Helen M Pattison

Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction

Context The relationship between subclinical thyroid dysfunction and disorders of cognition and mood is unclear. Contribution The authors studied 5868 general practice patients 65 years of age or older with a detailed medical history, thyroid tests, and standardized tests of cognition and mood. They found no association between subclinical thyroid dysfunction and anxiety, depression, or cognitive impairment in prediction models that adjusted for age, sex, social deprivation, medications, and comorbid diseases. Implications This study provides good evidence that subclinical thyroid dysfunction is not related to disorders of cognition and mood in older persons. The Editors The advent of automated sensitive assays for thyroid hormones and thyroid-stimulating hormone (TSH) and the increasingly widespread use of such tests have led to a substantial increase in the identification of mild thyroid dysfunction, especially in elderly patients. This, in turn, has led many physicians to treat subclinical (also known as mild) dysfunction. However, the clinical significance of mild thyroid dysfunction remains uncertain, and evidence on the efficacy or safety of treatment is limited (13). Subclinical thyroid dysfunction is characterized by an abnormal serum level of TSH in association with normal serum levels of thyroid hormone. Subclinical hypothyroidism is defined biochemically as an increased serum TSH level with a normal serum free thyroxine (T4) level, and subclinical hyperthyroidism as a decreased serum TSH level with normal levels of free T4 and free triiodothyronine. One postulated consequence of minor abnormalities of thyroid function, especially subclinical hypothyroidism, is an effect on cognitive functioning and mood. The association between overt hypothyroidism and cognitive dysfunction is well established (4, 5), although more recent evidence suggests that this association is confounded by mood (6). Whether a similar association exists with mild or subclinical hypothyroidism is uncertain. Some studies report no association between subclinical hypothyroidism and measures of cognition (5, 79), whereas others have identified between-group differences in cognitive functioning when patients with subclinical hypothyroidism were compared with euthyroid controls (10). A recent study (11) with a case-matched design demonstrated no differences in cognitive functioning between subclinically hypothyroid and euthyroid patients, although the criteria for defining subclinical hypothyroidism were atypical (an upper TSH limit of 3.5 mIU/L) and external validity was reduced by the exclusion of patients with serious illness or a history of cardiovascular disease. Associations between subclinical hypothyroidism and depression have also been described (6, 10, 12, 13), but many of these studies were based on small samples and were subject to selection and recruitment bias. An association between subclinical dysfunction and anxiety has also been demonstrated (14). Nevertheless, the largest reported study to date (30589 patients) (15) showed no association between subclinical hypothyroidism and depression or anxiety, findings that have been reported elsewhere (9, 11). A recent systematic review that aimed to determine any association between thyroid dysfunction and cognitive function and mood concluded that evidence is insufficient to confirm or refute an association with subclinical hypothyroidism or subclinical hyperthyroidism (1). We used standard diagnostic criteria to examine these possible associations in a large community-based cohort of persons 65 years of age or older (the Birmingham Elderly Thyroid Study). We recorded measures of thyroid function, cognitive functioning, depression, and anxiety and report on associations after controlling for the confounding effects of comorbid illness and medication use. Methods Recruitment and Participants Participants were recruited from 20 primary care practices in central England. The sample was selected to encompass patients from a range of socioeconomic backgrounds. To maximize generalizability to the primary care population, all patients who did not have an active diagnosis of thyroid disease were included. Patients were excluded if they had received antithyroid treatment within the previous 12 months or were currently receiving treatment for a thyroid disorder, or if their family physician deemed that contact was inappropriate (for example, because of recent bereavement or inability to give informed consent). All other patients 65 years of age or older were eligible and were invited to participate by letter. Because the uptake rate was only 14.6% among the first 699 patients older than 85 years of age who were contacted, recruitment was subsequently limited to patients 65 to 84 years of age (inclusive) for the remainder of the study, although previously contacted patients who were older than 84 years of age remained eligible. Patients who accepted the invitation received an appointment with a research or trained primary care nurse at their usual primary care practice or their home. Ethical approval was obtained from the Multi-Centre Research Ethics Committee (Scotland), and local approval was confirmed before commencement of the study. Written informed consent was obtained from all participants. Measurements and Sample Size Patients were placed under no restrictions on eating or medication use before serum samples were obtained for testing. Serum samples were obtained during normal office hours and were treated and collected according to the practices usual procedure for blood collection. Serum TSH and free T4 were measured by using a chemiluminescent immunoassay (Adiva Centaur [Bayer Diagnostics, Newbury, United Kingdom]) in the Regional Endocrine Laboratory of the University Hospital Birmingham National Health Service Trust. Interassay coefficients of variation were 4.4% to 10.9% over 0.41 to 24.5 mIU/L for the TSH assay and 8.2% to 9.8% over 8.2 to 54.9 pmol/L for the free T4 assay. The laboratory reference range was 0.4 to 5.5 mIU/L for TSH and 9.0 to 20.0 pmol/L for free T4. Serum free triiodothyronine was measured by chemiluminescent assay (Avida Centaur) in all cases in which the TSH level was less than 0.4 mIU/L or a within-range TSH level was accompanied by an elevated free T4 level. The reference range for the triiodothyronine assay was 3.5 to 6.5 pmol/L, and the interassay coefficient of variation was 4.2% to 6.9% over 4.0 to 16.0 pmol/L. The Index of Multiple Deprivation 2004 (16) was calculated for each participant on the basis of his or her postal code. This proxy measure of socioeconomic deprivation encompasses 7 domains: income; employment; health and disability; education, skills, and training; barriers to housing and services; living environment; and crime. All major current or previous medical diagnoses and current drug therapies were recorded on the basis of patient reporting and validation from primary care records. Diagnoses were categorized in line with recognized disease groupings. Medications that are known to interact with thyroid function, anxiety, depression, or cognition were coded under generic headings. Cognition was assessed by using the Folstein Mini-Mental State Examination (MMSE) (17), which is widely used to determine cognitive status in clinical and research settings, and the Middlesex Elderly Assessment of Mental State (MEAMS) (18), which was developed as a screening test to detect gross impairment of specific cognitive skills in elderly persons and systematically surveys the major areas of cognitive performance. Aspects covered by MEAMS include orientation, learning, memory, numeracy, perception, attention, and language skills. Both tests comprise a range of tasks that all elderly persons without cognitive impairment should be able to complete, regardless of intelligence. Possible scores on the MMSE range from 0 to 30. Subtests in MEAMS can be used alone, or a combined score can be produced (range, 0 to 12). In both tests, higher scores indicate less dysfunction. Nurses were trained in the administration of all tests to the required standard. Symptoms of depression and anxiety were self-reported by using the Hospital Anxiety and Depression Scale (HADS) (19), which consists of 7 items for depression and 7 for anxiety. Each item is scored from 0 to 3, and the maximum total score on each scale is 21. Scores of 8 to 10 indicate mild disorder, scores of 11 to 14 indicate moderate disorder, and scores of 15 or greater indicate severe anxiety or depression. Assuming a prevalence of 9% for subclinical hypothyroidism and 6% for subclinical hyperthyroidism, a planned sample size of 6200 patients was sufficient to detect a difference between the subclinical and euthyroid groups of 0.4 unit (SD, 2.2) in MMSE score (20) and 0.7 unit (SD, 3.6) in HADS score (21), with 90% power and 5% significance. Data Management and Coding Participants were classified according to serum free thyroid hormone and TSH levels into 1 of 5 categories: overt hypothyroidism, subclinical hypothyroidism, euthyroidism, subclinical hyperthyroidism, and overt hyperthyroidism. Euthyroidism was further subdivided into quartiles before analysis. Participants who could not be categorized on the basis of thyroid function results were excluded from analyses. Table 1 shows details of criteria for classification. Table 1. Values Used to Categorize Thyroid Status In cases where only 1 item per scale was missing on the HADS data, the missing value was imputed by using mean scores. Missing values on MEAMS and MMSE were not imputed because of the heterogeneity of individual tests (which measured distinct aspects of cognitive processing) and the fact that some processes are assessed by only 1 or 2 items. Participants for whom data were incomplete were excluded from corresponding analyses. Statistical Analysis Analyses were done by using SAS software, version 9.1 (SAS Institute, Inc., Cary, North C

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia: the ECLIPSE trial.

BACKGROUND Heavy menstrual bleeding (HMB) is a common problem, yet evidence to inform decisions about initial medical treatment is limited. OBJECTIVES To assess the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena®, Bayer) compared with usual medical treatment, with exploration of womens perspectives on treatment. DESIGN A pragmatic, multicentre randomised trial with an economic evaluation and a longitudinal qualitative study. SETTING Women who presented in primary care. PARTICIPANTS A total of 571 women with HMB. A purposeful sample of 27 women who were randomised or ineligible owing to treatment preference participated in semistructured face-to-face interviews around 2 and 12 months after commencing treatment. INTERVENTIONS LNG-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone). Women could subsequently swap or cease their allocated treatment. OUTCOME MEASURES The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period and then again at 5 years. Secondary outcomes included general quality of life (QoL), sexual activity, surgical intervention and safety. Data were analysed using iterative constant comparison. A state transition model-based cost-utility analysis was undertaken alongside the randomised trial. Quality-adjusted life-years (QALYs) were derived from the European Quality of Life-5 Dimensions (EQ-5D) and the Short Form questionnaire-6 Dimensions (SF-6D). The intention-to-treat analyses were reported as cost per QALY gained. Uncertainty was explored by conducting both deterministic and probabilistic sensitivity analyses. RESULTS The MMAS total scores improved significantly in both groups at all time points, but were significantly greater for the LNG-IUS than for usual treatment [mean difference over 2 years was 13.4 points, 95% confidence interval (CI) 9.9 to 16.9 points; p < 0.001]. However, this difference between groups was reduced and no longer significant by 5 years (mean difference in scores 3.9 points, 95% CI -0.6 to 8.3 points; p = 0.09). By 5 years, only 47% of women had a LNG-IUS in place and 15% were still taking usual medical treatment. Five-year surgery rates were low, at 20%, and were similar, irrespective of initial treatments. There were no significant differences in serious adverse events between groups. Using the EQ-5D, at 2 years, the relative cost-effectiveness of the LNG-IUS compared with usual medical treatment was £1600 per QALY, which by 5 years was reduced to £114 per QALY. Using the SF-6D, usual medical treatment dominates the LNG-IUS. The qualitative findings show that womens experiences and expectations of medical treatments for HMB vary considerably and change over time. Women had high expectations of a prompt effect from medical treatments. CONCLUSIONS The LNG-IUS, compared with usual medical therapies, resulted in greater improvement over 2 years in womens assessments of the effect of HMB on their daily routine, including work, social and family life, and psychological and physical well-being. At 5 years, the differences were no longer significant. A similar low proportion of women required surgical intervention in both groups. The LNG-IUS is cost-effective in both the short and medium term, using the method generally recommended by the National Institute for Health and Care Excellence. Using the alternative measures to value QoL will have a considerable impact on cost-effectiveness decisions. It will be important to explore the clinical and health-care trajectories of the ECLIPSE (clinical effectiveness and cost-effectiveness of levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia) trial participants to 10 years, by which time half of the cohort will have reached menopause. TRIAL REGISTRATION Current Controlled Trials ISRCTN86566246. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 88. See the NIHR Journals Library website for further project information.

A Randomized Controlled Trial of the Effect of Thyroxine Replacement on Cognitive Function in Community-Living Elderly Subjects with Subclinical Hypothyroidism: The Birmingham Elderly Thyroid Study

CONTEXT Subclinical hypothyroidism (SCH) and cognitive dysfunction are both common in the elderly and have been linked. It is important to determine whether T4 replacement therapy in SCH confers cognitive benefit. OBJECTIVE Our objective was to determine whether administration of T4 replacement to achieve biochemical euthyroidism in subjects with SCH improves cognitive function. DESIGN AND SETTING We conducted a double-blind placebo-controlled randomized controlled trial in the context of United Kingdom primary care. PATIENTS Ninety-four subjects aged 65 yr and over (57 females, 37 males) with SCH were recruited from a population of 147 identified by screening. INTERVENTION T4 or placebo was given at an initial dosage of one tablet of either placebo or 25 microg T4 per day for 12 months. Thyroid function tests were performed at 8-weekly intervals with dosage adjusted in one-tablet increments to achieve TSH within the reference range for subjects in treatment arm. Fifty-two subjects received T4 (31 females, 21 males; mean age 73.5 yr, range 65-94 yr); 42 subjects received placebo (26 females, 16 males; mean age 74.2 yr, 66-84 yr). MAIN OUTCOME MEASURES Mini-Mental State Examination, Middlesex Elderly Assessment of Mental State (covering orientation, learning, memory, numeracy, perception, attention, and language skills), and Trail-Making A and B were administered. RESULTS Eighty-two percent and 84% in the T4 group achieved euthyroidism at 6- and 12-month intervals, respectively. Cognitive function scores at baseline and 6 and 12 months were as follows: Mini-Mental State Examination T4 group, 28.26, 28.9, and 28.28, and placebo group, 28.17, 27.82, and 28.25 [not significant (NS)]; Middlesex Elderly Assessment of Mental State T4 group, 11.72, 11.67, and 11.78, and placebo group, 11.21, 11.47, and 11.44 (NS); Trail-Making A T4 group, 45.72, 47.65, and 44.52, and placebo group, 50.29, 49.00, and 46.97 (NS); and Trail-Making B T4 group, 110.57, 106.61, and 96.67, and placebo group, 131.46, 119.13, and 108.38 (NS). Linear mixed-model analysis demonstrated no significant changes in any of the measures of cognitive function over time and no between-group difference in cognitive scores at 6 and 12 months. CONCLUSIONS This RCT provides no evidence for treating elderly subjects with SCH with T4 replacement therapy to improve cognitive function.

Educational Intervention Improves Anticoagulation Control in Atrial Fibrillation Patients: The TREAT Randomised Trial

Background Stroke prevention in atrial fibrillation (AF), most commonly with warfarin, requires maintenance of a narrow therapeutic target (INR 2.0 to 3.0) and is often poorly controlled in practice. Poor patient-understanding surrounding AF and its treatment may contribute to the patient’s willingness to adhere to recommendations. Method A theory-driven intervention, developed using patient interviews and focus groups, consisting of a one-off group session (1–6 patients) utilising an “expert-patient” focussed DVD, educational booklet, self-monitoring diary and worksheet, was compared in a randomised controlled trial (ISRCTN93952605) against usual care, with patient postal follow-ups at 1, 2, 6, and 12-months. Ninety-seven warfarin-naïve AF patients were randomised to intervention (n=46, mean age (SD) 72.0 (8.2), 67.4% men), or usual care (n=51, mean age (SD) 73.7 (8.1), 62.7% men), stratified by age, sex, and recruitment centre. Primary endpoint was time within therapeutic range (TTR); secondary endpoints included knowledge, quality of life, anxiety/depression, beliefs about medication, and illness perceptions. Main Findings Intervention patients had significantly higher TTR than usual care at 6-months (76.2% vs. 71.3%; p=0.035); at 12-months these differences were not significant (76.0% vs. 70.0%; p=0.44). Knowledge increased significantly across time (F (3, 47) = 6.4; p<0.01), but there were no differences between groups (F (1, 47) = 3.3; p = 0.07). At 6-months, knowledge scores predicted TTR (r=0.245; p=0.04). Patients’ scores on subscales representing their perception of the general harm and overuse of medication, as well as the perceived necessity of their AF specific medications predicted TTR at 6- and 12-months. Conclusions A theory-driven educational intervention significantly improves TTR in AF patients initiating warfarin during the first 6-months. Adverse clinical outcomes may potentially be reduced by improving patients’ understanding of the necessity of warfarin and reducing their perception of treatment harm. Improving education provision for AF patients is essential to ensure efficacious and safe treatment. The trial is registered with Current Controlled Trials, ISRCTN93952605, and details are available at www.controlled-trials.com/ISRCTN93952605.

Levonorgestrel Intrauterine System versus Medical Therapy for Menorrhagia

BACKGROUND Menorrhagia is a common problem, yet evidence to inform decisions about therapy is limited. In a pragmatic, multicenter, randomized trial, we compared the levonorgestrel-releasing intrauterine system (levonorgestrel-IUS) with usual medical treatment in women with menorrhagia who presented to their primary care providers. METHODS We randomly assigned 571 women with menorrhagia to treatment with levonorgestrel-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined estrogen-progestogen, or progesterone alone). The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) (ranging from 0 to 100, with lower scores indicating greater severity), assessed over a 2-year period. Secondary outcomes included general quality-of-life and sexual-activity scores and surgical intervention. RESULTS MMAS scores improved from baseline to 6 months in both the levonorgestrel-IUS group and the usual-treatment group (mean increase, 32.7 and 21.4 points, respectively; P<0.001 for both comparisons). The improvements were maintained over a 2-year period but were significantly greater in the levonorgestrel-IUS group than in the usual-treatment group (mean between-group difference, 13.4 points; 95% confidence interval, 9.9 to 16.9; P<0.001). Improvements in all MMAS domains (practical difficulties, social life, family life, work and daily routine, psychological well-being, and physical health) were significantly greater in the levonorgestrel-IUS group than in the usual-treatment group, and this was also true for seven of the eight quality-of-life domains. At 2 years, more of the women were still using the levonorgestrel-IUS than were undergoing the usual medical treatment (64% vs. 38%, P<0.001). There were no significant between-group differences in the rates of surgical intervention or sexual-activity scores. There were no significant differences in serious adverse events between groups. CONCLUSIONS In women with menorrhagia who presented to primary care providers, the levonorgestrel-IUS was more effective than usual medical treatment in reducing the effect of heavy menstrual bleeding on quality of life. (Funded by the National Institute of Health Research Health Technology Assessment Programme; ECLIPSE Controlled-Trials.com number, ISRCTN86566246.).

Be SMART: examining the experience of implementing the NHS Health Check in UK primary care.

BackgroundThe NHS Health Check was designed by UK Department of Health to address increased prevalence of cardiovascular disease by identifying risk levels and facilitating behaviour change. It constituted biomedical testing, personalised advice and lifestyle support. The objective of the study was to explore Health Care Professionals’ (HCPs) and patients’ experiences of delivering and receiving the NHS Health Check in an inner-city region of England.MethodsPatients and HCPs in primary care were interviewed using semi-structured schedules. Data were analysed using Thematic Analysis.ResultsFour themes were identified. Firstly, Health Check as a test of ‘roadworthiness’ for people. The roadworthiness metaphor resonated with some patients but it signified a passive stance toward illness. Some patients described the check as useful in the theme, Health check as revelatory. HCPs found visual aids demonstrating levels of salt/fat/sugar in everyday foods and a ‘traffic light’ tape measure helpful in communicating such ‘revelations’ with patients. Being SMART and following the protocolrevealed that few HCPs used SMART goals and few patients spoke of them. HCPs require training to understand their rationale compared with traditional advice-giving. The need for further follow-up revealed disparity in follow-ups and patients were not systematically monitored over time.ConclusionsHCPs’ training needs to include the use and evidence of the effectiveness of SMART goals in changing health behaviours. The significance of fidelity to protocol needs to be communicated to HCPs and commissioners to ensure consistency. Monitoring and measurement of follow-up, e.g., tracking of referrals, need to be resourced to provide evidence of the success of the NHS Health Check in terms of healthier lifestyles and reduced CVD risk.

Intrapartum tests for group B streptococcus:accuracy and acceptability of screening

Please cite this paper as: Daniels J, Gray J, Pattison H, Gray R, Hills R, Khan K on behalf of the GBS Collaborative Group. Intrapartum tests for group B streptococcus: accuracy and acceptability of screening. BJOG 2011;118:257–265.

Reducing the risk of sexually transmitted infections in genitourinary medicine clinic patients: a systematic review and meta-analysis of behavioural interventions

Objectives: Are behavioural interventions effective in reducing the rate of sexually transmitted infections (STIs) among genitourinary medicine (GUM) clinic patients? Design: Systematic review and meta-analysis of published articles. Data sources: Medline, CINAHL, Embase, PsychINFO, Applied Social Sciences Index and Abstracts, Cochrane Library Controlled Clinical Trials Register, National Research Register (1966 to January 2004). Review methods: Randomised controlled trials of behavioural interventions in sexual health clinic patients were included if they reported change to STI rates or self reported sexual behaviour. Trial quality was assessed using the Jadad score and results pooled using random effects meta-analyses where outcomes were consistent across studies. Results: 14 trials were included; 12 based in the United States. Experimental interventions were heterogeneous and most control interventions were more structured than typical UK care. Eight trials reported data on laboratory confirmed infections, of which four observed a greater reduction in their intervention groups (in two cases this result was statistically significant, p<0.05). Seven trials reported consistent condom use, of which six observed a greater increase among their intervention subjects. Results for other measures of sexual behaviour were inconsistent. Success in reducing STIs was related to trial quality, use of social cognition models, and formative research in the target population. However, effectiveness was not related to intervention format or length. Conclusions: While results were heterogeneous, several trials observed reductions in STI rates. The most effective interventions were developed through extensive formative research. These findings should encourage further research in the United Kingdom where new approaches to preventing STIs are urgently required.

Pulse oximetry screening for congenital heart defects in newborn infants: An evaluation of acceptability to mothers

Background Introducing neonatal screening procedures may not be readily accepted by parents and may increase anxiety. The acceptability of pulse oximetry screening to parents has not been previously reported. Objective To assess maternal acceptability of pulse oximetry screening for congenital heart defects and to identify factors predictive of participation in screening. Design and setting A questionnaire was completed by a cross-sectional sample of mothers whose babies were recruited into the PulseOx Study which investigated the test accuracy of pulse oximetry screening. Participants A total of 119 mothers of babies with false-positive (FP) results, 15 with true-positive and 679 with true-negative results following screening. Main outcome measures Questionnaires included measures of satisfaction with screening, anxiety, depression and perceptions of test results. Results Participants were predominantly satisfied with screening. The anxiety of mothers given FP results was not significantly higher than that of mothers given true-negative results (median score 32.7 vs 30.0, p=0.09). White British/Irish mothers were more likely to participate in screening, with a decline rate of 5%; other ethnic groups were more likely to decline with the largest increase in declining being for Black African mothers (21%, OR 4.6, 95% CI 3.8 to 5.5). White British mothers were also less anxious (p<0.001) and more satisfied (p<0.001) than those of other ethnicities Conclusions Pulse oximetry screening was acceptable to mothers and FP results were not found to increase anxiety. Factors leading to differences in participation and satisfaction across ethnic groups need to be identified so that staff can support parents appropriately.

Self measurement of blood pressure: a community survey.

New technology means that self-measurement or testing of blood pressure (BP) is potentially available for many people but few data exist on how common it is. A community survey in Birmingham, UK in June 2005 (2931 responders; response rate 54%) of self-testing of BP showed that 9% of a randomly selected population sample had self-tested their own BP. Greater public awareness of BP through self-testing has the potential to improve the detection and treatment of BP but this will only be possible if professionals are aware of it.