Hospital Clínico Universitario de Valencia

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

BACKGROUND: Activating mutations in the epidermal growth factor receptor gene (EGFR) confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small-cell lung cancer. We evaluated the feasibility of large-scale screening for EGFR mutations in such patients and analyzed the association between the mutations and the outcome of erlotinib treatment. METHODS: From April 2005 through November 2008, lung cancers from 2105 patients in 129 institutions in Spain were screened for EGFR mutations. The analysis was performed in a central laboratory. Patients with tumors carrying EGFR mutations were eligible for erlotinib treatment. RESULTS: EGFR mutations were found in 350 of 2105 patients (16.6%). Mutations were more frequent in women (69.7%), in patients who had never smoked (66.6%), and in those with adenocarcinomas (80.9%) (P<0.001 for all comparisons). The mutations were deletions in exon 19 (62.2%) and L858R (37.8%). Median progression-free survival and overall survival for 217 patients who received erlotinib were 14 months and 27 months, respectively. The adjusted hazard ratios for the duration of progression-free survival were 2.94 for men (P<0.001); 1.92 for the presence of the L858R mutation, as compared with a deletion in exon 19 (P=0.02); and 1.68 for the presence of the L858R mutation in paired serum DNA, as compared with the absence of the mutation (P=0.02). The most common adverse events were mild rashes and diarrhea; grade 3 cutaneous toxic effects were recorded in 16 patients (7.4%) and grade 3 diarrhea in 8 patients (3.7%). CONCLUSIONS: Large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in decisions about treatment.

BACKGROUND: Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. METHODS: We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival. RESULTS: A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months. CONCLUSIONS: Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Committee; LVH: left ventricular hypertrophy; LVM: left ventricular mass; PDE-5: phosphodiesterase-5; PPAR-γ: peroxisome proliferators-activated receptor-γ; PWV: pulse wave velocity; SBP: systolic blood pressure; WHO: World Health Organization. Introduction In the 2 years since the publication of the 2007 guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) [1], research on hypertension has actively been pursued and the results of new important studies (including several large randomized trials of antihypertensive therapy) have been published. Some of these studies have reinforced the evidence on which the recommendations of the 2007 ESH/ESC guidelines were based. However, other studies have widened the information available in 2007, modifying some of the previous concepts, and suggesting that new evidence-based recommendations could be appropriate. The aim of this document of the ESH is to address a number of studies on hypertension published in the last 2 years in order to assess their contribution to our expanding knowledge of hypertension. Furthermore, some critical appraisal of the current recommendations of the ESH/ESC, as well as of other guidelines, might be a useful step toward the preparation of a third version of the European guidelines in the future. The most important conclusions are summarized in boxes. The points that will be discussed are reported in Box 1.Box. 1Assessment of subclinical organ damage for stratification of total cardiovascular risk The 2007 ESH/ESC guidelines recommend total cardiovascular risk be evaluated in each patient to decide about important aspects of treatment: the blood pressure (BP) threshold at which to commence drug administration, the target BP to be reached by treatment, the use of two-drug combinations as the initial treatment step, and the possible addition to the antihypertensive treatment regimen of lipid-lowering and antiplatelet agents [1]. Among the criteria to assess total cardiovascular risk, the European guidelines consider subclinical organ damage to be a very important component, because asymptomatic alterations of the cardiovascular system and the kidney are crucial intermediate stages in the disease continuum that links risk factors such as hypertension to cardiovascular events and death. On the basis of a number of criteria (prognostic importance, prevalence in the population, availability and cost of the assessment procedures, etc.), the 2007 European guidelines considered detection of organ damage as important for the diagnostic and prognostic evaluation of hypertensive patients. They further subdivided the different types of organ damage into (1) those that can be identified by relatively simple and cheap procedures [electrocardiogram, serum creatinine, estimated glomerular filtration rate (eGFR), and measurement of urinary protein excretion in order to detect microalbuminuria or proteinuria], which were thus regarded as suitable for routine search in the whole hypertensive population, and (2) those that require more complex procedures or instrumentations (echocardiogram, carotid ultrasonography, pulse wave velocity), which were for this reason only recommended for a more in-depth characterization of the hypertensive patient. Since then, other studies have added useful information on the importance of detecting subclinical organ damage in the hypertensive population, strengthening the recommendation to use the most easily available and the least costly procedures in the routine examination of individuals with hypertension. Heart A few recent papers have revived interest in the power of the electrocardiogram to predict the risk of cardiovascular events. In a prospective survey including 7495 American adults, a new indicator of left ventricular hypertrophy (LVH), the Novacode estimate of left ventricular mass index that is based on both voltage and strain pattern criteria, has been reported to be significantly related to 10-year cardiovascular mortality [2]. The relation remained significant after adjusting for age, SBP, smoking, cholesterol, and diabetes. Furthermore, in the LIFE trial, the investigators have reported that in hypertensive patients with electrocardiographic LVH, left bundle branch block identifies individuals at increased risk of cardiovascular mortality (hazard ratio 1.6), sudden cardiovascular death (hazard ratio 3.5), and hospitalization for heart failure (hazard ratio 1.7) [3]. Finally, a very recent prospective study [4] focused on the R-wave voltage in lead aVL as being rather closely associated with left ventricular mass (LVM), and additionally predictive of incident cardiovascular events even when hypertension is not accompanied by electrocardiographic LVH (9% higher risk for each 0.1 mV higher R-wave). Additional evidence is also available on the predictive power of cardiac abnormalities, as detected by echocardiography, an approach of continuing interest because of its ability to more directly and precisely quantify LVM and geometric LVH patterns. A retrospective study has recently updated information from more than 35 000 normotensive and hypertensive participants with normal left ventricular ejection fraction [5]. Despite normal left ventricular function, an abnormal left ventricular geometric pattern was found in 46% of the patients (35% left ventricular concentric remodeling and 11% LVH), and the associated risk of all-cause mortality was twice as large as that of patients with normal left ventricular geometry. Although in another study on an African–American population, the relationship between left ventricular geometric patterns and all-cause mortality was markedly attenuated after adjusting for baseline variables, and remained significant only in men [6], the increased risk associated with LVH has been confirmed by other observations. In a prospective study on a cohort of 1652 Greek hypertensive patients followed up for 6 years, echocardiographic LVH was significantly associated with either a composite of all-cause mortality and cardiovascular events (hazard ratio 1.53) and with stroke (hazard ratio 2.01), after adjustment for major cardiovascular risk factors [7]. Furthermore, a retrospective analysis of 1447 Japanese hypertensive patients who participated in the CASE-J trial showed that cardiovascular events occurred about 2.6 times more frequently in patients with a LVM index 125 g/m2 or more compared with those with a LVM index below this value [8]. Finally, in the PAMELA population, echocardiographic LVH was associated with a four-fold to five-fold significant increase in cardiovascular morbidity and mortality when data were adjusted for a large number of potential confounders, including office, home, and ambulatory BP values. A 10% increase in LVM increased the risk more markedly when baseline LVM was already abnormal, but an increasing risk was evident also when calculated from LVM values within the normal range [9]. Blood vessels The relationship of carotid intima–media thickness (IMT) and plaques with subsequent cardiovascular events, already discussed in the 2007 guidelines, has been further strengthened by data from ELSA [10], which have shown that baseline carotid IMT predicts cardiovascular events independent of BP (clinic and ambulatory) and this occurs both for the IMT value at the carotid bifurcations and for the IMT value at the level of the common carotid artery. This suggests that both atherosclerosis (reflected by the IMT value at the bifurcations) and vascular hypertrophy (reflected by the common carotid IMT) exert an adverse prognostic effect in addition to that of high BP. An adverse prognostic significance of carotid plaques (hazard ratio 2.3) has also been reported in a sample of residents of the Copenhagen County free of overt cardiovascular disease, which was prospectively followed for about 13 years [11]. Evidence has also accrued on the adverse prognostic value of arterial stiffening. In the Copenhagen County population, an increased pulse wave velocity (PWV >12 m/s) was associated with a 50% increase in the risk of a cardiovascular event [11]. Furthermore, an independent predictive value of PWV for cardiovascular events has been shown in Japanese men followed for 8.2 years [12]. Finally, indirect indices of aortic stiffness and wave reflection, such as central BP and augmentation index, have been confirmed as independent predictors of cardiovascular events in two recent studies [13,14]. In particular, in one of these studies of 1272 normotensive and untreated hypertensive patients, only central SBP consistently and independently predicted cardiovascular mortality after adjustment for various cardiovascular risk factors, including LVM and carotid IMT [14]. However, it should be emphasized that in most available studies, the additive predictive value of central BP beyond brachial pressure appears limited, which leaves the question whether central BP measurements should be regularly considered in the clinical profiling of hypertensive patients in need of further investigation. Kidney Several new data [15] reinforce the already solid evidence on the prognostic value of eGFR that was available at the time of the 2007 guidelines [1]. In the population of Gubbio (Italy), an eGFR in the lowest decile was associated with a significantly higher incidence of cardiovascular events (hazard ratio 2.14) [16], and in the above-mentioned Greek study [7], an eGFR between 15 and 59 ml/min per 1.73 m2 was associated with a 66% increase in the composite endpoint of all cause mortality and cardiovascular events after adjustment for baseline cardiovascular risk and independent of LVH [7]. Likewise, in a post hoc analysis of data from the VALUE trial [17], eGFR according to the MDRD formula was significantly predictive of all outcomes except stroke (with hazard ratios between 1.23 and 1.70 according to the different outcomes) and was more sensitive than calculation of the creatinine clearance value according to the Cockroft–Gault formula, which was only predictive of all-cause mortality. The baseline eGFR by the MDRD formula turned out to be importantly predictive of both renal and cardiovascular events also in the large number (n = 11 140) of type 2 diabetic patients included in the ADVANCE trial, even when data were adjusted for many potential confounders, including the concomitant urinary protein excretion value. For every 50% reduction of baseline eGFR the risk of cardiovascular events significantly increased 2.2-fold, the concomitant increase in the risk of cardiovascular death and renal events being 3.6-fold and 63.6-fold, respectively [18]. New evidence is also available to support the already large amount of data in favor of the prognostic value of the moderate increase in urinary protein excretion, defined as microalbuminuria [19,20]. In two population studies, the Gubbio study [16] and the Copenhagen County study [11], microalbuminuria was confirmed as an important predictor of cardiovascular outcome, the adjusted hazard ratio being, respectively, 2.15-fold and 3.10-fold greater in patients with microalbuminuria compared with those without. In the Gubbio study, the association of microalbuminuria with low eGFR had a multiplicative effect (hazard ratio 5.93). In the ADVANCE trial [18], a change from one clinical stage of albuminuria to the next was associated with a 1.6-fold, 2.0-fold, and 3.3-fold increase in the multivariate-adjusted risk of cardiovascular events, cardiovascular death, and renal events, respectively, this being the case also when the change from normoalbuminuria to microalbuminuria was involved. The effects of higher baseline urinary protein excretion and reduced eGFR were independent of each other and the association of microalbuminuria and an eGFR value less than 60 ml/min per 1.73 m2 brought about an additional increase in risk: 3.2-fold for cardiovascular events, 5.9-fold for cardiovascular mortality, and 22.2-fold for renal events. Additional measures of organ damage The 2007 European guidelines mention a number of additional measures of organ damage for which evidence of prognostic relevance was available, but no use in the clinical practice could be foreseen because of drawbacks of practical relevance, such as the high cost and low availability of the devices involved, the complexity and time consumption inherent in the procedures, and in several instances the lack of standardization of the values obtained between laboratories and across countries. Based on the evidence available in the last 2 years, no addition to the measures of organ damage included in the 2007 guidelines can be supported, although the growing availability of more sophisticated techniques and the reduced cost of their use brought about by technological progress, makes future additions likely. In this context, the use of nuclear magnetic resonance deserves special mention. Although not prospective in nature, a very recent study systematically employing nuclear magnetic resonance imaging in a group of 142 hypertensive patients without overt cardiovascular disease has provided the interesting information that silent cerebrovascular lesions are even more prevalent (44%) than cardiac (21%) and renal (26%) subclinical damage, and do frequently occur in the absence of other signs of organ damage [21]. Increasing evidence also relates these lesions to cognitive dysfunction [22,23], a problem of primary importance because of the senescence of the population [24]. With magnetic resonance imaging becoming more and more frequently employed in diagnostic procedures, silent cerebrovascular disease is likely to become more frequently investigated in prognostic and therapeutic studies in hypertension. The prognostic value of structural alterations in small subcutaneous arteries has recently been confirmed by two independent studies [25,26]. However, the invasive nature of this measurement prevents larger scale application of this method. A new noninvasive method for assessing the media–lumen ratio of small retinal arteries seems promising for large-scale evaluation [27], although its predictive value remains to be investigated. Evidence remains inconclusive on a marker of a vascular alteration that has been actively investigated in the past decade, namely endothelial dysfunction. In a population sample of individuals without overt cardiovascular disease (67% with hypertension and 22% with diabetes mellitus) from the Northern Manhattan study, measures of flow-mediated vasodilatation predicted the incidence of cardiovascular events, but this effect was not independent of traditional cardiovascular risk factors [28]. Likewise, in the large cohort of elderly patients of the Cardiovascular Health Study, flow-mediated vasodilatation added very little to the prognostic accuracy of traditional risk factors [29]. On the contrary, Muiesan et al.[30] have recently reported that in a small cohort (n = 172) of uncomplicated hypertensive persons followed for about 8 years, flow-mediated vasodilatation of the brachial artery below the median value was significantly associated with a 2.7-fold increase in incident cardiovascular events even after adjusting for all major cardiovascular risk factors. However, the same group of investigators also have reported that endothelial dysfunction in the subcutaneous vessels of hypertensive patients was not predictive of cardiovascular events [31], possibly because endothelial dysfunction in different vascular beds may have a different prognostic significance. Clearly, the prognostic value of endothelial dysfunction in hypertension remains to be further elucidated. It should be emphasized that the addition of new measures of organ damage to the assessment of total cardiovascular risk requires not only the demonstration of their prognostic importance, but it has to improve the power to predict the incidence of cardiovascular events. This is by no means easy to be documented, and indeed data are available that in some instances new risk factors of individual prognostic significance do not improve, when added to the others, the accuracy by which cardiovascular risk can be quantified, thus only making the diagnostic procedures more complex, time consuming, and costly. This is exemplified by the recent results of the Framingham study, which showed that inclusion of inflammatory markers did not lead to any substantial improvement in the accuracy (sensitivity and specificity) by which total cardiovascular risk was assessed [32]. Subclinical organ damage as a marker of high cardiovascular risk Although subclinical organ damage undoubtedly increases the level of cardiovascular risk, the question arises whether it always brings the patient into the high-risk category, that is, an absolute risk of at least 20 cardiovascular events in 10 years per 100 patients. The 2007 European guidelines classify hypertensive patients with subclinical organ damage among those with a high total cardiovascular risk. This is further supported by more recent evidence on the contribution of subclinical cardiac, vascular, and renal damage to the total cardiovascular risk. As regards to subclinical cardiac damage, analysis of the data provided by some of the major prospective studies indicates that in hypertensive patients, echocardiographic LVH, particularly if of the concentric variety, is associated with an incidence of cardiovascular events equal to or above 20% in 10 years [5,7,33]. An incidence greater than 20% in 10 years has also been reported for men, but not for women, with echocardiographic LVH in the Framingham population study [34]. Finally, in the hypertensive patients of the CASE-J trial, echocardiographic LVH was associated with a 10-year incidence of cardiovascular events of 24% compared with the 10% incidence seen in patients without LVH [8]. Similar evidence exists for vascular damage. In the elderly patients of the Cardiovascular Health Study [35], the 10-year incidence of major cardiovascular events was higher than 20% when the common carotid IMT was 1.06 mm or more (fourth and fifth quintiles) and below 10% in those with an IMT in the first quintile (<0.87 mm). In the hypertensive patients of the ELSA study [10], the incidence of all (major and minor) cardiovascular events was greater than 20% in 10 years when IMT (common carotid plus bifurcation) was in the third and fourth quartiles (≥1.16 mm) or when at least one plaque had been detected. In contrast, patients with IMT in the first or the smallest IMT quartile (<0.98 mm) had incident cardiovascular events below 10% in 10 years. In hypertensive patients, the 10-year incidence of major cardiovascular events was higher than 20% when carotid-femoral PWV (aortic stiffness) was 16.3 m/s or more (fifth quintile) and below 10% in those with an aortic stiffness in the first and second quintiles [36]. Furthermore, even asymptomatic peripheral vascular disease as detected by a positive ankle-brachial index has prospectively been found to be associated in men with an incidence of cardiovascular events approaching 20% in 10 years [37,38]. Finally, old and recent evidence leaves little doubt that in hypertensive individuals, renal subclinical organ damage is associated with a 10-year risk of cardiovascular events of 20% or more. It has already been reported some years ago that reduced renal function, defined by a serum creatinine more than 1.5 mg/dl is associated with a 10-year incidence of cardiovascular events 20% or more [39,40]. In the recent prospective cohort of Greek hypertensive patients [7], a low eGFR was associated with incident cardiovascular events of about 20% in 10 years, an even higher incidence being observed when low eGFR occurred together with LVH. Furthermore, in the hypertensive patients prospectively studied by Jensen et al.[41], the incidence of ischemic heart disease was 20% in 10 years in the presence of microalbuminuria and of only 5% in its absence. Also, in the Gubbio population study, the incidence of cardiovascular events was greater than 20% in 10 years, but only in those individuals in whom microalbuminuria in the highest decile was associated with eGFR in the lowest decile [16]. Over 78% of these patients had hypertension. The 2007 European guidelines classify patients with subclinical organ damage as being at high risk also when BP is in the high normal range, but admittedly evidence that this is invariably the case is less clear. In the general population of the Framingham study, no information was made available on the prognostic value of echographic LVH, separately in the normotensive and hypertensive population [34]. Furthermore, in the same population, the association of renal dysfunction with cardiovascular events was lost after adjustment for cardiovascular risk factors, including BP [42]. In the PREVEND population study [43], microalbuminuria (20–200 mg/l) was associated with only a 4.7% cardiovascular mortality in 10 years, that is, a moderate absolute risk according to the SCORE classification [44], and in the nonhypertensive, nondiabetic individuals of the Framingham study, a microalbuminuria above the median value was associated with a rate of incident cardiovascular events of only 8.8% in 10 years compared with a 2.9% rate in individuals with microalbuminuria below the median value [45]. Prognostic value of treatment-induced modifications of subclinical organ damage The 2007 European guidelines have emphasized that treatment-induced changes of organ damage affect the incidence of cardiovascular events, thereby recommending that organ damage be measured also during treatment. Reference was made to the data obtained in the LIFE study [46], in which hypertensive patients in whom treatment was accompanied by regression of echocardiographic LVH or a delayed increase in LVM had less incident cardiovascular events, including sudden death, than those in whom no regression from or earlier progression to LVH occurred. It was also mentioned that both in LIFE [47] and in other studies [48], a similar relationship was found between treatment-induced changes in and renal or cardiovascular events. This means compared with patients in whom treatment had little or no reduction in was associated with a reduced incidence of cardiovascular events and less progression to renal Since 2007, data on the relationship between treatment-induced changes in cardiac damage and cardiovascular have been by further of the LIFE study, which have shown that also treatment-induced changes in left left ventricular and in electrocardiographic signs of LVH with incident cardiovascular event rate Furthermore, have been that in changes in LVM during treatment affect cardiovascular Finally, the predictive power of treatment-induced IMT changes in the carotid arteries has for the first time been investigated in a recent analysis of ELSA trial This analysis to a predictive of IMT but the of these changes compared with the large individual in baseline IMT makes it to conclusions The of treatment-induced changes in with cardiovascular event incidence has been by some of the In this trial on a large number of high or very high cardiovascular risk patients, the group with a of an angiotensin-converting and an the study less increase in than the group on with one or the other but this effect was not accompanied by a reduction in cardiovascular events and was even associated with an increase in renal events However, these results do not the important that treatment-induced changes in can be a marker of the more or less effects of treatment because for the results are For in most patients had a normal renal and few overt which in a very number of the endpoint that for renal that is, renal Furthermore, in the very high cardiovascular risk population the of the system provided by the and might have an adverse effect of its that and the associated with a reduction in In favor of this are some recent of the ADVANCE study in patients with type 2 diabetes. In these patients, values of showed a independent association with both renal and cardiovascular events, the contribution of being to the concomitant values of eGFR [18]. Evidence on the important prognostic of subclinical organ damage to In both hypertensive patients and the general population, the presence of electrocardiographic and echocardiographic LVH, a carotid plaque or an increased arterial a reduced eGFR by the MDRD or microalbuminuria or increases the total cardiovascular risk, hypertensive patients into the high absolute risk The changes in or detected LVH by treatment the effects on cardiovascular events, thereby information on whether patients are more or less by the treatment Despite some recent results solid evidence suggests that this is the case also for treatment-induced changes in urinary protein excretion, although the problem remains for treatment-induced vascular assessing the presence of subclinical organ damage is of crucial importance in the hypertensive This assessment can use of simple and cheap procedures that can routine information and at various times during treatment. It can also on more sophisticated that can further cardiac and vascular In all organ damage assessment is useful because of the evidence that in the presence of two signs of organ damage when inherent to the same cardiovascular risk may be more markedly with an to the high cardiovascular risk It is not from published data whether subclinical organ damage can total cardiovascular risk to the high range also in patients with high normal BP. However, organ damage when it is particularly or or is accompanied by risk factors, is associated with a or increase in risk also in normotensive individuals and the 2007 guidelines recommend risk as a for the need of treatment in and patients. In this context, it is also important to that the of organ damage in patients that decide to the of several studies that the incidence of cardiovascular events is higher in than in untreated hypertensive patients even after adjustment for cardiovascular risk factors and past clinical This is with the that antihypertensive treatment even if a high total risk to a the that in treatment is organ damage when is not use of organ damage assessment may thus to a more about the of treatment and thus favor its greater Some of the discussed in of subclinical organ damage for stratification of total cardiovascular risk are summarized in Box approach guidelines on the management of hypertension recommend the of antihypertensive in all patients with a SBP or more a or and to the treatment in order for the patients to be below these values. They further recommend drug treatment to be within a BP range, that is, a SBP between and and a between and in patients with diabetes or a of cardiovascular or renal disease, at values The 2007 ESH/ESC guidelines have accompanied these recommendations with information on the evidence are based and a critical of this has recently been by of the in the of further information provided by recent The of the ESH document is to the and the type of evidence on which these recommendations are and thus the and

BACKGROUND: Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting. METHODS: We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines. RESULTS: Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P<0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P=0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P<0.001). CONCLUSIONS: Oral capecitabine is an effective alternative to intravenous fluorouracil plus leucovorin in the adjuvant treatment of colon cancer.

AIMS/HYPOTHESIS: The Di@bet.es Study is the first national study in Spain to examine the prevalence of diabetes and impaired glucose regulation. METHODS: A population-based, cross-sectional, cluster sampling study was carried out, with target population being the entire Spanish population. Five thousand and seventy-two participants in 100 clusters (health centres or the equivalent in each region) were randomly selected with a probability proportional to population size. Participation rate was 55.8%. Study variables were a clinical and demographic structured survey, lifestyle survey, physical examination (weight, height, BMI, waist and hip circumference, blood pressure) and OGTT (75 g). RESULTS: Almost 30% of the study population had some carbohydrate disturbance. The overall prevalence of diabetes mellitus adjusted for age and sex was 13.8% (95% CI 12.8, 14.7%), of which about half had unknown diabetes: 6.0% (95% CI 5.4, 6.7%). The age- and sex-adjusted prevalence rates of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined IFG-IGT were 3.4% (95% CI 2.9, 4.0%), 9.2% (95% CI 8.2, 10.2%) and 2.2% (95% CI 1.7, 2.7%), respectively. The prevalence of diabetes and impaired glucose regulation increased significantly with age (p < 0.0001), and was higher in men than in women (p < 0.001). CONCLUSIONS/INTERPRETATION: The Di@bet.es Study shows, for the first time, the prevalence rates of diabetes and impaired glucose regulation in a representative sample of the Spanish population.

Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor-positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor-positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

The aim of the present study was to assess reproducibility and relative validity of a self-administered FFQ used in the PREDIMED Study, a clinical trial for primary prevention of CVD by Mediterranean diet in a population at high cardiovascular risk. The FFQ was administered twice (FFQ1 and FFQ2) to explore reproducibility at 1 year. Four 3 d dietary records (DR) were used as reference to explore validity; participants therefore recorded their food intake over 12 d in the course of 1 year. The degree of misclassification in the FFQ was also evaluated by a contingency table of quintiles comparing the information from the FFQ2 and the DR. A total of 158 men and women (aged 55-80 years) were asked not to modify their dietary habits during the study period. Reproducibility for food groups, energy and nutrient intake, explored by the Pearson correlation coefficient (r) ranged 0.50-0.82, and the intraclass correlation coefficient (ICC) ranged from 0.63 to 0.90. The FFQ2 tended to report higher energy and nutrient intake than the DR. The validity indices of the FFQ in relation to the DR for food groups and energy and nutrient intake ranged (r) from 0.24 to 0.72, while the range of the ICC was between 0.40 and 0.84. With regard to food groups, 68-83 % of individuals were in the same or adjacent quintile in both methods, a figure which decreased to 55-75 % for energy and nutrient intake. We concluded that FFQ measurements had good reproducibility and a relative validity similar to those of FFQ used in other prospective studies.

Many important decisions on hypertension management must currently be taken without the support of evidence&#13;\nfrom large randomized controlled trials. The following issues appear in urgent need to be approached by simply&#13;\ndesigned trials.&#13;\n(1) Should antihypertensive drugs be prescribed to all patients with grade 1 hypertension, even when total&#13;\ncardiovascular risk is relatively low or moderate? Because of the very low rate of cardiovascular events&#13;\nexpected in these patients, a placebo-controlled trial using intermediate endpoints such as signs of organ&#13;\ndamage of recognized prognostic importance would be feasible, ethical, and clinically relevant.&#13;\n(2) Should antihypertensive drugs be prescribed to the elderly with grade 1 hypertension, and should antihypertensive&#13;\ntreatment achieve a goal of below 140/90mmHg also in the elderly? These trials could make use&#13;\nof hard cardiovascular outcomes and could be placebo-controlled.&#13;\n(3) Should antihypertensive drug treatment be started in diabetic patients or in patients with previous cerebrovascular&#13;\nor cardiovascular disease when BP is still in the high normal level, and should BP goal be below 130/&#13;\n80mmHg in these patients? These issues can be approached by placebo-controlled trials because no trial&#13;\nevidence is still available on the benefit of lowering high normal BP or of achieving BP goals below 130/&#13;\n80mmHg.&#13;\n(4) What are the lowest safe BP values to achieve by treatment in different clinical conditions? This issue should&#13;\nbe approached by trials comparing more or less intense BP-lowering treatment strategies in patients with&#13;\ndifferent cardiovascular risk levels.&#13;\n(5) Are lifestyle measures known to reduce BP also capable of reducing morbidity and mortality in hypertension?&#13;\nA controlled randomized trial using intermediate endpoints (organ damage) would be feasible and desirable&#13;\nin patients with high normal BP or grade 1 hypertension.

This document summarizes the available evidence and provides recommendations on the use of home blood pressure monitoring in clinical practice and in research. It updates the previous recommendations on the same topic issued in year 2000. The main topics addressed include the methodology of home blood pressure monitoring, its diagnostic and therapeutic thresholds, its clinical applications in hypertension, with specific reference to special populations, and its applications in research. The final section deals with the problems related to the implementation of these recommendations in clinical practice.

Hypertension in children and adolescents has gained ground in cardiovascular medicine, thanks to the progress made in several areas of pathophysiological and clinical research. These guidelines represent a consensus among specialists involved in the detection and control of high blood pressure in children and adolescents. The guidelines synthesize a considerable amount of scientific data and clinical experience and represent best clinical wisdom upon which physicians, nurses and families should base their decisions. They call attention to the burden of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers, to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents.

BACKGROUND AND PURPOSE: Headache disorders are very common, but their monetary costs in Europe are unknown. We performed the first comprehensive estimation of how economic resources are lost to headache in Europe. METHODS: From November 2008 to August 2009, a cross-sectional survey was conducted in eight countries representing 55% of the adult EU population. Participation rates varied between 11% and 59%. In total, 8412 questionnaires contributed to this analysis. Using bottom-up methodology, we estimated direct (medications, outpatient health care, hospitalization and investigations) and indirect (work absenteeism and reduced productivity at work) annual per-person costs. Prevalence data, simultaneously collected and, for migraine, also derived from a systematic review, were used to impute national costs. RESULTS: Mean per-person annual costs were €1222 for migraine (95% CI 1055-1389; indirect costs 93%), €303 for tension-type headache (TTH, 95% CI 230-376; indirect costs 92%), €3561 for medication-overuse headache (MOH, 95% CI 2487-4635; indirect costs 92%), and €253 for other headaches (95% CI 99-407; indirect costs 82%). In the EU, the total annual cost of headache amongst adults aged 18-65 years was calculated, according to our prevalence estimates, at €173 billion, apportioned to migraine (€111 billion; 64%), TTH (€21 billion; 12%), MOH (€37 billion; 21%) and other headaches (€3 billion; 2%). Using the 15% systematic review prevalence of migraine, calculated costs were somewhat lower (migraine €50 billion, all headache €112 billion annually). CONCLUSIONS: Headache disorders are prominent health-related drivers of immense economic losses for the EU. This has immediate implications for healthcare policy. Health care for headache can be both improved and cost saving.

BACKGROUND: Patients with type 1 diabetes mellitus and microalbuminuria often have elevated blood pressure while they are asleep, but it is not known whether the elevation develops concomitantly with microalbuminuria or precedes it. METHODS: We monitored 75 adolescents and young adults who had had type 1 diabetes with normal urinary albumin excretion and blood pressure for more than five years. Ambulatory blood-pressure monitoring was used to assess blood pressure at the initial evaluation and about two years later, at which time all subjects had normal urinary albumin excretion. Subsequently, subjects were monitored for the development of microalbuminuria. RESULTS: Microalbuminuria developed in 14 subjects, whereas the other 61 continued to have normal urinary albumin excretion. The mean (+/-SD) systolic pressure during sleep increased significantly in the subjects who ultimately had microalbuminuria (from 109.9+/-11.3 to 114.9+/-11.7 mm Hg, P=0.01) but not in the subjects with normal albumin excretion (from 106.0+/-8.8 to 106.4+/-14.8 mm Hg). The risk of progression to microalbuminuria was examined in relation to the ratio of systolic pressure during sleep to systolic pressure in the daytime. A ratio of 0.9 or lower, used to define a normal fall in nocturnal pressure, had a negative predictive value of 91 percent for the development of microalbuminuria. Moreover, the risk of microalbuminuria was 70 percent lower (95 percent confidence interval, 44 to 110 percent) in subjects with a ratio of 0.9 or less than in those with a ratio higher than 0.9 (P=0.01). CONCLUSIONS: In persons with type 1 diabetes, an increase in systolic blood pressure during sleep precedes the development of microalbuminuria. In those whose blood pressure during sleep decreases normally, the progression from normal albumin excretion to microalbuminuria appears to be less likely.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by the Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. A disclosure of their potential conflict of interest is reported on the websites of the ESH and the ESC.

This retrospective longitudinal study was undertaken in order to determine the incidence and reproductive impact of uterine malformations on women desiring to conceive during their reproductive years. A total of 3181 patients in whom the morphology of the uterus was ascertained by hysterosalpingography (HSG) and laparoscopy/laparotomy during the years 1980-1995 was included in the study. The population analysed included fertile, infertile and sterile patients. The overall frequency of uterine malformations was 4.0%. Infertile patients (6.3%) had a significantly (P < 0.05) higher incidence of Müllerian anomalies, in comparison with fertile (3.8%) and sterile (2.4%) women. Septate (33.6%) and arcuate (32.8%) uteri were the most common malformations observed. Each malformation was individually analysed in fertile and infertile patients, in order to ascertain its actual reproductive impact. The performance of the unicornuate and didelphys uteri was similar with a chance of having a living child of 37-40%. The reproductive potential of the bicornuate uterus showed a live birth rate of 62.5% and the septate uterus showed a live birth rate of 62%. In all these abnormalities, early miscarriages (25-38%) and preterm deliveries (25-47%) were quite common. The arcuate uterus presented a live birth rate of 82.7%. It is concluded that uterine anomalies are relatively frequent in fertile women, and more frequent in infertile patients. Nevertheless, fertile patients with normal reproductive performance do exist, and Müllerian defects can permit an absolutely normal obstetric outcome. The reproductive performance of the unicornuate and didelphys uteri was poor, while that of the septate and bicornuate uteri was better than expected. The arcuate uterus had no impact on reproduction.

Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression.

IMPORTANCE: There are inconsistencies in concept, criteria, practice, and documentation of brain death/death by neurologic criteria (BD/DNC) both internationally and within countries. OBJECTIVE: To formulate a consensus statement of recommendations on determination of BD/DNC based on review of the literature and expert opinion of a large multidisciplinary, international panel. PROCESS: Relevant international professional societies were recruited to develop recommendations regarding determination of BD/DNC. Literature searches of the Cochrane, Embase, and MEDLINE databases included January 1, 1992, through April 2020 identified pertinent articles for review. Because of the lack of high-quality data from randomized clinical trials or large observational studies, recommendations were formulated based on consensus of contributors and medical societies that represented relevant disciplines, including critical care, neurology, and neurosurgery. EVIDENCE SYNTHESIS: Based on review of the literature and consensus from a large multidisciplinary, international panel, minimum clinical criteria needed to determine BD/DNC in various circumstances were developed. RECOMMENDATIONS: Prior to evaluating a patient for BD/DNC, the patient should have an established neurologic diagnosis that can lead to the complete and irreversible loss of all brain function, and conditions that may confound the clinical examination and diseases that may mimic BD/DNC should be excluded. Determination of BD/DNC can be done with a clinical examination that demonstrates coma, brainstem areflexia, and apnea. This is seen when (1) there is no evidence of arousal or awareness to maximal external stimulation, including noxious visual, auditory, and tactile stimulation; (2) pupils are fixed in a midsize or dilated position and are nonreactive to light; (3) corneal, oculocephalic, and oculovestibular reflexes are absent; (4) there is no facial movement to noxious stimulation; (5) the gag reflex is absent to bilateral posterior pharyngeal stimulation; (6) the cough reflex is absent to deep tracheal suctioning; (7) there is no brain-mediated motor response to noxious stimulation of the limbs; and (8) spontaneous respirations are not observed when apnea test targets reach pH <7.30 and Paco2 ≥60 mm Hg. If the clinical examination cannot be completed, ancillary testing may be considered with blood flow studies or electrophysiologic testing. Special consideration is needed for children, for persons receiving extracorporeal membrane oxygenation, and for those receiving therapeutic hypothermia, as well as for factors such as religious, societal, and cultural perspectives; legal requirements; and resource availability. CONCLUSIONS AND RELEVANCE: This report provides recommendations for the minimum clinical standards for determination of brain death/death by neurologic criteria in adults and children with clear guidance for various clinical circumstances. The recommendations have widespread international society endorsement and can serve to guide professional societies and countries in the revision or development of protocols and procedures for determination of brain death/death by neurologic criteria, leading to greater consistency within and between countries.

BACKGROUND: Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability. METHODS: We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens. RESULTS: During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment. CONCLUSIONS: In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established.

BACKGROUND: Chronic graft-versus-host disease (GVHD) is the leading cause of later illness and death after allogeneic hematopoietic stem-cell transplantation. We hypothesized that the inclusion of antihuman T-lymphocyte immune globulin (ATG) in a myeloablative conditioning regimen for patients with acute leukemia would result in a significant reduction in chronic GVHD 2 years after allogeneic peripheral-blood stem-cell transplantation from an HLA-identical sibling. METHODS: We conducted a prospective, multicenter, open-label, randomized phase 3 study of ATG as part of a conditioning regimen. A total of 168 patients were enrolled at 27 centers. Patients were randomly assigned in a 1:1 ratio to receive ATG or not receive ATG, with stratification according to center and risk of disease. RESULTS: After a median follow-up of 24 months, the cumulative incidence of chronic GVHD was 32.2% (95% confidence interval [CI], 22.1 to 46.7) in the ATG group and 68.7% (95% CI, 58.4 to 80.7) in the non-ATG group (P<0.001). The rate of 2-year relapse-free survival was similar in the ATG group and the non-ATG group (59.4% [95% CI, 47.8 to 69.2] and 64.6% [95% CI, 50.9 to 75.3], respectively; P=0.21), as was the rate of overall survival (74.1% [95% CI, 62.7 to 82.5] and 77.9% [95% CI, 66.1 to 86.1], respectively; P=0.46). There were no significant between-group differences in the rates of relapse, infectious complications, acute GVHD, or adverse events. The rate of a composite end point of chronic GVHD-free and relapse-free survival at 2 years was significantly higher in the ATG group than in the non-ATG group (36.6% vs. 16.8%, P=0.005). CONCLUSIONS: The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).

CONTEXT: Supplemental perioperative oxygen has been variously reported to halve or double the risk of surgical wound infection. OBJECTIVE: To test the hypothesis that supplemental oxygen reduces infection risk in patients following colorectal surgery. DESIGN, SETTING, AND PATIENTS: A double-blind, randomized controlled trial of 300 patients aged 18 to 80 years who underwent elective colorectal surgery in 14 Spanish hospitals from March 1, 2003, to October 31, 2004. Wound infections were diagnosed by blinded investigators using Centers for Disease Control and Prevention criteria. Baseline patient characteristics, anesthetic treatment, and potential confounding factors were recorded. INTERVENTIONS: Patients were randomly assigned to either 30% or 80% fraction of inspired oxygen (FIO2) intraoperatively and for 6 hours after surgery. Anesthetic treatment and antibiotic administration were standardized. MAIN OUTCOME MEASURES: Any surgical site infection (SSI); secondary outcomes included return of bowel function and ability to tolerate solid food, ambulation, suture removal, and duration of hospitalization. RESULTS: A total of 143 patients received 30% perioperative oxygen and 148 received 80% perioperative oxygen. Surgical site infection occurred in 35 patients (24.4%) administered 30% FIO2 and in 22 patients (14.9%) administered 80% FIO2 (P=.04). The risk of SSI was 39% lower in the 80% FIO2 group (relative risk [RR], 0.61; 95% confidence interval [CI], 0.38-0.98) vs the 30% FIO2 group. After adjustment for important covariates, the RR of infection in patients administered supplemental oxygen was 0.46 (95% CI, 0.22-0.95; P = .04). None of the secondary outcomes varied significantly between the 2 treatment groups. CONCLUSIONS: Patients receiving supplemental inspired oxygen had a significant reduction in the risk of wound infection. Supplemental oxygen appears to be an effective intervention to reduce SSI in patients undergoing colon or rectal surgery. Trial Registration ClinicalTrials.gov Identifier: NCT00235456.