We're just doing some last-minute work on getting some slides loaded, and then we'll get going. While we're waiting, though, I'm going to take this opportunity, again, to thank everybody for coming and actively participating in the session yesterday. I thought it was excellent. We particularly appreciate those of you from representing professional societies that took time out of your busy schedules to come and work with us. I also wanted to give Nancy Rose an opportunity to put on a different hat. She's here as the official representative of ACOG, but she is also the program chair for the 2014 American College of Medical Genetics and Genomics annual meeting. And she has an announcement that would be of, I think, particular interest to the group. Well, thank you very much. I just told Mark I wanted to make a shameless and transparent solicitation for your platforms, because this is the group that we want to have submit, of course, to a meeting like ours. The American College of Medical Genetics and Genomics meeting is in March this year, and platforms will open, I believe, in a month, about April. Abstracts will be due by December, and, you know, meetings are, of course, only as good as what's submitted. So please be thinking ahead. It's already the end of January, and we would love your ideas for platforms for the meeting. Thank you. Platforms are highly visible. It's a large meeting, and something that particularly is this group, as we move more towards implementation, I think would really be good to get out in front of folks to have an organized session around some of the things that we've been doing. So this is another opportunity that we can sort of advertise and keep us from being a well-kept secret. And so what we'll do is to, when that announcement comes out, I'll have Nancy send that to us, and then we will distribute it to the group so that you'd have the link for the call for the sessions. I'm going to move up front, and we'll hit the recap of day one. All right, hopefully we'll have those up quickly. Yes, I think so. Yeah, even though M Williams did not do anything with it, it was T. Monoglio, who changed her name this morning to Tariq, which I think is really nice. So it's kind of a little bit more exotic, so it's cool. So after day one adjourned, the planning committee went and, as we always do, and kind of reflected on the, actually what we do is we have dinner, we have a lot of fun, and then we spent about five minutes reflecting on what happened the day before. But we did do some reflection. And we never have wine. And we never, no, there was no wine involved. At any rate, we spent some time thinking about what we had heard yesterday, and took that, and Tariq sort of reframed the key points into some action items. And so what we wanted to do this morning was to present those to you. And again, go through and have the opportunity to make sure that you can react and say, yeah, you got it right. No, we need to do this, that or the other thing. And that this will be our stepping off point for what we do next. So the preliminary action items, and this is related specifically to the professional society discussion which took up most of yesterday. Convene society representatives by conference call in about one month as the nascent coordinating committee. So another gnome de plume here that seems to be less objectionable than some of the other ones we came up with on the fly yesterday. And as part of that, we'll use the groups that we'd invited to this who have been engaged and are interested as the NITIS. But we don't want to be exclusive and say we got it right the first time. So we will extend invitations to other societies to be represented on the call. And we'll see if others wish to participate. We want to collect current approaches and develop and disseminate consensus best practices on what's happening with pharmacogenomics. Ideas relating to society reaction to direct to consumer testing. The ideas about when the state of the science is nearing the clinical horizon. In other words, how far are we along that implementation and translation path in competencies versus general knowledge in the education perspective. These are the things we're going to ask the professional societies to send to Gene. Links for available physician education materials for posting in G2C2 so that aggregation function that we talked about yesterday. The individual society's areas of interest. In other words, what in the genetics, genomics, personalized medicine space are you particularly interested in whether it's disease focused or something else. A process, and we'll get rid of the term pseudo guidelines, I promise. But the process for developing guidelines using the IOM definition of what a guideline is versus other types of guidance that we heard about yesterday that have been developed when you don't do a full guideline. There are other opportunities to inform your members about best practices or other things of that nature. We'll try and collect those types of process measures and how that works. And then also try and collect any current publications from the various societies in that range of a guideline and guideline-like substances that relate to genetics, genomics, and personalized medicine. We'd like to produce a white paper from this meeting that would include the compilation of the survey data that we talked about. Now it's not our expectation that we'll take everything in those surveys and somehow smash it into the white paper. But I think what we want to do is identify those areas that we talked about relating to education and to guidelines and that and see where the commonalities across different provider groups. And if people are willing to contribute that data share, I think that would be an interesting paper because most of that type of information either comes from other countries where they survey their physicians or it's specialty-based. So I think that would be somewhat novel. Develop a working group to address liability issues that are presented by the GM implementation. As we discussed this, the idea had been would we want to take time at an upcoming Genomic Medicine meeting to discuss the liability issues. We ultimately decided that there it probably wasn't an issue that would be of a great interest or would consume a lot of time of the group at large. And so we thought a working group would probably be the best way to deal with that and there hasn't been as much attention paid to the implications for professional liability that were raised by some of the societies yesterday. We'd like to be able to convene society's guideline producers to outline process and evidence needs. Maybe this would be at a Genomic Medicine meeting down the road that we would focus solely on guidelines. We'd also like to engage disease-specific institutes and see if we can get them to collaborate with society. So those are the items that we took away from yesterday's meeting and the floor is now open for any comments, questions, errors, omissions. Yes, Mark first? My only reservation is on pharmacogenomics. I'm not sure there's a society that has thoughtfully considered this for all of medicine. I mean, the theory American Society for Clinical Pharmacology and Therapy was could do that, but to my knowledge hasn't. And I'm just worried that by relying on the disease-specific societies, the one really won't get the best practices and a real consensus. So that's my reservation on pharmacogenomics. I don't know if Mary or anybody else has some thoughts. Yeah, I'll just reflect my thoughts and then we'll go to Mary. My view is that I think you could be right, but we'd have a better shot if we had different perspectives around the table in the sense that you might be able to identify some general principles that are common across the different disease-based entities, even though they may be considering different use cases. And if that was in fact the case, then that might be of some use and could then perhaps provide direction to another group. As you say, the ownership of that is somewhat up in the air. Yeah, I mean, you know, I've been active in ASCO as an oncologist. I mean, and ASCO's view of genomic medicine is completely related to the tumor genome. And so it's, you know, and even though there's plenty of good examples in oncology, the associations between germline variation and outcomes, the society certainly hasn't thought about this at the society board level. Mary? Well, I agree with what Mark is saying, but I think that would be the value of getting these people talking to each other. And I do think that CPIC deals with pharmacogenomics across all diseases, and we can provide some perspective to all of those groups that will be at least a common perspective, maybe people may not agree with it, but it has buy-in from the Pharmacogenomics Research Network, 12 countries, I don't know how many institutions, 80 or 90 members that work in pharmacogenomics. So I think it would be a way of bringing a common approach, make it available to all those different professional societies. Yeah, I think, you know, a lot of the things here when we talk about particular some of the policies around guideline development, the different societies have the opportunity to be very contentious, and possibly things where you're just going to say, you know what, this is just not something that we can work on or that we think we can bring much value. And so I think in some sense the function of a group like this would be to sort out all the different things that you could do and say, these are the things where, you know, we have a lot of energy to actually accomplish and then perhaps as assuming that there is some good output that you could then maybe begin to, with the good will that's been developed on the easy stuff, begin to approach some of the harder things. But, you know, these are all, I think the whole idea here is that we to some degree don't know what's going to happen until we actually pull things, pull groups together and the hope would be is that they would take some ownership and in some ways define what it is that they think is most important. John. Mark, can you go back to your first slide? Can you say a little more about what exactly you mean by best practices? Are you talking about best practices around clinical practice areas, around educating providers around these areas, around, you talk about guidelines later. So I'm assuming it's not best practices. Well, I think that the best practices refers to this as at least a nominal initial list of things that can we identify are there best practices relating to these four items. Now I don't think this should be looked at as the exclusive list. I think there are other things that could potentially be added to this list. But I think the way that this is constructed, it's really meant to refer to the list underneath there. Maybe I could just comment that, John, this is not the best clinical practice. This is almost the best societies practice. So, you know, what kind of advice should or could societies be giving to their members rather than what physicians should be doing? Thanks. Mike. For the white paper, I wonder if a survey could be sent out to all the professional societies, asking them just two or three questions. Like, one, how many hours of time would the practicing clinicians in your membership be willing to spend on genomics education? And two, what's your membership's top needs as far as clinical guideline-ish kind of things? But, I mean, you could probably put together a short list that goes out to the societies. And I think that would be powerful to put in a white paper rather than sort of the general ideas to actually have some things there to report. So there'd be a couple of things I would say about that. One is that if we were to do that, it could be done in conjunction with the invitation letter. The second thing, though, and I'll let Laura speak to this specifically because you and I have had discussions before about surveys that would arise from NIH. And there are fairly significant issues in terms of permissions that need to be obtained to actually do something like that. So I don't know if you have anything you want to add to that or? I would just say that it would be something that we can look at. And there may be limitations to what we can do, but there also may be ways to work around the rules we have. Okay. Did you have something specific to the survey question, Bruce? Okay. Then David, I think, oh, I'm sorry. Okay, Katie does. I was just going to say that that similar survey to what you're talking about was part of the data that informed the Secretary's Advisory Committee, the Genetics Health and Society Report on Education and Training, which just came out a couple of years ago. So actually, there's quite a lot of data in that report, and perhaps it could stand to be updated now. But I think some of that, of what could benefit this group, is actually in that survey. Yeah, that's a really good reminder. And I think that the other thing would be incumbent, as we synthesize this, is to look at the SACGHS and the SACDNC reports on education that both came out about two years ago. Both of them collected some of this information. So we could use that to enhance. David? Yeah, I guess I'm a little surprised to see liability singled out here in bullet two as something at that level as opposed to a much broader, it was on that slide, bullet two, address liability issues, as opposed to a much broader economic sort of consideration of positive and potential negative impacts of genomic medicine implementation. Reflecting on yesterday's discussion, which is mainly around education, is we didn't have a discussion around the economics business plan for sustainable models of education, training, how to get people. The only comment that I remember that stood out to me was Debra Leonard's talk representing CAP, where they have a bullet at the top on CAP pathologist transformation strategy. Number one, will it enable our members to control their professional economic destinies? And that's something the American College of Medical Genetics could learn from because we've failed to develop a healthy, sustainable business model that will attract young people into the field. And so I think if we're going to talk about educational needs, which are vast, we need to have some broader economic discussion about how to align incentives around implementation in an appropriate way in the economic impact of genomic medicine implementation. Yeah, and I think that to some degree that we'll hear about that from the payers work group meeting that occurred last fall that Derek is going to have a report out, and that was something that actually came out of discussions that we had here one or two meetings ago where we did raise the issues more in the context of how can we encourage payers to move some of the technologies into practice, but the scope of that could presumably be widened. So I think this group has led to some things that have been touching on the economic area, but that doesn't mean that we couldn't be looking at that more broadly. The other thing that relates to that was the whole discussion about societies working together and finding some efficiencies in work around collecting evidence data, et cetera, so that at least has a potential positive economic and sustainability component to it. Yeah. Bruce. Could you go back to the other slide for a second? This one or that one? That one. So with regard to approaches and consensus, I didn't see on there anything about genomic sequencing, whether wholly or otherwise, where I think you're inevitably going to bump into the areas of interest of different societies just because genes relevant to their interest will be encountered no matter what the original reason for doing the sequencing is. So it seemed a kind of obvious place for discussion about standards in terms of reporting and actions taken based on finding. Yeah, I think you're right. And I think it gets back to what Mary had said yesterday that, you know, if we frame the discussions around the perspective that the information will be there, how will you use it as opposed to should I do a gene test or not do a gene test that, you know, if we could frame the conversation from that perspective, then that might yield a different set of conclusions than the sort of the way business is running currently. Yeah, I agree with that. Yes. I don't know if this is consensual or was my personal obsession with data products. But for the budding new data scientists that are emerging out there in graduate programs and even in residences to some extent, there is this lack of a data resource where these issues can be investigated. And maybe this is something where the societies could together pull and develop something. Yeah, I think that that was something that we did spend some time talking about, although I'm not sure that we actually got to the point of an action item that would be, you know, what is the role of professional societies in terms of doing data aggregation or outcomes. But we did talk about concepts of safe harbors and some policy issues related to that. Terry? Yeah, and I think we, and Jonas, it's a good point that you make. Let's be sure that we focus the societies on the things that are relevant to the society. So a data resource is a big, big issue that NIH is pursuing on a kind of a grander scale. But what would be probably very helpful is for the professional societies to tell its members, boy, it would be really wonderful if you guys would put your data into this. And here's how we can help you, you know, avoid HIPAA issues or avoid other kinds of things. Does that make some sense? Martin? Yeah, I just was, I'm just thinking about what you presented. Thank you so much. With regards to the guidelines, could you maybe move it to the slide, because I couldn't really see, but what, is there something specific that, so convened societies' guideline producers to outline process and evidence needs? So is the goal, I'm just trying to understand what the goal is for this. Is it to identify how to use exome genome sequencing to diagnose, predict, or is it just much broader? I think this is really at a much more of a level of understanding how the different societies, what their process is to actually produce a guideline and to say, you know, everybody right now kind of has their own way of doing things. If there are some commonalities, could a group like this, you know, provide feedback to the individual society, say if we modified our process, then we could have perhaps a number of societies that had a process that looked relatively similar, which might then facilitate actually trying, you know, to do joint guidelines. I think, Terry, is that a fair statement? Exactly, yes. So I think we're far too early in the process to define what exactly these things are, and really we're talking about the process for doing it, since that consumed a fair amount of the discussion yesterday. Yeah, so that's what I was thinking of as, you know, this, I was at Rand for a while in this modified Delphi approach to when you don't have evidence, which is what I think we're grappling with, is to convene a bunch of experts, different stakeholders, to, you know, try and reach a certain level of agreement or disagreement on very specific items, and it's, so if it seems to me this would be a good place to try and do that. No, agreed, and I think where we're trying to figure out is how the various societies would take the output of that, and make guidelines out of it, so that we can have that process serve them best. Yes. Apologize for not having been here yesterday to hear this discussion, but it does sound like here you have come back around to talking about clinical practice guidelines. Is that, is that right, or are you still talking about the kind of guidelines on the previous page for what society's best practices would be? Yeah, so I think, again, we got into a little bit of a semantic discussion yesterday about, you know, what that term means, and what we ultimately decided was there are guidelines, which the IOM has just issued a white paper on. This is what constitutes what should be involved in producing a guideline, but we also heard in a number of the society's presentations yesterday that they produce other types of documents that guide their members' practice that do not reach the level of this systematic evidence review-based guideline, and they're, you know, called practice alerts or best practices, or these types of things. And so we're interested in exploring that whole range of things that kind of fall under the broad rubric of guidelines. Yes, Bob? I agree with you, and I think, you know, yesterday, the other, I think that you're saying as well, we recognize that at this stage in the game, for some of the genetic screening or what have you, even if we can get that number one A evidence, we probably would have to wait much longer. What do we do in the meantime? I think speaking from a cardiology point of view, if we had statements across several societies saying, you know, this is the level of consensus about this without true hard RCT evidence, I think it has meaning for all of us that we could refer to. Thank you. Terry? I might just know, Rose makes a good point that we have a bit conflated clinical best practices and society's best practices. And so we'll try to tease that out. That could be one of the things to talk about on the first conference call. Yeah. Good. Ned almost had a question, but friend in Colorado that always talks about being the skunk of the church picnic, I just say that Delphi techniques, expert consensus to an evidence-based person is a little grating. And it's OK. I mean, I understand. But recognize it's not an evidence-based guideline. And inherent in that are the risks of being wrong. That's why I keep coming back to a balanced approach more than just expert consensus of considering the risks of being wrong, the potential harms, and the potential benefits always have to be at the base. Or we end up with consensus guidelines, which we already have. Thank you. But that could be exactly what is discussed is what is OK to not so much about a specific test or condition, but more about the approach. Yeah. Great. Derek, why don't you go ahead and work your way up here, because we're just about done. I think we're, I didn't see any other hands, so unless there's any other, good. So we have it, I think, the takeaway we will refine these action items based on the discussion we had. And Terry, are you thinking that we'll send these around one more time? That would probably be a useful thing to do to everyone. So keep an eye out over the next few days for an email. And again, if you have any other thoughts that occur, we'll continue to refine this until we get it close to right.


Hello and welcome to this next segment of CD spectroscopy and MOSBA spectroscopy for chemist. My name is Arnab Dutta and I am an associate professor in the department of chemistry at IIT Bombay. So today we are going to discuss about the multiple applications of MOSBA spectroscopy. In this particular segment we will take different examples and try to rationalize how we can use MOSBA spectroscopy to understand the basic structure associated with this particular complex. So let us start. So over here we are going to talk about MOSBA spectroscopy to differentiate different complexes and obviously most of the complex will be iron based complex because we are going to use that fact that iron 57 is a MOSBA active isotope and over here the factors we are going to use is the delta value which is the isomer shift which is directly coordinated with the S electron density present inside the nuclei and also delta E Q value which is the quadrupole splitting which says about the electric field gradient around the molecule is nonzero which says the asymmetry around the molecule. So both this factor is going to be very important when you are discussing this system. So let us start with an example. The first example we are going to discuss about Prussian blue and Tarnbull's blue. So these are well known complexes coordination complexes prepared well back like 78 years back. And there is a lot of controversy about this structure. So we will find it out today how MOSBA spectroscopy helped us to understand what is the actual structure and resolve the absolute structure and move out any controversy remaining there. So let us look into it. So first we start with Prussian blue. So what is Prussian blue? So Prussian blue is a complex where we add iron 3 plus salt into a solution of FeCN6 4 minus that means iron is in plus 2 state. So it is a ferrocyanide system and in that ferrocyanide solution we add the iron plus 3 salt and it produces a very bright blue color complex in which we call the Prussian blue. And it is expected that the structure of this molecule is the following Fe 3 plus go outside and bind to it and 4 of this iron centers bind whereas inside this particular system act as a ligand and 3 of them are actually binds to complete the overall coordination geometry. 4 of the iron plus 3 and 3 of this particular ligand which has a charge of minus 4 so you can say it is charge balance. And then I look into it and then I found that there are two different iron centers present over here one is iron 3 and the other is iron 2 and iron 2 is present in that ligand system and iron plus 3 is present on the outside system. Then there is another compound called Tarn bulls blue which is prepared a little bit on the different way. So where iron plus 2 salt was added instead of iron 3 plus you say is iron 2 plus salt added into iron 3 CN 6 3 minus solution. So it is a very cyanide solution. So that is the different previously in Prussian blue iron plus 2 is a part of that complex anion and iron plus 3 salt is added from outside over here it is just swapped iron plus 2 salt added from outside and iron plus 3 now is a part of this complex anion. So then we try to find out what is actually happening on the structure of this Tarn bulls blue. So that is a little bit of ambiguity remain what is the structure of the Tarn bulls blue and that we will try to resolve by using our MOSBA spectroscopy. So let us start with Prussian blue one more time and as we just discussed the complex structure is iron 3 iron CN 6 3 this is iron plus 2 state. So that is the structure of Prussian blue and over here when we try to figure it out how the MOSBA spectra will look like for this complex. So let us first assume and predict what will be the MOSBA spectra for this particular complex. So that I am drawing MOSBA spectra for this complex over here there are 2 different system one is iron plus 3 and iron plus 2 let us look into the iron plus 2 system first is a iron plus 2 with 6 cyanide system 6 cyanide system bound to it. And over here you can see this is a iron plus 2 system by the 6 cyanides. So iron plus 2 will be a low spin complex because cyanides are strong pi acceptor ligand. Now if it is iron plus 2 in a low spin system how do you expect is d orbital splitting will be that will be T2G and EG iron plus 2 means a DC system because it is low spin all the electrons will be like that. So it is a T2G 3 EG 0 system. Over here you can see the electrons are very symmetrically present in this molecule all the T2G are filled up no electrons in the EG. So the valence contribution towards the electric field gradient will be 0 because it is quite symmetrically stable. And on the other hand coordination wise lattice contribution we expect no because it is a perfect octahedral geometry with 6 cyanide ligands. So lattice contribution for EFG is also 0. So this iron plus 2 sample because it is actually having valence contribution 0 lattice contribution 0 so that means it is not going to have any delta E Q value that is also going to be 0. So no splitting we will see only one band representing the isomer shift of this iron plus 2. So let us say we draw it that is we are saying iron plus 2 low spin system. Then comes what is the other system? Other system is an iron 3 which is coordinated from the outside and even it is a octahedral geometry it is going to follow up that is going to figure it out little bit differently because it is going to be a high spin system. Not only that the coordination geometry because it is going to be coordinated with the cyanide in a different way compared to the iron plus 2 over there. So it will be also coordinatively asymmetric. So all those systems says that now because it is co-ordinate asymmetric I am going to see actually a high spin iron 2 system whose electronic configuration will be as following iron plus m is d5. So you can see valence contribution will be again 0 whereas the lattice contribution will be present that means E fg will be not equal to 0 for that. So that is going to come over here. So what I expect my iron plus 3 system will be splitted up I will see a delta eq value and it is coming because of the lattice contribution. So that I am expecting for the system over here iron plus 3 high spin system. The question is where does the iron plus 3 should come the isotopic pattern. So over here the question is where do I expect the delta value the isomer shift should be there for this iron plus 3 system and over here there are two different factors one is it is iron plus 3 and as you know iron plus 3 should go the value to be honest on the left hand side. But over here there is another difference it is a high spin versus low spin and over here I say the low spin systems of iron they generally go to the more negative side of d electron density compared to iron in high spin state that goes to the more positive side this is a delta value. Now the question is why why does it happen so that we will cover a little bit later but for now we found that this high spin system will be on the positive side and the low spin system will be on the negative side. So what I expect this band will come something like that over here and this will be the iron 2 sorry iron 3 high spin system that is we are going to expect for this full system again iron 2 is low spin no contribution from the lattice or balance contribution so single line iron plus 3 outside high spin system coordinatively asymmetric there is a delta aq value but the question is why the delta value of iron plus 2 low spin is shifted towards the more negative side compared to the iron 3 high spin that we will cover a little bit later but this is what we are going to see and that clearly says that yes I have two different iron centers this is the iron 2 and this is the iron 3. Now we look into the turned bulls blue the turned bulls blue if you remember we actually put iron 2 from outside into a solution of iron 3 Cn6 3 minus and then we try to find out what will be the oxygen state of this system. So then we recorded the MOSBUS spectra of this turned bulls blue and what we see is the following large peak like this and signal like this which is particularly same as Prussian blue so they have the similar MOSBUS spectra so if it is having a similar MOSBUS spectra this is what turned bulls blue and the same as Prussian blue so it is saying that I still have a iron 2 low spin system I still have a iron 3 high spin system so how that is possible. So after looking into this MOSBUS spectra 3 scientists their name was Flak, Karlar and Neworth they actually look into the details and try to figure it out what is actually happening over there and they figure it out that this complex is actually started with iron 2 in the outside and Fe3 Cn6 in the 3 minus in the inside and then there is a electron exchange. One electron is getting transferred from the outer iron to the inner complex iron iron and they produce iron 3 on the outside and Fe2 Cn6 4 minus on the inside which further coordinate and give us and that is why we are getting the same MOSBUS spectra. So it is showing that all the turn bulls blue is reacted in a different way at the end it is going to showcase the similar structure because there is an electron exchange step happening and MOSBUS spectra is actually gave us the first hint that it is actually happening in this particular molecule. Now this work was further explored where we try to find out is it really what is actually happening. To find it out that this electron exchange actually happening in the turn bulls blue case to understand that there is another experiment what was done. So an experiment was done in the following way a 57 iron enriched sample was used because typically the iron 57 is quite low in concentration however if I can enrich the iron 57 sample I will see the signals much better and over there they took iron 57 plus 3 from outside and added up in a iron 2 Cn6 salt which is present inside and this is typical one so no enrichment there. So now when it forms the complex in the case this is the Prussian blue I am talking about because adding 3 plus outside 2 plus is inside so over here what do you expect because I am going to look into the enriched sample data right now because over here what happens enriched sample is almost 100 percent whereas the iron 2 sample how much 57 iron it has less than 1 percent or so so that means this is not going to show up very strongly compared to the 100 percent enriched sample. So I am going to see only where I have the enriched iron plus C sample. So as we know we are going to get a split structure so this single structure that we expected earlier over here this signal we are not seeing over here because it is not enriched so it is there but it is so one person that with respect to this it is almost invisible. So this is actually showing it is an iron 3 outside system in high spin and that is expected when we added. Now did the turn blue blue case and then they add iron 3 again to a solution of sorry this started with iron 2 sample and then added to iron 3 C and 6 3 minus sample and over here again the outside iron is 57 enriched sample and what they found in the Mosba spectroscopy that this signature looks exactly the same as Mosba spectroscopy they are identical what that means is over here I am again seeing the 57 iron nothing else and this signature is for iron 3 high spin but when I added it is iron 2 but during the reaction it actually exchange the electron and it becomes iron 3 in the outside and the complex ion becomes iron 2 and they created the complex they require and over here because of this electron exchange happening I am getting iron 57 as a result so that is why the signature is exactly same as Prussian group if it is an iron 2 which is not reacting with the sample then I would have got different signature replicable to iron 2 high spin system but over here I am getting iron 3 high spin system which is again proving the concept that yes the reaction is exchanging an electron in between so Mosba spectroscopy again come into the rescue to find out what is actually happening in the reaction media and this particular reaction with is done by Meyer and co-workers who actually rationally use an iron 57 in this sample and figure it out I am going to get the similar kind of result which showcase the electron exchange in between. So, now the next example I am going to follow so the previous example this is the first example of application now we go to the second example it is about an iron carbonyl complex Fe 3 CO 12. So, it is quite a popular complex tetra-iron dodeca carbonyl complex where 12 carbonyls are there and then there was a question what is the structure of this iron complex. So, people have figured it out there different possibilities so one thing was quite sure that the iron is actually forming a triangular interaction between them first and each of them can take 4 carbonyls. So, that is how it is actually looking into and over there in this complex you can say all the irons are identical carbonyls are all bridging. So, now if I do a Mosba spectroscopy of that I should get only one type of signal which shows that all the irons are actually identical in nature. Then there is another possibility all the irons are always counted on each other that each of them has only 2 carbonyls bound to it in the terminal position and the rest of them is actually bridging in nature. So, over here sorry I put a wrong system all the carbonyls are terminal over here in the previous case and over here carbonyls are 50% bridging and 50% terminal 6 of them are bridging 6 of them are terminal. And all the irons are still in a similar position. So, they are expected to be identical because you can see all of them have been 6 coordination 2 of them terminal and 4 of them are bridging each of them. So, in that is the case I should also get only one type of signal because all the irons are same and I am talking about Mosba spectra. So, that was the thought that we are going to look into and can I differentiate whether all of them are terminal and some of them bridging some of them are terminal yes by looking into the delta value I can predict that. So, with that in this mind people go and try to look how that looks like in the Mosba spectroscopy and what we found is the following it is one portion of the signal which is actually say I am saying a signal is actually having a large quadrupole splitting and there is another signature in between which you call the B signal which has another delta. So, there are 2 signatures over here A and B and the ratio of A and B we are looking into the area they have covered that is 2 is to 1. So, I get a signature of 2 different irons present for Fe3CO12 in Mosba spectroscopy. So, which says I have 2 different irons now how it can be properly rationalized. So, when you look into the complex structure one more time we find that one of the iron has all carbonyls in its terminal position whereas the rest of this 2 have only 3 of them and what is happening to the rest of this carbonyls. So, they are actually binding as bridging ligand. So, over here you can see the total 12 carbonyls over here this is going to the 4, 3, 3, 10, 11 and 12. So, these 2 iron are obviously going to be different and these are 2 of them in. So, these are the A centers which is shown over here in the Mosba spectroscopy. Whereas one iron is there which is obviously different because it has all terminal iron, terminal carbonyl and this terminal carbonyls ensures this iron is behaving differently compared to these 2 and that is the B type of iron which is shown over here. So, that is why we get 2 different iron centers and over here the ratio is 2 is to 1 for obvious reason and the A iron because it is having both terminal and bridging ligand it will be more asymmetric. So, A iron are more asymmetric because it has both bridging and terminal COs compared to B iron which is actually having only terminal CO. So, that is why for A electric field gradient will be nonzero, but that will be more asymmetric and more asymmetry in the delta E of G at the electric field gradient is actually reflected into high value of quadrupole splitting. Whereas on this thing we have terminal carbonyl but it is not perfect octahedral because it has 2 iron bound to it. So, it has asymmetric but asymmetric extent is actually low compared to this other 2 irons. So, that is why this also shows quadrupole splitting but at a lower extent compared to the A irons. So, that is how we can use a example of iron carbonyl complexes organometallic complex and use it with respect to Mosba spectroscopy to find out what is the absolute structure and we found in this particular complex it is neither this particular structure nor this particular structure it is having somewhere between this structure and Mosba spectroscopy showcase that how it is actually can be achieved. So, with that we will like to stop over here for this particular segment and from tomorrow we will try to provide further examples on Mosba applications. Thank you. Thank you very much.


What is going on guys? Today I am back with another Destiny 2 video and today guys I bring you my Trials of the Cyrus Looting results for going flawless. Now last week I played Trials, I played three games, kept running into teams of Midas, I just got fed up with it. This week I actually played with a decent team so a big shout out to Hazoo Dynasty and Rapid Car for helping me get into that seven and all flawless and end up right here to collect this loot. But before we go any further guys on this video I am giving away silver to win some simply drop a like and a video and leave a comment down below. Okay so we have whatever we can get from this place I'm not even sure to be honest. Coming here, going up these levels for the first time. I know you don't get any from these unless you spend your coins with them but I'm not gonna do that. I'll spend mine at the very last part. Let's have a quick look. Oh I Trials Engum here. Well let's see what's in that. So I've got the flowing grips, gifted nine and a dead end cure. Let's quickly take a look at that. I've got the legs of these. I got these last week from a drop and they look pretty cool actually. They do look pretty cool. I'm hoping to get the auto rifle. I seriously am. That's what I want. I want the auto rifle. Let me double check at that. I don't leave anything behind here. No, no, no. So let's go up again. Now how do we go up that way? This way. Now I'm not. What's going on? So I'm just flying around. Okay so I know Hawthorne's got a engram from me as well which we will open in this video also. Hopefully I get some. I need out of that. So what do you have for me? Do you have anything? I don't even know. Okay so I've got a legendary engram here too. That's pretty cool. You use relentless. What's do relentless? What's do relentless? What's do relentless? What's do relentless? What's do relentless? The pulse. Okay. Okay. Sounds quite good. Snapshot sites. We've got slideways. Head seat. Oh yes. Oh yes. Let's quickly check out what a shady looks like on this thing. My favourite shader. Oh yes. Loving that. Let's go up further. I'm liking this. I'm liking the amount of loot we get here.  Oh there we go. There we go. This is pretty cool. We actually quite a lot of loot to be honest. So this is the final floor I'm guessing because we jumped down to there. I've seen in people's videos. It's a lot of...  Didn't need to go this over the top. I don't think they did. Oh so we get to pick three weapons here. So we get either the pulse, the shotgun or the SMG. I don't know. I don't know. You know I won't take the SMG because if it's bad I can always infuse it. Oh I like that emblem. Let's quickly take a look at that. But yeah I ain't really a shotgun fan to be honest. I don't really... Oh there's a primary SMG. That's good. That's decent. That is decent. Looks pretty decent too. I like the design of these weapons actually and that looks crazy. Let's quickly have a look at that emblem. Oh that's nice. I'm going to get rid of some of these because I don't need them. I hate having something full as well. Just annoys me. So we go up here. Oh I'm being sucked into another dimension for that beautiful loot. Okay so we have landed and here we go. Let's go. Let's go. Oh there we go. Okay so we get the pick either or this is a choice. I think... What have I got? Are these not the same things? Floating boots and flowing boots. Okay so I'm going to take the chess piece anyway. Hey and I got the ninth or I got the you are worthy emblem and I also got the floating vest. Now we've also got points to spend. So let's go what we're going to get here. A prosecutor. Did I not just get that? Yes! Yes I would shout but my family was asleep so I can't but damn they only dropped a 296 though but still that's all right. So I've got the chess piece I can't wait to put all this on. But yeah we've got more engrams to open. I got the cloak. I got the cloak. I'm gonna get full trails gear here. Oh I like that as well. Looking pretty snazzy. Looking pretty snazzy. Let's go. I've got another one in me. I don't think I have. Oh it's so bad. No two more. Two more. So now I have to go to the tower and see what Hawthorne has for me. Because Hawthorne's got something for me. All right there. So that's what we're going to go and pick it up. So we'll resume the video when I get back there. Okay so upon getting to Hawthorne I've realized I've become a victim of the glitch yet again. A friend of mine actually went to the lighthouse yesterday and everybody eyes my clan received an engram from Hawthorne. I didn't. I'm pretty sure I got a notification pop up on the screen earlier that she has an engram for me and it just is not here. So what is going on? Now they're quick enough to fix other glitches like the trials glitch where people getting out of the map so they changed the map. They're quick enough to do stuff like that. But things like this where it rewards people. But yeah guys it is what it is. I can't do anything about that. But guys anyway I still got some decent loot. I can't complain. I got the gauntlets. I got the chest piece. I got the cloak. I got what I really wanted which was a prosecutor also rifle. I also got the pulse rifle and the SMG. So I can't really complain. I'm actually quite happy about that. And I also got the flawless emblem which is quite decent. So yeah quite happy with that. But guys that is it for another video. I hope you enjoyed it. Let me know down below in the comment section if you've been flawless yet. If you have what did you get. But thanks always for stopping by people and hopefully I will see you on that next one.


All right, what are we talking about for today's e-com lesson? If you're in the e-com system, I'm here on the farm, and it reminded me of an extremely important principle if you want to make money in e-com, extremely. And I call this the wake up in the morning framework. So people ask, and one most common question is the e-com, and an important question is what do you sell? You know, the four Ps of business, you have people, product, right? Promotions, placement. So e-com, you know, you need to know these four Ps. I also have the seven Ps and the 12 Ps, which I developed out of the four, which are kind of my own system. But we'll talk about that in another business lesson. Four Ps, people, you need good people around you to build your e-com business, product. You got to be selling the right thing at the right time in history, by the way. You could be selling the right thing at the wrong time in history, where there's no demand. It's not viral.  And placement, you have to know how to have the website and to ship the product, if it's physical or digital, so that it's placed in the hands of your paying customers. Let's talk about number two, which is product. You get the product thing wrong, and you could have the other three Ps working well, and it just stymies the whole thing. So what's this framework? The wake up in the morning, or I call it the millions of people wake up in the morning framework. Ask yourself, are you selling something that this today, this morning, millions of people around the world woke up and go, I need this solution? So give you an example. If you're selling underwater basket weaving program, digital product or some physical products, nobody woke up in the entire world, you're in a total addressable market. They call that your TAM, T-A-M, total addressable market. For people who woke up in the morning and said, I need that, it's like 100 people, and you're not going to get all 100 people, you get one customer, right? If you're selling something, I'll give you an example. I saw a product years ago. It was like a safety device for parents to put on their children, so if their kids are lost in any, whether they're kidnapped or accidentally lost, you can go find your kid. Kind of like you have iPhone find my phone. I was thinking, there's millions of people, parents who wake up who worry about their kids, worry anxiety. In fact, the emotion of anxiety, if you talk to an evolutionary biologist, probably we evolved anxiety in great part to protect our children. So there's millions of people who wake up fearing for the safety or anxious about the safety of their children. So this passes if that's a product that you find, various products, by the way, you can take this business idea. That's a powerful business tool. Powerful business tool because people go, huh, I'm worried about my kids. This solves the problem.  Like there's hidden devices and stuff that people wouldn't see. So that's a great e-com business to build. That's an insanely good e-com business. So I wanted to, this is a free version of the more advanced e-com lessons that I have. I'm going to keep talking on this subject, but for those of you who aren't in my paid e-com program and you're just in, you know, watching my YouTube, that's a little tidbit practical business that you can launch, you know, things that help and for pets too.  Solve a problem that millions of people not only woke up thinking about, but actually have high levels of emotional pain around it and then your ad pops up on Facebook or they're on your email list and you hit them with the product. They go to your website and they buy. It's literally, that is a fundamental causation correlation. That is a causative having high appetite products that millions of people woke up globally thinking about. You solve the problem. That is causative in massively scaling your e-com business. So little practical tip now, if you want to hear the lesson, I'm going to keep recording. I like to give away free value to the world, but I also have for the community who's willing to get in there and work and I've got the e-com programs not that expensive. I'll put a link right below or you can go to tidalopiz.com slash podcast e-com. That'll redirect you. I'll redirect you to a page not that expensive tidalopiz.com slash podcast e-com. The word podcast and then e-c-o-m-m, tidalopiz.com slash podcast e-com. Go get the program. It's not that expensive. I got 100% refund policy if you don't want it. I want to show people what I've learned. I've been doing e-com as long as a long time. I started an e-com up to digital products. I've done physical products, companies, done hundreds of millions in revenue with different e-com products. I've learned a couple of things. I bring in the best teachers. I'll put a link somewhere in the corner if you're listening to the audio. I just want to give you this free tidbit practical business. You can Google how to find some of those companies that manufacture those find location type GPS devices. Of course, people do this for their cars too, by the way, like low jack tracking all that. Tracking devices to keep people or objects safe is a great e-com product. I just want to give you that value for free if you want to go deeper and go through the paid certification program to really learn e-com. Click the link below or I'll see you over on tidbit.com slash podcast e-com. I'll keep recording. I'm going to keep recording this full lesson for those who are in the e-com community.


The systematic review and meta-analysis found that patients with diabetes have an increased risk of failure and death during tuberculosis treatment. The risk ratio R for the combined outcome of failure and death is 1.69, while the R of death is 1.89. Diabetes also increases the risk of relapse. However, there was no evidence for an increased risk of tuberculosis recurrence with drug-resistant strains among people with diabetes. The studies assessing sputum culture conversion after two to three months of tuberculosis therapy were heterogeneous. The findings highlight the need for increased attention to treatment of tuberculosis in people with diabetes, which may include testing for suspected diabetes, improved glucose control, and increased clinical and therapeutic monitoring. This article was authored by Hart Jessica E, John Christie Y, Harry's Anthony D, and others. We are article.tv, links in the description below.


This is stock number 9766 we are here at Summit Automotive in Fond du Lac, Wisconsin You're new and used heavy-duty truck headquarters today. We are checking out this extremely clean 2016 Ram 2500 crew cab short box this truck has the 6.7 liter Cummins diesel From this HD video you will be able to tell that not only is this truck probably one of the coolest looking Rams we have on our lot, but it is probably one of the cleanest as well Blue streak pearl metallic is the color we shoot all of our videos in 1080p So if you have HD capabilities on your computer tablet or a smartphone device turn them on now because it's like you're right here Looking at the truck with me Factory chrome step bars it comes with the 20 inch painted alloy rims with the chrome pockets and it has Gladiator X-com tires on these are 35 by 12 and a half R20 LT's and they have right around half the tread left You can see the frame and underbody is very clean on this truck. Looks like it has a leveling lift kit Probably a two and a half or three inch leveling kit Front fender is in excellent shape didn't see any dents or dings on that the hood is in excellent shape as well It does have the clearance lights up top Front grill is in nice shape Headlight lenses are nice and clear It does have the sonar on the front of the bumpers and you can see that that bottom valance is in excellent shape as well passenger side front tire And rim is in excellent condition as well then see any stuffster scrapes on that And the passenger side tire has just as much tread as the driver side As you go down this side of the truck you can see just how clean the body is How reflective and mirror like that paint is We take these HD videos So if you are far away or even if you're close by and just cannot make a trip down You can still see the truck here the truck and of confidence in the vehicle that you're looking at before you even get here We sell a lot of trucks out of states We want to make sure that our all of our customers including our out-of-state customers have the confidence that they're dealing with the right people and the right truck Very clean down that side More rockers all look really nice This back rim is in nice shape as well No scuffs or scrapes on that back tires have just as much tread as the front tires And you can see just how clean that frame and under body is It's like that all the way underneath Looks like it has been DEF deleted But very clean underneath here aftermarket exhaust Rear bumper is in excellent condition as well. No dents or dings on that The rear tailgate is in really nice shape as well Didn't see any dents on that and it has a spray and bed liner It also has the LED bed lighting that tailgate shuts nice and solidly As you go down this side of the truck just as clean as that passenger side See just how nice and clean that body is on the bed there Paint is very shiny Back rim is an excellent condition as well Very clean down this side of the truck Does have the fold-out tow mirrors. They are heated have built-in directional signals So inside the bighorn package this one has leather seats black leather I believe they are aftermarket leather in here power driver seat factory floor mats throughout Power windows power locks power mirrors the cool thing about these mirrors is that they power fold in and Power fold out as well. And this one does have auto headlamps As we hop inside the truck here you can see that it has the seven inch tft display has 27,284 miles has your compass outside temperature Trailer brake gain range to empty all that good stuff in there, and you can set those up however you want Has a heated leather wrapped steering wheel Cruise controls on the right Bluetooth and information center controls on the left comes with the six-speed automatic transmission Has the 8.4 touchscreen radio This is where your backup camera shows up Also has your heated seats and heated steering wheel Buttons you can check out the backup camera without actually putting it in reverse You do get your dual climate control Factory brake controller more heated seat and steering wheel buttons Stability control tow haul factory exhaust brake and then your front and rear bumper sensors You can turn those off or on Has a turned-out four-wheel drive has a hundred fifteen volt hundred fifty watt plug-in and The passenger seat is Very clean as well. No rips or tears on that truck smells very clean inside I'd be highly surprised if it was ever smoked in Headliner is nice and clear And it has the power sliding rear window with the home link buttons as well Then you have the assistant 911 in the mirror which are features of the vehicle You never have to pay a subscription for So something cool about this radio now it doesn't does not have navigation You can add nav to this radio for five hundred ninety five bucks. Ask your sales professional about that because it can be done here at the dealership and then down here you have a Cell phone holder which is kind of a neat deal We'll take a quick look at the back seats and then check out under the hood Back seats are just as clean as the front seats No rips or tears back here Does have that power sliding rear window latch child safety system These seats fold up for extra storage And you also get the load floor Which is nice if you got pets you can put them both down and they have a nice flat place layer if you got muddy boots or tools put them on there and Yeah, looks like they did have some subwoofers a little bit of extra speaker wires back here and There is in-floor storage as well Take a quick look under the hood. I Personally like to thank you for checking out the video today. This is a very sharp good-looking truck and She's all ready to go engine bay is very clean runs very smooth This truck has been fully safe to get inspected by our service shop as a fresh oil and filter change all the fluids have been checked and topped off and This truck is 100% ready to go To see more pictures of this truck or one of our other 450 new and used cars trucks SUVs minivans Wranglers half tons three quarter tons one tons you name it. We got it go to our website www.summitauto.com full pictures and descriptions of every single vehicle on our lot videos of every single used vehicle that we have All at summit auto.com if you want to check out just our used inventory you can go do trucks on 41.com that's trucks on 41.com and Check out just our used inventory right there And if you want to make this truck yours give us a call right now<PHONE_NUMBER> ask for one of our sales associates to make this truck yours today Once again that number is<PHONE_NUMBER> and if you'd like to check out more HD videos like this one You can go to youtube.com slash summit auto Remember to like subscribe and share on this video and all the videos that you see there In fact in a second you will see a link to subscribe to our YouTube channel on your left It links more heavy-duty truck videos like this one on your right If you have not been to our website on the bottom link to this vehicle on our website click those check us out And we really look forward to helping with this super clean 2016 ram 2500 crew cab short box big horn. Thanks again