A comparison of seven random-effects models for meta-analyses that estimate the summary odds ratio.

Comparative trials that report binary outcome data are commonly pooled in systematic reviews and meta-analyses. This type of data can be presented as a series of 2-by-2 tables. The pooled odds ratio is often presented as the outcome of primary interest in the resulting meta-analysis. We examine the use of 7 models for random-effects meta-analyses that have been proposed for this purpose. The first of these models is the conventional one that uses normal within-study approximations and a 2-stage approach. The other models are generalised linear mixed models that perform the analysis in 1 stage and have the potential to provide more accurate inference. We explore the implications of using these 7 models in the context of a Cochrane Review, and we also perform a simulation study. We conclude that generalised linear mixed models can result in better statistical inference than the conventional 2-stage approach but also that this type of model presents issues and difficulties. These challenges include more demanding numerical methods and determining the best way to model study specific baseline risks. One possible approach for analysts is to specify a primary model prior to performing the systematic review but also to present the results using other models in a sensitivity analysis. Only one of the models that we investigate is found to perform poorly so that any of the other models could be considered for either the primary or the sensitivity analysis.

The influence of preoperative determinants on quality of life, functioning and pain after total knee and hip replacement: a pooled analysis of Dutch cohorts.

BACKGROUND: Previous research has identified preoperative determinants that predict health related quality of life (HRQoL), functioning and pain after total knee or hip arthroplasty (TKA/THA), but these differed between studies and had opposite directions. This may be due to lack of power and not adjusting for confounders. The present study aims to identify the preoperative determinants that influence health related quality of life (HRQoL), functioning and pain after total knee or hip arthroplasty (TKA/THA). METHODS: We pooled individual patient from 20 cohorts with OA patients data (n = 1783 TKA and n = 2400 THA) in the Netherlands. We examined the influence of age, gender, BMI and preoperative values of HRQoL, functioning and pain on postoperative status and total improvement. Linear mixed models were used to estimate the effect of each preoperative variable on a particular outcome for each cohort separately. These effects were pooled across cohorts using a random effects model. RESULTS: For each increase in preoperative point in HRQoL, the postoperative HRQoL increased by 0.51 points in TKA and 0.37 points in THA (SF-36 scale). Similarly, each point increase in preoperative functioning, resulted in a higher postoperative functioning of 0.31 (TKA) and 0.21 (THA) points (KOOS/HOOS-ADL scale). For pain this was 0.18 (TKA) and 0.15 (THA) points higher (KOOS/HOOS-pain scale) (higher means less pain). Even though patients with better preoperative values achieved better postoperative outcomes, their improvement was smaller. Women and patients with a higher BMI had more pain after a TKA and THA. Higher age and higher BMI was associated with lower postoperative HRQoL and functioning and more pain after a THA. CONCLUSIONS: Patients with a better preoperative health status have better outcomes, but less improvement. Even though the independent effects may seem small, combined results of preoperative variables may result in larger effects on postoperative outcomes.

Long-Term Outcomes of Patients With Recent-Onset Rheumatoid Arthritis After 10 Years of Tight Controlled Treatment: A Randomized Trial.

BACKGROUND: Treat-to-target therapy is effective for patients with rheumatoid arthritis (RA), but long-term results of continued targeted treatment are lacking. OBJECTIVE: To evaluate long-term outcomes in patients with early RA after 10 years of targeted treatment in 4 treatment strategies. DESIGN: Randomized trial. (Nederlands Trial Register: NTR262 and NTR265). SETTING: The Netherlands. PATIENTS: 508 patients with early active RA. INTERVENTION: Sequential monotherapy (strategy 1), step-up combination therapy (strategy 2), or initial combination therapy with prednisone (strategy 3) or with infliximab (strategy 4), all followed by targeted treatment aiming at low disease activity. MEASUREMENTS: Functional ability (Health Assessment Questionnaire [HAQ] score) and radiographic progression (Sharp-van der Heijde score) were primary end points. Survival in the study population was compared with the general population using the standardized mortality ratio. RESULTS: 195 of 508 of patients (38%) dropped out of the study (28% in strategy 4 vs. 40% to 45% in strategies 1 to 3, respectively). At year 10, mean HAQ score (SD) was 0.57 (0.56); 53% and 14% of patients were in remission and drug-free remission, respectively, without differences among the strategies. Over 10 years, mean HAQ scores were 0.69, 0.72, 0.64, and 0.58 in strategies 1 to 4, respectively (differences not clinically relevant). Radiographic damage was limited for all strategies, with mean Sharp-van der Heijde estimates during follow-up of 11, 8, 8, and 6 in strategies 1 to 4, respectively (P = 0.15). Standardized mortality ratio was 1.16 (95% CI, 0.92 to 1.46) based on 72 observed and 62 expected deaths, with similar survival among the 4 strategies (P = 0.81). LIMITATION: Dropout rate varied by strategy. CONCLUSION: In patients with early RA, initial (temporary) combination therapy results in faster clinical improvement and targeted treatment determines long-term outcomes. Drug-free remission, with prevention of functional deterioration and clinically relevant radiographic damage, and normalized survival are realistic outcomes. PRIMARY FUNDING SOURCE: Dutch College of Health Insurance Companies, Schering-Plough, and Janssen.

Prevalence of Symptomatic and Asymptomatic Thrombosis in Pediatric Oncology Patients With Tunneled Central Venous Catheters.

BACKGROUND: Pediatric oncology patients with tunneled central venous catheters (CVCs) are at increased risk to develop venous thromboembolic events (VTEs), but the true prevalence of (a)symptomatic VTE is unknown. Aim of this study was to evaluate the prevalence of (a)symptomatic VTE in pediatric oncology patients with tunneled CVCs. PROCEDURE: All patients were included in the Aristocaths study: a randomized controlled multicenter trial investigating the prophylactic effect of 70% ethanol locks on CVC-associated bloodstream infections (CABSIs) were eligible for this study. We assessed the following outcomes: (i) symptomatic VTE and (ii) asymptomatic CVC-related VTE (using ultrasound [US]). Follow-up was 6 months, unless patients developed one of the following events: VTE, CABSI, CVC removal, or death. RESULTS: We included 305 patients (hematologic malignancy, n = 148; solid tumor, n = 157), median age 9 years (range, 1-18 years). Symptomatic VTE was detected in 8 of 305 patients (2.6%; 95% confidence interval [CI]: 1.1-5.1%), which was related to the CVC in three patients. Patients (185/305) were evaluated with US: 11 of 185 (5.9%; 95% CI: 3.0-10.4%) patients had asymptomatic CVC-related VTE. CONCLUSIONS: Prevalence of both symptomatic VTE and asymptomatic CVC-related VTE was low compared to other studies, which may be explained by the inclusion of patients with solid tumors, reduction of CABSI by ethanol, use of tunneled CVCs, and use of US.

Attrition in Long-Term Nutrition Research Studies: A Commentary by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Early Nutrition Research Working Group.

Long-term follow-up of randomised trials and observational studies provide the best evidence presently available to assess long-term effects of nutrition, and such studies are an important component in determining optimal infant feeding practices. Attrition is, however, an almost inevitable occurrence with increasing age at follow-up. There is a common assumption that studies with <80% follow-up rates are invalid or flawed, and this criticism seems to be more frequently applied to follow-up studies involving randomised trials than observational studies. In this article, we explore the basis and evidence for this "80% rule" and discuss the need for greater consensus and clear guidelines for analysing and reporting results in this specific situation.

Xerosis and pruritus as major EGFRI-associated adverse events.

PURPOSE: The objective of this sub-analysis of the BeCet study (NCT01136005) was to examine health-related quality of life (HRQoL) of patients experiencing dermatological adverse events (AEs) during the first 6 weeks of epidermal growth factor receptor inhibitor (EGFRI) treatment. METHODS: Patients (n = 85) treated with EGFRI completed five questionnaires during the first 6 weeks of treatment. 77 patients provided enough data for the sub-analysis. Experienced AEs were reported in the Dermatological Reactions Targeted Therapy-Patients (DERETT-P), a symptom experience diary for patients treated with targeted therapy. The impact of EGFRI-associated dermatological adverse events on HRQoL was examined using four HRQoL questionnaires; the Functional Assessment of Cancer Therapy-EGFRI (FACT-EGFRI-18), the Functional Assessment of Cancer Therapy-General (FACT-G), the 36-Item Short Form Health Survey (SF-36), and the Skindex-16. RESULTS: During the first 6 weeks of EGFRI treatment, physical discomfort was the most significantly affected domain. In the entire study population, xerosis (dry skin) (22.3 %) and pruritus (itchy skin) (16.9 %) were reported as the most impactful AEs. For patients experiencing a papulopustular eruption (acneiform rash) pruritus (24.2 %), xerosis (18.9 %), and papulopustular eruption (6.3 %) were reported as the most impactful AEs. Papulopustular eruption, xerosis, and pruritus all showed a significant negative effect on HRQoL, displayed in FACT-EGFRI-18 scores. CONCLUSIONS: In addition to papulopustular eruption, xerosis and pruritus are major EGFRI-associated dermatological AEs with an impact on HRQoL, which warrant more attention in clinical practice and research.

Effectiveness and cost-effectiveness of a proactive, goal-oriented, integrated care model in general practice for older people. A cluster randomised controlled trial: Integrated Systematic Care for older People--the ISCOPE study.

BACKGROUND: older people often experience complex problems. Because of multiple problems, care for older people in general practice needs to shift from a 'problem-based, disease-oriented' care aiming at improvement of outcomes per disease to a 'goal-oriented care', aiming at improvement of functioning and personal quality of life, integrating all healthcare providers. Feasibility and cost-effectiveness of this proactive and integrated way of working are not yet established. DESIGN: cluster randomised trial. PARTICIPANTS: all persons aged ≥75 in 59 general practices (30 intervention, 29 control), with a combination of problems, as identified with a structured postal questionnaire with 21 questions on four health domains. INTERVENTION: for participants with problems on ≥3 domains, general practitioners (GPs) made an integrated care plan using a functional geriatric approach. Control practices: care as usual. OUTCOME MEASURES: (i) quality of life (QoL), (ii) activities of daily living, (iii) satisfaction with delivered health care and (iv) cost-effectiveness of the intervention at 1-year follow-up. TRIAL REGISTRATION: Netherlands trial register, NTR1946. RESULTS: of the 11,476 registered eligible older persons, 7,285 (63%) participated in the screening. One thousand nine hundred and twenty-one (26%) had problems on ≥3 health domains. For 225 randomly chosen persons, a care plan was made. No beneficial effects were found on QoL, patients' functioning or healthcare use/costs. GPs experienced better overview of the care and stability, e.g. less unexpected demands, in the care. CONCLUSIONS: GPs prefer proactive integrated care. 'Horizontal' care using care plans for older people with complex problems can be a valuable tool in general practice. However, no direct beneficial effect was found for older persons.

Fetal brain imaging in isolated congenital heart defects - a systematic review and meta-analysis.

Congenital heart defects (CHDs) are associated with neurodevelopmental (ND) delay. This study aims to assess evidence for impaired prenatal brain development, in fetuses with CHD. A systematical search was performed, and 34 studies evaluating the fetal brain [magnetic resonance imaging (MRI) or ultrasound] in isolated CHD were included (1990-2015). Data regarding cerebral abnormalities, head circumference growth and middle cerebral artery flow were extracted. Prenatal MRI was studied in ten articles (445 fetuses), resulting in a pooled prevalence of 18% (95%CI -6%; 42%) for combined structural and acquired cerebral abnormalities. Prenatal head circumference was studied in 13 articles (753 fetuses), resulting in a pooled z-score of -0.51 (95%CI -0.84; -0.18). Doppler was studied in 21 articles (1412 fetuses), resulting in a lower middle cerebral artery pulsatility index (z-score -0.70 95%CI -0.99; -0.41) in left-sided CHD only. We conclude that prenatal MRI and ultrasound demonstrate brain abnormalities, delay in head growth and brainsparing in subgroups of CHD. However, large MRI studies are scarce, and ultrasound data are biased towards severe and left-sided CHD. Long-term follow-up studies correlating prenatal findings with postnatal ND outcome are limited, and data are lacking to support counseling families regarding ND outcome based on prenatal findings suggestive of altered brain development. © 2016 John Wiley & Sons, Ltd.

Uric acid is not associated with decline in renal function or time to renal replacement therapy initiation in a referred cohort of patients with Stage III, IV and V chronic kidney disease.

BACKGROUND: Although many studies have suggested an association between higher uric acid (UA) and both development of chronic kidney disease (CKD) and faster decline in renal function in Stage I and II CKD, it is not clear whether this effect is consistent throughout higher CKD stages. The aim of this study was to investigate the association between baseline UA and renal outcomes in patients with established CKD (Stages III-V). METHODS: We analysed data in the Swedish Renal Registry-Chronic Kidney Disease (SRR-CKD), which is a nationwide registry of referred CKD patients. Patients with a visit between January 1(st), 2005 and December 31(st), 2011 were followed until initiation of renal replacement therapy (RRT), death, referral to primary care or end of follow-up. Decline in renal function was assessed with a linear mixed model using all estimated glomerular filtration rate (eGFR) assessments recorded during median 28 months of follow-up, adjusting for important confounders such as demographic factors, primary renal disease, age, sex, relevant medication, diet, blood pressure and body mass index. RESULTS: There were 2466 patients with a baseline UA measurement {mean [standard deviation (SD)] of 7.81 [1.98] mg/dL}. The mean decline in renal function was -1.48 (95% CI -1.65; -1.31) mL/min/1.73 m(2) per year. The overall adjusted change in decline in renal function per unit increase in baseline UA was 0.08 (95% CI -0.01; 0.17) mL/min/1.73 m(2) per year indicating no association between higher UA levels and decline in renal function. In Stage III, IV and V CKD patients, the mean decline in renal function was -1.52 (95% CI -1.96; -1.08), -1.52 (95% CI -1.72; -1.32) and -1.19 (95% CI -1.75; -0.64) mL/min/1.73 m(2) per year, respectively. The adjusted change in the decline in renal function per unit increase in baseline UA was -0.09 (95% CI -0.30; 0.13) in Stage III CKD, 0.16 (95% CI 0.04; 0.28) in Stage IV CKD and 0.18 (95% CI -0.09; 0.45) in Stage V CKD. The overall adjusted hazard ratio for start of RRT was 0.97 (95% CI 0.93-1.02). For Stage III, IV and V CKD, it was 0.99 (95% CI 0.73-1.34), 0.97 (95% CI 0.91-1.03) and 0.99 (95% CI 0.91-1.07), respectively. CONCLUSION: UA is not associated with the rate of decline in renal function or time to start of RRT in Stage III, IV and/or V CKD patients.

Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke.

BACKGROUND: Combined oral contraceptives (COCs) have been associated with an increased risk of arterial thrombosis, i.e. myocardial infarction or ischemic stroke. However, as these diseases are rare in young women and as many types of combined oral contraception exist, the magnitude of the risk and the effect of different hormonal contents of COC preparations remain unclear. OBJECTIVES: To estimate the risk of myocardial infarction or ischemic stroke in users compared with non-users of different types, doses and generations of combined oral contraception. SEARCH METHODS: We searched electronic databases (MEDLINE (1966 to July 08, 2015), EMBASE (1980 to July 08, 2015), Popline (1970 to July 08, 2015) and LILACS (1985 to July 08, 2015) for eligible studies, without language restrictions. SELECTION CRITERIA: We included observational studies that recruited women in the reproductive age group (18 to 50 years) and compared the risk of myocardial infarction or ischemic stroke between users and non-users of COCs. DATA COLLECTION AND ANALYSIS: Two review authors independently selected relevant studies and extracted data. We pooled relative risks ()(combined odds ratios and one incidence rate ratio) and 95% confidence intervals (CIs) for myocardial infarction or ischemic stroke in users versus non-users of COCs.We combined the outcomes of myocardial infarction and ischemic stroke and also analysed these outcomes separately. Analyses were stratified according to estrogen dose and progestagen type. MAIN RESULTS: In total, we identified 1298 publications through the search strategy. We included 28 publications reporting on 24 studies. COC users were at increased risk of myocardial infarction or ischemic stroke compared with non-users: relative risk (RR) 1.6 (95% CI 1.3-1.9).These RRs were similar for myocardial infarction (1.6, 95% CI 1.2 to 2.1) and ischemic stroke (1.7, 95% CI 1.5 to 1.9). The risks did not vary clearly according to the generation of progestagen or according to progestagen type. When we stratified preparations according to estrogen dose, the risk of myocardial infarction or ischemic stroke seemed to increase with higher doses of estrogen. AUTHORS' CONCLUSIONS: This meta-analysis showed that the risk of myocardial infarction or ischemic stroke was 1.6-fold increased in women using COCs . The risk was highest for pills with > 50 microgram estrogen. When combined with the results of studies on the risk of venous thrombosis in COC users, it seems that the COC pill containing levonorgestrel and 30 µg of estrogen is the safest oral form of hormonal contraception.

Aortic valve repair versus replacement for aortic regurgitation: effects on left ventricular remodeling.

BACKGROUND: Left ventricular (LV) reverse remodeling after aortic valve replacement (AVR) for aortic regurgitation (AR) is associated with superior prognosis. The outcomes of valve-sparing aortic root replacement techniques on LV performance have not been compared with LV reverse remodeling in AVR. The present evaluation compared the extent of long-term LV reverse remodeling in patients with aortic root pathology and/or AR who underwent aortic valve repair (AVr) with patients who underwent AVR. METHODS: A total of 226 patients (54.7 ± 14.3 years, 63% male) with AR or aortic root pathology who underwent AVr (n = 135) or AVR with the Freestyle® stentless aortic root bioprosthesis [Medtronic, Inc.; Minneapolis, Minnesota] (n = 91) were included in the present retrospective evaluation. LV volumes and ejection fraction were assessed preoperatively, postoperatively (before hospital discharge) and during follow-up. RESULTS: Baseline characteristics were comparable between patient groups, except for higher prevalence of bicuspid aortic valve anatomy among AVR patients (38% vs. 16%, p < 0.001). In addition, patients undergoing AVR had significantly larger LV end-diastolic and end-systolic volumes than their counterparts. After a median follow-up of 46 months (interquartile range: 17 to 78 months), both groups of patients showed a significant and sustained reduction in LV end-diastolic and end-systolic volumes, with significantly larger reduction in patients undergoing AVR. Ejection fraction decreased significantly postoperatively and improved later during follow-up similarly in both groups. The incidence of significant AR at long-term follow-up was comparable among groups (AVr: 8% vs. AVR: 7%). CONCLUSIONS: LV reverse remodeling occurs after AVR and AVr, reaching comparable LV volumes and function after a median of four years of follow-up.

Effectiveness of Psychotherapy in Personality Disorders Not Otherwise Specified: A Comparison of Different Treatment Modalities.

OBJECTIVE: Although personality disorder not otherwise specified (PDNOS) is highly prevalent and associated with a high burden of disease, only a few treatment studies in this patient group exist. This study is the first to investigate the effectiveness of different modalities of psychotherapy in patients with PDNOS, i.e., short-term (up to 6 months) and long-term (more than 6 months) outpatient, day hospital, and inpatient psychotherapy. METHOD: A total of 205 patients with PDNOS were assigned to one of six treatment modalities. Effectiveness was assessed over 60 months after baseline. The primary outcome measure was symptom severity, and the secondary outcome measures included psychosocial functioning and quality of life. The study design was quasi-experimental, and the multiple propensity score was used to control for initial differences between treatment groups. RESULTS: All treatment modalities showed positive outcomes, especially in terms of improvements of symptom severity and social role functioning. At 12-month follow-up, after adjustment for initial differences between the treatment groups, short-term outpatient psychotherapy and short-term inpatient psychotherapy showed most improvement and generally outperformed the other modalities concerning symptom severity. At 60 months after baseline, effectiveness remained but observed differences between modalities mostly diminished. CONCLUSION: Patients with PDNOS benefit from psychotherapy both at short-term and long-term follow-up. Short-term outpatient psychotherapy and short-term inpatient psychotherapy seem to be superior to the other treatment modalities at 12-month follow-up. At 60-month follow-up, treatments showed mostly comparable effectiveness. KEY PRACTITIONER MESSAGES: The effectiveness of different modalities of psychotherapy in patients with PDNOS (i.e., short-term vs long-term; outpatient versus day hospital versus inpatient psychotherapy) has not yet been compared. Different modalities of psychotherapy are effective for patients with PDNOS, and positive effects remain after 5 years. In patients with PDNOS short-term (less than 6 months) outpatient psychotherapy and short-term inpatient psychotherapy seem to be superior to the four other treatment modalities at 12-month follow-up. At 60-month follow-up, treatments showed mostly comparable effectiveness.

Cognitive impairment and risk of stroke: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND AND PURPOSE: Cognitive impairment is linked to vascular risk factors and brain vascular pathologies. Several studies have tested whether subjects with cognitive impairment have higher risk for stroke. The aim of this study was to systematically review available evidence on the association between cognitive impairment and risk of stroke to obtain precise effect estimates of the association and to identify which cognitive domains associate most with incident stroke. METHODS: PubMed, EMBASE, and Web of Science were searched from January 1, 1980, to October 1, 2013, without language restriction. Only prospective cohort studies were included. From each study, data on the association between cognitive impairment and stroke estimated with hazard ratios or relative risks with 95% confidence interval (CI) were extracted. For each study, risk of stroke per SD lower performance in various cognitive tests was calculated. RESULTS: Twelve studies were included, comprising 82,899 participants of whom 3043 had an incident stroke. The pooled relative risk per SD lower global cognitive performance was 1.19 (95% CI, 1.12-1.27). Each SD lower score in executive function or attention was associated with 1.14-fold (95% CI, 1.06-1.24) higher risk of stroke. Lower scores in memory were associated with 1.07-fold (95% CI, 1.02-1.12) higher risk of stroke, and lower scores in language were associated with 1.08-fold (95% CI, 1.02-1.16) higher risk of stroke. CONCLUSIONS: Cognitive impairment is associated with higher risk of stroke. The associations were not significantly different for executive function, memory, and language.

Incident cancer risk after the start of aspirin use: results from a Dutch population-based cohort study of low dose aspirin users.

Observational and intervention studies suggest that low dose aspirin use may prevent cancer. The objective of this study was to investigate the protective effect of long term low dose aspirin use (≤100 mg daily) on cancer in general and site-specific cancer among low dose aspirin users in the Dutch general population. We conducted a population-based cohort study with detailed information on aspirin exposure and cancer incidence. Only incident (new) low dose aspirin users, who were included in the linkage between PHARMO and the Eindhoven Cancer Registry (1998-2010) and free of cancer before the start of follow up were included. A Cox proportional hazard model with cumulative aspirin use as a time-varying determinant was used to obtain hazard ratios (HR). Duration of aspirin use amongst 109,276 incident low dose aspirin users was not associated with a decreased risk of any of the site-specific cancers or cancer in general (adjusted HR per year of aspirin use for all cancers: 1.02, 95% confidence interval [CI] 1.00-1.04, HR of >6 years aspirin use compared to <2 years: 1.17, 95% CI 1.02-1.34). After adjusting for current and past aspirin use, 2-6 years of low dose aspirin use was associated with a reduced colorectal cancer risk compared to <2 years of aspirin use (adjusted HR 0.75, 95% CI 0.59-0.96). However, a clear dose-response relationship was not observed (adjusted HR >6 years aspirin use 0.95, 95% CI 0.60-1.49). Our results do not support the primary prevention of cancer among long term aspirin users.

Effect of ß-blockers on platelet aggregation: a systematic review and meta-analysis.

AIMS: Platelets play an important role in cardiovascular disease, and ß-blockers are often prescribed for cardiovascular disease prevention. ß-Blockers may directly affect platelet aggregation, because ß-adrenergic receptors are present on platelets. There is uncertainty about the existence and magnitude of an effect of ß-blockers on platelet aggregation. The aim of this study was to perform a systematic review and meta-analysis of the effect of ß-blockers on platelet aggregation. METHODS: MEDLINE and EMBASE were searched until April 2014. Two reviewers independently performed data extraction and risk of bias assessment. Type of ß-blocker, population, treatment duration and platelet aggregation were extracted. Standardized mean differences were calculated for each study and pooled in a random-effects meta-analysis. RESULTS: We retrieved 31 studies (28 clinical trials and three observational studies). ß-Blockers decreased platelet aggregation (standardized mean difference -0.54, 95% confidence interval -0.85 to -0.24, P < 0.0001). This corresponds to a reduction of 13% (95% confidence interval 8-17%). Nonselective lipophilic ß-blockers decreased platelet aggregation more than selective nonlipophilic ß-blockers. CONCLUSIONS: Clinically used ß-blockers significantly reduce platelet aggregation. Nonselective lipophilic ß-blockers seem to reduce platelet aggregation more effectively than selective nonlipophilic ß-blockers. These findings may help to explain why some ß-blockers are more effective than others in preventing cardiovascular disease.

Comparing a marginal structural model with a Cox proportional hazard model to estimate the effect of time-dependent drug use in observational studies: statin use for primary prevention of cardiovascular disease as an example from the Rotterdam Study.

When studying the causal effect of drug use in observational data, marginal structural modeling (MSM) can be used to adjust for time-dependent confounders that are affected by previous treatment. The objective of this study was to compare traditional Cox proportional hazard models (with and without time-dependent covariates) with MSM to study causal effects of time-dependent drug use. The example of primary prevention of cardiovascular disease (CVD) with statins was examined using up to 17.7 years of follow-up from 4,654 participants of the observational prospective population-based Rotterdam Study. In the MSM model, the weight was based on measurements of established cardiovascular risk factors and co-morbidity. In general, we could not demonstrate important differences in results from the Cox models and MSM. Results from analysis on duration of statin use suggested that substantial residual confounding by indication was not accounted for during the period shortly after statin initiation. In conclusion, although on theoretical grounds MSM is an elegant technique, lack of data on the precise time-dependent confounders, such as indication of treatment or other considerations of the prescribing physician jeopardizes the calculation of valid weights. Confounding remains a hurdle in observational effectiveness research on preventive drugs with a multitude of prescription determinants.

Combined oral contraceptives: venous thrombosis.

BACKGROUND: Combined oral contraceptive (COC) use has been associated with venous thrombosis (VT) (i.e., deep venous thrombosis and pulmonary embolism). The VT risk has been evaluated for many estrogen doses and progestagen types contained in COC but no comprehensive comparison involving commonly used COC is available. OBJECTIVES: To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives. SEARCH METHODS: Electronic databases (Pubmed, Embase, Web of Science, Cochrane, CINAHL, Academic Search Premier and ScienceDirect) were searched in 22 April 2013 for eligible studies, without language restrictions. SELECTION CRITERIA: We selected studies including healthy women taking COC with VT as outcome. DATA COLLECTION AND ANALYSIS: The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported.Two independent reviewers extracted data from selected studies. MAIN RESULTS: 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 0.19 and 0.37 per 1 000 person years, in line with previously reported incidences of 0,16 per 1 000 person years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk. AUTHORS' CONCLUSIONS: All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol. Risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate and drospirenone were similar, and about 50-80% higher than with levonorgestrel. The combined oral contraceptive with the lowest possible dose of ethinylestradiol and good compliance should be prescribed-that is, 30 µg ethinylestradiol with levonorgestrel.

Doxycycline for stabilization of abdominal aortic aneurysms: a randomized trial.

BACKGROUND: Doxycycline inhibits formation and progression of abdominal aortic aneurysms (AAAs) in preclinical models of the disease, but it is unclear whether and how this observation translates to humans. OBJECTIVE: To test whether doxycycline inhibits AAA progression in humans. DESIGN: Randomized, placebo-controlled, double-blind trial. (Dutch Trial Registry: NTR 1345) SETTING: 14 Dutch hospitals. PATIENTS: 286 patients with small AAAs between October 2008 and June 2011. INTERVENTION: Daily dose of 100 mg of doxycycline (n = 144) or placebo (n = 142) for 18 months. MEASUREMENTS: The primary outcome measure was aneurysm growth at 18 months, as estimated by repeated single-observer ultrasonography. Secondary outcomes included growth at 6 and 12 months and the need for elective surgery. RESULTS: Mean aneurysm diameter (approximately 43 mm) and other baseline characteristics were similar in both groups. Doxycycline treatment was associated with increased aneurysm growth (4.1 mm in the doxycycline group vs. 3.3 mm in the placebo group at 18 months; difference, 0.8 mm [95% CI, 0.1 to 1.4 mm]; P = 0.016 mm). Twenty-one patients receiving doxycycline and 22 patients receiving placebo had elective surgical repair (Kaplan­Meier estimates were 16.1% for those receiving doxycycline and 16.5% for those receiving placebo; difference, -0.4% [CI, -9.3% to 8.5%]; P = 0.83). Time to repair was similar in the groups (P = 0.92). LIMITATIONS: This study focuses on patients with small AAAs. As such, whether the data can be extrapolated to larger AAAs (>55 mm) is unclear. The high number of elective repairs (n = 43) was unanticipated. Moreover, the study did not follow patients who withdrew because of an adverse effect. CONCLUSION: This trial found that 18 months of doxycycline therapy did not reduce aneurysm growth and did not influence the need for AAA repair or time to repair. PRIMARY FUNDING SOURCE: The Netherlands Organisation for Health Research and Development, and the NutsOhra Fund.

CASINO: surgical or nonsurgical treatment for cervical radiculopathy, a randomised controlled trial.

BACKGROUND: Cervical radicular syndrome (CRS) due to a herniated disc can be safely treated by surgical decompression of the spinal root. In the vast majority of cases this relieves pain in the arm and restores function. However, conservative treatment also has a high chance on relieving symptoms. The objective of the present study is to evaluate the (cost-) effectiveness of surgery versus prolonged conservative care during one year of follow-up, and to evaluate the timing of surgery. Predisposing factors in favour of one of the two treatments will be evaluated. METHODS/DESIGN: Patients with disabling radicular arm pain, suffering for at least 2 months, and an MRI-proven herniated cervical disc will be randomised to receive either surgery or prolonged conservative care with surgery if needed. The surgical intervention will be an anterior discectomy or a posterior foraminotomy that is carried out according to usual care. Surgery will take place within 2-4 weeks after randomisation. Conservative care starts immediately after randomisation. The primary outcome measure is the VAS for pain or tingling sensations in the arm one year after randomisation. In addition, timing of surgery will be studied by correlating the primary outcome to the duration of symptoms. Secondary outcome measures encompass quality of life, costs and perceived recovery. Predefined prognostic factors will be evaluated. The total follow-up period will cover two years. A sample size of 400 patients is needed. Statistical analysis will be performed using a linear mixed model which will be based on the 'intention to treat' principle. In addition, a new CRS questionnaire for patients will be developed, the Leiden Cervical Radicular Syndrome Functioning (LCRSF) scale. DISCUSSION: The outcome will contribute to better decision making for the treatment of cervical radicular syndrome. TRIAL REGISTRATION: NTR3504.

Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis.

BACKGROUND: Alzheimer disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Nutritional compounds are postulated to play a role in the pathophysiological processes that are affected in AD. We here provide the first systematic review and meta-analysis that compares plasma levels of micronutrients and fatty acids in AD patients to those in cognitively intact elderly controls. A secondary objective was to explore the presence of different plasma nutrient levels between AD and control populations that did not differ in measures of protein/energy nourishment. METHODS: We screened literature published after 1990 in the Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for AD patients, controls, micronutrient, vitamins, and fatty acids, resulting in 3397 publications, of which 80 met all inclusion criteria. Status of protein/energy malnutrition was assessed by body mass index, mini nutritional assessment score, or plasma albumin. Meta-analysis, with correction for differences in mean age between AD patients and controls, was performed when more than five publications were retrieved for a specific nutrient. RESULTS: We identified five or more studies for folate, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, copper, iron, and zinc but fewer than five studies for vitamins B1 and B6, long-chain omega-3 fatty acids, calcium, magnesium, manganese, and selenium (the results of the individual publications are discussed). Meta-analysis showed significantly lower plasma levels of folate and vitamin A, vitamin B12, vitamin C, and vitamin E (P < .001), whereas nonsignificantly lower levels of zinc (P = .050) and vitamin D (P = .075) were found in AD patients. No significant differences were observed for plasma levels of copper and iron. A meta-analysis that was limited to studies reporting no differences in protein/energy malnourishment between AD and control populations yielded similar significantly lower plasma levels of folate and vitamin B12, vitamin C, and vitamin E in AD. CONCLUSIONS: The lower plasma nutrient levels indicate that patients with AD have impaired systemic availability of several nutrients. This difference appears to be unrelated to the classic malnourishment that is well known to be common in AD, suggesting that compromised micronutrient status may precede protein and energy malnutrition. Contributing factors might be AD-related alterations in feeding behavior and intake, nutrient absorption, alterations in metabolism, and increased utilization of nutrients for AD pathology-related processes. Given the potential role of nutrients in the pathophysiological processes of AD, the utility of nutrition may currently be underappreciated and offer potential in AD management.