A review of the NG17 recommendations for the use of basal insulin in type 1 diabetes.

AIMS: To revisit the data analysis used to inform National Institute of Health and Care Excellence (NICE) NG17 guidance for initiating basal insulin in adults with type 1 diabetes mellitus (diabetes). METHODS: We replicated the data, methodology and analysis used by NICE diabetes in the NG17 network meta-analysis (NMA). We expanded this data cohort to a more contemporary data set (extended 2017 NMA) and restricted the studies included to improve the robustness of the data set (restricted 2017 NMA) and in a post hoc analysis, changed the index comparator from neutral protamine Hagedorn (NPH) insulin twice daily to insulin detemir twice daily. RESULTS: The absolute changes in HbA1c were similar to those reported in the NG17. However, all 95% credible intervals for change in HbA1c point estimates crossed the line of null effect, except for detemir twice daily (in the NICE and extended 2017 NMAs) and NPH four times daily. In the detemir twice-daily centred post hoc analysis, the 95% credible intervals for change in HbA1c crossed the line of null effect for all basal therapies, except NPH. CONCLUSIONS: In NG17, comparisons of basal insulins were based solely on efficacy of glycaemic control. Many of the trials used in this analysis were treat-to-target, which minimize differences in HbA1c . In the NMAs, statistical significance was severely undermined by the wide credible intervals. Despite these limitations, point estimates of HbA1c were used to rank the insulins and formed the basis of NG17 guidance. This study queries whether such analyses should be used to make specific clinical recommendations.

Improving management of glycaemic control in people with T2DM in primary care: estimation of the impact on the clinical complications and associated costs.

BACKGROUND: To estimate the potential benefits in terms of avoided complications and cost reduction if the Spanish health system would encourage the intensification of treatment for better glycaemic control in adults with Type 2 diabetes from the current HbA1c target used in clinical practice of 68 mmol/mol to a target of 53 mmol/mol. METHODS: The IQVIA Core Diabetes Model (version 9.0) was used to model the impact of these changes in respect of micro- and macrovascular complications and the associated costs. The modelling was based on data derived from the SIDIAP-Q population database from Catalonia, taking a random cohort of 10,000 people with type 2 diabetes and dividing it into sub-groups based on their baseline HbA1c. RESULTS: The CDM modelling showed that the average cost reduction per person varies depending on baseline HbA1c. The model estimates that after 25 years, people with a baseline HbA1c between 48 and 58 mmol/mol and > 75 mmol/mol show an average cost reduction of €6027 and €11,966, respectively. Applying the per-person cost reduction to the cohorts of the prevalent population in Spain (1,910,374) the overall estimated cost reduction was €14.7 billion over 25 years. The improvements in outcomes resulted in an estimated reduction of more than 1.2 million complications cumulatively over 25 years, of which more than 550,000 relate to diabetic foot and more than 170,000 related to renal disease. CONCLUSION: Over a 25 year period, Spain could considerably reduce costs and avoid major complications if, on a population level, more ambitious glycaemic control, according to Spanish or EU guidelines, could be achieved among people with type 2 diabetes by reducing the HbA1c threshold for treatment intensification. Although there is a slower trajectory for benefits in earlier years, there is a much more rapid benefit gain between years 5 and 15.

Estimating the impact of better management of glycaemic control in adults with Type 1 and Type 2 diabetes on the number of clinical complications and the associated financial benefit.

AIM: To estimate potential cost avoidance through modest and achievable improvements in glycaemic control in adults with Type 1 or Type 2 diabetes mellitus in the UK healthcare system. METHODS: The IMS Core Diabetes Model was used to examine the impact of improved glycaemic control (indicated by reduction in HbA1c level), in a representative cohort of adults with Type 1 or Type 2 diabetes. The cumulative incidence of microvascular and macrovascular complications was modelled across 5-year periods to a 25-year time horizon. Complication costs were applied to the data to estimate potential accrued cost avoidance. RESULTS: Significant cost avoidance of ~£340 m is apparent in the first 5 years, increasing to ~£5.5bn after 25 years of sustained improvement in control. The overwhelming majority of cost avoidance arises from reductions in microvascular complications. In people with Type 1 diabetes the greatest cost avoidance comes from a reduction in renal disease (74% of cost avoidance), while in people with Type 2 diabetes it is generated by a reduction in foot ulcers, amputations and neuropathy: 57% cost avoidance). Greater cost reduction is accrued more rapidly in people with higher starting HbA1c levels. CONCLUSION: Modest improvements in glycaemic control generate significant reductions in the incidence and, therefore, cost of microvascular complications in people with Type 1 or Type 2 diabetes. This study provides clear support for the premise that prioritized and sustained investment in early and better intervention can provide concrete financial benefits in both the short and longer term.

Evidence of frequent dosing errors in paediatrics and intervention to reduce such prescribing errors.

WHAT IS KNOWN AND OBJECTIVE: Drug prescribing is an essential part of inpatient care, and prescription errors/omissions have the potential to lead to disastrous consequences. Paediatric inpatient prescribing is particularly sensitive to error due to the weight-adjusted dosing of many medications prescribed in the acute setting. Previous studies have described a high incidence of error in adult drug chart completion, although no studies to date have assessed the error seen in the paediatric setting or accuracy of weight-adjusted dosing. Our objective was to determine the degree of error seen in paediatric drug prescribing for patients admitted under the care of oral and maxillofacial surgery and to explore practical and accessible methods through which error can be reduced. METHODS: We retrospectively evaluated inpatient drug charts to assess the prescribing practices seen for patients admitted under the care of oral and maxillofacial surgery in an NHS children's hospital and compared these findings against established hospital standards. The study also examined the distribution and variability of weight-adjusted dose prescribing in an attempt to set targets for auditing improvements following the implementation of changes. RESULTS AND DISCUSSION: Prescriptions were completed by a combination of doctors from maxillofacial and anaesthetic teams, with similar error rates seen in both specialties. 13% of drug charts contained one or more errors in frequency prescribing. For weight-adjusted drugs, a median under-dosage of -5·4% was noted, with an IQR of -12 to -0·6. Our study has confirmed that errors are common both in the manual completion of paediatric prescription charts and in the calculation of weight-adjusted doses. WHAT IS NEW AND CONCLUSION: We conclude that inaccuracies in prescription chart completion are a frequent occurrence and that dosage and frequency-prescribing errors may potentially act synergistically to create a significant disparity between the recommended and actual amount of drug that is delivered. Our study demonstrates a clear bias towards under-prescribing weight-adjusted doses which may be contributing to reduced efficacy of analgesia, among other drugs. Simple methods can be implemented on a specialty basis to improve the accuracy of both drug chart completion and weight-adjusted dosing.

Hydraulic conductivity assessment of falling head percolation tests used for the design of on-site wastewater treatment systems.

The suitability of a location for an on-site wastewater treatment process (for areas which lack access to centralised wastewater treatment systems) requires an assessment of the permeability of the soil into which the effluent will be discharged. In many jurisdictions this is determined using some type of in-situ percolation test. Falling head percolation tests, which give a value of percolation time (PT) that is empirically related to the notion of hydraulic conductivity, are widely used as they are relatively simple to carry out, but the test does not have a sound theoretical framework and test methods are not standardised internationally. In comparison, the saturated hydraulic conductivity of a soil obtained from a constant head well permeameter test is independent of test conditions, and so is a more suitable metric for design. A database of over 900 falling head tests carried out across a range of different subsoil types in Ireland has been collated, all with the inherent limitations of the existing regulative framework regarding the percolation test and soil texture assessment. These tests were then modelled using Hydrus 2-D numerical modelling simulations to determine equivalent field saturated hydraulic conductivity (Kfs) values and thereby provide a correlation with PT values across the range of subsoil conditions. In addition, falling head tests have been carried out in parallel to constant head permeameter tests in the field and compared against the relationship derived from the broad dataset of simulated results. This revealed an optimal solution by which to determine Kfs from the field permeameter test (using parameters recommended for most structured soils from clays to loams). The trendline based on Irish data was also compared against more generic formulations of the relationship between PT, and Kfs and shown to match closely, particularly the Reynolds (2016) 'unified' methodology. Finally, the Irish threshold PT limits for on-site wastewater treatment have been converted to Kfs values and compared against other international standards.

An Update on Health-Related Quality of Life and Patient-Reported Outcomes in Hidradenitis Suppurativa.

Hidradenitis suppurativa is a common inflammatory skin condition which causes recurrent abscesses, sinuses and scarring in the axillae, groin and inframammary areas. As well as causing significant physical distress due to pain and discharge, the condition impacts psychological well-being with markedly impaired quality of life. Patients suffer pain, embarrassment and psychological distress with impairment of their work and intimate relationships marking it as one of the most distressing dermatological conditions. Numerous studies have documented markers of psychological distress encompassing the physical effects such as pain and itch, affects on mood and impaired function.

Dual-task gait speed assessments with an electronic walkway and a stopwatch in older adults. A reliability study.

BACKGROUND/OBJECTIVES: Slow gait speed prospectively predicts elevated risk of adverse events such as falls, morbidity, and mortality. Additionally, gait speed under a cognitively demanding challenge (dual-task gait) predicts further cognitive decline and dementia incidence. This evidence has been mostly collected using electronic walkways; however, not all clinical set ups have an electronic walkway and comparability with simple manual dual-gait speed testing, like a stopwatch, has not yet been examined. Our main objective was to assess concurrent-validity and reliability of gait speed assessments during dual-tasking using a stopwatch and electronic walkway in older adults with mild and subjective cognitive impairment (MCI and SCI). DESIGN: Cross-sectional, reliability study. SETTING: Clinic based laboratory at an academic hospital in London, ON, Canada. PARTICIPANTS: 237 walk tests from 34 community-dwelling participants (mean age 71.84 SD 5.38; 21 female - 62%, 13 male - 38%) with SCI and MCI. were included from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. INTERVENTION: Each participant performed seven walk tests: three single gait walks at their normal pace, three dual-task walks (walking and counting backwards by one, by sevens, and naming animals), and one fast walk. MEASUREMENTS: Gait speed (cm/s) for each walk was measured simultaneously with an electronic walkway (Zeno Mat®) and a handheld stopwatch (Ultrak chronometer®). Dual-task cost (DTC) was calculated for the three individual dual-task walks as [((single gait speed - dual-task gait speed) / single gait speed) ∗ 100]. Level of agreement between the two measurement methods was analyzed using Pearson correlations, paired t-tests, and Bland-Altman plots. RESULTS: Gait speed was consistently lower when measured with the stopwatch than with the electronic walkway (mean speed difference: 10.6 cm/s ± 5.1, p < 0.001). Calculating DTC, however, yielded very similar results with both methods (mean DTC difference: 0.19 ± 1.18, p = 0.872). The higher the DTC, the closer the measurement between methods. CONCLUSION: Assessing and calculating DTC with a stopwatch is simple, accessible and reliable. Its validity and reliability were high in this clinical sample of community older adults with SCI and MCI.

Fate of the mate: the influence of delayed graft function in renal transplantation on the mate recipient.

Delayed graft function (DGF) in a deceased-donor renal recipient is associated with allograft dysfunction 1-year posttransplant. There is limited research about the influence to allograft function on the mate of a DGF recipient over time. Using a retrospective cohort design, we studied 55 recipients from a single center. The primary outcome was the change in glomerular filtration rate (GFR) 1-year posttransplant. The secondary outcome was the GFR at baseline. We found that mates to DGF recipients had a mean change in GFR 1-year posttransplant of -11.2 mL/min, while the control group had a mean change of -0.4 mL/min. The difference in the primary outcome was significant (p = 0.025) in a multivariate analysis, adjusting for cold ischemic time, panel reactive antibody level, allograft loss, human leukocyte antibody (HLA)-B mismatches and HLA-DR mismatches. No significant difference between groups was found in baseline GFR. In conclusion, mates to DGF recipients had a significantly larger decline in allograft function 1-year posttransplant compared to controls with similar renal function at baseline. We believe strategies that may preserve allograft function in these'at-risk'recipients should be developed and tested.

Chromosome size-dependent control of meiotic recombination.

Smaller chromosomes have higher rates of meiotic reciprocal recombination (centimorgans per kilobase pair) than larger chromosomes. This report demonstrates that decreasing the size of Saccharomyces cerevisiae chromosomal DNA molecules increases rates of meiotic recombination and increasing chromosome size decreases recombination rates. These results indicate that chromosome size directly affects meiotic reciprocal recombination.

Lipid lowering targets are easier to attain than those for treatment of hypertension in type 2 diabetes.

AIM: To assess the impact of therapeutic strategies to reduce cardiovascular risk in patients with type 2 diabetes. METHODS: Five-hundred patients with type 2 diabetes were studied, using retrospective case note analysis in 1997 (followed by a unit policy targeting vascular risk) and again in 2001. RESULTS: The mean BP of the hypertensive patients was unchanged, 151/83 +/- 23/12 mmHg (1997) and 149/84 +/- 19.1/9.8 mmHg (P=0.2) (2001) (despite increase in patients receiving 23 antihypertensives (4.2% to 18.0%, P<0.01). The mean cholesterol improved from 5.34 +/- 1.1 mmol/L to 4.72 +/- 0.94 mmol/L (P<0.01). 2.9% compared with 44.6% (P<0.01) of hypercholesterolaemic patients, achieved target cholesterol. Antiplatelet therapy increased from 27.6% to 61.2% (P<0.01). Reduced mean HbA1c, 7.91 +/- 1.61% to 7.12 +/- 1.41% (P<0.01). CONCLUSION: Improved lipid profiles, aspirin uptake and glycaemic control, but no improvement in blood pressure targets were achieved. Additional strategies are required to achieve cardiovascular risk factor targets.

Endocrine-metabolic function in remission-phase IDDM during administration of cyclosporine.

We have studied the endocrine-metabolic status of patients in non-insulin-receiving (NIR) remission of insulin-dependent diabetes mellitus (IDDM) within 6-60 mo of diagnosis during administration of cyclosporine, in comparison with nondiabetic subjects. IDDM patients in NIR remission were recognized when target glycemic control (plasma glucose and mean capillary blood glucose levels less than 7.8 mM before meals) was maintained without administration of insulin for at least 2 wk. In so-called isoglycemic tests, 50 g glucose was administered orally, and the glycemic curve was simulated in a subsequent study by programmed intravenous infusion of glucose. Under these conditions, the subjects with diabetes exhibited obvious glucose intolerance: acute beta-cell responses to intravenous glucose were virtually absent but significant, although subnormal responses were present after oral glucose. The responses of plasma immunoreactive gastric inhibitory polypeptide to oral glucose were normal. After bolus intravenous injections of glucose, the patients with diabetes again exhibited glucose intolerance; acute responses of immunoreactive insulin (IRI) and C-peptide were present, although grossly obtunded. On intravenous infusion of arginine (30 g in 30 min), the patients with diabetes showed substantial but subnormal increases in plasma IRI and C-peptide. Intravenous infusion of arginine elicited increments of plasma immunoreactive glucagon (IRGI) in both groups, and this response was slightly exaggerated in the patients with diabetes. On ingestion of a standard mixed meal (Sustacal) delivering 600 cal, there was a modest but significantly greater increase in plasma glucose levels in the diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome size-dependent control of meiotic reciprocal recombination in Saccharomyces cerevisiae: the role of crossover interference.

In the yeast Saccharomyces cerevisiae, small chromosomes undergo meiotic reciprocal recombination (crossing over) at rates (centimorgans per kilobases) greater than those of large chromosomes, and recombination rates respond directly to changes in the total size of a chromosomal DNA molecule. This phenomenon, termed chromosome size-dependent control of meiotic reciprocal recombination, has been suggested to be important for ensuring that homologous chromosomes cross over during meiosis. The mechanism of this regulation was investigated by analyzing recombination in identical genetic intervals present on different size chromosomes. The results indicate that chromosome size-dependent control is due to different amounts of crossover interference. Large chromosomes have high levels of interference while small chromosomes have much lower levels of interference. A model for how crossover interference directly responds to chromosome size is presented. In addition, chromosome size-dependent control was shown to lower the frequency of homologous chromosomes that failed to undergo crossovers, suggesting that this control is an integral part of the mechanism for ensuring meiotic crossing over between homologous chromosomes.

Natural course of remission in IDDM during 1st yr after diagnosis.

OBJECTIVE: To describe the natural course of clinical remission in insulin-dependent diabetes mellitus (IDDM) when insulin dose is minimized without loss of target glycemia and to identify factors that predict clinical remission. RESEARCH DESIGN AND METHODS: Ninety-five patients, who were placebo-treated control subjects in the Canadian-European multicenter randomized trial of cyclosporin A in recent-onset IDDM, were studied. RESULTS: The mean insulin dose decreased during the first months after diagnosis, with a nadir at 3 mo, when 27% of the patients did not require insulin to maintain target glycemia. At 1 yr, 10% of patients still did not need insulin. Patients not receiving insulin who had glycosylated hemoglobin within the normal range were called remitters. Mean basal and glucagon-stimulated C-peptide values were significantly (P less than 0.025) higher in remitters than nonremitters at the start of the study. Therefore, all patients were divided into those with values above the mean stimulated C-peptide (0.4 nM) and those with values below the mean at entry. The probability of entering a remission with a stimulated C-peptide greater than 0.4 nM was 10 times as high (P less than 0.05) as for those with a stimulated C-peptide below this level. Surprisingly, the beginning and end of the remission were associated with neither major changes in C-peptide levels nor islet cell antibody and insulin-antibody titer. A more rapid loss of stimulated C-peptide occurred in patients who lacked HLA-DR3 and -DR4 (P less than 0.05 at mo 9). CONCLUSIONS: This study shows a higher spontaneous clinical remission rate than expected during the 1st yr after diagnosis. Preserved beta-cell function at entry predicts a greater chance of entering a remission, and a more rapid loss of beta-cell function was seen in patients without HLA-DR3 and -DR4.

Clinical trials of cyclosporin in IDDM.

The results of uncontrolled trials in immunomodulation of insulin-dependent diabetes mellitus (IDDM) led to randomized controlled trials in Canada and Europe. In the Canadian open study, the rate of clinical remissions (target control of glycemia maintained with less than or equal to 0.15 U.kg-1.day-1 insulin) was unexpectedly high among 81 subjects who had been treated with cyclosporin for at least 3 mo (mean serum trough levels approximately 125 ng/ml by radioimmunoassay). Subjects entered the study within 14 wk of onset of symptoms and received 6 wk of insulin therapy. The clinical remission rate at 1 yr was 46%; of these patients, 84% were not receiving insulin. An effect on beta-cell function was suggested by recovery of plasma glucagon-stimulated C-peptide levels into the normal range in many patients, with maintenance of levels through 1 yr in patients in remission. On the basis of these findings, the French and Canadian-European study groups conducted randomized double-blind controlled trials of cyclosporin, which confirmed the results of the open studies in terms of clinical remission. The Canadian-European study also demonstrated enhancement of beta-cell function by cyclosporin by 3 mo, which was maintained for 1 yr. In the Canadian open study, most patients relapsed within a few weeks after discontinuation of cyclosporin, indicating the need for longer-term immunomodulatory therapy for maintenance of remission. The nature and degree of structural change in kidney biopsies from patients in these studies are under assessment. The results strongly support the hypothesis that autoimmune mechanisms mediate beta-cell damage in many patients with IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Pea polyubiquitin genes: (I) structure and genomic organization.

Four polyubiquitin genes, PUB1, PUB2, PUB3 and PUB4, were isolated from a pea (Pisum sativum L. cv Alaska) genomic library and completely sequenced. They represent all of the four polyubiquitin genes of the ubiquitin gene family in pea. The coding regions of the genes contain five or six coding units arranged as tandem repeats. The different coding repeats of the four genes share homologies between 75 and 97%, encoding the same protein of 76 amino acids identical to those from other higher plants. The open reading frames of PUB1, PUB2 and PUB4 terminate in the additional amino acid, phenylalanine (F), and PUB3 terminates in isoleucine (I). The polyubiquitin genes all contain intron sequences ranging from 584 to 1114 bp immediately 5' to the ATG initiation codon of the first coding sequence. Of the four genes, three are associated with long AT-rich (85.4-89.4% A+T) sequences ranging from about 331 to 478 bp at their 5' or 3' ends. The PUB4 gene was found to be linked to a moderate to highly repetitive DNA at its 5' flanking sequence. The greater sequence homology between different genes than among individual repeating units of a gene suggests that the polyubiquitin genes may have arisen by gene duplication of a single gene sequence.

Angiotensin(1-7) is an antagonist at the type 1 angiotensin II receptor.

OBJECTIVE: The present study investigated the antagonism of the amino-terminal heptapeptide fragment of angiotensin II ([des-Phe8]-angiotensin II; Ang(1-7)) to angiotensin II (Ang II) both in vitro in rabbit aortae and in vivo in rats. METHODS AND RESULTS: In rabbit isolated endothelium intact aortic rings Ang(1-7) caused a concentration-related rightward displacement of the Ang II curve and depressed the maximum response to Ang II. By applying the data to a Schild plot an apparent pA2 of 5.5 was calculated. This depression of maximum response could be reversed by co-incubation of Ang(1-7) with the competitive angiotensin antagonist losartan. Ang(1-7) had no effect on the contractile responses of several other agonists. Intravenous infusion of 10 or 100 micrograms/kg per min Ang(1-7) had no effect on the resting blood pressure in the anaesthetized rat but inhibited Ang II-induced pressor responses. CONCLUSION: The present results show that Ang(1-7) is a specific non-competitive antagonist of Ang II at type 1 angiotensin II receptors.

The association of thirst, sodium appetite and vasopressin release with c-fos expression in the forebrain of the rat after intracerebroventricular injection of angiotensin II, angiotensin-(1-7) or carbachol.

The effect intracerebroventricular injections of angiotensin II (0.1 nm), angiotensin-(1-7) (1 or 100 nm) and carbachol (500 ng) on c-fos expression was examined in the forebrain of Lister hooded rats. Intense staining of the c-Fos protein was found in the median preoptic nucleus, organum vasculosum of the lamina terminalis, subfornical organ, paraventricular nucleus and supraoptic nucleus after angiotensin II and carbachol Angiotensin II caused significantly more c-fos expression in the ventral median preoptic nucleus and organum vasculosum of the lamina terminalis than carbachol, whereas in the paraventricular and supraoptic nuclei this was reversed, with carbachol having a greater effect on c-fos expression in these areas. Angiotensin-(1-7), however, only induced c-Fos protein in the organum vasculosum of the lamina terminalis and median preoptic nucleus with the number and the intensity of staining of the nuclei significantly less in both areas than after angiotensin II or carbachol. Separate groups of Lister rats were given i.c.v. injections of the same substances at the same doses, but excluding the lower dose of angiotensin-(1-7), and the intakes of water and 1.8% NaCl over 60 min were measured. Angiotensin II stimulated intakes of both water and NaCl. The effect on water intake was almost immediate (<1 min), whereas NaCl intake did not usually start until at least 5 min after injection. Over 60 min, water (12.4 +/- 1.0 ml) and NaCl (4.2 +/- 0.9 ml) intakes were significantly greater than water (1.1 +/- 0.2 ml) and NaCl (0.6 +/- 0.5 ml) intakes of the controls. Carbachol caused less drinking than angiotensin II, the water intake over 60 min being significantly less (4.8 +/- 0.7 ml) and the latency of response greater (>5 min). Carbachol, unlike angiotensin II, had little effect on NaCl intake (0.7 +/- 0.4 ml). Angiotensin-(1-7) had no effect on water (1.1 +/- 0.3 ml) or NaCl (0.3 +/- 0.3 ml) intakes. The plasma levels of vasopressin were measured after i.c.v. injection of the same three substances in the same doses, again excluding the lower dose of angiotensin-(1-7), in further groups of rats. Angiotensin II and carbachol caused an approximate five-fold increase in plasma vasopressin levels compared to cerebrospinal fluid-injected rats, but angiotensin-(1-7) had no effect on vasopressin release. Therefore, three compounds with widely differing effects on thirst, sodium appetite and vasopressin release induce distinctive patterns of c-fos protein expression in the forebrain. By combining experimental approaches in this way it is possible to determine areas of the brain which are involved in certain behavioural and endocrine responses.

Surveying physicians to determine the minimal important difference: implications for sample-size calculation.

The minimal important difference (MID) is the smallest benefit of treatment that would result in clinicians recommending it to their patients. The MID is necessary to calculate sample size for randomized clinical trials, but its chosen value is often arbitrary. This study set out to determine the practicability of surveying physicians to elicit the MID for clinical trial sample-size calculation. Using a mail survey, we elicited the MID of different physician specialties (family medicine, internal medicine, vascular surgery) for using propranolol to slow abdominal aortic aneurysm (AAA) growth assuming that propranolol was efficacious in this condition. We used different outcome measures (growth rate or proportion of patients requiring surgery) and different methods of data presentation for the proportion of patients requiring surgery (absolute risk reduction or number needed to treat). The MID varied significantly by physician specialty, experience with AAA and propranolol, and the method used to elicit the MID. Consequently, sample-size calculations using these various MIDs varied from 116 to 3015. Future attempts to elicit the MID need to consider carefully who is surveyed, how data are presented, and how opinions are elicited.

Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice.

STUDY OBJECTIVE: To compare quality of life and exercise capacity (primary aim), and drug usage (secondary aim), between groups of patients with irreversible chronic airflow limitation (CAL) who were undergoing theophylline Theo-Dur; Key Pharmaceuticals; Kenilworth, NJ) therapy guided by n of 1 trials or standard practice. DESIGN: Randomized study of n of 1 trials vs standard practice. SETTING: Outpatient departments in two tertiary care centers. PATIENTS: Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators, and who were unsure whether theophylline was helping them following open treatment, were randomized into n of 1 trials (N=34) or standard practice. INTERVENTIONS: The n of 1 trials (single-patient, randomized, double-blind, multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo) followed published guidelines. Standard practice patients stopped taking theophylline but resumed it if their dyspnea worsened. If their dyspnea then improved, theophylline was continued. In both groups, a decision about continuing or stopping the use of theophylline was made within 3 months of randomization. MEASUREMENTS AND RESULTS: The primary outcomes (the chronic respiratory disease questionnaire [CRQ] and 6-min walk) were measured at baseline, 6 months, and 12 months by personnel blinded to treatment group allocation. No between-group differences (n of 1 minus standard practice) were seen in within-group changes over time (1 year minus baseline) in the CRQ Physical Function score (point estimate on the difference, -2.8; 95% confidence limits [CLs], -8.2, 2.5), CRQ Emotional Function score (point estimate on the difference, 0.5; 95% CLs, -4.7, 5.7), or 6-min walk (point estimate on the difference, 8 m; 95% CLs, -26, 44 m). No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months. In 7 of 34 n of 1 trial patients (21%), dyspnea improved during theophylline treatment compared with placebo treatment. CONCLUSIONS: Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity, or reduce drug usa e, over 1 year compared to standard practice. Under the objective conditions of an n of 1 trial, 21% of patients with CAL responded to theophylline. There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators, but the use of n of 1 trials to guide this decision did not yield clinically important advantages over standard practice.