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Old 12-11-2015, 04:43 PM #21
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Although I continue reviewing the DiPALS report from SiTraN, I have another observation to note:

Again reviewing the numbers along the lower horizontal edge of the graph:

37 36 26 13 6 4
37 29 14 06 4 1

These appear to be the number of patients remaining alive at the start and then at end of each six month period thereafter. The lower numbers are regarded as the DPS stimulation group. Consider the following:

-7 -5 +5 +5 -1

These numbers are the differences in the number of patients who left the study (passed away) at each six month interval. Two things to note:

1. In the six month periods ending at eighteen months and two years the DPS stimulation group had five more survivors than the NIV only group.

2. The -7 in the first six months probably includes the five who opted out and the one found during surgery not to be able to accomodate the DPS device (total of six). They didn't immediately die.

So adjusted, the numbers would be:

-1 -5 +5 +5 -1

. . . far closer than you would think (the DPS stimulation group clearly prevailed in two of the five periods) . . . . Important question is: the stati of those six are (were they still alive at thirty months)? A difference of only one in a period is probably too close to call but two such periods leaned to the NIV only group and in the second period the NIV only group was clearly ahead.

Further, Table 4 lists one DPS stimulation patient as dying of hypothermia . . . correct me if I am wrong, isn't hypothermia freezing to death? How can the DPS device cause one to freeze to death, stimulation or no stimulation?
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"Thanks for this!" says:
Thelma (12-12-2015)

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Old 12-11-2015, 04:54 PM #22
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One further comment on the UK's MNDA comments on DiPALS results . . . :

Their MNDA says the DPS harmed patients but the DiPALS writing committee report only says such patients might have been hurt AND their MNDA says the DPS ". . . was not beneficial . . ." whereas the DiPALS writing committee regarded the efficacy as 'low' rather than non-existent. Apparently the MNDA is not careful in its choice of words.
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Old 12-11-2015, 04:57 PM #23
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Exclamation Please further note

I have only accessed ELECTRONIC editions of these documents, I continue to search for authentic print editions. It is very easy to manipulate electronic documents.
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Old 12-12-2015, 07:07 PM #24
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Default what is ethical about death that would require contemplation

on witholding care or treatment. the end is not debatable



Quote:
Thanks for your question. Current guidelines recommend non invasive ventilation (NIV) for people with MND with breathing problems. When the researchers designed the trial, they didn’t know what the effects of diaphragm pacing would be, so it was considered unethical to effectively withhold recommended care (by not starting NIV and only giving pacing). That’s the reason that both were given.

With best wishes,
Research Development Team
MND Association
Can we see your final draft and not wait
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Old 12-14-2015, 12:32 PM #25
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Thelma, I am not sure whether your apparent question is directed to the MNDA or myself?

I continue to wonder whether the data they are analyzing is the French data; one might say, since their study was challenged on the basis of ethics by a researcher in the U.S., they would be wise to allow an independent authority to do the analysis. Such authority may have never met ANY of the patients . . . there are not many authorities in this area to begin with . . . imagine you were one and they gave you 'all the data,' via computer, and asked you to do the analysis. So you do the best you can . . . .

Such would improve the ethics posture of the trial but may opportune errors unlike those discoverable in nearly venues of research. You likely would only know the patients by some code rather than name.
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Old 12-22-2015, 02:12 PM #26
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(¿Thelma?) . . .

This year is likely the first where the number of patients who began using the patients and could be discovered via the web are fewer than the number of patients who were using the pacer but died . . . at this moment, the numbers are 10 new, 22 passed for 2015 . . . in the several prior years they today are:

2015 10 22
2014 26 13
2013 30 13
2012 34 05
2011 12 04 (not a full year . . . fda approval was in September).
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Old 12-23-2015, 11:35 AM #27
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Post survival brief for pacing patients we've lost this year

Survival (in months) of those pacing ALS patients we've lost this year:


all 23:median38

14 14 22 25 27 27 29 29 35 37 38 38 40 41 48 52 55 56 56 57 63 81 84


bulbarOnset

14 25 38 41 52 56


unknownOnset

27 29 35 37 38 40


infoNeeded

14 14 27 27 29 29 35 37 38 38 40 48 56



dataComplete

22 25 41 52 55 56 57 63 81 84


Thirteen patients have one or more unspecified dates (usually onsetDate). Their survival period is likely six to twelve months or more the currently specified here.


In this small group of bulbar onset also sees median of 38, much higher than medians of 20 (pre-riluzole) and 27 (post-riluzole). Medians for 'complete' sets have tended to be less than 36 months, here we see 38 plus likely at least six months. Note the dataComplete set shows median as 55-56 . . .19 to 20 months better than upper level studies (they sometimes show as high as 36 months) . . . even though thirty percent of cases are bulbar!


I believe we will see further {modest} improvements. Of the 150 patients I have found, I saw three blood clots reports and one stroke after implant. One of the blood clots was fatal. The investigation reported no link to the pacer though and I have seen no report regarding FDA changes to the requirements for the procedure.
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Old 12-23-2015, 01:47 PM #28
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Post Three UK pacer users have remarks in the web . . .

Liz Pick
'Pulses' help motor neurone disease patient breathe
http://www.bbc.com/news/uk-england-21663483

Mohan of www.alsforums.com
http://www.alsforums.com/forum/members/mohan.html

Malcolm Chattle
Major trial gives hope to motor neurone disease sufferers
https://www.sheffield.ac.uk/news/nr/...field-1.174450
http://medicalxpress.com/news/2012-0...e-disease.html
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Old 12-28-2015, 05:34 PM #29
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Lightbulb In depth report on DPS in ALS (Onders et alia)

Identification of unexpected respiratory abnormalities in patients with amyotrophic lateral sclerosis through electromyographic analysis using intramuscular electrodes implanted for therapeutic diaphragmatic pacing

http://www.americanjournalofsurgery....598-4/fulltext

selected excerpts:
"Control of respiration is incompletely understood in normal subjects and even less in ALS. . . .

"Some patients had minimal or absent dEMG activity but strong diaphragm contraction when the electrodes were stimulated. . . .

" . . . With disuse, the intact motor units of the diaphragm will rapidly convert to Type IIb fast-twitch muscle fibers . . . .

" . . . There is a growing evidence that ALS patients have sleep-disordered breathing that is most often because of central mechanisms. . . .

". . . dEMG burst activity improved for some patients after DP conditioning or a rhythmic breathing pattern would continue when DP was not being used. Fig. 1 highlights the dEMG improvement in burst activity. . . .

". . . DP may improve automatic respiratory control. . . .

". . . Death can occur within hours of DP withdrawal indicating that there can be a rapid loss of control leading to respiratory failure with DP cessation. . . .

"(evidence of) NIV causing diaphragm activitiy suppression; (4) identification of unilateral abnormalities with a loss of control of the diaphragm from respiratory control centers in the brainstem; (5) DP improves diaphragm burst activity and helps in maintaining the respiratory pacemaker. . . .

"(DP may) also delay the death of those motor neurons. . . .

"The fifth finding is a growing area of research in respiratory physiology. There is evidence that the respiratory system is able to "fight back" and trigger spontaneous compensatory plasticity that can maintain respiration in the face of motor neuron loss. . . .

"The plasticity although somewhat persistent was shown to wane when DP is discontinued. For example, in one case a patient with DP became intubated secondary to aspiration pneumona and DP was stopped for several days at an outside hospital. Prior to the event the patient had large dEMG burst activity and was using DP as the primary mode of ventilation even though he was late in his disease. When re-evaluated, the patient had no dEMG volitional burst activity and DP could no longer maintain ventilation. The plasticity seen from DP may rapidly degenerate when DP is stopped in ALS patients. . . .

"Because DP prevents diaphragm atrophy from NIV suppression, DP can decrease the need for NIV during the day. . . .

"If the dEMG shows no burst activity but the diaphragm was stimulable then the patient requires 24 hours pacing to maintain diaphragm function. . . .

"DP therapy is optimum when the patient has unused motor units that DP can drive and dEMG shows the patient has instability of control of those units. . . .

"In conclusion, these dEMG findings demonstrate that ventilatory dysfunction in ALS is likely much more complex than just denervation atrophy of the diaphragm. Significant areas of central dysregulation were seen along with interesting observations of apparent asymmetric central dysfunction."

Onders recommends patients should have DP active whenever they are on BiPAP . . . "We've now realized that just being on the ventilator in your intensive care unit, if you get pneumonia, actually changes your brain stem control of respiration. There's actually adverse effects in your pre-Botzinger complex."
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Old 01-07-2016, 11:17 AM #30
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Post high variance

Quick note, re: DiPALS report . . . :

Even though implanting but not activating the DPS may be a mistake, such trial might well be scientific . . . I say I would not have approved because a need to compensate for the 'short-circuit' effect of the probe may exist. Yet I remain uncertain as to whether such would matter. It might not. The issue may be unknown . . . unknown from my perspective certainly - maybe someone knew. However, the issue might be moot . . . variance from 'norm' in pilot samples in ALS is not well study to the best of my knowledge and belief. Are there any researchers who would doubt variance in pilot samples is large in ALS, more likely larger in ALS than many other diseases? Most would have to admit substantial variance in pilot samples is likely but there is very little discussion of sample variance in the recent papers. The high variance may partially explain the results the DiPALS writing group reports. Its 20-20 hindsight though.

How difficult would disturbing an ALS clinical study be . . . How frail is the effect being exploited in the DPS treatment?
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