Japanese patients (69–80 h vs 60–90 h), but Cmax, AUC, and Ctroughwere generally higher in Japanese patients (1.5- to 1.7-fold). ANOVA models that adjusted for body weight suggested that PK differences could be mostly attributed to between-study body weight differences. PD assays demonstrated inhibition of blood pAKT at Day 15 (27.6%–61.4%). Modest antitumor activity was observed with a best response of stable disease (SD) lasting longer than 42 weeks; patients who achieved SD had various diagnoses, including neuroendocrine carcinoma and esophageal cancer. Conclusion MK-2206 at doses up to 60 mg or 200 mg has a long terminal half-life and can be safely administered on either qod or qw dosing schedules. Higher exposures were observed in Japanese patients, but this could be explained by body weight differences. Disclosure All authors have declared no conflicts of interest.

Adolescent Time Use Clusters: A Systematic Review

Recent research suggests that patterns or clusters of time use may affect health in ways that cannot be explained by the effect of individual behaviors alone. The aim of this research was to systematically review the literature examining adolescent time use clusters and associated correlates. Systematic searches of six online databases for relevant observational studies were conducted. At least two authors reviewed abstract and full text selection meeting eligibility criteria. Included studies were quality scored, had data extracted, and cluster types and cluster associations interpreted. Nineteen studies were identified for inclusion, and 18 of them investigated cluster-correlate associations. Twenty-nine cluster types were identified, characterized by both individual (e.g., church) and co-occurring behaviors (e.g., physical activity and screen [technoactive]). Nineteen correlate categories were identified (e.g., socioeconomic and weight status). Consistent patterns of cluster-correlate association were found. For example, the technoactive cluster type is more likely to be male and to have low school orientation. Despite the between-study differences, consistent cluster and cluster-correlate patterns were still evident. Cluster analysis of adolescent time use behaviors appears to be an emerging and useful classification technique, one which may have implications for targeted health-related interventions.

Pharmacogenetics of pain and analgesia

Pain severity ratings and the analgesic dosing requirements of patients with apparently similar pain conditions may differ considerably between individuals. Contributing factors include those of genetic and environmental origin with epigenetic mechanisms that enable dynamic gene-environment interaction, more recently implicated in pain modulation. Insight into genetic factors underpinning inter-patient variability in pain sensitivity has come from rodent heritability studies as well as familial aggregation and twin studies in humans. Indeed, more than 350 candidate pain genes have been identified as potentially contributing to heritable differences in pain sensitivity. A large number of genetic association studies conducted in patients with a variety of clinical pain types or in humans exposed to experimentally induced pain stimuli in the laboratory setting, have examined the impact of single-nucleotide polymorphisms in various target genes on pain sensitivity and/or analgesic dosing requirements. However, the findings of such studies have generally failed to replicate or have been only partially replicated by independent investigators. Deficiencies in study conduct including use of small sample size, inappropriate statistical methods and inadequate attention to the possibility that between-study differences in environmental factors may alter pain phenotypes through epigenetic mechanisms, have been identified as being significant.

A meta-analysis of correlated behaviours with implications for behavioural syndromes: mean effect size, publication bias, phylogenetic effects and the role of mediator variables

In evolutionary and behavioural ecology, increasing attention is being paid to the fact that functionally distinct behaviours are often not independent from each other. Such phenomenon is labelled as behavioural syndrome and is usually demonstrated by phenotypic correlations between behaviours like activity, exploration, aggression and risk-taking across individuals in a population. However, published studies disagree on the strength, and even on the existence of such relationships. To make general inferences from this mixed evidence, we quantitatively reviewed the literature using modern meta-analytic approaches. Based on a large dataset, we investigated the overall relationship between behaviours that are expected to form a syndrome and tested which factors can mediate heterogeneities in study outcomes. The average strength of the phenotypic correlation between behaviours was weak; we found no effect of the phylogeny of species but did observe significant publication bias. However, even accounting for this bias, the mean effect size was positive and statistically different from zero (r = 0.198). Effect sizes showed considerable heterogeneity within species, implying a role for population-specific adaptation to environmental factors and/or between-study differences in research design. There was a significant positive association between absolute effect size and repeatability of behaviours, suggesting that within-individual variation of behavioural traits can set up an upper limit for the strength of the detected phenotypic correlations. Moreover, spatial overlap between the contexts in which different behaviours were assayed increased the magnitude of the association. The small effect size for the focal relationship implies that a huge sample size would be required to demonstrate a correlation between behaviours with sufficient statistical power, which is fulfilled only in very few studies. This suggests that behavioural syndromes often remain undetected and unpublished. Collectively, our meta-analysis revealed a number of points that might be worth to consider in the future study of behavioural syndromes.

Mortality in diabetes compared with previous cardiovascular disease: A gender-specific meta-analysis

Diabetes has been described as a cardiovascular disease (CVD) risk equivalent. There is evidence, however, that its impact may differ between women and men. For this reason, our study aimed to obtain gender-specific hazard ratios (HRs) comparing diabetes and CVD patients in terms of all-cause, CVD and coronary heart disease (CHD) mortality. Individuals with diabetes (without CVD) and those with CVD (without diabetes) were examined through a systematic review of articles that provided gender-specific HRs for mortality. Searches included Medline, Embase and the Cochrane Library database (from January 1998 to December 2009) and exploded MeSH headings [cardiovascular diseases, risk, epidemiologic studies, case-control studies, cohort studies, mortality, outcome assessment (health care), sex factors, survival analysis and diabetes mellitus, type 2]. Two observers selected and reviewed the studies and hierarchical Bayesian random-effects models were used to combine HRs, thereby accommodating any between-study differences through inclusion of a between-study variance in HRs. Out of 5425 studies, nine were relevant (0.17%). CVD and CHD mortality in men was lower for diabetes alone (CVD mortality HR: 0.82, 95% CrI: 0.69-0.98; CHD mortality HR: 0.73, 95% CrI: 0.65-0.83). In contrast, rates appeared to be higher in women with diabetes alone (CVD mortality HR: 1.29, 95% CrI: 0.79-2.26; CHD mortality HR: 1.28, 95% CrI: 0.75-2.22), although wide credible intervals precluded any definitive conclusions. All-cause mortality in men was similar for diabetes and previous CVD (HR: 1.02, 95% CrI: 0.93-1.12) whereas, among women, it was at least as high and possibly higher for diabetes alone (HR: 1.25, 95% CrI: 0.89-1.76). Compared with previous CVD, diabetes alone leads to lower CVD and CHD mortality risk in men, and similar all-cause mortality. In contrast, although further studies are needed, it is possible that diabetes leads to higher CVD, CHD and all-cause mortality in women.

Epicatechin ingested via cocoa products reduces blood pressure in humans: a nonlinear regression model with a Bayesian approach

Four meta-analyses of randomized controlled trials (RCTs) based on the classical random-effects model showed that cocoa consumption can reduce systolic blood pressure (SBP) and diastolic blood pressure (DBP). Because epicatechin is suggested to be responsible for the treatment effect, changes in blood pressure should depend on the dose of ingested epicatechin, which may explain the between-study differences. The objective was to quantify the effect of epicatechin ingested via cocoa products on changes in SBP and DBP. A nonlinear meta-regression model was chosen to investigate the impact of the epicatechin dose on changes in SBP and DBP. A Bayesian approach using Markov chain Monte Carlo methods was applied for an appropriate treatment of the nonlinearity. Data from 16 RCTs on SBP and 15 RCTs on DBP were included. The dose of epicatechin ingested via cocoa products influenced the changes in SBP and DBP. The asymptotic limit for the reduction was estimated at -4.6 mm Hg (95% CI: -5.4, -3.9 mm Hg) for SBP and at -2.1 mm Hg (95% CI: -2.7, -1.6 mm Hg) for DBP. An intake of 25 mg epicatechin/d led to a mean reduction of -4.1 mm Hg (95% CI: -4.6, -3.6 mm Hg) in SBP and of -2.0 mm Hg (95% CI: -2.4, -1.5 mm Hg) in DBP. Blood pressure reduction by consumption of cocoa products depends on the dose of ingested epicatechin, which explains most of the between-study differences in classical meta-analyses. Similar effects may be achieved by consumption of other foods that are also rich in epicatechin.

Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis.

Mesothelin is currently considered the best available serum biomarker of malignant pleural mesothelioma. To examine the diagnostic accuracy and use of serum mesothelin in early diagnosis, we performed an individual patient data (IPD) meta-analysis. The literature search identified 16 diagnostic studies of serum mesothelin, measured with the Mesomark enzyme-linked immunosorbent assay. IPD of 4,491 individuals were collected, including several control groups and 1,026 patients with malignant pleural mesothelioma. Mesothelin levels were standardized for between-study differences and age, after which the diagnostic accuracy and the factors affecting it were examined with receiver operating characteristic (ROC) regression analysis. At a common diagnostic threshold of 2.00 nmol/L, the sensitivities and specificities of mesothelin in the different studies ranged widely from 19% to 68% and 88% to 100%, respectively. This heterogeneity can be explained by differences in study population, because type of control group, mesothelioma stage, and histologic subtype significantly affected the diagnostic accuracy. The use of mesothelin in early diagnosis was evaluated by differentiating 217 patients with stage I or II epithelioid and biphasic mesothelioma from 1,612 symptomatic or high-risk controls. The resulting area under the ROC curve was 0.77 (95% CI, 0.73 to 0.81). At 95% specificity, mesothelin displayed a sensitivity of 32% (95% CI, 26% to 40%). In patients suspected of having mesothelioma, a positive blood test for mesothelin at a high-specificity threshold is a strong incentive to urge further diagnostic steps. However, the poor sensitivity of mesothelin clearly limits its added value to early diagnosis and emphasizes the need for further biomarker research.

Predictors of patient cognitive therapy skills and symptom change in two randomized clinical trials: the role of therapist adherence and the therapeutic alliance.

Previous research has found that therapist adherence to concrete, problem-focused cognitive therapy (CT) techniques predicts depressive symptom change (e.g., Feeley, DeRubeis, & Gelfand, 1999). More recently, Strunk, DeRubeis, Chui, and Alvarez (2007) demonstrated that in-session evidence of patients' use of CT skills was related to a lower rate of relapse in the year following CT for depression. The current investigation attempts to integrate and extend these findings within 2 separate samples of patients and therapists. Drawing from the CT samples (N = 105, mean age = 40 years, female = 62%, White = 82%) of 2 published randomized clinical trials of depression treatment, we conducted analyses to examine whether therapist adherence to concrete CT techniques (Collaborative Study Psychotherapy Rating Scale) and the quality of the therapeutic alliance (Working Alliance Inventory) predict patients' use of CT skills (Performance of Cognitive Therapy Strategies) and subsequent Beck Depression Inventory symptom change. Results indicated a differential pattern of prediction in the 2 samples. In one, CT techniques exhibited a stronger association with patient CT skills and symptom change than did the alliance, whereas the reverse pattern emerged in the second sample. A baseline symptom severity × CT techniques interaction indicated that between-study differences in intake depression severity might in part explain the process-outcome differences. The present findings suggest that the nature of the therapy sample examined may moderate process-outcome findings in psychotherapy research. The implications of these results and directions for future research are discussed.

PROTOCOL: Systematic Review Protocol: Later School Start Times for Supporting the Education, Health and Well‐being of High School Students

PROTOCOL: Systematic Review Protocol: Later School Start Times for Supporting the Education, Health and Well‐being of High School Students

P3-07-12: Value of Preoperative Ultrasound-Guided Axillary Lymph Node Biopsy for Preventing Futile Sentinel Node Procedures in Breast Cancer: A Systematic Review and Meta-Analysis.

Abstract Purpose: Women affected with invasive breast cancer generally undergo sentinel node biopsy (SNB) of the axilla, which is followed by axillary dissection if lymph node metastases are found. This systematic review and meta-analysis aims to evaluate the utility of preoperative axillary ultrasound-guided needle biopsy in terms of staging the axilla and preventing futile SNB. Methods: We systemically searched Pubmed, Embase and Cochrane through March 14, 2011, for studies addressing preoperative assessment of axillary lymph node (ALN) status by axillary ultrasound and biopsy. Eligible studies had to report on biopsy indication and method, and true and false positive and negative outcomes. A pooled estimate was calculated for prevalence of futile SNB (defined as the proportion of patients needing secondary ALN dissection after a negative axillary ultrasound and biopsy) and sensitivity (defined as the proportion of patients with ALN involvement detected by axillary ultrasound and biopsy). Results: Twenty-three studies were included which reported on a total of 6205 procedures. The pooled prevalence of futile SNB was 25% (95% CI = 23% to 27%) and the pooled sensitivity was 51% (95% CI = 43% to 59%). There was substantial heterogeneity across studies for both futile SNB prevalence (I2 = 60.5) and sensitivity (I2 = 93.3), which could not be explained by between-study differences in biopsy technique, inclusion criteria, biopsy indication or study design. Sensitivity was increased in studies with a high prevalence of axillary lymph node metastases. Conclusion: Preoperative axillary ultrasound guided biopsy is a useful step in the process of axillary staging as around fifty percent of breast cancer patients with axillary involvement can be identified pre-operatively and are spared a two step surgical intervention. Still, one in four women with a US biopsy ‘proven’ negative axilla have ALN involvement on SNB and need to undergo completion axillary dissection. New techniques may be able to reduce the prevalence of futile SNB. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-12.

Functional Heterogeneity of Macaque Lateral Intraparietal Neurons

The macaque lateral intraparietal area (LIP) has been implicated in many cognitive processes, ranging from saccade planning and spatial attention to timing and categorization. Importantly, different research groups have used different criteria for including LIP neurons in their studies. While some research groups have selected LIP neurons based on the presence of memory-delay activity, other research groups have used other criteria such as visual, presaccadic, and/or memory activity. We recorded from LIP neurons that were selected based on spatially selective saccadic activity but regardless of memory-delay activity in macaque monkeys. To test anticipatory climbing activity, we used a delayed visually guided saccade task with a unimodal schedule of go-times, for which the conditional probability that the go-signal will occur rises monotonically as a function of time. A subpopulation of LIP neurons showed anticipatory activity that mimicked the subjective hazard rate of the go-signal when the animal was planning a saccade toward the receptive field. A large subgroup of LIP neurons, however, did not modulate their firing rates according to the subjective hazard function. These non-anticipatory neurons were strongly influenced by salient visual stimuli appearing in their receptive field, but less so by the direction of the impending saccade. Thus, LIP contains a heterogeneous population of neurons related to saccade planning or visual salience, and these neurons are spatially intermixed. Our results suggest that between-study differences in neuronal selection may have contributed significantly to the findings of different research groups with respect to the functional role of area LIP.

Discordance in National Estimates of Hypertension Among Young Adults

In the United States, where coronary heart disease (CHD) is the leading cause of mortality, CHD risk assessment is a priority and accurate blood pressure (BP) measurement is essential. Hypertension estimates in the National Longitudinal Study of Adolescent Health (Add Health), Wave IV (2008)-a nationally representative field study of 15,701 participants aged 24-32-was referenced against NHANES (2007-2008) participants of the same age. We examined discordances in hypertension, and estimated the accuracy and reliability of blood pressure in the Add Health study. Hypertension rates (BP: ≥ 140/90 mm Hg) were higher in Add Health compared with NHANES (19% vs. 4%), but self-reported history was similar (11% vs. 9%) among adults aged 24-32. Survey weights and adjustments for differences in participant characteristics, examination time, use of antihypertensive medications, and consumption of food/caffeine/cigarettes before blood pressure measurement had little effect on between-study differences in hypertension estimates. Among Add Health participants interviewed and examined twice (full and abbreviated interviews), blood pressure was similar, as was blood pressure at the in-home and in-clinic examinations conducted by NHANES III (1988-1994). In Add Health, there was minimal digit preference in blood pressure measurements; mean bias never exceeded 2 mm Hg; and reliability (estimated as intraclass correlation coefficients) was 0.81 and 0.68 for systolic and diastolic BPs, respectively. The proportion of young adults in NHANES reporting a history of hypertension was twice that with measured hypertension, whereas the reverse was found in Add Health. Between-survey differences were not explained by digit preference, low validity, or reliability of Add Health blood pressure data, or by salient differences in participant selection, measurement context, or interview content. The prevalence of hypertension among Add Health Wave IV participants suggests an unexpectedly high risk of cardiovascular disease among US young adults and warrants further scrutiny.

Diurnal variation in the salivary melatonin responses to exercise: relation to exercise-mediated tachycardia

Salivary melatonin concentration is an established marker of human circadian rhythmicity. It is thought that melatonin is relatively robust to the masking effects of exercise. Nevertheless, the extent and even the direction of exercise-related change is unclear, possibly due to between-study differences in the time of day exercise is completed. Therefore, we aimed to compare melatonin responses between morning and afternoon exercise, and explore the relationships between exercise-related changes in melatonin and heart rate. At 08:00 and 17:00hours, seven male subjects (mean±SD age, 27±5years) completed 30min of cycling at 70% peak oxygen uptake followed by 30min of rest. Light intensity was maintained at ~150lx. Salivary melatonin (ELISA) and heart rate were measured at baseline, 15min during exercise, immediately post-exercise and following 30min recovery. Melatonin was ≈15pgml(-1) higher in the morning trials compared with the afternoon (P=0.030). The exercise-related increase in melatonin was more pronounced (P=0.024) in the morning (11.1±8.7pgml(-1)) than in the afternoon (5.1±5.7pgml(-1)). The slope of the heart rate-melatonin relationship was significantly (P=0.020) steeper in the morning (0.12pgml(-1)beats(-1)min(-1)) than in the afternoon (0.03pgml(-1)beats(-1)min(-1)). In conclusion, we report for the first time that the masking effect of moderate-intensity exercise on melatonin is approximately twice as high in the morning than the afternoon. The much steeper relationship between heart rate and melatonin changes in the morning raises the possibility that time of day alters the relationships between exercise-mediated sympathetic nervous activity and melatonin secretion.

Lung volume and pharyngeal stability in sleeping humans: the knee bone is connected to the thigh bone

in 1988 the Journal of Applied Physiology published a seminal article by William Van de Graaff ([13][1]) demonstrating that inflation of the thorax in anesthetized dogs decreased upper airway resistance independently of upper airway muscle activity. The mechanism underlying this effect was shown to

Does Parental Education have a Moderating Effect on the Genetic and Environmental Influences of General Cognitive Ability in Early Adulthood?

Hereditary influences account for a substantial proportion of the variance in many cognitive abilities. However, there is increasing recognition that the relative importance of genetic and environmental influences may vary across different socioeconomic levels. The overall goal of the present study was to examine whether parental education has a moderating effect on genetic and environmental influences of general cognitive ability in early adulthood (age 19.6 +/- 1.5). Participants were 5,955 male twins from the Vietnam Era Twin (VET) Registry. Significant effects of parental education on mean level of general cognitive ability scores were found, but a model without moderating effects of parental education on genetic or environmental influences on cognitive scores proved to be the best fitting model. Some, but not all, previous studies have found significant moderating effects; however, no consistent pattern emerged that could account for between-study differences regarding moderating effects on genetic and environmental influences.

Is type 2 diabetes an amyloidosis and does it really matter (to patients)?

Degeneration of pancreatic islet beta cells is increasingly ranked as a key disease mechanism in type 2 diabetes [1, 2], but it is not entirely clear what the underlying molecular processes might be and how they attack insulin production, ultimately causing type 2 diabetes [3, 4]. However, recent studies based on quantitative measurements in post mortem pancreatic tissue from humans with type 2 diabetes have reinforced earlier observations concerning the probable role of lowered beta cell numbers [5, 6] and pointed to a linkage between beta cell disappearance and beta cell apoptosis [7, 8]. ‘Glucotoxicity’ and ‘lipotoxicity’ are widely discussed possible causes of beta cell failure, but both are thought to exert their effects only after significant metabolic deterioration and functional islet impairment are already well underway [9] and so cannot be the prime movers. So what might the initiating insults be? Recent data from genome-wide association studies have highlighted the impact of particular alleles of certain susceptibility genes, giving further support to the idea that beta cell abnormalities are fundamental in the pathogenesis of this disease [4]. Some of these alleles encode variants of certain beta cell proteins linked to insulin production and/or secretion, and can hasten the development of functional islet deterioration and diabetes onset in carriers [1, 2]. However, currently identified alleles do not provide an explanation for most cases of ‘common or garden’ type 2 diabetes [10]. Against this background, Zraika et al. in this issue of Diabetologia have reviewed aspects of another, underappreciated phenomenon, which could well initiate beta cell degeneration in type 2 diabetes [11]. As they point out, it has long been known that many [8, 12–14] or perhaps most [15, 16] type 2 diabetic patients are found to have islet amyloid deposits adjacent to their beta cells [17] when post mortem pancreatic tissue is examined histologically. Although islet amyloid has also been reported to occur in numbers of humans not known to have diabetes, the author of a major study cautioned that ‘nondiabetic persons with hyaline islets may represent individuals with undiagnosed or potential diabetes’ [18]. Varying sensitivities of different histological methods may also have contributed to betweenstudy differences in prevalence estimates [11]. Islet amyloid, or hyaline as it was once known [12], has the beta cell hormone human amylin or human islet G. J. S. Cooper (*) : J. F. Aitken : S. Zhang School of Biological Sciences, and Maurice Wilkins Centre of Excellence for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand e-mail: g.cooper@auckland.ac.nz