Sunday, 24 July 2016

ThinkHand: how important is your arm and hand function to you?

Did you know that hand functions involving power and precision probably evolved separately? #ThinkHand #MSBlog #MSResearch

"If you a veteran visitor to this blog you will be aware that as an extension of our length-dependent axonopathy (LENDAXON) and therapeutic lag hypotheses we are proposing that progressive trials in people already using a walking stick (EDSS = 6.0 and 6.5) or wheelchair (EDSS>=7.0) should focus on upper limb (arm and hand) function as the primary outcome. This proposal is supported by many data sets and is strongly supported by the recent results of the ASCEND trial (natalizumab in SPMS). Although this trial was negative overall it showed that natalizumab was effective in maintaining upper limb function compared to placebo in pwSPMS. Despite presenting and writing about the LENDAXON and therapeutic lag hypotheses, lobbying pharma and discussing things face-to-face with colleagues there seems to be some resistance to adopting our ideas and trial proposal. We are hoping to change things at ECTRIMS; we have had one of our Blog Surveys on the importance of arm and hand function to pwMS accepted as a poster and there will be a debate on this exact issue as well. Dr K or Dr Schmierer will be making the case for trials in more advanced MS using upper limb function as the primary outcome."

"We also planning to launch an initiative around ECTRIMS to allow pwMS to perform their own 9-hole peg test (9-HPT), i.e. a self- or home-administered 9-HPT, so that you can start monitoring your own arm and hand function. If we don't get people to ThinkHand then the chances of getting effective treatments for people with more advanced MS will remain slim. One of the problems we face is that both the 9-HPT and the ABILHAND (a patient-related outcome measure or PROM) to assess arm and hand function are designed and weighted towards assessing precision, rather than power, tasks. It is clear from the evolution of the hand (see abstract below) that we need both precision and power. As MS impacts on both of these functions we may need newer and better outcome measures that are more sensitive to change to measure these functions in more detail. We also believe that the current upper-limb outcome measures are not that meaningful to pwMS; Alison Thomson in our group is hoping to change that as well. She is currently ruminating on how to develop and improve on the current PROMS; she is passionate about making a PROM that reflects the impact MS is having on your life."

"To help expand the data set for our ECTRIMS poster; I would appreciate it if you could help by completing another, more detailed survey on arm and hand function. Thank you."

Richard W Young. Evolution of the human hand: the role of throwing and clubbing. J Anat. 2003 Jan; 202(1): 165–174.

It has been proposed that the hominid lineage began when a group of chimpanzee-like apes began to throw rocks and swing clubs at adversaries, and that this behaviour yielded reproductive advantages for millions of years, driving natural selection for improved throwing and clubbing prowess. This assertion leads to the prediction that the human hand should be adapted for throwing and clubbing, a topic that is explored in the following report. It is shown that the two fundamental human handgrips, first identified by J. R. Napier, and named by him the ‘precision grip’ and ‘power grip’, represent a throwing grip and a clubbing grip, thereby providing an evolutionary explanation for the two unique grips, and the extensive anatomical remodelling of the hand that made them possible. These results are supported by palaeoanthropological evidence.

Cancer Risk with Mitoxantrone

Buttmann M, Seuffert L, M├Ąder U, Toyka KV. Malignancies after mitoxantrone for multiple sclerosis: A retrospective cohort study. Neurology. 2016 Jun 7;86(23):2203-7.

OBJECTIVE:To assess the therapy-related risk of malignancies in mitoxantrone-treated patients with multiple sclerosis.
METHODS:This retrospective observational cohort study included all mitoxantrone-treated patients with multiple sclerosis seen at our department between 1994 and 2007. We collected follow-up information on medically confirmed malignancies, life status, and cause of death, as of 2010. Malignancy rates were compared to the German national cancer registry matched for sex, age, and year of occurrence.
RESULTS: Follow-up was completed in 676 of 677 identified patients. Median follow-up time was 8.7 years (interquartile range 6.8-11.2), corresponding to 6,220 person-years. Median cumulative mitoxantrone dose was 79.0 mg/m(2) (interquartile range 50.8-102.4). Thirty-seven patients (5.5%) were diagnosed with a malignancy after mitoxantrone initiation, revealing a standardized incidence ratio of 1.50 (95% confidence interval [CI] 1.05-2.08). Entities included breast cancer (n = 9), colorectal cancer (n = 7), acute myeloid leukemia (n = 4, 0.6%), and others (each entity n = 1 or 2). The standardized incidence ratio of colorectal cancer was 2.98 (95% CI 1.20-6.14) and of acute myeloid leukemia 10.44 (95% CI 3.39-24.36). It was not increased for other entities including breast cancer. Multivariate Cox regression identified higher age at treatment initiation but neither cumulative mitoxantrone dose (>75 vs ≤75 mg/m(2)) nor treatment with other immunosuppressive drugs or sex as a risk factor. Fifty-five patients had died, among them 12 of a malignancy and 43 reportedly of other causes.
CONCLUSIONS: While the overall incidence of malignancies was only mildly increased, the risk of leukemia and colorectal cancer was heightened. If confirmed, posttherapy colonoscopy could become advisable.

Mitoxantrone is an anti-cancer drug that is not licenced in the UK ut is sometimes used to treat MS. Its use is limited because it can cause damage to the heart muscles meaning that you can only take a limited number of doses. It is already known that there is a increased risk of cancer. In this German cohort followed for up to a number of years, they report that 5% of people got cancer so that is 1 in 20 people. Whilst life is assocaited with a cancer risk, this appears high and is one of the reasons that our use of ths agent has dwindled. It is strange that there is a resistance against cladribine and I wonder if such people will supply mitoxantrone when the risk of cancer is probably higher.

Saturday, 23 July 2016

SurveySpeak: is wound healing a problem on DMTs?

I am sick and tired of my current DMT; it seems to be affecting wound healing. What about you? #SurveySpeak #MSBlog 

"Prof B (aka the MouseDoctor) was speaking to a person with MS who mentioned to him that since starting drug X they had noticed that minor cuts and abrasions were taking much longer to heal. The process of wound healing is complex and uses many of the same biological processes that the immune system uses to function. Therefore it is quite possible that some DMTs that are used in MS may impact on wound healing. To assess whether or not this is an anecdote, or a real phenomenon, ProfB has asked me to do a quick poll. We would therefore appreciate it if you could complete the following survey. Thank you."

Eming et al. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med. 2014 Dec 3;6(265):265sr6.

The cellular and molecular mechanisms underpinning tissue repair and its failure to heal are still poorly understood, and current therapies are limited. Poor wound healing after trauma, surgery, acute illness, or chronic disease conditions affects millions of people worldwide each year and is the consequence of poorly regulated elements of the healthy tissue repair response, including inflammation, angiogenesis, matrix deposition, and cell recruitment. Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies. The search for clinical strategies that might improve the body's natural repair mechanisms will need to be based on a thorough understanding of the basic biology of repair and regeneration. In this review, we highlight emerging concepts in tissue regeneration and repair, and provide some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies.

Assessing Animal Data is it Pants or Not?

EAE #MSresearch #MSBlog
This week ProfB presented to a group of students on EAE and left his slides on the blog. The students also had a session on experimental design. Central to this is how to analyse data. Someone commented on this.

I must admit we are all pretty bad a statistics, but it seems that some EAEologists are worse than others

Someone I know had a grant sent back because the referees were saying that they had to analyse their EAE data in a certain way, that was........statistically wrong.

It is amazing how many people do their EAE analysis in the wrong way. 

They often use a test called a Student's t test to measure the severity of a neurological score. 

Here signs are given a arbitaory score say 0-5 see in the example below. This test assumes a few things such that the measurement item is continuous (such as height where you could be 1m tall or 2m tall but also everything in between as an example of parametric data), but a few other things too. If those assumuptions are not evident you need to use non-parametric analysis such as the Wilcoxon/Mann Whitney U tests.

It is amazing that 65% of the EAE paper published in Nature/Science/Cell journals assume neurological scores are parametric and of those a whopping 67% of studies use a t test to analyse their data. This is in my humble opinion not correct.

In the picture you can see the crux of the problem. In EAE you get T cells infiltrating the spinal cord and in the picture above the cells are red. In the picture above look at the extra amount of red between 0 = normal and 1 = limp tail. Now look at the difference between 3 = paresis= partial paralysis and 4 = hindlimb paralysis. So the amount of red detween 0 and 1 and 3 and 4 is not the same  yet they get an arbitary score of diffeence of 1. But you can see there is more red in 3 than 1 and more red in 4 than 3. So the neurological score is non-linear and non-parametric meaning that non-parametric statistics should be used. This is based on ranking from the smallest to the largest. Does this mak a difference?

It can do. This is an real example that we use to teach, It was a nature paper and the animal experiment was the culmination of the work. In the study they used a t test and showed the drug gave a signficant inhibition (p=0.029)...Yipppie they said. But if only the referees had asked them to do it properly.  Look at the graph and the drug drops the neurological score by about a half

Or does it?
They seem to show the actual scores of individual animals and yes if you do a t test it is P=0.029. But looking at the data 5 animals have no disease but the drug does essentialy nothing in the six animals that got disease. 

However if you do non-parametric statistics the result is P=0.082 and so the drug does nothing and the value of the Nature paper is flushed down the loo. 

So the paper may not get a mention because of the idea but as a teching example of data analysis

Was it a fluke where it just happened that 5 animals failed to get disease. We never know because the work was not repeated. So looks like there is no quality control which is a problem with some EAE studies.

So when you read EAE papers look out for the way the data is analysed. Does it pass the "snack you in the eye test" or are the results pants?

Pharma is having to deposit trial data  with the regulators so that it can be re-analysed by others requesting the info. It is a probably only a matter of time before they make people deposit raw data when they publish (people are asking about this), so the data can be re-analysed. This will be fun and games. How many other studies will fail?

Should we not do these posts and pretend it is all great?
It clearly isn't

Mapping the Brain

Glasser MF, Coalson TS, Robinson EC, Hacker CD, Harwell J, Yacoub E, Ugurbil K, Andersson J, Beckmann CF, Jenkinson M, Smith SM, Van Essen DC. A multi-modal parcellation of human cerebral cortex. Nature. 2016 Jul 20. doi: 10.1038/nature18933. [Epub ahead of print]

Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas. Making an accurate areal map has been a century-old objective in neuroscience. Using multi-modal magnetic resonance images from the Human Connectome Project (HCP) and an objective semi-automated neuroanatomical approach, we delineated 180 areas per hemisphere bounded by sharp changes in cortical architecture, function, connectivity, and/or topography in a precisely aligned group average of 210 healthy young adults. We characterized 97 new areas and 83 areas previously reported using post-mortem microscopy or other specialized study-specific approaches. To enable automated delineation and identification of these areas in new HCP subjects and in future studies, we trained a machine-learning classifier to recognize the multi-modal 'fingerprint' of each cortical area. This classifier detected the presence of 96.6% of the cortical areas in new subjects, replicated the group parcellation, and could correctly locate areas in individuals with atypical parcellations. The freely available parcellation and classifier will enable substantially improved neuroanatomical precision for studies of the structural and functional organization of human cerebral cortex and its variation across individuals and in development, aging, and disease.

Think of a political map (These are designed to show governmental boundaries of countries, states, and counties, the location of major cities, and they usually include significant bodies of water. Differing colours are often used to help the user differentiate between nations). it shows us where we are but it gives us borders between counties and the countries which may give an impression how we may be different from or similar to our neighbours. This study made use of the Human Connectome project which is plotting out how the nerves are interconnected.

                       210p = parcellation group and 210v= 210 in a validation group

In this study they have down the same thing with the brain. Over 440 young adults were scanned and they have divided the cortex (outside of the brain) into 180 different counties (which have been called parcels like plots of land) in each half of the brain. Most previous parcellations were based on only one neurobiological property (such as architecture, function, connectivity or topography). In this study the finger print of each parcel was made (e.g. majority didn’t vote brexit; kilt not national costume; famous for spa water; in gods own country, so with just 4 categories = Harrogate) and in this study information included measurements of size; brain function; connectivity between regions; spacial organization of cells in brain tissue; and levels of myelin and used these to create borders. In the study this approach confirmed the existence of 83 previously reported brain areas but also found 97 new areas. This map was then tested in 210 different people and the map was found to be accurate (ordinance survey standardJ) but the size of the parcel may vary between different people. This was validated in another 210 people. However this is just the beginning as the map doesn’t yet include the biochemical underpinnings of the brain. 

Just as ProfGs tube map started with a few stations there will be more to come. By parcelling these areas it will help us to make structure to function relationships in even finer detail just as we map the hippocampus to memory and the cerebellum to movement. This may help us to delineate problems associated with MS where lesions in one area or pathway of the brain may link to different signs and symptoms.