Sunday, 31 July 2016

Game over the ref has stopped the transfer market

The Research Excellence Framework (REF) is a method of how the UK Government assesses Reserach Excellence and this dictates how it gives £2 billion a year to Higher Education Centres. This occurs every 5-6 years and the next one in in 2020/2021.

In the past the Universities have selected who they return (you only get paid for those you submit), based on their performance which influences their ranking. They play as many mind games as possible within the rules to maximize their chances of a high ranking  

This process costs hundreds of millions of Pounds. But we all know Cambridge will come top and the top 5 can be predicted.

This created a culture of bullying in some places and there was a case last time when a person sent out a global email complaining of the bullying threat of sacking and stress that the reseach had been put under...to which you thought they are going to get sacked...only to find out that this was a timed launch and the person had commtted suicide two weeks before. 

It also created a transfer market were salararies and lab funds could be boosted by the cost of poaching,or stopping poaching to keep staff, so that places can boost their ranking and hnce cash.

The rules have been changing each year so what's in store for  REF 2020/2021. Well we had some in sight this week with the publication of the Lord Stern Report .

                               Not this Stern but some will get a shock by the recommendations



President of the British Academy Lord Nicholas Stern was commissioned by the government to carry out the review of the Research Excellence Framework (REF) to ensure future university research funding is allocated more efficiently, offers greater rewards for excellent research and reduces the administrative burden on institutions.



If you want to read it CLICK here


Recommendation 1: All research active staff should be returned in the REF. So no fudge factor but those under performing in research will become treachers

Recommendation 2: Outputs should be submitted at Unit of Assessment level with a set average number per FTE but with flexibility for some faculty members to submit more and others less than the average


Rather than asessing the indivduals within the unit on their research outputs the Unit gets assessed on its research outputs so less emphasis of the individual so the the stars of the unit can contribute more and the not so big stars can constribute less than currently in place. This would make it cheaper for the institutions to do

Recommendation 3: Outputs should not be portable.
So work done in one place can't be used to support the rankings in another place so now the transfer window is closed.

This means no University is going to buy in a mega MS Research lab  and give them losts of cash just before the next ref, they are not going to coax in  some Foreign MS Research Lab to take their past track record. Now it is going to be based on future potential not past glory. So the transfer market would swtich not to the end of the REF cycle but to the beginning, with the risk of underperformance if the facilities needed are not in place. You always have downtime with a move.

There were more
Let's see what gets adopted, but the Head Honchos will be thinking how to maximize their output. However some of the moves like stopping the outputs being portable should have been implemented many years ago, but if it had, TeamG would not be at Barts one suspects ,as we moved in the transfer window.

ClinicSpeak: what matters to you?

Are you happy with the way you are treated? Have your say! #ClinicSpeak #MSBlog #HaveYourSay


"I typically read the BMJ on my way to work on a Monday morning and the NEJM on a Thursday morning. Hence my frequent posts from the BMJ and NEJM on a Monday and a Thursday, respectively. I am no different to most and would be the first to admit that I am a slave to habit. However, this week's BMJ has several juicy articles on Pharma behaving badly so I had to read them last night (more on that later in the week) and as the BMJ was next to my bed when I woke this morning I had to finish it."

"There is enough material in this issue of the BMJ for a week's worth of posts. However the article that caught my eye is one on 'what matters to you' as a patient in a healthcare system. I am very interested in exploring this issue further, particularly as it has relevance to our #ThinkHand campaign; so please feel free to comment. Please note positive comments are as valuable as negative comments. I am personally at a cross-roads when it comes to the way I feel about our healthcare and social care systems and how they address the needs for pwMS and their families. I think the current system, which is largely Victorian in design, is out-dated and out-moded, which is why we are trying to start the discussion about re-configuring our MS services it. So don't hold back be as brazen and critical as you want; as Mouse Doctors says I have developed a very thick skin."

Sosena Kebede. Ask patients “What matters to you?” rather than “What’s the matter?” BMJ 2016;354:i4045.

Excerpts:

.... Maureen Bisognano, one of the keynote speakers at this year’s International Forum on Quality and Safety in Healthcare in Gothenburg, Sweden, told delegates that we should ask our patients, “What matters to you?” rather than, “What is the matter?”....

..... The question “What matters to you?” tries to get to the essence of patient centered care, which the Institute of Medicine has listed as one of the priorities for quality improvement.....

.... The emphasis on diagnostic skill sets alone, however, has led to approaches in which care is designed around disease and the doctor dictating treatment to the patient.....


..... We now recognize that a patient centered approach—where care is structured around patients’ needs, values, and preferences and where they and their loved ones are given opportunities to co-design their treatment plan—leads to better outcomes.....

..... The question “What matters to you?” allows patients to disclose their interests, values, and preferences—as full humans, not just recipients of care....

..... The “sick role,” even for a brief time, is a disempowering and depersonalizing state in which patients have to abide by healthcare professionals’ rules—think for a moment about hospital gowns, intravenous line poles, bed pans, call buttons, bed alarms, blood draws, medical team rounds . . . yet each patient is a son or daughter, sibling, parent, grandparent, spouse, employee, employer, and so on, and each has his or her own identity and unique place in life.....

...... The question “What matters to you?” allows patients to disclose their interests, values, and preferences, and it gives the clinical team a chance to appreciate patients as full humans and not just as recipients of care. This is essential to encourage caregivers’ empathy toward patients......

...... Research has shown that patients value the quality of interaction with their caregivers, and their perception of this correlates with their overall satisfaction. Asking patients what’s important to them is an invitation to a collaborative communication space that recognizes the importance of good rapport for successful care delivery. In turn, good communication has been shown to increase patient adherence to treatment recommendations......

...... Asking questions to find out what really matters to our patients is a great opportunity to improve quality in service delivery.....

..... The optimal way to engage patients and their loved ones in their own care is still not fully clear. Moreover, barriers to engagement include some patients’ inability to fully engage (for social or cultural reasons) and providers’ reluctance to engage with patients (owing to time constraints or a lack of clarity on effective methods).....

..... Methods such as the modified Delphi panel, feedback surveys, and patient advisory committees are some of the ways we can try to engage patients. From personal experience, the value of meeting with our patients with the sole intention of finding out what matters to them cannot be overstated.....

...... I recently asked one of my patients what mattered to her, after attempted pain control did not alleviate her distress. In between tears, she told me about her hobbies and family. A lot of what matters to our patients is outside of our clinical armamentarium, and our success in meeting their needs demands our ability to integrate our care with their lives outside of our four walls......

ProfGs skin


Benign MS

Zivadinov R, Cookfair DL, Krupp L, Miller AE, Lava N, Coyle PK, Goodman AD, Jubelt B, Lenihan M, Herbert J, Gottesman M, Snyder DH, Apatoff BR, Teter BE, Perel AB, Munschauer F, Weinstock-Guttman B. Factors associated with benign multiple sclerosis in the New York State MS Consortium (NYSMSC).
BMC Neurol. 2016 Jul 15;16(1):102. doi: 10.1186/s12883-016-0623-2.
BACKGROUND:This retrospective analysis explored prognostic factors associated with a benign multiple sclerosis (BMS) disease course at baseline and over the 4-year follow-up.
METHODS:Patients from the centralized New York State Multiple Sclerosis Consortium registry were classified as having BMS according to 3 different criteria centered on disease duration and disability. Additional analyses explored prognostic factors associated with BMS using the most conservative disability criteria (Expanded Disability Status Scale ≤2 and disease duration ≥10 years).
RESULTS:Among 6258 patients who fulfilled eligibility criteria, 19.8 % to 33.3 % were characterized as having BMS, at baseline depending on classification criteria used. Positive prognostic factors for BMS at baseline included female sex (p < 0.0001) and younger age at onset (p < 0.0001); negative prognostic factors included progressive-onset type of MS and African-American race. Of the 1237 BMS patients (per most conservative criteria), 742 were followed for a median of 4 years to explore effect of disease-modifying treatment (DMT) on benign status. DMT (p = 0.009) and longer disease duration (p = 0.007) were the only significant positive predictors of maintaining BMS at follow-up. The protective effect was stronger for patients taking DMT at both enrollment and follow-up (OR = 0.71; p = 0.006).
CONCLUSIONS:There is a need for development of more reliable prognostic indicators of BMS. Use of DMT was significantly associated with maintaining a benign disease state.

ProfG is not a fan of the term Benign MS as it is is only something that can be done retrospectively but if you do follow people who do not accumulate disability there are a number of factors associated with this. However, these only affect risk and nothing is absolute but if you are taking DMT you are less likely to worsen.

Saturday, 30 July 2016

CrowdSpeak: using survival analysis makes Charcot 2 cheaper

An alternative power calculation for the Charcot 2 project.  #MSResearch #CrowdSpeak #Crowdacure #MSBlog

"In response to a comment by 'Stats is my name', (Friday, July 29, 2016 9:36:00 pm): 'But you can't compare shedders at 1 month vs shedders at 3 months. You can only compare like with like so you should use the numbers by time period'. This got me thinking about the study design. Even though EBV salivary shedding is intermittent there is no reason why a study design based on a survival analysis, i.e time to an event or in this case time to EBV shedding, won't work."

An example of a survival curve from Wikipedia

The following is a correction from when the post went live:

"Survival analysis is a branch of statistics for analysing the expected duration of time until one or more events happen, such as death in biological organisms. It is also called reliability theory or reliability analysis in engineering, duration analysis or duration modelling in economics, and event history analysis in sociology. Survival analysis attempts to answer questions such as: what is the proportion of a population which will survive past a certain time? It is necessary to define 'lifetime'. In the case of our study survival can be defined as being free of EBV shedding. I therefore propose randomising pwMS to placebo, or FamV, and then do monthly saliva samples and follow them up until we have enough events (shedding events). In the placebo arm we would expect 45% of subjects to shed EBV by 6 months and we predict that this figure will be reduced by 80%, i.e. to 9.2%, in the group of subjects being treated with FamV. With a power of 80% and an alpha of 5% we will need 44 subjects (22 per arm) to have enough events. This study will be followed until for a variable period after the last subject has been randomised."


Calculated using StatsToDo

"In comparison the proposed power calculations using a proportional analysis: based on the conservative assumption that the antiviral drug will only be 80% effective in suppressing EBV reactivation over 6 months with monthly salivary sampling, a power of 80% and an alpha of 5%, we would need at least 36 subjects or 18 per arm. With a 10% dropout rate this design would need 40 subjects."

"I am now going to armed with the above information and speak to our statistician to find-out which is the best study design. Once again thank you for your advice and support. It is truly very inspiring to have the community help by suggesting ideas about statistics. In this way the Charcot 2 study is going truly be a study designed and funded by the community."



Click here to find out more!

CoI: Team G are the recipients of a grant from Crowdacure that was used to perform this research.

Need for Spasticity Agents

Rønning OM, Tornes KD.Need for symptomatic management in advanced multiple sclerosis. Acta Neurol Scand. 2016. doi: 10.1111/ane.12631. [Epub ahead of print]

OBJECTIVE:A majority of patients with advanced multiple sclerosis (MS) need symptomatic treatment. Many MS-related symptoms may not be recognized and thus are not treated. We conducted a study to estimate the prevalence of inadequate symptomatic treatment of patients with advanced MS.
METHODS:Patients with advanced MS admitted to a specialist MS rehabilitation clinic were included in this study. Severity was assessed using the Expanded Disability Status Scale (EDSS). The information we collected included age of onset, initial course, time to sustained disability, pharmacological treatment, degree of spasticity, pain and bladder dysfunction, and unmet needs of symptomatic treatment.
RESULTS: In total, we assessed demographic and clinical characteristics in 129 patients with a mean age of 56 years and a median EDSS of 7.5. The proportion with inadequate symptom treatment was regarding spasticity 46%, pain 28%, and bladder dysfunction 23%.
DISCUSSION:This study showed that a large proportion of patients with advanced MS had lack of symptomatic treatment. These patients probably under use neurological specialist services. Better symptomatic treatment could contribute to improving quality of life of people with MS

This paper says that nearly 50% of people with disability due to MS get inadequate control of their spasticity. So we need more effective anti-spastic agents. We have been developing one and have an ongoing clinical trial.


CoI We are developing and anti-spastic agent

The Sixth Amendment-Spasticity trial

The Sixth Amendment of the US constitution guarantees the right to a Speedy Trial and Impartial panel of Assessors (Jury).We want to do the same. 

Double blind trials have a impartial set of assessors who are there to monitor the good and bad effects of any test drug but how do we make it more speedy.....simple its the Sixth Amendment. 

Every time you want to change anything in the trial you need to make an amendment that goes through ethical review.

The Sixth Amendment to our trial indeed provides more speed. 


The trial was in two parts. In the first part the drug dose was increased to check that it was safe in people with MS, determine how people with MS handle and respond to the drug; to assess efficacy and to see the doses that are tolerated. Then people get the maximum tolerated dose or placebo twice a day for a few weeks.


This had meant coming into hospital every day to do the first part. and so it helped if you lived locally to be shipped backwards and forwards from home each day or you were put up in a hotel during this time. 


The doctors are happy that the drug appears as safe in people with MS and that everyone tolerates the maximum tested dose and therefore the sixth amendment terminates the need to continue with the first part of the trial.

The study (both part I and II)  is blinded and placebo controlled and the results won't be looked at until everyone is recruited. The trial was always powered on the second part of the study and therefore you now only have to visit the hospital a few times for a couple of hours. 

So now there is less commitment needed in terms of time spent at the hospital making it easier to do the study 


There are now centres in London (Barts and UCL) and Liverpool and Sheffield that are actively recruiting and more are being added so if you can commute (e.g. via a taxi/ train-taxi) to one of these sites or want a hotel when things are inconvenient then contact the sites below or get your neurologist to contact the sites. 


The Neuroscience Research Centre, The Walton Centre NHS Foundation Trust
Liverpool, United Kingdom, L9 7LJ
Contact: Susan Whittam    0151 529 5666    susan.whittam@thewaltoncentre.nhs.uk   
Principal Investigator: Dr Wojciech Pietkiewicz         
The Royal London Hospital
London, United Kingdom, E1 1BB
Contact: Maria Espasandin    02035940637/8    Maria.Espasandin@bartshealth.nhs.uk   
Contact: Kimberley Allen-Philbey    02035941765    Kimberley.Allen-Philbey@bartshealth.nhs.uk   
Principal Investigator: Dr Clarence Liu         
The National Hospital for Neurology and Neurosurgery
London, United Kingdom, WC1N 3BG
Contact: Dr Rachel Farrell         
Contact: Michelle Liddicut       Michelle.Liddicut@uclh.nhs.uk   
Principal Investigator: Dr Rachel Farrell         
Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust
Sheffield, United Kingdom, S10 2JFS
Contact: Kamel Bouakline    0114 271 3339    kamel.bouakline@sth.nhs.uk   
Principal Investigator: Dr Siva Nair         

To participate in the study you need to have lower limb spasticity

Whilst you can use a wheel chair, you will also need to be able to walk 10m as part of the study and get on the bed for assessment.
This was selected for academic and logistical reasons, 


I am sorry to say this is placebo-controlled trial and not an add-on study, but their are scientific reasons to justify this.

Therefore to be eligible, you will need to be drug-free or be willing to come off your drug to do the trial. I am led to believe that this can be a revelation, as one may appreciate how sedative current medications can be and you will get a tailored symptom management plan once the study is complete.

CoI: I am a founder and consultant to Canbex Therapeutics who are performing this trial.

Friday, 29 July 2016

CrowdSpeak: Why am I a bottleneck?

Thank you we now have our power calculations for the Charcot 2 project? #MSResearch #CrowdSpeak #Crowdacure #MSBlog

"David Holden successfully completed all the lab work on the saliva samples and sent me the spreadsheet several weeks ago. I only managed to analyse them two days ago. We have achieved what we wanted to with the samples and now know how many people with MS shed virus in their saliva. This has allowed me to do two sets of power calculations for the proposed trial of our antiviral drug in pwMS."

"This is the summary, or headline, results. Before reading them I need to explain what some of the jargon or stats speak is. In summary sample size determination is the process of defining the number of observations, or replicates, to include in a clinical trial. The sample size is an important feature of any clinical study in which the goal is to make inferences about the population from which the study subjects are recruited. In practice, the sample size is critical to make sure we have sufficient statistical power to answer the question in hand; for example in our proposed study, do we have enough subjects to confident that our drug works in suppressing lytic EBV infection in the salivary glands of pwMS. Although the sample size calculation uses real data we have to make some basic assumptions, for example how effective we expect the drug to be when tested in pwMS. We also have to set other variables, i.e. the actual power of the study and the so called alpha. Traditionally in medical trials the power of studies is set at 80% or 90%, i.e. we have an 80% or 90% chance based on the number of subjects studied to get a positive result. In comparison, the alpha sets the level of significance we are prepared to accept; we typically set this at 5% using a one- or two-sided comparison. This means that if we get a significant result there is a 5% chance of the result being a false positive result. False positive results are not that uncommon in research, which is why we have to reproduce results in second, or follow-on, studies. Please also note the power calculations, i.e. the size of the study, determines its cost."


CrowdaCure EBV Viral Shedding Trial Power Calculation Output


Proposed Power Calculations for a 6-month study
In the INSPIRE samples, which collected monthly saliva for 6 months, 9 out of 20 subjects with MS (45%) shed EBV, i.e. had a detectable EBV virus in their saliva, on at least one occasion.  Based on this data we are now able to do a power calculation of a trial to assess the ability of an antiviral drug to suppress EBV lytic reactivation in the salivary glands.


Power calculation 1: Based on the conservative assumption that the antiviral drug will only be 75% effective in suppressing EBV reactivation over 6 months with monthly salivary sampling we will need at least 29 trial subjects per arm. This calculation is based on having a power of 90% and an alpha of 5%.


Power calculation 2: Based on the conservative assumption that the antiviral drug will only be 80% effective in suppressing EBV reactivation over 6 months with monthly salivary sampling we will need at least 18 trial subjects per arm. This calculation is based on having a power of 80% and an alpha of 5%.


Proposed Power Calculations for a 3-month study
In the Sheffield cohort, which collected monthly samples for 3 months, 44 out of 119 subjects with MS (37%) shed EBV, i.e. had a detectable EBV virus in their saliva, on at least one occasion.  Based on this data we are now able to do a power calculation of a trial to assess the ability of an antiviral drug to suppress EBV lytic reactivation in the salivary glands.


Power calculation 1: Based on the conservative assumption that the antiviral drug will only be 75% effective in suppressing EBV reactivation over 3 months, with monthly salivary sampling, we will need at least 38 trial subjects per arm. This calculation is based on having a power of 90% and an alpha of 5%.


Power calculation 2: Based on the conservative assumption that the antiviral drug will only be 80% effective in suppressing EBV reactivation over 3 months, with monthly salivary sampling, we will need at least 24 trial subjects per arm. This calculation is based on having a power of 80% and an alpha of 5%.

"In the Charcot Project 2 we are using viral shedding of EBV as a readout for antiviral drugs targeting EBV. If our lead drug Famciclovir suppresses virus in saliva then we will be confident of it also being suitable as a treatment for infectious mononucleosis. This hasn't escaped our attention, nor has the case report below. This is why IM is one of our major focuses going forward and forms part of Charcot 3."

"Some of you may ask why are you behind schedule in getting these results out? It is my fault I have too many balls in the air and not enough bandwidth or time to do everything I am involved in. One of my team has called me the bottleneck in the system. When we have our annual research strategy meeting in a few weeks time I am going to hopefully address this problem. May be I should be called Prof. Bottleneck rather than Prof G?"


"Once more, thank you for your support. The money raised has give us the necessary results that we can now use to develop a protocol for our next study. I sincerely hope we will now be able to leverage these results to get funding for our study."



Click here to find out more!


Goldani. Treatment of severe infectious mononucleosis with famciclovir. J Infect. 2002 Feb;44(2):92-3.

We report a patient with severe acute infectious mononucleosis who was successfully treated with famciclovir. A 15-year-old male was admitted with a 6-week history of fever, malaise, generalized lymphadenopathy, and hepatosplenomegaly, the patient was acutely ill with a temperature of 39.0 degrees C. Oropharyngeal examination revealed enlarged tonsils partially obstructing the airways. EBV serology obtained during admission showed a positive Monospot test, virus capsid antigen IgM, 1:320, Epstein-Barr nuclear and early antigen, negative. After 72 hours of treatment with famciclovir(500 mg t.i.d.), the patient was afebrile with important regression of the lymphadenopathy, enlarged tonsils and hepatosplenomegaly. Because acute infectious mononucleosis may be associated with extensive and prolonged disease, the potential therapeutic role of famciclovir in the treatment of severe forms of the disease deserves further studies.

CoI: Team G are the recipients of a grant from Crowdacure that was used to perform this research.

Learning from other conditions may teach us something-Obrigado

Meyer S, Woodward M, Hertel C, Vlaicu P, Haque Y, Kärner J, Macagno A, Onuoha SC, Fishman D, Peterson H, Metsküla K, Uibo R, Jäntti K, Hokynar K, Wolff AS; APECED patient collaborative, Krohn K, Ranki A, Peterson P, Kisand K, Hayday A.
AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies. Cell. 2016 Jul 14. pii: S0092-8674(16)30792-9.

APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.


The autoimmune regulator  (AIRE) is mutated in the rare autoimmune syndrome Autoimmune Polyendocrinopathy Syndrome type 1 (APS-1a problem of the endocrine glands that make hormones), also known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED).  These patients are also susceptible to chronic Candidiasis (of skin and nails and mucosal (gut) surfaces caused by a Candidia fungus. This fungus also causes "thrush")



T lymphocyte tolerance is essential for limiting autoimmune disease. Tolerance occurs “centrally” (in the thymus) when developing thymocytes (cells from the thymus) with strongly self-reactive T cell receptors (TCRs) (Antigen recognition receptors are autoimmune targeting) are deleted following engagement of self-antigen-derived peptides presented by major histocompatibility complex (MHC) antigens (Each T cell attacks a foreign substance presented within a MHC molecule which it identifies with its receptor. T cells have receptors which are generated by randomly shuffling gene segments. Each T cell attacks a different substance. T cells that attack the body's own proteins are eliminated in the thymus. Medullary thymic epithelial cells (mTEC) express major proteins from elsewhere in the body (so called "tissue-restricted antigens"), and T cells that respond to those proteins are eliminated through cell death (apoptosis), thus it is thought that AIRE therefore drives negative selection. So the self recognitition element that T cells must see to form a productive immune reaction. This + infection gives protective immunity against infection. This plus self can lead to autoimmunity. This needs to be avoided so in the thymus these cells are programmed to commit suicide with is known as negative selection. The cells that can recognise the MHC but are not reactive to self are selected and this process in part of positive selection) . The expression of thousands of tissue-specific self-antigens (TSAs) by medullary thymic epithelial cells (mTEC) is directly promoted by AIRE, a poorly understood transcriptional regulator.

There are also several mechanisms of peripheral (in the lymph glands and the blood) T cell tolerance, including requirements for co-stimulatory signals for the activation of naive T cells; the expression of molecular “brakes” (e.g., CTLA-4, PD-1) by activated T cells; and the suppression of effector T cells  by FOXP3-expressing T-regulatory (T-reg) cells. 



Central (in the case of B cells in the bone marrow) and peripheral tolerance mechanisms likewise shape the B cell compartment. Thus, self-reactive B cells developing in the bone marrow may be censored by clonal deletion, clonal anergy (non-responsiveness), or B cell receptor (BCR) editing in which secondary gene rearrangements replace the initial BCR with a new specificity Peripheral (in the lymph glands and the blood) B cell tolerance is less well characterized but tolerance is imposed as transitional B cells differentiate into naive B cells via T cell dependent mechanisms. Likewise, T cell help is required in the germinal centres where antibody forming plasma cells are created. The question that then arises is whether major defects in central T cell tolerance provoke wide-ranging losses of B cell tolerance at either or both of these stages. An approach to examine this in people who are AIRE-deficient, whose under-expression of TSAs in the thymus is predicted to lead to increased numbers of peripheral autoreactive T cells. 



Thus, people with APS1/APECED have autoantibodies against limited set of TSAs such as products affecting exocrine glands and they block type I interferons and TH17-related cytoines so they do not get rid of Candida infections. These people harboured autoreactive (neutralising antibodies) and by looking at their sequences it appears  that the autoantibodies particularly develop by dysregulated reactions in the germinal centres, where T cells not tolerized in the thymus promote the competitive outgrowth and affinity maturation of B cells that were initially primed to exogenous antigen(s) but whose mutated IgGs bind to self-proteins. 

What has this got to do with MS? Maybe nothing, but in this study they report how autoimmunity may be blocked. However, it gives us ideas about how autoimmunity can develop. So Obrigado Cinara for bringing this to our attention. There are some testable ideas that come from this. 

I am often told that we give our ideas away too cheaply so will need to explain at a later date, when the paper comes out:-)

Thursday, 28 July 2016

ThinkHand: what iconic image captures hand function best?

There is a PROM for hand function; what do you make of it? #ThinkHand #MSBlog #MSResearch

"Thank you for engaging with our #ThinkHand Campaign; response to the survey has been excellent. We are hoping to get more than additional 400 responses by mid August for our ECTRIMS poster."





"In addition, to the survey there are another two things we need help with from this post."

"Firstly, I would like you comments on the ABILHAND patient-related outcome measure. Does this capture hand function for you? What items are missing? I personally can think of several items that are missing and I don't have MS."



"Secondly, we need an iconic image of a hand to make #ThinkHand stick. For example, what image would you want see on a #ThinkHand campaigners T-shirt? It needs to instantly recognisable; the image has to make the general public and the MS community say 'Yes, I know how important hand function is to people with MS; let's do something about it'. The following are examples of images that may, or may not cut the mustard."







"Thank you!"

Wednesday, 27 July 2016

ClinicSpeak & BrainHealth: finally a version for MSers

In case you thought we had haven't forgotten you we haven't; #BrainHealth for all! #ClinicSpeak #MSBlog

MS a B cell disease.....Wait a minute on not quite yet, T cells are hanging on

Schuh E, Berer K, Mulazzani M, Feil K, Meinl I, Lahm H, Krane M, Lange R, Pfannes K, Subklewe M, Gürkov R, Bradl M, Hohlfeld R, Kümpfel T, Meinl E, Krumbholz M. Features of Human CD3+CD20+ T Cells. J Immunol. 2016 Jul 13. pii: 1600089. [Epub ahead of print]

Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3+CD20+ T cells has been described that is also targeted by the anti-CD20 mAb rituximab. Because the existence of cells co-expressing CD3 and CD20 is controversial and features of this subpopulation are poorly understood, we studied this issue in detail. In this study, we confirm that 3-5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3+CD20+ T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; in the cerebrospinal fluid of MS patients they occur at a frequency similar to B cells. Phenotypically, these T cells are enriched in CD8+ and CD45RO+ memory cells and in CCR7- cells. Functionally, they show a higher frequency of IL-4-, IL-17-, IFN-γ-, and TNF-α-producing cells compared with T cells lacking CD20. CD20-expressing T cells respond variably to immunomodulatory treatments given to MS patients: they are reduced by fingolimod, alemtuzumab, and dimethyl fumarate, whereas natalizumab disproportionally increases them in the blood. After depletion by rituximab, they show earlier and higher repopulation than CD20+ B cells. Taken together, human CD3+CD20+ T cells pervade lymphatic organs and the cerebrospinal fluid, have a strong ability to produce different cytokines, and respond to MS disease modifying drugs.

As ocrelizumab arrives MS is being described as a B cell disease, but to feed a lifeline to the T cell brigade it has been shown that a small subset of T cells express CD20 and these get depleted. Is this why rituximab/ocrelizumab works? I am not sure. However it seems that B cell depletion can reduce antigen presenting cell function and this is maybe why it works. Maybe it is because it is removing EBV infected B cells

B Regulatory Cells

Piancone F, Saresella M, Marventano I, La Rosa F, Zoppis M, Agostini S, Longhi R, Caputo D, Mendozzi L, Rovaris M, Clerici M.B Lymphocytes in Multiple Sclerosis: Bregs and BTLA/CD272 Expressing-CD19+ Lymphocytes Modulate Disease Severity. Sci Rep. 2016 Jul 14;6:29699. doi: 10.1038/srep29699.

B lymphocytes contribute to the pathogenesis of Multiple Sclerosis (MS) by secreting antibodies and producing cytokines. This latter function was analyzed in myelin olygodendrocyte protein (MOG)-stimulated CD19+ B lymphocytes of 71 MS patients with different disease phenotypes and 40 age-and sex-matched healthy controls (HC). Results showed that: 

1) CD19+/TNFα+, CD19+/IL-12+ and CD19+/IFNγ+ lymphocytes are significantly increased in primary progressive (PP) compared to secondary progressive (SP), relapsing-remitting (RR), benign (BE) MS and HC; 

2) CD19+/IL-6+ lymphocytes are significantly increased in PP, SP and RR compared to BEMS and HC; 

3) CD19+/IL-13+, CD19+/IL-10+, and CD19+/IL-10+/TGFβ+ (Bregs) B lymphocytes are reduced overall in MS patients compared to HC. B cells expressing BTLA, a receptor whose binding to HVEM inhibits TcR-initiated cytokine production, as well as CD19+/BTLA+/IL-10+ cells were also significantly overall reduced in MS patients compared to HC. Analyses performed in RRMS showed that fingolimod-induced disease remission is associated with a significant increase in Bregs, CD19+/BTLA+, and CD19+/BTLA+/IL-10+ B lymphocytes. 

B lymphocytes participate to the pathogenesis of MS via the secretion of functionally-diverse cytokines that might play a role in determining disease phenotypes. The impairment of Bregs and CD19+/BTLA+ cells, in particular, could play an important pathogenic role in MS.
Just as we know of effector and regulatory T cells there are effector and regulatory B cells. As we are depleting B cells it is important to realise that regulatory cells may get depleted. Animal studies indicate that CD20 B cell depletion can inhibt enhanced or do nothing to EAE, depending on the timing of administration. On balance CD20 B cell depletion and CD19 B cell depletion appears to inhibit relapsing MS but Acaticept that was also supposed to deplete B cells appeared to make MS worse, presumably because it affects B regulatory cells.

Tuesday, 26 July 2016

NewsSpeak & OffLabel: maybe off-label prescribing will be come a global reality?

 When it comes to putting your money where your mouth is the US is right up there! #NewsSpeak #OffLabel

"The Patient-Centered Outcomes Research Institute (PCORI) will fund four comparative clinical effectiveness studies in MS (see below). Well done to all the successful PIs."

"Let's hope the rituximab data is good enough for NHS England  to adopt off-label prescribing in MS; at present they won't. At last, we will know which of the two heavy-weight orals, fingolimod or DMF, is superior. It is good news for the field that someone is prepared to fund an independent head-2-head study. The importance of this trial cannot be underestimated; with fingolimod coming off-patent we need new data to over-turn the 2nd-line indication we have for prescribing fingolimod in Europe. A cheap small-molecule oral therapy, with high-efficacy, will almost certainly lower the entry level price for treating MS. However, I am a bit disappointed that teriflunomide was not included in this head-2-head study; when you look at the subgroup analyses I think teriflunomide is more efficacious long-term than the headline results of the phase 3 trials indicate. I predict teriflunomide would have a reasonable chance of holding its own in terms of efficacy against both DMF and Fingolimod. Another point is that teriflunomide is also coming off-patent soon; so another cheap entry level drug to mix it up."


Four Studies to Assess Effectiveness of Multiple Sclerosis Treatments Receive $19.6 Million in Funding from PCORI: Studies will give patients evidence to help them choose among therapies. PCORI July 19, 2016

Press release

WASHINGTON, D.C. (July 19, 2016) – The Patient-Centered Outcomes Research Institute (PCORI) Board of Governors today approved nearly $20 million to fund four comparative clinical effectiveness research (CER) studies that will assess several therapies used to treat multiple sclerosis (MS) or its symptoms.

Two studies will compare the benefits and harms of various treatments collectively known as disease-modifying therapies (DMTs) that aim to reduce MS attacks or slow the disease’s progression. Another will evaluate the effectiveness of medications used to treat fatigue, a common, often debilitating problem for people with MS. The fourth will assess whether people with MS in rural and low-income areas can get similar benefits from rehabilitation therapies if they are provided via telehealth versus in a clinic.

The studies will be designed and conducted with significant input from patients, family caregivers, and other healthcare stakeholders. Each will include people with MS; nurses, physicians or other clinicians; or representatives of other stakeholder groups on their research teams. The four awards were among 35 totaling $153 millionapproved today by PCORI’s Board.

“PCORI is delighted to make these new awards addressing crucial evidence gaps and questions of vital interest to the more than 400,000 people in the U.S. living with multiple sclerosis,” said PCORI Executive Director Joe Selby, MD, MPH. “These studies will provide significant new evidence to help patients, their families and their clinicians decide more confidently which of the therapies available to them will work best given their needs and preferences.”

"These PCORI awards are a welcome and much-needed infusion of new MS research funding for important real-world questions about treatment strategies and their effectiveness," commented Bruce Bebo, PhD, Executive Vice President, Research, at the National Multiple Sclerosis Society, a group representing patients that will be an engaged stakeholder partner in several of the studies. "The projects should provide important evidence for the best ways to address troubling symptoms like fatigue, and the potential for using technology to deliver needed rehabilitation approaches to people in remote areas," he added.

The four projects approved today are:

Rituximab: An $8.5 million study comparing the effectiveness of rituximab, a biologic drug, to other commonly used disease-modifying therapies in individuals with the relapsing-remitting form of the disease. Rituximab is increasingly being used as an MS therapy in Sweden and the United States. The study will be based at Karolinska Institute in Sweden and conducted in collaboration with Kaiser Permanente Southern California. In particular, it will assess the comparative safety outcomes of the medications.

Excercise -based rehab: A $5.8 million study of whether patients get as much benefit from an exercise-based rehabilitation program delivered via Internet or telephone as when the therapy is provided in a clinic. Evidence shows that exercise, yoga, and other such therapies can alleviate symptoms and improving function, but clinics that can provide such services are scare in rural and low-income areas. The trial, led by a research team based at the University of Alabama at Birmingham, will be conducted in Alabama and Mississippi.

Fatigue: A $1.9 million study of three medications frequently used to relieve fatigue in people with MS. There is little evidence about how well these drugs – amantadine, modafinil, and methylphenidate -- work compared to one another in providing relief for MS-related fatigue. The trial will be led by a team based at the University of California at San Francisco.

Fingolimod vs. DMF: A $3.3 million award for the first pragmatic trial comparing the benefits and harms of the oral DMTs fingolimod and dimethyl-fumarate. These drugs are commonly used to treat MS and are believed to be similarly effective, but both have side effects and they have not been compared directly to one another. The trial will be led by a research team based at the Foundation of the Carlo Besta Neurological Institute in Milano, Italy, and include sites in the United States, Europe, and Israel.

The new studies address evidence gaps and questions that people with MS and other healthcare stakeholders identified as their top priorities through PCORI’s process for topic selection. A multi-stakeholder workshop in April 2015 brought together patients and participants representing groups advancing research on the disease as well as clinicians, government agencies, industry, and health insurance plans to refine the questions that became the focus of PCORI’s funding announcements.

All of the awards are approved pending completion of a business and programmatic review by PCORI staff and issuance of a formal award contract.

Progressive dwindling

PLoS One. 2016 Jul 21;11(7):e0159210. doi: 10.1371/journal.pone.0159210.

Progressive Dwindling in Multiple Sclerosis: An Opportunity to Improve Care.

Martin JE, Raffel J, Nicholas R.

Abstract

INTRODUCTION:

In the general ageing population, 40% of deaths occur following a prolonged trajectory of "progressive dwindling," characterised by chronic accumulation of disability and frailty, and associated with increased dependency and reduced reserves. Those who progressively dwindle are poorly catered for by current healthcare systems and would benefit from a coordinated approach to their medical and social care, known as formative care. People with multiple sclerosis (pwMS) may be more likely to progressively dwindle, and may be appropriate targets for formative care pathways.

OBJECTIVES:

To determine the proportion of pwMS who follow a progressive dwindling trajectory prior to death. To relate trajectory to place of death, and examine what factors predict the progressively dwindling trajectory.

METHODS:

A retrospective observational study of 582 deceased pwMS enrolled in the UK MS Tissue Bank, including death certificates and extensive clinical summaries.

RESULTS:

73.7% of pwMS had a "progressively dwindling" trajectory of dying. This was predicted by those who reach MS disease milestones earlier. 72.5% of pwMS died an MS-related death, which was predicted by an aggressive disease course from onset. Those who progressively dwindled were equally likely to die in hospital as those with other trajectories to death.

CONCLUSIONS:

The progressively dwindling trajectory of dying is very common in pwMS, and can be predicted by earlier disease milestones. Pathways could target pwMS in these years prior to death, to improve care.


 Tipping point

This article brings to the surface the problem with MS research - an enterprise focused on basic science research, or what I call pop science that ignores the immediate needs of our patients. Moreover, frustratingly, what we preach in public is very different from our private thoughts. There is very little impetus to work towards finding solutions for progressive disease. You note, that I don't mention cure. We should be aiming towards the tipping point; the small changes (Sisyphus effect) that have a big impact (snowball effect).

Progressive dwindling is the progressive chronic illness before death. Broadly speaking, in an aging population four broad trajectories of dying have been described (Bowman and Meyer 2004):
  • 20% sudden deaths e.g. heart attack
  • 20% follow a rapid decline e.g. cancer
  • 20% as a result of acute exacerbations of chronic disorders e.g. infective exacerbation of chronic obstructive airways disease.
  • 40% follow a prolonged period of 'progressive dwindling' e.g. Alzheimer's, progressive MS (Figure 1)
Figure 1: cause of death in 582 people with MS (UKMSTB - UK MS Tissue Bank Jan 1998-Feb 2015)

The care pathway for the latter 40% is haphazard at best, focused predominantly at the major centers with access to multidisciplinary teams. There is little in the way of formative care provision in order to improve quality of life. This need is more pressing in MS than any other neurological disorder as it spans most of adulthood.

Martin et al. point out that those who progressively dwindled had an earlier age of onset, progression (earlier achievement of disease milestones suggesting aggressive disease course) and were wheelchair bound.  Moreover, they were more likely to die in hospital (not at a hospice, as in cancers) than in their own residence, which may be interpreted as failure of care.

This research points to a disconnect between active treatment (DMTs) and end of life care in MS with progressive dwindling occurring for several years. This is a serious concern as this research points to at least 74% people with MS having this trajectory before death (NB: this figure may be biased as it is retrospectively collected, and is from a brain bank database). A more formative strategy is needed that can deal early with care planning and readily with complex care needs and increased rates of cognitive disability.

Monday, 25 July 2016

Th17 important in MS

Bühler U, Fleischer V, Luessi F, Rezk A, Belikan P, Graetz C, Gollan R, Wolf C, Lutz J, Bar-Or A, Siffrin V, Zipp F. Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment. Mult Scler. 2016 . pii: 1352458516658559. [Epub ahead of print]

OBJECTIVE: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity.
METHODS:Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients (n = 33), untreated RRMS patients (n = 13), and healthy controls (n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients.
RESULTS: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untreated patients and healthy controls. Whereas group comparison for CD4+IL-17+ numbers also differed, CD4+IFN-γ+ and CD4+IL-22+ counts were not increased. CD4+IL-17+ cells not only expressed but also secreted IL-17. In natalizumab-treated patients, IL-17+ cell frequency was found to correlate with T1-hypointense lesions, but was not an indicator for rebound activity after treatment discontinuation, except in one patient who experienced a fulminant rebound, and interestingly, in whom the highest IL-17+ cell levels were observed.
CONCLUSION: Increased lymphocytes and CD4+IL-17+ cells in the blood of RRMS patients receiving natalizumab corroborate the drug's mechanism of action, that is, blocking transmigration to CNS. Correlation between IL-17-expressing lymphocytes and T1-hypointense lesions underlines the important role of these cells in the disease pathology


MS is caused by Th17 cells becuase this now dogma. So when we give natalizumab there are more CD4, IL-17 cells in the blood and the numbers correlate with T1-hypointense lesion.Therefore this validates the value of Th17 in disease pathogenesis. 

However, proof is really getting rid of CD4+, IL-17+ T cells and it having an impact on MS.

However, so far depletion of CD4 T cells did not have a marked impact on MS lesions (although depletion levels were correlated relapse) and interleukin 17 neutralising antibodies reduced gadolinium lesions by about 50%. This gets the Th17ers mouths watering but remember beta interferon is much more effective than that and so many things do much better.

We need to be cautious until this action is shown

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.