The association of age at psoriasis onset and HLA-C*06:02 with biologic survival in patients with moderate-to-severe psoriasis: a cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

BACKGROUND: Few studies have used real-world data to investigate the association between biologic therapy survival and age at psoriasis onset or HLA-C*06:02 status in patients with moderate-to-severe psoriasis. The robustness of these studies is limited by small sample size, short follow-up and diverse safety and effectiveness measures. OBJECTIVES: To describe biologic survival and explore whether the response to biologics is modified by age at psoriasis onset or HLA-C*06:02 status in patients with moderate-to-severe psoriasis. METHODS: Data from patients in the UK and the Republic of Ireland registered in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) from 2007 to 2022 on a first course of adalimumab, etanercept, secukinumab or ustekinumab with at least 6 months' follow-up and a subset of BADBIR patients with available HLA-C*06:02 information registered to Biomarkers and Stratification To Optimise outcomes in Psoriasis (BSTOP) were analysed. Patients aged ≥ 50 years at treatment initiation were classified into early-onset psoriasis (EOP) (presenting in patients ≤ 40 years of age) and late-onset psoriasis (LOP) (presenting in patients > 40 years of age). BADBIR patients with available information in BSTOP were categorized as HLA-C*06:02- or HLA-C*06:02 + . Biologic survival was defined as treatment discontinuation associated with ineffectiveness or occurrence of adverse events (AEs). Adjusted survival function and hazard ratio (aHR) with 95% confidence interval (CI) were estimated using a flexible parametric model to compare discontinuing therapy between age at psoriasis onset and HLA-C*06:02 groups. Each model included exposure (biologics), effect modifier (age at onset or HLA-C*06:02 status), interaction terms and several baseline demographic, clinical and disease severity covariates. RESULTS: Final analytical cohorts included 4250 patients in the age at psoriasis onset group [2929 EOP (69%) vs. 1321 LOP (31%)] and 3094 patients in the HLA-C*06:02 status group [1603 HLA-C*06:02+ (52%) vs. 1491 HLA-C*06:02- (48%)]. There was no significant difference between EOP and LOP in drug survival associated with ineffectiveness or AEs for any biologics. However, compared with patients who were HLA-C*06:02-, patients who were HLA-C*06:02 + were less likely to discontinue ustekinumab for reasons associated with ineffectiveness (aHR 0.56, 95% CI 0.42-0.75). CONCLUSIONS: HLA-C*06:02, but not age at psoriasis onset, is a predictive biomarker for biologic survival in patients with psoriasis. Findings from this large cohort provide further, important information to aid clinicians using biologic therapies to manage patients with psoriasis.

Effectiveness and survival of methotrexate versus adalimumab in patients with moderate-to-severe psoriasis: a cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

BACKGROUND: Most information on the comparative effectiveness and survival of methotrexate (MTX) and adalimumab (ADA) in the treatment of psoriasis is from randomized control trials and may not translate to the everyday clinical setting. OBJECTIVES: To determine the real-world effectiveness and survival of MTX and ADA in patients with moderate-to-severe psoriasis registered in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR). METHODS: Eligible patients were registered in BADBIR, ≥ 16 years of age and receiving a first course of MTX or ADA between September 2007 and December 2021, with ≥ 6 months of follow-up. Effectiveness was defined as achieving an absolute Psoriasis Area and Severity Index (PASI) ≤ 2 reported ≥ 13 weeks after the treatment start date until the stop date. The average treatment effect (ATE) was estimated using inverse probability of treatment weighting with propensity score, including baseline covariates. ATE results were presented as risk ratios (RR). A flexible parametric model was used to estimate adjusted standardized average survival, defined as treatment discontinuation associated with ineffectiveness or the occurrence of adverse events (AEs) at 6, 12 and 24 months. Restricted mean survival time (RMST) at 2 years of treatment exposure was calculated. RESULTS: In total, 6575 patients (median age 44 years; 44% female) were analysed; 2659 (40.4%) were prescribed MTX and 3916 (59.5%) ADA. The proportion of patients achieving PASI ≤ 2 was higher in the ADA cohort (77.4%) than in the MTX cohort (37.4%). ADA was more effective than MTX [RR 2.20, 95% confidence interval (CI) 1.98-2.45]. Overall survival associated with ineffectiveness or AEs was lower in the MTX cohort than in the ADA cohort at 6 months [survival estimate 69.7 (95% CI 67.9-71.5) vs. 90.6 (95% CI 89.8-91.4)], 1 year [survival estimate 52.5 (95% CI 50.4-54.8) vs. 80.6 (95% CI 79.5-81.8)] and 2 years [survival estimate 34.8 (95% CI 32.5-37.2) vs. 68.6 (95% CI 67.2-70.0)]. The difference in RMST (years) overall, or when stratified by ineffectiveness and AEs, was 0.53 (95% CI 0.49-0.58), 0.37 (95% CI 0.33-0.42) and 0.29 (95% CI 0.25-0.33), respectively. CONCLUSIONS: Patients on ADA were twice as likely to be clear or nearly clear of psoriasis and were less likely to discontinue their medication than patients on MTX. Findings from this real-world cohort provide important information to aid clinicians managing patients with psoriasis.

Effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters and methotrexate for patients with moderate-to-severe psoriasis: a cohort study from BADBIR.

BACKGROUND: Real-world data evaluating effectiveness and persistence of systemic therapies for patients with psoriasis are limited. Objectives To determine the effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters (FAEs) and methotrexate in patients with moderate-to-severe psoriasis. METHODS: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), a prospective, multicentre pharmacovigilance register of patients with moderate-to-severe psoriasis receiving biologic and/or conventional systemic therapies, were analysed. Eligible patients were ≥ 16 years of age receiving a first course of acitretin, ciclosporin, FAEs or methotrexate between 2007 and 2021 with ≥ 6 months' follow-up. Effectiveness was defined as achieving absolute Psoriasis Area and Severity Index (aPASI) ≤ 2 reported ≥ 4 weeks after treatment start date until date of cessation. To identify baseline clinical variables associated with treatment effectiveness, we used multivariable logistic regression models estimating the adjusted odds ratio (aOR) of achieving aPASI ≤ 2. To describe drug persistence associated with ineffectiveness, occurrence of adverse events or other reasons for discontinuation, survival estimates with 95% confidence intervals (CIs) were obtained using a flexible parametric model. Results were obtained using multiple imputed data. RESULTS: In total, 5430 patients were included in the analysis. Overall, 1023 (19%) patients were receiving acitretin, 1401 (26%) patients were on ciclosporin, 347 (6%) patients were on FAEs, and 2659 (49%) patients were receiving methotrexate at registration. The proportion of patients who achieved aPASI ≤ 2 was lower for those treated with acitretin [n = 118 (21%)] compared with those receiving ciclosporin [n = 233 (34%)], FAEs [n = 43 (29%)] and methotrexate [n = 372 (32%)]. Factors associated with ineffectiveness included prior experience to previous nonbiologic systemic therapies (acitretin) (aOR 0.64, 95% CI 0.42-0.96), male sex (methotrexate) (aOR 0.58, 95% CI 0.46-0.74), comorbidities (aOR 0.70, 95% CI 0.51-0.97) and alcohol consumption (≤ 14 units per week) (ciclosporin) (aOR 0.70, 95% CI 0.50-0.98). Persistence associated with all reasons for discontinuation showed better survival for methotrexate compared with acitretin, ciclosporin and FAEs cohorts at 12 months [survival estimate 46.1 (95% CI 44.0-48.3), 31.9 (95% CI 29.4-34.7), 30.0 (95% CI 27.5-32.4) and 35.0 (95% CI 29.9-40.9), respectively]. CONCLUSIONS: The real-world effectiveness and persistence of acitretin, ciclosporin, FAEs and methotrexate were generally low. Previous nonbiologic systemic therapies, male sex, comorbidities and alcohol consumption were risk factors associated with treatment ineffectiveness.

Dactylitis is an indicator of a more severe phenotype independently associated with greater SJC, CRP, ultrasound synovitis and erosive damage in DMARD-naive early psoriatic arthritis.

OBJECTIVE: To characterise the impact of dactylitis in disease-modifying antirheumatic drug (DMARD)-naive early psoriatic arthritis (PsA). METHODS: Patients with early PsA meeting the classification criteria for PsA (CASPAR) were recruited. Clinical outcomes were recorded, and ultrasonography was conducted to assess grey scale (GS) and power Doppler (PD) synovitis, periarticular cortical bone erosions and enthesitis. The cohort was dichotomised by the presence or absence of dactylitis. RESULTS: Of 177 patients with PsA, those with dactylitis (dactylitic PsA (81/177, 46%)) had higher tender joint count (p<0.01), swollen joint count (SJC) (p<0.001) and C reactive protein (CRP) (p<0.01) than non-dactylitic PsA. Dactylitis was more prevalent in toes (146/214 (68.2%)) than fingers (68/214 (31.8%)); 'hot' dactylitis was more prevalent than 'cold' (83.6% vs 16.4%). Ultrasound (US) synovitis and erosions were significantly more prevalent in dactylitic PsA (p<0.001 and p<0.001, respectively). Exclusion of dactylitis in dactylitic PsA confirmed significantly greater SJC (3 vs 1, p=0.002), US synovitis (GS ≥2: 20.6% vs 16.1%, p<0.001, or PD ≥1: 5.1% vs 3.3%, p<0.001) and erosions (1.1% vs 0.5% joints, p=0.008; 26.1% vs 12.8% patients, p=0.035%) than non-dactylitic PsA. Synovitis (GS ≥2 and/or PD ≥1) occurred in 53.7% of dactylitis. No substantial differences were observed for US enthesitis. CONCLUSION: Dactylitis signifies a more severe disease phenotype independently associated with an increased disease burden with greater SJC, CRP, US-detected synovitis and bone erosions in DMARD-naive early PsA and may be a useful discriminator for early risk stratification.

Machine-learning, MRI bone shape and important clinical outcomes in osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVES: Osteoarthritis (OA) structural status is imperfectly classified using radiographic assessment. Statistical shape modelling (SSM), a form of machine-learning, provides precise quantification of a characteristic 3D OA bone shape. We aimed to determine the benefits of this novel measure of OA status for assessing risks of clinically important outcomes. METHODS: The study used 4796 individuals from the Osteoarthritis Initiative cohort. SSM-derived femur bone shape (B-score) was measured from all 9433 baseline knee MRIs. We examined the relationship between B-score, radiographic Kellgren-Lawrence grade (KLG) and current and future pain and function as well as total knee replacement (TKR) up to 8 years. RESULTS: B-score repeatability supported 40 discrete grades. KLG and B-score were both associated with risk of current and future pain, functional limitation and TKR; logistic regression curves were similar. However, each KLG included a wide range of B-scores. For example, for KLG3, risk of pain was 34.4 (95% CI 31.7 to 37.0)%, but B-scores within KLG3 knees ranged from 0 to 6; for B-score 0, risk was 17.0 (16.1 to 17.9)% while for B-score 6, it was 52.1 (48.8 to 55.4)%. For TKR, KLG3 risk was 15.3 (13.3 to 17.3)%; while B-score 0 had negligible risk, B-score 6 risk was 35.6 (31.8 to 39.6)%. Age, sex and body mass index had negligible effects on association between B-score and symptoms. CONCLUSIONS: B-score provides reader-independent quantification using a single time-point, providing unambiguous OA status with defined clinical risks across the whole range of disease including pre-radiographic OA. B-score heralds a step-change in OA stratification for interventions and improved personalised assessment, analogous to the T-score in osteoporosis.

Comprehensive flow cytometric reference intervals of leukocyte subsets from six study centers across Europe.

A group of European FOCIS Centers of Excellence adapted panels of the Human Immunophenotyping Consortium (HIPC) for whole blood analysis. Using four core panels [T/regulatory T cell/B/natural killer (T/Treg /B/NK) and myeloid cells] the main leukocyte populations were analyzed in a clinical-diagnostic setting in a harmonized manner across different platforms. As a first step, the consortium presents here the absolute and relative frequencies of the leukocyte subpopulations in the peripheral blood of more than 300 healthy volunteers across six different European centers.

A study of 51 subtypes of peripheral blood immune cells in newly diagnosed young type 1 diabetes patients.

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing beta cells in pancreatic islets. Various immune cell populations are involved in disease development and natural course. However, to our knowledge, so far there are no comprehensive comparative investigations of all main immune cell populations and their most important subsets at the onset of disease. Therefore, in the current study, we analyzed 51 peripheral blood immune cell populations in 22 young T1D patients and in 25 age-matched controls using a comprehensive polychromatic flow cytometry panel developed for whole blood by the COST Action no. BM0907 ENTIRE (European Network for Translational Immunology Research and Education: From Immunomonitoring to Personalized Immunotherapy) consortium. We found that in T1D patients, frequencies and absolute counts of natural killer (NK) cells, dendritic cells (DC) and T cells, as well as their respective subsets, were significantly altered compared to controls. Further, we observed that changes in several cell populations (e.g. CD14+ CD16+ non-classical monocytes, plasmablasts) were dependent on the age of the patient. In addition to age-related changes, we also found that alterations in immune cell patterns were associated with parameters such as the presence of ketoacidosis and C-peptide serum levels. Our study provides a foundation for future studies investigating different cell lineages and their role in T1D and illustrates the value of polychromatic flow cytometry for evaluating all main peripheral immune cells and their subsets in whole blood samples.

Psychometric Properties of an Arabic Pain Anxiety Symptoms Scale-20 (PASS-20) in Healthy Volunteers and Patients Attending a Physiotherapy Clinic.

PURPOSE: The aim of this study was to cross-culturally adapt the PASS-20 questionnaire for use in Libya. METHODS: Participants were 71 patients (42 women) attending the physiotherapy clinic, Ibn Sina Hospital, Sirt, Libya for management of persistent pain and 137 healthy unpaid undergraduate students (52 women) from the University of Sirt, Libya. The English PASS-20 was translated into Arabic. Patients completed the Arabic PASS-20 and the Arabic Pain Rating Scales on two occasions separated by a 14-day interval. Healthy participants completed the Arabic PASS-20 on one occasion. RESULTS: The internal consistency (ICC) for pain patient and healthy participant samples yielded a good reliability for the total score, cognitive anxiety, fear of pain, and physiological anxiety. The test-retest reliability of the Arabic PASS-20 score showed high reliability for the total score (ICC = 0.93, p < 0.001), escape/avoidance (ICC = 0.93, p < 0.001), fear of pain (ICC = 0.94, p < 0.001), and physiological anxiety subscales (ICC = 0.96, p < 0.001) and good reliability for the cognitive anxiety (ICC = 0.85, p < 0.001). Inspection of the Promax rotation showed that each factor comprised of five items were consistent with the theoretical constructs of the original PASS-20 subscales. CONCLUSION: The Arabic PASS-20 retained internal consistency and reliability with the original English version and can be used to measure pain anxiety symptoms in both pain and healthy individual samples in Libya.

Age-dependent improvements in survival after hospitalisation with acute myocardial infarction: an analysis of the Myocardial Ischemia National Audit Project (MINAP).

BACKGROUND: recent studies report an age-dependent decline in mortality after acute myocardial infarction (AMI). OBJECTIVE: to investigate age-dependent improvements in survival after hospitalisation with AMI. DESIGN: population-based cohort study using data from the Myocardial Ischaemia National Audit Project. SUBJECTS: a total of 583,466 patients with AMI admitted to 247 hospitals between 1 January 2003 and 31 December 2010. METHODS: six-month relative survival (RS) was calculated from the ratio of observed to expected survival using an age-, sex- and biennial year-matched population from the Office for National Statistics. Risk-adjusted mortality rates (RMAR) were estimated using shared frailty regression. Data were stratified by age group, AMI phenotype [(ST-elevation myocardial infarction, (STEMI) and non-STEMI, (NSTEMI)] and period of admission to hospital. RESULTS: for STEMI, there was an increase in RS for patients aged 65-80 years (84.8 versus 89.2%) and those over 80 years (68.0 versus 71.8%), but not for patients aged 18 to <65 years (96.4 versus 96.9%). For NSTEMI patients aged 18 to <65 years RS was higher, but stable (95.5 versus 96.8%) and improved for patients aged 65-80 years (83.2 versus 88.5%) and patients aged >80 years (68.3% versus 75.5%). Likewise, RMAR improved for patients aged ≥65 years, were stable and higher for patients <65 years. CONCLUSIONS: there were significant improvements in survival after hospitalisation with AMI in the older but not younger patients. The scope for further reductions in mortality is likely to be much greater for older than younger patients with AMI.

Risk of Paradoxical Eczema in Patients Receiving Biologics for Psoriasis.

Importance: Biologics used for plaque psoriasis have been reported to be associated with an atopic dermatitis (AD) phenotype, or paradoxical eczema, in some patients. The risk factors for this are unknown. Objective: To explore risk of paradoxical eczema by biologic class and identify factors associated with paradoxical eczema. Design, Setting, and Participants: This prospective cohort study used data from the British Association of Dermatologists Biologics and Immunomodulators Register for adults treated with biologics for plaque psoriasis who were seen at multicenter dermatology clinics in the UK and Ireland. Included participants were registered and had 1 or more follow-up visits between September 2007 and December 2022. Exposures: Duration of exposure to tumor necrosis factor (TNF) inhibitors, interleukin (IL) 17 inhibitors, IL-12/23 inhibitors, or IL-23 inhibitors until paradoxical eczema onset, treatment discontinuation, last follow-up, or death. Main Outcomes and Measures: Incidence rates of paradoxical eczema, paradoxical eczema risk by biologic class, and the association of demographic and clinical variables with risk of paradoxical eczema were assessed using propensity score-weighted Cox proportional hazards regression models. Results: Of 56 553 drug exposures considered, 24 997 from 13 699 participants were included. The 24 997 included exposures (median age, 46 years [IQR, 36-55 years]; 57% male) accrued a total exposure time of 81 441 patient-years. A total of 273 exposures (1%) were associated with paradoxical eczema. The adjusted incidence rates were 1.22 per 100 000 person-years for IL-17 inhibitors, 0.94 per 100 000 person-years for TNF inhibitors, 0.80 per 100 000 person-years for IL-12/23 inhibitors, and 0.56 per 100 000 person-years for IL-23 inhibitors. Compared with TNF inhibitors, IL-23 inhibitors were associated with a lower risk of paradoxical eczema (hazard ratio [HR], 0.39; 95% CI, 0.19-0.81), and there was no association of IL-17 inhibitors (HR, 1.03; 95% CI, 0.74-1.42) or IL-12/23 inhibitors (HR, 0.87; 95% CI, 0.66-1.16) with risk of paradoxical eczema. Increasing age (HR, 1.02 per year; 95% CI, 1.01-1.03) and history of AD (HR, 12.40; 95% CI, 6.97-22.06) or hay fever (HR, 3.78; 95% CI, 1.49-9.53) were associated with higher risk of paradoxical eczema. There was a lower risk in males (HR, 0.60; 95% CI, 0.45-0.78). Conclusions and Relevance: In this study, in biologic-treated patients with psoriasis, paradoxical eczema risk was lowest in patients receiving IL-23 inhibitors. Increasing age, female sex, and history of AD or hay fever were associated with higher risk of paradoxical eczema. The overall incidence of paradoxical eczema was low. Further study is needed to replicate these findings.

Ultrasound shows swollen joints are the better proxy for synovitis than tender joints in DMARD-naïve early psoriatic arthritis.

Objective: To evaluate the relationship between clinical examination/US synovitis in DMARD-naïve early PsA. Methods: Eligible patients underwent matched clinical/US 44-joint assessment for tender and/or swollen joints (TJ/SJ) and US synovitis [grey scale (GS) ≥ 2 or power Doppler (PD) ≥ 1]. Statistical agreement between TJ/SJ, GS ≥ 2 and PD ≥ 1 was calculated by prevalence-adjusted and bias-adjusted κ (PABAK). To derive probabilities of GS ≥ 2/PD ≥ 1, mixed-effects logistic regression-modelled odds of US synovitis in TJ/SJ were conducted. Results: In 155 patients, 5616 joints underwent clinical/US examination. Of these joints, 1039 of 5616 (18.5%) were tender, 550 of 5616 (9.8%) were swollen, 1144 of 5616 (20.4%) had GS ≥ 2, and 292 of 5616 (5.2%) had PD ≥ 1. GS ≥ 2 was most prevalent in concomitantly tender and swollen joints [205 of 462 (44%)], followed by swollen non-tender joints [32 of 88 (36.4%)], tender non-swollen joints [148 of 577 (25.7%)] and non-tender non-swollen joints (subclinical synovitis) [759 of 4489 (16.9%)]. Agreement between SJ/PD ≥ 1 was high at the individual joint level (82.6-96.3%, PABAK 0.65-0.93) and for total joints combined (89.9%, PABAK 0.80). SJ/GS ≥ 2 agreement was greater than between TJ/GS ≥ 2 [73.5-92.6% vs 51.0-87.4% (PABAK 0.47-0.85 vs PABAK 0.35-0.75), respectively]. Swelling was independently associated with higher odds of GS ≥ 2 [odds ratio (OR) (95% CI); 4.37 (2.62, 7.29); P < 0.001] but not tenderness [OR = 1.33 (0.87, 2.06); P = 0.192]. Swelling [OR = 8.78 (3.92, 19.66); P < 0.001] or tenderness [OR = 3.38 (1.53, 7.50); P = 0.003] was independently associated with higher odds of PD ≥ 1. Conclusion: Synovitis (GS ≥ 2 and/or PD ≥ 1) was more likely in swollen joints than in tender joints in DMARD-naïve, early PsA. Agreement indicated that swollen joints were the better proxy for synovitis, adding to greater understanding between clinical and US assessments.

Quality of life trajectories in survivors of acute myocardial infarction: a national longitudinal study.

AIM: To define trajectories of perceived health-related quality of life (HRQoL) among survivors of acute myocardial infarction (AMI) and identify factors associated with trajectories. METHODS: Data on HRQoL among 9566 survivors of AMI were collected from 77 National Health Service hospitals in England between 1 November 2011 and 24 June 2015. Longitudinal HRQoL was collected using the EuroQol five-dimension questionnaire measured at hospitalisation, 1, 6 and 12 months post-AMI. Trajectories of perceived HRQoL post-MI were determined using multilevel regression analysis and latent class growth analysis (LCGA). RESULTS: One or more percieved health problems in mobility, self-care, usual activities, pain/discomfort and anxiety/depression was reported by 69.1% (6607/9566) at hospitalisation and 59.7% (3011/5047) at 12 months. Reduced HRQoL was associated with women (-4.07, 95% CI -4.88 to -3.25), diabetes (-2.87, 95% CI -3.87 to -1.88), previous AMI (-1.60, 95% CI -2.72 to -0.48), previous angina (-1.72, 95% CI -2.77 to -0.67), chronic renal failure (-2.96, 95% CI -5.08 to -0.84; -3.10, 95% CI -5.72 to -0.49), chronic obstructive pulmonary disease (-3.89, 95% CI -5.07 to -2.72) and cerebrovascular disease (-2.60, 95% CI -4.24 to -0.96). LCGA identified three subgroups of HRQoL which we labelled: improvers (68.1%), non-improvers (22.1%) and dis-improvers (9.8%). Non-improvers and dis-improvers were more likely to be women, non-ST-elevation myocardial infarction (NSTEMI) and have long-term health conditions, compared with improvers. CONCLUSIONS: Quality of life improves for the majority of survivors of AMI but is significantly worse and more likely to decline for women, NSTEMI and those with long-term health conditions. Assessing HRQoL both in hospital and postdischarge may be important in determining which patients could benefit from tailored interventions. TRIAL REGISTRATION: NCT01808027 and NCT01819103.

Statistics on mortality following acute myocardial infarction in 842 897 Europeans.

AIMS: To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments. METHODS AND RESULTS: National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 patients, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART)] and the UK [n = 247, 662 529 patients, Myocardial Ischaemia National Audit Project (MINAP)] between 2003 and 2013. There were lower rates of revascularization [STEMI (43.8% vs. 74.9%); NSTEMI (27.5% vs. 43.6%)] and pharmacotherapies at time of hospital discharge including [aspirin (82.9% vs. 90.2%) and (79.9% vs. 88.0%), ß-blockers (73.4% vs. 86.4%) and (65.3% vs. 85.1%)] in the UK compared with Sweden, respectively. Standardized net probability of death (NPD) between admission and 1 month was higher in the UK for STEMI [8.0 (95% confidence interval 7.4-8.5) vs. 6.7 (6.5-6.9)] and NSTEMI [6.8 (6.4-7.2) vs. 4.9 (4.7-5.0)]. Between 6 months and 1 year and more than 1 year, NPD remained higher in the UK for NSTEMI [2.9 (2.5-3.3) vs. 2.3 (2.2-2.5)] and [21.4 (20.0-22.8) vs. 18.3 (17.6-19.0)], but was similar for STEMI [0.7 (0.4-1.0) vs. 0.9 (0.7-1.0)] and [8.4 (6.7-10.1) vs. 8.3 (7.5-9.1)]. CONCLUSION: Short-term mortality following STEMI and NSTEMI was higher in the UK compared with Sweden. Mid- and longer-term mortality remained higher in the UK for NSTEMI but was similar for STEMI. Differences in mortality may be due to differential use of guideline-indicated treatments.

Excess mortality and guideline-indicated care following non-ST-elevation myocardial infarction.

BACKGROUND: Adherence to guideline-indicated care for the treatment of non-ST-elevation myocardial infarction (NSTEMI) is associated with improved outcomes. We investigated the extent and consequences of non-adherence to guideline-indicated care across a national health system. METHODS: A cohort study ( ClinicalTrials.gov identifier: NCT02436187) was conducted using data from the Myocardial Ischaemia National Audit Project ( n = 389,057 NSTEMI, n = 247 hospitals, England and Wales, 2003-2013). Accelerated failure time models were used to quantify the impact of non-adherence on survival according to dates of guideline publication. RESULTS: Over a period of 1,079,044 person-years (median 2.2 years of follow-up), 113,586 (29.2%) NSTEMI patients died. Of those eligible to receive care, 337,881 (86.9%) did not receive one or more guideline-indicated intervention; the most frequently missed were dietary advice ( n = 254,869, 68.1%), smoking cessation advice ( n = 245,357, 87.9%), P2Y12 inhibitors ( n = 192,906, 66.3%) and coronary angiography ( n = 161,853, 43.4%). Missed interventions with the strongest impact on reduced survival were coronary angiography (time ratio: 0.18, 95% confidence interval (CI): 0.17-0.18), cardiac rehabilitation (time ratio: 0.49, 95% CI: 0.48-0.50), smoking cessation advice (time ratio: 0.53, 95% CI: 0.51-0.57) and statins (time ratio: 0.56, 95% CI: 0.55-0.58). If all eligible patients in the study had received optimal care at the time of guideline publication, then 32,765 (28.9%) deaths (95% CI: 30,531-33,509) may have been prevented. CONCLUSION: The majority of patients hospitalised with NSTEMI missed at least one guideline-indicated intervention for which they were eligible. This was significantly associated with excess mortality. Greater attention to the provision of guideline-indicated care for the management of NSTEMI will reduce premature cardiovascular deaths.

Sex Differences in Treatments, Relative Survival, and Excess Mortality Following Acute Myocardial Infarction: National Cohort Study Using the SWEDEHEART Registry.

BACKGROUND: This study assessed sex differences in treatments, all-cause mortality, relative survival, and excess mortality following acute myocardial infarction. METHODS AND RESULTS: A population-based cohort of all hospitals providing acute myocardial infarction care in Sweden (SWEDEHEART [Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies]) from 2003 to 2013 was included in the analysis. Excess mortality rate ratios (EMRRs), adjusted for clinical characteristics and guideline-indicated treatments after matching by age, sex, and year to background mortality data, were estimated. Although there were no sex differences in all-cause mortality adjusted for age, year of hospitalization, and comorbidities for ST-segment-elevation myocardial infarction (STEMI) and non-STEMI at 1 year (mortality rate ratio: 1.01 [95% confidence interval (CI), 0.96-1.05] and 0.97 [95% CI, 0.95-0.99], respectively) and 5 years (mortality rate ratio: 1.03 [95% CI, 0.99-1.07] and 0.97 [95% CI, 0.95-0.99], respectively), excess mortality was higher among women compared with men for STEMI and non-STEMI at 1 year (EMRR: 1.89 [95% CI, 1.66-2.16] and 1.20 [95% CI, 1.16-1.24], respectively) and 5 years (EMRR: 1.60 [95% CI, 1.48-1.72] and 1.26 [95% CI, 1.21-1.32], respectively). After further adjustment for the use of guideline-indicated treatments, excess mortality among women with non-STEMI was not significant at 1 year (EMRR: 1.01 [95% CI, 0.97-1.04]) and slightly higher at 5 years (EMRR: 1.07 [95% CI, 1.02-1.12]). For STEMI, adjustment for treatments attenuated the excess mortality for women at 1 year (EMRR: 1.43 [95% CI, 1.26-1.62]) and 5 years (EMRR: 1.31 [95% CI, 1.19-1.43]). CONCLUSIONS: Women with acute myocardial infarction did not have statistically different all-cause mortality, but had higher excess mortality compared with men that was attenuated after adjustment for the use of guideline-indicated treatments. This suggests that improved adherence to guideline recommendations for the treatment of acute myocardial infarction may reduce premature cardiovascular death among women. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02952417.

Use of relative survival to evaluate non-ST-elevation myocardial infarction quality of care and clinical outcomes.

Survival after non-ST-elevation myocardial infarction (NSTEMI) is high and non-cardiovascular death has become more frequent. Observational studies typically quantify quality of care and clinical outcomes using all-cause mortality, which nowadays may not reflect the impact of index NSTEMI. We review and investigate relative survival for quantifying longer term outcomes after NSTEMI. National cohort study of hospitalized NSTEMI (Myocardial Ischaemia National Audit Project; patients: n = 346 546, hospitals: n = 243, countries: England and Wales). Mortality rates derived from two relative survival techniques were compared with all-cause mortality, and the impact of relative survival adjusted patient characteristics compared with those from Cox proportional estimates. Cox proportional hazards models provide lower survival estimates because they include deaths from all causes, overestimate the impact of increasing age on survival, and underestimate temporal improvements in care. The Royston-Parmar model allows more accurate estimation of relative survival because it is flexible to the high early hazard of death after hospitalized NSTEMI. All-cause mortality gives an overall assessment of survival for a cohort of patients. Relative survival provides a more accurate and informed estimation of the impact of an index cardiovascular event and, if necessary, patient characteristics on survival.

Kinetic evidence for different mechanisms of interaction of black mamba toxins MT alpha and MT beta with muscarinic receptors.

By studying the influence of two toxins from the black mamba Dendroaspis polylepis on the kinetics of [3H]-N-methylscopolamine binding to muscarinic acetylcholine receptors from rat cerebral cortex, it was revealed that these toxins, MT alpha and MT beta, interact with the receptors via kinetically distinct mechanisms. MT beta bound to receptors in a one-step, readily reversible process with the dissociation constant K(d)=5.3 microM. The binding mechanism of MTalpha was more complex, involving at least two consecutive steps. A fast receptor-toxin complex formation (K(T)=3.8 microM) was followed by a slow process of isomerisation of this complex (k(i)=1.8 x 10(-2) s(-1), half-time 39 s). A similar two-step interaction mechanism has been established for a related toxin, MT2 from the green mamba D. angusticeps (K(T)=1.4 microM, k(i)=8.3 x 10(-4) s(-1), half-time 840 s). The slow isomerisation process delays the effect of MT alpha and MT2, but increases their apparent potency compared to toxins unable to induce the isomerisation process.

Purification and sequence determination of a new muscarinic toxin (MT4) from the venom of the green mamba (Dendroaspis angusticeps).

A toxin which partially inhibited [3H]N-methylscopolamine binding to rat brain muscarinic receptors was purified from the venom of green mamba, Dendroaspis angusticeps. The N-terminal sequence (up to 45 amino acids) was determined by automated Edman degradation of the whole molecule. The complete sequence was elucidated after enzymatic cleavage with endoproteinase Arg-C or endoproteinase Lys-C and peptide fragments purification. The identity of the C-terminal amino acid was confirmed by hydrazinolysis. The new toxin (MT4) had eight half-cystines and 66 amino acids. It differed from muscarinic toxin MT1 by a single substitution in position 57 (arginine in MT1, histidine in MT4), proximal to the sixth half-cystine.