Gender differences in management and outcome in non-ST-elevation acute coronary syndrome

Objective

To study gender differences in management and outcome in patients with non‐ST‐elevation acute coronary syndrome.

Design, setting and patients

Cohort study of 53 781 consecutive patients (37% women) from the Register of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS‐HIA), with a diagnosis of either unstable angina pectoris or non‐ST‐elevation myocardial infarction. All patients were admitted to intensive coronary care units in Sweden, between 1998 and 2002, and followed for 1 year.

Main outcome measures

Treatment intensity and in‐hospital, 30‐day and 1‐year mortality.

Results

Women were older (73 vs 69 years, p<0.001) and more likely to have a history of hypertension and diabetes, but less likely to have a history of myocardial infarction or revascularisation. After adjustment, there were no major differences in acute pharmacological treatment or prophylactic medication at discharge.Revascularisation was, however, even after adjustment, performed more often in men (OR 1.15; 95% CI, 1.09 to 1.21). After adjustment, there was no significant difference in in‐hospital (OR 1.03; 95% CI, 0.94 to 1.13) or 30‐days (OR 1.07; 95% CI, 0.99 to 1.15) mortality, but at 1 year being male was associated with higher mortality (OR 1.12; 95% CI, 1.06 to 1.19).

Conclusion

Although women are somewhat less intensively treated, especially regarding invasive procedures, after adjustment for differences in background characteristics, they have better long‐term outcomes than men.Since the beginning of the 1990s there have been numerous studies on gender differences in management of acute coronary syndromes (ACS). Many earlier studies,^{1,2,3,4,5,6,7,8} but not all,⁹ found that women were treated less intensively in the acute phase. In some of the studies, after adjustment for age, comorbidity and severity of the disease, most of the differences disappeared.^6,7 There is also conflicting evidence on gender differences in evidence‐based treatment at discharge.^{1,3,5,6,8,10,11}After acute myocardial infarction (AMI), a higher short‐term mortality in women is documented in several studies.^{2,5,6,7,12,13,14} After adjustment for age and comorbidity some difference has usually,^2,5,12,13 but not always,^11,14 remained. On the other hand, most studies assessing long‐term outcome have found no difference between the genders, or a better outcome in women, at least after adjustment.^7,10,13,14 Earlier studies focusing on gender differences in outcome after an acute coronary syndrome have usually studied patients with AMI, including both ST‐elevation myocardial infarction and non‐ST‐elevation myocardial infarction (NSTEMI).^{2,5,6,7,12,13,14} However, the pathophysiology and initial management differs between these two conditions,¹⁵ as does outcome according to gender.^11,16 In patients with NSTEMI or unstable angina pectoris (UAP), women seem to have an equal or better outcome, after adjustment for age and comorbidity.^{1,4,8,11,16,17} Studies on differences between genders, in treatment and outcome, in real life, contemporary, non‐ST‐elevation acute coronary syndrome (NSTE ACS) populations, large enough to make necessary adjustments for confounders, are lacking.The aim of this study was to assess gender differences in background characteristics, management and outcome in a real‐life intensive coronary care unit (ICCU) population, with NSTE ACS.     

Improved but still high short- and long-term mortality rates after myocardial infarction in patients with diabetes mellitus: a time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission

Objective

The aim of the study was to compare time‐trends in mortality rates and treatment patterns between patients with and without diabetes based on the Swedish register of coronary care (Register of Information and Knowledge about Swedish Heart Intensive Care Admission [RIKS‐HIA]).

Methods

Post myocardial infarction mortality rate is high in diabetic patients, who seem to receive less evidence‐based treatment. Mortality rates and treatment in 1995–1998 and 1999–2002 were studied in 70 882 patients (age <80 years), 14 873 of whom had diabetes (the first registry recorded acute myocardial infarction), following adjustments for differences in clinical and other parameters.

Results

One‐year mortality rates decreased from 1995 to 2002 from 16.6% to 12.1% in patients without diabetes and from 29.7% to 19.7%, respectively, in those with diabetes. Patients with diabetes had an adjusted relative 1‐year mortality risk of 1.44 (95% CI 1.36 to 1.52) in 1995–1998 and 1.31 (95% CI 1.24 to 1.38) in 1999–2002. Despite improved pre‐admission and in‐hospital treatment, diabetic patients were less often offered acute reperfusion therapy (adjusted OR 0.85, 95% CI 0.80 to 0.90), acute revascularisation (adjusted OR 0.78, 95% CI 0.69 to 0.87) or revascularisation within 14 days (OR 0.80, 95% CI 0.75 to 0.85), aspirin (OR 0.90, 95% CI 0.84 to 0.98) and lipid‐lowering treatment at discharge (OR 0.81, 95% CI 0.77 to 0.86).

Conclusion

Despite a clear improvement in the treatment and myocardial infarction survival rate in patients with diabetes, mortality rate remains higher than in patients without diabetes. Part of the excess mortality may be explained by co‐morbidities and diabetes itself, but a lack of application of evidence‐based treatment also contributes, underlining the importance of the improved management of diabetic patients.Patients with diabetes have higher short‐ and long‐term mortality rates after acute myocardial infarction (MI) than those without diabetes.^1,2,3,4 This pattern has remained even after the introduction of modern therapeutic principles.^5,6,7 According to US mortality rate trends diabetic patients have not experienced a similar mortality rate reduction as that seen in non‐diabetic patients.^8,9,10 Less use of evidence‐based treatment has been suggested as an important explanation.^{4,10,11,12,13,14} The systematic use of such therapy should decrease hospital mortality rate in diabetic patients so that it approaches that in those without diabetes.¹⁵The Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS‐HIA), covering almost all Swedish patients with MI, offers detailed information on treatment patterns and prognosis in unselected patients with and without diabetes. The aim of this study is to analyse time trends in treatment patterns and prognosis in order to see whether management has improved.     

Serial long-term evaluation of neointimal stent coverage and thrombus after sirolimus-eluting stent implantation by use of coronary angioscopy

Objective

Progression of neointimal stent coverage (NSC) and changes in thrombus were evaluated serially by coronary angioscopy for up to 2 years after sirolimus‐eluting stent (SES) implantation.

Design

Serial angioscopic observations were performed in 20 segments of 20 patients at baseline, and at 6 months and 2 years after SES implantation. NSC was classified as follows: 0, uncovered struts; 1, visible struts through thin neointima; or 2, no visible struts. In each patient, maximum and minimum NSC was evaluated. Existence of thrombus was also examined.

Results

The maximum NSC increased from 6 months to 2 years (1.2 (0.4) vs 1.8 (0.4), respectively, p = 0.005), while the minimum NSC did not change (0.7 (0.5) vs 0.8 (0.4), respectively, p = 0.25). The prevalence of patients with uncovered struts did not decrease from 6 months to 2 years (35% vs 20%, respectively, p = 0.29). Although there were no thrombus‐related adverse events, new thrombus formation was found in one patient (5%) at the 6‐month, and in four patients (20%) at the 2‐year follow‐up evaluations. Frequencies of thrombus inside the SES at baseline, 6 months and 2 years did not differ one from another (40%, 40% and 30%, respectively; p = NS).

Conclusions

Neointimal growth inside the SES progressed heterogeneously. Uncovered struts persisted in 20% of the patients for up to 2 years and subclinical thrombus formation was not a rare phenomenon.Recently, occurrence of late stent thrombosis (LST) after drug‐eluting stent implantation has became a major clinical concern.^1,2,3 A long‐term follow‐up study demonstrated that LST occurs at a constant rate of 0.6% a year for up to 3 years after drug‐eluting stent implantation.³ Pathological investigation shows that delayed arterial healing, characterised by an incomplete endothelialisation and persistence of fibrin, has a key role in the occurrence of LST.^4,5 Moreover, a powerful predictor of LST is the existence of uncovered struts without endothelialisation.⁵ We therefore proposed the hypothesis that the uncovered struts of a sirolimus‐eluting stent (SES) remain for an extended period of time.Coronary angioscopy provides a direct visualisation of the lumen and detailed information on the condition of neointimal stent coverage (NSC) and thrombus.^6,7,8 This imaging modality has the advantage of allowing the identification of an intracoronary thrombus.⁸ Presently, no long‐term angioscopic follow‐up data after SES implantation are available. We herein present our findings as derived from angioscopic examination, focusing on the long‐term serial changes in the NSC, especially the uncovered stent struts, and the presence of thrombus inside the SES.     

Serial long-term evaluation of neointimal stent coverage and thrombus after sirolimus-eluting stent implantation by use of coronary angioscopy

Objective

Progression of neointimal stent coverage (NSC) and changes in thrombus were evaluated serially by coronary angioscopy for up to 2 years after sirolimus‐eluting stent (SES) implantation.

Methods

Serial angioscopic observations were performed in 20 segments of 20 patients at baseline, at 6 months and at 2 years after SES implantation. NSC was classified as follows: 0, uncovered struts; 1, visible struts through thin neointima; or 2, no visible struts. In each patient, maximum and minimum NSC was evaluated. Existence of thrombus was also examined.

Results

The maximum NSC increased from 6 months to 2 years (mean (SD) 1.2 (0.4) vs 1.8 (0.4), respectively, p = 0.005), while the minimum NSC did not change (0.7 (0.5) vs 0.8 (0.4), respectively, p = 0.25). The prevalence of patients with uncovered struts did not decrease from 6 months to 2 years (35% vs 20%, respectively, p = 0.29). Although there were no thrombus‐related adverse events, new thrombus formation was found in 5% of 6‐month, and in 20% of 2‐year follow‐up evaluations. The prevalence of thrombus inside the SES at baseline, 6 months and 2 years was similar (40%, 40% and 30%, respectively; p = NS).

Conclusions

Neointimal growth inside the SES progressed heterogeneously. Uncovered struts persisted in 20% of the patients for up to 2 years and subclinical thrombus formation was not uncommon.Recently, occurrence of late stent thrombosis (LST) after drug‐eluting stent implantation has became a major clinical concern.^1,2,3 A long‐term follow‐up study demonstrated that LST occurs at a constant rate of 0.6% a year for up to 3 years after drug‐eluting stent implantation.³ Pathological investigation showed that delayed arterial healing, characterised by an incomplete endothelialisation and persistence of fibrin, has a key role in the occurrence of LST.^4,5 Moreover, a powerful predictor of LST is the existence of uncovered struts without endothelialisation.⁵ We therefore suggested that the uncovered struts of a sirolimus‐eluting stent (SES) remain for an extended period of time.Coronary angioscopy provides direct visualisation of the lumen and detailed information on the condition of neointimal stent coverage (NSC) and thrombus.^6,7,8 This imaging modality has the advantage of allowing the identification of an intracoronary thrombus.⁸ Presently, no long‐term angioscopic follow‐up data after SES implantation are available. Here we present our findings from angioscopic examination, focusing on the long‐term serial changes in the NSC, especially the uncovered stent struts, and the presence of thrombus inside the SES.     

Comparison of in vitro-specific blood tests with tuberculin skin test for diagnosis of latent tuberculosis before anti-TNF therapy

Introduction

Latent tuberculosis infection (LTBI) is detected with the tuberculin skin test (TST) before anti‐TNF therapy. We aimed to investigate in vitro blood assays with TB‐specific antigens (CFP‐10, ESAT‐6), in immune‐mediated inflammatory diseases (IMID) for LTBI screening.

Patients and methods

Sixty‐eight IMID patients with (n = 35) or without (n = 33) LTBI according to clinico‐radiographic findings or TST results (10 mm cutoff value) underwent cell proliferation assessed by thymidine incorporation and PKH‐26 dilution assays, and IFNγ‐release enzyme‐linked immunosorbent spot (ELISPOT) assays with TB‐specific antigens.

Results

In vitro blood assays gave higher positive results in patients with LTBI than without (p<0.05), with some variations between tests. Among the 13 patients with LTBI diagnosed independently of TST results, 5 had a negative TST (38.5%) and only 2 a negative blood assays result (15.4%). The 5 LTBI patients with negative TST results all had positive blood assays results. Ten patients without LTBI but with intermediate TST results (6–10 mm) had no different result than patients with TST result ⩽5 mm (p>0.3) and lower results than those with LTBI (p<0.05) on CFP‐10+ESAT‐6 ELISPOT and CFP‐10 proliferation assays.

Conclusion

Anti‐TB blood assays are beneficial for LTBI diagnosis in IMID. Compared with TST, they show a better sensitivity, as seen by positive results in 5 patients with certain LTBI and negative TST, and better specificity, as seen by negative results in most patients with intermediate TST as the only criteria of LTBI. In the absence of clinico‐radiographic findings for LTBI, blood assays could replace TST for antibiotherapy decision before anti‐TNF.TNFα blocker agents are approved for the treatment of immune‐mediated inflammatory diseases (IMID) and provide marked clinical benefit. However, they can reactivate tuberculosis (TB) infection in patients previously exposed to TB bacilli.^1,2 The presence of quiescent mycobacteria defines latent TB infection (LTBI).^3,4 Thus, screening for LTBI is necessary before initiating therapy with TNF blockers.⁵ However, to date, no perfect gold standard exists for detecting LTBI, and tuberculin skin test (TST) remains largely used. The recommendations for detecting LTBI differ worldwide.^3,6,7 In France, recommendations were established in 2002 by the RATIO (Research Axed on Tolerance of Biotherapies) study group for the Agence Française de Sécurité Sanitaire des Produits de Santé.^8,9 Patients are considered to have LTBI requiring treatment with prophylactic antibiotics before starting anti‐TNFα therapy if they had previous TB with no adequate treatment, tuberculosis primo‐infection, residual nodular tuberculous lesions larger than 1 cm³ or old lesions suggesting TB diagnosis (parenchymatous abnormalities or pleural thickening) as seen on chest radiography or weals larger than 10 mm in diameter in response to the TST. Adequate anti‐TB treatment was defined as treatment initiated after 1970, lasting at least 6 months and including at least 2 months with the combination rifampicin–pyrazinamide. The choice of the threshold of 10 mm for the TST result was established in 2002 in France since the programme of vaccination with bacille Calmette–Guérin (BCG) was mandated in France, and nearly 100% of the population has been vaccinated. Nevertheless, after July 2005, the threshold was decreased to 5 mm as in most of all other countries.¹⁰The TST is the current method to detect LTBI but has numerous drawbacks. Indeed, the TST requires a return visit for reading the test result. It has a poor specificity, since previous BCG vaccination and environmental mycobacterial exposure can result in false‐positive results in all subjects.^6,11,12 This poor specificity can lead to unnecessary treatment with antibiotics, with a significant risk of drug toxicity.^13,14,15 On the other hand, TST in IMID may often give a more negative reaction than in the general population, mainly because of the disease or immunosuppressive drug use.^16,17 This poor sensitivity can lead to false‐negative results, with a subsequent risk of TB reactivation with anti‐TNF therapy.The identification of genes in the mycobacterium TB genome that are absent in BCG and most environmental mycobacteria offers an opportunity to develop more specific tests to investigate Mycobacterium tuberculosis (M. tuberculosis) infection, particularly LTBI.¹⁸ Culture fibrate protein‐10 (CFP‐10) and early secretory antigen target‐6 (ESAT‐6) are two such gene products that are strong targets of the cellular immune response in TB patients. In vivo‐specific T‐cell based assay investigating interferon gamma (IFNγ) release or T‐cell proliferation in the presence of these specific mycobacterial antigens could be useful in screening for LTBI before anti‐TNF therapy. New IFNγ‐based ex vivo assays involving CFP‐10 and ESAT‐6 (T‐SPOT TB, Oxford Immunotec, Abingdon, UK) and QuantiFERON TB Gold (QFT‐G; Cellestis, Carnegie, Australia) allow for diagnosis of active TB, recent primo‐infection or LTBI.¹² These tests seem to be more accurate than the TST for this purpose in the general population.¹² To date, the performance of the commercial assays in detecting LTBI in patients with IMID receiving immunosuppressive drugs has not been demonstrated, and the frequency of indeterminate results is still debated.^19,20,21We aimed to investigate the performance of homemade anti‐CFP‐10 and anti‐ESAT‐6 proliferative and enzyme‐linked immunosorbent spot (ELISPOT) assays in detecting LTBI in patients with IMID before anti‐TNFα therapy. We analysed two subgroups of patients: those with confirmed LTBI independent of TST result, and those with LTBI based exclusively on a positive TST result between 6 and 10 mm.     

Socioeconomic status, pathogen burden and cardiovascular disease risk

Objective

Socioeconomic status (SES) is inversely associated with coronary heart disease (CHD) risk. Cumulative pathogen burden may also predict future CHD. The hypothesis was tested that lower SES is associated with a greater pathogen burden, and that pathogen burden accounts in part for SES differences in cardiovascular risk factors.

Methods

This was a cross‐sectional observational study involving the clinical examination of 451 men and women aged 51–72 without CHD, recruited from the Whitehall II epidemiological cohort. SES was defined by grade of employment, and pathogen burden by summing positive serostatus for Chlamydia pneumoniae, cytomegalovirus and herpes simplex virus 1. Cardiovascular risk factors were also assessed.

Results

Pathogen burden averaged 1.94 (SD) 0.93 in the lower grade group, compared with 1.64 (0.97) and 1.64 (0.93) in the intermediate and higher grade groups (p = 0.011). Pathogen burden was associated with a higher body mass index, waist/hip ratio, blood pressure and incidence of diabetes. There were SES differences in waist/hip ratio, high‐density lipoprotein‐cholesterol, fasting glucose, glycated haemoglobin, lung function, smoking and diabetes. The SES gradient in these cardiovascular risk factors was unchanged when pathogen burden was taken into account statistically.

Conclusions

Although serological signs of infection with common pathogens are more frequent in lower SES groups, their distribution across the social gradient does not match the linear increases in CHD risk present across higher, intermediate and lower SES groups. Additionally, pathogen burden does not appear to mediate SES differences in cardiovascular risk profiles.There is a socioeconomic gradient in coronary heart disease (CHD) mortality and cardiovascular disease risk in the USA, UK and many other countries.^1,2 Lower socioeconomic status (SES) is associated with a range of cardiovascular risk factors including smoking, adverse lipid profiles, abdominal adiposity, glucose intolerance and inflammatory markers.^3,4,5,6,7 Both early life SES and adult socioeconomic position appear to contribute to the social gradient.^5,8A history of infection may contribute to cardiovascular disease risk by stimulating sustained vascular inflammation. Evidence concerning the relevance of individual pathogens is mixed, but the cumulative pathogen burden, defined by positive serostatus for a range of pathogens, has been associated with coronary artery disease and carotid atherosclerosis in case–control^9,10,11 and longitudinal cohort studies.^12,13,14 Pathogen burden is also related to cardiovascular risk markers such as endothelial dysfunction,¹⁵ low high‐density lipoprotein (HDL)‐cholesterol¹⁶ and insulin resistance,¹⁷ in some but not all studies.^9,18It is plausible that pathogen burden could contribute to SES differences in cardiovascular disease risk. Exposure to infection is greater in lower SES groups, particularly in early life,¹⁹ and childhood infection is associated with endothelial dysfunction.²⁰ We therefore tested the hypothesis that lower SES is associated with greater cumulative pathogen burden in healthy middle‐aged and older adults. Seropositivity was measured for three pathogens, Chlamydia pneumoniae, cytomegalovirus (CMV) and herpes simplex virus 1 (HSV‐1), that have been associated with cardiovascular disease risk,^21,22,23 and have contributed to studies of cumulative pathogen burden.^10,12,14,15 We also determined whether variations in pathogen burden accounted for SES differences in cardiovascular risk factors.     

Endoscopic treatment of post-surgical bile duct injuries: long term outcome and predictors of success

Objective

To analyse the short and long term outcome of endoscopic stent treatment after bile duct injury (BDI), and to determine the effect of multiple stent treatment.

Design, setting and patients

A retrospective cohort study was performed in a tertiary referral centre to analyse the outcome of endoscopic stenting in 67 patients with cystic duct leakage, 26 patients with common bile duct leakage and 110 patients with a bile duct stricture.

Main outcome measures

Long term outcome and independent predictors for successful stent treatment.

Results

Overall success in patients with cystic duct leakage was 97%. In patients with common bile duct leakage, stent related complications occurred in 3.8% (n = 1). The overall success rate was 89% (n = 23). In patients with a bile duct stricture, stent related complications occurred in 33% (n = 36) and the overall success rate was 74% (n = 81). After a mean follow up of 4.5 years, liver function tests did not identify “occult” bile duct strictures. Independent predictors for outcome were the number of stents inserted during the first procedure (OR 3.2 per stent; 95% CI 1.3 to 8.4), injuries classified as Bismuth III (OR 0.12; 95% CI 0.02 to 0.91) and IV (OR 0.04; CI 0.003 to 0.52) and endoscopic stenting before referral (OR 0.24; CI 0.06 to 0.88). Introduction of sequential insertion of multiple stents did not improve outcome (before 77% vs after 66%, p = 0.25), but more patients reported stent related pain (before 11% vs after 28%, p = 0.02).

Conclusions

In patients with a postoperative bile duct leakage and/or strictures, endoscopic stent treatment should be regarded as the choice of primary treatment because of safety and favourable long term outcome. Apart from the early insertion of more than one stent, the benefit from sequential insertion of multiple stents did not become readily apparent from this series.Bile duct injury (BDI) occurs in 0.2 to 1.4% of patients following laparoscopic cholecystectomy and is a severe surgical complication.^1,2,3,4 BDI related morbidity is illustrated by increased hospital stay, poor long term quality of life and high rates of malpractice litigation.^5,6,7,8 Although surgical reconstruction, mainly a hepaticojejunostomy, is a procedure associated with low mortality and low morbidity if performed in a tertiary centre, this is only indicated in selected patients with BDI; a population‐based study from the USA demonstrated the detrimental effect of BDI on survival in patients who underwent surgical reconstruction.⁹ The majority of biliary injuries, including cystic duct leakage, common bile duct (CBD) leakage or bile duct strictures, can be treated successfully in 70–95% of the patients by means of endoscopic or radiological interventions.^{10,11,12,13,14,15,16}It has been suggested that endoscopic treatment is associated with an increased risk of re‐stenosis and biliary cirrhosis followed by end‐stage liver disease. However, reliable data about the long term outcome of endoscopic management of BDI are scarce and predicting factors for successful outcome are unreported. Several years ago reports from uncontrolled studies indicated that a more aggressive type of dilation treatment in patients with bile duct strictures, based on the sequential insertion of multiple stents, may be associated with a more favourable outcome and this treatment policy has been adapted in our clinic since the end of 2001.^17,18,19,20The purpose of this study was to analyse the short and long term outcome of stent treatment in BDI patients (including liver function test after long term follow up) and to determine factors that are predictive for successful outcome in patients who are stented for a bile duct stricture. In addition, the outcomes of patients treated before and after the introduction of sequential insertion of multiple stents were compared.     

Gender differences in management and outcomes in patients with acute coronary syndromes: results on 20,290 patients from the AMIS Plus Registry

Background

Gender differences in management and outcomes have been reported in acute coronary syndrome (ACS).

Objectives

To assess such gender differences in a Swiss national registry.

Methods

20 290 patients with ACS enrolled in the AMIS Plus Registry from January 1997 to March 2006 by 68 hospitals were included in a prospective observational study. Data on patients'' characteristics, diagnoses, procedures, complications and outcomes were recorded. Odds ratios (ORs) of in‐hospital mortality were calculated using logistic regression models.

Results

5633 (28%) patients were female and 14 657 (72%) male. Female patients were older than men (mean (SD) age 70.9 (12.1) vs 63.4 (12.9) years; p<0.001), had more comorbidities and came to hospital later. They underwent percutaneous coronary intervention (PCI) less frequently (OR = 0.65; 95% CI 0.61 to 0.69) and their unadjusted in‐hospital mortality was higher overall (10.7% vs 6.3%; p<0.001) and in those who underwent PCI (3.0% vs 4.2%; p = 0.018). Mortality differences between women and men disappeared after adjustments for other predictors (adjusted OR (aOR) for women vs men: 1.09; 95% CI 0.95 to 1.25), except in women aged 51–60 years (aOR = 1.78; 95% CI 1.04 to 3.04). However, even after adjustments, female gender remained significantly associated with a lower probability of undergoing PCI (OR = 0.70; 95% CI 0.64 to 0.76).

Conclusions

The analysis showed gender differences in baseline characteristics and in the rate of PCI in patients admitted for ACS in Swiss hospitals between 1997 and 2006. Reasons for the significant underuse of PCI in women, and a slightly higher in‐hospital mortality in the 51–60 year age group, need to be investigated further.Coronary artery disease and, in particular, acute coronary syndrome (ACS), is the leading cause of mortality and morbidity in the Western world, in both women and men.The benefits of reperfusion treatment for patients with ACS have been well established and it has become standard treatment for both women and men with ST‐segment elevation acute coronary syndrome (STE‐ACS); however, there is variation in the method of reperfusion chosen, and in which patients are considered eligible.¹ Controversies also exist about the type and the time of reperfusion and about its outcomes in patients presenting with unstable angina or non‐ST‐segment elevation (NSTE‐ACS).It has also been shown that women with acute myocardial infarction (AMI) are less likely than men to undergo reperfusion treatment,^2,3 and that there is a lack of awareness of risk among women.⁴ In addition, there are conflicting data from randomised trials about the benefit of early invasive treatment in women.^5,6,7 Differences in survival between men and women reported in some studies may not only reflect gender bias in management, but also differences in coronary anatomy, age and comorbidities. In the CADILLAC Trial, women had higher mortality than men after interventional treatment for AMI, which the authors attributed to smaller body surface area and more comorbidities.³ On the contrary, other authors have suggested that the higher mortality seen in women after an AMI might be explained by less aggressive treatment,⁸ and if women had access to the same quality of care as men, their survival would be the same.⁹ Finally, the results of outcome studies in unselected patients suggest that gender is not an independent predictor of mortality after percutaneous coronary intervention (PCI)^2,10 and that improvement in prognosis associated with reperfusion treatment is independent from it.^10,11,12,13 The data of 3100 female patients enrolled in the Euro Heart Survey ACS showed that female gender in the “real world” was not independently associated with worse in‐hospital mortality, irrespective of the type of ACS.¹⁴ The authors interestingly emphasised the need to evaluate outcomes of ACS in surveys or registries, rather than from data derived from clinical trials.¹⁴ This suggestion, however, did not solve the controversy since, in the New York angioplasty registry, in‐hospital mortality for female patients undergoing angioplasty after having reached hospital within 6 hours was 9.04% vs 4.42% for male (p<0.001) for the years 1993–6.¹⁵Thus, the aim of this study was to assess outcomes in unselected female and male patients admitted between 1997 and 2006 for ACS in Swiss hospitals and to put these results in the perspective of their baseline characteristics, comorbidities and management.     

A closer look at non-Hodgkin's lymphoma cases in a national Swedish systemic lupus erythematosus cohort: a nested case-control study

Objective

To investigate risk factors for non‐Hodgkin''s lymphoma (NHL) and analyse NHL subtypes and characteristics in patients with systemic lupus erythematosus (SLE).

Methods

A national SLE cohort identified through SLE discharge diagnoses in the Swedish hospital discharge register during 1964 to 1995 (n = 6438) was linked to the national cancer register. A nested case control study on SLE patients who developed NHL during this observation period was performed with SLE patients without malignancy as controls. Medical records from cases and controls were reviewed. Tissue specimens on which the lymphoma diagnosis was based were retrieved and reclassified according to the WHO classification. NHLs of the subtype diffuse large B cell lymphoma (DLBCL) were subject to additional immunohistochemical staining using antibodies against bcl‐6, CD10 and IRF‐4 for further subclassification into germinal centre (GC) or non‐GC subtypes.

Results

16 patients with SLE had NHL, and the DLBCL subtype dominated (10 cases). The 5‐year overall survival and mean age at NHL diagnosis were comparable with NHL in the general population—50% and 61 years, respectively. Cyclophosphamide or azathioprine use did not elevate lymphoma risk, but the risk was elevated if haematological or sicca symptoms, or pulmonary involvement was present in the SLE disease. Two patients had DLBCL‐GC subtype and an excellent prognosis.

Conclusions

NHL in this national SLE cohort was predominated by the aggressive DLBCL subtype. The prognosis of NHL was comparable with that of the general lymphoma population. There were no indications of treatment‐induced lymphomas. Molecular subtyping could be a helpful tool to predict prognosis also in SLE patients with DLBCL.Evidence of an increased risk to develop haematological malignancy, and especially non‐Hodgkin''s lymphoma (NHL) in autoimmune diseases, has been gathered since the 1970s. First studies of Sjögren''s syndrome,¹ then rheumatoid arthritis (RA)² and now in the last decade studies from uni‐/multicentre SLE cohorts^3,4,5,6,7,8 and national SLE cohorts^9,10 have consistently shown a markedly increased risk of NHLs. As for NHL subtype, knowledge is more limited. RA and SLE share several disease manifestations like arthritis and “extra‐articular manifestations” such as serositis, sicca symptoms and interstitial inflammatory lung disease. In RA, a pronounced over‐representation of diffuse large B cell lymphoma (DLBCL) has been reported from a large population‐based cohort.¹¹ This lymphoma subtype was also the most frequent in an international multicentre study with lupus patients.¹² In Sjögren''s syndrome, approximately 85% are MALT lymphomas,¹³ although a recent study from a mono‐centre primary Sjögren''s syndrome cohort—with patients fulfilling the American–European Consensus Group criteria¹⁴—showed a predominance of DLBCL.¹⁵The pathophysiological mechanisms for the enhanced risk of developing NHL in patients with chronic inflammatory diseases are still not fully understood. Similarities of a variety of immunological disturbances that characterise both rheumatic conditions and lymphomas have been suggested as a linkage between these disorders as well as a possible potentiation of immunosuppressive drugs or certain viral infections, especially Epstein–Barr virus (EBV).^5,16Recently, advances in molecular characterisation have enabled more detailed subclassification of lymphomas based on the molecular expression of the tumour cells. For DLBCL, two prognostic groups have been identified among DLBCL in the general lymphoma population depending on the resemblance of gene expression profile with normal germinal centre (GC) or activated B cells by using global gene expression profiling^17,18 and immunophenotyping of tumour cells.^19,20 The GC DLBC lymphomas had a significantly better survival than those with non‐GC subtype.^17,18,19,20 No such subtyping has been reported in SLE patients.In a previous register study of a population‐based national Swedish SLE cohort, a threefold increased risk of lymphoma was found.¹⁰ This nested case‐control study focuses on those SLE patients that developed NHL. Information on clinical manifestations and pharmacological (cytotoxic) treatment of the SLE disease was retrieved from patient records. The lymphomas were re‐examined and reclassified, and DLBCLs were further divided into GC or non‐GC subtypes by immunohistochemistry. The presence of EBV in the lymphomas was also analysed.     

Abnormal left ventricular longitudinal functional reserve in patients with diabetes mellitus: implication for detecting subclinical myocardial dysfunction using exercise tissue Doppler echocardiography

Background

Sublinical myocardial dysfunction occurs in a significant number of patients with type 2 diabetes. Assessment of ventricular long‐axis function by measuring mitral annular velocities using tissue Doppler echocardiography (TDE) is thought to provide a more sensitive index of systolic and diastolic function. We hypothesised that augmentation of left ventricular (LV) longitudinal contraction and relaxation during exercise would be blunted in patients with type 2 diabetes.

Methods

Mitral annular systolic (S′) and early diastolic (E′) velocities were measured at rest and during supine bicycle exercise (25 W, 3 min increments) in 53 patients (27 male, mean age 53±14 years) with type 2 diabetes and 53 subjects with age and gender‐matched control. None had echocardiographic evidence of resting or inducible myocardial ischaemia.

Results

There were no significant differences in mitral inflow velocities at rest between the two groups. E′ and S′ at rest were also similar between the groups. However, S′ (7.1±1.3 vs 8.3±1.8 cm/s at 25 W, p = 0.0021; 8.1±1.5 vs 9.1±2.0 cm/s at 50 W, p = 0.026) and E′ (8.5±2.3 vs 9.9±3.1 cm/s at 25 W, p = 0.054; 9.1±2.1 vs 10.9±2.5 cm/s at 50 W, p = 0.0093) during exercise were significantly lower in patients with diabetes compared with controls. Longitudinal systolic and diastolic function reserve indices were significantly lower in patients with diabetes compared with that of controls (systolic index, 0.6±0.70 vs 1.2±1.5 cm/s at 25 W, p = 0.029; 1.2±1.2 vs 2.1±1.6 cm/s at 50 W, p = 0.009; diastolic index, 1.9±1.2 vs 2.5±2.2 cm/s at 25 W, p = 0.07; 2.3±1.3 vs 3.2±2.2 cm/s at 50 W, p = 0.031).

Conclusion

In conclusion, unlike resting mitral inflow and annular velocities, changes of systolic and diastolic velocities of the mitral annulus during exercise were significantly reduced in patients with type 2 diabetes compared with the control group. The assessment of LV longitudinal functional reserve with exercise using TDE appears to be helpful in identifying early myocardial dysfunction in patients with type 2 diabetes.Cardiovascular disease is the most common cause of death in patients with type 2 diabetes.¹ Patients with diabetes are more likely to develop heart failure, and their outcome with heart failure is worse than that of patients without diabetes. The spectrum of diabetic heart disease involves a progression from the normal heart, to subclinical left ventricular (LV) diastolic and systolic dysfunction, followed by clinically overt symptomatic heart failure. Notably, subclinical LV dysfunction is common in patients with diabetes,² and the detection of subclinical LV dysfunction in these patients may provide an approach for identifying high‐risk individuals who may benefit from earlier and more active intervention to prevent heart failure.³ Although overt LV diastolic and systolic dysfunction can be readily identified by conventional diagnostic techniques including echocardiography, the initial stage of myocardial dysfunction may be concealed by various compensatory mechanisms.⁴ Previous studies using sophisticated echocardiographic techniques such as tissue Doppler, strain, strain rate and ultrasonic tissue characterisation have shown abnormal myocardial function in patients with diabetes but without overt heart disease.^{2,5,6,7,8,9,10} However, all of these observations were made in the resting state or non‐physiological inotropic stimulation. A useful and physiological technique for evaluating ventricular performance involves the measurement of the circulatory changes that occur during exercise. In patients with diastolic dysfunction, already impaired myocardial relaxation does not augment as much as seen in normal individuals during exercise.^11,12,13 Nagueh et al showed in a canine model that E′ increases with increased transmitral gradient in subjects with normal myocardial relaxation, whereas it remained unchanged in subjects with diastolic dysfunction.¹⁴ A similar result has been shown in human beings.¹⁵ However, the response of mitral annular systolic and diastolic velocities to exercise in patients with type 2 diabetes has not been explored previously. We hypothesised that augmentation of LV longitudinal contraction and relaxation during exercise would be blunted in patients with type 2 diabetes. Therefore, the purpose of this study was to evaluate resting LV longitudinal function and functional reserve during exercise in patients with type 2 diabetes using mitral annular velocities by tissue Doppler echocardiography (TDE).     

Troponin-I concentration 72 h after myocardial infarction correlates with infarct size and presence of microvascular obstruction

Objectives

The aim of this study was to use late gadolinium hyper‐enhancement cardiac magnetic resonance (LGE‐CMR) imaging to determine if a 72‐h troponin‐I measurement would provide a more accurate estimation of infarct size and microvascular obstruction (MVO) than serial creatine kinase (CK) or early troponin‐I values.

Methods

LGE‐CMR was performed 3.7±1.4 days after medical treatment for acute ST elevation or non‐ST elevation myocardial infarction. Infarct size and MVO were measured and correlated with serum troponin‐I concentrations, which were sampled 12 h and 72 h after admission, in addition to serial CK levels.

Results

Ninety‐three patients, of whom 71 had received thrombolysis for ST elevation myocardial infarction, completed the CMR study. Peak CK, 12‐h troponin‐I, and 72‐h troponin‐I were related to infarct size by LGE‐CMR (r = 0.75, p<0.0001; r = 0.56, p = 0.0003; r = 0.62, p<0.0001 respectively). Serum biomarkers demonstrated higher values in the group with MVO compared with those without MVO (Peak CK 3085±1531 vs 1471±1135, p<0.001; 12‐h troponin‐I 58.3±46.9 vs 33.4±40.0, p = 0.13; 72‐h troponin‐I 11.5±9.9 vs 5.5±4.6, p<0.005). The correlation between the extent of MVO and 12‐h troponin‐I was not significant (r = 0.16), in contrast to the other serum biomarkers (peak CK r = 0.44, p<0.0001; 72‐h troponin‐I r = 0.46, p = 0.0002).

Conclusion

A single measurement of 72‐h troponin‐I is similar to serial CK measurements in the estimation of both myocardial infarct size and extent of MVO, and is superior to 12‐h troponin‐I measurements.Prognosis after acute myocardial infarction is closely related to the extent of myocardial damage. The degree of damage can be estimated by serological testing and non‐invasive imaging methods (such as echocardiography). Measurement of cytosolic enzymes such as creatine kinase (CK) and the isoenzyme CK‐MB is still common clinical practice.¹ However, the utility of these markers in determining infarct size is limited by the requirement for multiple sampling to determine the peak values or area under the curve, and their lack of specificity for myocardial damage.²Twelve‐hour serum troponin measurements are routinely used in the diagnosis of myocardial ischaemia or infarction. Although such measurements are highly specific for myocardial damage, they may provide unreliable estimates of infarct size.³ Troponin is a structural protein of the contractile apparatus which is released into the circulation in a biphasic fashion after acute myocardial infarction (AMI). An initial peak occurs in the first 24 h, due to release from the cytosolic pool. While this peak provides a reliable marker of infarct size in an animal model of non‐reperfused infarction,⁴ the complex release kinetics result in a high variability in early troponin concentrations following reperfusion therapy.²In AMI, the presence of microvascular obstruction (MVO) could cause impaired wash‐out of cardiac biomarkers in the early phase, so that the acute concentrations may not accurately reflect the true extent of myocardial damage. A second phase of troponin release occurs after 72 h, resulting from intramyocardial protein degradation,⁵ and this “plateau” value seems to be relatively unaffected by early reperfusion therapy.² The troponin concentration at 72 h may therefore be less affected by release kinetics and coronary reperfusion, and hence provide a more reliable method to quantify myocardial damage and predict the presence of MVO.Cardiac magnetic resonance (CMR) can be used to image both acute and chronic myocardial infarction using the technique of late gadolinium hyper‐enhancement (LGE).^6,7 Several animal studies have validated this technique,^8,9 and in the canine model CMR quantification of infarct size has been shown to correlate closely (r = 0.99) with histological measurements using triphenyltetrazolium chloride staining.¹⁰ Areas of severe MVO within the infarct core can also be demonstrated by LGE‐CMR in man.¹¹ The high spatial resolution of the LGE‐CMR technique allows accurate measurement of in vivo infarct size.The aim of this study was to determine if a 72 h troponin (72‐h troponin‐I) measurement would provide a more accurate estimation of infarct size than serial CK or early troponin values.     

Microscopic measurement of inflammation in synovial tissue: inter-observer agreement for manual quantitative, semiquantitative and computerised digital image analysis

Objectives

To evaluate inter‐observer agreement for microscopic measurement of inflammation in synovial tissue using manual quantitative, semiquantitative and computerised digital image analysis.

Methods

Paired serial sections of synovial tissue, obtained at arthroscopic biopsy of the knee from patients with rheumatoid arthritis (RA), were stained immunohistochemically for T lymphocyte (CD3) and macrophage (CD68) markers. Manual quantitative and semiquantitative scores for sub‐lining layer CD3+ and CD68+ cell infiltration were independently derived in 6 international centres. Three centres derived scores using computerised digital image analysis. Inter‐observer agreement was evaluated using Spearman''s Rho and intraclass correlation coefficients (ICCs).

Results

Paired tissue sections from 12 patients were selected for evaluation. Satisfactory inter‐observer agreement was demonstrated for all 3 methods of analysis. Using manual methods, ICCs for measurement of CD3+ and CD68+ cell infiltration were 0.73 and 0.73 for quantitative analysis and 0.83 and 0.78 for semiquantitative analysis, respectively. Corresponding ICCs of 0.79 and 0.58 were observed for the use of digital image analysis. All ICCs were significant at levels of p<0.0001. At each participating centre, use of computerised image analysis produced results that correlated strongly and significantly with those obtained using manual measurement.

Conclusion

Strong inter‐observer agreement was demonstrated for microscopic measurement of synovial inflammation in RA using manual quantitative, semiquantitative and computerised digital methods of analysis. This further supports the development of these methods as outcome measures in RA.Microscopic measurement of inflammation in synovial tissue is employed globally by centres working in the field of arthritis research.¹ Adequate and comparable synovial tissue can be safely obtained using blind‐needle biopsy or rheumatological arthroscopy.^2,3,4 In the acquired samples, various parameters may be examined, including cell populations, vascularity, cytokines and adhesion molecules. In rheumatoid arthritis (RA), many of these have been found to relate to disease activity, severity, outcome, and to exhibit a change after treatment with corticosteroids, disease‐modifying antirheumatic drugs (DMARDs) and biological therapy.^{5,6,7,8,9,10,11,12,13,14,15}Several analysis techniques have been employed to measure these parameters. Semiquantitative analysis is a relatively quick method and therefore may facilitate examining large quantities of tissue.⁷ Quantitative analysis is time‐consuming but more sensitive than semiquantitative scoring to change in individual patients.¹⁶ It has been shown in previous studies that these methods can reflect overall joint inflammation when applied to relatively limited amounts of synovial tissue, even though inflammation may differ widely between individual sites in a single joint.^17,18,19 Computerised digital image analysis has been applied more recently in this area and has been shown to correlate well with conventional methods of measurement.^20,21,22This multi‐centre study was undertaken to standardise and validate the methods mentioned previously by evaluating inter‐observer agreement between multiple examiners in the measurement of selected parameters of inflammation in RA synovial tissue by manual quantitative, semiquantitative and computerised image analysis.     

Clinical value of multidetector CT coronary angiography as a preoperative screening test before non-coronary cardiac surgery

Objective

Myocardial scintigraphy and/or conventional angiography (CA) are often performed before cardiac surgery in an attempt to identify unsuspected coronary artery disease which might result in significant cardiac morbidity and mortality. Multidetector CT coronary angiography (MDCTCA) has a recognised high negative predictive value and may provide a non‐invasive alternative in this subset of patients. The aim of this study was to evaluate the clinical value of MDCTCA as a preoperative screening test in candidates for non‐coronary cardiac surgery.

Methods

132 patients underwent MDCTCA (Somatom Sensation 16 Cardiac, Siemens) in the assessment of the cardiac risk profile before surgery. Coronary arteries were screened for ⩾50% stenosis. Patients without significant stenosis (Group 1) underwent surgery without any adjunctive screening tests while all patients with coronary lesions ⩾50% at MDCTCA (Group 2) underwent CA.

Results

16 patients (12.1%) were excluded due to poor image quality. 72 patients without significant coronary stenosis at MDCTCA were submitted to surgery. 30 out of 36 patients with significant (⩾50%) coronary stenosis at MDCTCA and CA underwent adjunctive bypass surgery or coronary angioplasty. In 8 patients, MDCTCA overestimated the severity of the coronary lesions (>50% MDCTCA, <50% CA).No severe cardiovascular perioperative events such as myocardial ischaemia, myocardial infarction or cardiac failure occurred in any patient in Group 1.

Conclusions

MDCTCA seems to be effective as a preoperative screening test prior to non‐coronary cardiac surgery. In this era of cost containment and optimal care of patients, MDCTCA is able to provide coronary vessel and ventricular function evaluation and may become the method of choice for the assessment of a cardiovascular risk profile prior to major surgery.Since its introduction in the 1960s,¹ conventional coronary angiography (CA) has been considered the gold standard for the diagnosis of coronary artery disease because of its high contrast, temporal and spatial resolution.^2,3,4 In the past few years, we have witnessed a considerable increase in diagnostic and interventional procedures. Despite the high degree of accuracy (73–89%) of non‐invasive diagnostic tests such as exercise ECG, myocardial scintigraphy and stress‐echocardiography in detecting myocardial ischaemia,⁵ about 20% of patients undergoing CA due to a positive result of these non‐invasive tests, had no evidence of coronary lesions.^6,7Multidetector CT (MDCT), introduced into clinical practice in 2000, has demonstrated excellent technical characteristics for coronary artery evaluation. Results in the literature show a high degree of diagnostic accuracy in detecting significant coronary lesions and, particularly, an excellent capability of excluding them, due to negative predictive values ranging from 96 to 99%.^{8,9,10,11,12,13,14,15,16,17,18}Patients who are candidates for major non‐coronary cardiac or vascular surgery, such as heart valve replacement, aortic aneurysm and aortic dissection, require a complete assessment of potentially dangerous co‐morbidities. There is a 5 to 10% perioperative cardiac morbidity rate during vascular surgery, even in patients at low risk for coronary disease.¹⁹ According to Paul et al.²⁰ there is a 17% risk of severe multivessel disease in low clinical risk asymptomatic patients undergoing vascular surgery. American College of Cardiology/American Heart Association (ACC/AHA) guidelines for preoperative evaluation before major surgery recommend stratification of ischaemic heart disease with clinical and non‐invasive tests.^19,20,21,22 The diagnostic accuracy is 68 to 77% for exercise ECG and 73 to 85% for stress‐echocardiography. Myocardial scintigraphy provides an accuracy of 87–89% in patients with normal resting ECG, with a radiation exposure ranging from 4.6 to 20 mSv,²³ almost equivalent to MDCT coronary angiography (MDCTCA). However, for certain high‐risk patients, ACC guidelines suggest proceeding directly with coronary angiography rather than performing a non‐invasive test. Therefore, in clinical practice, CA is often performed before major vascular or cardiac surgery. Considering that millions of surgical procedures are probably performed every year worldwide (eg, 95 000 heart valve replacements/year in the USA),^6,7 several hundred thousand negative CAs are still performed.After some years of validation studies comparing MDCTCA with CA, studies on clinical utility are now warranted to demonstrate whether and how this technique can change and improve the current management of patients. The purpose of this study is to evaluate the clinical impact of MDCTCA as a preoperative screening test for cardiac risk assessment in patients who are candidates for major non‐coronary cardiac surgery and who are asymptomatic for ischaemic heart disease.     

Faecal S100A12 as a non-invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome

Objective

S100A12 is a pro‐inflammatory protein that is secreted by granulocytes. S100A12 serum levels increase during inflammatory bowel disease (IBD). We performed the first study analysing faecal S100A12 in adults with signs of intestinal inflammation.

Methods

Faecal S100A12 was determined by ELISA in faecal specimens of 171 consecutive patients and 24 healthy controls. Patients either suffered from infectious gastroenteritis confirmed by stool analysis (65 bacterial, 23 viral) or underwent endoscopic and histological investigation (32 with Crohn''s disease, 27 with ulcerative colitis, and 24 with irritable bowel syndrome; IBS). Intestinal S100A12 expression was analysed in biopsies obtained from all patients. Faecal calprotectin was used as an additional non‐invasive surrogate marker.

Results

Faecal S100A12 was significantly higher in patients with active IBD (2.45 ± 1.15 mg/kg) compared with healthy controls (0.006 ± 0.03 mg/kg; p<0.001) or patients with IBS (0.05 ± 0.11 mg/kg; p<0.001). Faecal S100A12 distinguished active IBD from healthy controls with a sensitivity of 86% and a specificity of 100%. We also found excellent sensitivity of 86% and specificity of 96% for distinguishing IBD from IBS. Faecal S100A12 was also elevated in bacterial enteritis but not in viral gastroenteritis. Faecal S100A12 correlated better with intestinal inflammation than faecal calprotectin or other biomarkers.

Conclusions

Faecal S100A12 is a novel non‐invasive marker distinguishing IBD from IBS or healthy individuals with a high sensitivity and specificity. Furthermore, S100A12 reflects inflammatory activity of chronic IBD. As a marker for neutrophil activation, faecal S100A12 may significantly improve our arsenal of non‐invasive biomarkers of intestinal inflammation.The etiology of inflammatory bowel disease (IBD) consisting of ulcerative colitis and Crohn''s disease involves complex interactions among susceptibility genes, the environment, and the immune system. These interactions lead to a cascade of events that involve the activation of neutrophils, production of proinflammatory mediators, and tissue damage.¹ As intestinal symptoms are a frequent cause of referrals to gastroenterologists, it is crucial to differentiate between non‐inflammatory irritable bowel syndrome (IBS) and IBD. To date, there is a lack of biological markers to determine intestinal inflammation.^2,3 Therefore, invasive procedures are required to confirm the diagnosis of IBD. Furthermore, the natural history of chronic IBD is characterised by an unpredictable variation in the degree of inflammation. Biological markers are needed to confirm remission, detect early relapses or local reactivation, and to monitor anti‐inflammatory therapies reliably. Whereas serum markers of inflammation are still not very helpful,^3,4,5 assays that determine intestinal inflammation by detecting neutrophil‐derived products in stool show great potential.⁶An important mechanism in the initiation and perturbation of inflammation in IBD is the activation of innate immune mechanisms.^7,8 Among the factors released by infiltrating neutrophils are proteins of the S100 family.^9,10 One example is calprotectin, which is detectable in the serum and stool during intestinal inflammation.¹¹ Calprotectin was initially described as a protein of 36 kDa, but was later characterised as a complex of two distinct S100 proteins, S100A8 and S100A9.^12,13,14 In recent years, calprotectin has been proposed as a faecal marker of gut inflammation reflecting the degree of phagocyte activation.^{6,15,16,17,18,19,20} Unfortunately, variation in faecal calprotectin assays still impedes the routine use of this marker as a sole parameter in clinical practice. The observed variation may be caused by the broad expression pattern of calprotectin, which is found in granulocytes as well as monocytes and is also inducible in epithelial cells.^21,22 In this context, the elevation in lactose intolerance is notable.^16,17,23S100A12 is more restricted to granulocytes. It is secreted by activated neutrophils and is abundant in the intestinal mucosa of patients with IBD.^9,24 Overexpression at the site of inflammation and correlation with disease activity in a variety of inflammatory disorders underscore the role of this granulocytic protein as a proinflammatory molecule.²⁵ The binding of S100A12 to the receptor for advanced glycation endproducts (RAGE) leads to the long‐term activation of nuclear factor kappa B, which promotes inflammation.²⁶ In mouse models of colitis, blocking the interaction of S100A12 with RAGE has been proved to attenuate inflammation. Data on murine models of colitis as well as human IBD point to an important role for S100A12 during the pathogenesis of these disorders.^9,26,27In a previous study, we demonstrated that S100A12 is overexpressed during chronic active IBD and serves as a useful serum marker for disease activity in patients with IBD.⁹ De Jong et al.²⁸ recently reported that S100A12 can be detected in the stool of children with Crohn''s disease. The aim of our present study was thus to analyse S100A12 in stool samples as well as its expression in the intestinal tissue of patients with confirmed IBD or IBS and in the stool of a normal control group. We correlated faecal S100A12 levels with endoscopic and histological findings in the same patients and investigated the diagnostic accuracy of S100A12 to detect intestinal inflammation.     

Joint-specific hand symptoms and self-reported and performance-based functional status in African Americans and Caucasians: The Johnston County Osteoarthritis Project

Objective

To assess associations between joint‐specific hand symptoms and self‐reported and performance‐based functional status.

Methods

Participants were from the population‐based Johnston County Osteoarthritis Project. Symptoms in the distal interphalangeal (DIP), proximal interphalangeal (PIP), first carpometacarpal (CMC), and metacarpophalangeal (MCP) joints were assessed on a 30‐joint diagram of both hands. Self‐reported function was assessed by Health Assessment Questionnaire (HAQ) and performance‐based function by timed repeated chair stands and 8‐foot walk time. Separate multiple logistic regression models examined associations between symptoms in specific hand joint groups, symptoms in ⩾2 hand joint groups and number of symptomatic hand joints, and functional status measures, controlling for age, race/ethnicity, sex, body mass index, radiographic knee and hip OA, knee and hip symptoms and depressive symptoms.

Results

Those with symptomatic hand joint groups were more likely than those without these complaints to report more difficulty and require longer times for performance measures. Those with 2 or more symptomatic hand joint groups were more likely to have higher HAQ scores (OR = 1.97 (1.53 to 2.53)) and require more time to complete 5 chair stands (OR = 1.98 (1.23 to 3.18)) and the 8 foot walk test (OR = 1.49 (1.12 to 1.99)).

Conclusions

Joint‐specific hand symptoms are associated with difficulty performing upper‐ or lower‐extremity tasks, independent of knee and hip OA and symptoms, suggesting that studies examining functional status in OA should not ignore symptomatic joints beyond the joint site of interest, even when functional measures appear to be specific for the joint site under study.Osteoarthritis (OA) is a common cause of pain and disability.^1,2 Pain, aching or stiffness attributed to hand OA is associated with functional limitations in activities requiring use of the hands.^3,4 Individuals with OA of both the hands and knees have higher (worse) Health Assessment Questionnaire (HAQ) scores than those with isolated hand or knee OA.⁵ Unrecognised concomitant hand symptoms could potentially confound studies using the HAQ to follow symptoms of hip or knee OA, especially since a significant number of patients with isolated hip or knee OA alone will develop hand OA over time.⁵ Despite this, investigations of the impact of upper‐ or lower‐extremity OA traditionally use questions, functional tests or even selected components of the HAQ restricted to upper‐ or lower‐extremity function.^4,6,7 We have previously reported an association between knee pain and difficulty performing not just lower‐extremity tasks but upper‐extremity tasks as well, suggesting possible concomitant upper‐extremity involvement in the participants in the Johnston County Osteoarthritis Project.⁸ In this study, we examined associations between joint‐specific hand symptoms, as surrogate measures of hand OA, and self‐reported and performance‐based measures of functional status. Additionally, we evaluated whether these associations were independent of radiographic hip and knee OA and hip and knee symptoms, and whether these associations varied by race/ethnicity, sex, and the presence of knee or hip symptoms.     

Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840,149 screening colonoscopies

Objectives

To derive age and sex specific estimates of transition rates from advanced adenomas to colorectal cancer by combining data of a nationwide screening colonoscopy registry and national data on colorectal cancer (CRC) incidence.

Design

Registry based study.

Setting

National screening colonoscopy programme in Germany.

Patients

Participants of screening colonoscopy in 2003 and 2004 (n = 840 149).

Main outcome measures

Advanced adenoma prevalence, colorectal cancer incidence, annual and 10 year cumulative risk of developing CRC among carriers of advanced adenomas according to sex and age (range 55–80+ years)

Results

The age gradient is much stronger for CRC incidence than for advanced adenoma prevalence. As a result, projected annual transition rates from advanced adenomas to CRC strongly increase with age (from 2.6% in age group 55–59 years to 5.6% in age group ⩾80 years among women, and from 2.6% in age group 55–59 years to 5.1% in age group ⩾80 years among men). Projections of 10 year cumulative risk increase from 25.4% at age 55 years to 42.9% at age 80 years in women, and from 25.2% at age 55 years to 39.7% at age 80 years in men.

Conclusions

Advanced adenoma transition rates are similar in both sexes, but there is a strong age gradient for both sexes. Our estimates of transition rates in older age groups are in line with previous estimates derived from small case series in the pre‐colonoscopy era independent of age. However, our projections for younger age groups are considerably lower. These findings may have important implications for the design of CRC screening programmes.Most colorectal cancers (CRCs) develop from adenomas, among which “advanced” adenomas are considered to be the clinically relevant precursors of CRC. The natural history of colorectal adenomas is a decisive factor for the design of CRC screening measures and their cost effectiveness. Since advanced adenomas need to be removed once they are detected, any direct observation of their natural history would be unethical. Thus, available estimates for the progression of adenomas mostly stem from radiological surveillance data or from autopsy series collected prior to the colonoscopy era.^{1,2,3,4,5,6,7,8,9} However, these data are rather vague as they were derived from small and potentially selective samples. For example, a major source for the estimation of adenoma transition rates has been a retrospective review of Mayo Clinic records from 226 patients with colonic polyps ⩾10 mm in diameter in whom periodic radiographical examination of the colon was performed, and in whom 21 invasive carcinomas were identified during a mean follow up of 9 years.⁹ Despite the undoubted usefulness of available data sources from the pre‐colonoscopy era, sample size limitations did not allow reliable estimates of adenoma transition rates according to key factors, such as age and sex. Accordingly, a common estimate of these transition rates for all ages and both sexes has generally been assumed in previous studies on effectiveness and cost effectiveness of CRC screening.^{10,11,12,13,14,15,16,17} Given that sensitivity analyses in these studies showed that the advanced adenoma–carcinoma transition rate represents a very influential parameter,^10,11,13,18 its variation by age and sex might have a large impact on relative effectiveness and cost effectiveness of various screening schemes.The aim of this paper was to estimate risk for developing CRC according to age and sex among carriers of advanced adenomas by combining data from a large national colonoscopy screening database and national data on CRC incidence in Germany.