Is there a slide? Thank you. I'm going to be talking about the identification of patients in prolonged disorders of consciousness using the UK Functional Assessment Measure, UKFM plus FAM. It's predictive sensitivity analysis. Could I have the next slide, please? And I'm presenting this on behalf of my colleagues at King's College London, Norfolk Park Hospital in London and Auckland University Technology in New Zealand. So as we get ever better at saving lives, more patients are surviving with catastrophic brain injury and present to rehabilitation services still in prolonged disorders of consciousness or PDOC, as we call it for short. Some will remain in vegetative or minimally conscious states, while others will emerge into consciousness. And currently, the UK does not collect any systematic data to monitor directly whether patients emerge into consciousness or not. However, a Functional Independence Measure score, a FIM score of 18, which is the lowest possible score, has been used as a proxy for vegetative state by the Life Expectancy Project in the US. And in the UK, specialist rehabilitation services routinely collect the UKFM plus FAM on admission and discharge. So this analysis explores whether the total UKFM plus FAM scores can be used as a proxy to identify patients in vegetative and minimally conscious states, and if so, with what cut off points. So the design was a retrospective analysis of prospectively collected consecutive clinical cohort of 256 brain injured patients that presented to a single UK specialist PDOC evaluation programme, ours at Northwark Park, between 2007 and 2019. The UKFM plus FAM doesn't stand alone. It adds 12 items to the 18-item FIM to form a 30-item scale of motor, cognitive, communicative, and psychosocial function, with a total score range of 30 at the bottom to 210 at the top. Consciousness in this series was evaluated using validated and approved measures, including the Coma Recovery Scale revised, the CRSR, and the Wessex Head Injury Matrix, in accordance with the UK National Clinical Guidelines for Prolonged Disorders of Consciousness. So within our cohort, we had approximately two to one males to females. The mean age was 43 and a half years, so quite a young group. The mean time since onset of brain injury was 17 weeks, so just over four months, and the mean total FIM plus FAM scores on admission were 31.5, remembering that the bottom of the scale is 30, so quite low down at the bottom of that scale. If we look at the etiology of the brain injury, 40% had trauma, about a third had hypoxia, and a quarter had stroke. And if we look at the PDOC status at discharge, as confirmed by the Coma Recovery Scale and Wessex Head Injury Matrix, we found that 30% of patients had emerged, but a third, 34%, remained in a minimally conscious state, and 23%, so about a quarter, in vegetative state. So going over to table two, on the right-hand column, if we look at the total FIM FAM scores by PDOC status at discharge, amongst those who emerged, the mean FIM plus FAM score was 68.8 at discharge. If we look at those who remained in PDOC, the mean score was 32, and if we subdivide that into vegetative state and minimally conscious state, then for vegetative states, it was 30, right at the bottom of the scale, and minimally conscious states, 33.6. But 100% of patients who were discharged in vegetative states and two-thirds of those in minimally conscious state had a FIM plus FAM score of 31 or less. So if we look at a ROC curve for those who emerged versus those who remain in MCS, the area under the ROC curve was 0.95, which is quite high, and a cut-off point of between 35 and 36, respectively, identified those who'd emerged into consciousness with a sensitivity of 86%, specificity of 81%, positive predictive value, 92%, and a negative predictive value of 87%. So we took from this that the UK FIM plus FAM can provide an acceptable proxy for identifying patients in PDOC. A cut-off point between 35 and 36 marks the border between MCS and consciousness, but for additional clarity, for example, for the purpose of research, scores of less than 31 to 32 versus those of more than 35, respectively, may provide a more robust separation of those who remain in vegetative and minimally conscious state versus those who emerge into consciousness. And the importance of this is that in the UK, we don't yet have a registry for all of the patients who are in PDOC, but we do have a national registry for patients who attend specialist rehabilitation services, the UK Rehabilitation Outcomes Collaborative. It collects data on needs, inputs, and outcomes for all the patients admitted to those services in England. And now that we can use this data to identify those patients who remain in PDOC by their FIM FAM score, we can start to analyze the needs, inputs, and outcomes for those patients in PDOC using this information as a proxy. So it's already coming into some use. Thank you very much. I'm going to end there, and I'm going to introduce the next speaker, who is Stella Bart. Good afternoon, everyone. Thank you for the opportunity to speak to you all today. My name is Stella Bart and I work in clinical research at Spalding Rehabilitation Hospital at the Inspire Lab with Dr. Randy Trumbauer, where we study interventions to elicit neuroplasticity in clinically relevant motor recovery after a spinal cord injury. First slide, please. I'm also a medical student at the University of Massachusetts Chan School of Medicine pursuing physiatry, and this is my first AAPMNR conference. The title of the study is Blinding Integrity Analysis of a Randomized Clinical Trial to Test the Effects of Therapeutic Intravenous Hypoxia in Able-Bodied Adults, which took place at Spalding Hospital, Cambridge in Cambridge, Massachusetts. And I'd like to thank my fellow co-authors as well as their study subjects for their contributions to this research. Next slide, please. As you know, there is a critical unmet need for rehabilitation treatments that enhance functional recovery after a neurological injury such as SCI. The current standard of care is often limited for individuals who chronically live with varying degrees of paralysis, limited mobility, and other sequelae as a result of their injury. But how do we know if a treatment actually works? A randomized double-blind clinical trial is the most reliable method for assessing the effects of therapeutic interventions. However, due to the nature of interventions in this field, such as manual therapy, the use of devices such as stimulation units, it is often difficult, if not impossible, to provide a proper placebo and proper blinding of both subjects and clinical assessors. Analyzing blinding integrity in clinical trials is important because there's historically been a lack of properly blinded, placebo-controlled interventions in rehab medicine research. In the literature, blinding is often absent or underreported. Without true placebos and proper blinding, rehabilitation research is subject to bias and confounding effects from both study subjects and clinical assessors who may intentionally or unintentionally behave differently due to perceived treatments, motivation or lack thereof, expectations of specific outcomes, or placement into an obvious placebo group such as a no-treatment group. Overestimates or underestimates of treatment effects or bias at the trial level can lead to biased or inaccurate results and conclusions in systematic reviews. This is a problem. We need to be able to rigorously test the efficacy of clinical treatments to better translate them into standard clinical practice because we need to know if our interventions are responsible for the outcomes that we observe. Here, we investigated the ability to deliver blinded treatment and placebo interventions of the safe non-invasive treatment modality of therapeutic acute internment hypoxia or TAIH. TAIH has been previously shown to enhance locomotor recovery after spinal cord injury, so this was the target therapy of choice for our blinding integrity analysis. For the study, we hypothesized that our subjects would guess whether they received the true hypoxia treatment or sham treatment with an accuracy that was no better than random chance and that this blinding integrity analysis would have promising applications to similar clinical research in individuals with spinal cord injury. Figure one on the left depicts a single session of TAIH. During a true treatment session, a subject receives 15 episodes of 90 seconds of air with a 10% fraction of inspired oxygen alternated with 60 second intervals of room air with an approximate 21% fraction of inspired oxygen. A placebo or sham session mirrors the episodic nature of the TAIH treatment with all air delivery set to a 21% fraction of inspired oxygen. Figure two on the right shows the setup of our automated air delivery system. The apparent setup and delivery of real and sham interventions are identical. The air delivery system scrubs the air of oxygen to achieve the desired fraction of inspired oxygen depending on treatment randomization while maintaining the same flow rate. Brief periods of hypoxemia are achieved but we don't believe that hypercapnia is achieved during this modality. We monitor blood oxygen saturation, heart rate, and blood pressure throughout TAIH and sham sessions. Our study participants were 10 healthy able-bodied adults, four males, six females with a median age of 29.5. Each subject participated in two sessions of this randomized balanced crossover placebo controlled study. Five subjects randomly received TAIH for their first session and five subjects received the placebo sham treatment for their first session. The second session for each subject placed at least two weeks after the first for a washout period. Immediately after the conclusion of each session, which you can see is about 37 and a half minutes, the subject was asked which treatment they thought they had just received, TAIH or a sham. Next slide please. Here are our results. So despite significant changes in both blood oxygen saturation and heart rate during true TAIH sessions but not during sham sessions, if you look at figure three, subjects overall could not differentiate between the TAIH versus sham sessions. See figure four. Only three out of 10 subjects correctly identified a true TAIH session and four out of 10 subjects correctly identified a sham session giving us an overall accuracy of 35 percent. With additional sessions we may get closer to that 50 percent accuracy of random coin flip guessing. Maybe not. We have been studying the blinding integrity of TAIH versus sham in the spinal cord injury population yielding similar results so far. While TAIH is just one of many potential treatments for spinal cord injury, it's exciting that this modality appears to be able to be properly blinded with the treatment that is undetectable as being different from the placebo while achieving its potential therapeutic effects. It is our hope that proper blinding with other placebo controlled studies in rehab medicine will translate into clinical outcomes that accurately assess the treatment being studied without bias or other confounds and with the goal of optimizing clinical care for rehabilitation patients. Thank you so much for listening. Enjoy the rest of your AAPM-NR experience and I'll hand it off to Dr. Cynthia Camilla. Hi, I'm Dr. Cynthia Camilla. I am a professor emeritus at Rush University in Chicago, and I'm presenting this study on the part of my colleagues and co-investigators at multiple sites. The study looks at injections of incobotulinum toxin A at intervals of less than 10 weeks, and whether they are effective and safe for cervical dystonia patients with inadequate benefits from standard injection intervals. Next slide, please. This is a multicenter study that was designed to assess the efficacy and safety of incobotulinum toxin injections administered at shorter treatment intervals of less than 10 weeks, which is the short flex arm, compared to those administered at longer intervals of 12 to 16 weeks, which is the long flex arm. It was an open-label, randomized, non-inferiority study in CD subjects who reported less than 10 weeks benefit from prior injections of botulinum toxin, and who had been treated with at least three injection cycles over the past year. In both short and long flex groups, they received a total of eight injections. The primary outcome for efficacy was the change in twister severity scale assessed by a blinded investigator from baseline, so before the beginning of injections, to four weeks following their last or eighth injection series. Safety was assessed by the frequency and severity of adverse events monitored throughout the study. Assessment of immunogenicity was done, but due to protocol changes, insufficient numbers of patients were completed in this aspect of the study. All subjects were injected based on the usual methodology of the injecting physician. The results, there were 142 subjects randomized to the short flex treatment interval from six to 10 weeks, and 141 in the long flex treatment intervals of 12 to 16 weeks. There were no differences in demographics between the groups, with 72% women overall and a mean age of 57 years. The mean dosing of incubation line of toxin was similar in both groups, using approximately 270 units per treatment cycle. In the short flex, the mean injection interval was 54 days. In the long flex, the interval was 86 days. The primary outcome was the TWISTERS, which is a measurement of CD of cervical dystonia severity, the TWISTERS severity score at week four following injection eight. Our results demonstrated that in both groups, there was a significant reduction from the baseline to the fourth week following the eighth injection. Being 4.1 points in the short flex and 2.4 points in the long flex. And there were no significant differences between the groups. Likewise, when you look at responders, defined as those with greater than or equal to 20% improvement, there was no difference in the responder rate between the two groups. Overall, 74.5% of subjects reported at least one treatment associated adverse event. The most frequent was dysphagia, occurring in 25%, headache in 10%, and muscle weakness in 8%. But these did not differ between the short and the long flex group. Although complete immunogenicity panels were available for not many subjects, of approximately 40 who had complete data, there was no crease in antibodies found between the groups. In conclusion, incobotulinum toxin injections administered at shorter intervals at less of less than 10 weeks were effective and non-inferior to the long flex group for treating cervical dystonia with waning benefit. Shorter intervals did not increase the occurrence of adverse events, and there were no new safety concerns. This is important because many patients do report that their benefit does wane prior to the usual three-month interval that is used in many clinical practices. The results of this study suggest that one may be able to individualize treatment intervals such that patients responding that doesn't last the complete three months may be able to be injected at less than 10 weeks without compromise of safety or efficacy. I would now like to introduce the next speaker, Dr. Gerard Francisco. Thank you very much, Dr. Comella. Next slide, please. Next slide, please. Thank you. I am presenting on behalf of our international research group involving investigators in the US and the UK. My presentation this morning is largely based on the article, Biggest Nerve Stimulation Paired with Rehabilitation for Upper Limb Motor Function after Ischemic Stroke, a randomized blinded pivotal device trial which we published in the journal, The Lancet, last April. Biggest Nerve Stimulation, or VNS, is a well-established treatment for recalcitrant epilepsy and depression. Last August, the FDA approved VNS paired with rehabilitation to facilitate post-stroke upper limb recovery. In the field of rehabilitation, it is widely acknowledged that goal-directed high dosage therapy improves motor abilities after a stroke. It is also believed that this type of therapy encourages recruitment of residual motor networks in the central nervous system and takes advantage of the brain's plastic properties. VNS activates ascending neural networks that release plasticity-promoting neuromodulators such as acetylcholine and norepinephrine throughout the cortex. The combination of VNS and upper limb therapy magnifies the presynaptic input in the central nervous system, thereby influencing release of neuromodulators and strengthens postsynaptic receptor activation. We published two earlier pilot clinical studies which demonstrated that VNS paired with rehabilitation was superior in persons with long-term moderate to severe arm weakness versus controls. In these early studies, the total Fugl-Meyer assessment upper extremity scores improved significantly in persons with chronic stroke. Thus, VNS appeared to be a viable treatment to augment upper limb motor improvement even in the chronic stages when many stroke survivors are thought to have plateaued in their recovery. More recently, we completed an investigation comparing active VNS versus sham VNS paired with intensive upper limb training among stroke survivors with moderate to severe arm impairment to determine VNS's safety and efficacy. Between October 2017 and September 2019, we recruited 108 participants. Important inclusion and exclusion criteria included a history of unilateral supratentorial ischemic stroke that occurred at least nine months, but not more than 10 years prior to enrollment. Fugl-Meyer assessments for upper extremity of 20 to 50, which suggests moderate to severe impairment and the presence of active wrist flexion and extension and active thumb abduction and adduction. A complete list of the inclusion and exclusion criteria can be found in the papers referenced in the poster. Of the 108 participants recruited, 53 were randomly assigned to VNS and rehabilitation and 55 to sham VNS and rehabilitation. To maximize blinding, all participants were implanted with VNS. Implantation was done under general anesthesia in various outpatient centers. In-clinic rehabilitation therapy began the day after implantation and was provided three times per week for six weeks for a total of 18 sessions. In-clinic rehabilitation included a series of high repetition, task-based, individualized and progressive upper limb exercises such as reach and grasp, gross movement, object flipping, simulated eating tasks, inserting objects and opening and closing containers. The exact number of repetitions and tasks per session varied from participant to participant depending on their abilities, but that goal was set for 30 to 50 repetitions for each task resulting in a total of at least 300 repetitions per session. The VNS group received 0.8 milliamperes or lower if required for comfort, 100 microsecond, 30 Hertz stimulation pulses lasting 0.5 seconds during each movement repetition. The control group received zero milliampere pulses. Following the six weeks of supervised therapy, all participants, regardless of group assignment, started a therapist-prescribed daily home exercise program. The home program was designed to last about 30 minutes and included tasks following the same principles as the supervised in-clinic therapy. Outcome assessments were measured in days one and 90 after the completion of the six-week in-clinic therapy. Assessments were done by the same evaluator at baseline and at follow-up. A total of 107 completed the study intervention and were included in the per-protocol population. One participant received fewer than 12 therapy sessions, so was excluded from the per-protocol final analysis. Participants in both, excuse me, participants in both VNS and SHAM stimulation groups received a comparable mean number of stimulations per therapy session. Mean duration of each supervised in-clinic rehabilitation session was 90 minutes in the VNS group and 91 in the SHAM stimulation group. The primary outcome, change in Fugl-Meyer assessment upper extremity score from baseline to day one after in-clinic therapy was significantly higher in the VNS group than in the SHAM group. The mean change was five points in the VNS group as opposed to only 2.4 in the control group. With respect to the secondary outcomes, Fugl-Meyer assessment score at 90 days after in-clinic therapy was again significantly increased in the VNS group compared with the SHAM group. Also clinically meaningful response defined as at least a six point change on the Fugl-Meyer occurred in more participants in the VNS group than in the control group at day 90 following completion of in-clinic therapy. Another secondary measure, the Wolf-Motor function test functional score was significantly increased in the VNS group compared with the SHAM group. 43 of 53 patients or 81% in the VNS group and 76% in the SHAM group had at least one adverse event. The number of events, the number of participants reporting at least one event and the number of severe events were similar in both groups. There were no unexpected adverse events or serious adverse events reported associated with the device. There was one case of vocal cord palsy following device implantation in the control participant which resulted after five weeks. There were no deaths. In summary, our data demonstrate that it is still possible to achieve meaningful improvements many years after a stroke. Thus the improvements noted in the VNS group are not likely to be due to natural unexpected recovery. We demonstrated that clinically meaningful improvements in impairment and function were two to three times greater with VNS compared with SHAM stimulation. In contrast, other recent large clinical studies using devices to augment rehabilitation therapies have not demonstrated clinically important improvements in arm impairment or function. Thus vagus nerve stimulation combined with rehabilitation is a novel strategy to help people achieve improvement in arm and hand function after stroke and arm clinicians with the new means to further promote motor recovery beyond the first year post-stroke. Thank you. And I would like to introduce the next speaker, Dr. Steve Ashford. Thank you, Dr. Francisco. So I'm Steve Ashford, and I'm gonna be talking to you today about active functional goal achievement with integrated arm spasticity management, including the administration of botulinum toxin. Next slide, please. So I'm based at the Regional Hyperacute Rehabilitation Unit at Northway Park Hospital, London North West University Healthcare Trusts. Trust also at the Centre for Nursing, Midwifery and Health Research at University College London and King's College London. And I'm talking today on behalf of the Upper Limb International Spasticity Study 3 group. Goal attainment scaling is used to assess the effectiveness of rehabilitation in areas that matter most to patients and caregivers. In this analysis of the Upper Limb International Spasticity Study 3, we evaluate longitudinal goal achievement in those patients who chose goals that related to active function. Active function here refers to self-performance of tasks by patients rather than passive function, which is related to care tasks. The design of this study was prospective and observational in nature, and it examined repeated cycles of botulinum toxin plus other therapy interventions over a two-year period and was unique in the fact that it captured long-term changes in the patients going through this study. The setting was international and involved 53 secondary care centres across 14 countries. Participants were all adults with upper limb spasticity of varying etiologies, but predominantly the largest participating group was post-stroke. So in terms of intervention, patients were all treated with botulinum toxin focally for upper limb spasticity. They also received concomitant therapies. These were physical interventions, systemic antispasmodic agents, and pain agents. Significantly, we undertook a considerable amount of work to capture in some detail the physical agents applied, and in this active function subset, this was primarily around task practice intervention. So practicing tasks related to function, repetitive practice of those tasks, such as reach, grasp, incorporated into normal daily activities of daily living. The main outcome measures for this study were all contained within the Upper Limbs Spasticity Index, which is a battery of standardised measures which includes goal attainment scaling, and alongside goal attainment scaling were standardised measures such as the Arm Activity Measure, which was used to compare with goal attainment scaling and in particular has an active function subscale evaluating functional performance. Moving to the results, there were 1004 participants enrolled in the study and 285 of these set goals related to active function. If we think about the outcome following intervention, the GAST-T score for active function goals was 46.6, and if we refer to figure one, we can see that for goals across the whole study related to all areas of intervention, the accumulated GAST-T score was 49.5, so active function goal achievement was slightly lower. If we consider goal attainment scaling, we expect across all goals set for a particular individual, if they're all achieved as expected, we expect a T score of 50. So across all scores, this was slightly below, though close to that expected achievement of 50. For active function goals, as I've said, slightly below this, but we know that those active function goals are slightly more challenging to achieve. They're also slightly more challenging to predict, so we don't as clearly know how patients are going to respond. Interestingly, though, in this particular work, we have multiple cycles of treatment and intervention. So if we refer to figure two, we can see the percentage goal achievement in cycle one being 48.2, and if we move through to cycle seven, we get up to 76, 76% of goals achieved. So we can see that actually over time, that goal setting is refined, but also the achievement of those goals are improved. So we can see as patients move through multiple cycles of treatment, they're responding much more to this intervention, and probably the targeting of that intervention is more appropriate to the individuals receiving it. Interestingly, we also, as I mentioned, captured standardized measures, and in this instance, the arm activity measure has an active function subscale, and this also showed in significant improvements, and this was corresponded to the goal attainment scaling results that I've just presented. So here we show that early treatment cycles, goal achievement was lower than expected, but as I've just explained, that there may be some issues around targeting treatment specifically, and the challenges around goal setting. As we move through those treatment cycles, patients are more successful in achieving those outcomes, and we get up to 76% goal achievement. So in terms of a take-home message, active function goals involving tasks such as grasping, holding, and releasing are achievable in carefully selected people following residual, with residual control of voluntary movement, and usually requiring repeated cycles of botulinum toxin to be administered, and in combination with non-pharmacological physical task practice. Thank you for listening. I'm now going to ask my co-presenters to turn on their cameras and microphones, and we would be happy to take a limited number of questions. Thank you. Okay, perfect. All right, well, thank you so far for everyone who's out there listening and enjoying this presentation. So some of you have started writing some questions and comments in the chat dialog box. So at this point in time, please continue to fill that out and complete that. And what I'll start to do is I'm going to start to look at a couple of these questions and relay them back specifically to some of the speakers, and we will go from there. So one of them for Dr. Francisco was, who would you say is the optimal candidate for vagal nerve stimulation? Great, thank you so much for the question, Dr. Harvey. Very interesting question. As you very well know, because of the labeling, now that it is FDA approved, we will have to follow what is on that label, which is largely based on the subject population in our study. So this will be patients who are chronic up to 10 years, those who have some movement, in particular the distal upper extremity with more moderate rather than more severe impairment, those who do not have a significant sensory loss, especially proprioception, and those who are highly motivated, because this is a pretty intense therapy, not as intense as CIMT, but still a pretty intensive therapy over many weeks. So we are further refining this. Currently we are doing a post hoc analysis, trying to characterize which of the subjects, which of the 108 subjects, did better than the others. So hopefully we will be able to publish that this coming year. Okay, and then Andrew Kroll had written that in rural areas, what discipline would be the appropriate discipline of contact regarding vagus nerve stimulation implantation, or is this sort of thing only available at a tertiary care center? Well, right now it does not get available. So it's FDA approved, but we're still waiting for CMS to come up with the appropriate reimbursement codes. So hopefully in the coming months we will be able to offer this. And as with any new device, most likely it's going to start mostly in academic centers or those centers that participated in the study because of the expertise that they developed during their participation in the study. But since it is a very promising treatment, I am pretty sure that eventually more and more centers are going to be educated on how to apply VNS amongst the various clinical offerings they have for stroke rehabilitation. Okay, and then in the chat, someone had written to Dr. Kamala about the NATB and some of the toxins out there. She had responded back in the answer. One of the things I just wanted to inquire past that was for your next steps, or has there been any thought as to, with the next research project, studying other types of neurotoxins? So far as they're shorter intervals and the ability to use them without any detriment, at this point that would be, it is not currently planned. There have been past studies looking at neutralizing antibodies with the various toxins. And unfortunately, the results are pretty much all over the board insofar as the percentage of patients. Methodologies differ. The testing that's done differs. But we think that it's really not quite as important as it was initially, because many patients who have neutralizing antibodies continue with their clinical response. So we use the clinically determined resistance, which is called the unilateral brow injection, where you inject and you see whether it effaces the corrugator muscle, which I think is more reliable to determine whether or not a patient has enough neutralizing antibodies to counteract the effect of the botulinum toxin. Okay. And then as we're waiting for some more questions to come in, for Stella, with your project and the results that had come out, were you surprised with the results? A bit, yes, just because, you know, learning more about intermittent hypoxia and it's, you know, it's not the same as holding your breath where people say, you know, if I'm holding my breath, I can tell, but you get really hypercapnic at the same time. So with our treatment, we don't think that hypercapnia is necessarily existing. So it's just the hypoxia. And it's so brief, you know, people get down to around 70 to 80% SpO2, but it's only for a little bit that, you know, within that 90 seconds of hypoxia, you don't actually start to get hypoxic until maybe 60 seconds into that. And then it dips when you've already switched back to the norm, we call it normoxia, the regular room air. So I was a little bit surprised, but, you know, as I started getting more familiar with this treatment modality and talking to people and knowing what, because I was the one sitting there delivering it and then asking people and they're just completely convinced for very different reasons, you know, why they thought that they received the treatment or not. And then what, have you gone back to the drawing board thinking about kind of the next step or where you want to take it past that? So our lab does, we're working on some combinatorial treatments. And so one of our studies in SCI, we did caffeine versus placebo and hypoxia versus sham. So doing that combination. And that was also really interesting too, because people were equally bad at guessing if they received caffeine or not. So trying to guess if they got caffeine, trying to guess if they got the low oxygen, it was, it was really interesting to get those results too. So moving forward, just trying to figure out how to blind with combinatorial treatments and making sure that they actually work so that we're, you know, targeting the right populations and not wasting people's time or resources. Okay. And I'm going to scroll through and see if any more questions have come in now. Dr. Turner-Stokes, you had raised your finger. I didn't know if you wanted to say something or just. I know I had, I had a point that I think was interesting in Steve's paper and it resonates with actually Cynthia. So I thought it was worth making that connection here. So it's important to realize in Steve's paper with the seven different cycle, seven cycles, by no means, everybody required seven cycles in the two years, only a small minority required seven cycles. The majority, actually the average was four cycles in two years. But it was interesting that it was those people who had the seven cycles, they got better and better at setting active functional goals and therefore achieve them all. But then interestingly, as we went on in those cycles, the few people had the seven cycles, but more, a greater proportion of them had active function goals. And it follows from that, that it may well be that it is people who have the active function goals from spasticity management who need more frequent injection. And I was interested that that resonates with Cynthia's paper about that. There's a subgroup that requires, in order to achieve what they need to achieve from the benefits of botulinum toxin, they actually may require more frequent injection. And it's not a problem to do that, because actually, as Cynthia showed, it's well tolerated. And I think we're seeing exactly the same in spasticity. So I think we, it's a message, I think it's really important to get across to the audience, that those countries that have, you can't inject more frequently than three months, or you can only do so many in a year or so many in a lifetime, is a problem. We really have to not only alter the focus and the frequency and the injection technique, but also the total number of injections, depending on what it is you're trying to achieve. And I think that's a really important message. Absolutely, absolutely. And we had one question come in from Kim, asking if a short interval injection is as safe and effective as long interval injections, why would we consider doing a short interval injection if it costs more? I think, it's Steve here, I'll chip in there. I think in part, we've answered that in Lynn's comment, in that for some people it's necessary. I mean, I would say it's as simple as that, in that sometimes we need more frequent injections to achieve the goal, and it's sequential. We're building on the previous cycle of intervention. And bear in mind, certainly within spasticity management, it's not just about the botulinum toxin administration, as I mentioned in my talk, it's also about the other components of the rehab package that people are receiving. And it's important to remember also that there are care costs and other things that go into people becoming more dependent in between. So, as a result of them not being able to do the things they want to do, there may be costs to that. And we've demonstrated that in other areas of spasticity. So, in the context, for example, of comparing the cost of a botulinum toxin injection versus the cost of care, there's a huge difference, and costs of care are far more expensive. So, I think if we only focus on the medicinal costs, we're missing the bigger picture. But I think it's important to remember that each patient is really different, so that there isn't really a consistency necessarily of response. And one needs to assess whether the alterations or flexibility, is it safe? Is it safe to do these different intervals, different dosing, different muscles, et cetera, et cetera. So, your point is very well taken. Okay. We have about 45 seconds or so left. I was going to see if anyone else had any additional questions come in. And I guess I'll just ask real quick, with these injection studies, has anyone explored or looked at hand dominance and whether that could have played a role with treatment? Steve, you've looked at that. Yeah. So, we do capture that information. Obviously, it does play a role in the wider rehabilitation of individuals following arm impairment. Spasticity is only one component of it, and it's probably the more general issues around motor recovery, which are important here, and also what people are trying to do with their arm. If it's their dominant arm, there's obviously many more demands on it. Perfect. Perfect. All right. And that's great for timing. I want to thank everybody again for tuning into this session. It was a very great session. So, thank you again for your time. Thank you. Pleasure. Thank you very much. Thank you. Thank you.

UK Functional Assessment Measure

Functional Independence Measure

prolonged disorders of consciousness

vegetative state

therapeutic intravenous hypoxia

motor recovery

cervical dystonia

vagus nerve stimulation