Health First: An evidence-based alcohol strategy for the UK

Alcohol is taken for granted in the UK today. It is easy to get hold of, increasingly affordable, advertised everywhere and accepted by many as an integral part of daily life. Yet, despite this, the great majority of the population recognise the harm that alcohol causes. They believe that drinking damages health, drives anti social behaviour, harms children and families and creates huge costs for the NHS and the Police. They are right. Every year in the UK, there are thousands of deaths and over a million hospital admissions related to drinking. More than two in five (44%) violent crimes are committed under the influence of alcohol, as are 37% of domesti c violence incidents. One fifth of all violent crime occurs in or near pubs and clubs and 45% of adults avoid town centres at night because of drunken behaviour. The personal, social and economic cost of alcohol has been estimated to be up to £55bn for England and £7.5bn for Scotland. None of this should be taken for granted. The impact of drinking on public health and community safety is so great that radical steps are needed to change our relationship with alcohol. We need to imagine a society where low or no alcohol consumpti on is the norm, drunkenness is socially unacceptable and town centres are safe and welcoming places for everyone to use. Our vision is for a safer, healthier and happier world where the harm caused by alcohol is minimised. This vision is achievable. But only if we tackle the primary drivers of alcohol consumption. The evidence is clear: the most effective way to reduce the harm from alcohol is to reduce the affordability, availability and attractiveness of alcohol products. It is not enough to limit the damage once people are drunk, dependent, ill or dying. We need to intervene earlier in order to reduce consumption across the entire population. The tools are available. The ‘four Ps' of the marketing mix - price, product, promotion and place - are used by alcohol producers and retailers to increase their sales of alcohol. They can also be used by government to reduce alcohol sales, alcohol consumption and alcohol-related harm. Alcohol taxes are an effective public health measure as they raise prices and suppress demand. However, if they do not keep pace with both inflation and incomes, alcohol products will become more affordable over time. This has been the case in the UK. Deep discounting by retailers has also driven down the price of alcohol and encouraged heavy drinkers to maintain dangerous levels of consumption. These problems need to be tackled by a combinati on of more effective fiscal policy and controls on pricing and discounting. Alcohol products are an extraordinary anomaly. Unlike most food products, they are both remarkably harmful and excepti onally lightly regulated. As with other toxic products, the product label ought to communicate the content of the product and the risks of its consumpti on. Regulation should drive out products that appeal to young people while also incentivising the development and sale of lower strength products. The pervasive marketing of alcohol products in the UK is indefensible. Current restrictions are woefully inadequate: children and young people are regularly exposed to alcohol adverti sing in both old and new media. Only a complete ban on all alcohol advertising and sponsorship will make a lasting diff erence. Licensing practice in the UK is out of date. The focus on pubs and bars has allowed shops and supermarkets to become the dominant players in alcohol sales. Consequently, alcohol is now more available than it has ever been. This has driven pre-loading: getting drunk on cheap, shop-bought alcohol before heading out to late-opening night life. Licensing must focus on public health and seek to control the overall availability of alcohol as well as the effects of drunkenness. Beyond these populati on-level approaches, many more targeted measures are needed to reduce alcohol-related harm. Early interventi on by health and social care professionals is an important and underexploited opportunity to prevent problems developing. Stronger drink driving measures are also required. All these measures are needed. Together, they provide a template for an integrated and comprehensive strategy to tackle the harm from alcohol in the UK.Additional co-authors: Gerry McElwee, Dr Kieran Moriarty CBE, Dr Robin Purshouse, Dr Peter Rice, Alison Rogers, George Roycroft , Chit Selvarajah, Don Shenker, Eric Appleby, Dr Nick Sheron, and Colin Shevill

GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons

Elevated glycogen synthase kinase-3 (GSK-3) activity is associated with Alzheimer disease. We have found that collapsin response mediator proteins (CRMP) 2 and 4 are physiological substrates of GSK-3. The amino acids targeted by GSK-3 comprise a hyperphosphorylated epitope first identified in plaques isolated from Alzheimer brain. Expression of wild type CRMP2 in primary hippocampal neurons or SH-SY5Y neuroblastoma cells promotes axon elongation. However, a GSK-3-insensitive CRMP2 mutant has dramatically reduced ability to promote axon elongation, a similar effect to pharmacological inhibition of GSK-3. Hence, we propose that phosphorylation of CRMP proteins by GSK-3 regulates axon elongation. This work provides a direct connection between hyperphosphorylation of these residues and elevated GSK-3 activity, both of which are observed in Alzheimer brain

Calcium based signalling in guard cells.

Calcium is a ubiquitous intracellular signal responsible for controlling numerous cellular processes in both plants and animals. As an example, Ca2+ has been shown to be a second messenger in the signal transduction pathways by which stomatal guard cells respond to external stimuli. Regulated increases in the cytosolic concentration of free calcium ions ([Ca2+]cyt) in guard cells have been observed to be a common intermediate in many of the pathways leading to either opening or closing of the stomatal pore. This observation has prompted investigations into how specificity is encoded in the Ca2+ signal. It has been suggested that the key to generating stimulus-specific calcium signatures lies in the ability to access differentially the cellular machinery controlling calcium influx and release from intracellular stores. Several important components of the calcium-based signalling pathways have been identified in guard cells including cADPR, phospholipase C–InsP3, InsP6 and H2O2. These data suggest that the pathways for intracellular mobilization of Ca2+ are evolutionarily conserved between plants and animals

Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods: In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24). Interpretation: In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research