A practical evidence-based approach to management of type 2 diabetes in children and young people (CYP): UK consensus.

BACKGROUND: Type 2 diabetes in young people is an aggressive disease with a greater risk of complications leading to increased morbidity and mortality during the most productive years of life. Prevalence in the UK and globally is rising yet experience in managing this condition is limited. There are no consensus guidelines in the UK for the assessment and management of paediatric type 2 diabetes. METHODS: Multidisciplinary professionals from The Association of Children's Diabetes Clinicians (ACDC) and the National Type 2 Diabetes Working Group reviewed the evidence base and made recommendations using the Grading Of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. RESULTS AND DISCUSSION: Young people with type 2 diabetes should be managed within a paediatric diabetes team with close working with adult diabetes specialists, primary care and other paediatric specialties. Diagnosis of diabetes type can be challenging with many overlapping features. Diabetes antibodies may be needed to aid diagnosis. Co-morbidities and complications are frequently present at diagnosis and should be managed holistically. Lifestyle change and metformin are the mainstay of early treatment, with some needing additional basal insulin. GLP1 agonists should be used as second-line agents once early ketosis and symptoms are controlled. Glycaemic control improves microvascular but not cardiovascular risk. Reduction in excess adiposity, smoking prevention, increased physical activity and reduction of hypertension and dyslipidaemia are essential to reduce major adverse cardiovascular events. CONCLUSIONS: This evidence-based guideline aims to provide a practical approach in managing this condition in the UK.

Applying generalizability theory to examine assessments of subjective cognitive complaints: whose reports should we rely on - participant versus informant?

OBJECTIVES: This study aimed to apply the generalizability theory (G-theory) to investigate dynamic and enduring patterns of subjective cognitive complaints (SCC), and reliability of two widely used SCC assessment tools. DESIGN: G-theory was applied to assessment scales using longitudinal measurement design with five assessments spanning 10 years of follow-up. SETTING: Community-dwelling older adults aged 70-90 years and their informants, living in Sydney, Australia, participated in the longitudinal Sydney Memory and Ageing Study. PARTICIPANTS: The sample included 232 participants aged 70 years and older, and 232 associated informants. Participants were predominantly White Europeans (97.8%). The sample of informants included 76 males (32.8%), 153 females (65.9%), and their age ranged from 27 to 86 years, with a mean age of 61.3 years (SD = 14.38). MEASUREMENTS: The Memory Complaint Questionnaire (MAC-Q) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). RESULTS: The IQCODE demonstrated strong reliability in measuring enduring patterns of SCC with G = 0.86. Marginally acceptable reliability of the 6-item MAC-Q (G = 0.77-0.80) was optimized by removing one item resulting in G = 0.80-0.81. Most items of both assessments were measuring enduring SCC with exception of one dynamic MAC-Q item. The IQCODE significantly predicted global cognition scores and risk of dementia incident across all occasions, while MAC-Q scores were only significant predictors on some occasions. CONCLUSIONS: While both informants' (IQCODE) and self-reported (MAC-Q) SCC scores were generalizable across sample population and occasions, self-reported (MAC-Q) scores may be less accurate in predicting cognitive ability and diagnosis of each individual.

Dietary Patterns and Cognitive Health in Older Adults: Findings from the Sydney Memory and Ageing Study.

OBJECTIVES: Systematic reviews report dietary patterns may be associated with cognitive health in older adults. However, inconsistent findings have been reported and relevant research lacks large scale studies. This study aims to examine the associations of dietary patterns and cognitive function among older adults in an Australian ageing cohort. DESIGN: A population-based, cross-sectional analysis of the baseline phase of the Sydney Memory and Ageing Study, a well-characterised Australian ageing study. SETTING: The Sydney Memory and Ageing Study was initiated in 2005 to examine the clinical characteristics and prevalence of mild cognitive impairment (MCI). PARTICIPANTS: Non-demented community-dwelling individuals from English-speaking background (N = 819) aged 70-90 recruited from two areas of Sydney, following a random approach to 8914 individuals on the electoral roll in the Sydney Memory and Ageing study. MEASUREMENTS: The Cancer Council of Victoria Food Frequency Questionnaire was used to assess dietary intake. Scores for Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH) diet and the Dietary Guidelines Index (DGI 2013) were generated. Two patterns - a Prudent healthy and a Western dietary pattern - were derived using principal components analysis (PCA). Neuropsychological tests were used to assess global cognition and six cognitive domains. Multivariate linear modelling assessed the relationship between dietary patterns and cognitive domain scores. RESULTS: Mediterranean diet and DASH diet were both positively linked to visuospatial cognition (P=0.002 and P=0.001 respectively). Higher intake of legumes and nuts was related to better performance in global cognition (ß=0.117; 95% CI:0.052, 0.181; P<0.001) and language and visuospatial cognitive domains. The Prudent healthy diet was associated with better global cognition (ß=0.307; 95% CI: 0.053, 0.562; P=0.019) in women and a Western diet was related to poorer global function (ß=-0.242; 95% CI: -0.451,-0.034; P=0.023) and executive function (ß=-0.325; 95% CI: -0.552,-0.099; P=0.005) in men. CONCLUSION: In this analysis, higher adherence to the Mediterranean diet, DASH diet, Prudent healthy diet and greater consumption of legumes and nuts were associated with better cognition among older adults.

Parity and the risk of incident dementia: a COSMIC study.

AIMS: To investigate the association between parity and the risk of incident dementia in women. METHODS: We pooled baseline and follow-up data for community-dwelling women aged 60 or older from six population-based, prospective cohort studies from four European and two Asian countries. We investigated the association between parity and incident dementia using Cox proportional hazards regression models adjusted for age, educational level, hypertension, diabetes mellitus and cohort, with additional analysis by dementia subtype (Alzheimer dementia (AD) and non-Alzheimer dementia (NAD)). RESULTS: Of 9756 women dementia-free at baseline, 7010 completed one or more follow-up assessments. The mean follow-up duration was 5.4 ± 3.1 years and dementia developed in 550 participants. The number of parities was associated with the risk of incident dementia (hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02-1.13). Grand multiparity (five or more parities) increased the risk of dementia by 30% compared to 1-4 parities (HR = 1.30, 95% CI = 1.02-1.67). The risk of NAD increased by 12% for every parity (HR = 1.12, 95% CI = 1.02-1.23) and by 60% for grand multiparity (HR = 1.60, 95% CI = 1.00-2.55), but the risk of AD was not significantly associated with parity. CONCLUSIONS: Grand multiparity is a significant risk factor for dementia in women. This may have particularly important implications for women in low and middle-income countries where the fertility rate and prevalence of grand multiparity are high.

Injury-related hospitalisation in community-dwelling older people across the cognitive spectrum: A population based study.

OBJECTIVES: To describe the injury profile, hospitalisation rates and health outcomes for older people with cognitive impairment and to determine whether these differ from those with normal cognition. METHODS: Participants were 867 community-dwelling 70-90 year olds enrolled in the population-based longitudinal Sydney Memory and Ageing Study (MAS). Participant's cognitive status was classified as normal, mild cognitive impairment (MCI) and dementia at baseline, then 2, 4 and 6 years' follow-up. MAS records were linked to hospital and death records to identify injury-related hospitalisations for the 2-year period following each assessment. RESULTS: There were 335 injury-related hospitalisations for participants; 222 (25.6%) participants had at least one injury-related hospitalisation. The injury-related hospitalisation rate for participants with MCI (63.0 [95%CI 51.6-74.4] per 1000 person-years) was higher than for people with normal cognition (39.3 [95%CI 32.4-46.1] per 1000 person-years) but lower than people with dementia (137.1 [95%CI 87.2-186.9] per 1000 person-years). Upper limb fractures (22.1%) were the most common injuries for participants with normal cognition, and non-fracture head injuries for participants with MCI and dementia (25.9% and 23.3% respectively). Participants with dementia had a higher proportion of hip fractures (20.0%, p = 0.0483) than participants with normal cognition. There was no difference in 30-day mortality between participants with normal cognition, MCI and dementia (3.9%, 1.7%, 3.3% respectively). CONCLUSION: Older people with objectively defined MCI are at higher risk of injury-related hospitalisation than their cognitively intact peers, but lower risk than people with dementia. Falls-risk screening and fall prevention initiatives may be indicated for older people with MCI.

The Vascular Behavioral and Cognitive Disorders criteria for vascular cognitive disorders: a validation study.

BACKGROUND AND PURPOSE: The Vascular Behavioral and Cognitive Disorders (VASCOG) criteria for vascular cognitive disorders were published in 2014, but their concurrent and predictive validity have not been examined. METHODS: Participants (N = 165, aged 49-86 years) were from Sydney Stroke Study, a longitudinal study of post-stroke cognitive impairment and dementia. Diagnoses using the National Institute of Neurological Disorders and Stroke - Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN), the Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), criteria for vascular dementia (VaD) were made by consensus at multidisciplinary case conferences. Diagnoses for mild vascular cognitive disorder (mVCD) and VaD using VASCOG, DSM-5 and the Vascular Impairment of Cognition Classification Consensus Study (VICCCS) criteria were made by two study authors. Agreement levels between criteria sets were examined using Cohen's kappa (κ). The ability of VaD diagnoses to predict mortality over 10 years and of mVCD to predict dementia over 5 years was investigated. RESULTS: The VASCOG criteria yielded rates of mVCD slightly lower than for DSM-5 and VICCCS. VaD rates were similar for all criteria, although slightly lower for DSM-IV. Agreement between the VASCOG, VICCCS and DSM-5 criteria was excellent for VaD and mVCD (κ = 0.83-1.0), but lower for VaD between VASCOG and the other criteria (κ = 0.47-0.63). VaD-based mortality predictions were similar for the VASCOG, VICCCS and DSM-5 criteria, and higher than those for other criteria. The prediction of incident dementia within 5 years from mVCD was slightly lower with VASCOG criteria than with DSM-5 and VICCCS criteria. CONCLUSIONS: The VASCOG criteria have greater sensitivity, modest concurrent validity and better predictive validity than older criteria for VaD, but are comparable to DSM-5 and VICCCS criteria. Their operationalization and inclusion of a mild VCD category make them useful for clinical and research applications.

Phase 2 multicentre study of single-agent ofatumumab in previously untreated follicular lymphoma: CALGB 50901 (Alliance).

Rituximab monotherapy has proven efficacy in treatment-naïve, asymptomatic advanced-stage follicular lymphoma (FL). Ofatumumab is a fully humanized anti-CD20 monoclonal antibody with increased CD20 affinity and complement-dependent cytotoxicity. This phase 2 trial (NCT01190449) evaluated ofatumumab in patients with untreated, low/intermediate-risk FL International Prognostic Index (FLIPI), advanced-stage FL to determine single-agent efficacy. Patients with measurable disease in stages III/IV or bulky stage II, regardless of Groupe d'Etude des Lymphomes Folliculaires criteria, received 4 weekly 1000 mg doses followed by four extended induction doses once every 8 weeks. Primary endpoint was overall response rate (ORR) to 1000 mg; secondary endpoints were progression-free survival (PFS) and safety. Fifty-one patients were enrolled. Fifteen patients were randomized to 500 mg prior to discontinuing that arm for slow accrual. Among 36 patients on the 1000 mg arm, ORR was 84%, median PFS was 1·9 years and median response duration was 23·7 months. All patients remain alive. No grade 4 infusion reactions or grade 3/4 infections occurred. Grade 3 infusion reactions occurred in 25% in the 1000 mg arm only (all first infusion); all but two patients continued on study. Discontinuation was 6% for the total study population. Ofatumumab monotherapy administered by extended induction in untreated, low/intermediate-risk FLIPI, advanced-stage FL is well tolerated and active. Activity appears similar to that reported with single-agent rituximab.

The impact of type 2 diabetes and body mass index on cerebral structure is modulated by brain reserve.

BACKGROUND AND PURPOSE: Body mass index (BMI), hyperglycaemia and type 2 diabetes and their interactive effects are associated with brain volume atrophy in ageing. It remains to be established if these risk factors are particularly concerning in individuals with high or low brain volumes. METHODS: Demographics, venous blood and magnetic resonance imaging data were collected for 494 healthy community-living adults aged 53-78 (mean 65) years, as part of the Personality and Total Health Through Life study. Associations between BMI, blood glucose, diabetes status and brain volume (whole brain, grey matter, white matter and subcortical structures) were investigated using quantile regression. RESULTS: Quantile regression revealed vulnerability to BMI × glucose interactions particularly in lower volumes and significant main effects for type 2 diabetes particularly in higher volumes. Diabetes was most strongly associated with brain volumes. The association between BMI, blood glucose and diabetes was not consistent across the full range of brain volumes. CONCLUSION: Explicit investigation of the upper and lower boundaries of brain volume distributions was valuable. We found evidence of protective reserve from higher brain volumes and that a combination of high BMI and higher blood glucose was particularly concerning for individuals with lower brain volumes.

Differentiation of Alzheimer's disease based on local and global parameters in personalized Virtual Brain models.

Alzheimer's disease (AD) is marked by cognitive dysfunction emerging from neuropathological processes impacting brain function. AD affects brain dynamics at the local level, such as changes in the balance of inhibitory and excitatory neuronal populations, as well as long-range changes to the global network. Individual differences in these changes as they relate to behaviour are poorly understood. Here, we use a multi-scale neurophysiological model, "The Virtual Brain (TVB)", based on empirical multi-modal neuroimaging data, to study how local and global dynamics correlate with individual differences in cognition. In particular, we modeled individual resting-state functional activity of 124 individuals across the behavioural spectrum from healthy aging, to amnesic Mild Cognitive Impairment (MCI), to AD. The model parameters required to accurately simulate empirical functional brain imaging data correlated significantly with cognition, and exceeded the predictive capacity of empirical connectomes.

Genetic and Environmental Influences on Language Ability in Older Adults: Findings from the Older Australian Twins Study.

We used a sub-sample from the Older Australian Twins Study to estimate the heritability of performance on three tests of language ability: Boston Naming Test (BNT), Letter/Phonemic Fluency (FAS) and Category/Semantic Fluency (CFT) Tests. After adjusting for age, sex, education, mood, and global cognition (GC), heritability estimates obtained for the three tests were 0.35, 0.59, and 0.20, respectively. Multivariate analyses showed that the genetic correlation were high for BNT and CFT (0.61), but low for BNT and FAS (0.17), and for FAS and CFT (0.28). Genetic modelling with Cholesky decomposition indicated that the covariation between the three measures could be explained by a common genetic factor. Environmental correlations between the language ability measures were low, and there were considerable specific environmental influences for each measure. Future longitudinal studies with language performance and neuroimaging data can further our understanding of genetic and environmental factors involved in the process of cognitive aging.

Multi-Institutional, Prospective Clinical Utility Study Evaluating the Impact of the 92-Gene Assay (CancerTYPE ID) on Final Diagnosis and Treatment Planning in Patients With Metastatic Cancer With an Unknown or Unclear Diagnosis.

PURPOSE: Metastatic cancers of unknown primary or with unclear diagnoses pose diagnostic and management challenges, often leading to poor outcomes. Studies of the 92-gene assay have demonstrated improved diagnostic accuracy compared with standard pathology techniques and improved survival in patients treated on the basis of assay results. The current study assessed the clinical impact of the 92-gene assay on diagnostic and treatment decisions for patients with unknown or uncertain diagnoses. METHODS: Patients in this prospective, multi-institutional, decision-impact study included those for whom the 92-gene assay was ordered as part of routine care. Participating physicians completed electronic case report forms that contained standardized, specialty-specific questionnaires. Data collection included patient and tumor characteristics and clinical history. The key study objective of clinical impact was calculated on the basis of changes in final diagnosis and treatment after testing. RESULTS: Data collection included 444 patients, 107 physicians (73 oncologists and 34 pathologists), and 28 sites. Molecular diagnoses from 22 different tumor types and subtypes across all cases were provided in 95.5% of patients with a reportable result (n = 397). Physicians reported that the 92-gene assay was used broadly for diagnostic dilemmas that ranged from single suspected tumor type (29%) to a differential diagnosis of two or more suspected tumor types (30%) or cancers of unknown primary (41%). Integration of 92-gene assay results led to a change in the recommended treatment in 47% of patients. CONCLUSION: Findings from this clinical utility study demonstrate that the 92-gene assay led to a change in treatment decisions in every other patient case. These data additionally define the role of this assay in clinical practice and strongly support the consideration of molecular tumor typing in the diagnosis and treatment planning of patients with metastatic cancer with unknown or uncertain diagnosis.

Intragastric balloon as an adjunct to lifestyle programme in severely obese adolescents: impact on biomedical outcomes and skeletal health.

Intragastric Balloons are a temporary, reversible and safer option compared to bariatric surgery to promote significant weight loss, leading to improved metabolic outcomes. However, due to subsequent weight regain, alternative procedures are now preferred in adults. In adolescents, more amenable to lifestyle change, balloons may be an alternative to less reversible procedures. Our aim was to assess the tolerability and efficacy of the intragastric balloon in severely obese adolescents and the impact of associated weight loss on biomedical outcomes (glucose metabolism, blood pressure, lipid profiles) and bone density. A 2-year cohort study of 12 adolescents (BMI >3.5 s.d., Tanner stage >4) following 6 months intragastric balloon placement was carried out. Subjects underwent anthropometry, oral glucose tolerance test, and DEXA scans at 0, 6 and 24 months. The results showed clinically relevant improvements in blood pressure, insulin: glucose metabolism, liver function and sleep apnoea at 6 months. Changes were not sustained at 2 years though some parameters (Diastolic BP, HBA1c, insulin AUC) demonstrated longer-term improvement despite weight regain. Despite weight loss, bone mass accrual showed age appropriate increases. In conclusion, the intragastric balloon was safe, well tolerated and effective in supporting short-term weight loss and clinically relevant improvement in obesity-related complications, which resolved in some individuals. Benefits were not sustained in the majority at 2 years.

Body mass index is associated with cortical thinning with different patterns in mid- and late-life.

OBJECTIVE: High BMI at midlife is associated with increased risk of dementia as well as faster decline in cognitive function. In late-life, however, high BMI has been found to be associated with both increased and decreased dementia risk. The objective of this study was to investigate the neural substrates of this age-related change in body mass index (BMI) risk. METHODS: We measured longitudinal cortical thinning over the whole brain, based on magnetic resonance imaging scans for 910 individuals aged 44-66 years at baseline. Subjects were sampled from a large population study (PATH, Personality and Total Health through Life). After attrition and exclusions, the final analysis was based on 792 individuals, including 387 individuals aged 60-66 years and 405 individuals aged 44-49 years. A mixed-effects model was used to test the association between cortical thinning and baseline BMI, as well as percentage change in BMI. RESULTS: Increasing BMI was associated with increased cortical thinning in posterior cingulate at midlife (0.014 mm kg-1 m-2, confidence interval; CI=0.005, 0.023, P<0.05 false discovery rate (FDR) corrected). In late-life, increasing BMI was associated with reduced cortical thickness, most prominently in the right supramarginal cortex (0.010 mm kg-1 m-2, CI=0.005-0.016, P<0.05 FDR corrected), as well as frontal regions. In late-life, decreasing BMI was also associated with increased cortical thinning, including right caudal middle frontal cortex (0.014 mm kg-1 m-2 (CI=0.006-0.023, P<0.05 FDR corrected). CONCLUSIONS: The pattern of cortical thinning-in association with increasing BMI at both midlife and late-life-is consistent with known obesity-related dementia risk. Increased cortical thinning in association with decreasing BMI at late-life may help explain the 'obesity paradox', where high BMI in midlife appears to be a risk factor for dementia, but high BMI in late-life appears, at times, to be protective.

Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Celecoxib in Addition to Standard Chemotherapy for Advanced Non-Small-Cell Lung Cancer With Cyclooxygenase-2 Overexpression: CALGB 30801 (Alliance).

Purpose Tumor overexpression of cyclooxygenase-2 (COX-2) has been associated with worse outcome in non-small-cell lung cancer (NSCLC). In Cancer and Leukemia Group B (CALGB) 30203, we found that the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved progression-free and overall survival in patients with moderate to high COX-2 expression by immunohistochemistry (IHC). CALGB 30801 (Alliance) was designed to prospectively confirm that finding. Patients and Methods Patients with NSCLC (stage IIIB with pleural effusion or stage IV according to American Joint Committee on Cancer [sixth edition] criteria) were preregistered, and biopsy specimens were analyzed for COX-2 by IHC. Patients with COX-2 expression ≥ 2, performance status of 0 to 2, and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin plus pemetrexed for nonsquamous NSCLC and carboplatin plus gemcitabine for squamous histology. Patients were randomly assigned to celecoxib (400 mg twice per day; arm A) or placebo (arm B). The primary objective was to demonstrate improvement in progression-free survival in patients with COX-2 index ≥ 4 with hazard ratio of 0.645 with approximately 85% power at two-sided significance level of .05. Results The study was halted for futility after 312 of the planned 322 patients with COX-2 index ≥ 2 were randomly assigned. There were no significant differences between the groups (hazard ratio, 1.046 for COX-2 ≥ 4). Subset analyses evaluating histology, chemotherapy regimen, and incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Elevation of baseline urinary metabolite of prostaglandin E2, indicating activation of the COX-2 pathway, was a negative prognostic factor. Values above the third quartile may have been a predictive factor. Conclusion COX-2 expression by IHC failed to select patients who could benefit from selective COX-2 inhibition. Urinary metabolite of prostaglandin E2 may be able to identify patients who could benefit from COX-2 inhibition.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

Strength measures are better than muscle mass measures in predicting health-related outcomes in older people: time to abandon the term sarcopenia?

There is no clear consensus on definition, cut-points or standardised assessments of sarcopenia. We found a lower limb strength assessment was at least as effective in predicting balance, mobility and falls in 419 older people as muscle mass-based measures of sarcopenia. INTRODUCTION: There is currently no consensus on the definition, cut-points or standardised assessments of sarcopenia. This study aimed to investigate whether several published definitions of sarcopenia differentiate between older people with respect to important functional and health outcomes. METHODS: Four hundred nineteen community-living older adults (mean age 81.2 ± 4.5, 49 % female) completed assessments of body composition (dual-energy X-ray absorptiometry), strength, balance, mobility and disability. Falls were recorded prospectively for a year using monthly calendars. Sarcopenia was defined according to four skeletal mass-based definitions, two strength-based definitions (handgrip or knee extensor force) and a consensus algorithm (low mass and low strength or slow gait speed). Obesity was defined according to percentage fat mass or waist circumference. RESULTS: The four skeletal mass-based definitions varied considerably with respect to the percentage of participants classified as sarcopenic and their predictive accuracy for functional and health outcomes. The knee extension strength-based definition was equivalent to or better than the mass-based and consensus algorithm definitions; i.e. weaker participants performed poorly in tests of leaning balance, stepping reaction time, gait speed and mobility. They also had higher physiological fall risk scores and were 43 % more likely to fall at home than their stronger counterparts. Adding obesity to sarcopenia definitions identified participants with greater self-reported disability. CONCLUSIONS: A simple lower limb strength assessment was at least as effective in predicting balance, functional mobility and falls in older people as more expensive and time-consuming muscle mass-based measures. These findings imply that functional terms such as muscle weakness or motor impairment are preferable to sarcopenia.

Midlife managerial experience is linked to late life hippocampal morphology and function.

An active cognitive lifestyle has been suggested to have a protective role in the long-term maintenance of cognition. Amongst healthy older adults, more managerial or supervisory experiences in midlife are linked to a slower hippocampal atrophy rate in late life. Yet whether similar links exist in individuals with Mild Cognitive Impairment (MCI) is not known, nor whether these differences have any functional implications. 68 volunteers from the Sydney SMART Trial, diagnosed with non-amnestic MCI, were divided into high and low managerial experience (HME/LME) during their working life. All participants underwent neuropsychological testing, structural and resting-state functional MRI. Group comparisons were performed on hippocampal volume, morphology, hippocampal seed-based functional connectivity, memory and executive function and self-ratings of memory proficiency. HME was linked to better memory function (p = 0.024), mediated by larger hippocampal volume (p = 0.025). More specifically, deformation analysis found HME had relatively more volume in the CA1 sub-region of the hippocampus (p < 0.05). Paradoxically, this group rated their memory proficiency worse (p = 0.004), a result correlated with diminished functional connectivity between the right hippocampus and right prefrontal cortex (p < 0.001). Finally, hierarchical regression modelling substantiated this double dissociation.

Intra-gastric balloon as an adjunct to lifestyle support in severely obese adolescents; impact on weight, physical activity, cardiorespiratory fitness and psychosocial well-being.

BACKGROUND: Severe adolescent obesity (body mass index (BMI) >99.6th centile) is a significant public health challenge. Current non-invasive treatments, including community-based lifestyle interventions, are often of limited effectiveness in this population, with NICE guidelines suggesting the use of bariatric surgery as the last line of treatment. Health professionals are understandably reluctant to commission bariatric surgery and as an alternative, the use of an intra-gastric balloon as an adjunct to a lifestyle programme might offer a reversible, potentially safer and less invasive option. OBJECTIVES: Explore the use of an intra-gastric balloon as an adjunct to a lifestyle support programme, to promote weight loss in severely obese adolescents. Outcomes included weight loss, waist and hip measurements, psychosocial outcomes including health-related quality of life (HRQoL) and physical self perceptions, physical activity and cardiorespiratory fitness. METHOD: Non-randomised pilot study. RESULTS: Twelve severely obese adolescents (5 males, 7 females; mean age 15 years; BMI >3.5 s.d.; puberty stage 4 or more) and their families were recruited. Mean weight loss at 12 months (n=9) was 3.05 kg±14.69; d=0.002, P=0.550, and a BMI Z-score (n=12) change of 0.2 s.d.; d=0.7, P=0.002 was observed at 6 months with a large effect, but was not sustained at 12 months (mean change 0.1 s.d.; d=0.3, P=0.146). At 24 months (n=10), there was a weight gain from baseline of +9.9 kg±1.21 (d=0.4; P=0.433). Adolescent and parent HRQoL scores exceeded the minimal clinical important difference between baseline and 12 months for all domains but showed some decline at 24 months. CONCLUSION: An intra-gastric balloon as an adjunct to a lifestyle support programme represents a safe and well-tolerated treatment approach in severely obese adolescents, with short-term effects on weight change. Improvements in psychosocial health, physical activity and cardiorespiratory fitness were maintained at 12 months, with varying results at 24 months.

Application of Targeted Mass Spectrometry for the Quantification of Sirtuins in the Central Nervous System.

Sirtuin proteins have a variety of intracellular targets, thereby regulating multiple biological pathways including neurodegeneration. However, relatively little is currently known about the role or expression of the 7 mammalian sirtuins in the central nervous system. Western blotting, PCR and ELISA are the main techniques currently used to measure sirtuin levels. To achieve sufficient sensitivity and selectivity in a multiplex-format, a targeted mass spectrometric assay was developed and validated for the quantification of all seven mammalian sirtuins (SIRT1-7). Quantification of all peptides was by multiple reaction monitoring (MRM) using three mass transitions per protein-specific peptide, two specific peptides for each sirtuin and a stable isotope labelled internal standard. The assay was applied to a variety of samples including cultured brain cells, mammalian brain tissue, CSF and plasma. All sirtuin peptides were detected in the human brain, with SIRT2 being the most abundant. Sirtuins were also detected in human CSF and plasma, and guinea pig and mouse tissues. In conclusion, we have successfully applied MRM mass spectrometry for the detection and quantification of sirtuin proteins in the central nervous system, paving the way for more quantitative and functional studies.