The impact of an epilepsy nurse competency framework on the costs of supporting adults with epilepsy and intellectual disability: findings from the EpAID study.

BACKGROUND: The development of a nurse-led approach to managing epilepsy in adults with an intellectual disability (ID) offers the potential of improved outcomes and lower costs of care. We undertook a cluster randomised trial to assess the impact on costs and outcomes of the provision of ID nurses working to a designated epilepsy nurse competency framework. Here, we report the impact of the intervention on costs. METHOD: Across the United Kingdom, eight sites randomly allocated to the intervention recruited 184 participants and nine sites allocated to treatment as usual recruited 128 participants. Cost and outcome data were collected mainly by telephone interview at baseline and after 6 months. Total costs at 6 months were compared from the perspective of health and social services and society, with adjustments for pre-specified participant and cluster characteristics at baseline including costs. Missing data were imputed using multiple imputation. Uncertainty was quantified by bootstrapping. RESULTS: The intervention was associated with lower per participant costs from a health and social services perspective of -£357 (2014/2015 GBP) (95% confidence interval -£986, £294) and from a societal perspective of -£631 (95% confidence interval -£1473, £181). Results were not sensitive to the exclusion of accommodation costs. CONCLUSIONS: Our findings suggest that the competency framework is unlikely to increase the cost of caring for people with epilepsy and ID and may reduce costs.

The challenge of a 2-year follow-up after intervention for weight loss in primary care.

BACKGROUND: Many weight loss programmes show short-term success, but long-term data in larger studies are scarce, especially in community settings. Attrition is common and complicates the interpretation of long-term outcomes. OBJECTIVE: To investigate 2-year outcomes and explore issues of attrition and missing data. SUBJECTS: A total of 772 overweight and obese adults recruited by primary care practices in Australia, Germany and the UK and randomised to a 12-month weight loss intervention delivered in a commercial programme (CP) or in standard care (SC). MEASUREMENT: Weight change from 0-24 and 12-24 months including measured weights only and measured and self-reported weights, using last observation carried forward (LOCF), baseline observation carried forward (BOCF), completers-only and missing-at-random (MAR) analyses. RESULTS: A total of 203 participants completed the 24-month visit. Using measured weights only, there was a trend for greater 24-month weight loss in CP than in SC, but the difference was only statistically significant in the LOCF and BOCF analyses: LOCF: -4.14 vs -1.99 kg, difference adjusted for centre -2.08 kg, P<0.001; BOCF: -1.33 vs -0.74 kg, adjusted difference -0.60 kg, P=0.032; completers: -4.76 vs -2.99 kg, adjusted difference -1.53 kg, P=0.113; missing at random: -3.00 vs -1.94 kg, adjusted difference -1.04 kg, P=0.150. Both groups gained weight from 12-24 months and weight regain was significantly (P<0.001) greater for CP than for SC in all analysis approaches. Inclusion of self-reported weights from a further 138 participants did not change the interpretation of the findings. CONCLUSION: Initial weight loss was poorly maintained during the no-intervention follow-up, but both groups did have lower weight over the 24 months. Attrition was high in both groups, and assumptions about missing data had considerable impact on the magnitude and statistical significance of treatment effects. It is vital that trials on weight loss interventions consider the plausibility of these differences in an analytical approach when interpreting research findings and comparing data between studies.

A review and re-interpretation of a group-sequential approach to sample size re-estimation in two-stage trials.

In this paper, we review the adaptive design methodology of Li et al. (Biostatistics 3:277-287) for two-stage trials with mid-trial sample size adjustment. We argue that it is closer in principle to a group sequential design, in spite of its obvious adaptive element. Several extensions are proposed that aim to make it even more attractive and transparent alternative to a standard (fixed sample size) trial for funding bodies to consider. These enable a cap to be put on the maximum sample size and for the trial data to be analysed using standard methods at its conclusion. The regulatory view of trials incorporating unblinded sample size re-estimation is also discussed.

Clinical and genetic study of 46 Italian patients with primary lymphedema.

Primary lymphedema is characterized by altered morphological development of lymphatic vessels causing fluid accumulation in interstitial spaces. In familial forms, it is primarily transmitted as a dominant Mendelian trait with heterozygous mutations in genes involved in lymphangiogenesis. We used PCR and direct sequencing to analyze the region of the fms-related tyrosine kinase 4 (FLT4) gene encoding the "tyrosine-kinase domain" and the single exon of the forkhead box C2 (FOXC2) gene in 46 Italian probands with primary lymphedema, 42 of whom had familial forms. We identified 12 mutations in 12 patients (12/46, 26%), six in the FLT4 gene and six in the FOXC2 gene. Most of the mutations (9/12, 75%) were new, and none were identified in 100 healthy subjects or listed in the NCBI dbSNP. A clear relation emerged between genotype and phenotype because 4/5 (80%) probands with onset at birth showed FLT4 mutations and 4/5 (80%) probands without distichiasis and with FOXC2 mutations had an amino-acid substitution outside the forkhead domain. Besides the allelic heterogeneity shown by unique mutations in each proband, the absence of mutations in almost 75% of familial cases of primary lymphedema also suggests genetic heterogeneity.

Serum is not required for ex vivo IFN-gamma ELISPOT: a collaborative study of different protocols from the European CIMT Immunoguiding Program.

The Cancer Immunotherapy Immunoguiding Program has conducted an IFN-gamma ELISPOT proficiency panel to examine the influence of serum supplementation of test media on assay performance. Sixteen European laboratories analyzed the same PBMC samples using different locally established protocols. Participants generated two simultaneous data sets-one using medium supplemented with serum and one without serum. Performances of the two test conditions were compared by quantifying: (1) the number of viable cells, (2) background spot formation induced in the medium only control and (3) the ability to detect antigen-specific T cell responses. The study demonstrated that the number of viable cells recovered and the overall background spot production were not significantly different between the two conditions. Furthermore, overall laboratory performance was equivalent for the two test conditions; 11 out of 16 laboratories reported equal or greater detection rates using serum-free medium, while 5 laboratories reported decreased detections rates under serum-free conditions. These results show that good performance of the IFN-gamma ELISPOT assay can be achieved under serum-free conditions. Optimization of the protocol for serum-free conditions should result in excellent detection rates and eliminate the requirement of serum batch and stability testing, allowing further harmonization of the assay.

Response definition criteria for ELISPOT assays revisited.

No consensus has been reached on how to determine if an immune response has been detected based on raw data from an ELISPOT assay. The goal of this paper is to enable investigators to understand and readily implement currently available methods for response determination. We describe empirical and statistical approaches, identifying the strengths and limitations of each approach to allow readers to rationally select and apply a scientifically sound method appropriate to their specific laboratory setting. Five representative approaches were applied to data sets from the CIMT Immunoguiding Program and the response detection and false positive rates were compared. Simulation studies were also performed to compare empirical and statistical approaches. Based on these, we recommend the use of a non-parametric statistical test. Further, we recommend that six medium control wells or four wells each for both medium control and experimental conditions be performed to increase the sensitivity in detecting a response, that replicates with large variation in spot counts be filtered out, and that positive responses arising from experimental spot counts below the estimated limit of detection be interpreted with caution. Moreover, a web-based user interface was developed to allow easy access to the recommended statistical methods. This interface allows the user to upload data from an ELISPOT assay and obtain an output file of the binary responses.

A prospective analysis of dietary energy density at age 5 and 7 years and fatness at 9 years among UK children.

OBJECTIVE: To analyse whether high dietary energy density (DED) is associated with increased fat mass and risk of excess adiposity in free-living children. DESIGN: Longitudinal, observational cohort study. SUBJECTS: Six hundred and eighty-two healthy children from the Avon Longitudinal Study of Parents and Children. MEASUREMENTS: Diet was assessed at age 5 and 7 years using 3-day diet diaries, and DED (kJ g(-1)) was calculated excluding drinks. Fat mass was estimated at age 9 years using Dual-Energy X-ray Absorptiometry. To adjust for body size, fat mass index (FMI) was calculated by dividing fat mass (kg) by height (m(5.8)). Excess adiposity was defined as the top quintile of logFMI. RESULTS: Mean DED at age 5 years was higher among children with excess adiposity at age 9 years compared to the remaining sample (8.8+/-0.16 vs 8.5+/-0.07 kJ g(-1)), but there was no evidence of an association with excess adiposity at age 9 years (odds ratio (OR)=1.14, 95% confidence interval (CI) 0.90-1.44) after controlling for potential confounders. Mean DED at age 7 years was higher among children with excess adiposity compared to the remaining sample (9.1+/-0.12 vs 8.8+/-0.06 kJ g(-1)) and a 1 kJ g(-1) rise in DED increased the odds of excess adiposity at 9 years by 36% (OR=1.36, 95% CI 1.09-1.69) after controlling for potential confounders. CONCLUSION: Higher DED at age 7 years, but not age 5 years, is a risk factor for excess adiposity at age 9 years, perhaps reflecting deterioration in the ability to compensate for extra calories in an energy-dense diet. DED tracks strongly from age 5 to 7 years suggesting intervention to alter dietary habits need to commence at younger ages to prevent the formation of preferences for energy dense foods.

Stepwise haplotype analysis: are LD patterns repeatable?

A variety of techniques exist to describe and depict patterns of pairwise linkage disequilibrium (LD). In the current paper, a new log-linear framework is proposed for the summarisation of local interactions among single nucleotide polymorphisms (SNPs). Our approach provides a straightforward means of capturing the diversity of higher-order LD relationships for small numbers of loci by investigating inter-marker interactions. Our method was applied to a dataset of 76 SNP markers spanning a genomic interval of length 2.8 megabases. The analysis of three short sub-regions is described in detail here. Model and graphical representations of contiguous markers in medium to high LD are presented. In the regions studied, evidence for sub-structure was detected, supporting the view that the genomic reality is complex. Interestingly, a critical evaluation of the method by bootstrapping showed that while some LD relationships were captured in a highly repeatable fashion, the majority were not. Large numbers of small interactions, both direct and indirect, mean that many models can adequately summarise the data at hand. Our results suggest that repeatability should be further investigated in the application of LD-based approaches.

Early echographical assessment of minimal lesions of cavernosum corpora and tunica albuginea in subjects with erectile dysfunction, suggestive of La Peyronie's disease.

The aim of the study is to evaluate the incidence and the echographic characteristics of minimal lesions of cavernosum corpora and tunica albuginea (TA) in subjects reporting erectile dysfunction (ED), which could suggest the suspicious of La Peyronie's disease (LPD). In total, 185 patients (pts) underwent dynamic penile Ultrasound Color Doppler (USCD) for ED. None of the pts presented any clinical symptoms or any clinical findings for LPD. In this study we evaluated, using USCD, thickness, echogenicity, regularity of the surface profile of the dorsal TA, the intercavernous and the intercaverno-spongeous septa, and the extension of the eventual pathologic lesions. In all, 16 pts (8.7%) presented minimal lesions at the ultrasound examinations. In nine of these pts (56%) the lesion was localized at the dorsal position, in six (38%) on the intercavernous septum and in one patient (6%) in both positions. The dorsal lesions were represented in nodular form in four pts (4%), and in diffuse form in five pts (55%). The nodular form was present in all the intercavernous septal lesions observed. As reported in the literature, USCD represents the investigative technique of choice in the study of LPD and in ED. Furthermore, the results of this study suggest that this technique could allow the localization of minimal lesions attributable to LPD during a preclinical phase of this disease. The localization of these lesions could permit to start a therapeutic approach during an early phase of the disease.

Specificity of the salivary cortisol dexamethasone suppression test across psychiatric diagnoses.

One hundred forty-eight psychiatric inpatients, 12 outpatients, and 17 normal controls were given the 1.0-mg overnight Dexamethasone Suppression Test (DST), with salivary cortisol concentrations being measured as the dependent variable. Based on the Structured Clinical Interview for DSM-III, the patients were diagnosed as having major depression with melancholia (n = 21), nonmelancholic major depression (n = 50), mania (n = 15), schizophrenia (n = 32), dementia (n = 6), substance dependence/abuse n = 18), and miscellaneous (n = 18). Neither the melancholic major depressives nor the entire group of major depressives had significantly higher salivary cortisol pre- or postdexamethasone as compared with all the other patients combined, nor did the melancholic patients have significantly higher cortisol than the nonmelancholic depressives. The inpatients as a group had significantly higher pre- and postdexamethasone cortisol values than the normal controls; cortisol values for the outpatients were intermediate between these two groups. Illness severity (in the depressives), length of time in hospital before the DST, and medication regimen were all unrelated to DST outcome. Thus, in this study, the salivary cortisol DST showed little clinical utility in discriminating major depressives with and without melancholia from other patients with a broad range of psychiatric diagnoses. The test did distinguish between hospitalized psychiatric patients and normal control subjects and between depressed inpatients and depressed outpatients, indicating that hospitalization-related variables contributed to DST outcome.

A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease.

BACKGROUND: Previous studies suggest a potential benefit from nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD). Prescribing NSAIDs, however, carries the risk of significant gastrointestinal adverse events. OBJECTIVES: To study whether treatment with an NSAID prevents expected decline in AD patients and evaluate whether co-administration of the gastro-protective agent, misoprostol, with an NSAID is safe in AD. METHODS: The efficacy and safety of diclofenac in combination with misoprostol (D/M) was evaluated in 41 patients with mild-moderate AD in a prospective 25-week, randomized, double-blind placebo-controlled trial. Efficacy measures comprised the Alzheimer's Disease Assessment Scale cognitive and noncognitive subsections, Global Deterioration Scale, Clinical Global Impression of Change, Mini-Mental State Examination, Instrumental Activities of Daily Living, Physical Self-Maintenance Scale, and a caregiver-rated Global Impression of Change. RESULTS: There were no group differences with any of the outcome measures in an intent-to-treat analysis. There were some nonsignificant trends for the placebo group to have deteriorated more than the D/M-treated patients. Withdrawal rates were 12 of 24 in the D/M group and 2 of 17 in the placebo group. There were no serious drug-related adverse events. CONCLUSIONS: This pilot study, with small treatment numbers, did not demonstrate a significant effect of NSAID treatment in AD, but the trends observed justify further investigations with a larger number of participants. D/M is safe in AD patients, but its tolerability is not optimal.

Patterns of disease in concordant parent-child pairs with multiple sclerosis.

BACKGROUND: Although the exact etiology of MS remains elusive, there is good evidence that genetic factors play an important role. These factors are likely to be polygenic, exerting both independent and interactive effects on the expression of MS. They may determine susceptibility and/or shape the clinical course. METHODS: The authors studied clinical phenotype in 245 concordant parent-child pairs recruited from a national register of familial disease over a 10-year period. Data were examined in order to determine the effect of parental sex on expression of disease in the offspring. RESULTS: Allowing for the observed sex ratio of 2.6 F:1 M in this group of patients, sex pairings of parents and offspring were close to those expected. When assessed independently there was no evidence that either the sex of the affected offspring or the line of inheritance influenced disability, age at onset, or disease course. However, trends were observed toward greater disability and an increased frequency of primary progressive disease in offspring of affected fathers and an earlier age at onset in offspring of affected mothers. The highest mean Expanded Disability Status Scale score was observed in male offspring of affected fathers (5.64) and this group was also more likely to have primary progressive disease (OR 1.92). Thirty-one percent of families had an additionally affected offspring with no preferential maternal or paternal transmission. CONCLUSIONS: In offspring of concordant parent-child families with MS who are at high risk of inheriting increased numbers of susceptibility genes there is no evidence for a parent of origin effect distorting sex ratios in affected offspring, but parent of origin may influence disability and disease course as well as increasing the risk to additional offspring within the same family. The mechanism of these effects is not clear but may result from interactions between genes encoded at different loci (epistasis), which each independently influence susceptibility and phenotype.

Use of computerized neuropsychological tests (CANTAB) to assess cognitive effects of antihypertensive drugs in the elderly. Cambridge Neuropsychological Test Automated Battery.

OBJECTIVE: To establish reliability and ease of use of the Cambridge Neuropsychological Test Automated Battery (CANTAB) in assessing changes in cognitive function induced by antihypertensive drugs. DESIGN AND METHODS: Standard neuropsychological testing was combined with CANTAB in a double-blind 18-week cross-over study in elderly hypertensives taking perindopril or hydrochlorothiazide/triamterene (HT). Cognitive effects were assessed by employing tests of attention, visuospatial and verbal memory, learning, reasoning, planning, problem solving, speed and coordination. Affect was assessed using two different depression-rating scales. RESULTS: Perindopril and the diuretic had no adverse effects on the various aspects of cognitive function. Mood, as assessed by the Hamilton Depression Rating Scale and the Beck Depression Inventory, was improved on Perindopril, and the error rate in the motor screening test was lower. Ambulatory blood pressure monitoring showed both drugs achieved effective 24-h control. CONCLUSIONS: The ease of use and the ability to adjust the level of testing to the requirements of individual patients, together with the reliability of longitudinal test/re-test results, indicates that CANTAB is an important addition to the methods available to quantitate adverse central nervous system drug effects. The other purpose of the study was to assess any adverse cognitive effects of perindopril against a drug HT believed to have no adverse central nervous system effects. In this context, perindopril was free of adverse effects in all the objective tests employed. In addition, there was a benefit seen in two independent assessments of depression (the Hamilton and the Beck rating scales).

Pre- and post-dexamethasone salivary cortisol concentrations in major depression.

Seventy patients fulfilling DSM-III criteria for major depression were given the 1.0 mg overnight dexamethasone suppression test, with salivary cortisol concentrations being measured as the dependent variable. Using both the DSM-III and the Research Diagnostic Criteria, we categorized the patients into four groups based on increasing frequency of endogenous symptomatology. Among these four groups there were no significant differences in salivary cortisol concentrations either before dexamethasone or eight, 16, and 24 h after dexamethasone. Similarly, there were no significant differences among the groups in either the ratios of post- to pre-dexamethasone salivary cortisol or the frequencies of positive tests based on several criterion levels of cortisol for the three post-dexamethasone samples. Multiple regression analyses indicated that the Hamilton depression rating scale item "somatic anxiety" was significantly negatively related to post-dexamethasone cortisol concentrations. We conclude that, for our sample of major depressives, the salivary cortisol dexamethasone suppression test showed no utility as a laboratory correlate of depressive episodes with endogenous features.

The predictive power of the salivary cortisol dexamethasone suppression test for three-year outcome in major depressive illness.

Seventy patients satisfying DSM-III and Research Diagnostic Criteria for major depression were given a salivary cortisol dexamethasone suppression test, with samples collected at 0700 h, 1500 h and 2300 h after dexamethasone. The patients were classified as nonsuppressors (mean post-dexamethasone salivary cortisol concentration greater than or equal to 2.0 ng/ml, N = 27) and suppressors (mean post-dexamethasone salivary cortisol concentration less than 2.0 ng/ml, N = 43). At 3-yr follow-up there was no difference in illness outcome as assessed by the life table method or by the length of rehospitalisation for several periods after the index episode. In multiple regression and discriminant function analyses, with outcome as the dependent variable (readmitted within 1 yr, readmitted between 1 and 3 yr, not readmitted), the mean post-dexamethasone salivary cortisol concentration was not significantly predictive of outcome.

Serum interleukin-6 and interleukin-6 soluble receptor in Alzheimer's disease.

Serum levels of interleukin-6 (IL-6) and interleukin-6 soluble receptor (IL-6sR) were measured in 41 patients (23 female and 18 male, mean age 72.5 years) with Alzheimer's disease (AD) and in 32 controls (14 women and 18 men, mean age 69.2 years) using enzyme-linked immunosorbent assays (ELISA). Proportions of individuals with detectable serum IL-6 concentrations did not differ significantly between patients and controls. There was however, a significant decrease in IL-6sR levels in Alzheimer's patients when compared with controls. Our results suggest that there is a dysregulation of IL-6 and its soluble receptor in AD.

Fluid balance, vasopressin and withdrawal symptoms during detoxification from alcohol.

Nineteen patients were studied during the first 4 days after withdrawal from alcohol. Plasma vasopressin was raised (P less than 0.05) and fluid retention occurred (P less than 0.05), with falls in haematocrit (P less than 0.01) and calculated plasma osmolality (P less than 0.02), which were consistent with expansion of plasma volume. Despite these changes mean total body water was within normal limits although there were substantial inter-individual variations. There was no correlation between any measure of fluid balance and the severity of withdrawal symptoms.

The relationship of cerebral atrophy and T1 in alcoholics: an MRI study.

There was a significant correlation between two measures of cerebral atrophy (the ventricle to brain ratio and the relative cerebral volume) and T1 in 19 detoxified alcoholics. This provides further evidence that T1 is a marker of structural damage in alcoholics although the partial volume effect of CSF may contribute to this finding. This has implications for studies comparing alcoholics to normal controls and suggests that better ways of excluding CSF need to be found.