Thanks, Nick. Welcome back, everybody. Nick did warn Dr. Felden that he was going to have to deal with the post-prandial type. He's the first batter on Dr. Lunch. But he's going to keep us all awake and update on pediopathic entrepreneurial hypertension. For those of you who don't know, we just recently completed one of the best and biggest multi-center trials in the treatment of pediopathic entrepreneurial hypertension, the IIHT, and those results are continuing to come out and I'm just going to address that. Dr. Felden is the chair at the Department of Ophthalmology at the University of Rochester back in New York. He did his residency at Albert Einstein. Or was that Med School? That's what's going on right now. Okay, and then fellowship with Bill Hoyt in San Francisco. Yeah, there's a neurosurgery fellowship on your bio. What's that about? That was your research in neurosurgery. Okay. Physiology.  We did some transcranial work. Dr. Felden is one of those rare individuals who can combine basic and clinical research, clinical care, surgical care, teaching and administration. We're really delighted to have him with us last night. He gave a fantastic talk, kind of bringing together the clinical care and basic science research around thyroid disease and we're so glad he could be with us this afternoon. It's great to be here and to thank everyone for the invitation. I look at Randy Olson as being one of my mentors and we have a great relationship. And I must say that this is really bringing close to Newcastle because your neural ophthalmology group are much more expert in the path of intracranial hypertension than I am. And usually what happens is that the residents begged me to give them lectures on thyroid eye disease. So I never talked to them about thyroid eye disease. So I'm assuming that there's maybe a little room for some getting caught up on intracranial hypertension even though much of the great work has really come out of this institution and then sort of the mother institution at the University of Iowa that sort of gave rise to the interest of intracranial hypertension. So I hope that I'll get corrected for any misstatements I make and we'll all learn. So it turns out that intracranial hypertension has had a few other names in its history. Pseudotimer cerebri, really nobody liked that term because it's had the word timbre in it and people forgot about Pseudotimer. And then the residents would always get confused between orbital Pseudotimer and Pseudotimer cerebri and they'd use them sort of interchangeably which would be great except the diseases are completely different. And then benign intracranial hypertension was actually popular until really the Iowa group said you know it's not so benign patients are going blind and we really shouldn't sort of color bias the outcome of these patients serious enough by calling it benign. So now we call it IIH which is mouthful and so someone in the eyes could come up with a better name for it and I'm sure there's room to change it once again. I'm going to start out with a case. This patient is a 27 year old 5 foot 3 woman which in my house is tall but in most cases in short and overweight and she had a history of a renal stone actually. She was treated with IV antibiotics including vancomycin but wasn't really treated with tetracycline or anything like that and within nine days she developed blurred vision and her vision as you can see was really reduced 2400 in the right eye, 27 in the left eye and this is like you know the grand fuba of papillodema and this is about as bad as papillodema again so this is not your usual case. A lot of hemorrhage, a lot of dis- swelling in both eyes and the blind spot as you might expect was it was increased in the central scatomas in both eyes and here you can see on goldmonde fields yes we still do goldmonde fields and you can see that there's a bilateral synesthesia in the central scatoma. A bit about the criteria for making a diagnosis of an apathic endocrinal hypertension. So up until very recently it's the modified antichriteria that we have used and so we have to have the right symptoms, headache, nausea, vomiting, transcriptional aspirations or papillodema with no localizing signs but you're allowed to have diplopia from a non-localizing six nerve paracist. Patients otherwise in good shape or awake and alert. There's no evidence of thrombosis on CT MRI and the LP was supposed to be greater than 250, 25 centimeters of water. I used 25, 250 millimeters and 25 centimeters interchangeably so if I slid it's not 10 times the amount of hypertension. And there's no other explanation for the region of pain or pressure. So this is the criteria that we traditionally use. And then it got a little bit more complicated and I won't bring you through all this but this is a new classification with Kathleen being involved and this with Doug Friedman who was my fellow and was at the Palm Island Institute for a long period of time before moving to Southwestern and things began to change in terms of what's included and I'd just like to call attention to the fact that there is such a thing as a pseudo tumor cerebrine syndrome without papillodema and this is kind of a new concept. People had intermittently reported well you can have high pressure and no papillodema. I had always had a little saying I have a number of sort of maxims that I use for optic nerve disease and the maximum that corresponds to this is that the optic discs are not the manometer of the central nervous system and so you don't have like a gauge sitting there at 260 and turns into papillodema and at 240 it goes to you have no papillodema. So different people have different tolerances for different pressures in terms of developing papillodema but there are other things that have to be present to make sure this isn't a different kind of headache for instance empty cella that you can have flattening as opposed to your glow and that you can have a transverse sinus stenosis. So these are things just to be aware of that still in evolution exactly what we mean by elevated intercranial pressure. So what are the hypotheses? Well because we don't know everything you say is plausible. So Dr. Sugarman did a bunch of studies where he said you know these patients are heavy and they have weight on their inferior vena cava and their superior vena cava and so they just can't circulate their blood and you get high venous pressure and this is what the underlying pressure problem is but really it doesn't really fit for most people that this is a logical extension. Sleep apnea is regularly associated with patients who have IIH but it's not the other way around. If you go to sleep clinic you can examine thousands of patients and they don't have IIH nor do they have AION or all the other things. I think that having sleep apnea just means you're more susceptible to just about everything including IIH. Hormonal influences, again you know the vast majority of patients are women why should that be so? Well maybe there's some hormonal influences but no one's really identified what those hormonal influences might be. Of course you can increase CSF production and in certain papillomas that involve the coriaplexus you can actually get increased CSF production and overcome the absorption system. This is like overproduction.  Decrease CSF absorption is probably what's going on most of the time but we don't know exactly why. I did see one interesting article just recently we haven't had time to read in detail yet talking about aqua porn 4 defects being associated with IIH so it'll be interesting to follow up to see whether that has any validity. And then there's a lot been said about functional or mechanical destruction of venous sinuses. So if you raise somebody's intracranial pressure the tissue pressure collapses or can collapse segments of the venous system. On the other hand if you collapse a segment of the venous system then you get higher venous pressure which often has to be higher intracranial pressure. So these are some of the ideas but the fact of the matter is that we just don't know. And we were hoping that the study I'm going to talk to you about today was going to give us some more clues and it has not been satisfying as one would. So the clinical presentation as I've already alluded to is obesity on women usually with a recent weight gain and headaches that are often constant horizontal binocular diplopia at distance because they have abducting a paracet transient obscurations of vision which are usually postural induced in the last seconds at a time they can be in one eye or both. Some patients do get nausea and vomiting in association with it which really makes it confusing for patients who may be treated for migraine for a period of time because they have nausea, vomiting, and headache and here's another syndrome with nausea, vomiting, and headache. Pulsatile tinnitus is the noise in the ear this is not the high-pitched sort of wine that is common but rather this is a whooshing sound that is sometimes pulsing a mild stiff neck because of increased pressure but there are no localizing symptoms. So of course you always want to see if we can find a cause so if you eat polar bear liver then you are in fact at some risk to develop hyperbiderminosis A which can give you papillohemus you know at least all the third-year residents know all about Nalodixic acid and tetracycline I've never seen Nalodixic acid used as an antibiotic in my entire career but Cypro is an analog of Nalodixic acid and can cause the syndrome so that's just a little purlin. Cortico is steroid use either coming on or coming off so it's really complicated and it's used by some people in the treatment of IAH so it really becomes complicated and we try not to use cortico steroids closed head trauma probably from venous stenosis or temporary venous stenosis and then history of waggulopathies again we think about venous stenosis maybe perhaps associated with the signs so the vision can be fine and often is fine but as a matter of fact the IAH treatment trial had patients who didn't have much vision loss and that's one of the strengths and one of the weaknesses of that study and we'll get to it in a little bit they can have acquired dyschromatopsin after in people area defect visual field defects of any type and as I said they can have amnesis peresis the papillodema is usually bilateral and symmetric and I'll show you some evidence for that later the neurologic exam there has been some thought about with all that elevated venous pressure the arterial circulation must be affected in some way and perhaps the core of profusion is compromised but very few patients we see are confused or somnolent or anything like that so we want to do some tests the first thing we do is to get an imaging test so I would say imaging first and then L.P you wouldn't want to image something and find that the pseudo tumor was really not pseudo and that you end up causing complications by doing an L.P when you meet each other so we get MRIs and MRVs in our institution if the patient is the typical onset we usually don't get MRVs we just get MRIs some places do both all the time anybody who's atypical should have an MRV or now I guess they're getting CTVs as well lumbar puncture so I used to do them all myself and the problem was about four hours a week I was doing L.P's and then they found out I didn't have hospital privileges to do L.P's because I'm an ophthalmologist so I had to go back and get privileges and prove that I actually didn't paralyze anybody in doing the L.P's but now we have a PA who does them under fluoroscopy and I can tell you that it's just a wonderful thing to have when you know that person's doing them right because doing them wrong is a real problem you can't say anything about how that patient is what that patient's opening pressure is if they're sitting up squeezing there's a hundred ways to do it wrong they're all equally easy as doing it right but if you do it right to get a pressure you can rely on and I do a test in those cases of happiness, pharmacosis we like to make sure that there's no underlying cause for menace so Lars Friesen who happened to be a fellow with Bill Hoyt when I was a medical student didn't got to know him extremely well very very detailed and individual who is truly brilliant and has done a lot to help us with our understanding of optic nerve he was sort of the premier disc-gazer for decades and he came up with a system of Patholedema that allowed us all to talk about the same things and so this was what was used in the IHGT study so just to review briefly, basically stage zero is a normal disc or a not normal disc but with no C-shaped halo that's very confusing and it causes a lot of consternation amongst all of us and I'll show you why when we get to the results of the trial stage one is the C-shaped halo and it doesn't always project well but basically what it is is you see white a white fuzzy area that doesn't include the macular-capular bundle so if you see white around the disc but it doesn't include the macular-capular bundle then that is stage one stage two is that the halo goes all the way around there's elevation and there's the border there's no major vessel observation so zero, one, two all depend upon what the nerve fiber layer around the disc looks like three, four, and five talk about vessels so in three there has to be at least partial obscuration of one vessel and four you have to have some obscuration of all vessels and in five you have to have complete obscuration of at least one vessel on the disc and again you can say there's room for interpretation with all these things but in general it turned out to be fairly reliable and in the study we were both judged by the principal investigator at the site as well as by photography which is where my so this is what we did in addition to looking at the qualitative classification we actually we can stereo the disc we can blow them up so the size of the beach ball which allows you to see a lot of detail and stereo and we can do a lot of things that help us to actually calculate the area that is involved and when we do that we came up with two different areas and so we came up with what we call the area of white which is the halo so the halo goes all the way around and we looked at the vertical and the horizontal and we calculate the area of the halo and then we calculate the area which we call the dark zone and you can see that on the hill of the apple edema outside the white zone it's still elevated off the surface of the retina and so it comes out as a dark shadow and it also is the inflection point of the vessels and so you can then get an area of dark and we looked at both of these separately and it goes together and so what happens when you try to do a treatment trial but here we actually here's an example from the patient in the IHDP and here here's what they look like at baseline so this is pretty much all the way around there are several vessels obscuring this was called a level 4 and then one month into the study you can see that it still got halo all the way around but now you can see the vessels you couldn't see well before and now it's a 2 and then you look back at month 8 and it was still a 2 and then 2 into a 1 at 9 months so this is a really nice case study of how you can follow Abla Dema look at response to treatment and if you now look at it from the standpoint of the area of white you can see the area of white goes down mostly at the beginning and then it slows down and similarly the total area also continues to go down and then flatten and so in other words this disc size is not very much different than this or this disc size but is different from this one from the first one so we have a nice correlation between the qualitative and the quantitative then we took this quantitative assessment and we started looking at it against other parameters and the reason I show you this is that first of all it's published if you're really interested in the data it's all there but the really there are a lot of things that really didn't help us very much and so you can see that the curves really are not too exciting there's a lot of scatter when you're trying to correlate it with visual fields, visual acuity, color vision all those things it doesn't always correlate as well as you might want it to so what are the management principles of IAH traditionally we have a few things available to us we have medical therapy of which weight loss is the mainstay and we all recommend the patients lose weight of course it's easier said than done in the IHTT we actually had an obesity specialist group work with each individual in role to lose weight and they actually lost a lot of weight which was helpful and then Dymox his own mind has always been the mainstay of treatment for 40-50 years but never shown in a class 1 level study, no perspective study that demonstrated was useful but everybody tended to use it a lesser known drug when I find very useful for patients who are not tolerant Dymox is neptazine so if you're doing 25 250 milligrams of Dymox twice a day which is really low dose you'd be doing 25 milligrams of neptazine twice a day so it has 10 times the potentity but it also seems to have less side effects and so I use it in patients who seem to be sensitive to pyramid there are no clinical studies but it is a mild carbonic amyloid inhibitor it's really good because it gets rid of their headache it helps their headache and it's also a hunger suppressant so it really decreases people's appetite and so they lose weight so a lot of people they don't tolerate Dymox they'll go into pyramid remember that it is pyramid that can cause swelling so every once in a while you can compound your difficulties with the pyramid Lasix is interesting Lasix is sort of the fallback drug they can't tolerate Dymox oh they're pregnant, oh they're this and so we put them on Lasix there's really no good studies that demonstrate that Lasix is really effective patients really don't like it it makes them pee all the time and you have to watch their potassium and it's more complicated patients don't like it so as I mentioned before we want to avoid steroids if at all possible because of rebound on tapering and because the side effects include weight gain and we know that steroids can either start with the onset of using corticosteroids or IH can start as you discontinue it so it's really hard to manage if you have a vision loss you can sometimes rescue their vision for a period of time with a short course of steroids so surgery is generally used when medical therapy fails and the surgical therapies that have come about have been usually optic nerve fenestration and there's one eye or both eyes that take LP shunts which are trying not to use anymore because even though they work about 50 to 60% will have some complication soon after they have the LP shunt put in they get infected, they get disconnected your lower back was just never made total of the shunt so ventricular perineal shunting it takes a little bit more skill you have to stereotactically place the catheter you can get intergranular hemorrhages you can get swelling so it's not completely without problems it has the same effectiveness in the LP shunt and even though the initial success rate is high they also have substantial failure rate so it's certainly not a panacea and we and the neurosurgeons hate doing them so it's not like you have to convince them you want to do an optic nerve fenestration they're sending them to us won't you please do an optic nerve fenestration we have to tell them no it's not indicated you really need to do this shunt so optic nerve fenestration there are really two ways to approach it I still use the medial approach that was first standardized in the ischemic optic neuropathy decompression trial I think you're looking at under as much power as you want in a microscope and this is very early on I think John Kelpner in the 70's published this shunt that occurs between the subarachnoid space and the interorbital space demonstrating fluid but there's also been some demonstrations the scarring takes place and some people feel that the scarring takes place may protect the nerve from swelling but also cause further vision loss down the line because the pressure on the nerve back and the disc is still there and you haven't really done anything for the pressure so I don't know if this is going to work or not I don't think it will work but it was just a 10 seconds showing you a gush of CSF from a super sharp blade so a long time ago now I guess almost 10 years ago I wanted to look at what the effectiveness of surgery for IH was because nobody had actually done any systematic research and literature there's much more data on looking at optic nerve sheath fenestration because ophthalmologists were seeing those patients and got visual fields but if you're being referred from a neurologist to a neurosurgeon or to a neuroradiologist they somehow never stopped in the ophthalmologist's office and so most of them just had subjective my vision's better my vision's not better or thus they had a visual acuity on them which has been a very good measure but basically what it demonstrated is that we really don't have too much data on many of the surgical procedures except for optic nerve sheath fenestration which has like an 80% effectiveness so this is in terms of vision improvement 80% so it's a pretty good thing to do if the patient's having vision loss there's not that much to say about it relative to headache because of course ophthalmologists never send their patients to a neurologist so they can ask about whether their headache is better and so we don't really know much about the effect of optic nerve sheath fenestration on headache so let me go through these are my wall slides so these are the part of the official slide set or the IHTT and this has all been published now and I'm going to show you a few things that haven't been published or have been published in subsequent in subsequent to the initial data so here's the steering committee and you can see that we have really good representation from Jim Corbett, Deb Friedman and Mark Coopersmith, Mike Wall all people who have really invested interest in IAH over their entire careers and here is the study basically it was diet plus placebo or diet plus acetazolamide and the acetazolamide could go up to 4 grams so the deal was if they could drag themselves in the office and they weren't complaining too much you increase the dose and you kept increasing the dose and normally I would say the clinical idea was you got to 2 grams and you pretty much stopped but now we feel much more comfortable about going up to 4 grams in order to get effectiveness and so then you monitored them and the perimetry was the outcome measure and this photos were taken at regular intervals and at 6 months there was statistical comparison of these two groups here are the centers and you can see that I don't think you're that far north I think you're kind of more like there you're right you're there well you can see that it's heavily east coast based I guess we have more patients that have the disease or something but Rochester was one of the centers and he was another center but there was involvement across the country and actually in Canada what was the the BMI and this cohort and it was hefty so I think the definition of obesity is greater than 25 is that correct so these people were obese, obese or an obeseist the initial symptoms of IAH headache and vision loss with the first two headache plus vision loss pulsatile tinnitus and then there were a few that were asymptomatic look how what a small percentage actually had diplopia so I think it's overemphasized that you should have diplopia we just don't see that many and the frequency of symptoms again headache and TBLs are the most frequent interestingly back pain turned up we don't know if this is back pain before or after the LP but certainly one of the complaints pulsatile tinnitus dizziness which is interesting because one wouldn't expect necessarily them to be busy, photophobia perhaps related to headache and again neck pain vision loss so you can see the relative frequency of many symptoms that occur some expected and some unexpected so John Kaltener tells us that this is the most common field effect that's experienced which looks kind of like an archaea interestingly the lower field seems to be more susceptible than the upper field in many of these patients how about the severity of apoledema well you know this is a nice bell shaped curve remember that these patients really didn't have more than a couple of dBs of depression on their visual field and so we are seeing only the mild IIH cases and it's interesting that it's sort of a bell shaped curve around grade 2 to grade 3 and almost no grade 5 and of course there are virtually no grade 0s in the study eye there were some in the non-study eye one of the things that I wasn't published is what was the symmetry between the eyes so this is a calculation that I've performed in my lab looking at symmetry and because unilateral apoledema is always in differential diagnosis you know is this ischemicopic neuropathy or papillopathy of some sort or is it apicneuritis or is this IIH and so it turns out that virtually almost all but 5% had within one grade the either direction of the study eye and that's really helpful to us because you know the more advanced IIH patients they almost always have bilateral disease but even in the milder disease bilateral bilaterality is certainly the rule and again we looked at the relationship of apoledema and visual loss we'd really like to say well the less edema you have the better your pressure and the better your vision didn't look out that way at all seems to be completely random and similarly we said well you know if the metometer of the central nervous system really is the object of this then there should be a really good relationship with the CSF pressure and with mediation and that didn't work out either however what did work out is that we found to the .05 level that there was a benefit to using a cytosolamine and in doing it by increasing the doses in the way that I just described and most of the effect took place in the first three months and so after that you can see that these lines are almost parallel between the placebo group and the cytosolamine group but what you see is that you've got an improvement immediately in the cytosolamine group within a month but not in the placebo group and that accounts for most of the difference what about symptoms well you can see here that the cytosolamine plus diet seem to improve TBOs post-alternatives, dizziness, photophobia, neck pain and visual loss very nicely the diet seem to improve the diet along with placebo seem to improve some more vague symptoms like Pogba's dysfunction and the particular pain so that's not too unexpected percent improvement difference over six months you can see that with these cytosolamine that you got tremendous improvement in the transfer of visual obscuration some improvement in headache severity and some improvement in the frequency of headaches so what was the average dose of medication? well it turns out that if you you needed a lot more placebo to get an effect if there was one so that's not too surprising what was surprising I think to most of us is that people tolerated 2.5 on average and many people were actually on four grams a day and the effect of cytosolamine on freezing grade was fairly significant the effect of placebo courses in the other direction so how many treatment failures were there? there were seven treatment failures in this whole study which basically says you can leave most of these pages alone to define on the other hand since we wanted to find out if cytosolamine would actually help it turns out that there is a significant difference between the treatment and the placebo oh by the way I guess I should point out that all the patients who failed had high degrees on freezing scale this just shows you the change in path of emigrate in the worst eye over time and you can see that the placebo's did pretty well they gradually got better but they never got down to where the cytosolamine group is and this is just to remind you again the progression from grade zero to grade five what is interesting is to look at baseline in six months so here's the baseline up here and you can see this sort of as I already showed you kind of a distribution in both the baseline of both the study group and the cytosolamine group but then when you look at six months you can see that the lower numbers zero and one are predominant at the cytosolamine group but you're still somewhat normally distributed in the placebo group this is again something that isn't in the study it's just a little study I did which says well what's the all those disc hemorrhages mean and what you find out is that the patients who failed have a lot more disc hemorrhages but on the other hand there were also higher grades of papillodema and so when you have higher grade of papillodema you're probably more likely to have disc hemorrhages I'm not quite sure what it means but I now know that disc hemorrhage is not a good thing one of the sub studies was to look at OCT and to look at OCT volumes of the nerve so here you see papillodema grades from zero to grade four they didn't have any grade fives in the subgroup they couldn't measure them and here you see the OCT and you can see that it's a pretty good correlation that as you go up in papillodema grade you get more and more volume and this is the three dimensional reconstruction of those curves so it's very free and it may allow us to be more quantitative moving forward and here you can see over time this is volume over time and the placebo and you see the zolomite groups and you can again see that you can use disc-volumism measurement to demonstrate the differences between the zolomite and the placebo there's also a very interesting phenomena where so this is getting back to umbilical science so we have the RPE that comes in in papillodema and then as it gets better and you treat them then it reflects posteriorly and then you come out of these so this may be a sign to tell you whether papillodema is progressing or regressing um we did look at disc area versus disc volume and it is an amazingly good correlation which I guess one would expect but what it really means is the z-axis doesn't add much in terms of understanding if you can quantitate the difference is OCT is much easier to quantitate than taking measurements using big screens but the correlation is just amazing between total area and OCT volume and the baseline baseline non-study odd and in six months study on non-study odd so very tight correlations and that's I guess reassuring but stay tuned because we didn't address a whole bunch of problems especially we didn't address patients with it really worried us with more severe symptoms and signs of high age and we didn't look at any of the surgical arms so we started two other studies in the light study which I think is a conclusion now and the light study was just to continue those same patients in group one to see what happened to them long term basically what happened to them is they got bored and didn't show up for their follow-up appointments um and in the surgical side we now have the site and the site is we'll find out probably within a few weeks whenever October we'll find out whether they're going to fund this project which is a natural extension and the site study is looking again at parametric mean deviation but these are patients who have from minus 8 to minus 30 to be lost on the visual field instead of like 0 to 6 and they're going to be randomized into a zolomide and this is medical treatment optic nursing fenestration or CSF shunt technique and we're going to try to figure out what maximum medical therapy does and this is the same thing that we just talked about versus doing surgery they're going to be monitored in the visual field and now OCT is the other outcome measure and then we're going to look at the results and see how they fare so let's get back to that patient I should so what did we do with this patient I've given you all this data and talked all about this disease but here you have this patient in front of you in front of you has 20 terrible vision in both eyes and is really probably the clock is really ticking so what did we do the patient had already been taking 1.5 grams per day of diamonds at the time she was referred so I really didn't think we had a whole lot of time to figure out whether or not maybe going to 2 grams or 2.5 grams is going to be effective so she went and had a right optic fenestration and I mean this is great 2040 vision remember that was just a really bad 2400 vision pre-operatively she comes back first post-operative visit 2040 and left drive we didn't touch hand motion so I think we have an idea what happened operated on the wrong eye so what happened to this patient here's the visual field so in the right eye there's just this big blind spot but overall pretty good and this is the left eye I mean just disastrous probably going to skip it well did she have an ATV now? that was one of my thoughts my other thought was it was the resident's fault well the resident the resident then said it was the medical student's fault is there an APD? yeah there is an APD but it's sort of but not the one you think about so here's what happened this patient had a vitreous hemorrhage probably because of hyper-revalation during the time of surgery and it's one of the very few patients I've seen with IIH develop a breakthrough of hemorrhage into the vitreous and when I last saw the patient after one of my retina colleagues cleaned all this up the visual field was 2030 in the right eye 2100 in the left eye it wasn't completely resolved there was no APD at that time and the color plates were back to normal so just to show you when you think you've seen everything then you get to see one more so thank you very much for the opportunity how many have missed this when you were going through there did they follow weight loss compared to the placebo comparison was there a difference? yeah interestingly there was a difference but it wasn't due to the use of the diamox a very sophisticated system but the patients on diamox because it takes away your appetite because it makes coca-cola taste bad your tongue is vibrating all the time so when you took away the dependent variables looked at them as independent variables there was no difference due to the weight about the same thank you Dr. Fowler for a great presentation we have two questions for you so question number one you mentioned a series of online 250 milligrams so do you prefer to use 250 milligrams tablets or 500 milligrams capsules and a second question so what do you usually do when you have a patient with kidney stones medications wise so the first question if I heard it correctly is that correct 250 milligrams 250 versus 500 yeah so of course they went in 250 milligram increments for the purposes of the study but I use the long release 500 milligram capsules and as I increase it what I do is I ask the patient are they more symptomatic from the diamox in the evening and as I build up I'll give them I'll give them more when they're less symptomatic from their diamox related effects but I don't know that anybody again there's no study that shows that one's better than the other but you can almost depend upon patients trying to take medication four times a day aren't going to take it four times a day so you're very fortunate if you take it twice a day and the other question oh kidney stones so we had one patient who had kidney stones the patient here who had the history of kidney stones it turns out that even if they had a kidney stone that you can put them back on and they probably do fine you have to make sure that they're look at their urine from time to time make sure there aren't much oxalic crystals that are forming but in general you can put them back on and this patient tolerated without any recurrences so I noticed in your review from 2007 you had the stent placements as a treatment but you didn't mention that it's been kind of hot in the press in the last five years are you guys doing stenting a lot? so we're not doing stenting not because they don't want to do stenting but I have serious concerns about stenting and the stents the time that I published this back in 2007 there were only about 30 published cases of stents now of course there are probably hundreds these are venous stents yeah venous stents so they go right into the transverse sinus so it's like taking a nail and sticking it in somebody's transverse and a holiday there were initially a lot of complications and there were serious complications like hemorrhages I think the procedure is about to save for over the years and people are more skilled at putting them in and the shunts are better but the problem is that most centers are not making a really good differentiation between stenosis true stenosis and secondary narrowing and so they're all going to get better if you if you take care of the narrowing then you've taken care of part of the circle the vision cycle so it's going to help it get better but if they truly have stenosis it's not going to get better really until you do that or until you have a permanent shunt solution so I didn't emphasize in this talking it's not part of the site so there wasn't not a lot of enthusiasm putting this into the other study what's your experience here we don't do it very often there are certain centers Australia likes to do them if you're south of the equator there's a different fluid dynamic than we expect any other questions thanks again there are certain centers


Hi there and thank you for joining my talk what the AST I Like starting my talks off with a question and I know raising raising your hand in this Virtual talk is really difficult. Um, but I still want you to either participate in the chat or at least You know think about this question. Have you ever used? One of these tools angular web pack ESLint prettier parcel view typescript Babel Because in the next 30 minutes, I want to talk to you about What these tools have in common what they're using under the hood? Why these concepts are useful for you to know? Even if you're not trying to build the next ESLint web pack or similar tool and Also, why it's just generally useful to have this in your tool belt Before we start and I want to briefly introduce myself. My name is Dominic I work as a developer evangelist at a company called Twilio if you haven't heard of Twilio where cloud communications platform meaning we have apis and SDKs to allow you to integrate different means of communication such as voice video SMS email to fact authentication or similar into your applications My pronouns are he and him and you can find me anywhere on the internet under the condo So if you're free to send me an email or a DM on Twitter So I want you to think about how do we modify and find code on a regular basis? Typically the way at least it works for me if I'm trying to find something in my project And I'm trying to batch fix it is the first thing I'm going to try is command or control F That works pretty well if you're trying to find like Want a variable once the moment you're trying to use it more often and you're trying to replace it in a bunch of files It gets it gets more tricky and you're starting to Try to fiddle around with settings and hoping that you're not modifying too much or too little and then your tests Hopefully will catch any things you might be breaking and so that can be incredibly frustrating especially if you have to do the same thing multiple times and so the way You might resort to solving that at least it personally is to go the route of writing a bash script or something similar That uses tools like grab or sad to fix things on a regular basis But that means you need to use regular expressions and similar things to kind of Duct tape things together and at least I don't feel that confident with regular expressions as much as I use them in the past There's always things where it was either too flexible or too strict and I kept fiddling around with it And it wasn't catching the right things and that means we're building tools that are unreliable and hard to maintain To deal with our code bases, and that's not a great feeling at least for me personally But that also gets me back to the tools that we use on a regular basis because all of these have something in common with Find and replace and that is they take some code Run some magic on it and produce some output And I want to talk to you about exactly that said magic and in order to talk to you about that magic We first need to talk about how the compiler works because effectively all of these tools use the same concept under the hood If you've never worked with a compile or never looked at how a compiler works under the hood That's okay. We'll still cover it step by step. So you should be able to keep up The first thing here is we have some input in this case for example new symbol one and The compiler will perform what is called a lexical analysis on that that means it will turn that Text into a set of tokens so a list of tokens Representing the different parts of the code that we have you can imagine this being the equivalent of taking a text written in English And then turning it into a list of words and punctuations and then the next step is to perform syntax analysis on this so that means we're taking the tokens that we already have and Creating some structure around them in the shape of an AST so an abstract syntax tree That represents how the program is actually structured so imagine this as if you're turning words and punctuation into Sentences representing as part of paragraphs and those sentences contain information of What what part is the subject? What part is a verb? You know and giving all of that detailed information rather than just having a list of words and punctuations And then you can perform actions on those ASTs But then the last step is co-generation so that means we're taking the AST and we're turning that into some output So this can be machine code. This can be another programming language But generally we're turning it into some sort of output So now that we talked about how those general steps work in In the grander scheme of things let's dive into each of these steps a bit more into detail So first step is lexical analysis. You might also hear about it as tokenization So that means we're taking some example code and I don't want to use the classic hello world here so instead I'm going to use a function called isPanda because I love pandas and It receives one argument in this case a string with a panda emoji in it And we want to turn this into tokens so you could build your own tokenizer But there's plenty of tokenizers especially for JavaScript that you can use in my case I'm going to use as Prima and I'm going to call tokenize on that and that will give us a list of tokens So that will look roughly like this I dropped a couple of pieces of information here to fit it on the slide like what are the line numbers and Things like that, but roughly this is what you would get four tokens one is an identifier is panda two punctuators an opening and a closing parenthesis and in between it is a string that has the string value of a panda now this information if you've ever written a Code editor theme or generally like a syntax highlighting theme You might be familiar with these words of identifier punctuator string because that's typically what is being used in real real practical examples such as syntax highlighting So most code editors use tokenization at some point to do some syntax highlighting Some do additional work on top of that for more advanced highlighting But under the hood at least the basic syntax highlighting is often done by tokenization The token formats might differ though. So for example VS code did some extra work to do very to do important and performance improvements on These syntax highlighting and tokenization part of things and if you want to read about that you can check out this blog post But once we have those tokens the next step would be to turn these tokens into an abstract syntax tree So that is the syntax parsing side of things So we take this list of tokens or list of objects and we turn them into a nested object that represents of a tree of our Program is structured so at the top we have a program and then that has a body which In this case only has one expression statement Which has a call expression in it that consists out of a call E Which is what is being called and a set of arguments in this case only one argument, which is a literal of a panda emoji The format that you've seen there is called es tree It's a spec that was derived of the ast format that Mozilla uses internally in their spider monkey engine But it has been Altered and extended from there. So if you're using tools like a spremar or a babel they use derivatives offset spec but with some additions that help them with their functionality and goals And also Facebook and others have extended this to add functionality like JSX and others into the language to give you some practical examples of why you would want to have an ast in the first place is To visit the different nodes to do things such as linting So if you're if you build a linter or use a linter such as ESLint, TSLint or JSHint You would want to do analysis often not just purely on the format of your code But you want more detailed rules that could for example be around How you name your classes and rather than having to look through an entire array to try to find the class Keywords somewhere and then see what's following instead. You could navigate a tree and look for class decorators class declarations and then See how they fit into the grander scheme so you can do much more advanced linting Another example that sort of fits into that sound same realm is code analysis. So for example, Angela Uses this to build a language service that you can use in your code editor to get better autocomplete The way they're doing that is by turning their HTML templates into ASTs and then being able to tell you based on where your cursor is and how your template is connected to your To your component what things are available and improve your autocomplete there Another example is bundling. So if you've used a bundler like webpack or parcel before those are using ASTs under the hood Because while bundling in the past might have been just concatenating JavaScript files these days in the world of Components and modules and things like that You need to understand how things fit together and you can do one on the one hand optimizations on this, but you can also better, you know fit things together without Adding them in the wrong order and things like that. And so that is exactly where ASTs come into place The nice thing though about ASTs is that they are not only helpful when you're traversing the code But they're also incredibly helpful for modifying themselves because if you've ever had to modify a Text or a list versus modifying an object you might know that it's easier to modify the object Especially if you have to take things out in the middle of a program in the middle of an object Versus taking things out of the middle of an array or the middle of a text So let's look at our AST again And in this case we can actually do an optimization here that would be a good use for modifying an AST So if we look at the expression statement, we have one expression in it. It's a call expression and it Really we can see that if you call isPanda and you give it the value of a Panda mode It will always be true so we can actually do an improvement here and Take out that expression and replace it with just a literal that has the value true in it and therefore Significantly shrinking our code and if you would do that same execution across your entire code base, you know You would eliminate a bunch of code So there is a bunch of practical examples But the one that might be most most familiar to you if you're writing JavaScript these days is Babel so Babel actually uses that concept in all of their transformations whether you're down transpiling or you're Using some of the additional plugins that people have built if you're not familiar with Babel it's a down transpiler that allows you to take code that you might have used in a Written in more modern JavaScript and transpile it to ES5 or ES3 compatible JavaScript or compatible to exactly the browsers that you're targeting But you can also do things like extending a language so as I said JSX does this where really we're just having a AST that has these JSX tags in it and then we modify it to turn those JSX tags Into function calls because that's really how JSX is implemented is All of these tags are being turned into function calls to things like react.createElement or Preact H function and then the third example is Language transpiling so that means we're taking a language such as TypeScript and We're removing all of the TypeScript specific syntax so we can turn it into some JavaScript code That we can then execute now obviously TypeScript does a bunch of other things as well But that's for example how the Babel transform for TypeScript works The one that I thought was really cool is code coverage if you've used code coverage in the past such as Istanbul for example you might have Wondered how it actually works under the hood how it plugs into things and the way it does it we can actually look under the hood and We can do that using the NYC CLI from Istanbul by calling NYC instrument giving it a giving it a file And then giving it an output directory and looking at the output So let's say we have a sumJS file that we want to unit test and want to see how good our test coverage is We have this function in it called sum that takes two parameters and adds it up and then we export that function Now if we run NYC instrument on this This is the code that we get out of it We have a variable declaration at the top that we'll look at in a second and then we have Three added counter incrementers added to it So we have two that end with s0 and s1 and one with f0 and those are function and statement counters And basically that means if we're running our unit test against this file instead We're able to actually tell How often functions have been called how often statements have been called because we can then look into that Object that is at the top and there's a coverage data object as part of this that contains all of these counters For each of those segments for each of these statements functions and branches And also it contains a statement map a function map and a branch map So that later we can look at what are the statements functions and branches that have zero counters and then Inform the user exactly which ones haven't been called in where they are Now if you want to learn more about the code coverage aspect There's a great blog post that I recommend recommend you to read that dives a bit more into that ast transformation Another example is running other languages and browsers. So I'm not talking about web assembly here But instead I'm talking about a pretty concrete example of code combat so I worked on code combat a couple of years ago as a Google summer of code and One thing they do is they aim at teaching kids how to code using different programming languages such as Python or JavaScript or coffee script or Lua and They don't they execute all of the code inside the browser But they're doing that without shipping a an entire Python runtime or an entire coffee script runtime Instead they use a tool called Esper that they built that takes some Python code for example on the left and converts that into an ast that looks similar to the JavaScript one and Then modify that that ast to fix function calls that might be different in JavaScript so for example, we have a Print function call here, which the equivalent will be console logs on the right side in the ast you can actually see there's a call expression to console log and and It also gives you some additional information so that they can do frame execution and kind of like Steps through things without having to teach kids how a debugger works But all of that is powered by ast and that's super powerful. It's not perform it necessarily You're not you wouldn't want to do this to execute production code in the browser But I still think it's a very cool application Once you've modified your ast the last step is rendering your ast So that means we're turning it into output So we have for example our optimized ast here now and we want to turn that into some code So we'll use a library such as ES code gen that knows how to turn an ast into some code and Then we just get the statement true because that's how we optimized it There's some really practical examples that I personally love using one of them is called prettier If you haven't used prettier it's a code formatting tool if you've used prettier You might have been as excited about as I am and the reason why it works so well is Because it takes your code converts it into an ast and then reprints it based on its own instructions Which means that it doesn't really care in which way you wrote your initial code or it doesn't screw Up your code by writing it in the wrong way Doesn't just randomly insert new lines instead it fully understand your code and just prints it based on the rules you gave it and so that's really cool and Minification works in a very similar way like it's just taking an ast and they might do some modifications on the ast to change Variable names or similar things But then it just prints it out into a minified way Rather than just removing white spaces because that could cause trouble in some situations But let's say you're not planning to build the next web pack or be able or similar why would you care about this? One of the good examples that I think we cannot we might all be able to leverage or be able to transform plugins You don't necessarily have to build one for a new cutting edge feature Those can be useful for just improving your own day-to-day developer experience Without having to use grab or said and without having to use regular expressions or at least less regular expressions A good similar example is what react it react has a project called rec code mod That is powered by another tool that Facebook built called just code shift which works similar to Babel in terms of like building transform plugins but they have an entire library of different scripts that you can run to Update your code based for the latest react APIs and similar things And so that is super useful because if you feel like you're doing something on a regular basis Or you want to have certain macros as part of your code base, you know as your code base is growing These tools can be hugely useful for you Um, and so I figured rather than talking More about this we would actually build a plugin together So this is a website called ast explorer that I personally love using to understand how ast's work and play around with them So let's clean up some things here. Um, the top left corner is Where we put our input code the bottom right corner is where our output code is the top right is Where we see the ast and then on the bottom left, we can change or build our transform plugin We chose here already the baby babylon 7 Parcer that's the one that Babel uses and then we have Babel v7 Here as the transform you can for example choose JS code shift here and so If you're a JavaScript developer like me chances are high you use console log to You know debug your things but I was thinking the other day of like the console log is sort of like the general debugging Way, then I would say breakpoints is probably alerting so let's Use this alert statement here. Sorry for that And What we want to do is we want to make sure we're not actually shipping any Alert statements to our customers because why they might be useful for us during development We definitely don't want them to break the experience for customers So we're gonna build a Babel plugin that will remove or change all alert statements to console errors So we don't have to worry about them and they just pop up in the logs The way we do this is by defining a visitor here so visitors are Different functions based on different types of notes that Babel might encounter so that we can tell it What to do during those so we actually click on alert here? We can see it's an identifier But it's wrapped in a call expression and this call expression is really what we're interested in and so we're gonna create a visitor here called call expression and It's a function that receives a path every time it was encountered. That's what we get And so the first thing we want to do here is let's just rename Name this so path that node and then if we go here the callee is what we want to change So we're gonna create a new identifier here. I'm just gonna call this console error and Now we can see on the right here that we have console error Apply to both of these not just cons not just to alert and that means we need to first filter What we're actually doing so I'm gonna actually filter for I'm gonna do sort of like what is called an early exit. So I'm gonna check if We have an identifier as Part of the callee and has a name of alert And because I said we're gonna do an early exit. I actually want to return if this is not the case So if we don't have an identifier with the alert statement I forgot a closing parentheses is here Then we want to change it to console error. So now you can see console log state, but console error didn't Alert didn't say change it to console error And this works even if we have this insider function, for example, so if we do alert here We can see it's still adjusting that so that's great But and similarly, you know, if we would break this up over multiple lines, this is still working We didn't have to work around, you know any formatting things like you would have to when you write a regular expression, for example Now the problem though comes when we do things such as For example redefining a local function here that Just throws an error for example, or let's do return alert So this this is just a local function that we defined meaning that this alert here is actually actually Right, like we want to keep this and not replace this with console error So the cool thing with tools like Babel and others that are ast part is we have much more understanding of the code This will be really hard to do with just regular expressions and token tokenization, for example, but In the case of Babel we have access to the scope and that means we can check for bindings Which means is there a binding for the word alert? Here and if there is we just want to return so that means The alert inside this run function is never actually changed while the global one is still being changed We can take this one step further I don't like the fact that you know, we still have an alert here and that could cause some confusion In the output. So what we're going to do is we actually going to Rename inside the scope We're going to rename alert And what this is going to do is it's going to change alert to a unique name In this case, that still is as close to alert as possible. So it starts by putting an underscore there but if we would for example define a Variable here now called alert underscore alert It would change it to alert two and then similarly if we would have another one here alert two It would change it to alert three and similar It will always try to avoid a clash in the in the respective scope in which we rename this so that's super useful because We don't have to worry about creating clashing variable names as we're changing our code here Similarly, you know, we can for example modify the code entirely if we see the global ones and we just remove the node There's a lot of different things you can do you can insert other things you can modify Things based on various different rules if you want to learn all of the different things you can do with it I would recommend you to check out the Babel plug-in handbook because as much as it hasn't been edited for a while There's a lot of really useful Information in there in terms of what you can do how you can replace, you know one node with multiple nodes how you can Replace it with a source string if you don't want to build an entire Entire tree just by using additional nodes and generating those So there's a lot of things you can do and I recommend you to check out that handbook if you're interested in Exploring more things you can do with it All right, let's get back into the slides to wrap things up So in summary, there's a few things I want you to take away one you already use tokens and ASTs daily They're in all of the tools basically that make your life easier Tokens represent format, you know, they're representing how your code is written and ASTs represent the structure They don't care if you used curly braces around your if statement or if you used to wrote it in one line That also makes ASTs easier to manipulate because you do not have to worry about what parts are code syntax and what parts are actual statements and it makes it safer for cold alterations because you can just take out a node and Put a new node in rather than having to see if you're removing the right amount of elements from an array or Removing the right parts of a string Yes tree is there for interoperability. So a lot of different tools use yes tree as the foundation of their AST And that means you don't have to reinvent the wheel There's a lot of tools to create ASTs a lot of tools to walk ASTs and a lot of tools to render ASTs and you can use all of these different tools to build either your own Tools that you might share with the community or just internal things that are going to be useful for you as you're building your apps Because that means you can replace things like grab or said when you're modifying your code If you want to learn more about ASTs I would recommend you to check out the AST Explorer and just play around with it You know put some code in try to figure out what you're trying to change Click on things because it will highlight the different parts of the AST Play around with different parsers and see what kind of information they give you. There's a lot of fun things to do And then read the Babel plug-in handbook Even if you're not planning to build your own Babel plug-in if you want to learn more about ASTs. It's a it's a great thing to to read The nice thing is also all of the things I showed you are open source Which means that now that you know what ASTs are you can look for them in the different tools that you're using or Different code bases to see what's actually happening under the hood I also wrote a blog post about this topic if you want to rather read up on this In in the shape of a blog post it covers a lot of the same things that I covered in this talk But if you prefer reading it, that's a good format And with that if you want to check out the slides I uploaded them on the on this URL at the left and I'll also tweet about them later if you have any questions feel free to reach out to me as I said You can reach me anywhere on the internet at the Kundal So feel free to send me an email or send me a DM on Twitter with that I'd like to thank you all for your attention and have a great day


Okay, so I was sitting at my desk and this came across to me and I wanted to share with you guys and see if you are just as confused or dumbfounded as I am. Now the person that makes this statement has complained in the past that people use his name, his phase, for clicks, views and so forth. So I'm not going to use his name, I'm going to cover his face up, I'm going to distort his voice, but I want you just to pay attention to what he says because to me this makes absolutely no sense whatsoever. See if you see or hear anything that causes alarm to you. Sometimes you call out a demon by name, right? So not necessarily like just lust or the things that we would think in our natural mind, but there's like demonic names in the spiritual realm. Can you kind of unpack that a little bit? Now this person whom this lady is interviewing, you don't know who this guy is, clearly this person has been disguised perfectly. There's no way you could know who this person is, but they're asking when you do cast demons out, why do you do so by name? Do you have to do so by name? Now we believe those of us who actually read the read our scriptures. Now what could be wrong could be wrong. And we've asked for proof, biblical proof, scriptures where a Christian has a demon or has been demonized or whatever the fervorage you want to use give us proof. But the question is, why do you have to call them out by name? Yeah. So demons are personalities. So when the demon says its name, it's not like where we're born and we're the only one that's like a name. But it would be like anger is it's the personality of the spirit. I want to make it through this pretty timely. But when you say that demons are their personality, I'm going to need some scriptures for that. I think I understand what you're trying to get to, that they are what they really are. They bring about this particular personality of this. I get that, but we don't have any scriptures for that. I would love to see I would love to see one, though. I really would. So Jezebel, anger, bitterness, resentment, murder, these are the personalities of the demons. So Ephesians six says we battle not against flesh and blood and the Greek translation is, but we battle persons without bodies. OK, there's my first issue. One of my first issues I shouldn't have. I guess I got a bunch of first issues, which didn't make sense to have a first issue. But it's one of my big issues. He says the Greek translation is persons without bodies. It could be. It could be. I've never heard of that. It'd be a new one by me. Well, the way we find out is let's just go to simply look at the scriptures and let's see Ephesians six twelve's. Ephesians six twelve says for our struggle is not against flesh and blood or we wrestle not against flesh and blood, but against rulers against the powers against the world forces of this darkness against spiritual forces of wickedness in heavenly places. Now, one more time, let's listen to what he says. I want to make sure I'm investigating the right word. So Ephesians six says we battle not against flesh and blood and the Greek translation is, but we battle persons without bodies. So he says we battle persons without bodies. Let's go see. He says for for we wrestle not against flesh and blood. OK, so the word the Greek word that's over here for flesh and blood, which is like you would say it, haima, which is blood and flesh. Sarka, which is flesh, so obviously against people. We're not a battling against them, but against rulers. And so this is our castes, which is rulers against powers, exuces, OK, so far so good. But I'm not seeing what he's saying. Also against the world forces or world rulers. OK, so so far, not seeing what he says. And then also against darkness. No, I'm sorry, of this darkness, of this dark world and then also against spiritual forces. Numitika, Tain, Pune, Pune, yes, Pune, yes. So this these are evil spirits or spiritual forces of wickedness in high places. Now, maybe I missed what he said. Let me just hear what he said again, because I may have gotten I may not have heard correctly. Ephesians six says we battle not against flesh and blood and the Greek translation is, but we battle persons without bodies. OK, so persons without bodies. That's not in the scriptures. That's not in the scriptures. So we're battling persons or personalities without bodies. That is not biblical. Why he why he used the Greek or why he brought up the Greek or invoke the Greek. The Greek he says means persons without bodies. No, it does not. And there's a problem. If you want to twist the scriptures to make that statement, you have to do so intentionally. Or maybe ignorantly, someone told you that and you ran with it. But you should know better. That's not in the scriptures. So strike one on that part. Let's keep going. So these are personalities that come and live inside of people, according to Matthew 12, and then a lot of people don't realize that their personality becomes like that spirit. And again, according to Matthew 12, that is not what it says. But so I don't belabor the point. Let's just let's keep moving. So some people might say, well, how could there be a spirit of murder in you and a spirit of murder in me if there's only one spirit of murder? But it's not. It's the demon naming its function. So when a demon gives you its name, it's its function. So Jesus, the man of the tombs, the legion was the demons name. Or Jesus, like the Bible says, he's not giving us a spirit of fear, but of power, love and sound mind. So fear is a spirit that God hasn't given us. And that spirit causes us to be fearful, intimidated, timid. No, he's saying we don't have that. That is not our spirit.  So you don't know who this person is, but people like him, they'll take this passage and say the opposite of what is actually saying. He says that God did not give us a spirit of fear, this adjective, this fear describing the spirit. God didn't give us that. So he takes it as though we do have it or some do have it, but it was given to them, not by God, but by the devil or by a demon. That's not what this passage says. This is clear. I suggest you read into the passage. What he did say was he gave us the ability. He gave us one spirit of or he gave us power or the ability. He gave us love. He gave us discipline. Now, are we saying that those are also a spirit that there's a spirit of love, a spirit of power, a spirit of a sound mind? So are there angels or demons that also have that same personality according to the way he speaks? Or are these just things that God has given us as believers, the spirit in the spirit that we have these things? These are, for example, love. That's a byproduct of the spirit. That's a fruit of the spirit. So to his discipline or sound mind or the way we see another passage, put self control, sober mindedness, those are fruits of the spirit. When you have the spirit in you, these are what you have not fear. Now, I don't want to make that point because he's getting ready to say something that just makes me scratch my head and say, huh, and I'm wondering, am I the only one getting this? Did I miss something? Am I misunderstanding something? So oftentimes when we do deliverance, you want to call them out by name because they respond to their name. It's like a dog. You could yell at a dog, but you have authority over it when you know the dog's name. So that's why I say it's a lot better if you call the demon out by name because it'll get a response out of it.  We don't have to come out. So we like to be specific and calling them out by name. So this is the part that just made me scratch my head. I mean, am I the only one not getting this? So you're going to call the specific demon out by name, how you know the specific demon's name. I guess the demon has to cooperate and tell you every time, even though we only have one example of that happiness. Jesus asking, asking Legion and Legion space, we're saying there's a bunch of us, but I'll leave that alone. But the absolutely astonishing statement was that we'll call that demon out because if we just call them out in general, what are we saying that all of them want to come out? Why wouldn't you call if you do assume you do have the ability to cast out demons and call all of them out? Why wouldn't you just call out every last demon?  According to how you guys believe, why not just do that? Why not make one deliverance once and for all? Do like, I guess, how we believe that Jesus did for us, you know, whom the sun sets free is free indeed, thoroughly, continuously, according to the word that's used there in the Greek, Antos, which is referring to this. Why not do it the way that Jesus did for us? Why don't you do the same thing? Why not call them all out at the same time? Am I missing something here? Is it just me or did I just hear him say, we'll just call up a one individually, maybe two individually, but otherwise they'll all come out. Anyway, you guys tell me what you think. I was a bit confused, and so maybe you guys can help me out.


Want to start the the vlog today with a special mention to Carol in her family in Houston Carol is a fan of the vlog and a viewer and a Subscriber but more importantly I would just say like a friend even though we don't know each other Carol And I don't know your family, but I feel like we're we're connected here on YouTube and other places And so it just thoughts and prayers go out to everyone at Houston, especially Carol I just hoping that you know everything's okay. It's like you feel kind of helpless Because you can't help But you know we can at least send our send our thoughts and prayers and support to the people of the greater Houston area So I just went to the gas station to load up on gas and really top it off Nice because gas prices are probably gonna go up because there's so much oil refinery Refining refinery happening in Houston area.  So all right on we're to Yes, I am buying baby food Not for the boys for moi for this adventure. It's gonna help to eat baby food along the way. So I'm just trying to find the right flavors that will feel good to the stomach After some mileage And some vertical Do you have any recommendations what flavors might feel good on the gut? I'm looking at the Green beans and peas definitely not Kiwi and kale that looks pretty good. I want protein protein Not just sugar protein Oh my my Weeks ago on day night. We I ran Dan Taylor loft and got their $25 sunglasses 50% off and then they broke in my purse. It wasn't even like a kid broke them.  I know thriftiness Talbot's For a pair of black flats close toad That's good quality and I just cannot find them and I always try and wait for the sales to get the good deal And then my size is always gone. So Today I went into Talbot's to pay almost full price.  But when I was there There was 70% off their markdown So they already had stuff on sale and then whatever price was written in red You got 70% off of that and that's just genius and I'm sure many of you have already thought of this But I bought stuff for next summer to wear and at a fraction for I saved hundreds and hundreds I mean, I think I saved $800 today not that I would ever pay for price for all that but It was pretty amazing and I felt victorious and this was one of them and these shoes which we'll show you when we're walking because they're to die for and Actually another pair of shoes. It was amazing. The shoes were like $24 each for good quality Talbot shoes. So I'm pretty Success And now we're going to PF Changs. Remember we went there with Kate great. Well because we were smart we bought Gift certificates or coupon whatever you want to put it from Costco. We're winning basically we they get the universe gave us $40 just for being smart They just said here you go. Here's $40. Just do have that. We have that. Okay. There's actually 50 on this I did 10 in cash last time though Actually basically They're looking real good here If James was amazing big hit never ever Disappoints and the one of those fortune cookie said your optimism will lead to great success So I'm not going to tell you yet what I'm doing, but I will tell you the day it's starting Saturday Probably or two to four a.m. Ish is the start window. So getting this a good sign. It's a good sign Very good sign and and you have 500 subscribers. Oh, yeah Love you all moment and to answer Dave's question. How can Dave asked a great question? How could I help? God bless you Dave. What did you say? Come to my house and help me fold laundry. Dave if you want to help the vlog Listen, get on a plane. Get on a plane. Bring your true love. Let's do this. Cindy, I believe. You can put the boys to bed Boy, I cannot get a grip on my laundry. No Dave. I'll give you a we'll give you a real answer soon Dave thinking of us that was so generous and thoughtful to say what can I do to help that was You're a good man. So Let's just say after this event that is going to take place on Saturday and Sunday epicness epicness I'll have a little better grip on everything. We're just kind of leaning on this fortune cookie We're leaning in leaning in leaning into the positivity. We close out the vlog. I've done. Yeah Put a fork in me. I'm done. See beauty. Work hard and love each other See you tomorrow Perfect. I know after driving your car today, you know it's hard


Opponents of Enbridge Energy's proposed Line 3 replacement pipeline are focusing on fighting the project in new ways. This comes after a Minnesota regulatory panel took one of its final steps in approving the project. The Public Utilities Commission unanimously rejected petitions by environmental and tribal groups that asked the panel to reconsider its June Route approval. Executive Director of Honor of the Earth, Winona LaDuke, issued a statement saying in part, now would be the time to have vision at the PUC, a clear understanding of intergenerational liability and courage, now would be the time to ensure the PUC promotes infrastructure for the future. Enbridge also released a statement saying in part, we are pleased commissioners voted unanimously to reform their approval of the project's route permit and allow the major energy infrastructure project to move forward. Enbridge adds that they have also reached an agreement with the Leech Lake Band of Ojibwe regarding the scope and process for removal of the existing Line 3 pipeline. If you enjoyed this segment of Lakeland News, please consider making a tax-deductible contribution to Lakeland PBS.


Let's quickly recap the main ideas from section 2.6 of active calculus on derivatives of inverse functions. Our main goals for this section are to find derivative rules for some important functions that are the inverses or computational opposites of other important functions. Those functions are the natural logarithm function, that's the inverse of the function y equals e to the x, and the arc sine function, which is the inverse of the sine function. We'll state those two rules in a minute, but remember in calculus the process is just as important as the results. So not only the rules themselves, but the method by which we get them is important. So let's focus on that first. To get the derivative of y equals the natural logarithm of x, we use the fact that the natural logarithm is the inverse function for y equals e to the x. That means that if y is equal to ln of x, then e to the y is equal to x. This is actually the definition of the natural logarithm, and this dual relationship between the exponential and logarithmic function is essential for working with either one. Anyway, since e to the y equals x, we can differentiate both sides with respect to x to get y prime times e to the y equals one, and so solving we get y prime equals one over e to the y, and e to the y is equal to x. Therefore, for any positive number x, the derivative of natural logarithm of x is one over x. Now we don't have to re-derive this result every time we want to use it. We just use the result. But study and master this process of getting the rule, because that process can be applied to generate new derivative rules if we need them. For example, we can apply the same process to find the derivative of y equals arc sine of x. When we write y equals arc sine of x, what we mean is that x is the angle whose sine is y, that is sine of y equals x. Differentiating both sides with respect to x here gives us y prime times cosine y equals one, and so y prime is equal to one over cosine of y. Now the fundamental trigonometric identity says that sine squared y plus cosine squared y equals one. So therefore, if sine of y equals x, then sine squared of y equals x squared. And so solving for cosine y, we get cosine y equals the square root of one minus x squared. That allows us to simplify the derivative to y prime equals one over the square root of one minus x squared, and that's the derivative of arc sine of x. Again, the process is at least as important as the result here. To get this derivative formula, we wrote out what we wanted to differentiate, we then used the definition of an inverse function to rewrite that. Then we took a derivative using the chain rule and then simplified the result. This is a general derivation technique that will work with any inverse function. In fact, one general result we have from the section is that if f is differentiable with an inverse function called g, then for any x in the domain of g prime of x, we have that g prime of x is one over f prime of g of x. Again, we don't need to re-derive these derivative rules whenever we need to use them. We just use the results. But the process is important for generating new derivative rules, as you will do in your activities when you develop derivative formulas for the arc tangent function.


The presidential candidate of the new Nigerian People's Party NNPP in the 2023 election, Rabi Kwan-Kwasew has lent his voice to the court for a further and transparent investigation into the accidental military airstrike in Kaduna state. He urged the federal government to ensure that the Wissom's military era banning does not go the way of previous incidents with no action taken to avert a recurrence. Kwan-Kwasew has appeared to the government in warm meaning Nigerians to support the victims, most of whom lost their breadwinners in the mishap. The record that schools were injured and 85 people died during the airstrike in the Tundunbury village of Igabiloko government area of Kaduna state. As long as governments and all other stakeholders allow this to continue to happen, probably God knows the next victim. It could be you, it could be me, it could be any other person. That is why I very much support the issue of thorough investigation and of course punish all those who are found wanting in this particular situation. And I believe that a government and all of us should keep our eyes and be our brothers and sisters keep us.  And it could happen to anybody, anywhere in this country. And I'm happy that I came, I saw them, I was moved, I was shocked by what I have seen, especially the children, the women and the old who are affected.


Vital Biosafety Practices Working with biological agents comes with certain risks. You can minimize the risks at our university by following these safety practices. First, you should know that, besides your supervisor, there is a biosafety officer in your department. Before any activity with a biological agent, you must contact them for a risk assessment and authorization. Some activities must also be reported to or authorized by the Federal Coordination Center for Biotechnology. Biological agents can consist of or be contained in organisms such as viruses, parasites, fungi and bacteria, genetically modified organisms, clinical material of human or animal origin and more. Some of these represent a potential biohazard to humans, animals and the environment. Organisms are assigned to one of four risk groups based on their characteristics. A risk assessment of activities with these organisms determines the biosafety level for the laboratory. Biosafety level 4 requires the highest containment standards and safety measures. When working with biological agents, you must follow these specific laboratory biosafety measures to prevent both accidental exposure and the release of organisms. The safety measures are governed by four principles. The first is substitution. Whenever possible, replace the biohazard with a safer alternative. The other principles concern technical arrangements, organizational practices and instructions and personal protective equipment. Of course, all of this must be backed up by good microbiological practices. Store biological agents in leak-proof containers or vials and in designated fridges or refrigerators. The containers must always be labeled with the name, the nature and the acquisition date of the agent, as well as the name of the person responsible. Organisms in risk group 2 or higher must be stored in a laboratory of biosafety level 2 or higher. Unlabeled containers must not be used and must be reported immediately to the biosafety officer. Always keep containers closed, except for immediate use. Refrigerators and freezers containing biohazards must either be locked or located in a restricted area with controlled access. Keep records of the stock, check it regularly and dispose of unneeded materials. When biological agents need to be transported, only trained personnel are allowed to do so. For transport inside the building, secure the properly labeled container in double packaging. For transport from building to building, use a robust and leak-proof container as a third layer of outer packaging. For national and international shipping, consult the dangerous goods safety advisor from the risk management department. Biological waste should be avoided or kept to a minimum. If biological waste is generated, it must be inactivated by autoclaving or validated chemical inactivation procedures. Depending on the biosafety level, it can be mandatory to have an autoclave in the building or laboratory. Check the inactivation efficiency of the autoclave regularly. When autoclaving, use autoclaveable bags. For sharp objects, use the autoclaveable sharp-proof containers. After inactivation, remove or cross out any biohazard symbol. For disposal, separate liquids from solids and ensure safe and cool intermediate storage. For this purpose, use the original UN-approved disposal containers provided by the university. Label the biological waste and follow the university's disposal guidelines. Use personal protective equipment as determined by the risk assessment of your activities. Contact your supervisor for instructions concerning what equipment you need and how to properly wear it. If you notice damaged material or infrastructure, or if there is an incident, report it to your supervisor and biosafety officer. We want to protect your health and the environment. We're here to make your workplace safer.


Troy I know when you worked out out in California there were upwards of 15 or 16 teams who are interested in you What made the Yankees such an appealing fit for you? For numerous reasons I think obviously I'm a guy that appreciates baseball history and you know, you don't have to You know look very far to see what a great franchise it's been and all the great things they've accomplished and how much they've won So that was definitely intriguing You know obviously Derek Tudor was my favorite player, so I definitely had something to do with it So there was multiple, you know Boxes that I wanted to check for the next team that was gonna You know that I was gonna play for and I would say the Yankees check most of them and If not all of them, so I'm excited to be in Yankee and looking forward to this year I know one of the boxes they also checked was the ability for you to play shortstop But I want to go back to something you said about cheater We know you've worn number two throughout your career. What was it about cheater that you as a young player? Enjoyed or looks to that made you want to wear the same number You know, I think I had Derek I think a winning he's known as a winner More than that just being a professional on off the field. I've got to know him a little bit Even since you know, I was playing against him when I was a little bit younger The respect that he had for the game and and the opponents and going the extra mile to Just handle his way handle himself and You know the most professional way that I that I've seen any player His presence, you know, I can go on and on but uh, You know talk about just a stud in every way


Thank you all right, so am I oh, yeah, look at that whoa So I'm gonna just talk through my perspective as the I'm one of the PIs of the Coordinating Center and So I'm just gonna walk through the questions kind of one by one So I think we should catalog and evaluate the existing training across the UDN this has not been a primary focus of ours here to four and Then we can identify what would be best pursued at the network level at a very in-depth conversation Thanks to David Adams bringing me up to speed on the many activities at the UDP and I think those do deserve An intentional assessment And we should identify gaps in the in the current training So our current training is is focused on you know on clinicians primarily on researchers But we may need to educate a broader range of people if we're to disseminate this model which I think many of us represents of the future of medicine for instance hospital administrators and Just an article came out recently About basic science researchers not knowing how to speak to patients and and preparing them to have those interactions Which will certainly increase over time So currently we have the UDP has nine distinct training activities fellowships genome school clinical rounds Several other sites also have training components, and we are planning to create CME CME courses So as I said previously we should review what we're doing and see what works and what doesn't as David Adams pointed out We need to have data sets and materials that can be used for training so that we have we have material to work on to to to educate people and And David also pointed out that we should not underestimate the power of direct outreach like site visits So either people coming in or us going out in order to disseminate what what good the UD UDN brings So this is just a quote from the two mats Matt might is is our patient and family advisor at the coordinating center He's urging us to collaborate and share share everywhere share early share often And so this is something that really does drive us We should certainly continue to share data with DB gap and and we will And as mentioned before we share with phenome central which is based out of out of Toronto and the sick kids hospital and Brings us into matchmaker exchange, and we certainly should continue to do that because that's where we're going to find matching cases second cases third cases Finally something that I think we need to do more of is share more information via the internet and Matt might has been Instrumental in emphasizing the importance of this when I talked to him about where we need to share data You know we went through DB gap phenome central and he said well, how about Wikipedia? That's where a lot of people get their information So I think we should intentionally do this more often So we share data with a variety of sources and we have just started a patient web pages project Where an unsolved case or a case with a rare diagnosis where they're looking to find a community We create a web page to search engine optimization and help them find find their community And Matt might has had great success with that And so we're we're drawing upon his expertise to do that and we have a number of patients who are interested So We need to have expanded curation because we're not just talking about data sharing We want to share high quality data and as Bill mentioned the the cataloging of human phenotype ontology terms and phenotypes is is no small undertaking and it's not typical Clinical care, so that's something I think where we need to Continue to be the vigilant and expand our ability to be vigilant and we should Make sharing with the internet part of our our practice Collaboration all right, so we see the value certainly of partnering with with other Undiagnosed diseases clinics around the country and a lot of that I think has been happening through the UDN International oddly enough where we come together and speak But we should integrate some of that into our into our you know business as usual at the UDN And I don't think we've done that here before So we should proactively build collaborations with extra UDN researchers as Many have mentioned there's a huge network of researchers out there and finding them is tough for patients It's tough for us too, but we need to devote Time and energy to find these to find these researchers to pair them with patients such as the Transition after their UDN visit is fruitful and generates the kind of scientific knowledge that that this network promises to do And there are all these projects across also funded by NIH that that may be relevant to us and Thank you. Thank you John and up until this point. We haven't actively been working together I think you know as a UDN it's fair to say we've been focused on getting up and running And I think now is a time for us to look outward and build bridges such that we can reduce the redundancy and and learn Learn from these other projects and potentially work on cases together So and as I alluded to before the collaborations aren't just Biomedical and as a number of people have said there's the research clinical distinction, which is a sort of an ethical Question implications for payers implications for how you run your clinics and and those kind of collaborations would be would be helpful to have to so We're currently participating in UDN international and we're accepting applications for international collaborative clinical sites You can find the application on our website Our 21s and supplements are being given out to explore gene function. They're sort of impromptu Collaborations focused on specific UDN cases. I know this guy who's good at this I think I'll match his patient up with that person and that's of course expanded with a network and the UDN is being studied by Sociologists based at UCLA. So yes, they they observe our our activities and we'll come back to us someday telling us what we're like so Should we be more international it makes sense to have a forum to share these practices and and most of all I think to encourage data-sharing at a global level and what level of support should they have should collaborations have I think they should have more support than they do now because as in talking to David Adams They do take a lot of effort to maintain these collaborations outside of the UDN and make sure that the information comes back into the UDN And so with that I'll thank the members of the UDN David Adams the people who created this slide template and you for listening


He's very tech savvy now here. Here's what I will say, you know, I was asked about this earlier I was more, you know, kind of like a like a googly-eyed schoolgirl saying how Appreciate if I was that he would even take the time to even think about me and you know It's really very you know it our interaction has been very limited But the way that he's treated me has been really cool, but his techs game is nice


The key moments to rewire your brain are during those reactions and look when we first start to do this it's not going to feel natural it's not going to feel believable but the trick is to continue to do it over and over and over again and create repetition out of it and then eventually you have less resistance to that thought you start to believe it more it starts to feel more natural and as you get more used to that you'll have less intruding thoughts so you'll have less thoughts too correct and eventually you won't feel that trigger you won't feel that fear anymore because you've trained your brain your conscious mind and your subconscious mind not to have that fear anymore which is why we have all these opposing thoughts anyway