Competition is a core aspect of arcade and casual games. Having a leaderboard with the best players and their scores really sparks players' engagement. That said, how to implement a leaderboard? Loot Locker is a service that provides solutions for indie games, especially for database management. So it's perfect for that kind of stuff. It has all sorts of where-to-use tools that help us implement all those fancy features that online multiplayer games require. Account authentication, leaderboards, assets and inventory management, triggers if you want to make in-game events and reward players, push-a-thin billing, which is cool if you want to make money out of your game, right? And even more, you name it. So in this series of videos, we are going to see how I implemented these features on Moons Teaser, because it really needed them. The first thing we need to do is to create an account on Loot Locker. For that, we can go to my.lootlocker.io and click on Create Free Account. After logging in, we need to create a new game. For that, just click on the New Game Green button. Click on Setup New Game to create a game from scratch and enter some settings for your games, such as its genre, name and other stuff. Then select the platforms you want to publish the game. I chose Android for Moons Teaser. After you set your game up, Loot Locker would display a dashboard where you can manage it. There are some struggles about what to do next, including how to set up a leaderboard, but let's focus on the first step, which is to authenticate players' accounts. To sign in the player to a new PlayStation, Loot Locker offers a cool API that allows us to make guest logins. In a guest login, as long as you pass the same valid player ID, Loot Locker will either create or retrieve the player data on their database. So for instance, here on Moons Teaser, if the person is playing on Windows, Linux or HTML5, the game uses the OS Unique ID to login. This way, unless the player changes the OS, we can retrieve their data. In this project, I've also set up the Google Play service add-on, which allows me to use the player's Google Play account to sign into the game. Let me know if you want a video about how to install and use this plugin, because it's essential for people wanting to make games for Android. Nonetheless, back to the video. If the player is on an Android device, the game uses the add-ons signing method to retrieve a dictionary that has a key to the player's ID. Then I can use this ID on the Loot Locker singleton so it can authenticate a new player session. Let's see how this singleton works. In order to perform a login, we are going to mess with dark sorcery. HP requests. I've been avoiding this kind of knowledge my whole life, but it was inevitable. The time has come. To use such powerful magic in Godot Engine, we are going to use a special node. One capable of ending such power and become a vessel so we can control this chaotic force, the HP request node. The main feature of this node is that it encapsulates all the procedures necessary to perform HP connections in a single method called request, which can pass the URL, some header arguments, the connection method you usually post or get, and the request body, which is what we should pay most attention to. When the request completes, the HP request emits a signal with some important data. The most important one is the body of the response given by the other side of the connection. In this case, the Loot Locker servers. Okay, quite confusing, right? So let's see in practice what this all means. To make a login on Loot Locker, we do a request to the following URL. The header should contain this text. Then we should use the httpclient.method post for the connection method. And finally, for the request data, we should pass a JSON dictionary with the following structure. The game key, which we can get on the Loot Locker dashboard so we can go to the game and then settings, game settings, API, and there is the game API key so you can copy and paste this text there. Then we have the game version which you can pass any alphanumerical value so we can just maintain and control the version of the game that you are using. Then we have the player identifier key which is the most important one. This is what we should ensure that we are passing the same data. This is where we are going to use the OS unique ID or the player's ID that we can get from the Google Play Store API. Then for testing purposes, we can pass another key, which is the development modes and pass the value true so we are just testing out this whole thing. With this, we should wait for a response from the Loot Locker servers. One troublesome aspect of dealing with network and especially with HTTP requests is the fact that while we don't get a response, the game still runs. This is what we call a synchrony when code processes can get out of synchrony. So we must use the yield keyword here to wait for the response. Using this keyword, we can stop the code from running until this object emits its signal. We can access the signal arguments as an array that the yield keyword returns. The fourth index of this array corresponds to the body of the response that we want to get from the Loot Locker service. So let's start it here on this response variable. We must pass this text as the JSON dictionary so we can access the important data. This dictionary has exactly what we need, the section token key. This is what tells us that the Loot Locker authenticated the player and a new section has begun. We need to start this section token so we can access it on further request moving on. Okay, this object will wait for the Loot Locker service response, but everything else still works. This means that players can, well, mess things up. So weird errors and bugs can occur. How do we prevent that? Well, I created an object to overlay everything and prevent interactions from the player. It also has some predefined text to communicate the current game state. So I called it network state label. The most important part is that it should consume inputs to prevent them from reaching other objects in the same tree. For that, I use the input callback to consume inputs and I've also set the mouse filter property to stop. This object has some animations to make the labels text more interesting. For instance, this is what it should display while authenticating. I turned this object into a single tone so other objects can easily access it. For instance, in the Loot Locker object, I call this method to play the authentication animation. And this other one, after we receive the service response to play the authentication successful animation. If everything goes well, we should get a successful login. We can even see this player data on our Loot Locker dashboard. Well, this is it for this video. Coming next, we are going to use this player data to create a leaderboard with the 10 highest scores. See you there. Thank you so much for watching. Keep developing and until next time.


Hello everyone, welcome to another Pilates India Expedition Sharing session. This session is going to be on women doing research. We have Prachi Singh with us, who is a PhD student at IASC Bangalore. And she'll be talking about her journey on person PhD and how it opens doors to many opportunities. Over to you Prachi. Thank you, Sukanya. Hi, everyone. I'm a PhD student in Indian Institute of Science Bangalore. I'm working in the area of speech processing. I try to apply algorithms of deep learning and machine learning in speakers, recombination, and audio segmentation. The popular voice devices like Siri, Alexa, and Google Home, they have some speech processing going on inside them. And I'm trying to improve the algorithm and to build on that. So with that, I would like to start the talk. I'm going to talk about a PhD, a door to many opportunities. So this topic I've chosen based on my experiences, because when I was working for an automobile company, I wanted to explore more and learn new things. So I decided to go for a PhD. But because of many stereotypes, people around me were not very supportive, including my parents. Because they were like, it will take a lot of time. And eventually, you'll become a professor. Instead, I can go and find another job, and so on. But I still chose this path because I wanted to experience student life again and explore new things. And I don't regret it. I want to inspire the youngsters who are watching me right now and other people to explore more and to also consider research and PhD as an option and for good reasons. I also want to highlight some of the key aspects which we have in the academia, like gender issues and all. So with that, let me begin with the quote by Nobel laureate Albert Sanz-Kerge. He said, research is to see what everybody else has seen and to think what nobody else has thought. So this is the outline of the talk. First, I will discuss various aspects of PhD, what it is about, and then I will discuss advantages of doing PhD in India, followed by some statistics related to gender gap. Then I want to uncover some facts and what myths we have regarding PhD. I also want to highlight some of the research and career opportunities during and after PhD. Then I would like to end the talk by highlighting some women scientists who are doing great work in India. So let's begin by asking the great question, that is, what is PhD actually about? So like if you consider here in the figure the big circle representing human knowledge, all of human knowledge. So when you start your primary school or high school, you gain some little knowledge. So that is represented by a small blue circle, then it grows to green circle. And when you do a bachelor's, it grows further. But it grows also, you gain some particular specialty. And when you do master's, it goes in that particular direction. And when you choose research, you have gone specific to that area of research.   But still it makes a difference. And it helps the science community and the world as a whole. So that's what I want to say. And apart from doing research, you also learn a lot of life lessons, which I have learned. So that I want to give example from my experience. Like when I joined PhD, I had no clue what area I will be working on. But then I had to read a lot to figure that out. So I had the freedom to choose whatever area I can. But still I have some time frame within which I should decide. And then I had flexibility to work as long as I want. So it is like freedom with responsibility. And once I decided, then I have to study more about that subject in depth. So I have to keep myself self-motivated because nobody will be guiding me all the time. There will be supervisor. But it is not like our bachelors or our school that the teacher will be always monitoring you. So you have to be self-motivated. And then you have to manage your time. And then many times you won't get what you desired or what you expected the results. So you have to have a lot of patience and you have to be optimistic. Then while writing paper, you have to be creative to express yourselves just that all other people understand it. See, I have learned and I have grown as a person during my three years of PhD. So here I want to highlight some of the expertise and skills which we learned while doing the PhD. So first is data analysis. So you have to collect a lot of data and analyze it. So it helps to build the ability to analyze and present complex data. Then there is testing and experimentation, which is basically helping to learn more problem-solving skills with a positive approach. Then there is publishing in reports and presentation in conferences, which is like helping us to present complex project in a comprehensive and precise way and gain good communication skills. Then we have to organize research seminars, which builds our confidence and gives us the ability to lead from the front. And the last important things are completion of PhD on time. Although it is flexible, but if you can finish it within time, then it shows that you have the ability to handle complete, tough projects in the given time period. And then you have to write a hundred plus of pages, this is that shows that you're good at analyzing, planning and collecting information in a productive way. So with this, I also, in the next section, I want to highlight, like what are the advantages of PhD in India? Like many people sometimes to think or many times think that going abroad and doing PhD will be more better. But as a personal experience, I want to show what are the benefits you will get if you do it in India. The first advantage is that you get scholarships whenever you join for PhD in a government institution. It provides monthly staff and to all the PhD students for a duration of five years. And it is sufficient to fulfill your basic needs. And also you can save on that because you will be living in a hostel and you will be provided with mass facility. So it will be a very cheap option compared to living outside. And the students can also apply for other industry or government fellowship based on the research proposal. Like the MAJRD is there, then PMRF has recently started for to encourage people to go for PhD. So it encourages people who are from IITs and NITs and who pass the entrance examination with certain cutoff to directly apply for this fellowship. And then they will be getting some 70,000 per month as a stipend, which is very good if you compared with the industry. And there are other for science streams. There are other UGC and then CSIR and then industry of Google fellowship and IBM. And there are many other. So next is the travel grant. So you receive travel grant from Institute for traveling and accommodation to attend conferences. So you get to explore new places across the globe and meet experts from various fields. So on the right side, I have shown the picture of a conference which I have attended last year. It was in Austria and it was a very great experience for me because this was my first international conference. So it helped me to stay updated. I've also put the recent trends in industry and meet people for internship and job prospects.  So it's like campus is spread around more than 100 acres of land. It is all full of greenery and fresh air and without any noise. So it's very searing to spend your time there. And we get all the facilities like playground, badminton, code, swimming pool, gym, et cetera to enjoy extracurricular activities. We can be part of various clubs like Tama Club, Dance Club. And in the first year, you get to interact with people from all around the world. So there are lots of benefits. But still, there are issues like there are not as many post-graduates as undergraduates. And also there is a ratio difference between men and women. So here I want to highlight some of the statistics. So this is representing the gender gap. So the blue color represent the men percentage across scientific career. And women is represented by orange color. This I have taken from Women in Science Forum of UNESCO. And it is showing that initially, although the ratio is equal when we are in high school or bachelor level, but as we grow in the scientific career, the gap is widening. With in top academic positions, there are only 11% women compared to 89% men. And there are only 3% female who won the Nobel Prize. So yeah, there is a gap. And even in this 2020, where we have all the facility, internet and all, we should be doing better, I feel. And if we see this in academics, so the women faculty ratio, here the plot is the access shows the women faculty percentage and the Y axis across various discipline in Indian scientific institutions. So we can see it is very less, like it is less than 30%. And for engineering, it's the most poor. This is taken from a website biaswatchinger.com which is managed by a professor from IIC. Dr. Vaishnavi. Here also, it's showing the percentage gap, like the Y axis is the women percentage and the X axis is the various Indian institution. So it is less than 50%. And mostly it is less than 20%. So that is a very, not a good thing. Like we should be having more women in all this field. So according to the February 2020 report by United Nation, India actually tops the world in producing female graduates in science, technology, engineering and maths, which is called STEM, but ranks 19 in employing them. So there are as many as 40% of Indians who graduate in STEM are women. Despite this, women cost you nearly 14% of the total 280,000 scientists, engineer and technologist in India. And two of the many reasons which was published in social psychology of education article in Springer this year are the stereotypes about science in the family, like parents and other family member think that based on the gender which is the better for women and for men. And then there is lack of information about careers in science. So from my part, since I have got this opportunity, I want to give highlight some of the aspects so that people get some more information and they can pursue career in science. There are some myths which people have which I also had. And based on the experiences, I want to highlight the facts so that you can take the right decision. So first is the PhD involves lots of studying. So everybody thinks and they'll get scared that okay, we have done enough studying, now we want to work and all. But I will say yes, it will involve studying, but you select your own subject, ideas, theories, which you are curious about and want to know in depth. So it is more, you will be enjoying while doing it rather than taking it as a hard work. So here I have just highlighted one comic. It is from a very famous phdcomics.com website. They actually make fun of PhD students. So I just wanted to put it for fun, like the guy is putting webcam and the other guy is getting scared, like okay, people will know how hard we work. Means it is like a sarcasm. So yeah, okay. Moving on. So other myth is that we can go only for teaching profession, but that is also not true because there are research position in Google, Microsoft and other big companies and organization like is so the audio. And then you have other opportunities. So it's not like you have to only teach. Here it's like people think it will take a lot of time and you have to do mtech, then only you can do PhD. But direct PhD is also the option. In fact, I am direct PhD student directly after bachelor I worked and then I joined as a PhD student. And I also was not sure of this option when I applied, I applied for mtech and then they gave me the option whether you want to go for PhD directly. And I was more than happy because eventually I was thinking to do it. And then I saved my two years and could do it. And yeah, then while working on PhD it's on your area and efforts that decide the duration. And within this range maybe three to six years you will explore more. You will meet new people across the globe and you will know what your passion actually is. So while you come out of the PhD you will be more confident to choose your profession and yeah, you have the liberty. Yeah, for girls it is another concern. Like for married women it will be difficult. So during PhD I can't get married and then it will get late. Like it's basically the concern of parents. But here actually there are many married women in my campus and they are doing very well with the family support and advisor support. And you have the flexibility to work according to your time rather than in companies you have to work fixed hours you have to finish or something over the deadlines. But here you have the flexibility. Yeah, so with this I want to show some research and career opportunities which are there during PhD after PhDs. So there are many potential areas which are all interconnected. So there is neuroscience where you explore how human cognitive abilities work and then you have to take lot of data or to analyze that. And then that data can be used in data science to do some other experiments. And this can be used to build machines. So then comes the artificial intelligence. Then people build robots by using the whatever data they have and train their models. So there is the mechatronics and there are other disciplines, aerospace, applied physics, neuroscience. And they're all interconnected. So it's not like you are working then you have to be in that field only. But you have to know a little bit of everything actually. It's not like you can do only one thing. The world is all connected. These are the some of the career opportunities. So in academia and industry, both places you have the opportunity. In academia you can go for a professor in various government institutions or postdoctoral fellow, which is like after PhD, if you want to work on your own for a few years in a lab. Yeah, then you can go for becoming a scientist in the organization like Ishrode, Yardu, NASA, CSIR and so on. And then other than that, you can go for science writing or you can become an analyst or scientific advisor. In industry you have options to join big companies and become a researcher. Like every big company have a research lab. They're publishing lots of paper and data scientist research program. And can you start even your own company? Like there are many PhDs who go for that. So there are many, many opportunities. Now to encourage the women who are watching me, I want to highlight some of the great works done by the women scientists in India. So the list is actually very long, but I have cut short to highlight some of them. So first is Sunita Sarawagi. She's a professor in computer science and she's working in the area of data mining and machine learning. She has won the Infosys prize of $100,000 in computer science and engineering and she's working on how to figure out how to extract information from the unstructured data and use it in a better way. Other professor, famous professor is Vibhita Vardhir. She is from Tartan Street of Fundamental Research and working in the area of neuroscience and she's working on how to decode human experiences and stress affect the circuitry of the brain so that we can figure out some of the psychic disorders which people develop. And she has also won many awards. Then there's a young scientist, Chandni. She is a system professor from instrumentation applied physics, ISC Langler. Her area of research is in interface of material science and experimental condensed metaphysics. She's trying to explore properties of graphene which is found in pencil and how it has potential application in physics. Then to highlight some of the scientists from the government organization, there is Ritu Karidhal. She is very famous for the mass orbiter mission and Chandrayaan too. She is part of ISRO. She has won ISRO Young Scientist Award. And then there is one entrepreneur also, Geetha Manjunath. She is the founder, CEO and CTO of Neera Mai who develops novel software to detect breast cancer. Then last but not the least, there is Dr. Rohini Godbele. She's a physicist in center for high energy physics, ISC Bangalore. And she is working in the area of particle physics. And she has won many national and international awards and one of them is Padma Shree which she recently won for her efforts in science and engineering into 2019. She has more than 150 papers and she is actively working to inspire young women to pursue science as a career. So yeah, there are many, many women out there and you can become one of them. So with this, I would like to thank Pycon India for giving this platform to express my views. I want to thank Sukanya for giving the opportunity. Thank you. It was a very nice and informative session. We have one question so far. To all those who are seeing this, please, you can keep your presentation on if you feel like. I can take the questions from the chat and we'll get back to you, okay? So to all those who are listening, if you have any questions, please put it in the chat. So one question from Rangaraj. What we have are all research papers after published will become a practical application or is there a mandate that the PhD research should become practical? No, it's not like that. It need not be go to industry. Actually, it takes a lot of time to, like whatever research we are doing to get to the industry because there is always a gap. And what we work, can be theoretical also, which will have application which somebody else will work on. So it need not be that it has to become a product. Hope that answers your question, Rangaraj. Yeah, any further questions? Okay, in which area are you pursuing your PhD from Neeraj Kumar Singhbhai? I'm working in the area of speech processing. Basically, I work in the conversational speech where many talkers are there and my task currently is to segment those speakers and to annotate the meetings because it has a lot of applications because it is used in many devices also. So you need to have separate segments for each speaker to understand what each speaker is saying. That's great. Do you want to, Prasid, do you want to share your social media handle so that people can reach out to you if they have questions? What would be the best way to reach out to you if they have questions? Maybe LinkedIn will be the best, should I share? Should I share? You can stop a presentation and you can just keep your video on for the moment. Okay, okay. Just a second. Yeah. There's another question from Sachin Goyal who would like to know, how is the work pressure strict deadlines? So in job, usually we have strict deadlines which helps to keep the learning pace high. So is it the same for PhD? Compared to job, I would say the pressure will be less. So means also it depends on your supervisor. Like some supervisor are very strict about the deadlines and some are lenient. So it is depending on that. But more or less it is not that much as in job. Any further questions? Okay, so a follow-up question to that is like, so the learning curve is steeper then. Ideally it should be yes, right? How about learning curve steeper then? How about the deadlines? What if you don't need deadlines? Actually deadlines is all relative because it depends on the your area. And you have to, there is minimum publications required if you want to finish your PhD. So if your area is like very fast growing then you have to publish fast. And if it is like more experimental work, like in biology generally takes a lot of time. So then it will need more time to experiment than the publication even if it is less then also it is fine. So it is all relative. Okay, there's a question from Julene who is asking, is it okay to apply randomly for any PhD? Actually no, I would say because PhD is very specific and if you apply randomly then you might not enjoy it and you might not be interested. So you should first know, actually you need not go in depth of what you actually want to do but a broad idea should be there. Okay, does it answer your question Julene? Yes, so yeah. So there's another question. Are you familiar with explainable AI Prachi? There's another question on explainable AI. So Neeraj Kumar is asking, what is the future of research in explainable AI? Is this topic related to your research also? Means I'm not directly working but yeah it is gaining a lot of interest and definitely it is a very potential topic because people are now interested in learning in knowing like how we can explain the models because earlier it was like people used to train the model but they used to think that okay how it happened, like how it worked but now it is like people want to know how we can explain like what is happening inside it. So it is a very good topic. There's another question. Do we have any platform to check whether the research is a duplicate one or not? Actually, please raise your hand probably. Okay, yeah there are websites where we can check plagiarism but actually I don't have those links right now but there are websites and then there is Google Scholar where you can keep yourself updated about recent publication. It mostly many publication will be there who are already published, which are already published. Right, okay. There's another question. I think they're already over time but yeah this would be okay. Two more questions and we'll end because we have already crossed the time. So from Julian we have what if two groups work on the same thing and one group publishes when the other is halfway. What to do then? Like two research groups working on same paper one already reached the end line other is still on their way. So how to deal with that situation or what to do then? So yeah, there is a lot of competition in PSG also like if somebody is already published and you are on your way then you have to deviate from some what different thing you should then focus on. Like there are cases like in ISC also like there was already one working on some new idea and then by the time he finished then already somebody published it. Then he had to little bit add another thing to showcase okay this is little different one from what is done. So there is always a little bit of competition. Great, yeah. Last question, I think it's mostly covered this but still I'll go ahead with the question. Where does the PhD needs to lead your career to? Is it a path to do a better job or is it a career choice in itself? Actually after PSG you can go for any career. So PSG is not actually a career choice in itself because after PSG also people go in management like for starting their own company they can do another management course. So it's not in on itself a career but it is heading towards some psych. If you have some idea where you want to go then a PhD is good. Great, great. So thank you Prachi. People had a lot of questions. So if anyone has any further questions we have two Zulip streams. Prachi could be available. Yeah, so you can ask your questions and so here I am posting the Zulip streams in the chat. You can go there, hang along and ask your Prachi any further questions if you have. I am Prachi. Yes, yes, sure. Thank you, thank you everyone for attending.


also known as redfish or channel bass, have experienced a recent surge of popularity that has resulted in a market shortage and higher prices, prompting investors to seriously consider raising these fish in captivity. Traditionally, red drum or commercially fish has two to three-year-old juveniles in shallow bays and estuaries. These three to eight-pound fish were captured from small boats, using gill nets and trot lines. Total landings from the Gulf and southeastern Atlantic states amounted to only four million pounds per year. Demand for this species dramatically increased during the early 80s due in large part to the nationwide introduction of blackened redfish by Chef Paul Prudham of New Orleans. As demand increased, purse saners began to target large offshore schools of adult red drum, typically 30 pounds or more. Between 1984 and 1985, landings increased from 3 million to 12 million pounds. This dramatic increase in production composed largely of breeding-sized fish, alarmed fisheries managers and conservationists. Concerned that the reproducing populations of red drum would be diminished below maximum sustainable levels, the Secretary of Commerce closed purse saning for this species in 1986. As a result of this closure in offshore federal waters and closures in some inshore state waters, supplies of red drum have fallen far below demand and prices have climbed from traditional levels of less than one dollar per pound to as much as three dollars per pound for whole fish. This has encouraged aquaculturists to attempt raising red drum on a commercial basis for the first time. The red drum is naturally a marine and brackish water species, but has been successfully grown in certain fresh waters and thus can be considered a candidate for fresh water as well as brackish water culture. Although commercial aquaculture of red drum has just begun, considerable information exists about fingerling production of this species because of extensive efforts to restock depleted populations of red drum in natural waters. For example, ongoing efforts by the Gulf Coast Conservation Association, Central Power and Light Company, and the Texas Parks and Wildlife Department result in the mass production and release of about 10 million one-inch red drum fingerlings into Texas Bays each year. The problem is that little information is available concerning culture of red drum from fingerling to market size. Potential red drum farmers hope to utilize much of the grow-out technology that has been successful in the thriving catfish farming industry. For that industry, 1979 production of only 40 million pounds raised in 30,000 acres has increased rapidly to current production of over 200 million pounds grown in 130,000 acres of ponds. Current farm gate value is approaching $400 million and significantly impacts the economy of the Mid-South. The first step in the process of raising red drum is collection of broodfish for spawning. This process may require a collecting permit depending upon the state in which you are operating. Contact your county extension agent or local fisheries biologist to determine the appropriate state and federal permits required for the various aspects of red drum aquaculture. The process of collecting 20 to 40-pound red drum for use as broodstock can be time-consuming. The best results have usually been attained by fishing during their fall spawning season near passes connecting Bays to the ocean. They've been captured with a variety of gear types including gill net, trot line, purse sain, and beach sain. However, hook and line capture generally causes the least stress, particularly if the fish are caught by the lip. To improve the chances of hooking the fish in the lip, a three to seven-odd circle tuna hook is recommended. If the fish are not highly stressed during capture and transport to the hatchery, this is a good time to determine their sex and degree of egg maturation before placing them in spawning tanks. The sex of adult fish can be determined by examining the openings near the vent. Males have a single urogenital papilla posterior to the anus. Females have separate urinary and genital orifices. The genital aperture is located among flaps of tissue between the urinary duct and the anus. During the fall spawning season, it's relatively easy to determine if fish are completely mature by putting a little pressure on the lower abdomen near the vent and observing whether eggs or milk flow freely. However, if females are not fully mature, their stage of maturation can be determined by inserting a small glass tube called a catheter into the obiduct, removing a small amount of ovarian material and examining it under the microscope. Fully developed eggs will be greater than half a millimeter in diameter and pale yellow in color. In the hatchery, it is possible to induce mature red drum to spawn through hormone injection, but this procedure is rarely used because it tends to excessively stress the valuable broodstock. It is much more productive to vary the temperature and photoperiod, thereby allowing multiple spawns of broodfish over an extended period. The idea is to manipulate the length of day, as well as the water temperature, to simulate the passage of seasons. Redfish spawn during the manipulated fall season. The length of the day is usually controlled with lights activated by automatic timers. Water temperature is regulated either directly by submerged heat exchangers or indirectly by controlling the ambient temperature with air conditioning and heating units. To avoid toxic effects of excretory waste in the broodfish tank, it is necessary to continually exchange water at a rate of at least 100% a day. If outdoor water were used, the expense of continually adjusting its temperature for only one pass through the system would be prohibitive. Consequently, most hatcheries have installed water reuse systems in which wastewater is treated and returned to the tank with little change in temperature. Reuse systems employ biological, mechanical, and germicidal treatments. Biological treatment relies on bacteria to convert toxic ammonia and nitrite to non-toxic nitrate. Both unionized ammonia and nitrite are toxic to fish at concentrations above one half part per million. Biological treatment is a natural process which can be accelerated by providing a large surface for attachment of bacteria and a continual flow of oxygenated water past that surface. These features have been incorporated into many different designs, all of which are effective. The rotating biodisk filter, for example, utilizes closely spaced fiberglass plates as a surface for attachment of bacteria. The rotating action provides continual exposure to both wastewater and air. A variation in design utilizes air conditioning filters as a surface for bacteria. Supplemental aeration between the plates assures that the bacteria receive sufficient oxygen to detoxify the water. In a third type of biofilter, hollow plastic balls provide the surface for bacteria. Oxygen is incorporated as the spray drips over the plastic balls. Biological filters tend to reduce the pH of the recycled water over time, so it's necessary to include oyster shell or a similar source of calcium carbonate in the treatment system to maintain pH within the range of 7.8 to 8.2. Mechanical treatment of wastewater involves the removal of suspended solids. This is most easily accomplished with an ordinary swimming pool filter. Particles trapped on the surface of the sand are flushed out by periodically backwashing the filter. The final step in the treatment process is control of parasites and other microorganisms which might infect the broodstock while they're in the conditioning process. Ultraviolet light has been commonly used, however ozone and photozone have also been effective. After these treatments, water is returned to the broodstock tank. A small laboratory is essential for maintenance of water quality. Basic instrumentation includes a refractometer used to measure salinity. The preferred salinity for spawning and hatching of red drum is 28 to 35 parts per thousand. An oxygen meter to determine both oxygen and temperature. Dissolved oxygen should be maintained above five parts per million. A spectrophotometer to accurately measure ammonia and nitrite concentrations. Both of these waste products are extremely toxic to fish, above one half part per million. And a pH meter. It's important to monitor the acidifying effect of the biofilter. Typically red drum are introduced into the temperature photo period conditioning cycle during the winter phase. They're fed a variety of cut fish, shrimp and squid. Small food fish have their air bladders cut so that they'll sink to the bottom and not get caught in the egg skimmer or drain system. Typically red drum are ferocious feeders while in the conditioning process. The natural annual cycle can be compressed to 150 days under controlled laboratory conditions. Initially temperature is lowered to 15 degrees centigrade and day length is reduced to nine hours. For 25 days both temperature and day length are gradually increased to a high of 30 degrees centigrade and 15 hours to simulate the passage of spring and summer. During the next 50 days temperature is reduced to 24 degrees centigrade and day length reduced to 12 hours to arrive at the simulated fall spawning season. Several days prior to spawning male red drum darken in color above the lateral line and begin drumming and courting the females. Females often show red swollen vents. Spawning usually occurs within three hours after the lights are turned off. Females typically spawn several hundred thousand eggs which are fertilized by milk from one or more accompanying males. Fertilized eggs are collected the following morning. Newly spawned red drum eggs are clear, spherical and approximately one millimeter in diameter. Their large golden oil droplet makes them buoyant and easy to collect by simply skimming the surface water of the maturation tank. The eggs are concentrated in an adjacent smaller tank lined with a fine mesh bag. In the morning following a spawn the eggs have been water hardened and can be handled with a soft net. A convenient way to estimate the number of eggs in a spawn is to pour them into a graduated cylinder and allow them to float to the top. The volume that they occupy is then multiplied by one thousand. In other words, one milliliter contains roughly one thousand eggs. Following enumeration, eggs are placed in an incubator tank with moderate aeration to keep the eggs stirred. Eggs hatch about twenty-four hours after fertilization. These are developing embryos. Thirty-five to forty hours after hatching the larvae absorb their yolk sacs and develop mouth parts. At this time they must be harvested from the incubator tank and fed. This is a simple but effective larva harvesting box. Water from the incubator is drained into the box where the larval fish are concentrated. Excess water flows out of the box through the screen on the stand pipe. A stream of bubbles from an air hose collar helps prevent the larvae from impinging on the overflow screen. A sample of the concentrated larvae is collected in order to estimate the total population. Fish of this size can be placed in water within an oxygenated bag and shipped for periods of up to twenty-four hours in tropical fish shipping boxes. During shipping, oxygen will diffuse into the water, maintaining a concentration sufficient to keep the larvae healthy. The next objective is to raise the microscopic larvae to inch-long fingerlings. There are basically two approaches to this phase in the red drum production. One technique utilizes fertilized outdoor ponds, while the other involves rearing larvae at high density in indoor tanks. The outdoor pond technique provides food to the larvae by stimulating high densities of small zooplankton through fertilization. Outdoor fingerling ponds are usually one to two acres in size, approximately three feet deep, and slope to drain into a harvest basin at one end. The pond is filled with seawater of at least twenty parts per thousand salinity, which is passed through a half-millimeter filter to eliminate predators such as fish and crabs. The seawater is then fertilized with a combination of inorganic and organic fertilizers. The inorganic fertilizer first stimulates a phytoplankton bloom. These microscopic plants give the pond its greenish or brown color and are the food for larger zooplankton on which larval fish feed. Subsequent additions of organic fertilizers stimulate the growth of zooplankton. A variety of fertilization regimes have been used to rear red drum. This is an example of one that has been successful at the Perry Bass Marine Fisheries Research Station in Palacios, Texas. As can be seen from this schedule, it's important to maintain the plankton bloom throughout the growth cycle by regular application of various fertilizers. Density and type of zooplankton should be monitored weekly throughout the grow-out cycle to assure an adequate food supply for the rapidly growing fish. Zooplankton are quantitatively sampled by pulling a net a given distance through each pond, or by pumping a measured volume of water through a filter which retains the plankton. The dominant zooplankton groups in a properly fertilized larval rearing pond are rotifers and copepods. Rotifers are one of the ideal foods for the first feeding red drum larvae because their small size is appropriate and their slow swimmers. A density of 100 to 200 rotifers per liter of pond water has resulted in good growth and survival of red drum larvae. Copepods are the other dominant type of zooplankton found in fertilized outdoor ponds. Nonplyae, the larvae of copepods tend to dominate newly fertilized ponds and are of suitable size for first feeding by red drum larvae. However, adult copepods which can reach lengths of several millimeters are too large for first feeding larvae. It's important to coordinate stocking of the pond with peak abundance of rotifers and larval copepods. Consequently, it is necessary to fill and fertilize ponds about 10 to 14 days before larvae are ready to stock. Numerous other invertebrates such as larval barnacles, crabs, mollusks, polykeets, and aquatic insects may be present at various times in sufficient number to provide a substantial portion of the larvae fish diet. After 30 to 40 days in the fertilized pond, fingerlings reach 1 to 2 inches in length and are ready to harvest for subsequent stocking into grow-out ponds. The pond is harvested by draining water through screens which prevent fish from escaping. The majority of the fish usually avoid the harvest basin until the pond is nearly empty. When the fingerlings enter the basin, they're collected with dip nets and placed in pre-wade buckets of water. The difference between the original weight of the bucket of water and the new weight of the bucket with red drum is calculated. This weight is divided by the average individual weight of the fish to estimate the number of fingerlings harvested. Fingerlings are transferred to the grow-out area in hauling containers equipped with oxygenation or aeration mechanisms. Oxygen should be maintained at or near saturation and should never fall below four parts per million. Another method of raising red drum fingerlings involves high-density culture of larval fish under controlled conditions. Rather than relying on a natural zooplankton bloom in an outdoor pond, specific types of plankton are cultured indoors. This involves culture of phytoplankton to feed rotifers. Rotifers as food for first feeding red drum and brine shrimp to feed advanced red drum larvae. The unicellular microalgae, tetraselmas or isochrisis have been the preferred species of phytoplankton for feeding rotifers. Each is relatively easy to grow and provides excellent nutrition of the proper size for rotifers. These can be purchased as pure cultures, which are sequentially transferred to larger volumes of sterile, nutrient-enriched seawater. This process culminates in the production of large quantities of microalgae. Rotifers are ideally suited to mass culture since under optimal conditions, concentrations of 150 to 200 rotifers per milliliter can be maintained for about a month in an algae-rich culture. In addition to algae, rotifers can also be grown on yeast and fish oil. This procedure reduces the time and labor involved in raising phytoplankton. Rotifers are harvested from the mass culture tank by draining a volume of the culture water through a 48-micron sieve. The rotifers are rinsed, counted, and introduced to the red drum larval tank at a density of 3 to 5 per milliliter. 9 to 11 days after hatching, red drum larvae begin the transition to a larger food. Brine shrimp or a convenient food at this stage, they can be purchased as dried inactive cysts, which are easily hatched in 24 hours by aerating them in seawater. They are harvested, counted, and fed to the red drum fry in a manner similar to the feeding of rotifers. 10-day-old red drum fry are voracious feeders, which consume a tremendous number of brine shrimp. A density of 1 to 2 brine shrimp per milliliter is maintained until the fish larvae are 15 to 20 days old, at which time they can be weaned to a less expensive, prepared diet. The most common method of growing red drum fingerlings to market size involves the use of outdoor ponds. The location chosen for grow-out ponds will have a great bearing on the potential success of the farm. In selecting a site, one should consider not only water and land, but infrastructure characteristics as well. Water quality and quantity are of primary importance. Red drum are known to be susceptible to low winter temperatures, particularly if temperature drops abruptly. They prefer temperatures between 24 and 30 degrees centigrade, and if exposed to rapid or prolonged exposure to temperatures below 10 degrees centigrade, become severely stressed and may die. For example, large-scale kills of wild red drum have been documented in shallow bays during unusually severe cold fronts. Low water temperature is undoubtedly the biggest risk factor associated with red drum grow-out. Management approaches to deal with the potential for winter mortality include stocking advanced fingerlings in the spring and harvesting marketable fish prior to winter, or overwintering the fish and waters kept warm by increased pond depth, geothermal heat, or a greenhouse cover. Red drum can tolerate a wide range of salinity. They've been collected in natural waters, ranging from nearly fresh to saltier than seawater. Preliminary data suggests that red drum raised in fresh water are less tolerant of cold temperatures than those raised in seawater. The least stressful salinity is thought to be near the middle of this range, about 10 to 30 parts per thousand. In some cases, red drum have grown remarkably well in fresh water. However, these situations generally involved power plant reservoirs with heated water, high levels of chlorides, and adequate calcium hardness. There is still much to be learned about commercial production of red drum in fresh water, but preliminary recommendations are to avoid fresh water when chloride levels are less than 150 parts per million. When calcium hardness is less than 100 parts per million, or when temperatures fall below 15 degrees centigrade. Do not underestimate the quantity of water needed for a pond grow-out system. A conservative rule of thumb is to provide a pumping capacity of 50 gallons per minute per surface acre of ponds. This could represent a major cost if water must be pumped from a considerable depth. It is important to select land which is suitable for pond construction. Desirable characteristics include soil with at least 25% clay to prevent seepage, elevation of at least 5 feet above sea level, and a water table at least 3 feet deep to allow for pond drainage and to reduce construction cost. And finally, topography that is nearly flat to reduce earth-moving cost. A final series of considerations in selecting a grow-out site is the available infrastructure. For example, once you determine the property's access to electricity, roads, feedmills, and processing plants. Pond design in general follows that which has proven successful for other warm water species, such as catfish. Ponds should be about 3.5 to 5.5 feet deep, with sloped bottoms to allow complete drainage. Size and layout of the ponds will vary depending on the type of culture to be practiced. That is extensive, semi-intensive, or intensive. Extensive systems involve use of large, natural water bodies which are not easily manipulated by typical management procedures. For example, extensive culture techniques are being used by brackish water impoundment owners in Louisiana. Semi-intensive systems utilize drainable ponds of 5 to 20 acres which are designed to facilitate water exchange, feeding, and aeration. One semi-intensive design uses 2.5 acre ponds for production of 1-year-old fish and 10-acre ponds for the production of 2-year-old fish to more efficiently utilize land. This design also allows for a more accurate assessment of survival as the fish are transferred between ponds. Regardless of the grow-out system employed, water quality must be maintained in the ponds for the fish to survive and grow. Dissolved oxygen levels fluctuate over a 24-hour period from a maximum in late afternoon to a minimum just before sunrise. If early morning readings are less than 4 parts per million, supplemental aeration and or water exchange should be employed to increase dissolved oxygen. If values consistently fall below 3.5 parts per million, feeding should be reduced or discontinued until conditions improve. A water exchange of 5 to 10% a day is suggested during the warmest part of the growing season, May through October. Aeration can be achieved by injecting air into the water or by spraying water into the air. A high-quality feed with roughly 40% protein is required for good growth. Pellet size is increased as fish grow larger. Feeding rates are determined by estimating survival and growth rate at least once a month. Distribution of feed in large ponds is often accomplished with mechanical blowers, just as it is in the catfish farming industry. Intensive systems are high-density culture units, which can be placed indoors to avoid problems with low winter temperature. At this indoor grow-out system near Rockport, Texas, fish are grown in fiberglass troughs or raceways that measure 45 feet long by 8 feet wide by 3 feet deep. These raceways have produced yields of up to 2,000 pounds of fish. Biofilters are used to detoxify waste and minimize replacement water requirements. Water movement is accomplished using airlift pipes in which water is drawn into the base of the pipe by the action of air being injected at a higher point. The water that is lifted with the air is discharged at the top of the pipe through elbows, which are oriented to create a single large circulation pattern within the tank. Backup systems for maintaining sufficient dissolved oxygen in the event of an equipment malfunction or a power failure are mandatory in high-density recirculating systems. Cylinders of compressed oxygen provide a temporary backup that is not dependent on electrical power. In an intensive culture operation, the fish derive all of their nutrition from a prepared diet. Thus, feed composition and the feeding regime are critical. Red drum fry are typically reared to juvenile size on trout or salmon feed containing 48% protein. Then they can be grown to harvestable size on a 40% protein diet. The food conversion ratio for a commercial intensive culture operation can be as low as 1.2 to 1. Feed can be distributed by hand with a continuous feeder or by using a demand feeder in which the fish activate the distribution mechanism themselves. Regardless of the distribution system used, it is important to offer feed in small amounts several times a day so that the fish will eagerly consume it as it hits the water. This lessens the quantity of uneaten decomposing feed, improves water quality and reduces the load on the biofilter. It's also important to routinely observe the feeding behavior of the fish and reduce or temporarily discontinue feeding if they lose their appetite. Although there are literally dozens of diseases and parasites which can affect red drum, one of the most common is the parasite amyladenium oscillatum. Since this parasite attaches to the gills and interferes with the respiration, heavily infected fish tend to congregate near the pond's surface, aerators or water inflow pipes in an attempt to obtain more oxygen from the water. Infected fish may also appear to cough water while trying to flush the parasite from their gills. While fish behavior is easily observed in raceway systems, their behavior is less obvious in turbid grow-out ponds. Therefore, it's a good practice to occasionally sacrifice a fish and check its gills for amyladenium infestation. Although the parasite has been successfully controlled using chelated copper at 4 to 6 mg per liter for 24 hours, maintaining good water quality through careful pond management is much more cost-effective. Harvesting and processing of red drum will probably utilize much of the same technology as is used by catfish farmers. Fish are concentrated by tractor-pulled sain and then transferred to live haul trucks with a hydraulic loader. Conventional fish processing equipment can be used to efficiently de-head, skin, and eviscerate fish. The fish can be filleted either mechanically or by hand. A variety of fresh and frozen market forms can be produced. In conclusion, there is a strong market-driven interest in aquaculture of red drum. This should continue to be the situation so long as wild stocks remain suppressed. It's fortunate that much is known about the process of spawning this fish, hatching its eggs, and rearing the larvae to fingerling size. However, our experience with grow-out techniques for red drum is limited. Despite the uncertainties, several commercial hatcheries and grow-out farms are already operating in Gulf and South Atlantic states. A few thousand pounds of farm-raised red drum have been harvested, but the business is still too young to allow accurate estimates of profitability. Many entrepreneurs feel that the potential for farming saltwater species such as red drum is great and that the size of this industry will soon rival the thriving catfish farming industry. As with any new business, one should weigh the commitments, the risks, and the potential profits carefully before making a decision about entering this field. If more detailed information is needed, contact your local county extension agent for assistance or request a copy of the manual on red drum aquaculture which is available from the Texas Agricultural Extension Service.


This is stock number 10505, we're here at Summit Automotive in Fond du Lac, Wisconsin, you're new and used heavy duty truck and ram headquarters. Today we are checking out this exceptionally clean 2017 ram 2500 crew cab short box. This truck has the Laramie Sport package, it also has the 6.4 liter V8 Hemi motor and it has been fully safe and inspected by our service shop has a fresh oil and filter change. All the fluids have been checked and topped off and this truck is 100% ready to go. Pearl white is the color, we shoot all of our videos in 1080p, 60 frames per second. So if you have HD capabilities on your computer, tablet, or smartphone device, I highly recommend turning them on right now because it is definitely like your light right here looking at the vehicle with me and the best way for you to ensure the quality and condition of the vehicle before seeing it in person. If you want to check out more photos or all the photos in the upper hand part of the screen is a link right to our website. Comes with the 20 inch painted alloy rims Michelin LT285 60R20 tires with about I'd say 70 to 80% of the tread left. They are Defender LTX's frame and under bodies in pretty nice shape. Laramie package gives you the blacked out headlight bezels. Laramie package gives you the projected lamp headlamps, the LED running lights, factory fog lights, front bumper, parking sensors. You can see it has the blacked out Ram logo and gloss black grille. You can see any dents or dings on that front bumper and the hood is in excellent condition as well. The passenger side fenders in really nice shape too and this passenger side rim is in really nice condition as well. You get the blacked out Hemi logo, blacked out Ram 2500 logo and as you go down this side the truck take note of 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 the trip down but you're still interested in purchasing the truck you can see the truck, hear the truck and have confidence in the vehicle that you're looking at before you even get here. That's why we offer the Summit Auto Fastpass option again in the upper right empire your screen link right to our website where you can apply for financing, get pre approved, see a payment quote, even appraise the trade off from the comfort of your own home. The frame and underbody and lower rockers look really great, has all the remaining factory exhaust and this back room is in really nice shape as well and the back tires have just a little bit less tread than the front but still at least I'd say 50% on there. You get the rear coil spring suspension which makes your ride a lot smoother when you're unloaded, rear bumpers in really nice shape, didn't see any major dents or dings on that and the tailgates in really nice condition as well. You get the blacked out Ram logo, this is a locking tailgate, comes with the spring and bed liner, the LED bed lights and the bed itself is in really nice shape too, didn't see any major dents on that and it has a back flip fold-up tonneau cover, that's in really nice shape and down the rest of the side of the truck just as clean as that passenger side didn't see any dents or dings in the box and for full disclosure this back rim is in really nice shape as well, has the enter and go system these mirrors fold up they have LED directional signals and they are heated and they also power fold in which we'll check out in just a second inside the Laramie package gives you the black leather interior, there are no rips or tears on the seats really nice condition, get a memory driver seat with lumbar we have weather tech floor mats throughout on this truck, auto headlamps, power windows power locks and those power fold-in mirrors like I said, now I just like showing both sides so that you know that they're both working and as we hop inside the truck here you can see that this one has 39,984 miles, leather wrap steering wheel, this is a heated steering wheel, cruise controls on the right, Bluetooth and information center controls on the left and audio controls on the back, comes with the six-speed automatic transmission, the 3C 8.4 inch touchscreen radio, AM FM and Sirius XM radio capabilities it also has the factory navigation system on it, this is also where your backup camera shows up you can do your radio here, your controls for your heated and cooled seats as well as your heated steering wheel and you can do your climate controls here and of course the navigation now if you didn't like doing your climate controls up there you can do them down here on the climate controls there has the factory brake controller, heated and cooled seat buttons as well your front and rear parking sensors and your stability control and tow-haul buttons has a 115 volt 150 watt plug-in, weather tech floor mat on that side and the passenger seat is in nice shape as well no rips or tears on that has the alpine sound system with the speakers in the ceiling there, map lights, power slide rear window and your home link buttons for garage door security systems and lighting systems, 911 and assist buttons in the mirror those are features of the vehicle and you can tell it has the alpine by that badge right there we'll take a quick look at the back seats and then we will check out under the hood these back seats are heated they have the latch child safety system for all your child car seat needs, power sliding rear window, no rips or tears back here these seats do fold up for extra storage and you do get a load floor which is nice if you got muddy boots or tools you put that down or if you got pets you can put both sides down they got a nice flat place to lay and then you have storage underneath there and then you can see your heated seat buttons are right there as well weather tech floor mat back here too and it does come with the child safety locks in the doors we'll take a quick look under the hood I would personally like to thank you for checking out the video today and hopefully from this HD video you'll be able to tell just how clean this truck is all the way around inside note under the hood we have the 6.4 liter Hemi motor engine bay is very clean runs very smooth this truck has been fully safe to and inspected by our service shop has a fresh oil and filter change all the fluids have been checked and topped off the truck has been gone through mechanically 100% and is 100% ready to go see more pictures of this truck or one of our other 450 new and used cars trucks SUVs minivans wranglers half tons to quarter tons one tons you name it we got to go to our website www.summitauto.com full pictures and descriptions of every single vehicle from two locations all at summit auto.com if you'd like to check out more HD videos 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 2017 ram 2500 crew cab short box larry me sport in pearl white thanks again


Welcome everyone to the Texas Art Institute Women's Symposium. It's my honor to present this topic in front of all of you, which is non-statin therapies for LDL cholesterol lowering. How do we rationally use them? These are my sources of support and other disclosures, none of which are related to what we are going to be talking about. So the objectives of the talk are that we want to discuss the recent CV outcomes trials with addition of non-statin medications to statin therapy. We want to discuss how we can identify major groups of patients who have demonstrated a CVD benefit with the use of these non-statin agents. The third is that we want to understand how to rationally use these non-statin therapies as recommended by the 2018 AHA ACC in multi-society cholesterol guidelines. And then I want to spend some time talking about newer therapeutic options, vampidoic acid and inclycerin. And I would like to mention this right now that although vampidoic acid is FDA approved, please note that inclycerin as of yet is not FDA approved. So with that, let's start out with what we know about LDL cholesterol lowering. Of course, this is no new news to any of you that LDL cholesterol lowering reduces ACVD events, whether it's primary prevention or secondary prevention. And these are the data from the very large individual patient level meta-analysis performed by the cholesterol treatment trialists. And what we know is that every millimole, about 39 milligrams per deciliter reduction in LDL cholesterol leads to about 20 to 25% reduction in major cardiovascular endpoints. Note that that is a relative risk reduction. And therefore statins remain the mainstay of therapy when we talk about whether primary prevention patients or secondary prevention patients. But the important thing is that despite treatment with statin therapy, residual risk persists. Statin therapy cuts down about one third of the risk that's there, but almost two thirds of the events continue to happen in these patients despite statin therapy. So statin therapies work, don't get me wrong. They work really well, they cut down quite a few events, but despite that, quite a few events in these patients continue to occur. Now, what could be the reason for that? Of course, there's a very long list of things and I'm not going to talk about residual risk today. So what we're going to basically concentrate on are two major reasons. One is LDL cholesterol goal achieved, but then there could be other risk factors, like other risk factors like hypertension, diabetes or inflammation, or it could be poor lifestyle. But the other thing here is that LDL cholesterol goal may not be achieved despite optimal statin therapy, whether that is because that patient is not a good responder, there are adherence related issues or they started out with a very high LDL cholesterol level. Then of course, then there's other list of triglyceride mediated residual risk, L-pyridylated mediated residual risk, but we are going to be focusing primarily on LDL cholesterol mediated risk today. So let's go back into the recent history and talk a little bit about where we have started out with non-statin therapies. Again, I'm going to take you through this journey for the last 10 years when we've had quite a few non-statin LDL cholesterol lowering that have led to improvement in cardiovascular outcomes. Again, I'm not going to talk about HDL raising therapies or triglyceride lowering therapies or L-pyridylate lowering therapies. Just focus on LDL cholesterol lowering therapies that are non-statins. So the first major study that came out looking at a non-statin was improved study, which looked at the use of isothermide in patients who were already on statin therapy in ACS population. And what we noticed there was at the end of seven years, there was about 14 to 15 milligrams per deciliter reduction in LDL cholesterol, which was associated with a 7% relative risk reduction in major vascular events over that seven-year period in this particular trial in about a 2% absolute risk reduction. So that's what we know about isothermide. The other thing that has happened in the past 15, 20 years is our understanding of the genetics and how they impact lipid lowering therapies and cardiovascular events. So this is one of the very early studies that came out looking at PCSK9 genetic mutations or polymorphisms showing that those patients in this data out of Eric's study, those patients who had no nonsense mutation, i.e., they are regular patients, if you look at their median LDL cholesterol levels and compare it to those who have nonsense mutations in PCSK9, whereby the function of PCSK9 goes down, in those patients who have these nonsense mutations, their LDL cholesterol distribution is shifted to the left. So very low levels of LDL cholesterol compared to the general population, but not just that. They had much more reduction in CHD events, almost 88% reduction in CHD events. And I would like to mention a concept here that's extremely important. If we lead to 10%, 20% LDL cholesterol reduction via a medication versus a mutation or a polymorphism, the risk reduction we get from polymorphism is always higher compared to similar LDL cholesterol reduction by a medication, whether that is statin therapy, whether that is a ZMI or a PCSK9 inhibitor. And that is because when somebody has a genetic polymorphism that is associated with lifelong lowering of LDL cholesterol. So it's the area under the curve that determines that those patients who have these genetic polymorphisms have had low levels of LDL cholesterol throughout their life versus somebody who was started on statin therapy or ZMI or PCSK9 in their middle Asia or even later. In those cases, they may not derive as much benefit. Now with that, what we know is that how PCSK9 works. So let's start out with a regular cycle of how LDL particle enters a hepatocyte and how it's metabolized. We all know that when LDL particle comes on the surface of the hepatocyte, it comes in contact with the LDL receptor. It is endocyte post. And then cholesterol is taken up whereas LDL receptor really goes back to the surface and is recycled. It's a very, very efficient system. And because of this recycling of the LDL receptor, more and more LDL particles are brought inside the hepatocyte. Well, what happens when PCSK9 binds to this complex of LDL receptor as well as LDL particle? If PCSK9 binds to this LDL receptor complex, then rather than LDL receptor being recycled, which is what keeps the system extremely efficient, that LDL receptor is degraded into the lysosome leading to lower levels of LDL receptors on the hepatocyte surface and consequently higher levels of LDL cholesterol in the serum. Of course, if we were to then inhibit PCSK9, whether it is due to genetic polymorphisms that I showed you, or if we give an antibody that binds to PCSK9 outside the hepatocyte surface, it does not allow PCSK9 to bind to the LDL receptor complex. And at that point, again, the LDL receptors are recycled that much more efficiently, leading to a very high LDL receptor density on the surface of the hepatocyte. And consequently, a lot of these LDL particles are brought inside the hepatocyte, leading to lowering of serum cholesterol levels. When we look at the outcome studies of PCSK9 inhibitors, of course, the two major trials that we have right now are the Fourier trial and the Odyssey outcomes trial. And most of you would know that these were patients with secondary prevention in whom PCSK9 inhibitors were used for these outcomes trials. Fourier trial was a trial, a very large trial of almost 28,000 patients with stable established ASCVD. So prior MI, prior stroke, symptomatic peripheral arterial disease, these patients were all on stacking therapy. And if their LDL cholesterol levels are above 70 milligrams per deciliter, or their non-HDL cholesterol levels were above 100 milligrams per deciliter, then they were randomized to either have a look command, one of the PCSK9 inhibitors, or placebo. And then these patients were followed for a median followup of about 2.2 years in this particular trial. What we know is that LDL cholesterol levels were lowered by close to 60%. Absolute reduction in LDL cholesterol of about 56 milligrams per deciliter. Median levels of LDL cholesterol were close to 30 milligrams per deciliter in this trial, one of the lowest we have seen in a randomized control trial of LDL cholesterol lowering. And what we found was that the use of evalucamab in stable but high-risk ACVD patients was associated with a 15% relative risk reduction, about 1.5 to 2% absolute risk reduction in the primary endpoint, which was a larger large endpoint, including CV death, MI stroke, revascularization for unstable angina, as well as hospitalizations for unstable angina. And when you looked at very hard outcomes, which was the CT secondary outcome, which included MI stroke or CV death, removing hospitalization for unstable angina or revascularization, again, what we see is about a 20% risk reduction that was relative and about 2% absolute risk reduction at a median followup of 2.2 years. As I mentioned, that there were quite a few patients who achieved very low levels of LDL cholesterol impact. If you look at the distribution of LDL cholesterol levels in this trial, what you will find is that 10% of patients actually achieved LDL cholesterol levels of 20 milligrams per deciliter or lower. So less than half a million, 10% of the patients, 40% of the patients achieved LDL cholesterol levels of 50 milligrams per deciliter or lower. And what we found in this particular study was that there was a monotonic relationship between achieved LDL cholesterol levels and cardiovascular outcomes. Of course, what you get is less and less as you move more and more down on this line, but the relationship itself is monotonic. With that, there were no safety concerns. Now, one of the concerns in those days was that maybe low levels of LDL cholesterol will lead to neurocognitive side effects. And this was an FDA mandated study. So it's a subgroup of Fourier study, which is known as the Ebbinghaus study, where these patients underwent quite an extensive neuropsychological battery that was done both pre and post, at least at 19 months of follow-up, there did not seem to be any significant impact of the use of Avalocomap or neurocognitive function in these patients. So remember, these were patients with stable ASCVD. Then we had another large outcome trial, Odyssey outcome trial, which was performed in patients with ACS. So now we are looking at patients who are higher risk because they had an acute coronary syndrome event in the last one up to 12 months. And then these patients again were receiving the standard of care at that time, which was marketed to high-intensity statin therapy. In fact, in most patients were on high-intensity and those who were not were on maximally tolerated statin therapy. And then they were randomized to another PCS-canine inhibitor, in this case, alirocuma or placebo. And the median follow-up here was a little bit longer, about 2.8 years. And then 44% of the patients had a follow-up of more than three years. And in these patients, again, the primary outcome was a four-point maze as opposed to five-point maze for the Avalocomap treatment, which was the four-year trial that we just talked about. So again, unstable adrenary coronal hospitalization was part of it, but revascularization was not. And when we look at what happened in this particular study, the use of alirocumap in this particular study was associated with a 60% reduction in LDL cholesterol. As you can see here, of course, there was a titration protocol here. So the achieved LDL cholesterol levels are not as low as what we saw in four-year trial. But again, even in this study, at a median follow-up of 2.8 years, there was a 15% relative risk reduction and 1.7% absolute risk reduction in the primary efficacy endpoint with the use of alirocumap in patients with ACS. Now, I've showed you data for ZMI, but I've showed you data for the two PCS canine inhibitors. But I think there is a lot of learning there that even among these patients who are secondary prevention patients, we can identify patients who are to derive the most benefit from the use of these non-statin therapies on top of statin therapies. So these are data, again, from improved trial. Remember, this is the trial where ZMI was given on top of moderate intensity statin therapy. So what these investigators did was they looked at these nine risk markers or risk indicators, which you can see are all very easily available from any EMR when we're evaluating these patients in our clinic. And if these patients had zero to one of these risk indicators, you will notice that the risk of events was very low at follow-up of seven years. As you accrue more of these, if you had two or more of these risk indicators, your risk of having an event was much higher. If you had three or more, your risk was 34%, which was the average risk in the placebo arm. In fact, if you had five or more of these risk markers, which would not be unusual if you look at these risk indicators, the event rates are close to 69 to 70%. So seven out of 10 patients, if they have more than five of these risk indicators would have a recurrent cardiovascular event, and that's no surprise. But that's not the entire story. When we look at the benefit of ZMI, that was also dependent on these risk markers. So if you had zero to one risk markers, you did not derive any benefit from the use of ZMI. If you had two of these, you derived a 2% absolute risk reduction, which was the average absolute risk reduction in this trial. But if you had three or more of these risk markers, the absolute risk reduction was 6%. So the numbers needed to treat was 16, much lower than 45, what you would need for two of these risk markers. And of course, when you have zero to one of these, there is no benefit. When you look at the same trial and you look at patients who had polyvascular disease, if they had atherosclerosis in more than one bed, they had ACS, but they also had schemic stroke or PAD, look at the event rates. The event rates are much higher, but at the same time, these patients derive a much larger absolute risk reduction with the use of ZMI. Similarly, when we look at Asias with polyvascular disease and diabetes, the event rates are even higher. But again, the absolute risk reduction is also higher and you only need to treat 10 to 11 patients to prevent one major vascular event in these particular patients. So the point being that even amongst these patients who are secondary prevention patients, they're not all created equal. Their risk profile is different and consequently the benefit they derive from the use of non statins is different as well. Similarly, when you look at patients with peripheral arterial disease, you find similar things when you look at the use of PCS-canine inhibitors. So it not only holds true for azatomide, but also for PCS-canine inhibitors. These are data from Fourier study. And when you look at patients with PAD, those patients have a much higher event rate compared to those who do not have PAD along with a Schemic Heart Disease or Schemic Stroke. But importantly, these patients derive a lot more benefit from the use of PCS-canine inhibitors compared to those who do not have peripheral arterial disease. If you look at data again from Fourier trials, patients who had their qualifying MI less than two years before the events, much higher event rates. If you had two or more MI's, much higher event rates. If you had residual multi-vessel CAD, much higher event rates. But at the same time, when you look at absolute risk reduction, much higher in those who had more recent MI, higher number of MI, as well as those who had multi-vessel disease that was present. So we can identify even for PCS-canine inhibitors which patients will derive the most benefit from the use of this class of therapy. You look at data from Odyssey Outcomes. Again, similar story. Look at the event rates in the placebo group, which by the way here is statin arm. Look at the event rates for those who have LDL cholesterol levels at baseline of 100 milligrams per desicc or higher. Much higher event rates compared to those who are below 100, but at the same time, the absolute risk reduction is much higher, 3.4% compared to 1.6%, which was the average absolute risk reduction in this particular trial. And therefore, when we identify these patients, the numbers needed to treat comes down drastically. We can have more impact of our therapies that may not be as easily accessible and maybe in some cases very expensive. So based on all of this, the 2018 AHA-ACC cholesterol guidelines are asking us as clinicians to also perform risk stratification when it comes to our secondary prevention patients. So not just primary prevention, we perform risk stratification, but also in secondary prevention. So they talk about two categories of secondary prevention patients. Patients not at very high risk and ACVD patients who are at high risk. And as you notice here, in both of them, high intensity statin therapy remains our first priority in terms of how we need to treat these patients. But then these guidelines identify a very high risk ACVD group, which again, based on what I just showed you, you can pretty much guess what that group will be. Those are patients who had major ACVD events, that is they had recent ACS, they have history of prior MI in the absence of this ACS event. So if they had multiple ACS events, history of Schemic Stroke, Symptomatic PAD. If these patients had two or more of these ACS events, well, they are very high risk. On the other hand, if they had one of these major ACVD events, and if they have two or more of these high risk conditions, which again would make sense, whether it's age more than or equal to 65, heterozygous FH, history of prior PCI or cabbage, diabetes, hypertension, chronic kidney disease, smoking, high LDL cholesterol, history of heart failure, or again, any of these, if you have those, if you have two of those and you have only one major ACVD event, again, you will fall into this very high risk ACVD group. And those are the patients where after intensifying statin therapy, the guidelines would recommend use of azetamide and sequential use of azetamide followed by PCS canine inhibitors if LDL cholesterol levels remain above 70 milligrams per deciliter, despite the use of statin therapy and azetamide. And of course, one may ask why that's the case. So again, the use of azetamide followed by the use of PCS canine inhibitors. And then the reason for that is if you look at a lot of simulation studies both within and outside, very large healthcare systems like VA, what you will notice is that a large majority of these patients will really drop their LDL cholesterol levels below 70 milligrams per deciliter by the use of high intensity statin therapy combined with azetamide. So as per the guidelines, identifying very high risk ACVD patients, maximizing statin therapy, statin adherence, and then using azetamide followed by PCS canine inhibitors as needed and reserving these therapies for our very high risk ACVD patients. Let's quickly pivot and talk about two other therapies that lower LDL cholesterol. The first one is Bampidioic acid. Now it works on the same pathway as statin but a little bit higher up. But the important thing is that this is a pro drug that has to be converted into an active drug inside the hepatocyte using this enzyme called ACS-VL1. And once that's done, it converts into an active compound. And then that is what actually leads to inhibition of an enzyme called ATP citrate-Liase which is higher up in this cholesterol synthesis. It's in the same pathway as HMG-CoA reductase which is inhibited by statin therapy. So much higher up in the same, but in the same pathway. And it leads to the same effect, increase in LDL receptors because cholesterol level inside the hepatocytes go down. But the important thing is that since ACS-VL1 is only present in the liver, but not in the skeletal muscle, there is this possibility that it will reduce the occurrence of statin associated musculoskeletal side effects that are sometimes very common in some of our patients who are taking statin therapy. Now, if you look at the genetics of ATP citrate-Liase, you will find that even genetics prove towards a possibility theological role of these patients. So genetics are supportive that this lowering LDL cholesterol using this mechanism will likely be beneficial, although we do not have any outcomes trials. If you look at the efficacy program related to bapidioic acid, we've had multiple trials, clear harmony, clear wisdom, clear serenity, clear tranquility. It's all clear and it's all a lot of wisdom and serenity and tranquility. When you look at these trials, what you see is that of course, a lot of high-risk patient populations were enrolled in these trials with a decent follow-up. And when you look at these trials and I'm using clear wisdom as one of the trials here, and as you can see here, clear wisdom is a trial that use patients with ACVD or heterozygous FH who are on maximally tolerated statin therapy overall, there was about a 15% reduction in LDL cholesterol. But as you can imagine, since it works on the same pathway as a statin, you have much larger reduction in LDL cholesterol among patients who are not taking statin therapy. Whereas those who are taking statin therapy, it's much lower reduction in LDL cholesterol, more like 15%. So for bapidioic acid, studies show that it lowers LDL cholesterol about 15 to 25% on a background of statin therapy. And as we discussed, there's higher LDL cholesterol reduction in patients not on statins. Again, there is a medication available that combines bapidioic acid and azetamide that leads to about 35% reduction in LDL cholesterol. As we discussed, it's not active in muscles. And overall, it has good safety profile, except two things that we need to know as clinicians. One is that it leads to uric acid increase. So those patients who have history of hyperuricemia or doubt, we need to follow the uric acid levels. And it has a small but appreciable increase in the incidence of tendon rupture, which needs to be kept in mind when we are treating these patients. We, of course, do not know whether it improves cardiovascular outcomes. We have some genetic data that would seem to point towards that. So there's a large global study right now going on in patients who have CV events or who have very high risk of CVD events who are statin intolerant, who are enrolled in a trial called Clear Outcomes. And this trial will tell us whether the use of bapidioic acid is associated with an improvement in cardiovascular outcomes. So we know that it lowers LDL cholesterol between 15 to 25% whether it improves cardiovascular outcomes we'll find out once the results of Clear Outcomes are out. So then let's talk about another group of medication that is not approved by FDA currently, which is Inclinceran. And that is an SIRNA. It's an RNA inhibition technology whereby you have small interfering RNA. It's a double-stranded RNA, which is delivered to the liver. You give it subcube. It has this gel-nac entity attached to it, which binds specific receptors on the hepatocyte surface. So very much targeting of the drug to the organ where it really needs to work. So it reduces the need to have very large doses which sometimes are required for this small interfering RNA molecules. But by targeting the tissue where it needs to act, it really lowers the dose that needs to be given for this particular drug. It has two strands. Again, it goes into the hepatocyte, binds this risk complex, this RNA complex. And when it binds that, again, the guide strand remains there. The passenger strand, which brings it there, dissociates. And once that happens, then it binds to the messenger RNA in the cytoplasm for PCS canine inhibitor. And once it binds to that messenger RNA, that messenger RNA for PCS canine is again degraded.  So again, remember PCS canine inhibitors bind here outside the hepatocyte, right? They bind the PCS canine protein. And this SIRNA actually binds to the messenger RNA of PCS canine basically doing the same thing but doing it inside the hepatocyte, allowing you to have very long action, duration of action, allowing you to not give the medication like every two weeks or every four weeks, what we do with the PCS canine inhibitors currently. So when we look at what is the efficacy data that's available for this medication, we have three large trials, Orion 9, 10 and 11. Orion 5 is still ongoing, but then we have data from 9, 10 and 11, which has looked at heterozygous FH patients, second prevention patients, as well as secondary and high risk primary prevention patients.  So on a stable situation, one would give this drug basically twice every year. So one could potentially tie it with a patient's visit to a primary care or a cardiologist's office and then be done with this, right? So the question is how does it work? When we look at this combined meta-analysis of Orion 9, 10 and 11, what we found was that it lowers LDL cholesterol by about 50%, very similar to PCS canine inhibitors. And again, lowers PCS canine levels by almost 80%. Overall, it seemed to be safe except self-limiting mild to moderate treatment associated adverse events at the injection site and a mild increase in bronchitis. But otherwise, no difference in muscle toxicity, liver toxicity, or hympliological problems in these trials when we combine data from Orion 9, 10 and 11 about 3,600 patients. We again, just like BAMPID-boic acid, there's an outcomes trial called Orion 4-CV outcomes trial that is ongoing with Inclinsterion right now looking at cardiovascular outcomes in patients with stable atherosclerosis. Those with MIFRs show or prefer arterial disease. And we'll see if this medication improves cardiovascular outcomes in addition to a lowering LDL cholesterol, which we know it does at this point. So if I have to look at the great journey of lipid lowering medications in the past three decades, really this is where we are. We started out with statins in 1990s. We of course had quite a few trials done with statin therapy in very many different times of patient populations. We of course on our way had some trials that did not show benefit. We had the trials related to fibroid therapies that did not turn out. We had trials related to HDL raising, aim high that did not work out. And then we have trials that have shown benefit. For example, Fourier and Odyssey outcomes. And now we are in this phase when we're looking at BAMPID-boic acid as well as Inclinsterion. So we have come a long way with a lot of therapeutic options available for clinicians to use on their high-risk patients. So what are our take home messages? Well, high-intensity statin therapy plus lifestyle that is healthy remains the first step in secondary ASCVD prevention. The 2018 AHA ACC multi-society cholesterol guidelines identify a very high-risk ASCVD group among secondary prevention patients. So we need to perform risk stratification even in our secondary prevention patients because these very high-risk ASCVD patients are the patients who have the highest absolute event rate. And therefore, these are the patients who will derive the highest absolute risk reduction with the use of non-statin therapies. For example, is that am I been PCS canine inhibitors? But remember that statin use and emphasis on statin adherence remains the first step before we perform a step-wise addition of ZMI or PCS canine and very high-risk patients. And several newer options may provide clinicians further non-statin options for lowering LDL cholesterol, Bapidioic acid being something that is FDA approved and in glycerin that is not FDA approved. Both of them are undergoing their CV outcomes trials right now. So again, with that, there's a lot of hope in the field of LDL cholesterol loading by non-statins. Thank you for your time. Take care.


Hi, I'm Diana Ibrahim with Cal OES. This week, following a major disaster declaration secured by Governor Gavin Newsom, Cal OES has opened disaster recovery centers in collaboration with federal, state, and local partners in San Diego County to help communities recover from the late January 2024 storms. Disaster recovery centers are a one-stop shop providing individuals, families, and business owners with help in person to recover from the storm. And with winter weather in full swing, cold temperatures, rainstorms, and snowfall continue to persist across the state, Cal OES continues to monitor for weather impacts and the State Operations Center remains ready to help Californians respond to and recover from any major weather. This weather is an important reminder to all Californians to sign up for local emergency alerts at leastoscalifornia.org forward slash alerts. And finally, Los Angeles Mayor Karen Bass and members of the City Council visited Cal OES's State Operations Center to discuss ongoing disaster resiliency in the area. To see more from us, go to news.calos.ca.gov and follow us on all of our social media channels.