Cross-cultural comparisons of aerobic and muscular fitness in Tanzanian and English youth: An allometric approach

Comparisons of physical fitness measures between children or within group measures over time are potentially confounded by differences in body size. We compared measures of strength (handgrip) and aerobic fitness (running-speed [20m shuttle-run]) of 10.0–15.9 year-olds from Dar es Salaam, Tanzania (n = 977) with schoolchildren from England (n = 1014) matched for age and sex. Differences in fitness were analyzed using general linear models, with allometric scaling for body size (mass and stature) and further adjustments for physical activity. Mean handgrip of Tanzanians was lower than English youth (F = 165.0, P<0.001, ηp2 = .079). The difference became trivial when run-speed was scaled for body size (ηp2 = .008). Running-speed of the English children was higher than in Tanzanians (F = 16.0, P<0.001, ηp2 = .014). Allometric scaling for accentuated this between-county difference in running-speed (ηp2 = .019) but when adjusted for physical activity between-country differences in running-speed were trivial (ηp2 = .008). These data contradict those studies showing poor muscular fitness in African youth and highlight the need for appropriate scaling techniques to avoid confounding by differences in body size. In contrast to those from rural areas, our sample of contemporary urban Tanzanians were less aerobically fit than European youth. Differences were independent of body size. Lower aerobic fitness of urban Tanzanian youth may be due to reported physical activity levels lower than those of English youth and lower still than previously reported in rural Tanzania

The dose-response association between V̇O2peak and self-reported physical activity in children

This is an accepted manuscript of an article published by Taylor & Francis in Journal of Sports Sciences on 13/05/2020, available online: https://doi.org/10.1080/02640414.2020.1756682 The accepted version of the publication may differ from the final published version.© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Background: Previous research into the association between aerobic fitness and physical activity in children is equivocal. However, previous research has always assumed that such an association was linear. This study sought to characterize the dose–response association between physical activity and aerobic fitness and to assess whether this association is linear or curvilinear and varies by sex, age and weight status. Methods: Physical activity (assess using the Physical Activity Questionnaire), aerobic fitness (20 m shuttle-run), BMI, screen-time and socio-demographic data were collected at ages 12, 14 and 16 years in (n = 1422) volunteers from 9 English schools. Multilevel-regression modelling was used to analyse the longitudinal data. Results: The analysis identified a significant inverted “u-shaped” association between VO2max and PAQ. This relationship remained having controlling for the influences of sex, age and weight status. Daily screen time >4 hours and deprivation were also associated with being less fit (P < 0.01). Conclusions: This longitudinal study suggests that the dose–response relationship between PA and aerobic fitness in children is curvilinear. The health benefits of PA are greater in less active children and that sedentary and less active children should be encouraged to engage in PA rather than more active children to increase existing levels of PA.Published versio

Structural role of Sfi1p–centrin filaments in budding yeast spindle pole body duplication

Centrins are calmodulin-like proteins present in centrosomes and yeast spindle pole bodies (SPBs) and have essential functions in their duplication. The Saccharomyces cerevisiae centrin, Cdc31p, binds Sfi1p on multiple conserved repeats; both proteins localize to the SPB half-bridge, where the new SPB is assembled. The crystal structures of Sfi1p–centrin complexes containing several repeats show Sfi1p as an α helix with centrins wrapped around each repeat and similar centrin–centrin contacts between each repeat. Electron microscopy (EM) shadowing of an Sfi1p–centrin complex with 15 Sfi1 repeats and 15 centrins bound showed filaments 60 nm long, compatible with all the Sfi1 repeats as a continuous α helix. Immuno-EM localization of the Sfi1p N and C termini showed Sfi1p–centrin filaments spanning the length of the half-bridge with the Sfi1p N terminus at the SPB. This suggests a model for SPB duplication where the half-bridge doubles in length by association of the Sfi1p C termini, thereby providing a new Sfi1p N terminus to initiate SPB assembly

‘At risk’ waist-to-height ratio cut-off points recently adopted by NICE and US Department of Defense will unfairly penalize shorter adults. What is the solution?

Objectives To a) demonstrate that adopting ‘at risk’ waist-to-height ratio (WHTR) cut-off points, recently approved by National Institute for Health and Care Excellence (NICE) and the United States Department of Defense (USDoD), will unfairly penalize shorter individuals and will be too lenient for taller individuals, b) to confirm that waist circumference (WC) of a sample of US service personnel, scales to approximately height0.5, supporting the notion that WC, to be independent of height (HT), should be normalized using WC.HT−0.5 (WHT•5R), and c) to identify the WHT•5R cut-off points that will reduce or eliminate this unwanted bias. Subjects/methods We employed a three independent cross-sectional sample design. All n = 58,742 participants underwent anthropometric assessment of body mass, stature and waist circumference. Results The allometric power-law model WC=a.HT^b for US service personnel identified the height exponent to be b= 0.418 (95 % CI 0.251–0.585), confirming that the simple body-shape index for WC to be independent of HT, should be WC.HT−0.5. Chi-square tests of independence and for linear trend confirmed that by adopting WHTR cut-off point, shorter individuals (both service personnel and non-service participants) will be over penalized (classified as being ‘at risk’). New WC independent-of-height ratio cut-off points were found to resolve this problem. Conclusions Adopting WHTR cut-off thresholds (either 0.5 or 0.55) will lead to shorter adults being unfairly classified as being ‘at risk’ in terms of their central adiposity and general health status. Adopting new WHT•5R cut-off point thresholds were found to greatly reduce or eliminate this bias

Cardiorespiratory fitness and activity explains the obesity-deprivation relationship in children

This study examined the association between obesity and deprivation in English children and whether cardiorespiratory fitness or physical activity (PA) can explain this association. Obesity was assessed using IOTF criteria in 8,398 10-16 year olds. Social deprivation was measured using the Index of Multiple Deprivation (IMD) (subdivided into 3 groups; high, mid and low deprivation). Obesity was analysed using binary logistic regression with stature, age and sex incorporated as confounding variables. Children's fitness levels were assessed using predicted VO2 max (20-metre shuttle run test) and PA was estimated using the PA Questionnaire for Adolescents or Children (PAQ). A strong association was found between obesity and deprivation. When fitness and PA were added to the logistic regression models, increasing levels in both were found to reduce the odds of obesity, although it was only by including fitness into the model that the association between obesity and deprivation disappeared. Including estimated PA into the model was found to be curvilinear. Initial increases in PA increase the odds of obesity. Only by increasing PA to exceed the 71(st) percentile (PAQ = 3.22) did the odds of being obese start to decline. In order to reduce deprivation inequalities in children's weight-status, health practitioners should focus on increasing cardiorespiratory fitness via physical activity levels in areas of greater deprivation

A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis.

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics

Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.

Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.GW, BM, SG, JC-U, AS, AG-M, CB, JJ, RL, AJL, SR, RS, LJ, VV-A, RM and RWW were funded by MedImmune; JP and VB were funded by AstraZeneca PLC; JW, RSA-L and JB were funded by NIHR Cambridge Biomedical Research Centre and Kidney Research UK; JS and JF were funded by Retrogenix Ltd

Statistical reanalysis of vascular event outcomes in primary and secondary vascular prevention trials.

BACKGROUND: Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. METHODS: Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan's multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. RESULTS: Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. CONCLUSIONS: Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Findings Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants’ systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Interpretation Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultraacute prehospital setting. Funding British Heart Foundation