Jonathan P. Bestwick

Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials.

OBJECTIVE To quantify the incremental effect of combining blood pressure-lowering drugs from any 2 classes of thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers over 1 drug alone and to compare the effects of combining drugs with doubling dose. METHODS Meta-analysis of factorial trials in which participants were randomly allocated to 1 drug alone, another drug alone, both drugs together, or a placebo. RESULTS We identified 42 trials (10,968 participants). With a thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mm Hg and 14.6 mm Hg combined with a drug from another class. The corresponding reductions were 9.3 mm Hg and 18.9 mm Hg with a beta-blocker, 6.8 mm Hg and 13.9 mm Hg with an angiotensin-converting enzyme, and 8.4 mm Hg and 14.3 mm Hg with a calcium channel blocker. The expected blood pressure reduction from 2 drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from 1 drug were, respectively, for thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers: 1.04 (95% confidence interval [CI], 0.88-1.20), 1.00 (95% CI, 0.76-1.24), 1.16 (95% CI, 0.93-1.39), and 0.89 (95% CI, 0.69-1.09); the overall average was 1.01 (95% CI, 0.90-1.12). Comparison of our results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of 1 drug had approximately one fifth of the equivalent incremental effect (0.22 [95% CI, 0.19-0.25]). CONCLUSION Blood pressure reduction from combining drugs from these 4 classes can be predicted on the basis of additive effects. The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.

Adherence to drugs that prevent cardiovascular disease: meta-analysis on 376,162 patients

OBJECTIVE Combination therapy, specifically with aspirin, cholesterol and blood pressure-lowering drugs, substantially reduces the risk of coronary heart disease, but the full preventive effect is only realized if treatment continues indefinitely. Our objective was to provide a summary estimate of adherence to drugs that prevent coronary heart disease, according to drug class and use in people who have had a myocardial infarction (secondary prevention) and people who have not (primary prevention). METHODS A meta-analysis of data on 376,162 patients from 20 studies assessing adherence using prescription refill frequency for the following 7 drug classes was performed: aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium-channel blockers, thiazides, and statins. Meta-regression was used to examine the effects of age, payment, and treatment duration. RESULTS The summary estimate for adherence across all studies was 57% (95% confidence interval [CI], 50-64) after a median of 24 months. There were statistically significant differences in adherence between primary and secondary prevention: 50% (CI, 45-56) and 66% (CI, 56-75), respectively (P=.012). Adherence was lower for thiazides (42%) than for angiotensin receptor blockers (61%) in primary prevention (P=.02). There were no other statistically significant differences between any of the drug classes in primary or secondary prevention studies. Adherence decreased by 0.15% points/month (P=.07) and was unrelated to age or whether patients paid for their pills. CONCLUSION Adherence to preventive treatment is poor and little related to class of drug, suggesting that side effects are not the main cause. General, rather than class-specific, measures at improving adherence are needed.

Meta-analysis of early nonmotor features and risk factors for Parkinson disease.

To evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population‐based screening.

Increased neurofilament light chain blood levels in neurodegenerative neurological diseases

Objective Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies. Methods We developed and applied a highly sensitive electrochemiluminescence (ECL) based immunoassay for quantification of NfL in blood and CSF. Results Patients with Alzheimer’s disease (AD) (30.8 pg/ml, n=20), Guillain-Barré-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control group of neurological patients without evidence of structural CNS damage (control patients, CP) (4.4 pg/ml, n=68, p<0.0001 for each comparison, p=0.002 for AD patients) and healthy controls (HC) (3.3 pg/ml, n=67, p<0.0001). Similar differences were seen in corresponding CSF samples. CSF and serum levels correlated in AD (r=0.48, p=0.033), GBS (r=0.79, p<0.0001) and ALS (r=0.70, p<0.0001), but not in CP (r=0.11, p=0.3739). The sensitivity and specificity of serum NfL for separating ALS from healthy controls was 91.3% and 91.0%. Conclusions We developed and validated a novel ECL based sandwich immunoassay for the NfL protein in serum (NfLUmea47:3); levels in ALS were more than 20-fold higher than in controls. Our data supports further longitudinal studies of serum NfL in neurodegenerative diseases as a potential biomarker of on-going disease progression, and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.

Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis

Objective To develop a population screening strategy for familial hypercholesterolaemia. Design Meta-analysis of published data on total and low density lipoprotein (LDL) cholesterol in people with and without familial hypercholesterolaemia according to age. Thirteen studies reporting on 1907 cases and 16 221 controls were used in the analysis. Included studies had at least 10 cases and controls with data on the distribution of cholesterol in affected and unaffected individuals. Main outcome measures Detection rates (sensitivity) for specified false positive rates (0.1%, 0.5%, and 1%) in newborns and in age groups 1-9, 10-19, 20-39, 40-59, and ≥60 years. Results Serum cholesterol concentration discriminated best between people with and without familial hypercholesterolaemia at ages 1-9, when the detection rates with total cholesterol were 88%, 94%, and 96% for false positive rates of 0.1%, 0.5%, and 1%. The results were similar with LDL cholesterol. Screening newborns was much less effective. Once an affected child is identified, measurement of cholesterol would detect about 96% of parents with the disorder, using the simple rule that the parent with the higher serum cholesterol concentration is the affected parent. Conclusions The proposed strategy of screening children and parents for familial hypercholesterolaemia could have considerable impact in preventing the medical consequences of this disorder in two generations simultaneously.

Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women

CONTEXT Thyroid hormone, requiring adequate maternal iodine intake, is critical for fetal neurodevelopment. Perchlorate decreases thyroidal iodine uptake by competitively inhibiting the sodium/iodide symporter. It is unclear whether environmental perchlorate exposure adversely affects thyroid function in pregnant women. Thiocyanate, derived from foods and cigarette smoke, is a less potent competitive sodium/iodide symporter inhibitor than perchlorate. OBJECTIVE Our objective was to determine whether environmental perchlorate and/or thiocyanate exposure is associated with alterations in thyroid function in pregnancy. DESIGN AND SETTING We conducted a cross-sectional study at health centers in Cardiff, Wales, and Turin, Italy. PATIENTS During 2002-2006, 22,000 women at less than 16 wk gestation were enrolled in the Controlled Antenatal Thyroid Screening Study. Subsets of 261 hypothyroid/hypothyroxinemic and 526 euthyroid women from Turin and 374 hypothyroid/hypothyroxinemic and 480 euthyroid women from Cardiff were selected based on availability of stored urine samples and thyroid function data. MAIN OUTCOME MEASURES Urinary iodine, thiocyanate, and perchlorate and serum TSH, free T(4) (FT(4)), and thyroperoxidase antibody were measured. RESULTS Urinary iodine was low: median 98 microg/liter in Cardiff and 52 microg/liter in Turin. Urine perchlorate was detectable in all women. The median (range) urinary perchlorate concentration was 5 microg/liter (0.04-168 microg/liter) in Turin and 2 microg/liter (0.02-368 microg/liter) in Cardiff. There were no associations between urine perchlorate concentrations and serum TSH or FT(4) in the individual euthyroid or hypothyroid/hypothyroxinemic cohorts. In multivariable linear analyses, log perchlorate was not a predictor of serum FT(4) or TSH. CONCLUSIONS Low-level perchlorate exposure is ubiquitous but did not affect thyroid function in this cohort of iodine-deficient pregnant women.

A comparative study of CSF neurofilament light and heavy chain protein in MS

Background: There is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH)). Methods: We evaluated the analytical and clinical performance of the UmanDiagnostics NF-light® enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) of a group of 148 patients with clinically isolated syndrome (CIS) or multiple sclerosis (MS), and 72 controls. We compared our results with referring levels of our previously-developed CSF NfHSMI35 assay. Results: Exposure to room temperature (up to 8 days) or repetitive thawing (up to 4 thaws) did not influence measurement of NfL concentrations. Values of NfL were higher in all disease stages of CIS/MS, in comparison to controls (p ≤ 0.001). NfL levels correlated with the Expanded Disability Status Scale (EDSS) score in patients with relapsing disease (rs = 0.31; p = 0.002), spinal cord relapses and with CSF markers of acute inflammation. The ability of NfL to distinguish patients from controls was greater than that of NfHSMI35 in both CIS patients (p = 0.001) and all MS stages grouped together (p = 0.035). Conclusions: NfL proved to be a stable protein, an important prerequisite for a reliable biomarker, and the NF-light® ELISA performed better in discriminating patients from controls, compared with the ECL-NfHSMI35 immunoassay. We confirmed and expanded upon previous findings regarding neurofilaments as quantitative markers of neurodegeneration. Our results further support the role of neurofilaments as a potential surrogate measure for neuroprotective treatment in MS studies.

Prevention of Neural Tube Defects: A Cross-Sectional Study of the Uptake of Folic Acid Supplementation in Nearly Half a Million Women

Background Taking folic acid supplements before pregnancy to reduce the risk of a neural tube defect (NTD) is especially important in countries without universal folic acid fortification. The extent of folic acid supplementation among women who had antenatal screening for Down’s syndrome and NTDs at the Wolfson Institute of Preventive Medicine, London between 1999 and 2012 was assessed. Methods and Findings 466,860 women screened provided details on folic acid supplementation. The proportion of women who took folic acid supplements before pregnancy was determined according to year and characteristics of the women. The proportion of women taking folic acid supplements before pregnancy declined from 35% (95% CI 34%–35%) in 1999–2001 to 31% (30%–31%) in 2011–2012. 6% (5%–6%) of women aged under 20 took folic acid supplements before pregnancy compared with 40% of women aged between 35 and 39. Non-Caucasian women were less likely to take folic acid supplements before pregnancy than Caucasian women; Afro-Caribbean 17% (16%–17%), Oriental 25% (24%–25%) and South Asian 20% (20%–21%) compared with 35% (35%–35%) for Caucasian women. 51% (48%–55%) of women who previously had an NTD pregnancy took folic acid supplements before the current pregnancy. Conclusions The policy of folic acid supplementation is failing and has led to health inequalities. This study demonstrates the need to fortify flour and other cereal grain with folic acid in all countries of the world.

Serum neurofilament light chain is a biomarker of human spinal cord injury severity and outcome

Background Neurofilaments (Nf) are major structural proteins that occur exclusively in neurons. In spinal cord injury (SCI), the severity of disease is quantified by clinical measures that have limited sensitivity and reliability, and no blood-based biomarker has been established to further stratify the degree of injury. We aimed to examine a serum-based NfL immunoassay as predictor of the clinical outcome in SCI. Methods Longitudinal measurement of serum NfL was performed in patients with central cord syndrome (CCS, n=4), motor-incomplete SCI (iSCI, n=10), motor-complete SCI (cSCI, n=13) and healthy controls (HC, n=67), and correlated with clinical severity, neurological outcome, and neuroprotective effect of the drug minocycline. Results Baseline NfL levels were higher in iSCI (21 pg/mL) and cSCI (70 pg/mL) than in HC (5 pg/mL, p=0.006 and p<0.001) and CCS (6 pg/mL, p=0.025 and p=0.010). Levels increased over time (p<0.001) and remained higher in cSCI versus iSCI (p=0.011) and than in CCS (p<0.001). NfL levels correlated with American Spinal Injury Association (ASIA) motor score at baseline (r=−0.53, p=0.004) and after 24 h (r=−0.69, p<0.001) and 3–12-month motor outcome (baseline NfL: r=−0.43, p=0.026 and 24 h NfL: r=−0.72, p<0.001). Minocycline treatment showed decreased NfL levels in the subgroup of cSCI patients. Conclusions Serum NfL concentrations in SCI patients show a close correlation with acute severity and neurological outcome. Our data provide evidence that serum NfL is of prognostic value in SCI patients for the first time. Further, blood NfL levels may qualify as drug response markers in SCI.

Randomised Trial of Text Messaging on Adherence to Cardiovascular Preventive Treatment (INTERACT Trial)

Background About one third of patients prescribed blood pressure or lipid-lowering drugs for the prevention of coronary heart disease and stroke do not take their medication as prescribed. We conducted a randomized trial to evaluate text messaging as a means of improving adherence to cardiovascular disease preventive treatment. Methods 303 patients taking blood pressure and/or lipid-lowering medications were randomly assigned to being sent text messages (Text group, 151) or not being sent them (No text group, 152). Texts were sent daily for 2 weeks, alternate days for 2 weeks and weekly thereafter for 22 weeks (6 months overall), using an automated computer programme. Patients were asked to respond on whether they had taken their medication, whether the text reminded them to do so if they had forgotten, and if they had not taken their medication to determine if there was a reason for not doing so. At 6 months, use of medication was assessed. Results Two patients were lost to follow-up, providing data on 301 for analysis. In the No text group 38/151 (25%) took less than 80% of the prescribed regimen (ie. stopped medication completely or took it on fewer than 22 of the last 28 days of follow-up) compared to 14/150 patients (9%) in the Text group – an improvement in adherence affecting 16 per 100 patients (95% CI 7 to 24), p<0.001. The texts reminded 98/151 patients (65%) to take medication on at least one occasion and lead to 20/151 (13%) who stopped taking medication because of concern over efficacy or side-effects, resuming treatment. Conclusions In patients taking blood pressure or lipid-lowering treatment for the prevention of cardiovascular disease, text messaging improved medication adherence compared with no text messaging. Trial Registration Controlled-Trials.com ISRCTN74757601