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The Global Registry of Acute Coronary Event (GRACE) risk score was developed in a large multinational registry to predict in-hospital mortality across the broad spectrum of acute coronary syndromes (ACS). Because of the substantial regional variation and temporal changes in patient characteristics and management patterns, we sought to validate this risk score in a contemporary Canadian population with ACS. The main GRACE and GRACE 2 registries are prospective, multicenter, observational studies of patients with ACS (June 1999 to December 2007). For each patient, we calculated the GRACE risk score and evaluated its discrimination and calibration by the c statistic and the Hosmer-Lemeshow goodness-of-fit test, respectively. To assess the impact of temporal changes in management on the GRACE risk score performance, we evaluated its discrimination and calibration after stratifying the study population into prespecified subgroups according to enrollment period, type of ACS, and whether the patient underwent coronary angiography or revascularization during index hospitalization. A total of 12,242 Canadian patients with ACS were included; the median GRACE risk score was 127 (25th and 75th percentiles were 103 and 157, respectively). Overall, the GRACE risk score demonstrated excellent discrimination ( c statistic 0.84, 95% CI 0.82-0.86, P < .001) for in-hospital mortality. Similar results were seen in all the subgroups (all c statistics ≥0.8). However, calibration was suboptimal overall (Hosmer-Lemeshow P = .06) and in various subgroups. GRACE risk score is a valid and powerful predictor of adverse outcomes across the wide range of Canadian patients with ACS. Its excellent discrimination is maintained despite advances in management over time and is evident in all patient subgroups. However, the predicted probability of in-hospital mortality may require recalibration in the specific health care setting and with advancements in treatment.

Since the introduction of newer, more potent P2Y12 receptor inhibitors (P2Y12ris), practice patterns and associated clinical outcomes in patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) and also requiring oral anticoagulation (OAC) have not been fully characterized. The Canadian Observational Antiplatelet Study was a prospective, multicenter, longitudinal, observational study (26 hospitals, December 2011 to May 2013) describing P2Y12ri treatment patterns and outcomes in patients with ST-elevation and non–ST-elevation MI undergoing PCI. We describe the clinical characteristics, treatment patterns, bleeding, and ischemic outcomes over the 15-month follow-up within and between the subgroups of patients discharged on either dual-antiplatelet therapy (DAPT) (acetyl salicylic acid [ASA]+P2Y12ri) or triple therapy (ASA+P2Y12ri+OAC). Of the 2,034 patients at discharge, 86% (n = 1,757) were on DAPT, whereas 14% (n = 277) were on triple therapy (50% warfarin, 50% non–vitamin K OAC [NOAC]). The frequency of newer P2Y12ri use (prasugrel or ticagrelor) was similar in the DAPT and triple therapy groups (28% vs 26%, respectively). In the triple therapy group, NOAC use was higher in those receiving a new P2Y12ri compared to those receiving clopidogrel (75% vs 41%, respectively, P < .0001). The unadjusted and adjusted events of major cardiovascular event (MACE) and bleeding were higher in the triple therapy group. For patients on triple therapy, the bleeding or MACE events were not significantly different between those on clopidogrel versus those on ticagrelor or prasugrel. In this observational study of MI patients requiring PCI, 1 in 8 were discharged on triple antithrombotic therapy, of whom 26% were on newer P2Y12ris. Patients on triple therapy had higher risk at baseline, with higher unadjusted and adjusted MACE and bleeding events compared to those on DAPT alone. Among triple therapy–treated patients, there was no difference in the MACE and bleeding events regardless of the P2Y12ri used.

Randomized trials have established the efficacy of antianginal medications in the treatment of chronic stable coronary disease. Using data from the Global Registry of Acute Coronary Events (GRACE) and Canadian Registry of Acute Coronary Events (CANRACE), we examined the temporal trends in antianginal use (beta blockers, calcium antagonists, and nitrates) before non-ST-elevation acute coronary syndrome presentation from 1999 to 2008 in 10,019 patients. The relationships among previous antianginal use, clinical characteristics on presentation, and in-hospital management and outcomes were examined. Beta blockers were the most commonly used agents, and there was a significant decline in the use of nitrates over time. Compared with patients not on any antianginal therapy before presentation, those on treatment were more likely to be older, female, and have a history of hypertension, diabetes, previous angina, and myocardial infarction; they were less likely to present with positive biomarkers (all p <0.001). Patients not on antianginal therapy before presentation were more likely to undergo coronary angiography and percutaneous coronary intervention and less likely to have recurrent ischemia during hospitalization (all p <0.001). In multivariable analysis, previous antianginal use was independently associated with lower use of coronary angiography in hospital (p = 0.034) but not with in-hospital mortality. In conclusion, there has significant temporal decline in nitrate use before non-ST-elevation acute coronary syndrome. Patients receiving antianginal therapy before presentation more frequently had preexisting cardiovascular disease and previous revascularization and were less likely to present with non-ST-segment elevation MI compared with patients on no antianginal therapies. Previous antianginal use was independently associated with a lower use of coronary angiography in hospital.

Background Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue neoplasm with a deceptively benign histological appearance. Local recurrences and metastases can manifest many years following excision. The FUS-CREB3L2 gene translocation, which occurs commonly in LGFMS, may be detected by reverse-transcriptase polymerase chain reaction (RT-PCR) and fluorescence in situ hybridisation (FISH). We assessed the relationship between clinical outcome and translocation test result by both methods. Methods We report genetic analysis of 23 LGFMS cases and clinical outcomes of 18 patients with mean age of 40.6 years. During follow-up (mean 24.8 months), there were no cases of local recurrence or metastasis. One case was referred with a third recurrence of a para-spinal tumour previously incorrectly diagnosed as a neurofibroma. Results Results showed 50% of cases tested positive for the FUS-CREB3L2 translocation by RT-PCR and 81.8% by FISH, suggesting FISH is more sensitive than RT-PCR for confirming LGFMS diagnosis. Patients testing positive by both methods tended to be younger and had larger tumours. Despite this, there was no difference in clinical outcome seen during short and medium-term follow-up. Conclusions RT-PCR and FISH for the FUS-CREB3L2 fusion transcript are useful tools for confirming LGFMS diagnosis, but have no role in predicting medium-term clinical outcome. Due to the propensity for late recurrence or metastasis, wide excision is essential, and longer-term follow-up is required. This may identify a difference in long-term clinical outcome between translocation-positive and negative patients.

Although randomized controlled trials support the use of intensive medical and invasive therapies for non-ST segment elevation acute coronary syndromes (NSTE-ACS), major bleeding is a serious treatment complication. We sought to determine the temporal trend of in-hospital major bleeding among patients with NSTE-ACS, in relation to the evolving management pattern. We identified 14 111 NSTE-ACS patients enrolled in 4 successive, prospective, multicenter registries (ACS I, 1999-2001; ACS II, 2002-2003; GRACE, 2004-2007; and CANRACE, 2008) in Canada between 1999 and 2008. We collected data on patient characteristics, use of cardiac medications and procedures on standardized case report forms. In all registries, major bleeding was defined a priori as life threatening or fatal bleeding, bleeding requiring transfusion of ≥2 U of packed red cells, or resulting in an absolute decrease in hemoglobin of >30g/L. A total of 14 111 patients had a final diagnosis of NSTE-ACS and were included in this study (3294 in the ACS-I registry, 1956 in the ACS-II registry, 7543 in GRACE, and 1318 in CANRACE). Over time, there was a substantial increase in the use of dual anti-platelet (aspirin and thienopyridine) therapy ( P for trend <.001), and in rates of in-hospital cardiac catheterization and percutaneous coronary intervention (both Ps for trend <.001). Overall, major bleeding was relatively infrequent (1.7%). There was no significant increase in the unadjusted rates of major bleeding over time ( P for trend = .19). In multivariable analysis adjusting for GRACE risk score and intensive treatment, enrolment period was not an independent predictor of bleeding ( P for trend = .98). There was no interaction between the enrolment period and the use of intensive medical and invasive management. Despite more widespread use of dual anti-platelet therapies and invasive cardiac procedures in the management of NSTE-ACS, the rate of major bleeding remains relatively low and has not increased significantly over time. Our findings suggest that physicians selectively target treatment for their patients, and these evidence-based therapies can be safely administered to ACS patients in clinical practice.

Randomized trials have established efficacy of clopidogrel in various types of acute coronary syndromes (ACS). The objective of this study was to examine the temporal trends and patterns of early clopidogrel use (within the first 24 hours of hospitalization) across the spectrum of patients with ACS in Canada. Using the multinational, prospective GRACE (Global Registry of Acute Coronary Events) and GRACE 2, we identified 11,177 patients who were admitted for ACS from January 2003 to December 2007 in Canada. Demographic information, clinical features, and treatment were recorded. We examined the early use of clopidogrel over time and in relation to the type of ACS, clinical features on presentation, and the mode of reperfusion therapy. Of the 11,177 patients with ACS, 3,091 (27.7%) had ST-elevation myocardial infarction (STEMI), 5,194 (46.5%) had non–STEMI, and 2,892 (25.9%) had unstable angina; the rates of early clopidogrel administration were 63.0%, 66.6%, and 57.2%, respectively ( P < .001). Overall, there was a significant increase in clopidogrel use over the period studied ( P for trend < .001). In patients with non–ST-elevation ACS (non-STEMI and unstable angina), clopidogrel use was higher among those with positive cardiac biomarkers compared to those without (67.1% vs 59.8%, P < .001) but similar in the groups with and without ST deviation. There was an inverse relationship between GRACE risk score and rates of early clopidogrel administration. In patients with STEMI receiving fibrinolytic therapy, only 55.7% of patients <65 years old received clopidogrel compared with 47.0% and 42.6% of patients 65 to 74 and >75 years old, respectively ( P for trend < .001). Although early use of clopidogrel therapy has increased over time across the spectrum of ACS, a significant proportion of eligible patients still do not receive this evidence-based therapy. There is a need to optimize the use of proven antiplatelet therapies to improve clinical outcome.

After surgery for a broken ankle, patients are usually instructed to avoid walking for 6 weeks (delayed weight-bearing). Walking 2 weeks after surgery (early weight-bearing) might be a safe and preferable rehabilitation strategy. This study aimed to determine the clinical and cost effectiveness of an early weight-bearing strategy compared with a delayed weight-bearing strategy. This was a pragmatic, multicentre, randomised, non-inferiority trial including 561 participants (aged ≥18 years) who received acute surgery for an unstable ankle fracture in 23 UK National Health Service (NHS) hospitals who were assigned to either a delayed weight-bearing (n=280) or an early weight-bearing rehabilitation strategy (n=281). Patients treated with a hindfoot nail, those who did not have protective ankle sensation (eg, peripheral neuropathy), did not have the capacity to consent, or did not have the ability to adhere to trial procedures were excluded. Neither participants nor clinicians were masked to the treatment. The primary outcome was ankle function measured using the Olerud and Molander Ankle Score (OMAS) at 4 months after randomisation, in the per-protocol population. The pre-specified non-inferiority OMAS margin was –6 points and superiority testing was included in the intention-to-treat population in the event of non-inferiority. The trial was prospectively registered with ISRCTN Registry, ISRCTN12883981, and the trial is closed to new participants. Primary outcome data were collected from 480 (86%) of 561 participants. Recruitment was conducted between Jan 13, 2020, and Oct 29, 2021. At 4 months after randomisation, the mean OMAS score was 65·9 in the early weight-bearing and 61·2 in the delayed weight-bearing group and adjusted mean difference was 4·47 (95% CI 0·58 to 8·37, p=0·024; superiority testing adjusted difference 4·42, 95% CI 0·53 to 8·32, p=0·026) in favour of early weight-bearing. 46 (16%) participants in the early weight-bearing group and 39 (14%) in the delayed weight-bearing group had one or more complications (adjusted odds ratio 1·18, 95% CI 0·80 to 1·75, p=0·40). The mean costs from the perspective of the NHS and personal social services in the early and delayed weight-bearing groups were £725 and £785, respectively (mean difference –£60 [95% CI –342 to 232]). The probability that early weight-bearing is cost-effective exceeded 80%. An early weight-bearing strategy was found to be clinically non-inferior and highly likely to be cost-effective compared with the current standard of care (delayed weight-bearing). National Institute for Health and Care Research (NIHR), NIHR Barts Biomedical Research Centre, and NIHR Applied Research Collaboration Oxford and Thames Valley.

Christine Korsgaard’s Self-Constitution: Agency, Identity, and Integrity is an impressive endeavour to synthesize the ethics of Plato and Kant in a comprehensive account of action and agency that locates the key to understanding both in self-constitution. A purportedly comprehensive account of action and agency will fail on its own terms if it cannot adequately account for some morally salient phenomenon. Korsgaard’s account fails to adequately account for the possibility of evil actions and evil people. If self-constitution is key to action and agency, then we must abandon the Platonic and Kantian elements that Korsgaard endorses. L’ouvrage de Christine Korsgaard intitulé Self-Constitution: Agency, Identity, and Integrity représente un remarquable travail de synthèse des éthiques platonicienne et kantienne qui, de manière exhaustive, rend compte de l’action et de l’agentivité sous le prisme de la constitution de soi. Toute tentative de saisie parfaite de l’action et de l’agentivité en termes propres ne saurait aboutir sans une prise en compte adéquate d’un quelconque phénomène moral saillant. L’approche de Korsgaard ne prend pas suffisamment en compte la possibilité du mal sous forme d’actions ou d’individus. Si la constitution de soi demeure centrale pour l’action et l’agentivité, alors il faudra mettre à l’écart les éléments platoniciens et kantiens que Korsgaard fait siens.

Gemella haemolysans is a Gram-positive coccus and commensal of the upper respiratory tract and oral mucosa that rarely causes clinically important infections. There is only one previous report of this organism causing periprosthetic infection, in a total knee arthroplasty. We present a case of septic loosening of an uncemented total hip arthroplasty due to G. haemolysans, in an asplenic patient with insulin dependent diabetes mellitus. Treatment with two-stage revision has been successful at 7 years of follow-up.