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Background Expediting cancer diagnosis may be achieved by targeted decreases in referral thresholds to increase numbers of patients referred for urgent investigation. Methods Clinical Practice Research Datalink data from England for 150,921 adults aged ≥40 were used to identify participants with features of possible cancer equating to risk thresholds ≥1%, ≥2% or ≥3% for breast, lung, colorectal, oesophago-gastric, pancreatic, renal, bladder, prostatic, ovarian, endometrial and laryngeal cancers. Results The mean age of participants was 60 (SD 13) years, with 73,643 males (49%). In 2016, 8576 consultation records contained coded features having a positive predictive value (PPV) of ≥3% for any of the 11 cancers. This equates to a rate of 5682/100,000 patients compared with 4601/100,000 Suspected Cancer NHS referrals for these cancers from April 2016–March 2017. Nine thousands two hundred ninety-one patient-consultation records had coded features equating to a ≥2% PPV, 8% more than met PPV ≥ 3%. Similarly, 19,517 had features with a PPV ≥ 1%, 136% higher than for PPV ≥ 3%. Conclusions This study estimated the number of primary-care patients presenting at lower thresholds of cancer risk. The resource implications of liberalising this threshold to 2% are modest and manageable. The details across individual cancer sites should assist planning of English cancer services.

Breathlessness is common in patients with advanced cancer and almost universal in advanced chronic obstructive pulmonary disease (COPD), but studies suggest their experiences of breathlessness vary. This report builds on these studies by providing quantitative evidence of differences in respiratory health-related quality of life (HRQoL) between these groups. Further, it explores the validity of the Chronic Respiratory Questionnaire (CRQ) in patients with cancer. The CRQ-Original was completed within baseline interviews for a randomised controlled trial of a palliative intervention for intractable breathlessness due to advanced disease. Independent samples Mann-Whitney U tests were performed to identify significant differences in median scores for the four CRQ domains (mastery, dyspnoea, emotional function, fatigue) in patients with advanced COPD (n=73) or advanced cancer (n=67). The Minimally Clinically Important Difference of 0.5 was applied to determine clinical significance. Patients with advanced COPD scored lower across all four CRQ domains. This was statistically significant for dyspnoea, mastery and emotional function (p<0.05), and clinically significant for the latter two, suggesting poorer respiratory HRQoL. Patients with breathlessness due to advanced COPD have worse respiratory HRQoL than those with advanced cancer. This may result from greater burden of breathlessness in COPD due to condition longevity, lesser burden of breathlessness in cancer due to its episodic nature, or variance in palliative referral thresholds by disease group. Our results suggest that greater access to palliative care is needed in advanced COPD, and that formal psychometric testing of the CRQ may be warranted in cancer. NCT00678405.

Cardiac autonomic regulation can be indirectly measured by heart rate variability (HRV). Low HRV, which can be induced by mental stress, is a predictor of risk of sudden cardiac death. Few studies have investigated cause-and-effect relationships between diet and HRV. Nut consumption is associated with CVD risk reduction, but the impact on HRV, particularly in response to stress, is unclear. Men and women (30–70 y) with above average risk of developing CVD were randomly assigned in a 6-week randomized, controlled, parallel arm trial to consume either whole almond or isocaloric control snacks (20% of daily estimated energy requirement). Control snacks contained the average nutrient profile of UK snacks. Five-minute periods of supine heart rate (HR) and HRV were measured at resting and during mental stress (Stroop color-word test) at baseline and six weeks. High frequency (HF) power, which reflects parasympathetic regulation of HR, was increased following almonds during the mental stress task relative to control (mean difference between groups 124 ms2; 95% CI 11, 237; p = 0.031, n = 105), but other indices were unaffected. Snacking on whole almonds instead of typical snacks may reduce risk of CVD partly by ameliorating the suppression of HRV during periods of mental stress.

Background/ObjectivesObesity in pregnancy has been associated with increased childhood cardiometabolic risk and reduced life expectancy. The UK UPBEAT multicentre randomised control trial was a lifestyle intervention of diet and physical activity in pregnant women with obesity. We hypothesised that the 3-year-old children of women with obesity would have heightened cardiovascular risk compared to children of normal BMI women, and that the UPBEAT intervention would mitigate this risk.Subjects/MethodsChildren were recruited from one UPBEAT trial centre. Cardiovascular measures included blood pressure, echocardiographic assessment of cardiac function and dimensions, carotid intima-media thickness and heart rate variability (HRV) by electrocardiogram.ResultsCompared to offspring of normal BMI women (n = 51), children of women with obesity from the trial standard care arm (n = 39) had evidence of cardiac remodelling including increased interventricular septum (IVS; mean difference 0.04 cm; 95% CI: 0.018 to 0.067), posterior wall (PW; 0.03 cm; 0.006 to 0.062) and relative wall thicknesses (RWT; 0.03 cm; 0.01 to 0.05) following adjustment. Randomisation of women with obesity to the intervention arm (n = 31) prevented this cardiac remodelling (intervention effect; mean difference IVS −0.03 cm (−0.05 to −0.008); PW −0.03 cm (−0.05 to −0.01); RWT −0.02 cm (−0.04 to −0.005)). Children of women with obesity (standard care arm) compared to women of normal BMI also had elevated minimum heart rate (7 bpm; 1.41 to 13.34) evidence of early diastolic dysfunction (e prime) and increased sympathetic nerve activity index by HRV analysis.ConclusionsMaternal obesity was associated with left ventricular concentric remodelling in 3-year-old offspring. Absence of remodelling following the maternal intervention infers in utero origins of cardiac remodelling.Clinical trial registry name and registration numberThe UPBEAT trial is registered with Current Controlled Trials, ISRCTN89971375.

K-rich fruit and vegetables may lower blood pressure (BP) and improve vascular function. A randomised controlled trial (ISRCTN50011192) with a cross-over design was conducted in free-living participants with early stages of hypertension (diastolic BP>80 and < 100 mmHg, not receiving BP-lowering medication) to test this hypothesis. Following a 3-week run-in period on a control diet, each subject completed four dietary 6-week dietary interventions (control+placebo capsules, an additional 20 or 40 mmol K+/d from fruit and vegetables or 40 mmol potassium citrate capsules/d) using a Latin square design with a washout period ≥ 5 weeks between the treatment periods. Out of fifty-seven subjects who were randomised, twenty-three male and twenty-five female participants completed the study; compliance to the intervention was corroborated by food intake records and increased urinary K+ excretion; plasma lipids, vitamin C, folate and homocysteine concentrations, urinary Na excretion, and body weight remained were unchanged. On the control diet, mean ambulatory 24 h systolic/diastolic BP were 132·3 (sd 12·0)/81·9 (sd 7·9) mmHg, and changes (Bonferroni's adjusted 95 % CI) compared with the control on the diets providing 20 and 40 mmol K+/d as fruit and vegetables were 0·8 ( − 3·5, 5·3)/0·8 ( − 1·9, 3·5) and 1·7 ( − 3·0, 5·3)/1·5 ( − 1·5, 4·4), respectively, and were 1·8 ( − 2·1, 5·8)/1·4 ( − 1·6, 4·4) mmHg on the 40 mmol potassium citrate supplement, and were not statistically significant. Arterial stiffness, endothelial function, and urinary and plasma isoprostane and C-reactive protein (CRP) concentrations did not differ significantly between the diets. The present study provides no evidence to support dietary advice to increase K intake above usual UK intakes in the subjects with early stages of hypertension.

The dicarboxylic acid hexadecanedioate is associated with increased blood pressure (BP) and mortality in humans and feeding it to rats raises BP. Here we aim to characterise the molecular pathways that influence levels of hexadecanedioate linked to BP regulation, using genetic and transcriptomic studies. The top associations for hexadecanedioate in a genome-wide association scan (GWAS) conducted on 6447 individuals from the TwinsUK and KORA cohorts were tested for association with BP and hypertension in the International Consortium for BP and in a GWAS of BP extremes. Transcriptomic analyses correlating hexadecanedioate with gene expression levels in adipose tissue in 740 TwinsUK participants were further performed. GWAS showed 242 SNPs mapping to two independent loci achieving genome-wide significance. In rs414056 in the SCLO1B1 gene (Beta(SE) = -0.088(0.006)P = 1.65 x 10-51, P < 1 x 10-51), the allele previously associated with increased risk of statin associated myopathy is associated with higher hexadecanedioate levels. However this SNP did not show association with BP or hypertension. The top SNP in the second locus rs6663731 mapped to the intronic region of CYP4Z2P on chromosome 1 (0.045(0.007), P = 5.49x10-11). Hexadecanedioate levels also correlate with adipose tissue gene-expression of the 3 out of 4 CYP4 probes (P<0.05) and of alcohol dehydrogenase probes (Beta(SE) = 0.12(0.02); P = 6.04x10-11). High circulating levels of hexadecanedioate determine a significant effect of alcohol intake on BP (SBP: 1.12(0.34), P = 0.001; DBP: 0.70(0.22), P = 0.002), while no effect is seen in the lower hexadecanedioate level group. In conclusion, levels in fat of ADH1A, ADH1B and CYP4 encoding enzymes in the omega oxidation pathway, are correlated with hexadecanedioate levels. Hexadecanedioate appears to regulate the effect of alcohol on BP.

Purpose Healthy microcirculation is important to maintain the health of tissues and organs, most notably the heart, kidney and retina. Single components of the diet such as salt, lipids and polyphenols may influence microcirculation, but the effects of dietary patterns that are consistent with current dietary guidelines are uncertain. It was hypothesized that compliance to UK dietary guidelines would have a favourable effect on skin capillary density/recruitment compared with a traditional British diet (control diet). Methods A 12-week randomized controlled trial in men and women aged 40–70 years was used to test whether skin microcirculation, measured by skin video-capillaroscopy on the dorsum of the finger, influenced functional capillary density (number of capillaries perfused under basal conditions), structural capillary density (number of anatomical capillaries perfused during finger cuff inflation) and capillary recruitment (percentage difference between structural and functional capillary density). Results Microvascular measures were available for 137 subjects out of the 165 participants randomized to treatment. There was evidence of compliance to the dietary intervention, and participants randomized to follow dietary guidelines showed significant falls in resting supine systolic, diastolic and mean arterial pressure of 3.5, 2.6 and 2.9 mmHg compared to the control diet. There was no evidence of differences in capillary density, but capillary recruitment was 3.5 % (95 % CI 0.2, 6.9) greater ( P  = 0.04) on dietary guidelines compared with control. Conclusions Adherence to dietary guidelines may help maintain a healthy microcirculation in middle-aged men and women. This study is registered at www.isrctn.com as ISRCTN92382106.

Endothelial dysfunction is a predictor for cardiovascular disease risk and is a key feature of atherosclerosis. Poor diet quality, including consumption of saturated fat-rich, high-refined carbohydrate snack foods, may have adverse effects on endothelial function. Thus, snack foods, which contribute an average of 20% of energy intake in the UK adult population, present an easily identifiable target to improve vascular health. Almonds are nutrient-dense foods that are rich in unsaturated fats, fibre, minerals and non-nutrient bioactives (NNB), and may have health benefits by displacing snacks high in refined carbohydrates, enriching the diet with micronutrients and NNB, and/or low lipid bioaccessibility. Human clinical trials have demonstrated LDL cholesterol-lowering effects of daily almond consumption, yet the effects on endothelial function are unclear. This study aimed to investigate whether replacing habitual snacks (20% estimated daily energy requirements) with almonds had any impact on endothelium-dependent vasodilation, measured by flow-mediated dilatation (FMD) using ultrasound imaging of the brachial artery following reactive hyperaemia. A randomised, controlled, parallel trial in adult regular snack consumers aged 30–70 y at moderate risk of cardiovascular disease was conducted, including a 2-week run-in period with control snacks and a 6-week intervention period. Control sweet and savoury mini muffin snacks were developed to replicate the average UK snack nutrient profile, which was calculated from snack foods identified in the UK National Diet and Nutrition Survey (NDNS) database (55% energy from carbohydrate, 36% total fat (14% saturated fat), and 10% protein). One hundred and nine volunteers (77 females and 32 males; mean age 56 y) were enrolled in the study and 107 were randomised to isocaloric treatments, 1) control muffins, or 2) dry roasted whole almonds; 105 participants completed the study. Almonds significantly increased FMD relative to control (mean difference 3.6%, 95% CI 1.7, 5.5; P < 0.001), indicating improved endothelial function, and LDL-cholesterol (mean difference -0.25 mmol/L, 95% CI -0.47, -0.03; P = 0.030) significantly decreased adjusted with sex, age and baseline BMI and baseline dependent outcome values. Snacking on whole almonds as a replacement for snacks high in refined starch and sugar, and low in fibre and unsaturated fatty acids, improves endothelial function. The results of this study provide further evidence for the importance of nuts in dietary strategies to reduce risk of cardiovascular disease.

Postprandial insulinaemia, triglyceridaemia and measures of inflammation are thought to be more closely associated with cardiovascular risk than fasting measures. Although hypertension is associated with altered fasting metabolism, it is unknown as to what extent postprandial lipaemic and inflammatory metabolic responses differ between hypertensive and normotensive individuals. Linear models adjusting for age, sex, body mass index (BMI), visceral fat mass (VFM) and multiple testing (false discovery rate), were used to investigate whether hypertensive cases and normotensive controls had different fasting and postprandial (in response to two standardised test meal challenges) lipaemic, glycaemic, insulinaemic, and inflammatory (glycoprotein acetylation (GlycA)) responses in 989 participants from the ZOE PREDICT-1 nutritional intervention study. Compared to normotensive controls, hypertensive individuals had significantly higher fasting and postprandial insulin, triglycerides, and markers of inflammation after adjusting for age, sex, and BMI (effect size: Beta (Standard Error) ranging from 0.17 (0.08), p = 0.04 for peak insulin to 0.29 (0.08), p = 4.4 × 10−4 for peak GlycA). No difference was seen for postprandial glucose. When further adjusting for VFM effects were attenuated. Causal mediation analysis suggests that 36% of the variance in postprandial insulin response and 33.8% of variance in postprandial triglyceride response were mediated by VFM. Hypertensive individuals have different postprandial insulinaemic and lipaemic responses compared to normotensive controls and this is partially mediated by visceral fat mass. Consequently, reducing VFM should be a key focus of health interventions in hypertension. Trial registration: The ClinicalTrials.gov registration identifier is NCT03479866.

The mitochondrial theory of ageing proposes that damage to mitochondria and diminished mitochondrial DNA (mtDNA) repair are major contributors to cellular dysfunction and age-related diseases. We investigate the prevalence of heteroplasmy in the mtDNA control region in buccal swab and blood derived samples for 178 women from the TwinsUK cohort (41 DZ pair 39 MZ pairs, 18 singletons, mean age 57.5 range 28-82) and its relationship to age, BMI and fasting insulin and glucose serum levels. The overall estimated prevalence of heteroplasmy for both tissues in the control region measured for 37 sites was 17%. The prevalence of heteroplasmy was higher among the older half of the study subjects than in the younger half (23% vs 10% p<0.03), primarily reflecting the increase in the prevalence of a heteroplasmic dinucleotide CA repeat in variable region II (VRII) with age. The VRII 523-524 heteroplasmic site (heteroplasmic in 25 subjects) was also associated with a decrease in BMI. In addition, concordance rates for common heteroplasmy were observed to be near complete for both dizygotic (DZ = 94%) and monozygotic twin pairs (MZ = 100%), consistent with previous reports that suggest variation in heteroplasmy rates between generations are determined by bottlenecks in maternal transmission of mitochondria. Differences in the prevalence of heteroplasmy were observed overall between samples derived from buccal swabs (19%) and blood (15%, p<0.04). These were particularly marked at position 16093 of hypervariable region I (HVI, 7% vs 0%, respectively, p<4×10(-11)). The presence of the C allele at position 16093 in blood was associated with the presence of heteroplasmy in buccal swabs at this position (p = 3.5×10(-14)) and also at VRII (p = 2×10(-4)) suggesting a possible predisposing role for this site in the accumulation of heteroplasmy. Our data indicate that BMI is potentially associated with control region heteroplasmy.