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On the hunt for rehab evidence



Neuro-rehab’s influence within one of 
the world’s most relied-upon healthcare research bodies is on the rise.

Cochrane, the global organisation with systematically reviews healthcare research and underpins many of the world’s official guidelines, has provided an annual update on its fledgling rehabilitation group.

The group was launched last year to bring together rehabilitation expertise and evidence and highlight gaps where new research is needed to inform rehab
decisions by professionals.

More than 230 collaborators from 49 countries backed its launch and its reach looks to have grown considerably since.

Cochrane is made up of a network of researchers, professionals, patients, 
carers and people interested in health with the mission of promoting evidence-informed decisions.

Within it, Cochrane fields are groups focused on particular healthcare areas, aimed at linking evidence produced by Cochrane
with the external stakeholders who need it.

The rehabilitation field was established to help rehab professionals make decisions by combining evidence gathered by systematic reviews with their own clinical expertise.

The group is headquartered in Brescia, Italy, and run in collaboration with the University of Brescia and the Don Gnocchi Foundation.

Its director, Stefano Negrini, said at the time of its launch: “Producing and increasingthe dissemination of the best available information on healthcare is critical for clinicians and patients everywhere in the world, especially in rehabilitation.

“Cochrane Rehabilitation will drive, on one side, evidence and methods developed by Cochrane to the world of rehabilitation and, on the other, convey priorities,needs and specificities of rehabilitationto Cochrane.”

The group’s goals include connecting rehabilitation “stakeholders” globally, translating evidence into knowledge for all areas of practice in rehab and disseminating Cochrane’s work more widely and internationally. 

Work is also underway in developing a register of rehab-relevant systematic reviews and rehab-based educational activities.

The group also influences the ongoing development of Cochrane’s review methods – and works to promote both the rehab community to Cochrane, and Cochrane to rehab networks.

William Levack, reviews committee chair at Cochrane Rehabilitation, says: “There was a clear gap for a rehabilitation group.

“When we first started talking about Cochrane Rehabilitation, an initial screening revealed the vast majority of Cochrane review groups had something to do with rehabilitation.

“There were at least four groups that contained over 20 reviews that related to rehab, while there are nine review groups that are directly relevant to neuro-rehab alone, so we wanted a group made up of people from all around the world in this field.

“If we think about Cochrane as a global, independent, non-pro t network of research professionals, patients and carers and so on, Cochrane Rehabilitation is all of that, but for people interested in rehabilitation. It exists for healthcare decisions in rehabilitation.

“The group is a two-way bridge. On one hand we want to share the work of Cochrane, but we also want to inform the work of Cochrane from the perspective of clinicians, patients and policymakers in rehabilitation.”

In the next 12 months, the rehabilitation group will oversee the publishing of a rehabilitation e-book which will share rehab knowledge, while also identifying priorities for new reviews and areas of neglect not yet covered by reviews.

A director of the rehabilitation field sits on Cochrane’s Knowledge Translation Advisory Board, while two “Cochrane Rehabilitation Units” have so far submitted their “Action Business Plan”; the Turkish Society of Physical Medicine & Rehabilitation and the Nursing, Midwifery and Allied Health Professions (NMAHP) Research Unit at Glasgow Caledonian University.

A third unit has been set up at the Physical and Rehabilitation Medicine Department of the University of Campania “Luigi Vanvitelli” in Naples, which will work with Cochrane rehab’s HQ in producing the new e-book.

Lectures, sessions and workshops have been held in around 20 meetings so far, meanwhile.

Cochrane’s overall aim is to inform better healthcare decisions by gathering and summarising the best health evidence from research in themed systematic reviews.

While directly helping professionals to make vital decisions about interventions, Cochrane’s work also heavily influences offcial guidelines.

In 2016, for example, almost 90 per cent of World Health Organization guidelines produced that year used Cochrane’s systematic reviews.

Cochrane’s editor-in-chief David Tovey says: “Systematic reviews look at all the available high-quality evidence to address a particular question through a comprehensive search.

“The findings of that search are fed through a filter and, as a result, you may get a pooled estimate of effects from all the studies. Using all of those studies you are increasing your power and precision.

“Most importantly, it also gives you an opportunity to look at the risk of bias in those studies and to look at the body of evidence and make judgements.”

Cochrane users range from doctors and nurses to patients, carers, researchers and funders, while its network of contributors spans 120 countries.

Each contributor is affiliated to the organisation through Cochrane groups, which include healthcare-related review groups, thematic networks, groups concerned with the methodology of systematic reviews and regional centres.

There is no one place or office that is ‘Cochrane’. Contributors and groups are based all around the world and the majority of work is carried out online.

Each group is a “mini-organisation” in itself, with its own funding, website, and workload. Contributors affiliate themselves to a group, or in some cases several groups, based on their interests, expertise, and/or geographical location.

As well as producing systematic reviews, Cochrane contributes to the development of the methods of evidence synthesis, in part by training people who undertake systematic reviews and in shaping primary research.

Neuro-rehab research gaps

Part of Cochrane’s work involves spotting neglected areas of research – of which there and many in neuro-rehab. Here are some recently identified areas which, although showing promise, lack the robust data needed to support definitive decisions:

Fitness training and traumatic brain injury recovery

A review of eight studies involving 67 participants concluded that: “There is low-quality evidence that fitness training is effective at improving cardiorespiratory deconditioning after TBI; there is insuficient evidence to draw any definitive conclusions about the other outcomes. Whilst the intervention appears to be accepted by people with TBI, and there is no evidence of harm, more adequately powered and well-designed studies are required to determine a more precise estimate of the effect on cardiorespiratory fitness, as well as the effects across a range of important outcome measures and in people with different characteristics (e.g. children).”

Interventions for eye movement disorders due to acquired brain injury

Cochrane analysed five studies, including one involving botulinum toxin and another which compared eye movement training with sham (false) training in people with mild traumatic brain injury. Cochrane said: “The included studies provide insufficient evidence to inform decisions about treatments specifically for eye movement disorders that occur following acquired brain injury. No information was obtained on the cost of treatment or measuresof participant satisfaction relating to treatment options and effectiveness.”

Respiratory muscle training and MS

Cochrane’s researchers looked at various trials, including two which tested inspiratory muscle training with a threshold device, three involving expiratory muscle training with a threshold device, and one based on breathing exercises. They concluded: “This review provides low-quality evidence that resistive inspiratory muscle training witha resistive threshold device is moderately effective post-intervention for improving predicted maximal inspiratory pressure in people with mild to moderate MS, whereas expiratory muscle training showed no significant effects. The sustainability ofthe favourable effect of inspiratory muscle training is unclear, as is the impact of the observed effects on quality of life.”

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Light therapy could stop epileptic seizures – study



The researchers were able to activate the brains of mice using light rather than an electrical current

Deep brain stimulation could prevent epileptic seizures, a new study has found.

Research in mice has revealed that low-frequency stimulation of specific brain areas, using light rather than electric current, could completely stop epileptic activity.

Traditionally, epileptic activity originating from one or more diseased brain regions in the temporal lobe is difficult to contain.

Many patients with temporal lobe epilepsy often do not respond to treatment with anti-epileptic drugs, and the affected brain areas must therefore be surgically removed – although this only gives freedom from seizures to around a third of patients.

Now, this new light-based therapeutic approach, investigated by scientists at the University of Freiburg, could yield a significant breakthrough for patients.

“As soon as we stimulated the brain region with a frequency of one hertz, the epileptic seizures disappeared. This effect was stable over several weeks,” says Professor Carola Haas, head of the research group at the department of neurosurgery at the University of Freiburg.

In the study, habituation, which can occur with drug therapy, did not take place. The brain region was stimulated for one hour daily.

In temporal lobe epilepsy, the hippocampus is often pathologically altered and usually represents the so-called focus of epileptic activity.

Previous studies have used precise genetic labelling techniques to map the fibre system and its synaptic contacts between the temporal lobe and hippocampus, which are typically preserved in temporal lobe epilepsy.

The researchers used this fibre system to manipulate hippocampal activity in a specific and temporally precise manner using light-dependent proteins.

Measuring brain waves showed that rhythmic activation of the diseased hippocampus at a low frequency of one hertz suppressed epileptic activity and prevented it from spreading.

Professor Haas and her team demonstrated that the anti-epileptic effect is largely due to the repeated activation of surviving granule cells in the seizure focus.

Single cell studies confirmed the assumption that the granule cells are less excitable due to the stimulation, making the epileptic seizure less likely to spread.

“It’s also possible that we have a widespread network effect because the stimulation can spread through the hippocampal circuitry,” Professor Haas adds.

In the future, the team, along with the medical physics department at the Medical Center – University of Freiburg, have plans to use magnetic resonance imaging to observe the entire brain during stimulation.

This technique could be used to identify additional brain regions that are affected by the stimulation. Corresponding findings on these could provide information on how they are connected and what further consequences stimulation has.

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Gene linked to long lifespans can protect from stress



"Without SAM, lamin can't form this strong barrier and DNA starts leaking out."

A gene linked to unusually long lifespans in humans protects brain stem cells from the harmful effects of stress, a new study has found.

Studies of humans who live longer than 100 years have shown that many share an unusual version of a gene called Forkhead box protein O3 (FOXO3).

That discovery led Dr Jihye Paik, associate professor of pathology and laboratory medicine at Weill Cornell Medicine, and her colleagues to investigate how this gene contributes to brain health during ageing.

In 2018, Dr Paik and her team showed that mice who lack the FOXO3 gene in their brain are unable to cope with stressful conditions in the brain, which leads to the progressive death of brain cells.

And their new study reveals that FOXO3 preserves the brain’s ability to regenerate by preventing stem cells from dividing until the environment will support the new cells’ survival.

Stem cells produce new brain cells, which are essential for learning and memory throughout our adult lives,” says Dr Paik.

“If stem cells divide without control, they get depleted. The FOXO3 gene appears to do its job by stopping the stem cells from dividing until after the stress has passed.”

Many challenges like inflammation, radiation or a lack of adequate nutrients can stress the brain. But Dr Paik and her colleagues looked specifically what happens when brain stem cells are exposed to oxidative stress, which occurs when harmful types of oxygen build up in the body.

“We learned that the FOXO3 protein is directly modified by oxidative stress,” she says.

This modification sends the protein into the nucleus of the stem cell where it turns on stress response genes.

The resulting stress response leads to the depletion of a nutrient called s-adenosylmethionine (SAM). This nutrient is needed to help a protein called lamin form a protective envelope around the DNA in the nucleus of the stem cell.

“Without SAM, lamin can’t form this strong barrier and DNA starts leaking out,” she says.

The cell mistakes this DNA for a virus infection, which triggers an immune response called the type-I interferon response. This causes the stem cell to go dormant and stop producing new neurons.

“This response is actually very good for the stem cells because the outside environment is not ideal for newly born neurons,” Dr Paik continues.

“If new cells were made in such stressful conditions they would be killed. It’s better for stem cells to remain dormant and wait until the stress is gone to produce neurons.”

The study may help explain why certain versions of the FOXO3 are linked to extraordinarily long and healthy lives – they may help people keep a good reserve of brain stem cells.

It may also help explain why regular exercise, which boosts FOXO3 helps preserve mental sharpness.

But Dr Paik cautions it is too early to know whether this new information could be used to create new therapies for brain diseases.

“It could be a double-edged sword,” Dr Paik adds.

“Over activating FOXO3 could be very harmful. We don’t want to keep this on all the time.”

To better understand the processes involved, she and her colleagues will continue to study how FOXO3 is regulated and whether briefly turning it on or off would be beneficial for health.

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Routine genetic tests ‘should be offered to all MND patients’



The Sheffield Institute for Translational Neuroscience made the conclusions from its research

Offering routine genetic testing for Motor Neurone Disease (MND) could improve knowledge of disease classification and impact clinical care, new research has concluded.

Routine testing may be appropriate for all MND patients – whether or not they have a family history of the disease – and could impact disease sub-classification and clinical care, the findings of the Sheffield Institute for Translational Neuroscience (SITraN) study revealed.

Currently only patients with a family history of MND, dementia, or who experience disease onset at a young age are routinely offered genetic screenings in the UK.

With the development of new therapies targeting specific genetic forms of the disease, researchers on the study – which was funded by the are recommending that all MND patients are offered a screening.

“Our study suggests that all patients with MND should, with careful counselling, be offered genetic testing,” says Professor Dame Pamela Shaw, Director of SITraN and the NIHR Sheffield Biomedical Research Centre.

“We hope that by screening all MND patients for gene mutations that are a known factor in MND, we can further our knowledge on subclassification of the disease, but also ensure that patients have access to clinical trials that are relevant for them personally.”

MND – also known as amyotrophic lateral sclerosis (ALS) – is an adult-onset neurodegenerative disease characterised by progressive injury and cell death of upper and lower motor neurons.

This leads to progressive failure of the neuromuscular system with death, usually from respiratory failure, within 2–5 years of symptoms in most cases.

Currently, there is no cure for MND – which affects 5,000 people in the UK and 450,000 people worldwide – and no effective treatments to halt or reverse the progression of this devastating disease.

Among the 100 patients who took part in the study, researchers found higher than expected genetic changes in the group of patients.

“Our study found that 42 per cent of patients involved in the screening showed variants in known MND-linked genes,” says Professor Janine Kirby, Professor of Neurogenetics at the University of Sheffield.

“This doesn’t mean that 42 per cent of MND cases are familial – but shows that some familial and sporadic cases can share the same genetic cause of disease.

“We found that 21 per cent of patients had a clinically reportable genetic alteration that has been proven to increase the likelihood of developing MND.

“Of these, 93 per cent had no family history of MND and 15 per cent met the inclusion criteria for a current MND gene therapy clinical trial.

“As future studies expand the number of verified genetic causes of MND, we will continue to see if they are also found in cases without a family history.

“This is increasingly important in light of the new personalised medicine treatments in development for MND that target a specific gene mutation to ensure that patients have access to potential treatments that could be beneficial to them.”

Dr Brian Dickie, director of research development at the MND Association, adds: “MND is a complex disease involving a complex mix of genetic and environmental factors.

“This latest research sheds more light on the genetic component and will hopefully lead to greater availability of genetic testing to aid earlier diagnosis and more tailored treatments in the future.

”This will provide an even clearer picture of the UK MND genetic landscape.’’

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