The effect of moving to East Village, the former London 2012 Olympic and Paralympic Games Athletes' Village, on mode of travel (ENABLE London study, a natural experiment)

Background Interventions to encourage active modes of travel (walking, cycling) may improve physical activity levels, but longitudinal evidence is limited and major change in the built environment / travel infrastructure may be needed. East Village (the former London 2012 Olympic Games Athletes Village) has been repurposed on active design principles with improved walkability, open space and public transport and restrictions on residential car parking. We examined the effect of moving to East Village on adult travel patterns. Methods One thousand two hundred seventy-eight adults (16+ years) seeking to move into social, intermediate, and market-rent East Village accommodation were recruited in 2013–2015, and followed up after 2 years. Individual objective measures of physical activity using accelerometry (ActiGraph GT3X+) and geographic location using GPS travel recorders (QStarz) were time-matched and a validated algorithm assigned four travel modes (walking, cycling, motorised vehicle, train). We examined change in time spent in different travel modes, using multilevel linear regresssion models adjusting for sex, age group, ethnicity, housing group (fixed effects) and household (random effect), comparing those who had moved to East Village at follow-up with those who did not. Results Of 877 adults (69%) followed-up, 578 (66%) provided valid accelerometry and GPS data for at least 1 day (≥540 min) at both time points; half had moved to East Village. Despite no overall effects on physical activity levels, sizeable improvements in walkability and access to public transport in East Village resulted in decreased daily vehicle travel (8.3 mins, 95%CI 2.5,14.0), particularly in the intermediate housing group (9.6 mins, 95%CI 2.2,16.9), and increased underground travel (3.9 mins, 95%CI 1.2,6.5), more so in the market-rent group (11.5 mins, 95%CI 4.4,18.6). However, there were no effects on time spent walking or cycling

Evaluating the effect of change in the built environment on mental health and subjective well-being: a natural experiment

Background Neighbourhood characteristics may affect mental health and well-being, but longitudinal evidence is limited. We examined the effect of relocating to East Village (the former London 2012 Olympic Athletes’ Village), repurposed to encourage healthy active living, on mental health and well-being. Methods 1278 adults seeking different housing tenures in East village were recruited and examined during 2013–2015. 877 (69%) were followed-up after 2 years; 50% had moved to East Village. Analysis examined change in objective measures of the built environment, neighbourhood perceptions (scored from low to high; quality −12 to 12, safety −10 to 10 units), self-reported mental health (depression and anxiety) and well-being (life satisfaction, life being worthwhile and happiness) among East Village participants compared with controls who did not move to East Village. Follow-up measures were regressed on baseline for each outcome with group status as a binary variable, adjusted for age, sex, ethnicity, housing tenure and household clustering (random effect). Results Participants who moved to East Village lived closer to their nearest park (528 m, 95% CI 482 to 575 m), in more walkable areas, and had better access to public transport, compared with controls. Living in East Village was associated with marked improvements in neighbourhood perceptions (quality 5.0, 95% CI 4.5 to 5.4 units; safety 3.4, 95% CI 2.9 to 3.9 units), but there was no overall effect on mental health and well-being outcomes. Conclusion Despite large improvements in the built environment, there was no evidence that moving to East Village improved mental health and well-being. Changes in the built environment alone are insufficient to improve mental health and well-being

Housing, neighbourhood and sociodemographic associations with adult levels of physical activity and adiposity: baseline findings from the ENABLE London study.

Objectives The neighbourhood environment is increasingly shown to be an important correlate of health. We assessed associations between housing tenure, neighbourhood perceptions, sociodemographic factors and levels of physical activity (PA) and adiposity among adults seeking housing in East Village (formerly London 2012 Olympic/Paralympic Games Athletes’ Village). Setting Cross-sectional analysis of adults seeking social, intermediate and market-rent housing in East Village. Participants 1278 participants took part in the study (58% female). Complete data on adiposity (body mass index (BMI) and fat mass %) were available for 1240 participants (97%); of these, a subset of 1107 participants (89%) met the inclusion criteria for analyses of accelerometer-based measurements of PA. We examined associations between housing sector sought, neighbourhood perceptions (covariates) and PA and adiposity (dependent variables) adjusted for household clustering, sex, age group, ethnic group and limiting long-standing illness. Results Participants seeking social housing had the fewest daily steps (8304, 95% CI 7959 to 8648) and highest BMI (26.0 kg/m2, 95% CI 25.5kg/m2 to 26.5 kg/m2) compared with those seeking intermediate (daily steps 9417, 95% CI 9106 to 9731; BMI 24.8 kg/m2, 95% CI 24.4 kg/m2 to 25.2 kg/m2) or market-rent housing (daily steps 9313, 95% CI 8858 to 9768; BMI 24.6 kg/m2, 95% CI 24.0 kg/m2 to 25.2 kg/m2). Those seeking social housing had lower levels of PA (by 19%–42%) at weekends versus weekdays, compared with other housing groups. Positive perceptions of neighbourhood quality were associated with higher steps and lower BMI, with differences between social and intermediate groups reduced by ~10% following adjustment, equivalent to a reduction of 111 for steps and 0.5 kg/m2 for BMI. Conclusions The social housing group undertook less PA than other housing sectors, with weekend PA offering the greatest scope for increasing PA and tackling adiposity in this group. Perceptions of neighbourhood quality were associated with PA and adiposity and reduced differences in steps and BMI between housing sectors. Interventions to encourage PA at weekends and improve neighbourhood quality, especially among the most disadvantaged, may provide scope to reduce inequalities in health behaviour

Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor–positive breast cancers

Introduction Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents. Methods Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor–positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed. Results By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid– and leucine-rich protein 1, an ER coactivator. Conclusions These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC

Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH Randomized Clinical Trial

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191

Late cardiotoxicity after low dose of anthracycline therapy for acute lymphoblastic leukemia in childhood

Introduction Late cardiotoxicity is a known complication of anthracycline therapy but the long-term effects of low cumulative doses are not well documented. We studied late cardiotoxicity in survivors of childhood acute lymphoblastic leukemia (ALL) treated with low anthracycline doses 10 to 20 years earlier. Methods Seventy-seven ALL survivors who received a cumulative anthracycline dose <250 mg/m(2) and were at least 10 years after treatment were evaluated for signs of clinical heart failure. Cardiac function was assessed by echocardiography including tissue Doppler measurements of the septal mitral annulus in 37 ALL survivors 10.6-18.3 years (median 13.3 years) after anthracycline treatment with cumulative doses of 180 (n=19) or 240 mg/m(2) (n=18). The control group consisted of 30 healthy volunteers matched for age, sex, BSA, and BMI. Results No clinical relevant cardiotoxicity was found. Left ventricular shortening fraction (SF) was significantly reduced in male ALL survivors. Three of the 19 male ALL survivors had an SF below 30%. Male ALL survivors showed a significantly lower early filling velocity to atrial contraction velocity ratio but myocardial velocity during early filling was comparable between patients and controls. ALL survivors had a significantly longer isovolumetric relaxation time (IVRT). Thirty percent of the ALL survivors have an abnormal IVRT compared to the normal range of the controls. Conclusion and implications for cancer survivors At a median of 13.3 years after exposure to cumulative doses of anthracyclines of 180 or 240 mg/m(2), no clinical relevant cardiotoxicity was found but subclinical cardiac abnormalities were present in 30% of the patients

Sensitive detection of Aβ protofibrils by proximity ligation - relevance for Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Protein aggregation plays important roles in several neurodegenerative disorders. For instance, insoluble aggregates of phosphorylated tau and of Aβ peptides are cornerstones in the pathology of Alzheimer's disease. Soluble protein aggregates are therefore potential diagnostic and prognostic biomarkers for their cognate disorders. Detection of the aggregated species requires sensitive tools that efficiently discriminate them from monomers of the same proteins. Here we have established a proximity ligation assay (PLA) for specific and sensitive detection of Aβ protofibrils via simultaneous recognition of three identical determinants present in the aggregates. PLA is a versatile technology in which the requirement for multiple target recognitions is combined with the ability to translate signals from detected target molecules to amplifiable DNA strands, providing very high specificity and sensitivity.</p> <p>Results</p> <p>For specific detection of Aβ protofibrils we have used a monoclonal antibody, mAb158, selective for Aβ protofibrils in a modified PLA, where the same monoclonal antibody was used for the three classes of affinity reagents required in the assay. These reagents were used for detection of soluble Aβ aggregates in solid-phase reactions, allowing detection of just 0.1 pg/ml Aβ protofibrils, and with a dynamic range greater than six orders of magnitude. Compared to a sandwich ELISA setup of the same antibody the PLA increases the sensitivity of the Aβ protofibril detection by up to 25-fold. The assay was used to measure soluble Aβ aggregates in brain homogenates from mice transgenic for a human allele predisposing to Aβ aggregation.</p> <p>Conclusions</p> <p>The proximity ligation assay is a versatile analytical technology for proteins, which can provide highly sensitive and specific detection of Aβ aggregates - and by implication other protein aggregates of relevance in Alzheimer's disease and other neurodegenerative disorders.</p

Generic Delivery of Payload of Nanoparticles Intracellularly via Hybrid Polymer Capsules for Bioimaging Applications

Towards the goal of development of a generic nanomaterial delivery system and delivery of the ‘as prepared’ nanoparticles without ‘further surface modification’ in a generic way, we have fabricated a hybrid polymer capsule as a delivery vehicle in which nanoparticles are loaded within their cavity. To this end, a generic approach to prepare nanomaterials-loaded polyelectrolyte multilayered (PEM) capsules has been reported, where polystyrene sulfonate (PSS)/polyallylamine hydrochloride (PAH) polymer capsules were employed as nano/microreactors to synthesize variety of nanomaterials (metal nanoparticles; lanthanide doped inorganic nanoparticles; gadolinium based nanoparticles, cadmium based nanoparticles; different shapes of nanoparticles; co-loading of two types of nanoparticles) in their hollow cavity. These nanoparticles-loaded capsules were employed to demonstrate generic delivery of payload of nanoparticles intracellularly (HeLa cells), without the need of individual nanoparticle surface modification. Validation of intracellular internalization of nanoparticles-loaded capsules by HeLa cells was ascertained by confocal laser scanning microscopy. The green emission from Tb3+ was observed after internalization of LaF3:Tb3+(5%) nanoparticles-loaded capsules by HeLa cells, which suggests that nanoparticles in hybrid capsules retain their functionality within the cells. In vitro cytotoxicity studies of these nanoparticles-loaded capsules showed less/no cytotoxicity in comparison to blank capsules or untreated cells, thus offering a way of evading direct contact of nanoparticles with cells because of the presence of biocompatible polymeric shell of capsules. The proposed hybrid delivery system can be potentially developed to avoid a series of biological barriers and deliver multiple cargoes (both simultaneous and individual delivery) without the need of individual cargo design/modification

Active design of built environments for increasing levels of physical activity in adults: the ENABLE London natural experiment study

Background Low physical activity is widespread and poses a serious public health challenge both globally and in the UK. The need to increase population levels of physical activity is recognised in current health policy recommendations. There is considerable interest in whether or not the built environment influences health behaviours, particularly physical activity levels, but longitudinal evidence is limited. Objectives The effect of moving into East Village (the former London 2012 Olympic and Paralympic Games Athletes’ Village, repurposed on active design principles) on the levels of physical activity and adiposity, as well as other health-related and well-being outcomes among adults, was examined. Design The Examining Neighbourhood Activities in Built Environments in London (ENABLE London) study was a longitudinal cohort study based on a natural experiment. Setting East Village, London, UK. Participants A cohort of 1278 adults (aged ≥ 16 years) and 219 children seeking to move into social, intermediate and market-rent East Village accommodation were recruited in 2013–15 and followed up after 2 years. Intervention The East Village neighbourhood, the former London 2012 Olympic and Paralympic Games Athletes’ Village, is a purpose-built, mixed-use residential development specifically designed to encourage healthy active living by improving walkability and access to public transport. Main outcome measure Change in objectively measured daily steps from baseline to follow-up. Methods Change in environmental exposures associated with physical activity was assessed using Geographic Information System-derived measures. Individual objective measures of physical activity using accelerometry, body mass index and bioelectrical impedance (per cent of fat mass) were obtained, as were perceptions of change in crime and quality of the built environment. We examined changes in levels of physical activity and adiposity using multilevel models adjusting for sex, age group, ethnic group, housing sector (fixed effects) and baseline household (random effect), comparing the change in those who moved to East Village (intervention group) with the change in those who did not move to East Village (control group). Effects of housing sector (i.e. social, intermediate/affordable, market-rent) as an effect modifier were also examined. Qualitative work was carried out to provide contextual information about the perceived effects of moving to East Village. Results A total of 877 adults (69%) were followed up after 2 years (mean 24 months, range 19–34 months, postponed from 1 year owing to the delayed opening of East Village), of whom 50% had moved to East Village; insufficient numbers of children moved to East Village to be considered further. In adults, moving to East Village was associated with only a small, non-significant, increase in mean daily steps (154 steps, 95% confidence interval –231 to 539 steps), more so in the intermediate sector (433 steps, 95% confidence interval –175 to 1042 steps) than in the social and market-rent sectors (although differences between housing sectors were not statistically significant), despite sizeable improvements in walkability, access to public transport and neighbourhood perceptions of crime and quality of the built environment. There were no appreciable effects on time spent in moderate to vigorous physical activity or sedentary time, body mass index or percentage fat mass, either overall or by housing sector. Qualitative findings indicated that, although participants enjoyed their new homes, certain design features might actually serve to reduce levels of activity. Conclusions Despite strong evidence of large positive changes in neighbourhood perceptions and walkability, there was only weak evidence that moving to East Village was associated with increased physical activity. There was no evidence of an effect on markers of adiposity. Hence, improving the physical activity environment on its own may not be sufficient to increase population physical activity or other health behaviours. Funding This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 8, No. 12. See the NIHR Journals Library website for further project information. This research was also supported by project grants from the Medical Research Council National Prevention Research Initiative (MR/J000345/1)