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Cognitive impairment from severe COVID-19 is like ageing 20 years

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The cognitive impairment from severe COVID-19 is similar to that sustained from 50 and 70 years of age

Cognitive impairment as a result of severe COVID-19 is similar to that sustained between 50 and 70 years of age and is the equivalent to losing 10 IQ points, say a team of scientists from the University of Cambridge and Imperial College London.

The findings, published in the journal eClinicalMedicine, emerge from the NIHR COVID-19 BioResource.

The results of the study suggest the effects are still detectable more than six months after the acute illness, and that any recovery is at best gradual.

There is growing evidence that COVID-19 can cause lasting cognitive and mental health problems, with recovered patients reporting symptoms including fatigue, ‘brain fog’, problems recalling words, sleep disturbances, anxiety and even post-traumatic stress disorder (PTSD) months after infection.

In the UK, a study found that around one in seven individuals surveyed reported having symptoms that included cognitive difficulties 12 weeks after a positive COVID-19 test.

While even mild cases can lead to persistent cognitive symptoms, between a third and three-quarters of hospitalised patients report still suffering cognitive symptoms three to six months later.

To explore this link in greater detail, researchers analysed data from 46 individuals who received in-hospital care, on the ward or intensive care unit, for COVID-19 at Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust.

Sixteen patients were put on mechanical ventilation during their stay in hospital. All the patients were admitted between March and July 2020 and were recruited to the NIHR COVID-19 BioResource.

The individuals underwent detailed computerised cognitive tests an average of six months after their acute illness using the Cognitron platform, which measures different aspects of mental faculties such as memory, attention and reasoning.

Scales measuring anxiety, depression and post-traumatic stress disorder were also assessed. Their data were compared against matched controls.

This is the first time that such rigorous assessment and comparison has been carried out in relation to the after effects of severe COVID-19.

COVID-19 survivors were less accurate and with slower response times than the matched control population – and these deficits were still detectable when the patients were following up six months later.

The effects were strongest for those who required mechanical ventilation.

By comparing the patients to 66,008 members of the general public, the researchers estimate that the magnitude of cognitive loss is similar on average to that sustained with 20 years ageing, between 50 and 70 years of age, and that this is equivalent to losing 10 IQ points.

Survivors scored particularly poorly on tasks such as verbal analogical reasoning, a finding that supports the commonly-reported problem of difficulty finding words.

They also showed slower processing speeds, which aligns with previous observations post COVID-19 of decreased brain glucose consumption within the frontoparietal network of the brain, responsible for attention, complex problem-solving and working memory, among other functions.

Professor David Menon from the Division of Anaesthesia at the University of Cambridge, the study’s senior author, said: “Cognitive impairment is common to a wide range of neurological disorders, including dementia, and even routine ageing, but the patterns we saw – the cognitive ‘fingerprint’ of COVID-19 – was distinct from all of these.”

While it is now well established that people who have recovered from severe COVID-19 illness can have a broad spectrum of symptoms of poor mental health – depression, anxiety, post-traumatic stress, low motivation, fatigue, low mood, and disturbed sleep – the team found that acute illness severity was better at predicting the cognitive deficits.

The patients’ scores and reaction times began to improve over time, but the researchers say that any recovery in cognitive faculties was at best gradual and likely to be influenced by a number of factors including illness severity and its neurological or psychological impacts.

Professor Menon added: “We followed some patients up as late as ten months after their acute infection, so were able to see a very slow improvement.

“While this was not statistically significant, it is at least heading in the right direction, but it is very possible that some of these individuals will never fully recover.”

There are several factors that could cause the cognitive deficits, say the researchers.

Direct viral infection is possible, but unlikely to be a major cause; instead, it is more likely that a combination of factors contribute, including inadequate oxygen or blood supply to the brain, blockage of large or small blood vessels due to clotting, and microscopic bleeds.

However, emerging evidence suggests that the most important mechanism may be damage caused by the body’s own inflammatory response and immune system.

While this study looked at hospitalised cases, the team say that even those patients not sick enough to be admitted may also have tell-tale signs of mild impairment.

Professor Adam Hampshire from the Department of Brain Sciences at Imperial College London, the study’s first author, said: “Around 40,000 people have been through intensive care with COVID-19 in England alone and many more will have been very sick, but not admitted to hospital.

“This means there is a large number of people out there still experiencing problems with cognition many months later. We urgently need to look at what can be done to help these people.”

Professor Menon and Professor Ed Bullmore from Cambridge’s Department of Psychiatry are co-leading working groups as part of the COVID-19 Clinical Neuroscience Study (COVID-CNS) that aim to identify biomarkers that relate to neurological impairments as a result of COVID-19, and the neuroimaging changes that are associated with these.

The research was funded by the NIHR BioResource, NIHR Cambridge Biomedical Research Centre and the Addenbrooke’s Charitable Trust, with support from the NIHR Cambridge Clinical Research Facility.

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Evening exercise benefits elderly hypertensives

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Evening exercise benefits elderly hypertensives

A study conducted at the University of São Paulo with 23 volunteers found that aerobic exercise performed in the evening benefits elderly hypertensives more than morning exercise.

Aerobic training is known to regulate blood pressure more effectively when practiced in the evening than in the morning.

Researchers who conducted a study of elderly patients at the University of São Paulo’s School of Physical Education and Sports (EEFE-USP) in Brazil concluded that evening exercise is better for blood pressure regulation thanks to improved cardiovascular control by the autonomic nervous system via a mechanism known as baroreflex sensitivity.

Leandro Campos de Brito, first author of the article, commented: “There are multiple mechanisms to regulate blood pressure, and although morning training was beneficial, only evening training improved short-term control of blood pressure by enhancing baroreflex sensitivity.

“This is important because baroreflex control has a positive effect on blood pressure regulation, and there aren’t any medications to modulate the mechanism.”

In the study, 23 elderly patients diagnosed and treated for hypertension were randomly allocated into two groups: morning training and evening training. Both groups trained for ten weeks on a stationary bicycle at moderate intensity, with three 45-minute sessions per week.

Key cardiovascular parameters were analysed, such as systolic and diastolic blood pressure, and heart rate after ten minutes’ rest. The data was collected before and at least three days after the volunteers completed the ten weeks of training.

The researchers also monitored mechanisms pertaining to the autonomic nervous system, which controls breathing, heart rate, blood pressure, digestion, and other involuntary bodily functions, such as muscle sympathetic nerve activity, which regulates peripheral blood flow via contraction and relaxation of blood vessels in muscle tissue, and sympathetic baroreflex sensitivity, assessing control of blood pressure via alterations to muscle sympathetic nerve activity.

In the evening training group, all four parameters analysed were found to improve: systolic and diastolic blood pressure, sympathetic baroreflex sensitivity, and muscle sympathetic nerve activity. In the morning training group, no improvements were detected in muscle sympathetic nerve activity, systolic blood pressure or sympathetic baroreflex sensitivity.

“Evening training was more effective in terms of improving cardiovascular autonomic regulation and lowering blood pressure. This can be partly explained as due to an improvement in baroreflex sensitivity and a reduction of muscle sympathetic nerve activity, which increased in the evening. For now, all we know is that baroreflex control is the decisive factor, from the cardiovascular standpoint at least, to make evening training more beneficial than morning training, since it induces the other benefits analysed. However, much remains to be done in this regard in order to obtain a better understanding of the mechanisms involved,” said Brito, who is currently a professor at Oregon Health & Science University’s Oregon Institute of Occupational Health Sciences in the United States, and continues to investigate the topic via circadian rhythm studies.

Baroreflex sensitivity regulates each heartbeat interval and controls autonomic activity throughout the organism.

“It’s a mechanism that involves sensitive fibres and deformations in the walls of arteries in specific places, such as the aortic arch and carotid body. When blood pressure falls, this region warns the brain region that controls the autonomic nervous system, which in turn signals the heart to beat faster and tells the arteries to contract more strongly. If blood pressure rises, it warns the heart to beat more slowly and tells the arteries to contract less. In other words, it modulates arterial pressure beat by beat,” Brito explained.

In previous studies, the EEFE-USP research group showed that evening aerobic training reduced blood pressure more effectively than morning training in hypertensive men (read more at: agencia.fapesp.br/34194), and that the more effective response to evening training in terms of blood pressure control was accompanied by a greater reduction in systemic vascular resistance and systolic pressure variability (read more at: agencia.fapesp.br/37432).

“Replication of the results obtained in previous studies and in different groups of hypertensive patients, associated with the use of more precise techniques to evaluate the main outcomes, has strengthened our conclusion that aerobic exercise performed in the evening is more beneficial to the autonomic nervous system in patients with hypertension. This can be especially important for those with resistance to treatment with medication,” Brito said.

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Revolutionising cancer treatment: intracellular protein delivery using hybrid nanotubes

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Revolutionising cancer treatment: intracellular protein delivery using hybrid nanotubes

A new hybrid nanotube stamp system has been developed which revolutionises precision medicine with high efficiency and cell viability rates for cancer treatment.

Precision medicine and targeted therapies are gaining traction for their ability to tailor treatments to individual patients while minimising adverse effects. Conventional methods, such as gene transfer techniques, show promise in delivering therapeutic genes directly to cells to address various diseases.

However, these methods face significant drawbacks, hindering their efficacy and safety. Intracellular protein delivery offers a promising approach for developing safer, more targeted, and effective therapies. By directly transferring proteins into target cells, this method circumvents issues such as silencing during transcription and translation and the risk of undesirable mutations from DNA insertion. Additionally, intracellular protein delivery allows for precise distribution of therapeutic proteins within target cells without causing toxicity.

A group of researchers led by Professor Takeo Miyake at Waseda University, Japan in collaboration with the Mikawa Group at the RIKEN Institute have now developed a hybrid nanotube stamp system for intracellular delivery of proteins. This innovative technique enables the simultaneous delivery of diverse cargoes, including calcein dye, lactate oxidase (LOx) enzyme, and ubiquitin (UQ) protein, directly into adhesive cells for cancer treatment.

The researchers explored the therapeutic potential of delivering LOx enzyme for cancer treatment. “Through our innovative stamp system, we successfully delivered LOx into both healthy mesenchymal stem cells (MSC) and cancerous HeLa cells. While MSC cells remained unaffected, we observed significant cell death in HeLa cancer cells following LOx treatment with viabilities decreasing over time. Our findings highlight the promising efficacy of intracellularly delivered LOx in selectively targeting and killing cancer cells, while sparing healthy cells, offering a targeted therapeutic strategy for cancer treatment,” explains Miyake.

Finally, the team successfully delivered 15N isotope-labeled UQ proteins into HeLa cells using the HyNT stamp system. This delivery allowed for the analysis of complex protein structures and interactions within the cells. In addition, optical and fluorescence imaging confirmed the presence of delivered UQ in HeLa cells, and nuclear magnetic resonance spectroscopy matched the intracellular UQ protein concentration with that of a solution containing 15N-labeled UQ. These results demonstrate the effectiveness of the stamp system in delivering target proteins for subsequent analysis.

The results demonstrate the remarkable capability of the HyNT stamp system in delivering LOx and UQ into a substantial number of adhesive cells, as required for regenerative medicine applications. The system achieved a notably high delivery efficiency of 89.9%, indicating its effectiveness in transporting therapeutic proteins into the target cells with precision. Moreover, the cell viability rate of 97.1% highlights the system’s ability to maintain the health and integrity of the treated cells throughout the delivery process.

The HyNT stamp system offers transformative potential in intracellular protein delivery, with applications spanning from cancer treatment to molecular analysis. Beyond medicine, its versatility extends to agriculture and food industries, promising advancements in crop production and food product development. With precise cell manipulation and efficient delivery, the HyNT stamp system is poised to revolutionize biomedical research, clinical practice, and diverse industries, paving the way for personalized interventions and shaping the future of modern medicine.

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Heat waves damage humans’ vital organs, shows new study

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Researchers from the University of California, Irvine have found evidence of the molecular causes of the damaging impact heat stress causes on the gut, liver and brain in the elderly.

The researchers suggest these findings point to the potential of developing precise prognostic and therapeutic interventions.

These organs have a complex and multidirectional communication system that touches everything from our gastrointestinal tract to the nervous system. Whether it is our brain affecting hunger or the liver influencing mental health, understanding the gut-liver-brain communication or “axis” is crucial to protecting human health.

Their study, which was conducted on mouse models, is published in the journal Scientific Reports, a Nature Portfolio journal. It is one of the first to fill the knowledge gap on the effects of heat stress on a molecular level of this crucial biological conversation.

“Inflammation in the brain and spine contributes to cognitive decline, compromises the ability to form new neurons and exacerbates age-related diseases,” said corresponding author, Saurabh Chatterjee, a professor of environmental & occupational health at the UC Irvine Program in Public Health. “By investigating the effects of heat stress on the gut-liver-brain crosstalk, we can better protect our increasingly vulnerable aging population.”

Using RNA analysis and bioinformatics to analyse elderly, heat-stressed mice, Chatterjee and his team found evidence of heat stress-affected genes in the brain and liver. A significant increase in the production of ORM2, a liver-produced protein, was observed in the heat-stressed mice. The control group of unstressed mice did not show a change, providing proof of organ dysfunction in the heat-stressed mice.

Researchers believe that increased secretion of ORM2 is a coping mechanism that may be due to gut inflammation and imbalance. In addition, ORM2 may impact the brain through a leaky blood-brain barrier, emphasizing intricate multi-organ crosstalk.

Additionally, the study shows the potential to use ORM2 for targeted biomarker interventions to prevent liver disease in heat exposure. This observation advances molecular insights into the pathophysiology of adverse heat events and will serve as a foundation for future research.

“Our findings have the potential to be used for the development of prognostic and therapeutic markers for precise interventions,” said Chatterjee. “In a dynamically changing global landscape, the imminent threat of climate change is evident in rising temperatures, raising concerns about intermittent heat waves. Our heating planet is undoubtedly leading to acute and chronic heat stress that harms the health of our aging population.”

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