A simplified approach to estimating the distribution of occasionally-consumed dietary components, applied to alcohol intake.

BACKGROUND: Within-person variation in dietary records can lead to biased estimates of the distribution of food intake. Quantile estimation is especially relevant in the case of skewed distributions and in the estimation of under- or over-consumption. The analysis of the intake distributions of occasionally-consumed foods presents further challenges due to the high frequency of zero records. Two-part mixed-effects models account for excess-zeros, daily variation and correlation arising from repeated individual dietary records. In practice, the application of the two-part model with random effects involves Monte Carlo (MC) simulations. However, these can be time-consuming and the precision of MC estimates depends on the size of the simulated data which can hinder reproducibility of results. METHODS: We propose a new approach based on numerical integration as an alternative to MC simulations to estimate the distribution of occasionally-consumed foods in sub-populations. The proposed approach and MC methods are compared by analysing the alcohol intake distribution in a sub-population of individuals at risk of developing metabolic syndrome. RESULTS: The rate of convergence of the results of MC simulations to the results of our proposed method is model-specific, depends on the number of draws from the target distribution, and is relatively slower at the tails of the distribution. Our data analyses also show that model misspecification can lead to incorrect model parameter estimates. For example, under the wrong model assumption of zero correlation between the components, one of the predictors turned out as non-significant at 5 % significance level (p-value 0.062) but it was estimated as significant in the correctly specified model (p-value 0.016). CONCLUSIONS: The proposed approach for the analysis of the intake distributions of occasionally-consumed foods provides a quicker and more precise alternative to MC simulation methods, particularly in the estimation of under- or over-consumption. The method is readily available to non-technical users in contrast to MC methods whereby the simulation error may be substantial and difficult to evaluate.

A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea.

BACKGROUND: Irritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D. METHODS: 120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment. RESULTS: Ondansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo -0.9, 95% CI -1.1 to -0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (p<0.001), lower urgency scores (p<0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, p<0.001. CONCLUSIONS: Ondansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.

Self and parent perspectives on health-related quality of life of adolescents born very preterm.

OBJECTIVES: To test whether health-related quality of life (HRQL) based on societal standards differs between very low birth weight/very preterm (VLBW/VP) and full-term (FT) adolescents using self and parent proxy reports. Also, to examine whether self and parent reported HRQL is explained by indicators of objective functioning in childhood. STUDY DESIGN: This prospective cohort study followed 260 VLBW/VP adolescents, 12 VLBW/VP adolescents with disability, and 282 FT adolescents. Objective functioning was assessed at 8.5 years; HRQL was assessed at 13 years with the Health Utilities Index Mark 3 (HUI3). RESULTS: Adolescents reported more functional impairment than their parents especially in the psychological aspects of health. The mean difference in HUI3 multi-attribute utility scores between FT and VLBW/VP adolescents was small (parents: 0.91 [95% CI, 0.90, 0.92] vs 0.88 [95% CI, 0.86, 0.90]; adolescents: 0.87 [95% CI, 0.85, 0.89] vs 0.84 [95% CI, 0.82, 0.86]), but high for VLBW/VP adolescents with disabilities (0.18, 95% CI, -0.04, 0.40). Objective function did not predict HRQL in FT adolescents but contributed to prediction of HRQL in VLBW/VP adolescents without disabilities. Different indicators of objective functioning were important for adolescent vs parent reports. More variation in HUI3 scores was explained by objective function in VLBW/VP parent reports compared with adolescent reports (25% vs 18%). CONCLUSIONS: VLBW/VP adolescents reported poorer HRQL than their FT peers in early adolescence. Improvement in HRQL as VLBW/VP children grow up is, at least partly, explained by exclusion of the most disabled in self reports by VLBW/VP adolescents and the use of different reference points by adolescents compared with parents.

Mother and child behaviour in very preterm and term dyads at 6 and 8 years.

AIM: Mothers of very preterm children have been reported to behave less sensitively and to be more controlling. It is unknown whether this is the result of maternal factors or due to maternal adaptation to children's cognitive problems. METHOD: We investigated a geographically defined prospective whole-population sample of very low birthweight (<1500 g) or very preterm (<32 wks' gestation; VLBW/VP) children (n = 267, 124 females, 143 males) and a comparison group born at term (n = 298, 146 females, 152 males) in Germany. Mother-child interactions were videotaped during a play situation and analysed with a standardized coding system at children's mean ages of 6 years 3 months and 8 years 5 months. RESULTS: At both 6 years 3 months and 8 years 5 months, VLBW/VP children were less task persistent and socially active (p<0.001) whereas their mothers behaved less sensitively and were more controlling than term mother-child dyads (p<0.001). Cross-sectional group differences in maternal behaviour remained when scores where adjusted for social factors but disappeared once adjusted for child IQ. High maternal sensitivity predicted higher task persistence (p<0.001), in particular in those children with cognitive problems. INTERPRETATION: Mothers of VLBW/VP children adapt their behaviour to their children's level of cognitive functioning. High maternal sensitivity is particularly beneficial for task persistence in children with cognitive deficits.

Risk of Hypersensitivity Reactions to Iopromide in Children and Elderly: An Analysis of 132,850 Patients From 4 Observational Studies and Pharmacovigilance Covering >288 Million Administrations.

PURPOSE: The aim of this study was to analyze the risk of hypersensitivity reactions (HSRs) to iopromide in children and elderly patients in comparison to adults. MATERIALS AND METHODS: Four observational studies were pooled and analyzed (analysis I). In addition, spontaneous reports from 1985 to 2020 from the pharmacovigilance database were evaluated (analysis II). All patients received iopromide for angiographic procedures or contrast-enhanced computed tomography in various indications. In analysis I, a nested case-control analysis, including a multivariable logistic regression model, based on pooled observational study data, was performed. Cases were defined as patients with a typical and unequivocal HSR; controls were patients without any recorded reaction. In analysis II, all spontaneous reports on HSRs after iopromide administration recorded in the pharmacovigilance database were descriptively analyzed. Exposure estimates on the size of the exposed age groups were derived from sales data and data from market research. The primary target variable was the risk of HSR to iopromide in children (<18 years) and elderly patients (≥65 years) compared with adults (≥18 to <65 years). RESULTS: In analysis I, a total of 132,850 patients were included (2978 children, 43,209 elderly, and 86,663 adults). Hypersensitivity reactions were significantly less frequent in children (0.47%) and elderly (0.38%) compared with adults (0.74%). The adjusted odds ratio (vs adults) for children was 0.58 (95% confidence interval, 0.34-0.98; P < 0.043), and that for the elderly was 0.51 (95% confidence interval, 0.43-0.61; P < 0.001), indicating a lower risk for both subpopulations as compared with adults. In analysis II, of the overall >288 million iopromide administrations, 5.87, 114.18, and 167.97 million administrations were administered to children, elderly, and adults, respectively. The reporting rate for HSRs in children (0.0114%) and elderly (0.0071%) was significantly lower as compared with adults (0.0143%) (P < 0.0001). CONCLUSIONS: Hypersensitivity reactions to iopromide were significantly less frequent in children and elderly compared with adults.

Management of smokers motivated to quit: a qualitative study of smokers and GPs.

BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) guidelines state that GPs should manage smokers motivated to quit by offering referral to Stop Smoking Services (SSS) and that nicotine addiction treatment (NAT) should be offered only to those who decline referral. OBJECTIVE: To explore how smokers motivated to quit are managed in the GP consultation, specifically how treatment and referral are negotiated from the perspectives of both parties. METHODS: Twenty patients, identified in a consultation with their GP as motivated to quit smoking, and 10 participating GPs were interviewed. Interviews were recorded, transcribed, coded and analysed using the framework approach. RESULTS: Three strategies (treatment and follow-up by the GP, referral to SSS without treatment and immediate treatment with referral for follow-up) were evidenced in patient and GP accounts. Most patients were satisfied with their management and how this was negotiated, but some expressed surprise or dissatisfaction with lack of immediate treatment and questioned the need for referral to SSS. GPs welcomed the availability of SSS but some felt it important that they themselves also continued to support a quit attempt. Several saw advantages in offering NAT at the time the patient was motivated to stop. CONCLUSIONS: Smokers appear less convinced than GPs about the value of referral to SSS, although these differences may be resolved through negotiation. An alternative strategy to that proposed by NICE, which may be more acceptable to some smokers, is immediate treatment with subsequent support from SSS.

Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial.

BACKGROUND: Raised blood pressure is common after acute stroke and is associated with an adverse prognosis. We sought to assess the feasibility, safety, and effects of two regimens for lowering blood pressure in patients who have had a stroke. METHODS: Patients who had cerebral infarction or cerebral haemorrhage and were hypertensive (systolic blood pressure [SBP] >160 mm Hg) were randomly assigned by secure internet central randomisation to receive oral labetalol, lisinopril, or placebo if they were non-dysphagic, or intravenous labetalol, sublingual lisinopril, or placebo if they had dysphagia, within 36 h of symptom onset in this double-blind pilot trial. The doses were titrated up if target blood pressure was not reached. Analysis was by intention to treat. This trial is registered with the National Research Register, number N0484128008. FINDINGS: 179 patients (mean age 74 [SD 11] years; SBP 181 [SD 16] mm Hg; diastolic blood pressure [DBP] 95 [SD 13] mm Hg; median National Institutes of Health stroke scale [NIHSS] score 9 [IQR 5-16] points) were randomly assigned to receive labetolol (n=58), lisinopril (n=58), or placebo (n=63) between January, 2005, and December, 2007. The primary outcome--death or dependency at 2 weeks--occurred in 61% (69) of the active and 59% (35) of the placebo group (relative risk [RR] 1.03, 95% CI 0.80-1.33; p=0.82). There was no evidence of early neurological deterioration with active treatment (RR 1.22, 0.33-4.54; p=0.76) despite the significantly greater fall in SBP within the first 24 h in this group compared with placebo (21 [17-25] mm Hg vs 11 [5-17] mm Hg; p=0.004). No increase in serious adverse events was reported with active treatment (RR 0.91, 0.69-1.12; p=0.50) but 3-month mortality was halved (9.7%vs 20.3%, hazard ratio [HR] 0.40, 95% CI 0.2-1.0; p=0.05). INTERPRETATION: Labetalol and lisinopril are effective antihypertensive drugs in acute stroke that do not increase serious adverse events. Early lowering of blood pressure with lisinopril and labetalol after acute stroke seems to be a promising approach to reduce mortality and potential disability. However, in view of the small sample size, care must be taken when these results are interpreted and further evaluation in larger trials is needed.

Effects of antihypertensive treatment after acute stroke in the Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS): a prospective, randomised, open, blinded-endpoint trial.

BACKGROUND: Up to 50% of patients with acute stroke are taking antihypertensive drugs on hospital admission. However, whether such treatment should be continued during the immediate post-stroke period is unclear. We therefore aimed to assess the efficacy and safety of continuing or stopping pre-existing antihypertensive drugs in patients who had recently had a stroke. METHODS: The Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS) was a UK multicentre, prospective, randomised, open, blinded-endpoint trial. Patients were recruited at 49 UK National Institute for Health Research Stroke Research Network centres from January 1, 2003, to March 31, 2009. Patients aged over 18 years who were taking antihypertensive drugs were enrolled within 48 h of stroke and the last dose of antihypertensive drug. Patients were randomly assigned (1:1) by secure internet central randomisation to either continue or stop pre-existing antihypertensive drugs for 2 weeks. Patients and clinicians who randomly assigned patients were unmasked to group allocation. Clinicians who assessed 2-week outcomes and 6-month outcomes were masked to group allocation. The primary endpoint was death or dependency at 2 weeks, with dependency defined as a modified Rankin scale score greater than 3 points. Analysis was by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Register, number ISRCTN89712435. FINDINGS: 763 patients were assigned to continue (n=379) or stop (n=384) pre-existing antihypertensive drugs. 72 of 379 patients in the continue group and 82 of 384 patients in the stop group reached the primary endpoint (relative risk 0.86, 95% CI 0.65-1.14; p=0.3). The difference in systolic blood pressure at 2 weeks between the continue group and the stop group was 13 mm Hg (95% CI 10-17) and the difference in diastolic blood pressure was 8 mm Hg (6-10; difference between groups p<0.0001). No substantial differences were observed between groups in rates of serious adverse events, 6-month mortality, or major cardiovascular events. INTERPRETATION: Continuation of antihypertensive drugs did not reduce 2-week death or dependency, cardiovascular event rate, or mortality at 6 months. Lower blood pressure levels in those who continued antihypertensive treatment after acute mild stroke were not associated with an increase in adverse events. These neutral results might be because COSSACS was underpowered owing to early termination of the trial, and support the continuation of ongoing research trials. FUNDING: The Health Foundation and The Stroke Association.

Leptin and coronary heart disease: prospective study and systematic review.

OBJECTIVES: This study sought to better determine the link between leptin and coronary heart disease (CHD). BACKGROUND: Circulating leptin is considered a risk factor for CHD but larger studies are needed. METHODS: Leptin levels were measured in 550 men with fatal CHD or nonfatal myocardial infarction and in 1,184 controls nested within a prospective study of 5,661 British men and set in context with a meta-analysis. RESULTS: Baseline leptin correlated with body mass index (BMI), blood pressure, total cholesterol, triglyceride, and inflammatory markers; correlations persisted after BMI adjustment. The within-person consistency of leptin values over 4 years (correlation coefficient: 0.79; 95% confidence interval [CI]: 0.73 to 0.83) was higher than those of some established cardiovascular risk factors. In a comparison of individuals in the top third with those in the bottom third of baseline leptin, the age- and town-adjusted odds ratio for CHD was 1.25 (95% CI: 0.96 to 1.62), decreasing to 0.98 (95% CI: 0.72 to 1.34) after adjustment for BMI. A systematic review identified 7 prospective reports with heterogeneous findings (I(2) = 60%, 13% to 82%). The combined adjusted risk ratio across all studies was 1.44 (95% CI: 0.95 to 2.16) in a comparison of extreme thirds of leptin levels. The inconsistency between studies was partially explained by sample size, with combined estimates from studies involving >100 CHD cases (1.28, 95% CI: 0.80 to 2.04) being somewhat weaker than those from smaller studies (1.81, 95% CI: 0.76 to 4.31). CONCLUSIONS: Previous studies appear to have overestimated associations of leptin and CHD risk. Our results suggest a moderate association that is largely dependent on BMI.