Cardiovascular disease risk in children : 'pre-clinical' markers and the impact of body composition, physical activity and cardiorespiratory fitness

Cardiovascular disease is one of the largest killers in the UK representing 30% of all global deaths. The underlying processes of the disease are thought to begin in childhood. Whilst traditional risk factors of CV disease (e.g. hypertension, hyperlipidemia, obesity, smoking, stress and sedentary lifestyles) are becoming increasingly prevalent within the younger generation there remains the need for the establishment of earlier or "pre-clinical" markers of future CV disease risk or current atherosclerotic load such as left ventricular (LV) mass, diastolic function and carotid intima-media thickness( cIMT). Further, assessing the association of these markers to other risk factors and then determining the impact of physical activity (PA) interventions is warranted. Initially we assessed the impact of body composition, PA and cardiorespiratory (CR) fitness upon left ventricular LV mass, carotid-intima media thickness (cIMT) and LV diastolic function in 218 9-11 year old primary schoolchildren. Pubertal status was assessed through a maturity offset calculation. LV mass, cIMT, and LV diastolic function were assessed via ultrasound. Body mass index was assessed via anthropometry whilst fat mass [FM] and lean mass [LM] were determined via dual X-ray absorptiometry. Average 3-day PA was recorded via a uni-axial accelerometer and CR (VO?peak) was determined from a graded treadmill test. Relationships were analysed using bivariate correlations and forced entry multiple regression. All children were classified as being below their peak height velocity. Together LM, FM, sex and moderate to vigorous (MV)PA accounted for 59% of the variance in LV mass with LM being the most important predictor (P<0.005). Sex, LM, FM and VO?peak explained only 19% variance in cIMT and just 9% of the variance in LV diastolic function was accounted for by LM, FM blood pressure and sex. Data for MVPA had no significant relationship to any cardiovascular (CV) variables although was negatively correlated with FM. The strong association between LV mass and body composition likely represents normal growth. The limited shared variance between predictor variables and cIMT and LV diastolic function suggests that those pre-peak height velocity children in the current cohort who were overweight, inactive and unfit were not yet at an increased CV disease risk. Thus there is a window of opportunity for intervention programmes to be implemented that reduce CV disease risk before adolescence and adulthood. Following this, an exploratory trial was conducted to introduce the use of PA interventions in pre-pubertal children. Sixty-one 10-11 year old Liverpool primary school children volunteered and were randomly assigned by school to a STEX programme (2 x 60 min sessions per week at a heart rate of ~145 beats min??), a PASS programme (weekly physical activity tasks and pedometer challenges) and a control (CON; no intervention). Pre-clinical CV measures and body composition were measured before and after the 9-week intervention period. The primary outcome variable was cIMT, with LV mass, LV diastolic function, and body composition defined as secondary outcomes. Delta (?) scores were analysed by ANCOVA, with baseline scores as the covariate. For the primary outcome, the probability that the population effect of the intervention is at least as great as the pre-specified minimum clinically importance difference (MCID) was estimated, to evaluate clinical relevance. All participants met 75% compliance criteria for STEX and PASS. The effect of the STEX intervention (compared with CON) was a mean benefit of -0.018mm for average maximum cIMT (90% CI, -0.039 to 0.002mm), and -0.016mm for average mean cIMT (90 % CI, -0.040 to 0.008mm). The probability (% chances) that the true population effect of the STEX intervention would be clinically beneficial was 79% for average maximum and 71% for average mean cIMT. The PASS intervention did not result in clinically important effects, and no other substantial changes were observed for the secondary outcome variables. The relatively high probability of clinically beneficial effects of the STEX intervention suggests that a larger, "definitive" randomised trial with longer follow-up is warranted to define the effectiveness of the intervention more precisely. As a consequence the longer PA intervention study observed 152 children aged 9 to 10 years over 12 months. All of the echocardiographic, body composition, CR fitness and PA variables mentioned were assessed as previously discussed. Children were randomly assigned by school to an intervention group. Control (no intervention), PASS (as before except delivered during school hours to enhance compliance), high intensity physical activity (the same as STEX but renamed due to the addition of another structured exercise group) or fundamental movement skill ([FMS] 2x 60 min sessions per week of skill based activities). These interventions took place over a year period with participants being assessed at baseline, approximately mid-way through and post-test (52 weeks). Initial factorial ANOVA analysis comparing all 3 intervention groups and a control group before, during and after the 12 month intervention period, found limited statistically significant evidence for a positive impact of PA interventions compared to controls in pre-pubertal children. However, after adjusting for confounding variables in an ANCOVA analysis some sporadic benefits of PA interventions on CV variables were uncovered. An increase in LV mass over 12 months, after adjustment, was lower in the HIPA group compared to CON group (11.5 g; 90% CI, 2.0 to 21.0 g). This change was also lower in the FMS group compared to CON group (13.8 g; 90% CI, 4.6 to 23.1 g). The ANCOVA adjusted change scores for both mean and max cIMT were less in the intervention groups compared to CON group but only in the PASS group were these differences significant (P<0.05). PASS increased its mean cIMT (-0.014mm less than control (90% CI, -0.002 to -0.030)). Somewhat surprisingly the intervention programmes had no positive effect on CR fitness (indeed this decreased), PA measures and/or body composition over and above changes observed due to growth. This thesis has provided a unique insight into the 'pre-clinical' CV disease risk factors in pre-pubertal children and the impact of differing PA activity interventions with this group. Interestingly the research has shown that within this population overweight/obese, inactive low CR fit individuals are generally not at a higher CV disease risk than their aged matched 'healthier' counterparts. When PA interventions are introduced in the short term positive changes in cIMT were seen, however, this is not reciprocated in longer PA interventions possibly due to a larger maturation effect over 12 months. Interestingly year long interventions provide some attenuation of growth-related changes in CV disease risk factors but these changes are generally small and sporadic. It is suggested that further research over a longer period of time with more 'at risk' populations is needed. The PA interventions adopted achieved high attendance and compliance records and thus may be transferable out of the research process. It is interesting to also speculate that future research may not need to administer high impact activity, as previously thought, as some positive data was obtained in more general lifestyle interventions involving more knowledge transfer

Physical activity guidelines and cardiovascular risk in children: a cross-sectional analysis to determine whether 60 minutes is enough

Background Physical activity reduces cardiovascular mortality and morbidity. The World Health Organisation (WHO) recommends children engage in 60 min daily moderate-to-vigorous physical activity (MVPA). The effect of compliance with this recommendation on childhood cardiovascular risk has not been empirically tested. To evaluate whether achieving recommendations results in reduced composite-cardiovascular risk score (CCVR) in children, and to examine if vigorous PA (VPA) has independent risk-reduction effects. Methods PA was measured using accelerometry in 182 children (9–11 years). Subjects were grouped according to achievement of 60 min daily MVPA (active) or not (inactive). CCVR was calculated (sum of z-scores: DXA body fat %, blood pressure, VO2peak, flow mediated dilation, left ventricular diastolic function; CVR score ≥1SD indicated ‘higher risk’). The cohort was further split into quintiles for VPA and odds ratios (OR) calculated for each quintile. Results Active children (92 (53 boys)) undertook more MVPA (38 ± 11 min, P  0.05). CCVR in the lowest VPA quintile was significantly greater than the highest quintile (3.9 ± 0.6, P < 0.05), and the OR was 4.7 times higher. Conclusion Achievement of current guidelines has positive effects on body composition and cardiorespiratory fitness, but not CCVR. Vigorous physical activity appears to have beneficial effects on CVD risk, independent of moderate PA, implying a more prescriptive approach may be needed for future VPA guidelines

Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials

Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand– foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs

Living with unsettled baby behaviours:Qualitative interview study exploring parental perceptions and experiences of help-seeking

Aim: To explore parents' perceptions/experiences of help-seeking for unsettled baby behaviours, including views and experiences of obtaining advice from primary healthcare professionals. Design: Semi-structured qualitative interviews. Methods: Recruitment occurred via social media, general practice and health visiting teams. Remote semi-structured interviews were conducted with parents of babies. Babies were under 12 months old at time of interview, and parents had perceived unsettled baby behaviours in their first 4 months of life. Interviews were transcribed and data analysed using reflexive thematic analysis. Results: Based on interviews with 25 mothers, four main themes were developed. ‘The need for answers’ highlighted parental uncertainty about what constitutes normal baby behaviour, leading to help-seeking from multiple sources. ‘The importance of health professionals’ and ‘Experiencing health professional support’ identified perceptions about limited access, communication, mixed advice and how these influenced parental perception/management of behaviours. ‘Foundations to help-seeking’ highlighted important roles of social support and online help for valued shared experiences, emotional and practical support. Conclusion: Health professional access and advice are important to parents, despite the increasing role of online help and importance of social support. More support and improved access to reliable sources of information is needed for parents. Implications for the Profession and/or Patient Care: Findings will inform future research and clinical practice to address parental uncertainties. Qualitative research with front-line health professionals is necessary. Impact: Findings can inform the development of resources to support professionals/families managing unsettled babies. Reporting Method: Standards for Reporting Qualitative Research. Public Involvement: A public contributor was involved throughout all stages of the research. Emerging findings were discussed at a parent group. What does this paper contribute to the wider global clinical community?: Addressing parental uncertainties is important; about what is normal, non-pharmacological approaches and when pharmacological intervention is required. A digital information/self-management intervention may be useful for parents/clinicians.</p

Thematic synthesis of the experiences of people with Hidradenitis Suppurativa: a systematic review

BackgroundAlthough Hidradenitis Suppurativa (HS) is known to affect quality of life, little summative knowledge exists on how HS impacts people living with the condition.Aimto synthesise experiences of people with HS within published qualitative research.MethodsSearches on databases MEDLINE, PsycINFO, EMBASE and CINHAL were conducted on 17th April 2020. Two independent reviewers screened 5512 publications. Study quality was assessed using the National Institute for Health and Care Excellence (NICE) quality appraisal checklist for qualitative studies. Thematic synthesis generated descriptive and analytic themes.ResultsFourteen studies were included. Four studies fulfilled most quality criteria, eight studies fulfilled some quality criteria, and two studies fulfilled few quality criteria. There were three final themes. 1) Putting the brakes on life - The physical, psychological and social consequences of HS resulted in people missing out on multiple life events. This could have a cumulative effect that influences the trajectory of someone’s life. 2) A stigmatised identity: concealed and revealed – People try to conceal their HS, visually and verbally, but this results anticipation and fear of exposure. Social support and psychological acceptance helped people cope. Connection with others with HS may have a specific role in preserving a positive self-identity. 3) falling through the cracks – Delayed diagnosis, misdiagnosis and lack of access to care were reported. People felt unheard and misunderstood by healthcare professionals, and healthcare interactions could enhance feelings of shame.ConclusionsThere needs to be improvements to clinical care to allow people with HS to live their life more fully