Experts advise against routine testing for prostate cancer
Routine testing for prostate cancer is not recommended for most men because the benefit is small and uncertain and there are clear harms, say a panel of international experts in The BMJ. But they acknowledge that some men, such as those with a family history of prostate cancer, may be more likely to consider screening and, for them, discussions about possible harms and benefits with their doctor are essential. An international panel made up of clinicians, men at risk of prostate cancer, and research methodologists carried out a detailed analysis of the latest evidence using the GRADE approach (a system used to assess the quality of evidence). A review including more than 700 000 men in clinical trials found that if screening reduces prostate cancer deaths at all, the effect is very small. Based on this, the panel advises against offering routine prostate-specific antigen (PSA) screening and says most men will decline screening because of the small and uncertain benefits and the clear harms. Clinicians need not feel obligated to systematically raise the issue with all their patients, and should engage in shared decision making for those considering screening. A linked editorial pointed to recent advances and active surveillance, “which have the potential to reduce the harms of testing”. In the meantime, the experts say conversations with patients requesting a PSA test “should explore their reasons for requesting a test, and include evidence-based discussions about possible harms and benefits of PSA testing, informed by the patient’s ethnicity and family history”.
Diclofenac associated with increased risk of major cardiovascular events
The commonly used painkiller diclofenac is associated with an increased risk of major cardiovascular events, such as heart attack and stroke, compared with no use, paracetamol use, and use of other traditional painkillers, finds a study published by The BMJ. The findings prompt the researchers to say that diclofenac should not be available over the counter, and when prescribed, should be accompanied by an appropriate front package warning about its potential risks. Diclofenac is a traditional non-steroidal anti-inflammatory drug (NSAID) for treating pain and inflammation and is widely used across the world. But its cardiovascular risks compared with those of other traditional NSAIDs have never been examined in large randomised controlled trials, and current concerns about these risks make such trials unethical to conduct. Researchers at Aarhus University Hospital in Denmark examined the cardiovascular risks of starting diclofenac compared with starting no NSAIDs, starting other traditional NSAIDs (ibuprofen or naproxen), and starting paracetamol. The results are based on national registry data for more than 6.3 million adults in Denmark with at least one year of continuous prescription records before study entry in January 1996. Participants were split into low, moderate and high baseline cardiovascular risk. Average age was 46–49 years among participants starting NSAIDs and 56 years among those starting paracetamol. After taking account of potentially influential factors, starting diclofenac during the study period (1996–2016) was associated with an increased rate of major adverse cardiovascular events within 30 days compared with starting other traditional NSAIDs or starting paracetamol. Events included irregular heart beat or flutter, ischaemic stroke, heart failure and heart attack. The increased risks applied to men and women of all ages and also at low doses of diclofenac. Starting diclofenac was also associated with an increased rate of cardiac death compared with no NSAIDs, and an increased risk of upper gastrointestinal bleeding compared with no NSAIDs, starting ibuprofen or paracetamol, but not with naproxen. When results were analysed by baseline cardiovascular risk, the absolute number of events per 1000 diclofenac starters per year also increased. This is an observational study, so no firm conclusions can be drawn about cause and effect. However, the study’s sample size is larger than most previous analyses of observational and randomised studies taken together.
Lipids in exercise-trained hearts versus failing hearts
Research from the Baker Heart and Diabetes Institute has examined what is happening to the lipids in the heart and circulating blood plasma during exercise compared with a failing heart as a novel way to advance prediction and treatment of heart failure. This first-of-its-kind study, published in Cell Reports, has identified novel lipids in the heart and plasma in a model of exercise compared with heart disease, and found that some of these lipids have potential as new targets for predicting and treating heart failure and atrial fibrillation. The study examined nearly 600 lipids in the heart and plasma of exercise-trained mice in comparison to mice with a failing heart. The researchers say that what is particularly exciting is the discovery of a number of novel lipids with unknown roles in the heart which may represent new biomarkers and/or drug targets for atrial fibrillation and heart failure. “While many studies have described functional, structural and genetic differences of the exercise-trained heart and diseased heart in the quest to advance prevention and treatment, a mechanism largely unexplored is the regulation of lipids,” they said. “Recent advancements in technology have allowed for this large-scale profiling work, which has opened up an unexplored pathway for the identification of novel biomarkers and drug targets for the failing heart.”
Lymph node structural cells rein in human immune responses
Research led by the Monash Biomedicine Discovery Institute has veered away from traditional immunology by turning the spotlight on the structural cells that build and support the immune-rich environment of lymph nodes. Published in PLoS Biology, the research shows that the fibroblastic reticular cells (FRCs) that form the inner structure of human tonsils and lymph nodes exert control over T cells and their response to infection. These larger structural cells provide both structural support and guidance to immune cells while they spend time in lymph nodes, and the researchers’ new work identifies four key mechanisms by which the FRCs act to dampen down T cell responses. The four mechanisms that FRCs use include pathways involving prostaglandin E2, the adenosine 2A receptor, indoleamine 2,3-dioxygenase, and transforming growth factor b. The authors were able to inhibit all four FRC mechanisms using existing drugs, and found that T cell responses were heightened in the process. Once T cells are no longer suppressed by FRCs, they are readily able to expand and proliferate. Using an entirely novel approach, the researchers, in collaboration with the University of Birmingham, examined the activation of T cells within live slices of a human tonsil and found that (in the presence or absence of key molecules) the T cells showed a heightened response when FRCs were inhibited. These findings will help researchers understand why T cells respond differently when activated in the test tube, compared with their response in a live human tissue, which contains a complex micro-environment and FRCs. The work may help efforts to improve immune responses in situations where T cells don’t work as well as they should, including in the elderly, who are very susceptible to infections such as influenza and whose immune system or vaccination response may benefit from being boosted.
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