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Take a look at a selection of our recent media coverage:

Incubation time reducing for COVID-19 variants

7th September 2022

The incubation time for emerging COVID-19 variants appears to have reduced over time which impacts on the required period of isolation

A systematic review and meta-analysis by a team from Beijing, China, has suggested that as the COVID-19 virus mutates, giving rise to new variants of concern, the overall incubation time (IT) has been steadily reducing and is as little as 3.4 days for the omicron variant.

The time before the symptoms of a viral infection first appear represents the incubation time (IT) and this metric helps with the differential diagnosis, especially when patients present with largely non-specific acute respiratory viral infection symptoms, because different viral infections have longer or shorter ITs. For example, according to the European Centre for Disease Prevention and Control, for disease outbreaks, the mean incubation period of Ebola virus disease has been estimated at 6.3 days but this can be as short as 2 days or as long as 21 days. In contrast, the IT for respiratory syncytial virus is short at about 3 to 5 days. Knowledge of the IT can often provide important information during an disease outbreak, for example, when infected individuals will be symptomatic and most likely to spread the disease. Some data suggests that the average serial interval for COVID-19 – the time from illness onset in a primary case (infector) to illness onset in a secondary case (infectee) – is close to or shorter than its median incubation period. In other words, there is likely to be a substantial proportion of secondary transmission prior to illness onset. 

For the present study, the Chinese team wanted to obtain an estimate of the incubation time for COVID-19 and with the emergence of several variants over time, whether the IT was any different. A further consideration was if the incubation time varied in adults compared to older adults or children and if the severity of infection had any impact.

The researchers searched through the major databases and included studies where the IT was one of the primary outcomes and which they set as the outcome of interest for their study. This was defined as the time from when the infection occurred to the onset of signs and symptoms or the first positive test.

Incubation time and COVID-19 variants

A total of 142 articles with 8,112 patients were included in the analysis, roughly two thirds of which (65.5%), where conducted between January 2020 and March 2020.

The estimated mean incubation time for COVID-19 was 6.57 days (95% CI 6.26 – 6.88 days) although in studies, this ranged from 1.80 to 18.87 days. In 119 studies that examined the original or wild strain of the virus, the mean IT was broadly similar (6.65 days).

However, when considering the different variants, it seemed that the mean IT time was reducing. For example, for the Alpha variant, the mean IT was 5 days (95% CI 4.94 – 5.06), 4.5 days for Beta, 4.41 days for Delta but only 3.42 days for the Omicron variant.

In subgroup analysis, the mean IT was 7.43 days in adults 60 years of age but this was not significantly different to the overall estimated mean. However, the mean IT in those under 18 years of age was 8.82 days and this was significantly different to the overall mean estimate (p < 0.001). There was no significant of disease severity on the mean IT.

The authors concluded that the incubation time of the COVID-19 variants appears to have become shorter over time although these differences were not significant but were a key factor in determining the isolation period.

Wu Y et al. Incubation Period of COVID-19 Caused by Unique SARS-CoV-2 Strains: A Systematic Review and Meta-analysis JAMA Netw Open 2022

Statins responsible for only slight excess of muscle pain

1st September 2022

A review of 19 studies suggests statins are responsible for only a small excess of muscle pain symptoms in patients prescribed these drugs

Statins cause only a small excess of the muscle pain symptoms experienced by patients according to the findings of a meta-analysis of 19 randomised controlled trials by researchers from the Cholesterol Treatment Trialists’ Collaboration, University of Oxford, UK.

Cardiovascular diseases (CVD) such as ischaemic heart disease and stroke, are the leading cause of global mortality and a major contributor to disability and cases of CVD nearly doubled from 271 million in 1990 to 523 million in 2019. Furthermore, large-scale evidence from randomised trials shows that statins reduce the risk of major vascular events by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. In terms of adverse effects, statins are known to cause myopathy, which is defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase, though this is rare. In fact, it has been reported that treatment of 10,000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy. However, less serious musculoskeletal pain has been observed with statins and in a population-based study of 5170 participants without arthritis, after controlling for confounders, statin use was associated with a significantly higher prevalence of musculoskeletal pain in any region, the lower back, and the lower extremities.

In an effort to provide a better understanding of the extent, severity and timing of adverse effects due to statins, the Oxford group examined individual level patient data from long-term, randomised, double-blind trials, to evaluate the effects of statin therapy on muscle events. The researchers looked at all adverse events including the timing of such events, the reasons for stopping statins, use of other medication and co-morbidities.

Statins and muscle events

A total of 19 placebo-controlled trials that included a total of 123,940 participants with a mean age of 63 years (28% women) were analysed.

Among the whole cohort, 27.1% of patients assigned to statins and 26.6% taking placebo, reported at least one episode of muscle pain or weakness during a median of 4.3 years. This represented a 3% relative increase (relative risk, RR = 1.03, 95% CI 1.01 – 1.06). In addition, the increased risk was similar for the different muscular symptoms, e.g., cramp or spasm (RR = 1.09), muscle fatigue or weakness (RR = 1.10) and myalgia (RR = 1.03).

When considering more intensive statin regimes (e.g., 40 – 80 mg atorvastatin) vs less intensive/moderate intensity regimes (e.g., atorvastatin 10 – 20 mg), the risk was slightly higher (RR = 1.08 vs 1.03) compared to placebo. During the first year of therapy, statins produced a 7% relative increase in muscle pain or weakness although there was no significant increase thereafter. The authors calculated that only 1 in 15 of the muscle-related effects reported by participants were due to the drug, adding that > 90% of all reports of muscle symptoms in patients allocated to statins were no due to the drug.

They concluded that while statins were responsible for a small proportional increase in reports of muscle pain, for patients prescribed the drugs and who report mild muscle symptoms, it is most likely that these symptoms were not due to the drug.

Cholesterol Treatment Trialists’ Collaboration. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials Lancet 2022

Greater regular physical activity reduces risk of adverse COVID-19 outcomes

31st August 2022

Greater regular physical activity appears to be protective and associated with a lower likelihood of adverse outcomes in COVID-19

Greater regular physical activity reduces the risk of infection, hospitalisation, severe illness and death from COVID-19 in comparison to those who are inactive according to the findings of a systematic review and meta-analysis by a team of Spanish researchers.

Some degree of physical activity is better than none but greater regular physical activity is best for optimal health outcomes according to a World Health Organisation guideline from 2020. Physical activity has a beneficial impact on the immune system and also appears to have protective associations against infectious disease mortality. Moreover, it also appears that the converse is true, particular in relation to COVID-19. For example, in a study of over 48,440 adult patients with a COVID-19, those who were physically inactive had a higher risk of hospitalisation, admission to intensive care and death compared to those who were consistently meeting physical activity guidelines. But the extent to which greater regular physical activity impacts on adverse COVID-19 outcomes has not been quantified and was the purpose of the present systematic review and meta-analysis by the Spanish team.

The researchers looked for studies in adult patients with and without a COVID-19 diagnosis, where the exposure of interest was physical activity and when the outcomes of interest, e.g., infection, hospitalisation, were measured. The outcomes were assessed and pooled using odds ratios and relative risks.

Greater regular physical activity and COVID-19 outcomes

A total of 16 studies with 1,853610 participants and a mean age of 53.2 years (53% women) were included in the analysis. The amount of physical activity was self-reported in most of the studies though in cases where it was measured, this involved direct assessment using accelerometers or smart devices.

Adults engaging in greater regular physical activity and in comparison to those who were classed as inactive, had a lower risk of infection with COVID-19 (relative risk, RR = 0.89, 95% CI 0.84 – 0.95, p = 0.014), hospitalisation (RR = 0.64, 95% CI 0.54 – 0.76, p < 0.001), severe illness (RR = 0.66, 95% CI 0.58 – 0.77)) and death (RR = 0.57, 95% CI 0.46 – 0.71, p = 0.001).

In subgroup analysis, the researchers found that the beneficial effects of greater regular physical activity were independent of both study design and the instrument used. The team also identified a non-linear dose-response relationship between physical activity when expressed as metabolic equivalent of task (MET)-min per week and severe COVID-19 illness and death but not for either infection or hospitalisation. In other words, there was a flattening of the dose response between regular physical activity and death at 500 MET-min per week and which is equivalent to 150 – 300 minutes of moderate intensity physical activity per week.

The authors concluded that their findings highlighted the importance of physical activity in lowering the risk of infection hospitalisation and severe outcomes in COVID-19, particularly where this level of activity matched the guideline-recommended amounts of 500-MET min/week.

Ezzatvar Y et al. Physical activity and risk of infection, severity and mortality of COVID-19: a systematic review and non-linear dose–response meta-analysis of data from 1 853 610 adults Br J Sports Med 2022

Leisure activities inversely associated with risk of all-cause dementia

23rd August 2022

A review has found that greater leisure activities are associated with a reduced risk of all-cause dementia including Alzheimer’s disease

Increased amounts of all types of leisure activities e.g., cognitive, physical and social reduce the risk of developing all-cause dementia (ACD) including Alzheimer’s disease (AD) and vascular dementia (VD) according to a systematic review and meta-analysis by a team of Chinese researchers.

Dementia is a syndrome characterised by a deterioration in cognitive function beyond that which might be expected from the usual consequences of biological ageing and currently, across the globe, affects some 55 million people. Although there are several types of dementia, the most common is Alzheimer’s disease, followed by vascular dementia. There is currently no cure for dementia and recommendations to reduce risk factors include switching to a healthy diet and staying mentally and socially active. Indeed, there is some evidence that cognitively stimulating leisure activities may delay the onset of dementia in community-dwelling elders although the value of such activities are uncertain. For example, one study found that neither intellectual or physical activity lifestyle factors were associated with AD biomarkers with another concluding that physical inactivity was not associated with all-cause dementia or Alzheimer’s disease.

With some uncertainty over whether any of these leisure activities impact on ACD, for the present study, the Chinese team undertook a systematic review and meta-analysis. They set out to assess the effect of three different forms of leisure activities: physical (PA), cognitive (CA) and social (SA). For the purposes of the study, PA was defined to include walking, playing sports etc, CA, reading books, writing for pleasure or solving crossword puzzles and SA anything that involved communication with others, e.g. attendance at social centres, volunteer work etc. The researchers used regression analysis to determine the relationship between the different leisure activities and ACD and both subtypes, adjusting their results for covariates such as age, gender, education and apolipoprotein E.

Leisure activities and all-cause dementia

The literature review identified a total of 38 eligible studies with 215, 818 participants and a mean age of 45 years at baseline.

Overall, 36 studies were used to investigate the relationship between the different activities and all-cause dementia. The analysis revealed that participation in leisure activities, compared to no participation, was associated with a 17% lower risk of developing ACD (relative risk, RR = 0.83, 95% CI 0.80 – 0.87, p < 0.001). In subgroup analysis, there was also a significant reduction for each of the different forms of activity, e.g., the relative risk for CA was 0.77 (95% CI 0.68 – 0.87).

For AD, there was an 18% lower risk for participation in leisure activities (RR = 0.82, 95% CI 0.74 – 0.90, p < 0.001) and again, while the lower risk was similar for PA and CA, it was non-significant for SA (RR = 0.89, 95% CI 0.63 – 1.26) although the latter activity assessment was based on only a single study.

For vascular dementia, the reduction was even greater at 32% (RR = 0.68, 95% CI 0.54 – 0.86, p = 0.007). However, this association was only significant for PA and not for CA although there were no studies which examined the relationship with SA.

The authors concluded that leisure activities including physical, cognitive and social, were all significantly associated with a reduced risk of incident dementia and that both PA and CA were linked to a lower risk of AD.

Su S et al. Leisure Activities and the Risk of Dementia: A Systematic Review and Meta-Analysis Neurology 2022

Emergency department pharmacists improve quality of medicine use

17th August 2022

A review found that an emergency department pharmacist provided several benefits, which together led to an improved quality of medicine use

The presence of an emergency department (ED) pharmacist as part of the clinical care team leads to improvements in the quality of medicines use according to the findings of a systematic review and meta-analysis by researchers from the School of Pharmacy and Pharmacology, University of Tasmania, Hobart, Tasmania, Australia.

The term ‘quality use of medicines’ (QUM) encompasses the wise selection of management options and choosing suitable medicines where indicated, together with ensuring that patients and carers have the knowledge and skills to use medicines safely and effectively. However, ensuring QUM within a busy emergency department is challenging with one analysis covering the period 2011 to 2020 finding that the most common prescribed medications mentioned in reports were epinephrine, insulin, hydromorphone, sodium chloride, heparin, Propofol, diltiazem, ketamine, and morphine. Furthermore, serious medication error events occurred most often at the prescribing stage (42.0%) with the most common medication error type being an incorrect dose (42%). Such errors might be reduced by having an ED pharmacist incorporated into the clinical team and there is already some evidence from a 2019 systematic review which concluded that pharmacy-led medication reconciliation significantly decreased the number of medication discrepancies. Nevertheless, the authors of the systematic review also noted how only one study investigated potential adverse drug events in patients receiving ED care and called for further studies to investigate the direct clinical impact of decreased medication discrepancies. Given that the impact and value of an ED pharmacist remains to be fully explored, for the present study, the Australian team undertook a systematic review and meta-analysis, specifically focusing on the effect of adult care, when departments had access to a pharmacist as part of the ED team.

A literature search was designed to uncover studies in which a pharmacist was a part of the ED team and where the impact was compared with usual care. The outcomes considered were changes in the rates or proportions of the medication-related outcomes such as medication errors, the appropriateness of prescribed medicines, length of hospital stay or re-admission.

Emergency department pharmacist and medication-related outcomes

The literature search identified a total of 31 eligible studies and which included 13,242 participants and with individual study sample sizes ranging from 34 to 3,594. The types of included studies were pre-post interventions, cohort studies and randomised, controlled trials.

Not every study could be used for all of the outcomes under examination. However, pooling results from 10 studies showed that an ED pharmacist intervention was associated with an average error rate decrease of 0.33/patient (95% CI -0.42 to -0.23, p < 0.001). Similarly, in a meta-analysis of 10 studies, use of emergency department pharmacists were associated with a 73% lower proportion of patients with at least one error (relative risk, RR = 0.27, 95% CI 0.19 – 0.40, p < 0.001).

Analysis of 7 studies indicated a 58% increased appropriateness of prescribing (RR = 1.58, 95% CI 1.21 – 2.06, p < 0.001) after input from pharmacists. Finally, there was a 30% reduced risk of re-presenting to ED (RR = 0.70, 95% CI 0.52 – 0.94, p = 0.02) and a 38% reduced risk of re-admission (RR = 0.62) after intervention by a pharmacist.

The authors concluded that their data showed how an ED pharmacist improved QUM and called for future studies to examine the cost-effectiveness of ED-based pharmacy interventions.

Atey TM et al. Impact of pharmacist interventions provided in the emergency department on quality use of medicines: a systematic review and meta-analysis Emerg M J 2022

Tinnitus affects millions of adults worldwide

16th August 2022

A systematic review has found that globally tinnitus affects around 740 million adults or around 14% of the world’s population

Tinnitus has been estimated to affect 14% of the world’s adult population or over 740 million people according to the findings of a systematic review and meta-analysis by a group of European researchers.

Tinnitus is defined as the perception of sound in the absence of a corresponding external acoustic stimulus and it best described as a symptom rather than a disease. Identified causes include noise trauma, metabolic diseases such as hypertension and diabetes, together with ear diseases including Meniere’s disease or lesions affecting the eighth cranial nerve. However, a problem for researchers trying to determine the prevalence of tinnitus, is the lack of a standard definition and in a previous meta-analysis of the prevalence, although 40 studies were identified, the authors noted that nearly half of the included studies had a high risk of bias and which therefore limited the generalisability of prevalence estimates.

In the present study, the European team sought to determine the global frequency of tinnitus using an initial umbrella review, which identifies published meta-analyses and a second traditional literature review of original publications. Combining the results, the researchers calculated a pooled estimate of the prevalence in both adults and children, together with an estimate of the prevalence of more severe tinnitus.

Overall tinnitus prevalence

A total of 113 eligible articles were identified although only 83 of these were used to estimate prevalence and 12 for incidence.

The pooled prevalence estimate for tinnitus in adults was 14.4% (95% CI 12.6 – 16.5%) although within the studies, estimates ranged from 4.1% to 37.2%. However, a problem identified in trying to assess prevalence was how studies had asked about tinnitus in different ways, leading to slight differences in prevalence. For example, when asked about ever experiencing tinnitus, the prevalence was 17.5% whereas only only 13.7% when asked if the condition had persisted for more than 5 minutes (13.7%) and slightly lower still, when assessed using a specific scale (9.3%).

Turning to children and adolescents, the estimated prevalence was 13.6% (95% CI 8.5 – 21%) and again there was a wide variation in prevalence (0.7% to 66.9%). There was also an age-related effect, for instance, the prevalence estimate was 13.7% among middle-aged adults and this rose to 23.6% in older adults, though there was little difference between the sexes (14.1% vs 13.1%, male vs female). There were also a significant geographical variation, with 5.2% of those in Africa affected and 21.9% of individuals from South America.

Finally, the researchers estimated that the pooled prevalence of severe tinnitus was 2.3% (95% CI 1.7 – 3.1%) and similar in children and adolescents (2.7%).

When converting the pooled prevalence into estimates of absolute numbers, the authors calculated that there were 749 (95% CI 655 – 858) million adults globally affected by tinnitus and 120 million with severe symptoms.

The authors concluded that their prevalence estimates of tinnitus were of a similar magnitude to the leading causes of years lived with disability such as hearing loss. They called for institutions such as the Global Burden of Disease to play a leading role to boost research on tinnitus and to improve the care of those affected.

Jarach CM et al. Global Prevalence and Incidence of Tinnitus: A Systematic Review and Meta-analysis JAMA Neurol 2022

Review finds quarter of children develop long COVID

2nd August 2022

A meta-analysis has identified how approximately a quarter of children and adolescents are likely to experience long COVID symptoms

The World Health Organization uses the term post COVID-19 conditions (i.e., long COVID), to define a condition that occurs among individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. To date, the currently available literature on long covid relates to the symptoms developed in adults, although one recent analysis that specifically focused on children and young people and who were followed-up for a median of 125 days, observed a range of symptoms including a higher incidence of diarrhoea and fatigue. Nevertheless, the complete range and frequency of long covid symptoms that develop in children and adolescents remains unclear and was the subject of the current study by the Mexican and US team. The researchers looked for any type of study that included children and discussed long COVID, which they defined as the presence of one or more symptoms for longer than 4 weeks after the acute infection.

Children and long covid

The search identified a total of 21 eligible studies with 80,071 children and adolescents and which were included in the meta-analyses. The number of patients in each of the studies ranged from 53 to 57,763 and the participant ages from 0 to 18 years and the authors identified more than 40 long-term clinical manifestations of long covid.

The overall prevalence of long covid in children and adolescents was 25.2% (95% CI 18.2 –33.0) although among children who had been hospitalised, this increased to 29.2% (95% CI 17.8–41.9). A wide range of symptoms were detected, with the most common (16.5%) being mood symptoms (e.g., sadness, tension, anger, depression, and anxiety) fatigue (9.7%), sleep disorders (8.4%) which encompassed insomnia, hypersomnia, and poor sleep quality. Other symptoms included headache (7.8%) and respiratory symptoms (7.6%).

The authors calculated that in comparison to controls, children with long COVID had a higher risk of persistent dyspnoea (OR 2.69, 95% CI 2.3 – 3.1), anosmia/ageusia (OR 10.7, 95% CI 2.5 – 46.0), and/or fever (OR 2.2, 95% CI 1.2 – 4.1). Based on their findings, they concluded that the results of the meta-analysis supported the continued monitoring of the impact of long covid on children and adolescents.

Lopez-Leon S et al. Long-COVID in children and adolescents: a systematic review and meta-analysis Sci Rep 2022



Meta-analysis finds antihistamines better than benzodiazepines for management of vertigo

26th July 2022

Antihistamines provide superior two hour relief of vertigo symptoms compared to benzodiazepines according to the results a meta-analysis

Antihistamines are able to provide a greater level of symptom relief, 2 hours post-dose in patients with vertigo in comparison to benzodiazepines. However, neither class of drugs seems to be better than placebo after only one week. These were the key findings from a systematic review and meta-analysis by researchers from the Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, US.

Vertigo is a symptom of vestibular dysfunction and described as a sensation of motion, most commonly rotational motion. The term dizziness is non-specific but usually refers to a sense of disorientation with vertigo being a subtype of dizziness. The sensation of dizziness is common condition and affects about 15% to 20% of adults annually and vestibular vertigo accounts for about a quarter of dizziness cases with an annual prevalence of 5%. Pharmacological treatments for the management of vertigo are referred to as vestibular suppressants and there are a wide of drug classes such as anticholinergics (scopolamine), antihistamines (cinnarizine), benzodiazepines (clonazepam) and dopamine receptor antagonist (prochlorperazine) and histamine-1 receptor antagonists (betahistine). In a 2017 updated clinical practice guideline, it was recommended that benzodiazepines and/or antihistamines could be used in the management of one of the most common forms of vertigo, benign paroxysmal positional vertigo. Despite this, there is an absence of comparative data for these two drug classes.

As a result, for the present study, the US team undertook a systematic review and meta-analysis to assess the efficacy of both drug classes in the management of acute vertigo due to any underlying cause. The team searched for randomised trials which included any antihistamine or benzodiazepine compared with an active comparator, placebo or no intervention in patients with acute vertigo and which had lasted for less than 2 weeks. The primary outcome of interest was the change in a 10 or 100-point vertigo or dizziness visual analogue scale (VAS) score at 2 hours post-treatment. Secondary outcomes included change in nausea VAS score at 2 hours and resolution of vertigo after one week and a month.

Antihistamines and improvement in vertigo scores

A total of 27 trials met the inclusion criteria, of which, 17 with 1586 participants were included in the meta-analysis.

For the primary outcome, 7 trials with 802 were included. Antihistamines were associated with a 16.1-point (95% CI 7.2 – 25) greater decrease in mean VAS vertigo scores compared to benzodiazepines. However, when compared to other active treatments, antihistamines performed to a similar extent (mean difference = 7.4, 95% CI -1.12 to 15.8).

For the secondary outcomes, after one week, there was no evidence to suggest a higher likelihood of complete symptom resolution from antihistamines (relative risk, RR = 1.03, 95% CI 0.56 – 1.89) or after 4 weeks. Similarly, the improvement with benzodiazepines was no better than placebo after one or 4 weeks.

The authors concluded that there was moderately strong evidence to show that single dose antihistamines provided better relief of vertigo symptoms after 2 hours than benzodiazepines. Furthermore, the evidence did not support an association between benzodiazepine use with an improvement in acute vertigo.

Hunter BR et al. Efficacy of Benzodiazepines or Antihistamines for Patients With Acute Vertigo: A Systematic Review and Meta-analysis JAMA Neurol 2022

Hyaluronic acid ineffective for pain management in knee osteoarthritis

21st July 2022

Intra-articular hyaluronic acid gives rise to a small but significant though clinically irrelevant reduction in knee osteoarthritis pain

The use of intra-articular hyaluronic acid (HA) produces a small, significant increase in knee osteoarthritis pain intensity compared to placebo although this reduction is less than the minimal clinically important difference according of a systematic review and meta-analysis by Swiss and Canadian researchers.

Osteoarthritis is a degenerative condition and which globally affects around 16% of those aged 15 and over but 22⋅9% of individuals aged 40 and over. One form of treatment is viscosupplementation with intra-articular hyaluronic acid and although it provides a clinically meaningful benefit to a large number of patients, emerging evidence indicates that this is largely a result of other factors, including the placebo effect. Nevertheless, a 2021 economic evaluation suggested that intra-articular HA may reduce the use of pain medications, such as non-steroidal anti-inflammatory drugs and opioids and potentially decreasing the overall treatment costs for knee OA over time. Furthermore, a recent US study found that despite the 2013 American Academy of Orthopaedic Surgeons clinical practice guideline recommendation against the clinical utility of hyaluronic acid, services continued to be widely implemented among Medicare beneficiaries. With its widespread use yet apparent lack of evidence, for the present study, the research team decided to perform a systematic review and meta-analysis to examine the evidence on the clinical benefits and safety of the intervention.

The team searched for randomised or quasi-randomised trials in which at least 75% of participants had clinically or radiologically confirmed knee osteoarthritis and where outcomes such as pain, function or adverse events were reported. The primary outcome was set as pain intensity with function and serious adverse events as the two secondary outcomes. Continuous outcomes were analysed as standardised mean differences (SMDs) such that when the SMD was > 0, this was indicative of a better outcome for HA. The researchers also determined that the minimal clinically important difference for HA was -0.37.

Hyaluronic acid and pain intensity

A total of 169 trials with 9,423 participants and a mean age of 62 years (59% women) and with a mean disease duration of 5.2 years were included in the analysis. The median follow-up time for patients after their HA injection was 13 weeks and 12 weeks for functional assessment.

Based on 24 trials (8997 randomised patients), there was a small, but significant though non-clinically relevant reduction in pain intensity after HA injection (SMD = -0.08, 95% CI -0.15 to -0.02, p = 0.02). Based on a 100 mm visual analogue pain scale, this equated to a 2 mm reduction in scores compared to placebo.

For the secondary outcome of function, the pooled estimate was a SMD of -0.11 (95% CI -0.18 to -0.05, p = 0.001) which again was much lower than the minimally important difference. In terms of adverse effects, the use of HA was associated with a significant increased risk of serious adverse events compared to placebo (relative risk = 1.49, 95% CI 1.12 – 1.98, p = 0.003). Overall, 3.7% of patients receiving HA and 2.5% of those given a placebo experienced a serious adverse event.

The authors concluded that HA was associated with a clinically irrelevant reduction in pain intensity and suggested that their findings do not support the broader use of this intervention for knee osteoarthritis.

Pereira TV et al. Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis BMJ 2022

Noradrenergic drugs in Alzheimer’s disease improve global cognition and apathy

19th July 2022

Noradrenergic drugs show a small but significant improvement in global cognition and apathy in the treatment of Alzheimer’s disease

Noradrenergic drugs produce a small but significant improvement in global cognition and apathy in patients with Alzheimer’s disease(AD) with no important effects on any other measures according to the findings of a meta-analysis by UK researchers.

The World Health Organisation (WHO) defines dementia as a syndrome in which there is deterioration in cognitive function beyond what might be expected from the usual consequences of biological ageing. WHO also estimates that worldwide in 2021, there were approximately 55 million people living with dementia and that AD, which is the most common form of dementia, may contribute to 60-70% of all cases. The neurotransmitter noradrenaline is released by the locus coeruleus and has become recognised as a contributor to various aspects of cognition, including attention, behavioural flexibility, working memory, and long-term mnemonic processes. Furthermore, the locus coeruleus is one of the first sites of tau deposition in AD and with noradrenergic dysfunction being an early sign in patients with AD, it would seem logical to use noradrenergic drugs as a treatment for the disease. Nevertheless, trials examining the value of noradrenergic drugs in AD have generally proved to be unsuccessful. Despite this, there has been no attempt to assess the overall impact of this drug class in AD which was the purpose of the present study. The UK team performed a systemic review and meta-analysis to assess the degree to which drugs, whose principle action is as a noradrenergic agent, could improve the cognition and behavioural aspects of AD.

They searched for trials that included patients with AD in which noradrenergic drugs, that increased levels of noradrenaline, were compared against placebo and where the studies reported on cognitive and neuropsychiatric (e.g., agitation, apathy) changes. The outcomes of interest were changes in measure of both global cognition and neuropsychiatric symptoms.

Noradrenergic drugs and Alzheimer’s disease outcomes

The search identified a total of 19 trials with 1811 patients and all of the studies were prospective, randomised trials and with a treatment duration of between 2 and 52 weeks. The most commonly used noradrenergic drugs were noradrenalin re-uptake inhibitors, alpha1 adrenergic receptor antagonists, alpha2 receptor agonists, alpha2 receptor antagonists and beta adrenergic receptor blockers.

For global cognition, the overall pooled effect size was small but statistically significant in comparison to placebo (standardised mean difference, SMD = 0.14, 95% CI 0.03 – 0.25, p = 0.01). To provide some perspective for this effect, the authors included the SMD for cholinesterase inhibitors from studies in AD which was 0.38. Although noradrenergic drugs had a positive effect on semantic memory (SMD = 0.20), the drugs had no significant effect on any of the other cognitive measures.

For neuropsychiatric measures the only measure for which there was a significant effect was apathy with a pooled SMD of 0.45 (95% CI 0.16 – 0.73, p = 0.002).

The authors concluded that pharmacotherapies targeting the noradrenergic system appeared to improve both cognition and apathy. In addition, they suggested these data provided a strong case for further trials to examine the value of these drugs in AD and other neurodegenerative diseases.

David MCB et al. Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic review and meta-analysis J Neurol Neurosurg Psychiatry 2022