These lengthy remarks are partially complete . . . :

Improvement of the biological characterization of the β-phram muscles affected by the Amyotrophic Lateral Sclerosis syndrome became practical due to the deployment of the pacer as a prospective treatment. Although large, there are only two β-phram muscles, whereas there are some 700 other muscles in the body human. Located and forming the base of the thorax the β-phram muscles are difficult to reach because they are entirely interior to the body. There may be several million neuro-muscular synapses in the β-phragm muscles and as many as several billion involved synapses in the anterior horns and upper motor neuron regions of the motor cortex. Breathing is autonomous, but subject to the free will of the human, with their will modifiable by circumstances influencing emotion, activity or sleep, yet tending to remain involuntary. Thus, the pulmonary nervous system likely has extensive interfacing in the brain.

Internet media reported the DiPALS Writing Group challenges the FDA HUD/HDE approval on grounds of efficacy but because the approval does not include an efficacy claim - the approval's purpose is to further research into the question of whether the treatment has efficacy since the Onders's group found some evidence of efficacy developed in patients after they were implanted - DiPALS was concerned about the estimated number of candidates needed to fill the study. The approval contends the surgical process is reasonable to regard as safe, admits the resultant data inferentially evidences efficacy, and lends plausibility to the claim about 70% of the patients may benefit from the treatment. The evidence shows implantation must be timely, however. Too late, the β-phram muscles will not respond to stimulation, too early, the stimulators may not be optimally placed, diminishing their research and therapeutic value. Although not overty stated, the most substantial issue in the DiPALS Writing Group's report for challenging the FDA HUD/HDE approval is their difficulty in finding 108 admissible candidates within the 759 applicants. The FDA disclosure implies circa 531 candidates might be found among them but only fifty-one candidates remained in screening when the study's halt occurred - thirty-four more were needed. The applicants of the DiPALS study neared 90% chance of losing candidacy before undergoing implantation; losses nearer 30% would be expected based on the FDA estimate. The manufacturer's recent web site update implies circa 300 such candidates ought to exist in an applicant pool of 759 patients where one might infer fallout might reach about 60% of the applicants and therefore the study ought to achieve its needed 108 cases. But the study reached a point were 67% of the remaining candidates were needed - the reality of the situation and the manufacturer's estimates 'agreed:' the study could not reach the required number of cases. The FDA estimate was not even close throughout the entire DiPALS trial; so why was the yield so low the study itself was in jeopardy? This vital question remains unexplored.

The best evidence I discovered before 2017 implies the treatment's leading edge of worth depends on the moment the surgical opportunity window opens and the trailing edge depends on when the β-phram muscles no longer respond to stimulation. Within the range, the treatment is thought to have value; outside the range, however, the treatment is thought to have little or no value. Even though qualified for the implant, a patient's β-phram muscles may be anywhere from completely unresponsive to 100% because their strength can only be finally determined during surgery at this time. The value of the treatment to a patient within the range decreases over time due to the neural regression observed in the syndrome. The rate each patient's regression develops may not be constant throughout the course of disease but most literature regards the rate as constant. The best administration of the treatment is believed to occur when implantation is made some time after the β-phram muscles become involved but before they become unresponsive to stimulation. I know of no journal paper presenting any surgeon's estimate of the percentage of involvement of each β-phram muscle measured during surgical implant, when the 'exterior' surface is 'fully' exposed for the surgical examination. The process of searching for the motor points of the β-phram muscles may require as many as one hundred stimulations to find the location and responsiveness of the neuromuscular junctions. A web video, apparently of Onders, presents medical imaging of one patient at a conference where the patient's starboard β-phram muscle was responsive but their port β-phram muscle apparently not. Onders indicated the patient was successfully implanted even though the patient's β-phram muscles were not bilaterally responsive. The motor point survey gives the greatest currently known insight into the health of the β-phram muscles but can only be done during surgery. There is no second chance, at a later time, to survey the motor points again, so the data from this study does not produce a sense of the regression's rate; the data shows the β-phram muscles' health at one 'freeze-frame' moment only. The doctors will know whether one of the muscles is in better shape than the other, as probably is the case because patients often report paralysis initiating on one side, but they will not know the rate the disease is causing the muscles to regress. In principle they could do the surgery again at a later time but practical issues may be prohibitive as ALS patients are thought to be poor candidates for surgery. An alternative does become possible however because, once implanted, each patient's β-phram muscles can undergo continuous electromyogram recordings. These recordings may be useful in finding the rate, if there is one. These recordings could show the disease processes 'live' and provide strong evidence on the question of the treatment's efficacy. With such live data, researchers may finally be able to interpolate the cause or, if there are multiple, the causes, of the ALS syndrome.

Irrespective of the work of others, the DiPALS Writing Group is obliged by the rules of science to base their report on the data they found in their study rather than data derived or observed in other studies. The DiPALS Writing Group did not corroberate or refute the observations of the lead research team on efficacy but their own data illuminated only ". . . low efficacy . . ." thereby raising the question of whether their trial's weighing of the treatment's benefit (median 28 months, n=37) cast doubt on the worth of the treatment in light of the risk factors associated with surgery. Of bulbar onset patients, in a large study, Forbes found the life expectancy median at 20 months (n=284?, 2004); in a small study, Turner found the median at 27 months (n=49, 2010). Riluzole was likely unavailable for the Forbes's patients but might have been for Turner's. The DiPALS median at 28 months (n<38, 2015) is only one month improvement over Turner or eight month improvement over Forbes but is much shorter than was expected for the study (the Onders study found +16 months AVERAGE of all the patients (rather than median) improvement in survival). Bulbar onset was not required of the DiPALS applicants, however. Yet one third of the DiPALS subjects who underwent implantation were bulbar onset. One can reasonably expect the AVERAGE to appear better than median in ALS but median was not in the original report - the median for the study (n=86, 2008) is likely higher than the Forbes, Turner and DiPALS medians though. I was going to challenge the DiPALS group on scientific grounds on some points but realized Lancet Neurology does not require its journal papers to be strictly based on science, so the points were moot - and made reading their paper more difficult.

*more soon*