Characterization of missing data patterns and mechanisms in longitudinal composite outcome trial in rheumatoid arthritis.

Background: Composite measures, like the Disease Activity Score for 28 joints (DAS28), are key primary outcomes in rheumatoid arthritis (RA) trials. DAS28 combines four different components in a continuous measure. When one or more of these components are missing the overall composite score is also missing at intermediate or trial endpoint assessments. Objectives: This study examined missing data patterns and mechanisms in a longitudinal RA trial to evaluate how best to handle missingness when analysing composite outcomes. Design: The Tumour-Necrosis-Factor Inhibitors against Combination Intensive Therapy (TACIT) trial was an open label, pragmatic randomized multicentre two arm non-inferiority study. Patients were followed up for 12 months, with monthly measurement of the composite outcome and its components. Active RA patients were randomized to conventional disease modifying drugs (cDMARDs) or Tumour Necrosis Factor-α inhibitors (TNFis). Methods: The TACIT trial was used to explore the extent of missing data in the composite outcome, DAS28. Patterns of missing data in components and the composite outcome were examined graphically. Longitudinal multivariable logistic regression analysis assessed missing data mechanisms during follow-up. Results: Two hundred and five patients were randomized: at 12 months 59/205 (29%) had unobserved composite outcome and 146/205 (71%) had an observed DAS28 outcome; however, 34/146 had one or more intermediate assessments missing. We observed mixed missing data patterns, especially for the missing composite outcome due to one component missing rather than patient not attending thier visit. Age and gender predicted missingness components, providing strong evidence the missing observations were unlikely to be Missing Completely at Random (MCAR). Conclusion: Researchers should undertake detailed evaluations of missing data patterns and mechanisms at the final and intermediate time points, whether or not the outcome variable is a composite outcome. In addition, the impact on treatment estimates in patients who only provide data at milestone assessments need to be assessed. Trial Registration ISRCTN Number: 37438295.

Improving the Interpretation of Afternoon Cortisol Levels and SSTs to Prevent Misdiagnosis of Adrenal Insufficiency.

BACKGROUND: Adrenal Insufficiency (AI), especially iatrogenic-AI, is a treatable cause of mortality. The difficulty in obtaining 9 am cortisol levels means samples are taken at suboptimal times, including a substantial proportion in the afternoon. Low afternoon cortisol levels often provoke short Synacthen tests (SSTs). It is important that this does not lead to patients misdiagnosed with AI, exposing them to the excess mortality and morbidity of inappropriate steroid replacement therapy. METHODS: This retrospective study collected 60 178 cortisol results. Medical records, including subsequent SSTs of initial cortisol results measured after midday were reviewed. RESULTS: Receiver operating characteristic analysis (area under the curve: 0.89) on 6531 suitable cortisol values showed that a limit of <201.5 nmol/L achieved a sensitivity and specificity of 95.6% and 72.6%, while a limit of <234 nmol/L had a sensitivity of 100% and a specificity of 59.5%. Out of 670 SSTs, 628 patients passed. Of these, 140 would have otherwise failed if only their 30-min cortisol was assessed without the 60-min value. A 30- and 60-min SST cortisol cutoff of 366.5 nmol/L and 418.5 nmol/L, respectively, can achieve a sensitivity of >95% on the Abbott analyser platform. CONCLUSION: An afternoon cortisol >234 nmol/L excludes AI on Abbott analyser platforms. In patients who have an afternoon cortisol <234 nmol/L, including both 30- and 60-min SST cortisol values prevents unnecessary glucocorticoid replacement therapy in 22.3% of individuals in this study. The Abbott analyser SST cortisol cutoffs used to define AI should be 366.5 nmol/L and 418.5 nmol/L at 30 and 60 min, respectively. All patients remained well subsequently with at least 1-year longitudinal follow-up.

The feasibility of the PAM intervention to support treatment-adherence in people with hypertension in primary care: a randomised clinical controlled trial.

The PAM intervention is a behavioural intervention to support adherence to anti-hypertensive medications and therefore to lower blood pressure. This feasibility trial recruited 101 nonadherent patients (54% male, mean age 65.8 years) with hypertension and high blood pressure from nine general practices in the UK. The trial had 15.5% uptake and 7.9% attrition rate. Patients were randomly allocated to two groups: the intervention group (n = 61) received the PAM intervention as an adjunct to usual care; the control group (n = 40) received usual care only. At 3 months, biochemically validated medication adherence was improved by 20% (95% CI 3-36%) in the intervention than control, and systolic blood pressure was reduced by 9.16 mmHg (95% CI 5.69-12.64) in intervention than control. Improvements in medication adherence and reductions in blood pressure suggested potential intervention effectiveness. For a subsample of patients, improvements in medication adherence and reductions in full lipid profile (cholesterol 1.39 mmol/mol 95% CI 0.64-1.40) and in glycated haemoglobin (3.08 mmol/mol, 95% CI 0.42-5.73) favoured the intervention. A larger trial will obtain rigorous evidence about the potential clinical effectiveness and cost-effectiveness of the intervention.Trial registration Trial date of first registration 28/01/2019. ISRCTN74504989. https://doi.org/10.1186/ISRCTN74504989 .

Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): A prospective, multi-centre therapeutic phase II parallel Randomised Control Trial.

INTRODUCTION: Focal therapy (FT) targets individual areas of cancer within the prostate, providing oncological control with minimal side-effects. Early evidence demonstrates encouraging short-medium-term outcomes. With no randomized controlled trials (RCT) comparing FT to radical therapies, Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (CHRONOS) will compare the cancer control of these two strategies. PATIENTS AND METHODS: CHRONOS is a parallel phase II RCT for patients with clinically significant non-metastatic prostate cancer, dependent upon clinician/patient decision, patients will enrol into either CHRONOS-A or CHRONOS-B. CHRONOS-A will randomize patients to either radical treatment or FT. CHRONOS-B is a multi-arm, multistage RCT comparing focal therapy alone to FT with neoadjuvant agents that might improve the current focal therapy outcomes. An internal pilot will determine the feasibility of, and compliance to, randomization. The proposed definitive study plans to recruit and randomize 1190 patients into CHRONOS-A and 1260 patients into CHRONOS-B. RESULTS: Primary outcome in CHRONOS-A is progression-free survival (transition to salvage local or systemic therapy, development of metastases or prostate-cancer-related mortality) and in CHRONOS-B is failure-free survival (includes the above definition and recurrence of clinically significant prostate cancer after initial FT). Secondary outcomes include adverse events, health economics and functional outcomes measured using validated questionnaires. CHRONOS is powered to assess non-inferiority of FT compared to radical therapy in CHRONOS-A, and superiority of neoadjuvant agents with FT in CHRONOS-B. CONCLUSION: CHRONOS will assess the oncological outcomes after FT compared to radical therapy and whether neoadjuvant treatments improve cancer control following one FT session.

Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis.

OBJECTIVES: Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum-resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo-controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers. METHODS: Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg. Patients received a single i.v. infusion over 1 h and were observed as inpatients overnight. A 12-week follow-up for clinical, rheumatological and laboratory assessments for safety, efficacy (DAS28-ESR) and biomarker analysis was performed. RESULTS: No infusion reactions or serious adverse drug reactions were noted. Adverse events were evenly distributed between placebo and BiP groups with no BiP-related toxicities. Haematological, renal and metabolic parameters showed no drug-related toxicities. Remission was only achieved by patients in the 5 and 15 mg groups, and not patients who received placebo or 1 mg BiP. Good DAS28-ESR responses were achieved in all treatment groups. The BiP responding patients showed significantly lower serum concentrations of CRP, 2 weeks post-infusion compared with pre-infusion levels, and of VEGF and IL-8 from the placebo group. CONCLUSION: BiP (⩽15 mg) is safe in patients with active RA. Some patients had clinical and biological improvements in RA activity. BiP merits further study. TRIAL REGISTRATION: ISRCTN registry, http://isrctn.com, ISRCTN22288225 and EudraCT, https://eudract.ema.europa.eu, 2011-005831-19.

A systematic review of randomised controlled trials in rheumatoid arthritis: the reporting and handling of missing data in composite outcomes.

BACKGROUND: Most reported outcome measures in rheumatoid arthritis (RA) trials are composite, whose components comprise single measures that are combined into one outcome. The aims of this review were to assess the range of missing data rates in primary composite outcomes and to document the current practice for handling and reporting missing data in published RA trials compared to the Consolidated Standards of Reporting Trials (CONSORT) recommendations. METHODS: A systematic search for randomised controlled trials was conducted for RA trials published between 2008 and 2013 in four rheumatology and four high impact general medical journals. RESULTS: A total of 51 trials with a composite primary outcome were identified, of which 38 (75 %) used the binary American College of Rheumatology responder index and 13 (25 %) used the Disease Activity Score for 28 joints (DAS28). Forty-four trials (86 %) reported on an intention-to-treat analysis population, while 7 trials (14 %) analysed according to a modified intention-to-treat population. Missing data rates for the primary composite outcome ranged from 2-53 % and were above 30 % in 9 trials, 20-30 % in 11 trials, 10-20 % in 18 trials and below 10 % in 13 trials. Thirty-eight trials (75 %) used non-responder imputation and 10 (20 %) used last observation carried forward to impute missing composite outcome data at the primary time point. The rate of dropout was on average 61 % times higher in the placebo group compared to the treatment group in the 34 placebo controlled trials (relative rate 1.61, 95 % CI: 1.29, 2.02). Thirty-seven trials (73 %) did not report the use of sensitivity analyses to assess the handling of missing data in the primary analysis as recommended by CONSORT guidelines. CONCLUSIONS: This review highlights an improvement in rheumatology trial practice since the revision of CONSORT guidelines, in terms of power calculation and participant's flow diagram. However, there is a need to improve the handling and reporting of missing composite outcome data and their components in RA trials. In particular, sensitivity analyses need to be more widely used in RA trials because imputation is widespread and generally uses single imputation methods, and in this area the missing data rates are commonly differentially higher in the placebo group.

Pars plana vitrectomy for vitreomacular traction syndrome: a systematic review and metaanalysis of safety and efficacy.

PURPOSE: To determine the safety and efficacy of pars plana vitrectomy for vitreomacular traction. METHODS: Articles reporting visual acuity change before and after pars plana vitrectomy were selected using a systematic literature review with predefined eligibility criteria. Visual acuities were converted to logarithm of the minimum angle of resolution (logMAR), weighted for study size, and pooled across studies. Safety outcomes were also pooled across studies. RESULTS: Twenty-one of 460 articles were eligible. Mean (±standard deviation) logMAR visual acuity improved from 0.67 ± 0.55 to 0.42 ± 0.45 (n = 259 eyes) after pars plana vitrectomy (from 20/94 to 20/53 Snellen). In series of at least 20 eyes, mean visual acuity improved in all 5 studies (sign test, P = 0.0625). Of 392 eyes, 9.2% lost visual acuity, 11.7% were unchanged, and 64.3% improved; 32.9% of 217 eyes gained ≥2 Snellen lines. The most common postoperative complications were cataract (34.7% of 304 eyes; 63.2% of 68 phakic eyes), epiretinal membrane (5.7% of 348 eyes), and retinal detachment (4.6% of 348 eyes). Cataract surgery was undertaken in 10.5% of eyes. CONCLUSION: The visual acuity gains after pars plana vitrectomy for vitreomacular traction are relatively modest, but visual acuity change may not fully reflect symptomatic relief.

Constructing multiplicative measures of beliefs in the theory of planned behaviour.

OBJECTIVE: Commonly used theories in health psychology involve multiplicative composites of measures, which have been used as predictors, mediators, and outcomes. The chosen scaling system can affect correlations with other variables. This study evaluated how best to construct composites in the context of the theory of planned behaviour (TPB), using hierarchical linear regression, a priori defined scaling systems, and optimal scaling. DESIGN: Longitudinal. METHODS: At baseline, 6 and 12 months, 365 trial participants (ProActive) completed questionnaires assessing salient beliefs, which were used to construct composites (indirect measures), and direct measures of instrumental and affective attitude, subjective norm, and perceived behavioural control towards becoming more physically active over the next 12 months. RESULTS: Linear regression supported a multiplicative model for indirect instrumental attitude and perceived control. Except for perceived control, associations between composites and direct measures were unaffected by different a priori scaling systems. Optimal scaling produced widely differing composites over time for subjective norm and affective attitude and a negative association between composite and direct measure for subjective norm. CONCLUSIONS: We recommend that researchers who use multiplicative composites first establish clear support for a multiplicative model, before they examine a range of meaningful scaling systems on theoretical and empirical grounds. Caution is needed when using optimal scaling without checking that a multiplicative model is supported and the resulting scaling system meaningful. STATEMENT OF CONTRIBUTION: What is already known on this subject? Multiplicative composites are included in commonly used theories in health psychology (e.g., theory of planned behaviour). Valid measures are needed as the choice of scaling system (e.g., unipolar or bipolar) can affect estimates of associations between composites and other variables. Ajzen has advocated the use of optimal scaling. What does this study add? The study shows that optimal scaling can result in meaningless measures. We recommend that health psychologists use optimal scaling with great caution and we provide alternative recommendations for constructing composites.

Bladder cancer diagnosis and identification of clinically significant disease by combined urinary detection of Mcm5 and nuclear matrix protein 22.

BACKGROUND: Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22. METHODS: 1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit. RESULTS: Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62-75%) and 93% negative predictive value (95% CI = 92-95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71-0.79) and 0.72 (95% CI = 0.67-0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88-99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69-74%). CONCLUSIONS: The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.

Adherence to hypoglycaemic medication among people with type 2 diabetes in primary care.

AIMS: To assess levels and correlates of adherence to hypoglycaemic medication among patients offered organised general practice diabetes care. METHODS: 60 patients prescribed oral hypoglycaemic medication were recruited to a two-month prospective study. Prescribed doses taken and days on which the prescribed number of doses was taken were measured by MEMS (Medication Event Monitoring System). RESULTS: Overall 99.1% of prescribed doses were taken (median, IQR: 96.8-100%), this was inversely correlated with daily dose frequency (Spearman's rho=0.37, p=0.004). Only 4 patients (6.7%) took less than 90% of prescribed doses. The prescribed dose was taken on 96.4% of days (median, IQR: 89.1-98.2%), this was correlated with age (rho=0.26, p=0.047) and inversely correlated with HbA(1c) levels (rho=-0.29, p=0.02) and daily dose frequency (rho=-0.33, p=0.009). Adherence to metformin was less than to other hypoglycaemic medication (Z=-3.48, p=0.0005). CONCLUSIONS: A dispensing practice with a well-run diabetes service can support high rates of adherence to hypoglycaemic medication. Before changing medication, low adherence might be considered as a possible cause of progressive hyperglycaemia, particularly among patients prescribed metformin more than once a day. Selective monitoring with MEMS may have a clinical as well as a research role in such people.

A comparison of technologies used for estimation of body temperature.

Body temperature measurement is an important clinical parameter. The performance of a number of non-invasive thermometers was measured by comparing intra- and inter-operator variability (n = 100) and clinical accuracy (n = 61). Variability was elevated in febrile compared to normothermic subjects for axillary and oral electronic contact thermometer measures and a temporal artery thermometer (p < 0.001 for both). Temporal artery thermometry and one mode of an infrared tympanic thermometer demonstrated significant clinical inaccuracy (p < 0.001 for both). Electronic contact thermometer repeatability and reproducibility are highly variable in febrile adults both in the axilla and oral cavity. Infrared thermometry of the skin over the superficial temporal artery is unreliable for measuring core body temperature, particularly in febrile subjects and patients in theatre. The infrared tympanic thermometers tested are acceptable for clinical practice; however, care should be exercised with the different modes of operation offered.

Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma.

PURPOSE: There is a lack of prognostic and predictive biomarkers in epithelial ovarian carcinoma, and the targeting of oncogenic signaling pathways has had limited impact on patient survival in this highly heterogeneous disease. The origin licensing machinery, which renders chromosomes competent for DNA replication, acts as a convergence point for upstream signaling pathways. We tested the hypothesis that Cdc7 kinase, a core component of the licensing machinery, is predictive of clinical outcome and may constitute a novel therapeutic target in epithelial ovarian carcinoma. EXPERIMENTAL DESIGN: A total of 143 cases of ovarian cancer and 5 cases of normal ovary were analyzed for Cdc7 protein expression dynamics and clinicopathologic features. To assess the therapeutic potential of Cdc7, expression was down-regulated by RNA interference in SKOV-3 and Caov-3 ovarian cancer cells. RESULTS: Increased Cdc7 protein levels were significantly associated with arrested tumor differentiation (P = 0.004), advanced clinical stage (P = 0.01), genomic instability (P < 0.001), and accelerated cell cycle progression. Multivariate analysis shows that Cdc7 predicts disease-free survival independent of patient age, tumor grade and stage (hazard ratio, 2.03; confidence interval, 1.53-2.68; P < 0.001), with the hazard ratio for relapse increasing to 10.90 (confidence interval, 4.07-29.17) for the stages 3 to 4/upper Cdc7 tertile group relative to stages 1 to 2/lower Cdc7 tertile tumors. In SKOV-3 and Caov-3 cells, Cdc7 siRNA knockdown triggered high levels of apoptosis, whereas untransformed cells arrest in G(1) phase and remain viable. CONCLUSIONS: Our findings show that Cdc7 kinase predicts survival and is a potent anticancer target in epithelial ovarian carcinoma, highlighting its potential as a predictor of susceptibility to small molecule kinase inhibitors currently in development.

Impulsivity in patients with borderline personality disorder.

This study investigated features of impulsivity in patients with borderline personality disorder (BPD) using the self-report Attention-Deficit Scales for Adults (ADSA) and computer-administered neurocognitive tasks. Forty-one patients with DSM-III-R BPD and 35 nonclinical control subjects were assessed by the ADSA, the National Adult Reading Test, and two computerized tasks mediated by the frontal lobes. Mean scores for seven ADSA scales (six of which relate to aspects of impulsivity) were significantly higher in the patient group compared with the control group. Also, the ADSA ratings for impaired coordination were increased in the BPD patients. The findings indicate that a range of aspects of impulsivity, as well as impaired coordination, are associated with patients selected on the basis of BPD. Also, in the patient group, but not in the control group, associations of the neurocognitive tasks indicated that, first, performance on a planning task related to dorsolateral frontal lobe functioning is correlated with aspects of impulsivity reflected by ADSA scale III ratings (involving disorganisation and lack of perseverance) and, second, performance on a decision-making task related to orbitofrontal functioning is correlated with ratings of impaired coordination. Further work is needed to establish the specificity of the findings.

Economic evaluation of Tobramycin nebuliser solution in cystic fibrosis.

BACKGROUND: The cost effectiveness of inhaled TOBIR tobramycin nebuliser solution (TNS) in CF and chronic pulmonary Pseudomonas aeruginosa infection has been shown in US but not in European studies. METHODS: An economic evaluation of TNS was undertaken in children and adults. Lung function and resource utilisation were recorded for 24 months before and during TNS therapy. Interventions were costed. RESULTS: Forty-one patients received TNS; 30 of them matched with a paired control on usual therapy. TNS cases received more inhaled and IV antibiotics in the year before TNS than controls, and were hospitalised more. In the TNS treated group mean days in hospital before and after (change) were 32.0, 24.2 (-7.8); days on IV antibiotics 55.4, 38.9 (-16.4); total cost 22,102 pounds, 28,394 pounds (+ 6292 pounds), composed of cost of TNS 0 pounds, 10,010 pounds (+ 10,010 pounds), cost of hospitalisation 10,897 pounds, 8552 pounds (- 2345 pounds), cost of drugs 11,205 pounds, 9832 pounds (- 1374 pounds). In 19 patients aged < 18 the change in days hospitalised was -10.7 and days on IVs -20.2. Incremental cost was 3830 pounds. CONCLUSIONS: TNS was associated with clinically and socially important reductions of hospital attendances and parenteral antibiotics. This would improve patients' quality of life and reduce interference with work and schooling. Its maximal acquisition cost of 10,010 pounds may be reduced by delays in prescribing and dispensing, and was offset by savings of approximately 3500-6200 pounds.