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12th September 2022
Adults who take just short of 10,000 steps/day, particularly if those steps are more intense, have a reduced dementia risk according to a study by a team from Denmark and Australia.
Dementia describes a syndrome in which there is a deterioration in cognitive function beyond what might be expected from the usual consequences of biological ageing and which according to the world health organisation, globally, affects around 55 million people.
In a 2020 report published in The Lancet, it was noted how there is a growing body of evidence that supports the nine potentially modifiable risk factors for dementia, one of which is physical inactivity. The authors recommended keeping cognitively, physically and socially active in midlife and later life although little evidence exists for any single specific activity protecting against dementia.
In an analysis of 15 cohort studies with over 47,000 adults, researchers concluded that taking more steps per day was associated with a progressively lower risk of all-cause mortality. Despite this benefit, evidence also suggests that step cadence, i.e., the number of steps per minute, or step intensity does not appear to be significantly associated with mortality.
With a lack of supportive evidence for the value of greater physical activity in reducing the risk of developing dementia, in the present study, researchers examined the association between daily step count as well as intensity and dementia risk.
They used data held within the UK Biobank where a cohort of over 100,000 individuals had agreed to wear an accelerometer on their dominant wrist 24 hours a day and 7 days a week, to measure physical activity. All were free of dementia at the start and as well as recording total daily steps, the researchers also examined step cadence.
This was divided into incidental steps, defined as fewer than 40 steps/minute, such as walking between rooms at home, purposeful steps, which > 40 steps/minute, for instance, while exercising and finally, peak 30-minute cadence, which was the average steps/minute recorded for the 30 highest, but not necessarily consecutive, minutes in a day.
The researchers estimated the optimal dose of steps, where the maximum significant dementia risk reduction was observed and the minimal dose, which was defined as the number of steps at which the risk reduction was 50% of the maximum. In regression models, adjustments were made for age, sex, lifestyle and co-morbidities.
Dementia risk and daily steps
The overall cohort included 78,430 individuals with a mean age of 61.1 years (55.3% female) and who were followed for a median of 6.9 years. During the follow-up period, 866 participants developed dementia at a mean age of 68.3 years.
The optimal dose of daily steps was 9826 and this led to a 51% lower risk of developing dementia (hazard ratio, HR = 0.49, 95% CI 0.39 – 0.62) and the minimal dose of 3826 steps/day (HR = 0.75, 95% CI 0.67 – 0.83).
For peak 30-minute cadence, the optimal dose was 112 steps/minute (HR = 0.38, 95% CI 0.24 – 0.60) and 6315 for purposeful steps.
The authors concluded that taking more daily steps was associated with a reduced dementia risk with the optimal dose just short of 10,000 steps/day and also that step intensity led to stronger associations. They suggested that future guidelines for dementia prevention should promote step-based recommendations.
del Pozo Cruz B et al. Association of Daily Step Count and Intensity With Incident Dementia in 78 430 Adults Living in the UK JAMA Neurol 2022
10th August 2022
A malaria monoclonal antibody provides protection against controlled infection in virtually all patients according to the findings of a phase 1 clinical trial by a US research team.
Malaria is an acute, febrile illness caused by Plasmodium falciparum (P. falciparum), a unicellular protozoan parasite, spread through the bites of infected female Anopheles mosquitoes. It is an extremely common disease and the World Health Organisation has estimated that in 2020 there were 241 million cases of malaria, leading to an estimated 627,000 deaths.
While there have been huge efforts directed towards the development of a vaccine, the available data suggests that the RTS,S/AS01 candidate malaria vaccine, has an efficacy of only 36.6%. Some research has shown how antibodies can prevent malaria by neutralising sporozoites (i.e., the infectious form of Plasmodium deposited into the skin when a mosquito bites) before they infect hepatocytes in the liver.
A recognised antibody target is the P. falciparum circumsporozoite protein, that is required for parasite motility and invasion of hepatocytes and in a 2021 study, it was shown that a malaria monoclonal antibody, CIS43LS, which targets this protein, prevented malaria after controlled infection.
For the current phase 1 trial, researchers modified the CIS43LS monoclonal antibody to create a more potent agent, L9LS and described its safety, pharmacokinetics and protective efficacy in health adults who had never been infected with malaria or received a vaccine.
Study participants were given either intravenous LSL9 at doses of 1, 5 and 20 mg/kg or a subcutaneous dose of 5 mg/kg, whereas some did not receive the monoclonal antibody and served as controls. Within 2 to 6 weeks after administration of LSL9, participants were exposed to bites on the forearm from the Anopheles stephensi mosquito which had been infected with P. falciparum.
Parasitaemia (i.e., the detection of parasites in the blood) was assessed after 21 days using a PCR test and for the purposes of the study, participants were considered to be protected by LSL9, if parasitaemia did not develop at this point in time. In cases where parasitaemia did occur, individuals were treated with 1 gm atovaquone and 400 mg of proguanil for 3 days.
Malaria monoclonal antibody and parasitaemia
A total of 27 participants were enrolled with a mean age of 24.5 years (50.3% female), 18 of whom received L9LS (and 9 serving as controls) with 5 receiving the drug subcutaneously. Controlled infection was administered to 23 participants (17 given L9LS and 6 controls).
The results showed the L9LS had dose linearity with the highest mean serum concentration of 914.2 mcg/ml from the 20 mg/kg intravenous dose and the estimated overall clearance was 46.1 ml/day with a half-life of 56 days.
Parasitaemia developed in 2 of the 17 participants given L9LS and all 6 controls (p < 0.001) and did not develop in those given 5 or 20 mg of intravenous L9LS. Interestingly, protection was afforded by serum concentrations of L9LS as low as 9.2 mcg/ml.
The authors concluded that these results indicated that prevention of malaria could be achieved after a single dose of L9LS and that further studies were needed to examine the value of the drug among infants and children.
Wu RL et al. Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria N Eng J Med 2022