Comparing screening based on the NHS Health Check and Polypill Prevention Programmes in the primary prevention of heart attacks and strokes.

OBJECTIVE: To compare the NHS Health Check Programme with the Polypill Prevention Programme in the primary prevention of heart attacks and strokes. DESIGN: Use of published data and methodology to produce flow charts of the two programmes to determine screening performance and heart attacks and strokes prevented. SETTING: The UK population. INTERVENTION: The NHS Health Check Programme using a QRISK score on people aged 40-74 to select those eligible for a statin is compared with the Polypill Prevention Programme in people aged 50 or more to select people for a combination of a statin and three low-dose blood pressure lowering agents. In both programmes, people had no history of heart attack or stroke. MAIN OUTCOME MEASURES: In 1000 people, the number of heart attacks and strokes prevented in the two programmes. RESULTS: In the hypothetical perfect situation with 100% uptake and adherence to the screening protocol, in every 1000 persons, the NHS Health Check would prevent 287 cases of a heart attack or stroke in individuals who would gain on average about 4 years of life without a heart attack or stroke amounting to 1148 years in total, the precise gain depending on the extent of treatment for those with raised blood pressure, and 136 would be prescribed statins with no benefit. The corresponding figures for the Polypill Prevention Programme are 316 individuals who would, on average, gain 8 years of life without a heart attack or stroke, amounting to 2528 years in total, and 260 prescribed the polypill with no benefit. Based on published estimates of uptake and adherence in the NHS Health Check Programme, in practice only 24 cases per 1000 are currently benefitting instead of 287, amounting to 96 years gained without a heart attack or stroke. CONCLUSIONS: The Polypill Prevention Programme is by design simpler with the potential of preventing many more heart attacks and strokes than the NHS Health Check Programme.

The polypill in the primary prevention of heart attacks and strokes: Overcoming barriers to implementation.

This commentary, linked to our paper in the same issue of the Journal of Medical Screening, discusses the reluctance to consider and adopt the polypill in the primary prevention of heart attacks and strokes, access to the polypill as a public health service, the formulation of the polypill in current use, its prescription as an unlicensed medicine, and what can be done to facilitate the adoption of the polypill approach as a routine public health service.

Modifiable risk factors for multiple sclerosis have consistent directions of effect across diverse ethnic backgrounds: a nested case-control study in an English population-based cohort.

BACKGROUND: Multiple sclerosis is a leading cause of non-traumatic neurological disability among young adults worldwide. Prior studies have identified modifiable risk factors for multiple sclerosis in cohorts of White ethnicity, such as infectious mononucleosis, smoking, and obesity during adolescence/early adulthood. It is unknown whether modifiable exposures for multiple sclerosis have a consistent impact on risk across ethnic groups. AIM: To determine whether modifiable risk factors for multiple sclerosis have similar effects across diverse ethnic backgrounds. METHODS: We conducted a nested case-control study using data from the UK Clinical Practice Research Datalink. Multiple sclerosis cases diagnosed from 2001 until 2022 were identified from electronic healthcare records and matched to unaffected controls based on year of birth. We used stratified logistic regression models and formal statistical interaction tests to determine whether the effect of modifiable risk factors for multiple sclerosis differed by ethnicity. RESULTS: We included 9662 multiple sclerosis cases and 118,914 age-matched controls. The cohort was ethnically diverse (MS: 277 South Asian [2.9%], 251 Black [2.6%]; Controls: 5043 South Asian [5.7%], 4019 Black [4.5%]). The age at MS diagnosis was earlier in the Black (40.5 [SD 10.9]) and Asian (37.2 [SD 10.0]) groups compared with White cohort (46.1 [SD 12.2]). There was a female predominance in all ethnic groups; however, the relative proportion of males was higher in the South Asian population (proportion of women 60.3% vs 71% [White] and 75.7% [Black]). Established modifiable risk factors for multiple sclerosis-smoking, obesity, infectious mononucleosis, low vitamin D, and head injury-were consistently associated with multiple sclerosis in the Black and South Asian cohorts. The magnitude and direction of these effects were broadly similar across all ethnic groups examined. There was no evidence of statistical interaction between ethnicity and any tested exposure, and no evidence to suggest that differences in area-level deprivation modifies these risk factor-disease associations. These findings were robust to a range of sensitivity analyses. CONCLUSIONS AND RELEVANCE: Established modifiable risk factors for multiple sclerosis are applicable across diverse ethnic backgrounds. Efforts to reduce the population incidence of multiple sclerosis by tackling these risk factors need to be inclusive of people from diverse ethnicities.

The Emergence and Progression of Motor Dysfunction in Individuals at Risk of Parkinson's Disease.

BACKGROUND: PREDICT-PD is a United Kingdom population-based study aiming to stratify individuals for future Parkinson's disease (PD) using a risk algorithm. METHODS: A randomly selected, representative sample of participants in PREDICT-PD were examined using several motor assessments, including the motor section of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III, at baseline (2012) and after an average of 6 years of follow-up. We checked for new PD diagnoses in participants seen at baseline and examined the association between risk scores and incident sub-threshold parkinsonism, motor decline (increasing ≥5 points in MDS-UPDRS-III) and single motor domains in the MDS-UPDRS-III. We replicated analyses in two independent datasets (Bruneck and Parkinson's Progression Markers Initiative [PPMI]). RESULTS: After 6 years of follow-up, the PREDICT-PD higher-risk group (n = 33) had a greater motor decline compared with the lower-risk group (n = 95) (30% vs. 12.5%, P = 0.031). Two participants (both considered higher risk at baseline) were given a diagnosis of PD during follow-up, with motor signs emerging between 2 and 5 years before diagnosis. A meta-analysis of data from PREDICT-PD, Bruneck, and PPMI showed an association between PD risk estimates and incident sub-threshold parkinsonism (odds ratio [OR], 2.01 [95% confidence interval (CI), 1.55-2.61]), as well as new onset bradykinesia (OR, 1.69 [95% CI, 1.33-2.16]) and action tremor (OR, 1.61 [95% CI, 1.30-1.98]). CONCLUSIONS: Risk estimates using the PREDICT-PD algorithm were associated with the occurrence of sub-threshold parkinsonism, including bradykinesia and action tremor. The algorithm could also identify individuals whose motor examination experience a decline over time. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Validation of a monoclonal unconjugated estriol antibody for use in prenatal maternal serum screening.

OBJECTIVES: Unconjugated estriol (uE3) is used as a marker for fetal aneuploidy in maternal serum screening tests. The goal of this study was to examine the validity of a new immunoassay for uE3 that uses a monoclonal antibody (m-uE3) rather than the more commonly used polyclonal antibody (p-uE3). SETTING: Assays were performed in the Special Chemistry laboratory at Women and Infants Hospital of Rhode Island. METHODS: Residual fresh (n = 100) and frozen (n = 533) second trimester serum samples from routine clinical care were tested using p-uE3 and/or m-uE3 assays. Assay results were compared between methods using Bland-Altman plots. A median equation was developed for m-uE3 results. Down syndrome risks were compared between the two assays in a case-control sample set (21 cases each matched with five controls for the completed week of gestation, duration of freezer storage and race). RESULTS: Log-transformed serum uE3 levels were highly correlated between the assays (r = 0.93, p < 0.001), with the m-uE3 assay levels yielding, on average, 23% higher (standard deviation of differences in log uE3 concentrations = 0.07) results. Assay and gestation-based median equations were calculated and used to convert m-uE3 concentrations to multiples of the median (MoM). The m-uE3 MoM values fit a log Gaussian distribution well with a log standard deviation of 0.11. Down syndrome risk results were not significantly different between assays. CONCLUSIONS: The m-uE3 assay, with results expressed in MoMs, is suitable for screening and as a monoclonal-based assay offers the advantage of a predictable and indefinite supply of antibody to perform the assay.

Association Between Antiepileptic Drugs and Incident Parkinson Disease.

Importance: Recent studies have highlighted an association between epilepsy and Parkinson disease (PD). The role of antiepileptic drugs (AEDs) has not been explored. Objective: To investigate the association between AEDs and incident PD. Design, Setting, and Participants: This nested case-control study started collecting data from the UK Biobank (UKB) in 2006, and data were extracted on June 30, 2021. Individuals with linked primary care prescription data were included. Cases were defined as individuals with a Hospital Episode Statistics (HES)-coded diagnosis of PD. Controls were matched 6:1 for age, sex, race and ethnicity, and socioeconomic status. Prescription records were searched for AEDs prescribed prior to diagnosis of PD. The UKB is a longitudinal cohort study with more than 500 000 participants; 45% of individuals in the UKB have linked primary care prescription data. Participants living in the UK aged between 40 and 69 years were recruited to the UKB between 2006 and 2010. All participants with UKB-linked primary care prescription data (n = 222 106) were eligible for enrollment in the study. Individuals with only a self-reported PD diagnosis or missing data for the matching variables were excluded. In total, 1477 individuals were excluded; 49 were excluded due to having only self-reported PD, and 1428 were excluded due to missing data. Exposures: Exposure to AEDs (carbamazepine, lamotrigine, levetiracetam, and sodium valproate) was defined using routinely collected prescription data derived from primary care. Main Outcomes and Measures: Odds ratios and 95% CIs were calculated using adjusted logistic regression models for individuals prescribed AEDs before the first date of HES-coded diagnosis of PD. Results: In this case-control study, there were 1433 individuals with an HES-coded PD diagnosis (cases) and 8598 controls in the analysis. Of the 1433 individuals, 873 (60.9%) were male, 1397 (97.5%) had their race and ethnicity recorded as White, and their median age was 71 years (IQR, 65-75 years). An association was found between AED prescriptions and incident PD (odds ratio, 1.80; 95% CI, 1.35-2.40). There was a trend for a greater number of prescription issues and multiple AEDs being associated with a greater risk of PD. Conclusions and Relevance: This study, the first to systematically look at PD risk in individuals prescribed the most common AEDs, to our knowledge, found evidence of an association between AEDs and incident PD. With the recent literature demonstrating an association between epilepsy and PD, this study provides further insights.

Alcohol and Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: A substantial body of research has examined the relationship between alcohol consumption and risk of Parkinson's disease (PD). OBJECTIVE: To provide an updated systematic review and meta-analysis of observational studies examining the relationship between alcohol consumption and risk of PD. METHODS: Eligible studies comparing PD risk in ever vs. never alcohol drinkers were sourced from six databases. Outcomes were pooled using standard meta-analysis techniques. Separate female and male estimates were generated from studies reporting sex-specific data. Additionally, cohort studies stratifying participants by quantity of alcohol intake were integrated in a dose-response analysis. RESULTS: 52 studies were included, totaling 63,707 PD patients and 9,817,924 controls. Our meta-analysis supported a statistically significant overrepresentation of never drinkers among PD subjects; odds ratio (OR) for ever drinking alcohol 0.84 (95% confidence interval (CI) 0.76 - 0.92). A subgroup analysis revealed similar effect estimates in females and males. A further synthesis of seven cohort studies suggested a negative, dose-dependent association between alcohol and risk of PD. CONCLUSION: In the absence of a known neuroprotective pathway, there may be reason to doubt a true biological effect. The role of survivor bias, selection and recall bias, misclassification, and residual confounding requires consideration. Alternatively, observations might be attributable to reverse causation if those predestined for PD alter their alcohol habits during the preclinical phase. Major limitations of our study include high between-study heterogeneity (I2 = 93.2%) and lack of adjustment for key confounders, namely smoking status.

Dementia risk in a diverse population: A single-region nested case-control study in the East End of London.

Background: Most evidence about dementia risk comes from relatively affluent people of White European ancestry. We aimed to determine the association between ethnicity, area level socioeconomic deprivation and dementia risk, and the extent to which variation in risk might be attributable to known modifiable clinical risk factors and health behaviours. Methods: In this nested case-control study, we analysed data from primary care medical records of a population of 1,016,277 from four inner East London boroughs, United Kingdom, collected between 2009 and 2018. The outcome measures were odds ratios for dementia according to ethnicity and deprivation, before and after the addition of major modifiable risk factors for dementia; and weighted population attributable risk for comparison between individual risk factors. Findings: We identified 4137 dementia cases and 15,754 matched controls (mean age for cases and controls were 80·7 years, (SD 8·7); 81·3 years, (SD 8·9) respectively, range 27-103). Black and South Asian ethnicity were both associated with increased risk of dementia relative to White (odds ratios [95% CI]: Black 1·43 [1·31-1·56]; South Asian 1.17 [1·06-1·29]). Area-level deprivation was independently associated with an increased risk of dementia in a dose-dependent manner. Black and South Asian ethnicity were both associated with a younger age at dementia diagnosis (odds ratios [95%CI]: 0·70 [0·61-0·80] and 0·55 [0·47-0·65], respectively). Population attributable risk was higher for ethnicity (9·7%) and deprivation (11·7%) than for any established modifiable risk factor in this population. Interpretation: Ethnicity and area-level deprivation are independently associated with dementia risk in East London. This effect may not be attributable to the effect of known risk factors. Funding: Barts Charity (MGU0366).

Multi-marker risk-based screening for prostate cancer.

OBJECTIVE: To determine prostate cancer screening performance using prostate specific antigen (PSA) along with other markers, expressing markers in age-specific multiples of the median (MoM), and age. METHODS: A prospective nested case-control study used stored serum from 571 men who died of, or with history of, prostate cancer (cases), and 2169 matched controls. Total, free and intact PSA, human kallikrein-related peptidase 2 (hK2), and microseminoprotein were measured and converted into MoM values. Screening marker distribution parameters were estimated in cases and controls. Monte Carlo simulation used these in a risk-based algorithm to estimate screening performance (detection rates [DRs] and false-positive rates [FPRs]). RESULTS: Almost all (99%) cases occurred aged ≥55. Marker values were similar in cases who did and did not die of prostate cancer. Combining age, total PSA and hK2 MoM values (other markers added little or no discrimination) yielded a 1.2% FPR (95% CI 0.2-4.8%) for a 90% DR (59-98%) in men who died of or with a prostate cancer diagnosis within 5 years of blood collection (risk cut-off 1 in 20), two-thirds less than the 4.5% FPR using total PSA alone measured in ng/ml for the same 90% DR (cut-off 3.1 ng/ml). Screening performance over 10 years yielded a 33% (22-46%) FPR for a 90% DR. CONCLUSION: Screening performed up to every 5 years from age 55 using the multi-marker risk-based screening algorithm for future prostate cancer achieves a high DR and a much lower FPR than using PSA alone, resulting in reductions in overdiagnosis and overtreatment.

The potential utility of smell testing to screen for neurodegenerative disorders.

INTRODUCTION: Loss of smell is a common early feature of neurodegenerative diseases including Alzheimer's and Parkinson's disease. Identifying these conditions in their early stages is important to understand more about early pathophysiological events and the development of disease modifying therapies. Smell testing may be an effective future tool for screening large populations for early neurodegeneration. AREAS COVERED: In this review, we appraise the evidence for, and discuss the likelihood of, the use of smell testing in large screening programs to detect early neurodegeneration. We evaluate the predictive power of smell tests for neurodegenerative disease, compare performance to other established screening programs, and discuss ethical and practical considerations and limitations. EXPERT OPINION: Even if disease modifying therapies were available for neurodegenerative disease, smell tests alone are unlikely to have high enough predictive power to be used in a future screening program. However, we believe they could be a valuable component of a short battery of tests or part of a stepwise process that together could more accurately identify early neurodegeneration in large populations.

Developing and assessing a new web-based tapping test for measuring distal movement in Parkinson's disease: a Distal Finger Tapping test.

Disability in Parkinson's disease (PD) is measured by standardised scales including the MDS-UPDRS, which are subject to high inter and intra-rater variability and fail to capture subtle motor impairment. The BRadykinesia Akinesia INcoordination (BRAIN) test is a validated keyboard tapping test, evaluating proximal upper-limb motor impairment. Here, a new Distal Finger Tapping (DFT) test was developed to assess distal upper-limb function. Kinetic parameters of the test include kinesia score (KS20, key taps over 20 s), akinesia time (AT20, mean dwell-time on each key) and incoordination score (IS20, variance of travelling time between key taps). To develop and evaluate a new keyboard-tapping test for objective and remote distal motor function in PD patients. The DFT and BRAIN tests were assessed in 55 PD patients and 65 controls. Test scores were compared between groups and correlated with the MDS-UPDRS-III finger tapping sub-scores. Nine additional PD patients were recruited for monitoring motor fluctuations. All three parameters discriminated effectively between PD patients and controls, with KS20 performing best, yielding 79% sensitivity for 85% specificity; area under the receiver operating characteristic curve (AUC) = 0.90. A combination of DFT and BRAIN tests improved discrimination (AUC = 0.95). Among three parameters, KS20 showed a moderate correlation with the MDS-UPDRS finger-tapping sub-score (Pearson's r = - 0.40, p = 0.002). Further, the DFT test detected subtle changes in motor fluctuation states which were not reflected clearly by the MDS-UPDRS-III finger tapping sub-scores. The DFT test is an online tool for assessing distal movements in PD, with future scope for longitudinal monitoring of motor complications.

Optimising classification of Parkinson's disease based on motor, olfactory, neuropsychiatric and sleep features.

Olfactory loss, motor impairment, anxiety/depression, and REM-sleep behaviour disorder (RBD) are prodromal Parkinson's disease (PD) features. PD risk prediction models typically dichotomize test results and apply likelihood ratios (LRs) to scores above and below cut-offs. We investigate whether LRs for specific test values could enhance classification between PD and controls. PD patient data on smell (UPSIT), possible RBD (RBD Screening Questionnaire), and anxiety/depression (LADS) were taken from the Tracking Parkinson's study (n = 1046). For motor impairment (BRAIN test) in PD cases, published data were supplemented (n = 87). Control data (HADS for anxiety/depression) were taken from the PREDICT-PD pilot study (n = 1314). UPSIT, RBDSQ, and anxiety/depression data were analysed using logistic regression to determine which items were associated with PD. Gaussian distributions were fitted to BRAIN test scores. LRs were calculated from logistic regression models or score distributions. False-positive rates (FPRs) for specified detection rates (DRs) were calculated. Sixteen odours were associated with PD; LRs for this set ranged from 0.005 to 5511. Six RBDSQ and seven anxiety/depression questions were associated with PD; LRs ranged from 0.35 to 69 and from 0.002 to 402, respectively. BRAIN test LRs ranged from 0.16 to 1311. For a 70% DR, the FPR was 2.4% for the 16 odours, 4.6% for anxiety/depression, 16.0% for the BRAIN test, and 20.0% for the RBDSQ. Specific selections of (prodromal) PD marker features rather than dichotomized marker test results optimize PD classification. Such optimized classification models could improve the ability of algorithms to detect prodromal PD; however, prospective studies are needed to investigate their value for PD-prediction models.

Slow Motion Analysis of Repetitive Tapping (SMART) Test: Measuring Bradykinesia in Recently Diagnosed Parkinson's Disease and Idiopathic Anosmia.

BACKGROUND: Bradykinesia is the defining motor feature of Parkinson's disease (PD). There are limitations to its assessment using standard clinical rating scales, especially in the early stages of PD when a floor effect may be observed. OBJECTIVE: To develop a quantitative method to track repetitive tapping movements and to compare people in the early stages of PD, healthy controls, and individuals with idiopathic anosmia. METHODS: This was a cross-sectional study of 99 participants (early-stage PD = 26, controls = 64, idiopathic anosmia = 9). For each participant, repetitive finger tapping was recorded over 20 seconds using a smartphone at 240 frames per second. From each video, amplitude between fingers, frequency (number of taps per second), and velocity (distance travelled per second) was extracted. Clinical assessment was based on the motor section of the MDS-UPDRS. RESULTS: People in the early stage of PD performed the task with slower velocity (p < 0.001) and with greater frequency slope than controls (p = 0.003). The combination of reduced velocity and greater frequency slope obtained the best accuracy to separate early-stage PD from controls based on metric thresholds alone (AUC = 0.88). Individuals with anosmia exhibited slower velocity (p = 0.001) and smaller amplitude (p < 0.001) compared with controls. CONCLUSION: We present a simple, proof-of-concept method to detect early motor dysfunction in PD. Mean tap velocity appeared to be the best parameter to differentiate patients with PD from controls. Patients with anosmia also showed detectable differences in motor performance compared with controls which may suggest that some were in the prodromal phase of PD.

Improving estimation of Parkinson's disease risk-the enhanced PREDICT-PD algorithm.

We previously reported a basic algorithm to identify the risk of Parkinson's disease (PD) using published data on risk factors and prodromal features. Using this algorithm, the PREDICT-PD study identified individuals at increased risk of PD and used tapping speed, hyposmia and REM sleep behaviour disorder (RBD) as "intermediate" markers of prodromal PD in the absence of sufficient incident cases. We have now developed and tested an enhanced algorithm which incorporates the intermediate markers into the risk model. Risk estimates were compared using the enhanced and the basic algorithm in members of the PREDICT-PD pilot cohort. The enhanced PREDICT-PD algorithm yielded a much greater range of risk estimates than the basic algorithm (93-609-fold difference between the 10th and 90th centiles vs 10-13-fold respectively). There was a greater increase in the risk of PD with increasing risk scores for the enhanced algorithm than for the basic algorithm (hazard ratios per one standard deviation increase in log risk of 2.75 [95% CI 1.68-4.50; p < 0.001] versus 1.47 [95% CI 0.86-2.51; p = 0.16] respectively). Estimates from the enhanced algorithm also correlated more closely with subclinical striatal DaT-SPECT dopamine depletion (R2 = 0.164, p = 0.005 vs R2 = 0.043, p = 0.17). Incorporating the previous intermediate markers of prodromal PD and using likelihood ratios improved the accuracy of the PREDICT-PD prediction algorithm.

Type 2 Diabetes as a Determinant of Parkinson's Disease Risk and Progression.

BACKGROUND: Type 2 diabetes (T2DM) and Parkinson's disease (PD) are prevalent diseases that affect an aging population. Previous systematic reviews and meta-analyses have explored the relationship between diabetes and the risk of PD, but the results have been conflicting. OBJECTIVE: The objective was to investigate T2DM as a determinant of PD through a meta-analysis of observational and genetic summary data. METHODS: A systematic review and meta-analysis of observational studies was undertaken by searching 6 databases. We selected the highest-quality studies investigating the association of T2DM with PD risk and progression. We then used Mendelian randomization (MR) to investigate the causal effects of genetic liability toward T2DM on PD risk and progression, using summary data derived from genome-wide association studies. RESULTS: In the observational part of the study, pooled effect estimates showed that T2DM was associated with an increased risk of PD (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.07-1.36), and there was some evidence that T2DM was associated with faster progression of motor symptoms (standardized mean difference [SMD] 0.55, 95% CI 0.39-0.72) and cognitive decline (SMD -0.92, 95% CI -1.50 to -0.34). Using MR, we found supportive evidence for a causal effect of diabetes on PD risk (inverse-variance weighted method [IVW] OR 1.08, 95% CI 1.02-1.14; P = 0.010) and some evidence of an effect on motor progression (IVW OR 1.10, 95% CI 1.01-1.20; P = 0.032) but not on cognitive progression. CONCLUSIONS: Using meta-analyses of traditional observational studies and genetic data, we observed convincing evidence for an effect of T2DM on PD risk and new evidence to support a role in PD progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial.

BACKGROUND: An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids. METHODS: We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994. FINDINGS: Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060-2810] in the metformin group vs 1770 mg [1020-2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI -0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (-3835 mm2, 95% CI -6781 to -888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01). INTERPRETATION: No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation. FUNDING: Barts Charity and Merck Serono.

Should fractional flow reserve follow angiographic visual inspection to guide preventive percutaneous coronary intervention in ST-elevation myocardial infarction?

AIMS: We aimed to quantify the effect of preventive percutaneous coronary intervention (PCI to non-infarct arteries) on cardiac death and non-fatal myocardial infarction (MI) in patients with ST-elevation myocardial infarction (STEMI) according to whether the decision to carry out preventive PCI was based on angiographic visual inspection (AVI alone) or AVI plus fractional flow reserve (FFR) if AVI showed significant stenosis (AVI plus FFR). METHODS AND RESULTS: Randomized trials comparing preventive PCI with no preventive PCI in STEMI without shock were identified by a systematic literature search and categorized according to whether they used AVI alone or AVI plus FFR to select patients for preventive PCI. Random effects meta-analyses and tests of heterogeneity were used to compare the two categories in respect of cardiac death and MI as a combined outcome and individually. Eleven eligible trials were identified. For cardiac death and MI, the relative risk estimates for AVI alone vs. AVI plus FFR were 0.39 (0.25-0.61) and 0.85 (0.57-1.28), respectively (P = 0.01 for difference), for cardiac death, alone the estimates were 0.36 (0.19-0.71) and 0.79 (0.36-1.77), respectively (P = 0.15 for difference), and for MI alone, 0.41 (0.23-0.73) and 0.98 (0.62-1.56), respectively (P = 0.04 for difference). CONCLUSION: In preventive PCI among STEMI patients, AVI alone achieves a ∼60% reduction in cardiac death and MI but selecting patients using FFR in AVI positive patients loses much of the benefit. Angiographic visual inspection is best used without FFR in this group of patients.

Reaching detection targets in familial hypercholesterolaemia: Comparison of identification strategies.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is a common and preventable cause of premature heart attack but in most nations only a small proportion of FH-positive individuals have been identified. The aim of this study was to estimate the time to close this FH detection gap. METHODS: We developed a model to estimate the time to identify different proportions of FH in the population for three identification strategies (i) Cascade Testing (FH-mutation testing in relatives of someone with an FH mutation) (ii) Child-parent Screening (testing children for cholesterol and FH mutations during 1-year immunisation and parents of FH-positive children) and (iii) Child-parent Cascade Screening (integrating the first two methods). We used publicly available data to compare the strategies in terms of the time to identify 25%, 50% and 75% of all FH cases in the UK (current target is 25% in 5 years). For Child-parent Cascade Screening, we applied the model to other populations that have reported FH identification levels. RESULTS: In the UK, 25% of FH individuals would be identified after 47 years for Cascade Testing, 12 years for Child-parent Screening and 8 years for Child-parent Cascade Screening; 50% identification after 146, 33 and 19 years and 75% after 334, 99 and 41 years respectively. For Child-parent Cascade Screening, the times to identify 50% FH were, for Netherlands, Norway, Japan, Canada, USA, Australia/NZ, South Africa and Russia, 0, 5, 13, 15, 16, 18, 21, and 30 years respectively. CONCLUSIONS: Child-parent Cascade Screening is the fastest strategy for identifying FH in the population. The model is applicable to any country to estimate the time to close the FH detection gap (www.screenfh.com).

Randomized Crossover Trial of Phosphate-binding Medication on Serum Phosphate Levels in Patients With Aortic Stenosis.

PURPOSE: Aortic stenosis is a common cause of valvular heart disease with no means of prevention. The recognized association between aortic stenosis and serum phosphate raises the possibility of preventing progression of the disorder by using phosphate-binding drugs, but there is uncertainty whether such treatment lowers serum phosphate levels in patients without diagnosed renal failure. This pilot study was conducted to answer this question in patients with aortic stenosis. METHODS: A randomized, double-blind, crossover trial of the phosphate-binding drug sevelamer was conducted in 72 patients. Patients were prescribed sevelamer 0.8 g (low-dose), sevelamer 2.4 g (high-dose), and matching placebo, 3 times daily with food; each regimen lasted 6 weeks and was allocated at random. Serum phosphate levels were measured at the end of each treatment period, and within-person levels were compared. FINDINGS: Sixty-one patients completed the 3 treatment periods. There was no significant difference in the mean end-treatment phosphate levels across all patients (3.38, 3.36, and 3.31 mg/dL with placebo, low-dose sevelamer, and high-dose sevelamer, respectively). Post hoc analysis showed a reduction in phosphate levels with increasing sevelamer dose in the highest baseline phosphate quartile group; a 0.3 mg/dL reduction (mean, 4.09 mg/dL with placebo, 3.95 mg/dL with low-dose sevelamer, and 3.79 mg/dL with high-dose sevelamer; Ptrend = 0.027). IMPLICATIONS: Sevelamer had no overall statistically significant effect in lowering serum phosphate levels, but a reduction was observed in patients with phosphate levels in the highest quartile group of the population distribution. This hypothesis-generating result requires confirmation in an independent study. If confirmed, a trial of sevelamer in preventing the progression of aortic stenosis may be justified in patients with high phosphate levels. ISRCTN Registry identifier: ISRCTN17365679.