Conducting research in individual patients: lessons learnt from two series of N-of-1 trials

BACKGROUND: Double-blind randomised N-of-1 trials (N-of-1 trials) may help with decisions concerning treatment when there is doubt regarding the effectiveness and suitability of medication for individual patients. The patient is his or her own control, and receives the experimental and the control treatment during several periods of time in random order. Reports of N-of-1 trials are still relatively scarce, and the research methodology is not as firmly established as that of RCTs. Recently, we have conducted two series of N-of-1 trials in general practice. Before, during, and after data-collection, difficulties regarding outcome assessment, analysis of the results, the withdrawal of patients, and the follow-up had to be dealt with. These difficulties are described and our solutions are discussed. DISCUSSION: To prevent or anticipate difficulties in N-of-1 trials, we argue that that it is important to individualise the outcome measures, and to carefully consider the objective, type of randomisation and the analysis. It is recommended to use the same dosages and dosage forms that the patient used before the trial, to start the trial with a run-in period, to formulate both general and individualised decision rules regarding the efficacy of treatment, to adjust treatment policies immediately after the trial, and to provide adequate instructions and support if treatment is adjusted. SUMMARY: Because of the specific characteristics of N-of-1 trials it is difficult to formulate general 'how to do it' guidelines for designing N-of-1 trials. However, when the design of each N-of-1 trial is tailored to the specific characteristics of each individual patient and the underlying medical problem, most difficulties in N-of-1 trials can be prevented or overcome. In this way, N-of-1 trials may be of help when deciding on drug treatment for individual patients

The dream-lag effect: Selective processing of personally significant events during Rapid Eye Movement sleep, but not during Slow Wave Sleep

Incorporation of details from waking life events into Rapid Eye Movement (REM) sleep dreams has been found to be highest on the night after, and then 5–7 nights after events (termed, respectively, the day-residue and dream-lag effects). In experiment 1, 44 participants kept a daily log for 10 days, reporting major daily activities (MDAs), personally significant events (PSEs), and major concerns (MCs). Dream reports were collected from REM and Slow Wave Sleep (SWS) in the laboratory, or from REM sleep at home. The dream-lag effect was found for the incorporation of PSEs into REM dreams collected at home, but not for MDAs or MCs. No dream-lag effect was found for SWS dreams, or for REM dreams collected in the lab after SWS awakenings earlier in the night. In experiment 2, the 44 participants recorded reports of their spontaneously recalled home dreams over the 10 nights following the instrumental awakenings night, which thus acted as a controlled stimulus with two salience levels, high (sleep lab) and low (home awakenings). The dream-lag effect was found for the incorporation into home dreams of references to the experience of being in the sleep laboratory, but only for participants who had reported concerns beforehand about being in the sleep laboratory. The delayed incorporation of events from daily life into dreams has been proposed to reflect REM sleep-dependent memory consolidation. However, an alternative emotion processing or emotional impact of events account, distinct from memory consolidation, is supported by the finding that SWS dreams do not evidence the dream-lag effect

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Use of and attitudes to the role of medication for acute whiplash injury: A preliminary survey of emergency department doctors

Objective: Describe current practice of medication prescribing for acute whiplash-associated disorders (WAD) in the ED and explore attitudes towards pregabalin prescription for WAD. Methods: Questionnaire-based survey in two EDs collected data on demographics and self-reported medication prescribing for WAD. Comfort in various scenarios for pregabalin prescribing was rated. Results: A total of 145/170 (85%) doctors responded; 42.8% were junior doctors. Self-reported medications prescribed were nonsteroidal anti-inflammatory drug (77.9% [95% confidence interval (CI) 70.1–84.2]), paracetamol (75.2% [95% CI 67.2–81.8]), opioids (43.5% [95% CI 35.3–51.9]) and benzodiazepines (11.0% [95% CI 6.6–17.6]). Most were comfortable to prescribe pregabalin in evidence-based or advised-by-specialists scenarios. Conclusions: Opioids appear to be over-prescribed. Further research into pregabalin prescription in ED is warranted

Comparative performance of Corymbia hybrids and parental species in subtropical Queensland and implications for breeding and deployment.

Eighty six full-sib Corymbia F1 hybrid families (crosses between C. torelliana and four spotted gum taxa: C. citriodora subsp. variegata, C. citriodora subsp. citriodora, C. henryi and C. maculata), were planted in six trials across six disparate sites in south-eastern Queensland to evaluate their productivity and determine their potential utility for plantation forestry. In each trial, the best-growing 20% of hybrid families grew significantly faster (P=0.05) than open-pollinated seedlots of the parent species Corymbia citriodora subsp. variegata, ranging from 107% to 181% and 127% to 287% of the height and diameter respectively. Relative performance of hybrid families growing on more than one site displayed consistency in ranking for growth across sites and analysis showed low genotype-by-environment interaction. Heritability estimates based on female and male parents across two sites at age six years for height and diameter at breast height, were high (0.62±0.28 to 0.64±0.35 and 0.31±0.21 to 0.69±0.37 respectively), and low to moderate (0.03±0.04 to 0.33±0.22) for stem straightness, branch size, incidence of ramicorns, and frost and disease resistance traits at ages one to three years. The proportion of dominance variance for height and diameter had reduced to zero by age six years. Based on these promising results, further breeding and pilot-scale family forestry and clonal forestry deployment is being undertaken. These results have also provided insights regarding the choice of a future hybrid breeding strategy