When a batter steps up to the plate front at bat one of two things can happen He will hit the ball or he will not hit the ball If he does hit the ball it will lead to something like a ground out a flyout or a base hit If he does not hit the ball that means he's been walked hit by the pitch or struck out something like that We know that the best pitchers the Roy Halladays and Randy Johnson's of the world strike out a lot of hitters and Do not walk a lot of hitters Weaker pitchers do just the opposite the Mike Mollers and Tyler greens of the world Sorry guys walk as many guys as they strike out But when the ball is hit Conventional thinking will tell you that if the ball was thrown by Randy Johnson It is less likely to result in a base hit and if it was thrown by Tyler green good Pitchers are better than weak pitchers regardless of whether the ball is hit or not, but is that actually true? Let's look at what the numbers have to say about our question If a batter is to hit a ball thrown by Randy Johnson Is it more likely to be an out than when that batter hits a ball thrown by Tyler green? Common stats like batting average use all at bats regardless of the outcome We need to only consider a part of the at bats the ones in which balls are hit into play and Luckily the stat exists for that called batting average on balls in play Or Babip for short Because fielder's have no opportunity to turn them into outs home runs are not considered balls hit into play when it comes to Babip Our hypothesis based on what is basically common knowledge over the past hundred years is that hitters who face Johnson would have a much lower Babip than those who faced green Thanks to a site called fan graphs which tracks every pitchers Babip for every season We can test this out pretty easily in 1995 Johnson pitched 214 innings he led the league with a 2.4a e r a and he won the Cy Young award the hitters who he faced had a Babip of 301 In other words 30% of the guys who hit a pitch that Johnson threw reach base safely The other 70% of balls that were hit into play resulted in outs That same season green through 140 innings and had an e r a of 5.31 which was good for a 19th best on the Phillies The hitters who he faced had a Babip of 313 That means 31% of the eyes who hit a ball thrown by green reach base safely Green's Babip differs by just 12 guys out of a thousand so his Babip is virtually the same as Johnson's Obviously, that's a fluke right? I just picked two seasons that I knew would work Okay, let's try it again in 1998 Johnson split time between the Mariners and the Diamondbacks But his season-long e r a 3.28 would have been in the top 10 of either league Hitters who faced Johnson in 1998 had a Babip of 320 Green's 1998 era was not fantastic at 5.03 This was the last season the green pitched in the major leagues But hitters who faced green in 1998 had a Babip of 254 almost 7% lower than Johnson's You're welcome to look at the numbers yourself, but this example is not a fluke Regardless of whether they are a quote-unquote good or poor pitcher the typical pitcher Babip over their career is Between 290 300 as we have seen with green and Johnson most seasons fall outside that range And there's little relation from one season to the next over a career though things tend to average out Take Johnson's career for example, which lasted over 20 years. He had seasons where his Babip range from 247 1990 all the way up to 348 in 2003 That might make it sound like his Babip increased over his career But the season after his highest season Babip in 2003 the following summer it fell back down to 264 which is the second lowest of his career Johnson's career Babip ended up at 291 Meanwhile green pitched for just four seasons in the 90s and his career Babip came out to 289 virtually identical to Johnson's Since this was first discovered by a guy named vorus McCracken in the late 90s People have been just as surprised as you probably are right now And as I was when I first learned it and many people have been trying to disprove it ever since And while it has not been disproven numerous studies have shown that pitchers do have some effect on balls and play I'll be at less control than what we had thought with our original hypothesis Numerous factors play a role on whether or not a ball hit into play will fall in for a hit The quality of the fielder is the size of the park remember home runs don't count as balls in play and the pitcher Groundball pitchers do tend to have lower Babips The biggest factor though, which tends to be frustrating for a lot of people appears to be luck Sometimes a batter will hit a line dry absolutely drill the ball Right into the glove of the shortstop Other times the shortstop is two feet to the left and the ball flies into the gap for a double The difference between those two scenarios is basically luck possibly. It's good positioning by the shortstop, but But from a batter's perspective, it's basically luck Now if you or I were to walk out onto the mound during a major league game and start a lobbying the ball in there We would probably have a higher Babbit than 300 But perhaps it's not as high as we would assume think about the home run derby If you were to put a normal defense behind the home run derby pitcher Who's throwing the ball exactly where the batter wants it? The batter would have a very good batting average for sure, but he would still be put out plenty of times So the next time your favorite pitcher gives up 10 hits in a game. Remember, he's probably not bad or likely He's just having an unlucky day


What is the hottest new small molecule in RCC? And we have asked Emilio Calvo from IDIT to answer this question. Please. Thank you very much, John. Yes, in the next 15 minutes, I will be talking on this topic what is the potentially best new molecule in kidney cancer. I will be talking not only on small molecules, but also on monoclonal antibodies. And I will be excluding on purpose the targeted team of therapeutic agents because this has been already reviewed yesterday by McDermott. So as you know, we have currently therapeutic agents that target multiple alternative pathways that are involved in kidney cancer. And these are currently under investigation. And this is because in spite of the fact that all the drugs are ideal for all the patients according to our prior colleagues, the approved treatments are not curative. The median overall survival remains optimal. And the patients, at the end of the day, progress of the disease. Also, drug resistance is a major challenge for the available agents that are BGF-targeted drugs or end-to-end inhibitors. And in addition, we have a lot of off-target effects that can occur with the BGF-targeted therapies and make it difficult for the patients to have these drugs because of clinically relevant toxicities. So the way that we are developing the novel agents in kidney cancers can be grouped in two different approaches. On one hand, we have the potential of trying to develop more selective BGF-RTKIs mid-to-drugs, trying to get less toxic agents and potentially more active. And here we have the paradigm of the BGF-RTK that have not been approved. But it is interesting to comment on that to explore that concept. And then we have drugs that are approaching or targeting different targets in the search of more activity. And the targets that are being more intensively exploring kidney cancer are CMET, Type 2, ALK-1, end-to-end inhibitors, and PI-3K-AKT end-to-end inhibitors. And for my talk, I will be grouping this into two different groups. The novel pure anti-angiogenic agents like the ones that are here on red, T-Bosani, again, just to explore the mid-to-BFRTKI failure paradigm, the CMET inhibitors, like Kavosantinib or Furetinib, then the Type 2 inhibitor regrafinib, and also the ALK-1 end-to-end inhibitor. And then I will talk also on the other group of agents that are novel PI-3K-AKT end-to-end inhibitors. So let's get started with the T-Bosani paradigm. As you know, this is probably the most potent T-K-A-I-B-F-R-TKI that we have currently compared to the ones that are available from a commercial point of view. And there was a randomized pi-botal phase three trial, the T-B-1, comparing head-to-head infest-line therapy, T-Bosani versus Saurafenib, more than 500 patients, and those progression on Saurafenib were allowed to receive T-Bosani in a separate protocol. This is a positive trial regarding the main primary and point progression-free survival. You can see that with T-Bosani, the PFS was the longest one that we have had in a randomized phase three trial, almost 13 months. It was statistically superior to the PFS of Saurafenib, named MAHMS, and also we compare with the other two phase three pi-botal trials for Suneet and Sampasopan if they are approved in phase-line therapy. It seems to be superior or at least comparable or not inferior to them. The issue was with the overall survival was not the primary and point, and you can see that the overall survival percentage after one year was similar for T-Bosani and Saurafenib, about 80%, and similar also for the other two drugs that are approved, Suneet and Sampasopanib. It is interesting to comment that only 15% of the patients on T-Bosani received second-line therapy and for Saurafenib are almost two-thirds of the patients were having second-line therapy with T-Bosani, so that might explain also this lack of difference in the secondary endpoint. But which is very interesting from our perspective is the very good tolerance profile that was shown for T-Bosani with only 10, 15% of patients requiring dose reduction, less than 20% of patients requiring dose interaction, which makes this drug a very easy drug to administer and also for potential combinational therapy. But at the end of the day, the regulatory agencies, the FDA, didn't approve this drug because it is already a very saturated field with four more TKIs already approved and because of some problems in the design, the overall survival results, crossovers, et cetera. At the end of the day, this is reflecting the need of not going for the similar mid-to-BJFR TKI drugs or empty or similar drugs and try to be more creative trying to get new, really novel agents to the market. So as an introduction for the novel angiogenic targets, you can see that there are many different angiogenic, pro-angiogenic factors that affect the angiogenesis process at different parts. The BGF, for example, is very important for endothelial cell activation, survival, proliferation of migration, but there are some other pro-angiogenic factors important for base membrane integration to formation, branching, and sprouting and also for maturation of the network of vessels like ALQ1, endogene, PDGF, S1P, or angiopoietins. And these are the targets of the drugs that are being explored currently in kidney cancer. Also important to understand is the concept of the second angiogenic switch that we have with kidney cancer that in comparison with the primary angiogenic switch that is dependent on the bone hippo endowed primary alteration. The second one is acquire resistance to angiogenesis inhibitors and tumor evolution with vascular embolization and produces and is driven by some other pro-angiogenic factors like hepatocyte growth factor and the semen receptor, assuming growth factor, et cetera, that can be also target for our new agents that are coming for kidney cancer patients. Some of the drugs are having the tibocyanic problem that are very similar to the ones that are already approved like Nintenanib, Linifanib, Sedidanib, I will not talk too much about them, but I think that this is already quite difficult for the pharma companies to get these type of drugs approved by the regulatory agents because of the saturation of the market. And then I will talk with further extension about the CMET, which is one target that is probably more advanced right now in kidney cancer regarding novel agents. The CMET is an important receptor tyrosine kinase that is binded by the hepatocyte growth factor, which is its natural ligand, and by doing so it activates different signaling pathways like the RAS, RAD, macanase, the FEC1, the PI3K, EKT, MTOR, and by doing that it is activating cell proliferation, cell invasion, epithelial mesenchymal transition, cell survival, and this signaling through CMET is activated sometimes in a constitutive way, but sometimes it's also activated by tumor hypoxia and very important acquired resistance to BF targeted agents. And we have two drugs that have been developed, Cabo-Santinib and Phuratinib, that needed CMET in addition to BFR2. Cabo-Santinib is probably the one that is most advanced nowadays. The first data of activity, we obtained them from a phase one drug interaction study that was presented by Dr. Ciori, with 25 patients with heavily treated advanced kidney cancer, with Cabo-Santinib 140 milligrams daily, you can see that the disease control rate at four months was very good, 70%, with different percentages of tumor regression from four to 60% and a very interesting PFS of 15 months. It was well tolerated, being the most severe side effects hypophosphatemia, hyponatomia, and phytic, in less than 30, 20% of patients. And here it is more easily seen the dynamic changes in tumor sizes for the 25 patients that were participating, most of them were having some degree of decrease of the tumor, in spite of being heavily protruded. On this basis, there are two randomized trials with Cabo-Santinib, one is the Alliance Calculative Phase II study in first line therapy, comparing to Sunitinib, the primary point is progression of free survival, 150 patients, and the data probably the result will have it at some point this year. And then there is a Pivotal Phase III study of Cabo-Santinib, 50 milligrams versus a better Lungsten milligrams, in progression to be a F-R-T-K-I first or second line therapy. But interestingly here in the two randomized trials is that the dose of Cabo-Santinib is less than 50% of the recommended dose in the phase one trials or the dose that is actually approved for thyroid medullary cancer. And this might be a challenge in order to demonstrate superiority of this drug because it is optimally dosed. Foretinib is also a drug that is inhibiting C-Met and BGFR too potently, but also in less potency type II. It is mainly developed for papillatic kidney cancer which depends on C-Met in many times. And this phase II trial with 75 patients was showing an overall response rate of 15% with disease stabilization of 88%. The tolerance was not that good with 30, 40% of patients with Sibir fatigue, nausea, vomiting, diarrhea, hypertension and 8-10 patients with pulmonary embolism. BFS, 10 months, and again the dynamic changes in tumor size 75% or less of the patients were having some degree of decrease and independently of patients of metaboration germline mutations or in the absence as well. The next one is the graphenib which is a multiple kinase inhibitor, BGFR, BGFR, fibroblast, gofato receptor but also in a very potent way, type II. There is a phase II for kidney cancer that was presented by Tom Asen with the graphenib, 160 millions per day. The primary endpoint was response rate, 50 patients were participating and only 10% of the patients were having disease progression, 40% were having objective partial response. The toxicity was also a little bit hard for the patients, 70% of them were having any type of grade III or IV toxicity, one third of them were having Sibir or life-threatening harmful to skin reaction, fatigue of any degree in half of the patients, the same for diarrhea, allopecia, mucositis, mainly grade I or II but it was hard. Especially there were two patients out of the 50 participating ones with grade IV cardiac ischemic events and two toxic dead. So this drug is not easy to administer which is something that we don't see with colorectal cancer, for example. And finally, the inhibitors of activating like NH1 or endocrine receptors, as you can see here, these receptors are members of the transforming growth factor beta superfamily. They are expressed on activated endothelial cells and very interestingly, the ALQ1 receptor loss produces the hereditary telangiotasia syndrome because it is affecting the maturation part of the angiogenesis, the network of new vessels, mature vessels. From a preclinical standpoint, it has been demonstrated as soon as it is synergistic with the protein fusion of ALQ constant fraction. And the drugs that we have in the clinic are several. We have the protein fusion protein of ALQ1 from gene intake and also from aceleron that binds and neutralizes the ligand of a bone MP9 and 10 which is a TGS beta ligand. Also we have a monoclonal antibody acting here against the ALQ receptor. And we have also another monoclonal antibody against the endocrine receptor for a tracon biopharmaceutical company. All of them are having good tolerance and the angiogenic activity. And in kidney cancer, the ones that are having some preliminary evidence of activity and clinical data are the one from aceleron, the Lantersep and a tracon 105 in phase one two mainly. Finally, the last type of drugs, the novel PSCK-AKT mTOR inhibitors, which is a very important pathway in kidney cancer as you already know. And the way to try to improve these RAPLOX is through a better inhibition of the mTOR inhibitors of different parts of the pathway PSCK or AKT and sometimes dual inhibition of these different parts. These are non-alosteric inhibitors. They directly block the ATP binding sites in the PSCK mTOR pathway. And you can see here the ones that are in the clinic, the specific inhibitor of mTOR complex one and two, the inhibitors of PSCK sometimes pump PSCK in ATP competitive way from Novartis, VKM, 220 and Bill, 719. Alosteric inhibitor of AKT from Merck, which has been suspended in kidney cancer because of toxicity. Then we have the ones that are more advanced dual PSCK and mTOR kinase inhibitor for gene intake and from Novartis. And finally, the periphozin one, which is in the clinical arena from 10 years ago, which is a PSCK-AKT dual inhibitor and there are some data in phase two studies. The ones from all these mTOR PSCK-AKT drugs that are a little bit more advanced is the pump PSCK mTOR inhibitor from gene intake. There is a randomized phase two trial with 80 patients comparing that with everolimus. And to conclude, BIFR inhibitors and mTOR inhibitors are still the backbone of kidney cancer, but they are probably at their very best plateau as single agents. So we need to get new targets and new drugs and very importantly, we have to base this in understanding and overcoming the resistance to these drugs. We can group them as novel pure anti-angiogenics or novel PI-3K-AKT mTOR inhibitors that are acting not only on endothelial cells but also in tumor cells. And from all these ones, the CMET-BFR2 inhibitor Cabo-Santinif is the most advanced ones between the novel drugs, again, excluding the T-cell modulators. Thank you very much.


I Think we ought to find out what caused it go back and retake the place United States Army picture Unofficial report produced for the armed forces and the American people Now to show you part of the big picture here is Sergeant Stewart Queen We Americans take Understandable pride in our roll call of heroes However, something more than pride Attaches to those among them who attain a heroic stature Without losing the common touch these fire the imagination and at the same time evoke affection Perhaps because it is easier to identify ourselves with them Here then was such a hero General Joseph W. Stillwell a Man who turned back from bitter to beat To help write an important chapter in American military history Joseph W. Stillwell was born in March of 1883 the place Palatka, Florida his childhood and early youth however were to be spent in Yonkers, New York Even in earliest years he bore the stamp in appearance and in character of much We consider typically American there was a love for sports and then these he excelled There were also mischievous high spirits perhaps too high Discipline was indicated and so the family decision to send Joseph Stillwell to the military academy at West Point The year was 1900 and the decision a fortunate one Few men could know as we know through hindsight that young men with qualities of courage and leadership Would be needed to serve the nation through ensuing years of crisis Between the lines of a yellowed-class yearbook. We can read hints of those qualities For the young quarterback. They were already winning a permanent niche among West Point's football immortals They were destined to serve him on fields broader than the gridiron Graduation from the Academy did not end Joseph Stillwell's Association with West Point the newly commissioned second lieutenant of infantry was to spend 11 of the next 14 years teaching a succession of classes his field of instruction foreign languages a Natural aptitude in these subjects was to prove as fortunate for the nation as was the decision to make the military his profession In the crowded years not spent at the Academy there would be assignment to service schools and tours of duty in the Philippines and at home Meanwhile history was setting the stage for the first of our century's major crises Worldwide conflagration In its flames untried American leadership would be tested and tempered Joseph Stillwell would be among those to receive their baptism of fire Was the patriotic song of the hour Over there sailed young American manhood to fight in the first international conflict of our history With the temporary rank of major Joseph Stillwell disembarked in France during the bleak disheartening December of 1917 There followed a brief period of service with a British division Then with his fluency in French he became liaison officer with the French 17th Corps For the young major there was no action at Burden Lafayre for service in this last engagement Stillwell now assistant chief of staff for the Army Corps received the distinguished service medal for military attainments of a high order Read the citation with the war's end It was now colonel Stillwell who went on to serve with the army of occupation within Germany until July of 1919 By now the enthusiastic scenes welcoming American troops back to civilian life were past history Nor for the returned professional soldier would there be any termination of service In full recognition of his talent for language Joseph Stillwell's next assignment of duty was to take him to Piquin There to study and attain fluency in the many Chinese dialects With him went his wife and their three children Two more would be born during the years in China The comfortable Stillwell home came to reflect his growing appreciation of Oriental art It was to earn him recognition as a connoisseur To the Chinese people around him the perceptive Stillwell brought his own humane understanding Out of it came mutual respect and warm regard One day in the future these would help forge military victory But before that day there were to be years of service for Joseph Stillwell Now he must return to the United States Beside him at Port Benning's Infantry Training School Fellow future general officers taught and studied George C. Marshall or more Bradley Names that were to become household words in a nation at war At Port Leavenworth's command and general staff school there were additional years of study Then once again it was born This time as military attaché to the United States Embassy in Piquin Here he remained as the clash of conflicting interests between Japan and the Awakening Giant China Led inevitably to incident and incident to all out war The incident was Manchuria The military machine of the Mikado required no ordnance The military machine of the Mikado required no ordnance The military machine of the Mikado required no ordnance The military machine of the Mikado required no ordnance For the military clique which then held power had long anticipated this day The overall plan was to decimate China and reduce her province by province Japan's modern air force would meanwhile be destroying China's sources of power to resist Chinese courage proved no defense against the perfected military efficiency of the enemy And as American observer was Colonel Joseph Stillwell It became his growing and unshakable conviction that the Chinese soldier was a first class fighting man He needed only first class equipment, first class leadership Chiang Kai-shek, the one leader able to preserve Chinese unity Was by now forced to withdraw to the interior city of Chongqing From here he sought endlessly to enlist the aid of other nations There had already occurred the Panai incident in which an American ship and Chinese waters had been sunk by Japanese bombers This had crystallized the American sentiment that had long inclined to sympathy for China Some as young Americans volunteered their services Acting unofficially as private citizens, one such group, the Flying Tigers Were winning fame as they took impressive toll of Japanese playing For China's armies engaged in their unequal struggle Arms and equipment were now made available To cut off these sources of material aid Japan systematically occupied or blockaded one after another of China's port cities In effect, she built a wall around China Deprived of needed supply from without A weakened China would be vulnerable to the heavy blows of the invading forces Once shattered, she could be conquered piecemeal The former American observer was now back home again serving at California's Presidium A major general, he commanded the Third Army Corps Step by step, history was setting the stage for its climactic tragedy Out of that tragedy, Joseph Stillwell would emerge to play a heroic role From a country stunned by disaster, General Stillwell was sent to China There to serve as Chief of Generalissimo Chiang Kai-shek's allied staff And with a small American staff to take nominal command of China's fifth and sixth armies The new responsibility brought him his third star In the absence of clear-cut allied command lines General Stillwell's first job was to help in the defense of Burma Burma offered the only route by which material aid could be fed into China China must be built up, made stronger and stronger Until her allies could join her in going over to the offensive That would be a far-off day, for her allies were preoccupied with other theaters of war The Burma, which was to no Stillwell's exploits Had ceased to be a modern Eden of song and romantic fiction It had become a battlefield General Stillwell and his Chinese, together without numbered British, free French and Dutch fought on, but the effort was doomed The Japanese steamroller pushed on It had administered humiliating defeats to the allies in the Pacific and elsewhere in Southeast Asia It had taken over thousands of square miles, together with peoples and resources Now it rolled across Burma India's borders lay open to attack Worst of all, that last vital land route the Burma Road lay useless Once again, the old lesson must be learned Courage alone is not enough For the allies, withdrawal became retreat Retreat a nightmare route The old Joseph Stillwell's full stature revealed itself Refusing the comforts his age and rank might have claimed He personally conducted one group of 400 battered troops, Burmese nurses and civilians To the safety of India There at New Delhi, he was to utter the now classic admission of defeat And announce his determination to go back and wipe it out Here was the honesty, the directness, the tough moral fiber that characterized the man The battered campaign hat and shirt sleeves now became a familiar sight As the job of regrouping and training began If a besieged China, cut off from her allies Must now depend on a limited number of transport planes The few that allied command could make available Forced into around the clock system, these were also bringing out of China The manpower that would be needed for that return to Burma In one such operation, 14,000 troops were carried without loss or mishap Limited two in number where the planes needed for the thousands of Chinese flyers in training And even for those units which must continue aerial warfare against the enemy within China American flying tigers were now a part of regular fighting forces And these still flew for their old leader, General Chennault And now another of Joseph Stillwell's goals must be pressed Nothing less than a new road to bypass the severed link of the old Burma road Modern machinery and trained manpower could clear at the Indian hand at the projected loop At the China end, it was a far different story Here it must be back-breaking manual labor with primitive tools Men, women, and even children threw themselves into the Herculean task China knew what was at stake and China responded Allied leadership in conference authorized greater aid And a newly organized Southeast Asia command Supreme commander was to be Admiral Lord Lewis Mountbatten His deputy, Lieutenant General Joseph Stillwell The increase in material aid was making greater demands upon air transport Suddenly the hitherto ignored operation captured the imagination of the outside world Flying over the hump became a familiar phrase Behind the phrase lay the reality of every type of plane available Many lacking modern instruments Flying back and forth in unpredictable weather Their route over uncharted and treacherous mountains The stockpile for this the step-child of the war effort was mounting The tools of battle were now ready and waiting to help settle an old score The sideshow war had been remembered Air power opened the prelude to attack And to sustain it, fighters and bombers of the newest types arrived in increasing numbers Soon the prelude to attack was no longer a curtain raiser But the first stage of fiery assault From China, from all parts of the British Commonwealth From India and Burma And from far off Africa, many tons were on the march And with General Stillwell's polyglot army, a growing number of American units Some were General Merrill's troops experienced fighters from the Pacific Theater Merrill's marauders was to be their popular name as they helped make history In the two years of preparation, General Stillwell had molded a machine to beat the enemy at his own game Mountain and jungle warfare Man-made weapons would exact casualties But losses even heavier were inflicted by malaria, dysentery, hepatitis And a wide range of tropical diseases For the men who fought, enemy metal could hit as hard Sickness could be as crippling as in any other theater For them, Burma was no sideshow And their isolated pockets of warfare often had to come by airdrop In twisting mild-deep canyons and jungle-covered terrain A miss by a few yards could be as bad as missing by a few hundred miles Seemingly everywhere was lean, raw-boned Uncle Joe as he was referred to generally Bluntness had also earned him the title Vinegar Joe Doubtless there were saltier names coined in the ranks Doubtless, too, Joseph Stillwell chuckled over them in private The overworked term soldier-soldier has lost much luster But Joseph Stillwell sharing the hardships and dangers of his men gave the phrase real meaning His was the unique capacity for commanding respect and obedience while evoking a genuine affection Perhaps no group regarded the general and the man with warmer feelings Than did the Chinese troops in his command It was no secret that General Su, as he was called, had consistently extolled their courage And promoted their welfare, often in the face of averse opinion from above Repaying that faith now were unbroken Chinese victories in the field Teams like the Salween and Irawadi rivers were back in the news But now these were scenes of successes It was the enemy who yielded as British-led Allied forces reclaimed more and more of Burma's soil North and south it was the same story, an old humiliation was being erased It was now two years since the retreat from Burma And the 61-year-old general could see his timetable for victory working out on schedule In the circumstances, a birthday celebration was a pleasant and well-earned respite The presence of a son, Colonel Joseph Stillwell Jr., marked it a family occasion as well Such respites must be few and far between The forgotten war in both south and north had reached its climax The enemy knew well that each mile of ground lost in northern Burma between India and China The Lido Road was growing On the heels of combat troops, often under enemy harassment, came the men who must hack out that road The land itself fought back Jungle growth would completely reclaim and obliterate in two weeks' time The work that neither the enemy nor disease nor climate could hold Against the enemy, there was the rifle always close by To fight the soil, every weapon from the axe to explosive charge was employed The work went on General Joseph Stillwell was almost literally dragging his road behind him Yet, as he pushed on and the enemy grudgingly yielded, the mule trail became a road In relative safety, engineering could expand the road into a solid truck room As it neared completion, the derisive phrase, impossible road, was heard less often Across jungle-covered plateaus it stretched Across rivers untamed since the creation Yet now they had been harness and bridged Across mountain ranges it traveled to narrow the gap between India and China Then inevitably came the Great Dead, the day when a first convoy could move along its 1,044-mile length The enemy had been pushed out of northeast Burma and the way lay clear Considering the difficulties and the hardships that had been born in shaping its tortuous route There seemed merit in the words of an American colonel who at the outset had said You don't have to be crazy to do this job, but it helps Yet the Lido Road was now a reality The first convoy rolled into Kumming, a token of the supply flow to follow Honoring the man who had weathered all opposition to build the route, it was renamed the Stillwell Road Four months later, Allied command could announce victory in Burma What of the man who had built the road and forged that victory? The tides and cross currents of events had taken him far from what would have been his hour of triumph Receiving his fourth star, General Stillwell came home to serve as commander of ground forces Then off to the Pacific for a tour of battle fronts and installations In the course of those next months, he became commander of the 10th Army Later he was to serve as commanding general at Okinawa But wherever the assignment, the Stillwell story remained unchanged He was still blunt unassuming Uncle Joe, the general with no patience for pomposity and pretence He was still the gaunt typical American who somehow reminded of the symbolic figure Uncle Sam More important, he was still the Joseph Stillwell with an understanding of the men in the ranks And a talent for winning their affection It was of course his own feelings being reflected as warm feelings always are Summer of 1945 was ending and so too history's most devastating war Like another great military leader who had vowed to return to the scenes of earlier defeat and erase its humiliation General Stillwell would welcome the date September the 2nd Aboard the battleship Missouri on that day General of the Army Douglas MacArthur submitted the formal surrender terms to a defeated enemy An end had come to the agonies of a tortured world Peace had come in victory and with honor Once again for General Stillwell, there was assignment to the presidio But now as a prelude to well-earned retirement At nearby Carmel was his family and the home he loved Here he had planned to pass the rich remaining years that lay ahead But now a new enemy struck This was the enemy within, one who would not be defeated On October 12th 1946, after a short illness, Stout hearted Joseph Stillwell died By his own instructions, ceremony was omitted His ashes strewn out on the Pacific whose waters play against the shores of beautiful Carmel Today at West Point, the general's old campaign hat and combat boots are treasured mementos There hangs to a portrait to recall Joseph W. Stillwell's career of service to his country To the men he led, an example and an inspiration to greatness This was General Joseph W. Stillwell Blunt, honest, unassuming And at the same time brilliant in leadership and magnificent in personal courage A man perfectly cast in the hero's role he was called to play upon history's stage Now this is Sergeant Stewart Queen, your host for the Big Picture The Big Picture is an official report for the armed forces and the American people Produced by the Army Pictorial Center Presented by the Department of the Army in cooperation with this state


So thank you for having me today to discuss this interesting topic is, as you mentioned, I've been in the GI world for some time and one of my main interests is the functional gastrointestinal disorders and motility disorders, as well as nutrition. So this is just, I mean, it's a very extensive topic and the main, my main goals for today is to discuss like the main, the gut-brain interaction, what is, what are the, what is the, the embryonal part, like then the microbiome, and then extrinsic factors that are involved in the functional GI disorders that help contribute to those disorders. And so I'm just brushing up on the general diagnosis and work up for all of these disorders and then just a treatment approach that we have here currently at our practice. So first we're going to discuss about understanding the gut-brain interaction, going, starting with the enteric nervous system. So as we know the enteric nervous system is the intrinsic innervation of the gastrointestinal tract. It's a complex network of neurons and glial cells that is located along the GI tract. It represents a very, very important component of the autonomic nervous system. And then it serves, it serves as we know as the intrinsic nervous system for the gut and it's capable of controlling most of the functions of the intestine independently of the central nervous system. As we see here on this graph, so the vagal neural crests derive cells. They enter approximately, so approximately from the oral end of the embryonic gut and then migrate along its entire length, giving rise to the majority of the glial cells in the enteric nervous system. Then the sacral neural crest cells, they enter the hindgut, this means hindgut, midgut and then the foregut, but so the sacral neural crest cells, they enter the hindgut and then migrate approximately in the oral direction to form the neurons in the glial and the distal portion of the gut. Here we can see, just like, as we already know from our anatomy and embryology, the my enteric plexus and the submucosal plexus, they are an essential component of the gut neuromusculature and control many aspects of the gut function, including coordinated muscular peristalsis. The enteric, I want to remember that the enteric nervous system is derived from the neural crest cells, as I mentioned, and then they are involved in a number of key processes, including the migration, as I mentioned, proliferation of the glial cells and later differentiation into the neurons and glial cells during the field life. So then this is just the proposed model from the Motodori Society that we will see multiple interacting brain networks that mediate the perception and modulation of the visceral pain. And then this model is replacing the previous conventional focus on individual brain regions and then controlling pain on one side and then separate from the enteric nervous system, kind of like two separate systems. However, this interesting integrative model proposes reciprocal interactions between the brain networks, which they describe it as the brain connectome, and then the networks made up by multiple cells in the gut, including the gut microbiota, which is the gut connectome. So then here we see the brain-to-gut interaction is mediated by the autonomic nervous system and then on the other way, the gut-to-brain interaction is mediated by neural endocrine and inflammatory pathways. So all of these interactions are very close knit and then they just evolve into a cycle that later on, if it's affected by different items that I will talk later, then that's when it leads to a disease. So then it leads us to another form of viewing the brain-gut axis and the more the unimportant theory of the gait control mechanism for the GI pain. So the pain that begins in the gut, it ascends to the dorsal horn of the spinal cord. It goes all the way up. Then remembering all of our anatomy goes into the second-order neurons into the midbrain and the limbic structures in the brain. Remember the limbic structures are the... Some of them are involved into the emotions that we put into that sensation, so that's important. And then the second-order neurons go into the third-order neurons and they go into the cortex where the pain is experienced. So the gait control theory relates to the brain's ability to reciprocally facilitate or block as a gait, basically, the ascending signal from the dorsal horn going into the brain so it can modulate how much it goes up and then thereby reducing the experience of the pain. So this is just moving a little bit forward into the therapy, like the psychotherapy aspects of these patients with functional GI disorders. A way that we can help control this gait is by distracting the patient, so distraction, focus attention, meditation, hypnosis, and also by neuromodulator medications that are involved in the neurodinergic and serotonergic pathways where we can control this theory. So this regulation of this brain gut pathway leads to chronic GI pain. They also... I was reviewing some mouse studies where they put a rectal probe and increased painful stimuli in the gut, like repetitive mechanical stimulation sensitizes the spinal cord and then there's up-regulation up in the spinal cord that leads to central hypersensitivity. So that's when we start referring to the term of hypersensitivity. These hypersensitivity at the level of the spinal cord amplifies the signal that's coming from the spinal cord up to the central nervous system and gives...leads from the acute state to a more chronic and persistent pain and then it's perceived, even if the stimuli is not as bad as it is, the brain perceives it as very no-sive. So then it just becomes chronic and amplified. So this is the theory behind why we have evidence that visceral hypersensitivity is a consequence of altered central pain processing in patients with, for example, irritable bowel syndrome or functional dyspepsia. So then these, after we know what's the basic physiology of the brain-gut system, then we're going to go into what factors affect this gut-brain interaction. And there's many, many factors. This is just one of the most important ones that we intervene, that we can intervene in our patient population and then it's the environment. So here in the environment, we have to consider social environment, the dietary. From the social environment, we already know that many of our patients are being bullied. I saw some data that at least 10% of the patients in the U.S. are being bullied. Also the parental influence of catastrophizing the symptoms as well as the seasons that I will delve a little bit more into that. Also the physical activity is very important. Physical activity plays an important prognostic factor in patients with chronic pain. Also other comorbidities, so for example, patients with functional GI disorders, 50 of them can have other comorbidities such as headache. So that's why it's very important to take a very good history. So then let's go into this. So this is an interesting study, a large retrospective study that they published in 2013. This is a database of 170 million patients where 20% of them were children and then 80% of them were adults and then they demonstrated the seasonal variation of the presentation of abdominal pain complaints and consultations for chronic or recurrent pain in children. So it's very interesting to see like how, and we see this in our clinic even now, how the frequency and the number of patients that consult to us about for chronic abdominal pain or for a new onset of abdominal pain decreases during the summer and then it just increases as the school year starts. So you see that brisk change. It would be interesting to see now that we have, now with this year of COVID, now that many patients have been at home and like they're not on that stressful environment to see if there's any changes. From just from my personal experience in my clinic, many of the patients that for example were having a difficult school environment or if they were having difficulties at school, they are thriving at home. So they're having excellent grades and they are, the symptoms have significantly improved. However, we also see the opposite and I'm pretty sure you've seen it in your practice that patients that were very social and really enjoy their interaction with peers, they are not doing as good and so they don't like the teaching mode. So what the authors in the study report is that like different factors may vary within the school year. So stress, anxiety, there's different sleeping patterns, which I will go into a little bit infection. So if you are in a different environment that you're exposed to different infections, dietary variations that we know are common in school. So then here it's just another show of like that is associated also with the consultation and depression. So here we see like in the summer months when they are more with the families and not at school, the consultation for depression also decreases. So it goes along, they go hand in hand. Some of the most common psychiatric diagnosis, they go hand in hand with the patients with functional abdominal pain. And it's interesting to see that what they reported is like that they speculate that there are no changes in the adult pattern because the adults don't have like we have like a straight line of schedule, stress, environment. So it doesn't really change in the summer. We just have some vacations, but it doesn't change. So that's why it's very linear pattern in the consultation for depression in adults and in the consultation for abdominal pain in adults as well. So going a little bit more deep into how sleep and stress affect the symptoms. So stress and anxiety may trigger GI symptoms in patients that have autonomic liability. So that goes back into our physiology. These patients get a decreased pain tolerance in response to stress. We see these decreased pain tolerance in patients with recurrent or chronic abdominal pain. We see that there's altered, it's been reported that altered sleep is highly prevalent in children with abdominal pain associated with unassociated functional GI disorders. As I mentioned before, like the changes in the sleeping patterns for kids when they are on summer versus when they are in school. So these changes and delays in the circadian rhythm has been associated with GI disturbances. And we know that serotonin and melatonin are essential neurotransmitters with roles that regulate mood and GI motility. And as I mentioned earlier, and as I will mention later on as well, is we use many serotonin-based medications that interfere in that cycle to manage these chronic pain in these patients. Another factor that affects these brain gut axis is pain catastrophizing. So this is a very interesting study that they did in Seattle. It's 70 patients and their mothers filling out a pain catastrophizing survey. All of these patients had a functional GI disorders. And then pain catastrophizing is characterized. But how do you perceive your pain? And when you catastrophize it, as you are perceiving it as highly threatening, dangerous, and beyond your ability to cope. So then it goes back into how we cope with negative experience and how we think how harmful they are, how dangerous they are. So this level of threat of the pain is what causes this catastrophizing. So in this study, they show that children of mothers that have higher in catastrophizing, so they said that this is the worst pain, is something is going on, there's something wrong. These children were more likely to utter anger words. So they had like some cue words in that survey. So they were more likely to utter anger words when talking about their abdominal pain. That were children with mothers lowering catastrophizing. So this is a very important factor in that we have to consider when we start, when we recommend psychotherapy or some of the behavioral methods to manage these conditions is how the families approach these symptoms, how they talk about them. So for example, one of the interesting, for example, one example that they mentioned in some of the lectures is that, for example, you have a kid playing soccer. So the mom is watching the kid playing soccer. She falls down.  Did you break a leg? And then another one will just stay there and then see what the kid did. And then at the end, she's like, oh, I saw that you fell. I saw that you hurt yourself, but you dealt with it. And then you kept playing and this is good. So just reinforcing those behaviors is the same with the abdominal pain. But for example, if we, in our setting of abdominal pain, so if we have a patient with chronic abdominal pain and then you have a mother that catastrophizes, so says there's something wrong and then they come to our office several, several times, the kid interprets it as like there's something wrong with me. There's something wrong and they haven't found anything, what's going on. And then this is a part that is very difficult into managing these patients with functional GI disorders is that some patients think that it's just a made up diagnosis that we haven't found the organic cause for it. And it's particularly frustrating. But once we explain the etiology and how we say kind of like separated, give like the physiology, like the nerve.  That kind of helps later on into the healing process. So this is a very important aspect that we evaluate in all of these families that have functional GI disorders and also help us guide what kind of management would fit into the family. Another factor is the diet. So we know what we all know about the FODMAP diet. And then in this study, they show that fructans can exacerbate some of the symptoms in a subset of patients with IBS. So this is a double blind placebo controlled study where they gave fructan and then they gave matzodextrin to patients with irritable bowel syndrome. This is a study from the Texas Children's and then they define fructans sensitivity. So they separated patients that were fructans sensitive versus insensitive. If there was a 30% or more increase in the abdominal pain following the fructan ingestion. However, it's very interesting that the fructans sensitive subjects, they did not differ from the patients that were fructan insensitive. So clinically different with respect on the hydrogen and methane excretion during the fructan challenge. So they didn't, both groups, they gave them different diets during like three or four weeks and then they measured how much of the hydrogen and the methane they excreted. So through the best test. And then they found that both of these groups, they had, there was no statistical difference between the amount of gas that they produced. However, patients that were fructan sensitive, it seemed to exacerbate several symptoms. And then another interesting part of the study is that they measured abdominal pain, they measured different labs. Again, they measured the hydrogen and methane production. And then they could not find any specific, for example, biomarker or predictor if a patient is going to be sensitive or not to fructans. So that's why from the Irritable Bowel Syndrome guidelines, the recommendation is to do a limited trial of low FODMAP diets. So low fructan, oligosaccharides and all of those sugars diet in patients with Irritable Bowel Syndrome. And then it's just a limited trial for a few weeks. And then you recommend the patients to slowly start reintroducing until the symptoms are tolerable. However, we have many patients that they start the diet and they continue with the symptoms. Then there's no point in just keeping the diet. We resume it and then we go into other therapies. But that is one of the recommendations for the management. So this is a very important part from the dietary therapy is this is one of the only dietary therapies that is recommended in patients with functional GI disorders and mainly Irritable Bowel Syndrome which is the most common one. It's present in about from all the big spectrum of functional GI disorders, Irritable Bowel Syndrome is about 10 to 20% of these patient populations. So this is very common. Then another very interesting aspect is how the microbiome plays a role into those gut brain axis. So we are already familiar that we have like there's the good bacteria and then the bad bacteria and how that balance and interaction helps a improved symptoms or changes the symptoms. But until recently we didn't know why specifically the microbiome is causing these change in the symptoms and then this change into the clinical presentations that we see. So in this study that it was published last year in Nature they saw that they discovered this factor a transcription factor which is called a real hydrocarbon receptor. It functions as a biosensor in intestinal neural circuits. And then these receptor, this transcription receptor is basically activated or suppressed depending on the microbiome that they have. So these study is made on rats. They had rats that were like given antibiotics so they did not have any gut flora versus rats that had just like the regular gut flora and they were fed with probiotics. So then they measured the activation of these transcription factor. And then they saw that in patients that had the healthy regular gut flora these transcription factor activated and it ended and it resulted in normal colonic transit time compared to the mice that didn't have any bacteria in their intestine, they had slower transit times. And then at the end of the study they feed the bacteria or like the diet from the mice that had the bacteria to the ones that did not have bacteria. And then they saw changes how these transcription factor activated and how the colonic transit time improved. So this is a very interesting study that I wanted to bring up and to see why the microbiome is so important into the gut motility and like the gut health in general. And then they were able to demonstrate, as I mentioned before, they were able to demonstrate how intrinsic neural networks of the colon exhibit these transcriptional profiles that are combined, that are affected by combined effects of the host genetic program. So if they had of course a knockout of that transcriptional factor of course they didn't respond to the diet so it's a combination of how your genome is configured versus the microbial colonization. In this study they just show like a normal healthy gut flora from mice but they did not show like dysbiosis or abnormal flora. So this is like ongoing studies. So this is just like another backup or more information that would help us decide the management in our patients. So for example, we recommend our patients, we do not recommend them to take probiotics as a standard of therapy. Actually the latest guidance lines for irritable bowel syndrome, they advise against and just giving probiotics to everybody is more guided therapy for patient for example is having diarrhea or if there is a concern for SIBO, they recommend more going into the nutritional therapy. So more eating prebiotic foods, for example, kefir that I know like there's some other studies that kefir has being reported as being a good factor in preventing C. diff infections and that sort of thing. So that's why the recommendation from the microbiome perspective is following a healthy whole food based diet that includes a lot of prebiotic foods and then if there is the interest not as a standard of care they can have periodic cycles of probiotics. It's not a standard recommendation but like our general practices is to recommend patients to kind of like cycle the strains in the probiotics not just like staying safe with one for example, cultural brand for years and years because we see many patients that do that. They have to take some breaks, change the diet and then that gives you promotes a healthy microbiome.  So what are the functional GI disorders? A group of disorders that have GI symptoms related to a combination of the factors that I mentioned before. So mortality disturbance that can be affected by the factors that I mentioned before, ulterior mucosal and immune function. As we saw some of the central autonomic nervous system affects into the mucosal and immune function. There's many studies that report that even the autonomic nervous system affects the entire nervous system and it changes the tight junctions and how much permeability the gut has and that can create for example, when they report the leaky gut so there's increased tight junctions and there's increased permeability to bacteria and then it can cause inflammation and symptoms. Alteration in the gut microbiome and altered CNS processing. So this is an overview of how the functional GI disorders are classified based on the room for criteria for pediatric population. It's classified into three groups, functional nausea and vomiting, functional abdominal pain disorders and functional defecation disorders. As I mentioned earlier, our number one, one and two diagnosis that we see more commonly in our GI practice is functional constipation and irritable bowel syndrome. Third would be functional dyspepsia definitely. And then we define these diagnosis and so what they recommend is that after appropriate medical evaluation, the symptoms cannot be attributed to any medical condition. So then by providing specific guidelines and I can share this PDF with you which establishes very specific diagnostic criteria for every single one of these disorders is that if a patient fits into the category, for example, irritable bowel syndrome. So a patient has abdominal pain related to defecation or they're related to alter bowel movement more than three months. So then if a patient fits into that clinical category and otherwise it's a healthy patient that is thriving and developing well and eating well, then the clinician we may or may not select to do testing and they will dwell into testing in a little bit. And another important part that we need to take into consideration is that all of these disorders can coexist with other medical conditions that have their result in GI symptoms. For example, we see irritable bowel syndrome and functional constipation in many, many of our patients that have inflammatory bowel disease. These conditions, this functional GI conditions unfortunately are associated with many psychological and behavioral alterations as I mentioned. That psychological part and behavior and the environment plays a big role into affecting the brain gut axis. So it's always important to just obtain a good history to see how we can guide the patient for management. And then recommendations for basic workups just the basic things that we are recommending. So we recommend, well, the guidelines recommend to perform celiac disease serologies. The celiac disease serologies we just do two of them is just the IgA level and tissue transglutaminase IgA. There is other markers for celiac disease. However, the tissue transglutaminase IgA has been demonstrated to be the one that is most cost effective and the most sensitive for celiac disease. So if we have a patient with diarrhea that we have suspicion for possible celiac disease, just to rule it out is just to do those serologies. Of course, the recommendation for fecal cut protecting is an excellent biomarker of chronic GI inflammation so that when it's an easy test to do and see reactive protein. So both of them is just to rule out inflammatory bowel disease. As a standard of care, the guidelines do not recommend serial infectious stool studies. Some patients end up having like serial stool culture, diarrhea, oven parasites. So what they recommend is to do them in the appropriate context. Of course, if there has been an exposure but otherwise there's no need to check serial oven parasites here in the United States. And then they do not recommend standard testing for food allergies and food sensitivities unless there is reproducible symptoms that are going on with food allergy. So that's why the history is very important. Based on the results of course from the fecal cut protecting CRP and the growth then we in the GI clinics then we decide to do go with endoscopy and colonoscopy or not. For the most part when patients are referred with when we suspect functional GI disorders we do these testing, we perform these testing. And then if they are negative we give reassurance to the family, start the therapy that involves the diet the psychological part perhaps some of the other medications and then if there's no change or if there's depending many concerns or if the patient is not getting away then we go with the endoscopic evaluation. So just moving on to the medical and the non-medical therapies. So we have to remember that pain is a modifiable experience. As I mentioned, there's many factors that affect our perception of pain. So it's perception in acute and potentially even more so in chronic situations is influenced and shaped and shaped by the supraspinal processes. So by a central processes such as emotions, cognitions and memories. So these, all of these factors the psychosocial affects the cognition and the mood effect they can provide either a placebo effect which is the positive effect or a no-cebo effect or negative effect. So that's how you interpret the pain. So with this in mind, with this context in mind that we can discuss the therapy. So this is just like the list of the brain gut therapies. More commonly we, depending on the patient if there's comorbidities for depression or anxiety we use neuro modulators. Most commonly we use amitriptyline in low doses. Some patients we have them in fluoxetine but most of them amitriptyline is very good. We decide between amitriptyline and the SSRIs based on their clinical presentation. If I have a patient that has a lot of diarrhea then I would just go with amitriptyline and then if they are having more of the constipation we go with a patient with any of the SSRIs. Near stimulation I will discuss the device later on and then cognitive behavioral therapy exposure. All of these psychological therapies go back into the catastrophizing and then the environment part from the family. So the goal of all of these therapies is to teach the parents and the families and the patients to cope with their own pain. Instead of having the parents take it away or interpreting it as something harmful and then just taking it away to make it better. So then it's giving all of these tools for the kids to deal with the pain and then to set expectations that it's not that the pain is gonna go away and it's something bad is like, yes, I can manage I can decrease it to this level and then it can be functional. And then these therapies reduce pain and disability over time. And it's very important to explain to them that pain doesn't, I mean, we don't have to equate like hurt with harm. So with a negative experience. So just some data behind cognitive behavioral therapy. It's been demonstrated in some brain imaging studies and behavioral studies that it reduces the activity and the emotion related brain regions. So particularly in the limbic system areas that I mentioned earlier. There's also reports that meditation and mainly hypnosis also targets specific centers in the brain and the limbic system. So it modulates. So for example, one of the, these techniques that has been studied the most as hypnosis and many centers use in is that it modulates the pain perception and the tolerance by affecting the corticalness of cortical activity. So that is one of the most important things to recommend to our patients. Locally, I am not familiar with any center that does hypnosis. And then all of most of these behavioral therapies we send them to either Mon Washington, KKI locally. And then there's some other psychiatric centers that provide these therapies. There's also here in Maryland, we don't have these psychological therapies to offer, but some of the patients we send them to what it's called Amos Clinic in Hopkins where they can have like this holistic approach from the psychological perspective, the gastroenterology perspective, the nutritional perspective. So it's kind of like a multidisciplinary approach, which is the goal. So by looking at all these list of medications, the goal is that it needs to be a multidisciplinary approach to manage these patients because only with medications, only with psychotherapy, only with diet, these patients do not improve. There's also reports in yoga, but these are just like just some case reports with small groups of people. Most of these data actually comes from India. So that's where we have. So just some approach into our medical therapy. So as a base, we always recommend dietary changes and lifestyle modification. It's very important to educate the families and provide reassurance. Again, as I mentioned, this is very important. Peppermint oil, some studies have reported that it decreases the sensitivity of the pain and then the spasm associated with it. Manage if there is suspicion for small bowel bacterial overgrowth. Courses of refactamine have a demonstrated improvement. If a patient is having poor weight gains, it's perhaps that we use it as an appetite stimulant as it increases the gastric accommodation. And then on top of it is the SSRIs that I have mentioned, I have a pending to manage the nerve pain and amy-tripsiline, which is the most common. So depending on how the patient, how mild, moderate or severe symptoms they are presenting, then we address it differently. So for example, if it's more milder forms and they're not having any impairment or disability or missing school, then we just go with the basic approach and then we move up the ladder. This is just to show how, as I mentioned, like the different categories of the pain, but how all of these medical, like medication management, many of them they don't have like data behind, like specific data behind to back up the use of these medications, for example. There's one very interesting study on amy-tripsiline where it showed that it's efficacy for improving pain in patients with functional GI disorders. This was a study, just an irritable bowel syndrome. It had the same efficacy as placebo effects. So placebo effect is 50% amy-tripsiline, also showed 50% improvement in these patient populations. So that's the studies that we have behind it, but we do have the physiology in mind and that's why we use these neuromodulator medications. So that's why it's recommended and that's why we use it in our practice. Then these brings me to the neuro-stimulation device which we are bringing to Maryland soon. It's called IDSTEM. So these device is based into the stimulation of be a peripheral nerve, so it's a peripheral nerve neuro-stimulator that goes into the limbic system and the idea is that it modulates the response to the pain. So this is, as I mentioned, it's a percutaneous electrical nerve feel stimulation and stimulates the neurovascular bundles in the ear. And then we use it as the idea is to use it for three or four consecutive weeks. So the patient would come to the clinic the beginning of the week, we put the device is just some stickers, so it's painless. The reported side effects basically is just irritation with the tape. They leave it in place for five days and then they take it off. They have two days of rest and then they come back the next week. So the theory and then the pathophysiology this goes back into the, as I mentioned the neurovascular areas in the ear, they connect with the many of the nerves that are involved into the limbic system which is how we experience our pain. So the data behind this study was published in 2017. And then this was again a randomized controlled study that it was, they had like a, what they call the sham device, so a device that didn't have any stimulation. They showed that 70% of these patients had failed other therapies and then most of them showed clinical response after having the device. So I'll show you this one as easier to see here. So the dotted line is the sham device, the failed line is the patients that had the IB stem device and then it's again after three weeks and then they had a follow-up appointment. So there was a significant improvement in the worst pain score and then this is just a composite pain score where they also measured quality of life and their overall functionality. So there was a significant improvement compared to no device to a sham device. So this study was in their initial study in 60 patients. Another result from this study is they assessed the disability and the degree of the disability and impacting their quality of life after having this device. So here we can see the baseline. The both groups had a moderate disability but then the patients that had a, after the one cycle of the IB stem device, they had now minimal disability. So this is a very, very good outcome for these patients and especially there's some patients that are, have significant impact in their quality of life. They cannot function. So this just gives them hope. The reports so far what we know after the six to 12 months is that the effect is sustained. So even after one cycle, so one cycle is four weeks of the treatment. So even after one cycle, there is persistent, at follow-up there is persistent improvement in the pain index, the disability index, which is important, the general somatic symptoms. And then of course this doesn't affect the depression scale because this is just another entity, but at least the pain related to the GI symptoms is improving. So that is very good for this device. This is just to show, to put this device between, compared to other interventions that we use nowadays. This is FDA approved for patients with 11 to 18 years of age. So it's the only one that's FDA approved for that treatment. These are the other medications that I mentioned earlier that are not FDA approved for the management of IBS. However, we still use it. And then the potential side effects is localized skin irritation that was reported only in 2% of that patient population. This is important to keep in mind when we use these kinds of medications in these patients populations. So for example, the anti-EA, the present medications have increased risk of suicidal ideation. They have increased risk of dementia with long-term use. And then just the side effects of these channel blockers. Sometimes they can have diarrhea, but that's why we use it for constipation. And then this is just to see other medical conditions that are associated with chronic functional GI disorders where we could potentially use, it's coming down the pipeline where we could potentially use this IB stem device. And this is another reason why we got it. We're planning to get it at Maryland soon. So far, it's been approved by the FDA for IBS, but it's coming down the pipeline for functional nausea, for cyclic vomiting, and then more importantly here, which is what we're also planning to use it. Once it's approved, this is for chemotherapy and do nausea and vomiting. We see it in many of our oncology patients. And then functional abdominal pain disorders in patients with cystic fibrosis, which is also very commonly seen. So just a few summarizing points what I discussed earlier is just that different sensitizing medical events like distention, inflammation, motility disorders, they can affect how you process and interpret the pain signals that are coming from the gut. There's also has to be a genetic predisposition. So for example, as I mentioned, this transcription factor, if it's expressed or not in the gut and how it affects the microbiome, then you could be more prone to have visceral hypersensitivity. All of these factors, along with sensitizing psychosocial events, as I mentioned, mothers catastrophizing in different social situations like bullying, they can affect and cause gastrointestinal problems. However, a patient can have all of these factors affecting it, but the most important factor is how you cope with the pain and how you interpret these pains. Do you interpret it as fearing or threatening? How do you cope with it? So there's different factors that affect with it, but if there is a good coping mechanisms and we help and intervene in these families at this juncture, then you can potentially improve the long-term outcome. So they can either accommodate with their symptoms and eventually there's reports that two thirds of these patients that have functional GI disorders in childhood, they do not continue with these symptoms in adulthood. So it's very promising. So if they learn how to accommodate and how to cope with these symptoms and then promote healthy nutritional and physical activity environment, then this person can have normal development and no disability. And we are of course trying to avoid patients that have chronic pain and disability. So that's our goal for our management and thank you.