Manchester Royal Infirmary

DOCUMENT REVIEWERS: Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Slavomira Filipova (Slovak Republic), Anthony Heagerty (UK), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Sang Hyun Ihm (South Korea), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China).

Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons: 1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures. 2. A number of treatment options exist for symptomatic diabetic neuropathy. 3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet. 4. Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life. Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the diabetic neuropathies. View this table: Table 1 Classification for diabetic neuropathies Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of diabetic neuropathy is also critical in clinical practice, as it may detect the earliest stages of neuropathy, enabling early intervention. Although screening for rarer atypical forms of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms. This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion …

Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.

The majority of dermal wounds are colonized with aerobic and anaerobic microorganisms that originate predominantly from mucosal surfaces such as those of the oral cavity and gut. The role and significance of microorganisms in wound healing has been debated for many years. While some experts consider the microbial density to be critical in predicting wound healing and infection, others consider the types of microorganisms to be of greater importance. However, these and other factors such as microbial synergy, the host immune response, and the quality of tissue must be considered collectively in assessing the probability of infection. Debate also exists regarding the value of wound sampling, the types of wounds that should be sampled, and the sampling technique required to generate the most meaningful data. In the laboratory, consideration must be given to the relevance of culturing polymicrobial specimens, the value in identifying one or more microorganisms, and the microorganisms that should be assayed for antibiotic susceptibility. Although appropriate systemic antibiotics are essential for the treatment of deteriorating, clinically infected wounds, debate exists regarding the relevance and use of antibiotics (systemic or topical) and antiseptics (topical) in the treatment of nonhealing wounds that have no clinical signs of infection. In providing a detailed analysis of wound microbiology, together with current opinion and controversies regarding wound assessment and treatment, this review has attempted to capture and address microbiological aspects that are critical to the successful management of microorganisms in wounds.

The diabetic neuropathies are heterogeneous, affecting different parts of the nervous system that present with diverse clinical manifestations. They may be focal or diffuse. Most common among the neuropathies are chronic sensorimotor distal symmetric polyneuropathy (DPN) and the autonomic neuropathies. DPN is a diagnosis of exclusion. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons. 1 ) Nondiabetic neuropathies may be present in patients with diabetes. 2 ) A number of treatment options exist for symptomatic diabetic neuropathy. 3 ) Up to 50% of DPN may be asymptomatic, and patients are at risk of insensate injury to their feet. As >80% of amputations follow a foot ulcer or injury, early recognition of at-risk individuals, provision of education, and appropriate foot care may result in a reduced incidence of ulceration and consequently amputation. 4 ) Autonomic neuropathy may involve every system in the body. 5 ) Autonomic neuropathy causes substantial morbidity and increased mortality, particularly if cardiovascular autonomic neuropathy (CAN) is present. Treatment should be directed at underlying pathogenesis. Effective symptomatic treatments are available for the manifestations of DPN and autonomic neuropathy. This statement is based on two recent technical reviews (1,2), to which the reader is referred for detailed discussion and relevant references to the literature. An internationally agreed simple definition of DPN for clinical practice is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” (3). However, the diagnosis cannot be made without a careful clinical examination of the lower limbs, as absence of symptoms should never be assumed to indicate an absence of signs. This definition conveys the important message that not all patients with peripheral nerve dysfunction have a neuropathy caused by diabetes. Confirmation can be established with …

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: Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. METHODS: Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. FINDINGS: We identified 203 patients with encephalitis. Median age was 30 years (range 0-87). 86 patients (42%, 95% CI 35-49) had infectious causes, including 38 (19%, 14-25) herpes simplex virus, ten (5%, 2-9) varicella zoster virus, and ten (5%, 2-9) Mycobacterium tuberculosis; 75 (37%, 30-44) had unknown causes. 42 patients (21%, 15-27) had acute immune-mediated encephalitis. 24 patients (12%, 8-17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7-65) and varicella zoster virus (two patients; 20%, 2-56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups-nine (56%, 30-80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR = 3·44). INTERPRETATION: Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. FUNDING: The Policy Research Programme, Department of Health, UK.

Clinical and neuropathological criteria forfrontotemporal dementia * Early loss of insight into the fact that the altered condition is due to a pathological change of own mental state.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

OBJECTIVE: To determine the frequency and constellations of anatomic, pathophysiologic, and environmental factors involved in the development of incident diabetic foot ulcers in patients with diabetes and no history of foot ulcers from Manchester, U.K., and Seattle, Washington, research settings. RESEARCH DESIGN AND METHODS: The Rothman model of causation was applied to the diabetic foot ulcer condition. The presence of structural deformities, peripheral neuropathy, ischemia, infection, edema, and callus formation was determined for diabetic individuals with incident foot ulcers in Manchester and Seattle. Demographic, health, diabetes, and ulcer data were ascertained for each patient. A multidisciplinary group of foot specialists blinded to patient identity independently reviewed detailed abstracts to determine component and sufficient causes present and contributing to the development of each patient's foot ulcer. A modified Delphi process assisted the group in reaching consensus on component causes for each patient. Estimates of the proportion of ulcers that could be ascribed to each component cause were computed. RESULTS: From among 92 study patients from Manchester and 56 from Seattle, 32 unique causal pathways were identified. A critical triad (neuropathy, minor foot trauma, foot deformity) was present in > 63% of patient's causal pathways to foot ulcers. The components edema and ischemia contributed to the development of 37 and 35% of foot ulcers, respectively. Callus formation was associated with ulcer development in 30% of the pathways. Two unitary causes of ulcer were identified, with trauma and edema accounting for 6 and < 1% of ulcers, respectively. The majority of the lesions were on the plantar toes, forefoot, and midfoot. CONCLUSIONS: The most frequent component causes for lower-extremity ulcers were trauma, neuropathy, and deformity, which were present in a majority of patients. Clinicians are encouraged to use proven strategies to prevent and decrease the impact of modifiable conditions leading to foot ulcers in patients with diabetes.

AIMS: To determine the incidence of, and clinically relevant risk factors for, new foot ulceration in a large cohort of diabetic patients in the community healthcare setting. METHODS: Diabetic patients (n = 9710) underwent foot screening in six districts of North-west England in various healthcare settings. All were assessed at baseline for demographic information, medical and social history, neuropathy symptom score, neuropathy disability score, cutaneous pressure perception (insensitivity to the 10 g monofilament), foot deformities, and peripheral pulses. Two years later, patients were followed up via postal questionnaire to determine the incidence of new foot ulcers. Cox's proportional hazards regression analysis was used to determine the independent, relative risk of baseline variables for new foot ulceration. RESULTS: New foot ulcers occurred in 291/6613 patients who completed and returned their 2-year follow-up questionnaire (2.2% average annual incidence). The following factors were independently related to new foot ulcer risk: ulcer present at baseline (relative risk (95% confidence interval)) 5.32 (3.71-7.64), past history of ulcer 3.05 (2.16-4.31), abnormal neuropathy disability score (> or = 6/10) 2.32 (1.61-3.35), any previous podiatry attendance 2.19 (1.50-3.20), insensitivity to the 10 g monofilament 1.80 (1.36-2.39), reduced pulses 1.80 (1.40-2.32), foot deformities 1.57 (1.22-2.02), abnormal ankle reflexes 1.55 (1.01-2.36) and age 0.99 (0.98-1.00). CONCLUSIONS: More than 2% of community-based diabetic patients develop new foot ulcers each year. The neuropathy disability score, 10 g monofilament and palpation of foot pulses are recommended as screening tools in general practice.

, 12 months behind schedule and 2 years after

Oxidative modification of low-density lipoprotein (LDL) enhances its uptake by macrophages in tissue culture and in vivo may underly the formation of arterial fatty streaks, the progenitors of atheroma. We investigated the possible protection which high-density lipoprotein (HDL) affords against LDL oxidation. The formation of lipoperoxides and thiobarbituric acid reactive substances when LDL was incubated with copper ions was significantly decreased by HDL. The enzyme, paraoxonase (E.C. 3.1.8.1), purified from human HDL, had a similar effect and thus may be the component of HDL responsible for decreasing the accumulation of lipid peroxidation products.

BACKGROUND: The pancreatic lesions of cystic fibrosis develop in utero and closely resemble those of chronic pancreatitis. Therefore, we hypothesized that mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene may be more common than expected among patients with chronic pancreatitis. METHODS: We studied 134 consecutive patients with chronic pancreatitis (alcohol-related disease in 71, hyperparathyroidism in 2, hypertriglyceridemia in 1, and idiopathic disease in 60). We examined DNA for 22 mutations of the CFTR gene that together account for 95 percent of all mutations in patients with cystic fibrosis in the northwest of England. We also determined the length of the noncoding sequence of thymidines in intron 8, since the shorter the sequence, the lower the proportion of normal CFTR messenger RNA. RESULTS: The 94 male and 40 female patients ranged in age from 16 to 86 years. None had a mutation on both copies of the CFTR gene. Eighteen patients (13.4 percent), including 12 without alcoholism, had a CFTR mutation on one chromosome, as compared with a frequency of 5.3 percent among 600 local unrelated partners of persons with a family history of cystic fibrosis (P<0.001). A total of 10.4 percent of the patients had the 5T allele in intron 8 (14 of 134), which is twice the expected frequency (P=0.008). Four patients were heterozygous for both a CFTR mutation and the 5T allele. Patients with a CFTR mutation were younger than those with no mutations (P=0.03). None had the combination of sinopulmonary disease, high sweat electrolyte concentrations, and low nasal potential-difference values that are diagnostic of cystic fibrosis. CONCLUSIONS: Mutations of the CFTR gene and the 5T genotype are associated with chronic pancreatitis.

OBJECTIVE: To determine associations of gestational diabetes mellitus (GDM) and obesity with adverse pregnancy outcomes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. RESEARCH DESIGN AND METHODS: Participants underwent a 75-g oral glucose tolerance test (OGTT) between 24 and 32 weeks. GDM was diagnosed post hoc using International Association of Diabetes and Pregnancy Study Groups criteria. Neonatal anthropometrics and cord serum C-peptide were measured. Adverse pregnancy outcomes included birth weight, newborn percent body fat, and cord C-peptide >90th percentiles, primary cesarean delivery, preeclampsia, and shoulder dystocia/birth injury. BMI was determined at the OGTT. Multiple logistic regression was used to examine associations of GDM and obesity with outcomes. RESULTS: Mean maternal BMI was 27.7, 13.7% were obese (BMI ≥33.0 kg/m(2)), and GDM was diagnosed in 16.1%. Relative to non-GDM and nonobese women, odds ratio for birth weight >90th percentile for GDM alone was 2.19 (1.93-2.47), for obesity alone 1.73 (1.50-2.00), and for both GDM and obesity 3.62 (3.04-4.32). Results for primary cesarean delivery and preeclampsia and for cord C-peptide and newborn percent body fat >90th percentiles were similar. Odds for birth weight >90th percentile were progressively greater with both higher OGTT glucose and higher maternal BMI. There was a 339-g difference in birth weight for babies of obese GDM women, compared with babies of normal/underweight women (64.2% of all women) with normal glucose based on a composite OGTT measure of fasting plasma glucose and 1- and 2-h plasma glucose values (61.8% of all women). CONCLUSIONS: Both maternal GDM and obesity are independently associated with adverse pregnancy outcomes. Their combination has a greater impact than either one alone.

Presents case reports of a 67‐yr‐old man and 2 women (aged 60 and 66 yrs) with primary cerebral atrophy in whom progressive breakdown in language and visual perception are attributed to loss of semantic information. This form of dementia is distinct from that of Alzheimer′s disease and is assumed to represent a form of circumscribed cerebral atrophy with emphasis of pathology in temporal rather than frontal regions of the brain.

BACKGROUND: An acceptable, standardised outcome measure to assess efficacy and effectiveness is needed across multiple disciplines offering psychological therapies. AIMS: To present psychometric data on reliability, validity and sensitivity to change for the CORE-OM (Clinical Outcomes in Routine Evaluation--Outcome Measure). METHOD: A 34-item self-report instrument was-developed, with domains of subjective well-being, symptoms, function and risk. Analysis includes internal reliability, test-retest reliability, socio-demographic differences, exploratory principal-component analysis, correlations with other instruments, differences between clinical and non-clinical samples and assessment of change within a clinical group. RESULTS: Internal and test-retest reliability were good (0.75-0.95), as was convergent validity with seven other instruments, with large differences between clinical and non-clinical samples and good sensitivity to change. CONCLUSIONS: The CORE-OM is a reliable and valid instrument with good sensitivity to change. It is acceptable in a wide range of practice settings.

ropathic pain (7–10), and this and other putative mechanisms will be discussed. The clinical features, diagnosis, and management of the focal and multifocal neuropathies will be described. A major portion of this review will discuss the clinical features, assessment, and management of the patient with the most common form of DN, diabetic distal sensory polyneuropathy (DPN). The late sequelae of DPN and their prevention will also be described. Finally, practical guidelines for the screening of DPN in clinical practice will be provided. For further details on this topic, please refer to recent reviews (11– 18).

CONTEXT: The cause of declining testosterone (T) in aging men and their relationships with risk factors are unclear. OBJECTIVE: The objective of the study was to investigate the relationships between lifestyle and health with reproductive hormones in aging men. DESIGN: This was a baseline cross-sectional survey on 3200 community-dwelling men aged 40-79 yr from a prospective cohort study in eight European countries. RESULTS: Four predictors were associated with distinct modes of altered function: 1) age: lower free T (FT; -3.12 pmol/liter.yr, P < 0.001) with raised LH, suggesting impaired testicular function; 2) obesity: lower total T (TT; -2.32 nmol/liter) and FT (-17.60 pmol/liter) for body mass index (BMI; > or = 25 to < 30 kg/m(2)) and lower TT (-5.09 nmol/liter) and FT (-53.72 pmol/liter) for BMI 30 kg/m(2) or greater (P < 0.001-0.01, referent: BMI < 25 kg/m(2)) with unchanged/decreased LH, indicating hypothalamus/pituitary dysfunction; 3) comorbidity: lower TT (-0.80 nmol/liter, P < 0.01) with unchanged LH in younger men but higher LH in older men; and 4) smoking: higher SHBG (5.96 nmol/liter, P < 0.001) and LH (0.77 U/liter, P < 0.01) with increased TT (1.31 nmol/liter, P < 0.001) but not FT, compatible with a resetting of T-LH-negative feedback due to elevated SHBG. CONCLUSIONS: Complex multiple alterations in the hypothalamic-pituitary-testicular axis function exist in aging men against a background of progressive age-related testicular impairment. These changes are differentially linked to specific risk factors. Some risk factors operate independently of but others interact with age, in contributing to the T decline. These potentially modifiable risk factors suggest possible preventative measures to maintain T during aging in men.

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.