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Abstract Background Due to ageing of the population the incidence of multimorbidity and polypharmacy is rising. Polypharmacy is a risk factor for medication-related (re)admission and therefore places a significant burden on the healthcare system. The reported incidence of medication-related (re)admissions varies widely due to the lack of a clear definition. Some medications are known to increase the risk for medication-related admission and are therefore published in the triggerlist of the Dutch guideline for Polypharmacy in older patients. Different interventions to support medication optimization have been studied to reduce medication-related (re)admissions. However, the optimal template of medication optimization is still unknown, which contributes to the large heterogeneity of their effect on hospital readmissions. Therefore, we implemented a clinical decision support system (CDSS) to optimize medication lists and investigate whether continuous use of a CDSS reduces the number of hospital readmissions in older patients, who previously have had an unplanned probably medication-related hospitalization. Methods The CHECkUP study is a multicentre randomized study in older (≥60 years) patients with an unplanned hospitalization, polypharmacy (≥5 medications) and using at least two medications from the triggerlist, from Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. Patients will be randomized. The intervention consists of continuous (weekly) use of a CDSS, which generates a Medication Optimization Profile, which will be sent to the patient’s general practitioner and pharmacist. The control group will receive standard care. The primary outcome is hospital readmission within 1 year after study inclusion. Secondary outcomes are one-year mortality, number of emergency department visits, nursing home admissions, time to hospital readmissions and we will evaluate the quality of life and socio-economic status. Discussion This study is expected to add evidence on the knowledge of medication optimization and whether use of a continuous CDSS ameliorates the risk of adverse outcomes in older patients, already at an increased risk of medication-related (re)admission. To our knowledge, this is the first large study, providing one-year follow-up data and reporting not only on quality of care indicators, but also on quality-of-life. Trial registration The trial was registered in the Netherlands Trial Register on October 14, 2018, identifier: NL7449 (NTR7691). https://www.trialregister.nl/trial/7449 .

Background Salt restriction may lower blood pressure variability (BPV), but previous studies have shown inconsistent results. Therefore, we investigated in an observational study and intervention trial whether urinary sodium excretion and salt intake are associated with 24‐hour BPV. Methods and Results We used data from the cross‐sectional population‐based Maastricht Study (n=2652; 60±8 years; 52% men) and from a randomized crossover trial (n=40; 49±11 years; 33% men). In the observational study, we measured 24‐hour urinary sodium excretion and 24‐hour BPV and performed linear regression adjusted for age, sex, mean blood pressure, lifestyle, and cardiovascular risk factors. In the intervention study, participants adhered to a 7‐day low‐ and high‐salt diet (50 and 250 mmol NaCl/24 h) with a washout period of 14 days, 24‐hour BPV was measured during each diet. We used linear mixed models adjusted for order of diet, mean blood pressure, and body mass index. In the observational study, 24‐hour urinary sodium excretion was not associated with 24‐hour systolic or diastolic BPV (β, per 1 g/24 h urinary sodium excretion: 0.05 mm Hg [95% CI, −0.02 to 0.11] and 0.04 mm Hg [95% CI, −0.01 to 0.09], respectively). In the intervention trial, mean difference in 24‐hour systolic and diastolic BPV between the low‐ and high‐salt diet was not statistically significantly different (0.62 mm Hg [95% CI, −0.10 to 1.35] and 0.04 mm Hg [95% CI, −0.54 to 0.63], respectively). Conclusions Urinary sodium excretion and salt intake are not independently associated with 24‐hour BPV. These findings suggest that salt restriction is not an effective strategy to lower BPV in the White general population. Registration URL: https://clinicaltrials.gov/ct2/show/NCT02068781

Abstract Shift workers may develop increased blood pressure.

Abstract Background Older patients (≥65 years old) experience high rates of adverse outcomes after an emergency department (ED) visit. Reliable tools to predict adverse outcomes in this population are lacking. This manuscript comprises a study protocol for the Risk Stratification in the Emergency Department in Acutely Ill Older Patients (RISE UP) study that aims to identify predictors of adverse outcome (including triage- and risk stratification scores) and intends to design a feasible prediction model for older patients that can be used in the ED. Methods The RISE UP study is a prospective observational multicentre cohort study in older (≥65 years of age) ED patients treated by internists or gastroenterologists in Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. After obtaining informed consent, patients characteristics, vital signs, functional status and routine laboratory tests will be retrieved. In addition, disease perception questionnaires will be filled out by patients or their caregivers and clinical impression questionnaires by nurses and physicians. Moreover, both arterial and venous blood samples will be taken in order to determine additional biomarkers. The discriminatory value of triage- and risk stratification scores, clinical impression scores and laboratory tests will be evaluated. Univariable logistic regression will be used to identify predictors of adverse outcomes. With these data we intend to develop a clinical prediction model for 30-day mortality using multivariable logistic regression. This model will be validated in an external cohort. Our primary endpoint is 30-day all-cause mortality. The secondary (composite) endpoint consist of 30-day mortality, length of hospital stay, admission to intensive- or medium care units, readmission and loss of independent living. Patients will be followed up for at least 30 days and, if possible, for one year. Discussion In this study, we will retrieve a broad range of data concerning adverse outcomes in older patients visiting the ED with medical problems. We intend to develop a clinical tool for identification of older patients at risk of adverse outcomes that is feasible for use in the ED, in order to improve clinical decision making and medical care. Trial registration Retrospectively registered on clinicaltrials.gov (NCT02946398; 9/20/2016).

Objective Older emergency department (ED) patients are at high risk of mortality, and it is important to predict which patients are at highest risk. Biomarkers such as lactate, high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), D-dimer and procalcitonin may be able to identify those at risk. We aimed to assess the discriminatory value of these biomarkers for 30-day mortality and other adverse outcomes.Design Prospective cohort study. On arrival of patients, five biomarkers were measured. Area under the curves (AUCs) and interval likelihood ratios (LRs) were calculated to investigate the discriminatory value of the biomarkers.Setting ED in the Netherlands.Participants Older (≥65 years) medical ED patients, referred for internal medicine or gastroenterology.Primary and secondary outcome measures 30-day mortality was the primary outcome measure, while other adverse outcomes (intensive care unit/medium care unit admission, prolonged length of hospital stay, loss of independent living and unplanned readmission) were the composite secondary outcome measure.Results The median age of the 450 included patients was 79 years (IQR 73–85). In total, 51 (11.3%) patients died within 30 days. The AUCs of all biomarkers for prediction of mortality were sufficient to good, with the highest AUC of 0.73 for hs-cTnT and NT-proBNP. Only for the highest lactate values, the LR was high enough (29.0) to be applicable for clinical decision making, but this applied to a minority of patients. The AUC for the composite secondary outcome (intensive and medium care admission, length of hospital stay >7 days, loss of independent living and unplanned readmission within 30 days) was lower, ranging between 0.58 and 0.67.Conclusions Although all five biomarkers predict 30-day mortality in older medical ED patients, their individual discriminatory value was not high enough to contribute to clinical decision making.Trial registration number NCT02946398; Results.

BackgroundOlder emergency department (ED) patients often have complex problems and severe illnesses with a high risk of adverse outcomes. It is likely that these older patients are troubled with concerns, which might reflect their preferences and needs concerning medical care. However, data regarding this topic are lacking.MethodsThis study is a sub study of a prospective, multicenter, observational cohort study among older medical ED patients (≥65 years). Patients or their caregivers were asked about their illness-related concerns during the first stage of the ED visit using a questionnaire. All concerns were categorized into 10 categories, and differences between patients and caregivers, and between age groups were analyzed. Odds Ratios were calculated to determine the association of the concerns for different adverse outcomes.ResultsMost of the 594 included patients (or their caregivers) were concerned (88%) about some aspects of their illness or their need for medical care. The most often reported concerns were about the severity of disease (43.6%), functional decline (9.4%) and dying (5.6%). Caregivers were more frequently concerned than patients (p7 days, loss of independent living and unplanned readmission within 30 days) (OR 2.32; 95%CI: 1.12-4.82). In addition, unspecified concerns were associated with mortality (OR 1.88; 95%CI: 1.09-3.22).ConclusionThe majority of older patients and especially their caregivers are concerned about their medical condition or need for medical care when they visit the ED. These concerns are associated with adverse outcomes and most likely reflect their needs regarding medical care. More attention should be paid to these concerns because they may offer opportunities to reduce anxiety and provide care that is adjusted to their needs.Trial registrationThis study was registered on clinicalTriagls.gov (NCT02946398).

BackgroundOlder emergency department (ED) patients are at risk for adverse outcomes, however, it is hard to predict these. We aimed to assess the discriminatory value of clinical intuition, operationalized as disease perception, self-rated health and first clinical impression, including the 30-day surprise question (SQ: "Would I be surprised if this patient died in the next 30 days" of patients, nurses and physicians. Endpoints used to evaluate the discriminatory value of clinical intuition were short-term (30-day) mortality and other adverse outcomes (intensive/medium care admission, prolonged length of hospital stay, loss of independent living or 30-day readmission).MethodsIn this prospective, multicentre cohort study, older medical patients (≥65 years), nurses and physicians filled in scores regarding severity of illness and their concerns (i.e. disease perception and clinical impression scores) immediately after arrival of the patient in the ED. In addition, patients filled in a self-rated health score and nurses and physicians answered the SQ. Area under the curves (AUCs) of receiver operating characteristics (ROCs) were calculated.ResultsThe median age of the 602 included patients was 79 years and 86.7% were community dwelling. Within 30 days, 66 (11.0%) patients died and 263 (43.7%) patients met the composite endpoint. The severity of concern score of both nurses and physicians yielded the highest AUCs for 30-day mortality (for both 0.75; 95%CI 0.68-0.81). AUCs for the severity of illness score and SQ of nurses and physicians ranged from 0.71 to 0.74 while those for the disease perception and self-rated health of patients ranged from 0.64 to 0.69. The discriminatory value of the scores for the composite endpoint was lower (AUCs ranging from 0.60 to 0.67). We used scores that have not been previously validated which could influence their generalisability.ConclusionClinical intuition,-disease perception, self-rated health and first clinical impression-documented at an early stage after arrival in the ED, is a useful clinical tool to predict mortality and other adverse outcomes in older ED patients. Highest discriminatory values were found for the nurses' and physicians' severity of concern score. Intuition may be helpful for the implementation of personalised medical care in the future.

El Comité Internacional de Editores de Revistas Mé-dicas (ICMJE, por sus siglas en inglés) considera que es una obligación ética compartir, de forma respon- sable, los datos generados por los ensayos clínicos, porque los participantes se han puesto en riesgo para ello.

Vascular calcification is an independent predictor of cardiovascular disease, and therefore, inhibition or regression of this processes is of clinical importance. The standard care regarding prevention and treatment of cardiovascular disease at this moment mainly depends on drug therapy. In animal and preclinical studies, various forms of cardiovascular drug therapy seem to have a positive effect on vascular calcification. In particular, calcium channel blockers and inhibitors of the renin−angiotensin−aldosteron system slowed down arterial calcification in experimental animals. In humans, the results of trials with these drugs are far less pronounced and often contradictory. There is limited evidence that the development of new atherosclerotic lesions may be retarded in patients with coronary artery disease, but existing lesions can hardly be influenced. Although statin therapy has a proven role in the prevention and treatment of cardiovascular morbidity and mortality, it is associated with both regression and acceleration of the vascular calcification process. Recently, nutritional supplements have been recognized as a potential tool to reduce calcification. This is particularly true for vitamin K, which acts as an inhibitor of vascular calcification. In addition to vitamin K, other dietary supplements may also modulate vascular function. In this narrative review, we discuss the current state of knowledge regarding the pharmacological and nutritional possibilities to prevent the development and progression of vascular calcification.

Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months. The primary endpoint is the difference in CAC-score progression between both groups. Secondary endpoints include changes in arterial structure and function, and associations with biomarkers. We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD.

Objectives: Hypertension is a major risk factor for white matter hyperintensities, lacunes, cerebral microbleeds and perivascular spaces, which are MRI markers of cerebral small vessel disease (SVD). Studies have shown associations between these individual MRI markers and cognitive functioning and decline. Recently, a total SVD score was proposed in which the different MRI markers were combined into one measure of SVD, to capture total SVD-related brain damage. We investigated if this SVD score was associated with cognitive decline over 4 years in patients with hypertension. Methods: In this longitudinal cohort study, 130 hypertensive patients (91 patients with uncomplicated hypertension and 39 hypertensive patients with a lacunar stroke) were included. They underwent a neuropsychological assessment at baseline and after 4 years. The presence of white matter hyperintensities, lacunes, cerebral microbleeds, and perivascular spaces were rated on baseline MRI. Presence of each individual marker was added to calculate the total SVD score (range 0-4) in each patient. Results: Uncorrected linear regression analyses showed associations between SVD score and decline in overall cognition (p=0.017), executive functioning (p

The present paper is the result of a workshop sponsored by the DFG Research Center/Cluster of Excellence MARUM "The Ocean in the Earth System", the International Graduate College EUROPROX, and the Alfred Wegener Institute for Polar and Marine Research. The workshop brought together specialists on organic matter degradation and on proxy-based environmental reconstruction. The paper deals with the main theme of the workshop, understanding the impact of selective degradation/preservation of organic matter (OM) in marine sediments on the interpretation of the fossil record. Special attention is paid to (A) the influence of the molecular composition of OM in relation to the biological and physical depositional environment, including new methods for determining complex organic biomolecules, (B) the impact of selective OM preservation on the interpretation of proxies for marine palaeoceanographic and palaeoclimatic reconstruction, and (C) past marine productivity and selective preservation in sediments. It appears that most of the factors influencing OM preservation have been identified, but many of the mechanisms by which they operate are partly, or even fragmentarily, understood. Some factors have not even been taken carefully into consideration. This incomplete understanding of OM breakdown hampers proper assessment of the present and past carbon cycle as well as the interpretation of OM based proxies and proxies affected by OM breakdown. To arrive at better proxy-based reconstructions "deformation functions" are needed, taking into account the transport and diagenesis-related molecular and atomic modifications following proxy formation. Some emerging proxies for OM degradation may shed light on such deformation functions. The use of palynomorph concentrations and selective changes in assemblage composition as models for production and preservation of OM may correct for bias due to selective degradation. Such quantitative assessment of OM degradation may lead to more accurate reconstruction of past productivity and bottom water oxygenation. Given the cost and effort associated with programs to recover sediment cores for paleoclimatological studies, as well as with generating proxy records, it would seem wise to develop a detailed sedimentological and diagenetic context for interpretation of these records. With respect to the latter, parallel acquisition of data that inform on the fidelity of the proxy signatures and reveal potential diagenetic biases would be of clear value.

R J M W Rennenberg1, A G H Kessels2, L J Schurgers3, J M A van Engelshoven4, P W de Leeuw1, A A Kroon11Department of Internal Medicine; 2Department of Clinical Epidemiology and Medical Technology Assessment; 3Department of Biochemistry (VitaK); 4Department of Radiology, University Hospital Maastricht and Cardiovascular Research Institute Maastricht (CARIM), The NetherlandsBackground: Several imaging techniques may reveal calcification of the arterial wall or cardiac valves. Many studies indicate that the risk for cardiovascular disease is increased when calcification is present. Recent meta-analyses on coronary calcification and cardiovascular risk may be confounded by indication. Therefore, this meta-analysis was performed with extensive subgroup analysis to assess the overall cardiovascular risk of finding calcification in any arterial wall or cardiac valve when using different imaging techniques.Methods and results: A meta-analysis of prospective studies reporting calcifications and cardiovascular end-points was performed. Thirty articles were selected. The overall odds ratios (95% confidence interval [CI]) for calcifications versus no calcifications in 218,080 subjects after a mean follow-up of 10.1 years amounted to 4.62 (CI 2.24 to 9.53) for all cause mortality, 3.94 (CI 2.39 to 6.50) for cardiovascular mortality, 3.74 (CI 2.56 to 5.45) for coronary events, 2.21 (CI 1.81 to 2.69) for stroke, and 3.41 (CI 2.71 to 4.30) for any cardiovascular event. Heterogeneity was largely explained by length of follow up and sort of imaging technique. Subgroup analysis of patients with end stage renal disease revealed a much higher odds ratio for any event of 6.22 (CI 2.73 to 14.14).Conclusion: The presence of calcification in any arterial wall is associated with a 3–4-fold higher risk for mortality and cardiovascular events. Interpretation of the pooled estimates has to be done with caution because of heterogeneity across studies.Keywords: calcification, cardiovascular risk, meta-analysis, imaging

Mohammad Hadi Zafarmand1,3, Yvonne T van der Schouw1, Diederick E Grobbee1, Peter W de Leeuw2, Michiel L Bots11Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, Str 6.131, 3584 CX, Utrecht, The Netherlands; 2Department of Internal Medicine, University Hospital Maastricht, PO Box 5800, NL-6202 AZ, Maastricht, The Netherlands; 3Persian Gulf Health Research Center, Department of Genomic Health, Bushehr University of Medical Sciences and Health Services, Moalem Street, Po Box 3631, Bushehr, IranBackground: The alanine allele of P12A polymorphism in PPARG gene in a few studies has been associated with a reduced or increased risk of acute myocardial infarction (AMI). Yet, the risk relation has not been confirmed, and data on ischemic stroke (IS) is scarce. We therefore investigated the role of this polymorphism on occurrence of AMI, coronary heart disease (CHD) and IS.Methods and findings: We performed a case-cohort study in 15,236 initially healthy Dutch women and applied a Cox proportional hazards model to study the relation of the P12A polymorphism and AMI (n = 71), CHD (n = 211), and IS (n = 49) under different inheritance models. In addition, meta-analyses of published studies were performed. Under the dominant inheritance model, carriers of the alanine allele compared with those with the more common genotype were not at increased or decreased risk of CHD (hazard ratio [HR] = 0.82; 95% confidence interval [CI], 0.58 to 1.17) and of IS (HR = 1.03; 95% CI, 0.14 to 7.74). In addition no relations were found under the recessive and additive models. Our meta-analyses corroborated these findings by showing no significant association. For AMI we found a borderline significant association under dominant (HR = 0.49; 95% CI, 0.26 to 0.94), and additive (HR = 0.51; 95% CI, 0.26 to 1.00) models which could be due to chance, because of small cases in this subgroup. The meta-analysis did not show any association between the polymorphism and risk of AMI under the different genetic models.Conclusions: Our study in healthy Dutch women in combination with the meta-analyses of previous reports does not provide support for a role of P12A polymorphism in PPARG gene in MI and CHD risk. Also our study shows that the polymorphism has no association with IS risk.Keywords: genetics, myocardial infarction, polymorphism, PPARG gene, risk factors, population-based

Willem J Verberk, Abraham A Kroon, Heidi A Jongen-Vancraybex, Peter W de LeeuwUniversity Hospital Maastricht, Department of Internal Medicine and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The NetherlandsPurpose: To review the literature on home blood pressure measurement (HBPM), to examine its validity and applicability for clinical practice and to provide recommendations regarding HBPM assessment.Findings: HBPM can eliminate the white coat effect and offers the possibility to obtain multiple measurements under standardized conditions, which increases knowledge of overall blood pressure value. Although it is not entirely capable of replacing ambulatory blood pressure measurement (ABPM), HBPM correlates better with target organ damage and cardiovascular mortality than office blood pressure measurement (OBPM), it enables prediction of sustained hypertension in patients with borderline hypertension, and proves to be an appropriate tool for assessing drug efficacy. Additional advantages of HBPM are that it may increase drug compliance and patient’s awareness of hypertension. Overall, OBPM yield higher blood pressure values than HBPM. Differences between OBPM and HBPM tend to increase with age and are generally higher in patients without antihypertensive treatment than in patients with antihypertensive treatment.Recommendations: Measurements should be performed according to accepted guidelines and recordings should be performed with a memory equipped automatic validated device. From the data reviewed here, we recommend that HBPM be assessed monthly by taking two measurements in the morning within 1 hour after awakening and two in the evening for three consecutive days, the data from the first day should be dismissed. A subject should be labeled hypertensive if his/her HBPM value is equal to or greater than 137 mmHg systolic and/or 84 mmHg diastolic.Keywords: blood pressure, hypertension, self-measurement, home measurement, ambulatory measurement, adherence

Background – White matter lesions (WMLs), asymptomatic lacunar infarcts, brain microbleeds (BMBs) and enlarged perivascular spaces (EPVS) have been identified as silent lesions due to cerebral small vessel disease (cSVD). All these markers have been individually linked to cognitive functioning, but are also strongly correlated with each other. The combined effect of these markers on cognitive function has never been studied and would possibly provide more useful information on the effect on cognitive function. Methods – Brain MRI and extensive neuropsychological assessment were performed in 189 patients at risk for cSVD (112 hypertensive patients and 77 first-ever lacunar stroke patients). We rated the presence of any asymptomatic lacunar infarct, extensive WMLs, any deep BMB, and moderate to extensive EPVS in the basal ganglia. The presence of each marker was summed to an ordinal score between 0 and 4. Associations with domains of cognitive function (memory, executive function, information processing speed and overall cognition) were analyzed with correlation analyses. Results – Correlation analyses revealed significant associations between accumulating cSVD burden and decreased performance on all cognitive domains (all p≤.001). Results remained significant for information processing speed (r=-.181, p=.013) and overall cognition (r=-.178, p=.017), after correction for age and sex. Testing of trend using linear regression analyses revealed the same results. Discussion – We tested a new approach to capture total brain damage resulting from cSVD and found that accumulation of MRI burden of cSVD is associated with decreased performance on tests of information processing speed and overall cognition, implying that accumulating brain damage is accompanied by worse cognitive functioning.

In the past few years, novel accomplishments have been obtained in carotid baroreflex activation therapy (BAT) for the treatment of resistant hypertension. In addition, this field is still evolving with promising results in the reduction of blood pressure and heart rate. This overview addresses the latest developments in BAT for the treatment of drug-resistant hypertension. Although not totally understood considering the working mechanisms of BAT, it appeared to be possible to achieve at least as much efficacy of single-sided as bilateral stimulation. Therefore unlike the first-generation Rheos system, the second-generation Barostim neo operates by unilateral baroreflex activation, using a completely different carotid electrode. Also significant improvements in several cardiac parameters have been shown by BAT in hypertensive patients, which set the basis for further research to evaluate BAT as a therapy for systolic heart failure. Yet important uncertainties need to be clarified to guarantee beneficial effects; hence not all participants seem to respond to BAT.

Rectal lesions without anal sphincter trauma in childbirth are only sporadically described in literature. We describe the case of a 29-year-old primigravida who delivered a child in frank breech presentation. During the second stage of labour a foot presented transanally through a rectal laceration with intact anal sphincters. The laceration was repaired immediately after delivery in theatre. Follow-up visits showed a properly cured laceration and no complaints of incontinence or foul discharge.

BACKGROUND: The M235T polymorphism in the AGT gene has been related to an increased risk of hypertension. This finding may also suggest an increased risk of coronary heart disease (CHD). METHODOLOGY/PRINCIPAL FINDINGS: A case-cohort study was conducted in 1,732 unrelated middle-age women (210 CHD cases and 1,522 controls) from a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model to study the association of the polymorphism with acute myocardial infarction (AMI) (n = 71) and CHD. In the case-cohort study, no increased risk for CHD was found under the additive genetic model (hazard ratio [HR] = 1.20; 95% confidence interval [CI], 0.86 to 1.68; P = 0.28). This result was not changed by adjustment (HR = 1.17; 95% CI, 0.83 to 1.64; P = 0.38) nor by using dominant, recessive and pairwise genetic models. Analyses for AMI risk under the additive genetic model also did not show any statistically significant association (crude HR = 1.14; 95% CI, 0.93 to 1.39; P = 0.20). To evaluate the association, a comprehensive systematic review and meta-analysis were undertaken of all studies published up to February 2007 (searched through PubMed/MEDLINE, Web of Science and EMBASE). The meta-analysis (38 studies with 13284 cases and 18722 controls) showed a per-allele odds ratio (OR) of 1.08 (95% CI, 1.01 to 1.15; P = 0.02). Moderate to large levels of heterogeneity were identified between studies. Hardy-Weinberg equilibrium (HWE) violation and the mean age of cases were statistically significant sources of the observed variation. In a stratum of non-HWE violation studies, there was no effect. An asymmetric funnel plot, the Egger's test (P = 0.066), and the Begg-Mazumdar test (P = 0.074) were all suggestive of the presence of publication bias. CONCLUSIONS/SIGNIFICANCE: The pooled OR of the present meta-analysis, including our own data, presented evidence that there is an increase in the risk of CHD conferred by the M235T variant of the AGT gene. However, the relevance of this weakly positive overall association remains uncertain because it may be due to various residual biases, including HWE-violation and publication biases.