PFO and stroke: what are the data?

Patent foramen ovale (PFO) is a frequent finding on echocardiography and occurs in over 25% of the population. In young patients with cryptogenic stroke, the frequency is much higher suggesting paradoxical embolization may be responsible for the clinical events. There are conflicting data from studies examining the association between PFO and stroke. The combination of atrial septal aneurysm and PFO, and PFO size and severity of right-to-left shunt may add additional risk but again the data are insufficient for definite conclusions. Available information suggests no difference in subsequent stroke in patients with PFO treated with aspirin or warfarin for secondary prevention. Endovascular closure is technically feasible, but not without the possibility of periprocedural complications. Comparison of medical and endovascular closure of PFOs in patients with stroke is ongoing in 2 major randomized trials.     

How ideology shapes the evidence and the policy: what do we know about cannabis use and what should we do?

In the United Kingdom, as in many places, cannabis use is considered substantially within a criminal justice rather than a public health paradigm with prevention policy embodied in the Misuse of Drugs Act. In 2002 the maximum custodial sentence tariff for cannabis possession under the Act was reduced from 5 to 2 years. Vigorous and vociferous public debate followed this decision, centred principally on the question of whether cannabis use caused schizophrenia. It was suggested that new and compelling evidence supporting this hypothesis had emerged since the re‐classification decision was made, meaning that the decision should be reconsidered. The re‐classification decision was reversed in 2008. We consider whether the strength of evidence on the psychological harms of cannabis has changed substantially and discuss the factors that may have influenced recent public discourse and policy decisions. We also consider evidence for other harms of cannabis use and public health implications of preventing cannabis use. We conclude that the strongest evidence of a possible causal relation between cannabis use and schizophrenia emerged more than 20 years ago and that the strength of more recent evidence may have been overstated—for a number of possible reasons. We also conclude that cannabis use is almost certainly harmful, mainly because of its intimate relation to tobacco use. The most rational policy on cannabis from a public health perspective would seem to be one able to achieve the benefit of reduced use in the population while minimizing social and other costs of the policy itself. Prohibition, whatever the sentence tariff associated with it, seems unlikely to fulfil these criteria.     

Nonsteroidal anti-inflammatory drugs and the heart: what is the danger?

Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX-2) inhibitors, or "coxibs," are used for a number of disease conditions for relief of pain and inflammation. Currently available data suggest concern for prothrombotic risk with coxibs and some NSAIDs, and the magnitude of risk may vary with individual agents. NSAIDs and coxibs also increase blood pressure, worsen hypertension control, and may precipitate heart failure, with important differences among agents. Physicians should consider patterns of risk and benefit in selecting the most appropriate agent for individual patients based on the individual gastrointestinal and cardiovascular risk profile.     

Precision medicine and the antiphospholipid syndrome: what is the future?

Clinical Rheumatology -     

Opening mitochondrial KATP in the heart – what happens, and what does not happen

There is considerable evidence that opening the mitochondrial ATP-sensitive potassium channel (mitoK_ATP) is cardioprotective in ischemia-reperfusion. Two prominent questions surround the role of mitoK_ATP in the cardiomyocyte: How does opening mitoK_ATP protect? What is the normal physiological role of mitoK_ATP in the heart? Before these questions can be addressed, it is necessary to agree on the bioenergetic consequences of opening mitoK_ATP, and this distills down to a single question – does opening mitoK_ATP cause significant uncoupling or not? The evidence strongly indicates that it does not and that reports of uncoupling and inhibition of Ca²⁺ uptake are the result of using toxic concentrations of K_ATP channel openers. Thus, opening mitoK_ATP results in increased K⁺ flux that is sufficient to change mitochondrial volume but is insufficient to cause significant depolarization of membrane potential. The volume changes, however, have significant bioenergetic consequences for energy coupling in the cell.     

High-sensitive troponin T measurements: what do we gain and what are the challenges?

Cardiac troponin (cTn) I and T are structural proteins unique to the heart. Detection of cTn in peripheral blood indicates cardiomyocyte damage. As acute myocardial infarction (AMI) is the most important cause of cardiomyocyte damage, cTns have become an integral part in the diagnosis of AMI. For this indication, cTns are superior to all other biomarkers and therefore are the preferred marker for the diagnosis of AMI. However, cTn indicates and provides an estimate of cardiomyocyte damage irrespective of its cause. The major limitation of contemporary cTn assays is that they are often not elevated during the initial hours of AMI. Recent advances in assay technology have led to more sensitive and precise cTn assays that will have a profound impact on clinical practice. High-sensitive cTn (hs-cTn) assays have two differentiating features from contemporary cTn assays: (i) detection of cTn in a majority of healthy persons and (ii) precise definition of what is 'normal' (=the 99th percentile). Recent multicentre studies have shown that hs-cTn assays improve the early diagnosis of patients with suspected AMI, particularly the early rule-out. To achieve best clinical use, cTn has to be interpreted as a quantitative variable. Rising and/or falling levels differentiate acute from chronic cardiomyocyte damage. The terms 'troponin-positive' and 'troponin negative' should therefore be avoided. 'Detectable' levels will become the norm and will have to be differentiated from 'elevated' levels. The differential diagnosis of a small amount of cardiomyocyte damage and therefore minor elevations of cTn is broad and includes acute and chronic cardiac disorders. The differential diagnosis of larger amount of injury and therefore more substantial elevations of cTn is largely restricted to AMI, myocarditis, and a rare patient with tako-tsubo cardiomyopathy.     

COVID-19 and myeloma: what are the implications for now and in the future?

The pandemic has affected every aspect of myeloma care. Immediate focus is minimising risk of contracting coronavirus disease 2019 (COVID-19) and the sequelae of infection. However, what does the future hold for our patients? What lessons will be taken forward to tackle myeloma in the fiscally constrained future? If we embrace the challenges that will emerge in the post-pandemic environment, the treatment delivered to patients could be more cost-effective and better tailored than before. Healthcare delivery post-COVID-19 will not return to how it was, and now is the time to invest in novel strategies to deliver the best possible outcomes for patients.     

Vaccination and autoimmune disease: what is the evidence?

As many as one in 20 people in Europe and North America have some form of autoimmune disease. These diseases arise in genetically predisposed individuals but require an environmental trigger. Of the many potential environmental factors, infections are the most likely cause. Microbial antigens can induce cross-reactive immune responses against self-antigens, whereas infections can non-specifically enhance their presentation to the immune system. The immune system uses fail-safe mechanisms to suppress infection-associated tissue damage and thus limits autoimmune responses. The association between infection and autoimmune disease has, however, stimulated a debate as to whether such diseases might also be triggered by vaccines. Indeed there are numerous claims and counter claims relating to such a risk. Here we review the mechanisms involved in the induction of autoimmunity and assess the implications for vaccination in human beings.     

Changing life-styles and osteoarthritis: what is the evidence?

Life-style modification, particularly exercise and weight reduction, is a core component of the management of osteoarthritis. In this chapter, the evidence for the efficacy of exercise, weight reduction and footwear is reviewed. Caveats to the evidence and the areas where further research is needed are highlighted. Long-term adherence to exercise and weight reduction is a key predictor of response, and strategies for increasing adherence are reviewed. Our discussion focuses predominantly on knee OA, to which most of the evidence relates but refers to other sites where appropriate.     

Tegaserod and other serotonergic agents: what is the evidence?

Through effects on gastrointestinal motor and secretory function as well as visceral sensation, serotonin (5-HT) plays a key role in the pathogenesis of irritable bowel syndrome (IBS). In particular, 5-HT3 and 5-HT4 receptors appear to be very important in IBS. This article critically appraises the evidence supporting the use of the 5-HT3 receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS. The safety profile and restricted-use program for alosetron is also reviewed. This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS.