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Sangre de Cristo Electric Association, Inc. > Carousel > Let's Get Creative
Let's Get Creative
Take an art-themed trip through Colorado's Western slope
By Heidi Kerr-Schlaefer
Wine festivals, art gallery openings, farmers markets, rodeos, film festivals, studio tours — the list of can't-miss events along the Colorado Creative Corridor is long.
Featuring five state-certified Creative Districts nestled in the mountains of western Colorado, the creative corridor offers visitors "art-centric" destinations along a 331-mile trail that links five of the Western Slope's most charming communities.
The towns on the Colorado Creative Corridor — Carbondale, Paonia, Crested Butte, Ridgway and Salida — are similar but also different. Each town offers an array of recreational and artistic experiences that make for a memorable vacation. But how did they end up pooling their resources to create the Colorado Creative Corridor? It started with Creative Districts.
While there are a number of places with designated creative areas around Colorado, 23 are officially certified through Colorado Creative Industries, an arm of the state Office of Economic Development. The certification program started five years ago.
Christy Costello is the program manager of Colorado Creative Industries, and she defines Creative Districts as "specific geographic areas with a high concentration of creative things happening." She says that this is typically a downtown main street area, but there are exceptions.
Art is often interpreted as putting brush to canvas, but these Creative Districts include numerous activities that stimulate minds and hearts, including culinary arts, graphic design, woodworking, metalworking, crafting spirits and even drawings on the top of lattes. If the endeavor requires creativity, it is part of the arts scene in a Creative District.
The most recent data, gathered in 2017, shows that there are 28,000 creative jobs in Colorado's certified Creative Districts, a 3% increase over 2016. Creative industry earnings were $1.6 billion, which represents a 4% gain in one year.
Every Creative District wants to attract cultural tourists, but, for the most part, these are tiny, rural towns with small budgets. The trick is finding a way to pool resources in order to entice these types of visitors into artistic, bucolic communities.
Creating the Corridor
With this in mind, the Colorado Creative Corridor was founded on the back of a napkin by forward-thinking people involved in Carbondale tourism.
Sara-Jane Johnson is a tourism consultant for Carbondale, and she had been eyeing the marketing matching grant offered by the Destination Development Program, part of the Colorado Tourism Office. Johnson knew that $50,000 would be extremely helpful to the Carbondale Creative District, but there was the issue of how to raise the required $25,000 matching money.
"We wanted to package the idea of a visitor-ready road trip idea," says Johnson, who says that the corridor was inspired, in part, by the Colorado Hot Springs Loop. That collaboration between multiple hot springs towns in Colorado had previously received the grant.
So, Carbondale reached out to its neighbors Crested Butte, Paonia, Ridgway and Salida, and each district chipped in $5,000 to reach the $25,000 goal. They received the grant in 2018 and again in 2019.
The mission of the Colorado Creative Corridor is simple: Bring more visitors to all of its towns. The creative corridor worked to achieve this goal by creating a brochure that outlines a road trip itinerary that offers all kinds of fun in each community along the route. The options include things like bike
trails, cooking classes, concerts, water sports, walking tours and more.
Visitors find all kinds of artistic objects at the shops and festivals in the creative corridor towns.
This year, the brochure is available in all the communities on the corridor as well as at Colorado's 10 Welcome Centers. In addition, it's available online at Colorado.com. They also utilize social media to spread the word about what's happening in the towns along the Colorado Creative Corridor.
"We all have small budgets so you have to be creative on this type of collaboration, no pun intended," says Andrea Steward, Carbondale chamber president. "The fee for using social media is only our time, so we allow each participating entity to access the Colorado Creative Corridor Facebook page and Instagram page. We can then promote what we are doing and support the other entities by sharing their information as well."
A monthly meeting helps to keep the mission on track, but it has evolved into an idea-sharing opportunity as well. Ten organizations are represented in the 30-minute meeting, and the conversations here have become priceless to everyone involved. The opportunity to meet face to face comes only twice a year at conferences, so this monthly connection is vital to the success of the Colorado Creative Corridor.
Here's a look at what's happening along the corridor this summer:
In the shadow of Mount Sopris, Carbondale stands as a testament to art and agriculture. The two industries have coexisted here for years. A big draw to the area is the Rio Grande ARTway along the Rio Grande Trail. The trail is used by more than 14,000 cyclists every year and the 1-mile ARTway stretch includes an array of approachable art.
In addition to public art, the thriving downtown features local culinary delights at restaurants such as Allegria, which sources food through local farms. Craft spirits and lodging coexist at Marble Distilling Co. & Distillery Inn, also downtown.
A short distance away is Dolores Way, a collection of creative industries, such as potters, soap makers and beer brewers. The town is also home to Powers Art Center, a showcase of work by American artist Jasper Johns.
More than 200 creative organizations exist in Carbondale, and visitors benefit from the long-lasting relationships that have developed between farmers and chefs and nature and artists.
Perhaps best known as a ski destination, Crested Butte offers visitors small-town charms beyond the slopes. This postcard perfect town is a magnet for those seeking recreational activities. As a result, in the summer the town comes alive with hikers and bikers. The region's rivers brim with anglers looking to hook a splendid trout, and its meadows and scenic trails see wildflower hunters gather in droves.
Downtown Crested Butte is sprinkled with creative businesses, such as art galleries, custom ski shops, a world renowned rum distillery and more. The town-managed public art program creates a lively atmosphere filled with ephemeral temporary installations and permanent displays that blend into the picturesque landscape.
Whether it's a visit to a well-maintained Crested Butte museum, a dance class with locals or taking in a musical performance at the Center for the Arts, a trip to this quintessential Colorado mountain town is one for the memory books.
Surrounded by the North Fork Valley, Paonia is home to more sheep than humans. In the summer, the green countryside is reminiscent of the rolling hills of France. Grapevines are prevalent and wild fruit trees grow on the side of quaint, country roads.
In addition to farm visits, cheese making, winery tastings and bike outings, the arts are palpable here. The tiny village of Paonia has long embraced artistic expression. Spontaneous drum circles seemingly erupt from nowhere and live music flows from local pubs, parks and traditional venues such as Paradise Theatre.
Since 2006, Paonia's Elsewhere Studio has hosted the Inspired Art at Work Project, a residency program featuring socially-engaged works that explore and address issues vital to preserving the natural world, quality of life and sense of place in the North Fork Valley.
The best time to experience the essence of Paonia is during the town's two signature events: Cherry Days in July and Mountain Harvest Festival at the end of September.
Artists in the corridor communities love to interact with visitors and share their art.
Photo by Renee Ramge Photography.
The tiniest town on the Colorado Creative Corridor, Ridgway is doing big things when it comes to art. Perhaps having a population of fewer than 1,000 people has forced Ridgway to be artistically innovative. Or perhaps it is its location, 15 minutes from Ouray and less than an hour from Telluride, that compelled a higher level of creative thinking. Whatever the reason, the residents want to give people a reason to stop in their community.
The little downtown is brimming with creative industries, such as art galleries and unique gift shops like Lupita's Bizarre Bazaar. Even local restaurants have gotten into the game. Several local haunts are often named as Colorado favorites by visitors who stop in town for tacos at Taco del Gnar or pizza at Colorado Boy.
Known as a destination for hot springs lovers, whether visitors stay at Chipeta Solar Springs Resort or soak for the day at Orvis Hot Springs, a getaway in Ridgway is downright enchanting. Some of this magic is provided by the Alley Poems Program. The program has Ridgway poets and visitors putting pen to paper; poetry appears around town, on walls, fences and other surfaces throughout the year.
Theatrical productions, musical performances, poetry readings and more grace the stage in corridor towns.
One of the original Colorado art communities, Salida is where artists and art appreciators have been coming for years. Many of the artists who visited stayed in town and opened galleries. Salida is literally brimming with art and it's everywhere, including on the sides of buildings.
Located along the panoramic Arkansas River, the SteamPlant Event Center is a draw for locals and visitors to the area. Built in 1887, the SteamPlant is a poster child for repurposed space. The plant was retired in 1963 but brought back to life in 1989 when it was converted into a theater. Today, the
SteamPlant has expanded into a conference center and hosts everything from weddings to musical events.
In many ways, Salida is an example of a community where the arts are driving the economy. This isn't to say each town along the Colorado Creative Corridor doesn't struggle with its own set of issues, but by creating this creative corridor, these communities are striving together toward a common goal of local economic success through art while providing a great road trip worthy route for visitors through western Colorado.
The fact is, whether a person travels specifically to seek art or for some other purpose, art has been shown to increase our happiness, and each town along the Colorado Creative Corridor has art in spades. Therefore, these towns enhance the enjoyment of all of their visitors.
Learn more at Colorado.com/fieldguide/colorado-creative-corridor.
Heidi Kerr-Schlaefer is a Colorado freelance writer specializing in festivals, travel and the West. She is the founder of HeidiTown.com and author of The Heidi Guide.


It is formed by a peak (shoulder), followed by a higher peak (head), and then another lower peak (shoulder).
A "neckline" is drawn by connecting the lowest points of the two troughs.
In this example, we can easily see the head and shoulders pattern.
Here you can see that this is just like a head and shoulders pattern, but it's flipped upside down.
With this formation, we would place a long entry order above the neckline.
You will learn about those later on in the course.


FFC is committed to producing the very best personal trainers in the fitness industry. Our goal is to deliver Birgu personal training courses that goes above and beyond the certificate 3 and certificate 4 fitness education industry norm.
Unlike other Birgu fitness instructor certification providers that mass produce fitness trainers on a production line, we only enrol small groups of students into our courses to ensure you receive the highest level of coaching and support.
During your time with FFC, the amount of support and coaching you'll receive will be unrivalled by any other Birgu personal training certification.
Your FFC tutor will be with you every step of the way to coach you and answer any questions you have whilst on your journey to becoming a first class Birgu personal trainer.
Our training facility provides the perfect learning environment. Unlike most other Birgu campuses that pack you into small overcrowded dorms, FFC offer you your own room conveniently located in the same building as the training facility and classroom.
In Birgu the weather can be very unpredictable. Our training campus is based in the coastal town of Denia – Southern Spain. So you'll be able to hone your outdoor fitness skills on Spain's famous Mediterranean beaches.
If you want to be a successful Birgu personal trainer then you need to learn from successful mentors that are 'in the field', training clients and running successful fitness businesses. Not from a school teacher in a classroom reading from a book that has no real life experience.
Unfortunately most Birgu personal trainer certification providers do not offer streetsmart business skills when completing your cert 3 and cert 4 Birgu fitness instructor qualification.
Live your passion & do something you love, visit our fitness training certifications and be a qualified fitness trainer.


This is the perfect course for those who have taken Zendesk Insights, I and want to take the next step. In this course, we'll describe for you under what circumstances you'll want to create a custom metric, then we'll teach you the steps involved, how to build a custom metric, and last, how to apply conditional formatting.
The time to complete this course is 1 hour.
Insights should be enabled before attending this training session.


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School of Medicine student competes on 'Jeopardy!'
03/25/2016 -PRNStudentsUMKC Strategic Marketing and Communications
Third-year medical student Kent Buxton appears on the television game show, "Jeopardy!" with host Alex Trebek.
Kent Buxton, a third-year student, made his debut on the game show "Jeopardy!" on Monday, March 28. The appearance fulfills a longtime dream for Buxton, who is studying to become an emergency medicine physician.
"I've wanted to be on Jeopardy since I was in high school playing quiz bowl at Notre Dame (in Cape Girardeau, MO)," Buxton said.
He finished third in Monday's contest. Only the winner advances to the next day's show.
That "Jeopardy!" seed might have been planted much earlier. Buxton's fun-fact story on the show involves his father accidentally training him to compete by drilling him on the names of the 50 states and their capitals when he was only about 3 years old.
Buxton tried out for the "Jeopardy!" college tournament in 2008, and got an audition in Chicago, but did not make it. Once Buxton was eligible for the adult show, he took his time pursuing "Jeopardy!" again.
"I figured it was better to wait until I was older since many competitors have a lot more life experiences that could help on the show," Buxton said.
Buxton taught for a several years, and served as a medical scribe in St. Louis hospitals before starting medical school at UMKC. He took the Jeopardy online test this past April, and auditioned June 30 at Crown Center.
"I had to skip one of my classes and write a five-page research paper as a make-up assignment in order to attend, but I was able to walk from school to the audition," he said. There, he took a written test and played a practice round.
In December, Buxton got the call he had been accepted.
"I was beyond excited," he said. "I flew to L.A. to tape the show two days before a microbiology exam that I wasn't totally prepared for."
Buxton said his heart raced during the taping but he eventually settled down. He joked around with host Alex Trebek: "What was it like being shoved into a phone booth with Shaq?"
"I cannot say how the game turned out, but I had a ton of fun," Buxton said before the show aired on March 28.
"Jeopardy!" is in its 32nd season in syndication, with 25 million viewers tuning in each week. Contestants participate in three rounds of trivia in which they give their responses in the form of a question. At the end of each show, the winner is named and that person returns in the next episode to defend his or her title as returning champion.
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Category Archives: Systems Therapeutics
Systems Therapeutics project
Systems Therapeutics: Diagram, Definitions and Illustrative Examples
Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. A systems therapeutics diagram has been constructed, consisting of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and finally the clinical level. These different levels of interactions then determine four different systems therapeutics categories. Illustrative examples of these four different systems therapeutics categories are provided, as well as a glossary of the systems components. The systems therapeutics diagram further suggests that the wide interpatient variability in therapeutic response characteristics to approved drugs is contributed to by variabilities in both of these two processes. It is hoped that the systems therapeutics framework advanced here will promote discussions regarding the need for better understanding of the determinants of therapeutic response characteristics of modern therapeutics.
Systems Therapeutics Illustrative Examples
While a large number of new drugs have been approved by regulatory agencies over the past several decades, and we have witnessed significant scientific advances in molecular understanding of pharmacologic mechanisms and disease processes, there have only been sporadic efforts towards the construction of frameworks for understanding how pharmacologic and pathophysiologic processes interact to produce therapeutic effects. One noteworthy effort was presented by Grahame-Smith & Aronson in the Oxford Textbook of Clinical Pharmacology and Drug Therapy, which describes the chain of events linking the pharmacologic effects of drugs to their clinical effects, including several examples (1). An earlier effort by this author on classification of drug action based on therapeutic effects was published in 1996 (2). More recent efforts have included a comprehensive white paper on quantitative and systems pharmacology by Sorger et al. of the QSP Workshop Group, including recommendations (3).
The purpose of this paper is to provide an updated summary of a systems therapeutics framework, depicting pharmacologic and pathophysiologic processes separately, thus enabling the presentation of the different biologic levels of interactions between these two processes. This paper summarizes and updates five previous iterations on the systems therapeutics framework posted on the Therapeutics Research Institute's website, TRI-institute.org, between April 2015 and February 2018 (4,5,6,7,8). During this period, this has included an evolving construction of a systems therapeutics diagram, four systems therapeutics categories, relevant definitions, and illustrative examples of the different categories, as well as a discussion of variabilities in pharmacologic and pathophysiologic processes.
Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response (see diagram below; click for a larger diagram).
The organizing principle underlying the systems therapeutics diagram presented above involves two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and finally the clinical level. The systems components for pharmacologic processes start with a pharmacologic response element, followed by a pharmacologic mechanism, a pharmacologic response, and a clinical effect, whereas the systems components for pathophysiologic processes start with an etiologic causative factor, followed by a pathogenic pathway, a pathophysiologic process, and a disease manifestation. The four different biologic levels of interactions between these two processes then determine the four systems therapeutics categories, i.e., Category I (at the molecular level), Category II (at the cellular level), Category III (at the tissue/organ level), and Category IV (at the clinical level), as previously outlined (4). Brief descriptions of the individual systems therapeutics components are provided in the glossary below, including examples for each component.
Both of these two processes are initiated by their own sets of initiators or drivers, i.e., a pharmacologic agent and an intrinsic operator, for the pharmacologic and pathophysiologic processes, respectively. On the pharmacologic process side, a pharmacologic agent, interacting with a pharmacologic response element, and its concentration or exposure, is the fundamental driver of pharmacologic processes. On the pathophysiologic process side, a hypothetical intrinsic operator is proposed as an integral systems component interacting with and influencing an etiologic causative factor, and serving as a driver of pathophysiologic processes. This hypothetical intrinsic operator is intended to cover different biologic entities being identified using advanced bioinformatics and network-based approached, as previously discussed (5,6).
The culminating result of the interaction between these two processes, independent of the biologic level of interaction, involves a clinical therapeutic response. While it is well recognized that there is a wide variability in the clinical therapeutic response of individual patients to a given approved drug (9,10), it is less well recognized that both of these two processes, pharmacologic and pathophysiologic, have their inherent variabilities. This systems therapeutics construct thus further suggests that interpatient variabilities in both of these active processes contribute to and thus are co-determinants of the ultimate patient therapeutic response characteristics, including range and extent of response, response variability, and responder rate. Presently, however, the relative contributions of each of these process variabilities to the ultimate therapeutic response are typically unclear, most significantly due to limited availability of data and methods, and are likely to vary from one therapeutic class to another. A general commentary (5) discussed variabilities in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression).
Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves the primary corresponding molecular entities, the pharmacologic response element and the etiologic causative factor, respectively.
Examples of Molecular-based Therapy – These can involve replacement therapies (hormones, enzymes, proteins, genes) or genome-based therapies (interference with altered gene products):
Examples of Metabolism-based Therapy – These can involve metabolism-based therapies (interference with a biochemical mechanism or a disease network-linked pathway):
Examples of Function-based Therapy – These can involve function-based therapies (modulation of a (normal) physiologic function or activity):
Examples of Symptom-based Therapy – These can involve symptom-based therapies (various symptomatic or palliative treatments):
Analgesics, e.g., Advil (ibuprofen) for Osteoarthritis
Below are illustrative examples for each of the four systems therapeutics categories. The charts follows the design of the systems therapeutics diagram discussed above. The pivotal connection between pharmacologic and pathophysiologic processes represents the fundamental or primary interaction between these processes (represented by a fat arrow), thus determining the systems therapeutics category; these are followed by dependent or secondary connections to the right (represented by thin arrows). The descriptions for the individual systems components were generated from generally available textbooks of pharmacology, pathophysiology and medicine, and other sources, but with an emphasis on a separation of pharmacologic and pathophysiologic concepts and processes, culminating in a therapeutic response.
Illustrative Example for Category I:
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator for Cystic Fibrosis.
See diagram below; click for a larger diagram.
Illustrative Example for Category II:
Proton Pump Inhibitors for Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD)
Illustrative Example for Category III:
Angiotensin-Converting Enzyme (ACE) Inhibitors for Hypertension
Illustrative Example for Category IV:
Non-Steroidal Anti-inflammatory Agents (NSAIDs) for Osteoarthritis
The systems therapeutics diagram has been constructed with the goal of serving to facilitate better understanding and discussion of the different types of successful therapies involving approved drugs. Importantly, this framework shows the pharmacologic processes and the pathophysiologic processes separately, rather than exhibiting a singular pharmacotherapeutic process, and thus illustrating at what biologic level the pharmacologic and pathophysiologic processes interact to result in a therapeutic response. The illustrative examples presented for the four different systems therapeutics categories offer descriptions of the two progressing processes in a storyboard-like fashion, highlighting at what biology level the pivotal interaction occurs between these two processes.
In addition to the systems components for pharmacologic processes and pathophysiologic processes are the two initiators or drivers of these two processes, one actual (pharmacologic agent), the other hypothetical (intrinsic operator). The former driver is well recognized, including its concentration or exposure, while the rationale for the latter is based on recent bioinformatics and network-based approaches indicating that disease initiation can involve interactions between genetic and non-genetic components, although major research efforts are needed to elucidate the nature of these interactions (5,11). Also, one can speculate that the wide range in the age of disease onset for different diseases, from first year of life to late in life, does suggest unrecognized driving factors acting on an etiologic causative factor. At the present time, however, we are not aware of any current pharmacologic agent/mechanism interacting with such a hypothetical intrinsic operator (which when identified could be represented as systems therapeutics Category Zero).
It is our hope that the systems therapeutics framework advanced here will help stimulate research towards better understanding of the relationships between the biologic levels of interactions between pharmacologic and pathophysiologic processes on one hand and the therapeutic response characteristics of modern therapeutics on the other. It has previously been noted that although this systems-based framework does not explicitly address interpatient variability in therapeutic response, this framework clearly suggests that variabilities in pharmacologic processes and pathophysiologic processes both contribute to the overall variability in therapeutic response. We further hope that this framework will stimulate research towards better qualitative and quantitative descriptions of the pharmacologic and pathophysiologic processes, including ways of defining the relative contributions of these two processes towards determining the overall therapeutic response characteristics.
Therapeutics Research Institute. Systems Therapeutics: Where Pharmacologic and Pathophysiologic Processes Interact, February 2017. http://tri-institute.org/9sPlA
Therapeutics Research Institute. Systems Therapeutics: Representative Illustrative Example for Category II. March 2018. http://tri-institute.org/nehUV
Barabasi AL, Gulbahce N, Loscalzo J (2011). Network medicine: a network-based approach to human disease. Nat. Rev. Genetics, 12:56-68
Below is a glossary of the individual systems components for the pharmacologic and pathophysiologic processes represented in the systems therapeutics diagram presented above. Examples for each systems component are from among approved treatments and diseases that have previously been addressed in individual posts on the Therapeutics Research Institute's website, TRI-institute.org.
A compound, could be a small molecule or a large bio-pharmaceutical, that initiates the pharmacologic process by interacting with a pharmacologic response element.
A native biologic element, could be a receptor or an enzyme, with which a pharmacologic agent interacts (pharmacologic interaction). Commonly referred to as a pharmacologic target.
H+/K+ ATPase (proton pump); and
cGMP-specific phosphodiesterase type 5 (PDE5).
Molecular mechanism of action, typically involving a molecular pathway resulting in a biochemical reaction (signal transduction).
Pharmacologic effect at the tissue/organ level mediated through a pharmacologic mechanism (pharmacodynamics).
A pharmacologic effect at the clinical level, which represents the pharmacologic basis for a therapeutic response (translation).
Currently typically not known
A genetic or non-genetic factor, upon interaction with an intrinsic operator (disease preindication), determines a disease specific progression.
Dihydrotestosterone (DHT)-induced growth factors and their receptors (in Benign Prostatic Hyperplasia); and
Molecular pathogenic pathway mediating ongoing disease progression (disease initiation).
DHT-induced growth factors stimulate proliferation of stromal cells (in Benign Prostatic Hyperplasia); and
Ongoing pathophysiologic process (pathogenesis).
Formation of discrete hyperplastic nodules in periurethral region (in Benign Prostatic Hyperplasia); and
Development of characteristic clinical signs and symptoms associated with a given disease (progression), typically independent of a specific etiologic causative factor.
Lower urinary tract symptoms (in Benign Prostatic Hyperplasia); and
Loss of bone mineral density and risk of bone fracture (in Osteoporosis).
Symptom relief and mucosal healing (e.g., after proton pump nhibitors in Acid Reflux and Ulcer Disease)
Improved erection (e.g., after PDE5 inhibitors in Male Erectile Dysfunction)
Decreased urinary frequency (e.g., after 5-alpha reductase inhibitors in Benign Prostatic Hyperplasia)
Decreased bone fractures (e.g., after bisphosphonates in Osteoporosis)
This entry was posted in Systems Therapeutics and tagged categories, diagram, modern therapeutics, pathophysiology, pharmacology, systems therapeutics, therapeutics on April 26, 2018 by ch30c.
Systems Therapeutics: Representative Illustrative Example for Category II
Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. A systems therapeutics diagram has been constructed (1), consisting of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, representing the four different biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ levels, and the clinical level, culminating in a therapeutic response. The interactions at these different biologic levels then determine the four different systems therapeutics categories, Categories I – IV. The above referenced summary only named therapeutic class examples for each of the four systems therapeutics categories, but did not include representative illustrative examples for each of these categories.
The purpose of this post is to provide an illustrative example for one of the systems therapeutics categories, Category II, where the pivotal interaction between the pharmacologic and pathophysiologic processes involves a fundamental biochemical mechanism at the cellular level, related to the disease evolution, although not necessarily an etiologic pathway. The illustrative example chosen for Category II involves Proton Pump Inhibitors for Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD). Future communications will provide illustrative examples for the other systems therapeutics categories.
Illustrative Example for Category II
The chart below (click for a larger view) illustrates the individual systems components for pharmacologic and pathophysiologic processes for Proton Pump Inhibitors for Gastroesophageal Reflux Disease (GERD) and Peptic Ulcer Disease (PUD), culminating in a therapeutic response.
This chart follows the design of the systems therapeutics diagram previously referenced (1), which includes definitions of the individual systems therapeutics categories and a glossary of the individual systems components. The chart was developed using OmniGraffle (The Omni Group, Seattle, WA). The bold connection between pharmacologic and pathophysiologic processes represents the pivotal interaction between these processes, which here is at the cellular level (Category II). The descriptions for the individual systems components were generated from generally available textbooks of pharmacology, pathophysiology and medicine, and other sources, but with an emphasis on a separation of pharmacologic and pathophysiologic concepts and processes, culminating in a therapeutic response.
The systems therapeutics framework referenced above (1), including a diagram, four categories, definitions and a glossary, was constructed with the goal of serving to facilitate discussion and understanding of the different types of FDA approved drugs. Importantly, this framework attempts to illustrate the pharmacologic processes and the pathophysiologic processes separately, rather than exhibiting a singular pharmacotherapeutic process, in contrast to previously published attempts, thus enabling highlighting at what level the pharmacologic process engages with the pathophysiologic process. It has previously been noted that this systems-based framework does not explicitly address interpatient variability in therapeutic response, although this framework clearly suggests that variabilities in pharmacologic processes and pathophysiologic processes both contribute to the overall variability in therapeutic response. A general commentary on variabilities in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression) has been previously published (2).
The chart presented in this publication has provided a representative illustrative example for one of the four systems therapeutics categories (Category II). It is hoped that this illustration will serve as a useful example of how the systems therapeutics framework can provide a framework for facilitating discussions concerning various aspects of different therapeutics, as well as suggesting areas in need of future research and better understanding.
Systems Therapeutics: Where Pharmacologic and Pathophysiologic Processes Interact. Therapeutics Research Institute, February 2017.
This post summarizes the systems therapeutics framework, including the systems therapeutics diagram, its four categories, related definitions, as well as a glossary. Note the example presented above for Category II was initially named as Category III.
Systems Therapeutics: Variabilities. Therapeutics Research Institute, May 2016.
This post discusses variability in pharmacologic processes (pharmacokinetics and pharmacodynamics) and pathophysiologic processes (disease initiation and disease progression). Note the systems therapeutics diagram in this post represents an earlier version of the diagram.
This entry was posted in Systems Therapeutics and tagged GERD, proton pump inhibitors, PUD, systems therapeutics, systems therapeutics diagram on March 15, 2018 by ch30c.
Systems Therapeutics: Updated Diagram
Two reports have been posted on Systems Therapeutics on this website, first, "Systems Therapeutics: A Diagram and Four Categories" in April 2015 (1), and second, "Systems Therapeutics: Variabilities" in May 2016 (2). The purpose of the underlying systems therapeutics diagram is to provide a high-level framework to facilitate discussions on how pharmacologic processes and pathophysiologic processes interact to produce a therapeutic response.
In essence, the systems therapeutics diagram consists of two rows of four parallel systems components for pharmacologic and pathophysiologic processes, each starting at the molecular level, through the cellular and tissue/organ levels, and finally the clinical level, culminating in therapeutic response. The pivotal interactions between the pharmacologic and pathophysiologic processes, at each of the four biologic levels, determine the four systems therapeutics categories, i.e., Category I (at the molecular level), Category II (at the cellular level), Category III (at the tissue/organ level), and Category IV (at the clinical level), as was outlined in the May 2015 post. In addition, each of these two processes, pharmacologic and pathophysiologic processes, have their inherent variabilities, as was outlined in the May 2016 post, which also suggested that variability on the pathophysiologic process side might be an important determinant of patient therapeutic response characteristics, including response variability and responder rate, in addition to variability on the pharmacologic process side, although it is unclear where the source of such variability might reside, including potentially at different levels.
Updated Diagram
The current report presents an updated systems therapeutics diagram, see below (click here for a larger graph), that includes the following modifications of the diagram presented in the May 2016 post:
On the pharmacologic processes side, the following systems components have changed names: "Pharmacologic Agent" has replaced "Drug" and "Drug Concentration", and "Pharmacologic Response Element" has replaced "Pharmacologic Target". The rationale is to use more neutral and descriptive terms, with an emphasis on an agent acting on an element in a pharmacologic pathway, resulting in a response. Here, the pharmacologic agent, and its concentration or exposure, is the undisputed fundamental driver of pharmacologic processes, including interpatient variability. Another change involves adding at the clinical level "Clinical Effect" as the last systems component on the pharmacologic processes side, corresponding to "Disease Manifestation" on the pathophysiologic processes side. The descriptors for the transitions from one systems component to another on the pharmacologic processes side, e., signal transduction, pharmacodynamics and translation, remain unchanged.
On the pathophysiologic processes side, the following systems components have changed names: "Intrinsic Operator" has replaced "Environmental" and "Factor", and "Etiologic Causative Factor" has replaced "Etiologic Factor". The main rationale is to simplify and depict similarly the initial events of both pharmacologic and pathophysiologic processes, with an emphasis on an etiologic factor in a disease network being driven by a hypothetical operator, eventually leading to manifestation of a disease. It is noted that this construct, incorporating a hypothetical systems component at the beginning of pathophysiologic processes, is intended in part to lump together different entities thought to influence "Etiologic Causative Factor" (as addressed in the May 2016 post, including etiome and network medicine), and in part to serve as a hypothetical driver of pathophysiologic processes, including interpatient variability. Whether this simple hypothesis survives the test of time is obviously unclear, but for now this "Intrinsic Operator" serves a role as an integral systems component. The descriptors for the transitions from one system component to another on the pathophysiologic process side, e., disease initiation, pathogenesis and progression, remain unchanged.
The systems therapeutics diagram, first introduced in the April 2015 post (1) has been modified twice, first in the May 2016 post (2), and now in the present report. Both modification have principally involved the system components at the beginning of the pharmacologic and pathophysiologic processes, how they are depicted and named.
This updated framework, highlighting how these parallel processes – pharmacologic and pathophysiologic – contribute to patient therapeutic response characteristics, also helps focus on areas where future basic research efforts are sorely needed, such as initiating disease process mechanisms and variability in disease process drivers.
It is our hope that those interested in this general subject will find the updated systems therapeutics diagram useful as an aid in thinking about the various determinants, known and unknown, of patient therapeutic response to approved drugs, while recognizing our limited understanding in this area at this time.
Therapeutics Research Institute: Systems Therapeutics: A Diagram and Four Categories, May 2015. http://tri-institute.org/niDFW
Therapeutics Research Institute: Systems Therapeutics: Variabilities, May 2016. http://tri-institute.org/TyQij
This entry was posted in Systems Therapeutics and tagged diagram, pathophysiology, pharmacology, systems therapeutics on October 1, 2016 by ch30c.
Systems Therapeutics: Variabilities
A systems therapeutics framework, "Systems Therapeutics: A Diagram and Four Categories", was recently presented on this website, tri-institute.org (2015), illustrating pharmacologic processes and pathophysiologic processes separately. This framework incorporated four different levels of interactions between these two fundamental processes, ranging from the molecular level, through the cellular and tissue/organ levels, to the clinical level; these four different levels of interactions are referred to as systems therapeutics categories. This conceptual framework builds on previous work by others, principally Grahame-Smith & Aronson (1992) and Post et al. (2005), and significantly expands previous work by Bjornsson (1996). The purpose of this initial work on systems therapeutics was to present a theoretical framework, which could be useful when examining different types of therapeutic effects; definitions and a few examples were presented for each systems therapeutics category.
Fundamental to considerations of therapeutic effects is the issue of interpatient variabilities, and determinants or drivers of such variabilities where these are understood, as discussed by Rowland & Tozer (2011) and Eichler et al. (2011). Variability in pharmacologic processes for approved drugs, principally in pharmacokinetics and pharmacodynamics, have been well recognized and characterized over that past several decades, although the final step, the translation from pharmacologic response to therapeutic effect, still remains elusive in many instances, particularly in drug discovery and development. Interpatient variability in pathophysiologic processes, from disease initiation to disease manifestations or signs and symptoms, however, has received much less attention than that in pharmacologic processes. Thus, when addressing interpatient variability in therapeutic response to approved drugs, including response range, response magnitude, responder rate, and lack of response, it is not always obvious to what extent interpatient variability in pathophysiologic processes, or disease progression, might contribute to the observed therapeutic response, in addition to variability in pharmacologic processes.
Since issues of such variabilities were not addresses in the previous paper, and considering their importance, the purpose of the present paper is to highlight key areas in systems therapeutics variabilities. Below is a graph of the systems therapeutics framework, illustrating the pharmacologic processes and pathophysiologic processes separately (click for a larger graph).
Variability in Pharmacologic Processes (Pharmacokinetics and Pharmacodynamics)
For the past three to four decades it has been assumed that interpatient variability in therapeutic effect is determined by individual differences in pharmacokinetics, pharmacodynamics and compliance. Note that the net effect of pharmacokinetics and compliance, the drug and its concentration at the site of action, as illustrated in the top left hand corner of the graph, can be considered as the initial determinant or driver of pharmacologic processes.
Variability is pharmacokinetics (PK), which covers drug absorption, distribution, drug metabolism and drug elimination, has been amply demonstrated. Tables of pharmacokinetic parameters of approved drugs are widely available and accessible, e.g., in textbooks and reviews of individual drugs or pharmacologic classes. A comprehensive table of pharmacokinetic parameters of approved drugs is included as an appendix by Thummel et al. (2011) in Goodman and Gilman's The Pharmacologic Basis of Therapeutics. This table lists for each drug its bioavailability, urinary excretion, plasma protein binding, clearance, volume of distribution, elimination half-life, peak time and peak concentration, typically expressed as mean ± standard deviation, but sometimes as mean and range in values. A coefficient of variation (CV) for clearance, one estimate of interpatient variation, of approx. 30% is common, but these can range considerably; obviously, the range in values can be significantly larger. A recent paper by Gao et al. (2011) on over 15 targeted anticancer drugs illustrates their wide pharmacokinetic variability, showing CV for exposure varying between approx. 25-82%, and trough levels varying between approx. 6-26 fold.
Variability in pharmacodynamics (PD), covering the relationship between drug concentration and pharmacological response intensity, has received less attention than that in pharmacokinetics. While there was an earlier belief that pharmacokinetic differences and compliance were more important as determinants of pharmacologic response than pharmacodynamic differences, it has become accepted that pharmacodynamic variability is at least as wide as pharmacokinetic variability, sometimes exceeding one order of magnitude, for early reviews see Levy et al. (1994) and Levy (1998). Commonly used examples of variation in pharmacologic response in the earlier literature involved various physiological, biochemical or related measures, e.g., pain relief and sedation, cardiovascular, anticoagulant, and metabolic measures. As a specific example, pharmacokinetic-pharmacodynamic modeling of the opioid analgesics fentanyl, alfentanil and trefentanil by Lemmens et al. (1994; cited in Levy 1998), using EEG as a pharmacodynamic measure, reported a range in CV for EC50 (drug concentration producing 50% of Emax, i.e., the maximum effect) of 47 to 85%. Interpatient variability in pharmacodynamics can be manifested in the different parameters of the concentration vs. response relationship, i.e., EC50, Emax, slope parameter of the sigmoid curve, and baseline; numerous factors may impact these.
Variability in Pathophysiologic Processes (Disease Initiation and Disease Progression)
While detailed descriptions of etiology, pathogenesis, pathophysiology, pathology, prognosis, and clinical manifestations and treatment of diseases are provided in textbooks of pathology and medicine, there is limited discussion of quantitative patient variability in disease progression over time. Ideally, such information would come from longitudinal studies on the natural history of diseases, but unfortunately, these are not available for most diseases, although clinically, such variability has been well recognized for centuries.
Disease pathophysiologic processes can be visualized as starting with disease initiation (refer to the bottom left hand corner of the graph). Recent work using advanced bioinformatics and network-based approaches has started to elucidate some of the components of disease initiation and their interactions. Although such work has not been directly aimed at variability, because of its promise in the future, two examples are included. First, Liu et al. (2009) introduced the term "etiome" to describe the combination of genetic and non-genetic etiologic factors associated with diseases; this publication identified 863 diseases as having both etiologic genetic and environmental factors (the latter referring to non-genetic factors in the broadest sense). Second, work by Barabasi et al. (2011) and others on so-called network medicine has sought to explore systematically the molecular connections and complexity of individual diseases and the molecular relationships among different (patho)phenotypes. The exciting promise of such approaches includes how these network constructs may connect with pathophysiologic processes or disease progression – systems pathobiology and clinical phenotypes – and thus contribute to determinants or drivers of individual patient's disease progression; see opinion paper by Loscalzo & Barabasi (2011).
As was mentioned above, there are only limited examples of the natural history of diseases or disease progression. However, data on disease progression over relatively short periods of time, involving repeated measures of disease status, are available and have been collected as part of clinical trials of drug efficacy, as part of control or placebo groups, and as analyzed by disease progress models using pharmacostatistical techniques. Note some assumptions may need to be made regarding the use of placebo groups as representative of natural history of disease. Several different disease progress models have been described, depending on the nature of the disease in question, including symptomatic and disease-modifying effects, and continuous or discontinuous progression, see for example Holford et al. (2012). Such pharmacometrics models have been developed for several diseases, e.g., Alzheimer's disease, Parkinson's disease, type-2 diabetes, depression, schizophrenia, chronic obstructive pulmonary disease, and osteoporosis; see summaries by Holford (2013). One example of disease progression involves assessment of cognitive deterioration in Alzheimer's disease by Ito et al. (2011), based on ADIS-cog measurements, which showed significant variability, with age, gender, APOEe4 genotype and baseline status determining the decline in cognition. Studies on Parkinson's disease have shown marked variability among patients on the rate of progression, assessed with global functional score, see Holford & Nutt (2008), suggesting there are distinct disease subtypes with different rates of progression.
Considering the significant interpatient variability in therapeutic response to approved drugs, including responder rate and response range, it is important to understand what processes contribute to such variability and their approximate contributions. This paper looked at three key areas, i.e., pharmacokinetic and pharmacodynamic variabilities in pharmacologic processes and disease progression in pathophysiologic processes; in addition, there was a brief introduction to bioinformatics efforts on disease initiation. Key comments are as follows:
There are well documented significant interpatient pharmacokinetic and pharmacodynamic differences; there are indications that the latter may be at least as wide as the former.
As expected, it is noted that reporting of PK parameters is better standardized than that of PD parameters. It is desirable that more uniform approaches are used in the reporting of PK and PD data and parameters, including the reporting of range in values.
It is recommended that the control or placebo data from disease progress models be routinely reported as an estimate of disease progression variability, including any caveats regarding placebo response.
It was noted during the preparation of this report that there are relatively few good up-to-date summaries/reviews on variabilities within these three key processes, particularly pharmacodynamics and disease progression.
Knowledge of variabilities in key underlying processes will provide better understanding of therapeutic response characteristics of approved drugs.
One looks forward to the time when bioinformatics approaches to disease initiation can be linked to pharmacometrics approaches to disease progression.
Barabasi AL, Gulbahce N, Loscalzo J (2011). Network medicine: a network-based approach to human disease. Nat. Rev. Genetics, 12:56-68.
Bjornsson TD (1996). A classification of drug action based on therapeutic effects. J. Clin. Pharmacol., 36:669-673 (p. 670, Fig. !).
Gao B, Yeap S, Clementis A, Balakrishnar B, Wong M, Gurney H (2012). Evidence for therapeutic drug monitoring of targeted anticancer therapies. J. Clin. Oncol., 30:4017-4025.
Grahame-Smith DG, Aronson JK (1992). Oxford Textbook of Clinical Pharmacology and Drug Therapy, Oxford University Press, Oxford (Chapter 5. The Therapeutic Process, pp. 55-66, Fig. 5.1).
Holford N, Nutt JG (2008). Disease progression, drug action and Parkinson's disease: Why time cannot be ignored. Eur. J. Clin. Pharmacol., 64:207-216.
Holford NHG, Mould DR, Peck CC (2012). Disease progress models. In: Principles of Clinical Pharmacology, Adkinson AJ, Huang SM, Lertora JJL, Markey SP, editors, Third edition, Academic Press, New York, pp. 369-382.
Holford N (2013). Clinical pharmacology = disease progression + drug action. Br. J. Clin. Pharmacol., 79:18-27.
Ito K, Corrigan B, Zhao Q, French J, Miller R, Soares H, Katz E, Nicholas T, Billing B, Anziano R, Fullerton T (2011). Disease progression model for cognitive deterioration from Alzheimer's Disease Neuroimaging Initiative database. Alzheimer's & Dementia, 7:151-160.
Lemmens HJM, Dyck JB, Shafer SL, Stanski DR (1994). Pharmacokinetic-pharmacodynamic modeling in drug development: application to the investigational opioid trefentanil. Clin. Pharmacol. Ther., 56:261-271 (p. 270, Table VI).
Levy G, Ebling WF, Forrest A (1994). Concentration- or effect-controlled clinical trials with sparse data. Clin. Pharmacol. Ther., 56:1-8 (p.2, Table 1).
Levy G (1998). Predicting effective drug concentrations for individual patients. Clin. Pharmacokinet., 34:323-333.
Liu YI, Wise PH, Butte AJ (2009). The "etiome": identification and clustering of human disease etiologic factors. BMC Bioinformatics, 10 (Suppl. 2):S14, 1-10.
Loscalzo J, Barabasi AL (2011). Systems biology and the future of medicine. Wiley Interdiscip. Rev. Syst. Biol. Med., 3:619-627.
Post TM, Freijer JI, DeJongh J, and Danhof M (2005). Disease system analysis: Basic disease progression models in degenerative disease. Pharm. Res., 22:1038-1049 (p. 1039, Fig. 1).
Thummel KE, Shen DD, Isoherranen N (2011). Design and optimization of dosage regimens: Pharmacokinetic data. In: Goodman and Gilman's The Pharmacological Basis of Therapeutics, Brunton, L, Chabner B, Knollman, B, editors, Twelfth edition, McGraw Hill, New York, p. 1891.
Therapeutics Research Institute (2015). Systems Therapeutics: A Diagram and Four Categories, April, 2015. tri-institute.org/niDFW.
This entry was posted in Systems Therapeutics and tagged PD variability, PK variability, systems therapeutics, variability on May 4, 2016 by ch30c.
Systems Therapeutics: A Diagram and Four Categories
While a large number of drugs have been approved by FDA over the past seven to eight decades, and there have been significant recent scientific advances in molecular and genomic understanding of diseases, there have only been sporadic efforts towards the construction of frameworks for understanding how pharmacologic and pathophysiologic processes interact to produce a therapeutic effect. One early noteworthy effort is presented in the Oxford Textbook of Clinical Pharmacology and Drug Therapy, which describes the chain of effects linking the pharmacologic effects of drugs to their clinical effects, including several examples.[1] More recent efforts have included a comprehensive white paper on quantitative and systems pharmacology by the QSP Workshop Group, including recommendations.[2] The purpose of this paper is to present a systems therapeutics diagram, which we hope can be useful when examining the different types of therapeutic effects, illustrating the different levels of interactions between pharmacologic and pathophysiologic processes.
Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact, resulting in a clinical therapeutic effect (see diagram below; for a larger diagram click here). The high-level systems therapeutics diagram presented here describes four different levels of interactions, involving corresponding locations along the pharmacologic and pathophysiologic process axes, ranging from the molecular level, through the cellular and tissue/organ levels, to the clinical level. These four different levels of interactions are referred to as systems therapeutics categories.
The systems therapeutics diagram presented lends itself to propose four systems therapeutics categories, corresponding to the four different levels of interactions between pharmacologic processes and pathophysiologic processes, as follows:
Category I – Molecular Level: Targets/Factors
Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves the primary corresponding molecular entities, the therapeutic agent and the etiologic factor, respectively.
Replacement Therapy
Gene Therapy, e.g., Glybera (alipogene tiparvovec) for Familial Lipoprotein Lipase Deficiency
Genome-based Therapy
Potentiation of a defective transport protein (CFTR), i.e., Kalydeco (ivacaftor) for Cystic Fibrosis
Inhibition of altered enzyme (BCR-ABL tyrosine kinase), e.g., Gleevec (imatinib) for Chronic Myelogenous Leukemia (CML)
HMG-CoA Reductase Inhibitors (statins) for Hypercholesterolemia, e.g., Lipitor (atorvastatin)
Biguanides for Type-2 Diabetes, e.g., Glucophage (metformin)
TNF-a Inhibitors for Rheumatoid Arthritis, e.g., Humira (adalimumab)
Inhibition of microtubule polymerization for Gout, e.g., Colcrys (colchicine)
Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves a modulation of a normal physiologic function, linked to the disease evolution, although not necessarily an etiologic pathway.
Examples – These can involve function-based therapies (modulation of a normal physiologic function or activity), resulting in a therapeutic effect:
PDE-5 Inhibitors for Male Erectile Dysfunction, e.g., Cialis (tadalafil)
Angiotensin II Blockers for Hypertension, e.g., Avapro (irbesartan)
Proton Pump Inhibitors for Gastric Reflux & Ulcer Disease, e.g., Nexium (esomeprazole)
Factor Xa Inhibitors for Thrombosis, e.g., Eliquis (apixaban)
Definition – The pivotal interaction between pharmacologic processes and pathophysiologic processes involves an effect directed at symptom(s) of a disease, but not directly its cause or etiology.
Antipyretics for lowering high body temperature, e.g., Tylenol (acetaminophen)
Analgesics for pain, e.g., Advil (ibuprofen)
Antihistamines for allergy, e.g., Allegra (fexofenadine)
Antitussives for cough suppression, e.g., Delsym (dextromethorphan)
The systems therapeutics framework presented above, including a diagram and four categories, has been constructed with the goal of serving to facilitate discussion and understanding of the different types of successful therapies involving FDA approved drugs. Importantly, this framework attempts to illustrate both the pharmacologic processes and the pathophysiologic processes, rather than exhibiting a singular pharmacotherapeutic process, in contrast to previous attempts, highlighting at what level the pharmacologic process engages with the pathophysiologic process. It is noted that this systems-based framework does not explicitly address interpatient variability in therapeutic response.
The examples listed above for the different systems therapeutics categories are provisional, pending more detailed descriptions of the pivotal interactions, including graphics ways to illustrate these. One important point this approach demonstrates and highlights is that many successful therapies are not directed at a specific known cause or etiology of a disease. However, it needs to be emphasized that the diagram and categories presented here represents work in progress, and that there are undoubtedly many other ways to accomplish our goal regarding systems therapeutics.
It is well recognized that there is considerable inter-patient variability in both pharmacologic processes and pathophysiologic processes (in addition to pharmacokinetic variability) – pharmacodynamic and "pathodynamic" variabilities – neither one of which is explicitly incorporated into the systems therapeutics framework presented here. Yet, these processes clearly represent the determinants of the overall variability in therapeutic response and clinical outcome of a given therapeutic agent, a topic of significant interest given the variable therapeutic response characteristics of approved drugs. We also note that our understanding of the "drivers" of these processes is limited, and that attempts to date to delineate these have been mostly descriptive, underscoring the necessity for much needed research.
This project of Systems Therapeutics is one of three current projects of the Therapeutics Research Institute, in addition to Progression of Modern Therapeutics and Patient Therapeutic Response Characteristics. It is our hope that the framework presented will help stimulate work towards better understanding of the relationships between the levels of interactions between pharmacologic and pathophysiologic processes on one hand and the therapeutic response characteristics of approved drugs on the other.
[1] Grahame-Smith DG, Aronson JK. Oxford Textbook of Clinical Pharmacology and Drug Therapy, Oxford University Press, Oxford, 1992 (Chapter 5. The Therapeutic Process, pp. 55-66).
[2] Sorger PK, Allerheiligen SRB, Abernethy DR, et al. Quantitative and systems pharmacology in the post-genomic era: New approaches to discovering drugs and understanding therapeutic mechanisms. An NIH white paper by the QSP workshop group. Bethesda: NIH, October 2011 (pp. 1-47)
This entry was posted in Systems Therapeutics and tagged approved drugs, systems therapeutics on April 17, 2015 by ch30c.


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Structure of the Ministry
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Next conference held on the work done regarding the implementation of Decree on "Simplification of the permission for the exploitation of some apartment buildings" issued by President of the Republic of Azerbaijan.
On April 16, 2019, conference on the work done and emerging problems regarding the implementation of Decree on "Simplification of the permission for the exploitation of some apartment buildings" issued by President of the Republic of Azerbaijan on February 19, 2019, was held at the administrative building of the State Agency for Control over Construction Safety of the Ministry of Emergency Situations.
Assistant to the President of Azerbaijan Republic for Economic Issues, Head of Department Ali Asadov, Minister of Emergency Situations Kamaladdin Heydarov, chairman of the State City-building and Architecture Committee Samir Nuriyev, chairman of the State Committee for Property Issues Karam Hasanov, Head of the Baku City Executive Authority Eldar Azizov, Deputy Prosecutor General, head of Anti-Corruption Department under the Prosecutor-General Kamran Aliyev, president of Azerenerji OJSC Balababa Rzayev, First Deputy Chairman of Azersu OJSC Teyyub Jabbarov, director general of SOCAR Azerigaz Production Unit Akbar Hajiyev, Deputy Chairman of Azerishig OJSC Ramil Yusifov, director of the Department for Communication, Construction and Utility Services of the Cabinet of Ministers Gasim Abdullayev, senior adviser of the service of the assistant for economic issues of the President of the Republic of Azerbaijan Feyruz Mustafayev, relevant heads of MES attended the conference.
Addressing the event, assistant to the President of Azerbaijan Republic for Economic Issues, Head of Department Ali Asadov spoke about the importance of the Decree on "Simplification of the permission for the exploitation of some apartment buildings" issued by President of the Republic of Azerbaijan Ilham Aliyev. A. Asadov emphasized that, in response to numerous appeals addressed to the President Ilham Aliyev, head of state demonstrating humanism once again proved that the citizen of Azerbaijan is in the center of the policy pursued by the Azerbaijani state. Assistant to the President also added that the main aim of this Decree is to provide normal life conditions of people. He noted that the work on the implementation of the issues according to the Decree is directly under the control of the head of state.
Addressing the event, Minister of Emergency Situations Kamaladdin Heydarov said that the Decree № 529 issued by President of the Republic of Azerbaijan Ilham Aliyev on February 19, 2019, on simplification of the permission for the exploitation of apartment buildings, which were under long-term exploitation but were not taken into operation by relevant state bodies was another progressive step taken by the head of state.
Calling the signing of this Decree next important step taken by the head of state to improve social welfare of the citizens, Minister recalled the first meeting held on March 14, added that the necessary work had been done by the relevant bodies over the past period and this process is constantly underway. K.Heydarov said that currently the number of apartment buildings was not taken into operation is 434 across the republic, 381 of them are in Baku.
Recalling set up of the headquarter with the participation of authorized representatives of the relevant bodies at the building of the State Agency for Control over Construction Safety, Minister said that representatives of 227 residential buildings (complex) were received at this headquarter till April 15, 2019, and necessary explanations were given to them. Minister noted that the inspection of buildings completed and the works regarding the shortcomings identified on this basis to be determined soon. K. Haydarov added that documents on 14 buildings were compiled and the opinion was correspondingly drawn up about the readiness of these buildings into operation and handed the State City-building and Architecture Committee of the Republic of Azerbaijan.
The heads of other bodies made speeches about the work done and the upcoming tasks at the conference.
Then the issues on the execution of the Decree were widely discussed, existing problems and ways of solving them were talked and relevant instructions were given to the bodies.
Information of MES's Press-service (video)
Ministry of Emergency Situations of the Republic of Azerbaijan continues to fulfill its responsibilities, including the protection of the population and territories from natural and man-made emergency situations. ...
Information of MES's Press-service (video, photo)
The "112" hotline of the Ministry of Emergency Situations received information about the detection of ammunition in Ahmedli settlement, Khatai district, Baku city. ...
MES will hold a training at the "28 May" metro station
Today, at around 01:00 PM, the Ministry of Emergency Situations and "Baku Metropolitan" CJSC will hold a joint tactical training on "Organization of activities during emergencies that may occur in Baku Metropolitan" at "28 May" metro station. ...
The Ministry of Emergency Situations of the Republic of Azerbaijan
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Q: working with memcpy for buffers I am trying to create a buffer of characters as shown:
#include<stdio.h>
#include<stdlib.h>
#include<string.h>
struct gvk{
  char a ;
  char b ;
  char c ;
};

int main(){
  char *buf;
  struct gvk k = {'A','B','C'};

  memcpy(buf, &k , 3*sizeof(char));
  printf("values in buf is %s\n",buf);
}

But my program is exiting saying "exited with non-zero status"
Where did I do wrong?

A: Collegue upper told you to allocate memory dynamically but since its much more error-prone, harder to work with (need to free memory) then with automatic arrays + you know the size in compile time, there is no reason to use dynamic allocation. I would recommend you to use automatic array instead. Also dont forget for one byte for null-terminating character.
char buf[4];

We are using dynamic allocation just if there is no other way. Even if you didnt know size of array in compile time, since c99 you may use VLA's.

Also compiler may add padding between/behind struct elements. Padding aligns structure members to "natural" address boundaries.
In your case it would probably look like this
struct gvk{
  char a ;   // 1B
  char b ;   // 1B
  char c ;   // 1B
             // 1B padding
};

Which means in this case it should work well, anyway you should avoid using memcpy(buf, &k , 3*sizeof(char)); on structures like this, because you might copy padding instead of real element of structure.

Also there is no need to explicitly type sizeof(char) which, by standard, has size 1 (B).

A: You have to allocate memory before using buf otherwise it is undefined behaviour.
You should declare it like this(Dynamically):
char *buf = malloc(sizeof(char)*4);

redpajama_set_name: RedPajamaStackExchange


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Category: podcasts
Plex adds support for podcasts, debuts personalized mobile apps
At CES in January, TechCrunch broke the news that media software maker Plex was planning to expand its service with the addition of new media content, starting with podcasts. Today, it's making good on that promise by launching support for podcasts into beta, along with a whole new look and more customization options for its Plex mobile apps.
While Plex got its start as a software application for organizing people's home media collections, it's been expanding over the past couple of years to add new features in support of cord cutters who want to watch TV via their antenna, and record those shows. It also acquired the streaming news startup Watchup in order to add a dedicated news hub within its app.
Earlier this year, the company spoke of its ambitions to continue adding more types of content to its media center software, including audio and video podcasts, followed by digital, web-first and
Original URL: http://feedproxy.google.com/~r/Techcrunch/~3/jQlZ2YS9RHU/
Podcasts Arrive in Google Play Music with Playlists for Curated Listening
Google's adding podcasts to Google Play Music on the web and Android today. As you'd expect, you'll be able to subscribe to a massive number of podcasts or browser through recommendations.
Original URL: http://feeds.gawker.com/~r/lifehacker/full/~3/NslN0X5Z9zs/podcasts-arrive-in-google-play-music-with-playlists-for-1771613658
Some Users Can Now Subscribe to Podcasts on Google Play Music
Google has been experimenting with the idea of adding podcasts to its Play Music service for a while, but now it seems the company is finally flipping the switch. For some users anyway.
Original URL: http://feeds.gawker.com/~r/lifehacker/full/~3/yNpLS_Urob8/some-users-can-now-subscribe-to-podcasts-on-google-play-1756800367


Take Part in Regional Issue Discussions!
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Our keynote speakers will be William Harrison,III, Director of Small Business Development, Air Force Research Laboratory; and Kim Frazier, Director, Growth Initiatives, The Entrepreneurs Center.
Mark your calendar NOW to attend the 2019 Summit on April 26, 2019. The Preliminary Agenda is posted in the Events Tab. The location is the Hilton Garden Inn at Austin Landing, directly off I-75. Registration will open on February 4, 2019.


'Tis the season to be jolly and deck your halls with the family Christmas tree. There are so many options available nowadays in artificial trees – pre-lit, color changing lights, timers, turntables, different colored foliage and more. With so many options and advances in artificial Christmas tree technology, what's the advantage of the classic, real Christmas tree?
They're actually a better choice for the environment.
Many people have the misconception that real Christmas trees are bad for the environment and contribute to deforestation. In reality, real Christmas trees are grown on farms, where they take around 7 years to mature to the sizes needed to fit in our homes. For each tree cut, approximately 3 seedlings are planted in the spring. While they are growing, Christmas trees absorb carbon dioxide and produce fresh oxygen. One acre of Christmas trees produces enough oxygen for 18 people, and there are about 1 million acres of Christmas trees being grown. Christmas trees are also an excellent use of the land, as they are most often grown where other crops will not thrive.
You're supporting small farmers and business owners and investing in something made in America.
Most Christmas tree farms are family businesses just like ours. With rare exception, any real Christmas tree you buy is grown in the USA by an American farmer. Our trees come from a farm in western North Carolina!
No setup, tear down, or storage issues.
Avoid the dread of having to match plastic branches with color coded slots and wondering how you're going to get it back in the box the end of the season. When you buy your real tree at Fossil Creek, we can put your stand on for you. At the end of the season, use a tree disposal bag to take it out of the house with no mess.
Let's be honest. The smell is the main event. No scented candle can match the glorious smell of fresh fir in your home.
While there are plenty of reasons to go artificial (our condolences to allergy sufferers), there are still many compelling reasons to stick with beautiful, natural fresh cut Christmas trees. We would love to be part of your family's Christmas tradition! Come see us to pick out the perfect Carolina Fraser fir for your home!


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Grow Through Life…!
August 19, 2021 August 20, 2021 friendsofcopey1
"If you change the way you look at things, the things you look at change." By Wayne Dyer
AudioCast…!
He deserves the credit!
https://friendsofcopey.com/wp-content/uploads/2021/08/Mykel-Thanks.1-1.mp3
Thank you for the positive feedback to the "audiocast" launched last week. Your comments were very positive and appreciated. However, I am not going to lose sight of my need to really get better at this new venture.
Dream Team III Profile
Suzanne Sanders is our newest member and as our track record verifies, she brings much to the educational effort. A brief profile of Suzanne's journey includes being an avid traveler. She has taught in three different states, and three international schools in Madrid, Prague, and Costa Rica.
Her educational experience includes being a Montessori teacher and Director for more than 20 years. She holds educational credentials for students ages 6 years thru15 years old.
As an added bonus, Suzanne resides in Copey. This provides additional opportunities for the Copey Learning Center to reach more students. She is planning to work both on-line and will provide in person education.
Suzanne says, "I love to connect with people. I love to see each student as an individual with many gifts and talents. I work to unlock that potential and allow them to shine." Suzanne further states, "I believe in teaching from a base level of love and respect for each individual student. Because of my Montessori background, I rarely teach in conventional ways but seek to make lessons interactive, collaborative and individualized to the needs of each student."
Thank you for your service to humanity!
Emery Reid…"Dream Teamer"
It was a real pleasure yesterday to visit briefly with Emery while he was working with his Copey students. Having been on "Dream Team I", Emery is familiar with the challenges and the English educational objectives since he was a member of "Dream Team I".
My plan is to provide an updated profile on Emery in my next Post. He has some great ideas on how to engage his Copey students this semester and we will share these with you.
What Is In Our Blogging Future…?
https://friendsofcopey.com/wp-content/uploads/2021/08/Future-Changes-8.19-2-2.mp3
Thank you for listening…! I promise I will get better over time. This quote I recently came across is inspiring. We are raising the aim considerably.
" The greater danger for most of us lies not in setting our aim too high and falling short, but in setting our aim too low and achieving our mark." By Michelangelo
A Change is Gonna Come..!
Be Led by Dreams!
3 thoughts on "Grow Through Life…!"
Good audio cast Brother Art!!
friendsofcopey1 says:
My Brother…thanks for reading and listening to the Post. This time you are the first "Friend" to respond and it is noted and appreciated. Blessings to you and the family.
Edward Hamilton Davis says:
Scrapper your sound quality is great. I think you are doing quite well with these audiocasts!


The pressure on governments to monitor their borders is a hot topic. The European Border Guard is charged with monitoring and protecting its (and the EU's) borders from people trafficking, smuggling, illegal immigration, arms smuggling, goods smuggling, combating terrorism as well as monitoring all sea, land and air security. It's a big operation and the two ES15s are an important tool in carrying out this vital task in an efficient manner.
People don't look up unless they are alerted. It's obvious that the quieter the aircraft the less opportunity to alert those on the ground to the fact that they are being watched and monitored. Operating at 7,000 feet makes the ES15 impossible to hear and if it is spotted then the profile is that of a glider. The ES15 doesn't attract attention which makes it ideal for this line of work.
There were a number of other aircraft in the evaluation including twin-engine fixed wing and helicopters. Ease of operation was another major factor in choosing the ES15. Pilot training is less onerous versus jet and twin-engined aircraft and with an hourly operating cost being less than a third of a twin engine aircraft it means that for the same budget the aircraft can provide an eye in the sky for longer periods.
The European Border Guard required the ability to provide imagery in real time to teams on the ground who can then direct forces to certain areas. The ES15 has a design that enables clean feeds of data which are not hampered by excessive heat from exhausts or engines. With multiple hard-points for antennas and space for power and back up power the Payload requirements from the European Border Guard matched the ES15 perfectly.


text:
All happy families are not alike...
Susan's Blog
Why Job Training Matters for Students w Autism
You can read my latest piece on autism and job training in Education Week, right here.
posted at 10:02 am	3 comments
A Mother's Dream
A few days ago, I dreamed Nat could speak– I mean, really talk, not just the hesitant monosyllabic speech he uses. In the dream, I was riding in an elevator with Nat and a pretty blonde woman, in her early forties. She sees him, 23 years old and sucking his thumb, but doesn't realize he is intellectually disabled. She says flirtatiously, "You must be a movie star to be doing that in public like that."
I answer for him, as I always do, brusquely defensive and self-righteous: "Actually, he is autistic." But then – Nat takes out his thumb and says, nonchalantly, as if he could talk all along: "Actually I do come from a long line of theater people."
I awoke gradually, uncertain that this was a dream, but each moment of dawning clarity brought more pain. It wasn't just Nat's talking that blew me away, it was the level of self-awareness and subtlety. I hadn't realized, after all these years, that I still wanted that so desperately. I think this flicker of desire must have come from a recent decision his doctor had made, to reduce Nat's medication. I had agreed that we should try this, because Nat has been doing so well for so long. We reduced his meds around a year ago and found that even though he seemed more on edge, he also seemed to be able to answer us more often. And anyway, the goal had never been to have him medicated forever; it was just supposed to have been a "buffer" against aggression that started 13 years ago. I can never forget that horrible afternoon when he was 10 and he attacked me in the subway station, simply because we were going a different way home. I struggled to fend off his clawing hands while keeping hold of his baby brother and the stroller at the same time. I was desperate to calm him, to soothe him. Events like that became common, so we turned to serious neuroleptic medication to help him.
While the decision to medicate made sense back then, I have learned over time that so much of parenting Nat has been about a kind of letting go, of hanging back to see what could happen. After all, we learned how well he could ride a bike because we (accidentally) let him ride off around the block, out of our view. In a mixture of choking fear for what might happen, and a small soft certainty that he'd be okay, we ran after him, knowing we could not overtake him. We had to wait, hearts in our mouths, for his safe return around the corner. We didn't really know for certain he could do it safely – and yet, didn't we? Somehow, it was okay. He came barreling down the hill towards us with a devious smile that seemed to say, "I told you so."
Taking Nat off his meds is a slower danger than a bike accident, but almost as much is at stake. Nat is living away from us, in a house with roommates and staff, taking care of himself in so many ways. He routinely makes meals, cleans, and decides how to spend his leisure time. He plays on a basketball team, and he works three days a week at a supermarket. I do not want to see this jeopardized by a return to outbursts and aggressive behavior. He could stand to lose so much. I dread the phone call from his day program or from the house staff, like what I used to get during his middle school days: "There's been an incident…" It's been peaceful for so long.
The fact is, though, that a less sedate Nat could mean a more alive Nat — alive in every sense of the word. He will likely feel more anxious simply because he will be more aware. He will experience noise and sensation more acutely. And yet, with some of that comforting haze lifted, he may see things more clearly. He might understand more. Isn't it his right, as a human being, to take this chance?
I guess, in this season of audacious hope, I feel my own sort of optimism: that maybe Nat at 23 can indeed handle a new, raw but heightened perception. Maybe with greater perception will come better communication, a stronger connection to the world, and all that it brings – delightful or frightening. Because parents will do anything to help their children grow. Mine is a mother's dearest hope; I have a mother's dream.
posted at 7:36 am	5 comments
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Copyright 2005–2017, Susan Senator.


text:
#2,342. Tarzan the Ape Man (1932)
Starring: Johnny Weissmuller, Maureen O'Sullivan, Neil Hamilton
Tag line: "He Knew Only The Law Of The Jungle...To Seize What He Wanted"
Trivia: Clark Gable was considered for the role of Tarzan, but was deemed too much of an unknown to play the ape man
Tarzan has been a popular cinematic hero since the days of silent movies, and in my lifetime alone there have been a number of films featuring Edgar Rice Burrough's famous jungle dweller. The year 1981 saw the release of John Derek's Tarzan the Ape Man (starring his wife, Bo Derek, as Jane); and Greystoke: The Legend of Tarzan, Lord of the Apes hit theaters in 1984. Even Disney threw their hat into the ring with an exceptional 1999 animated musical/adventure, and in 2016 Alexander Skarsgård played the title role in The Legend of Tarzan.
But for those of us who love the classics, Johnny Weissmuller will always be Tarzan, and 1932's Tarzan the Ape Man marked the first of many times he would portray this iconic character.
Jane Parker (Maureen O'Sullivan) has made the long journey from England to Africa to visit her father James (C. Aubrey Smith), who owns a trading post that borders the jungle. But while Jane is busy taking in the rustic beauty of her new surroundings, dear old dad is trying to raise enough cash to leave Africa once and for all, and with the help of his business partner Harry Holt (Neil Hamilton), he's concocted a scheme that will net more money than he's ever had before. In short, James and Harry are undertaking an expedition to find the fabled Elephant Graveyard, a place that, if it exists, will surely house enough ivory to make both of them extremely rich. Against the wishes of Harry and her father, Jane decides to tag along, and together the trio (as well as a handful of servants and guides) make their way deep into the jungle.
Many dangers lie ahead of them, including snakes and crocodiles, but one thing they didn't expect to find was Tarzan (Weissmuller), who, despite his obvious European lineage, lives among the creatures of the jungle, unable to speak or understand a word of English. Swinging through the trees from vine to vine, Tarzan abducts Jane (the first white woman he's ever seen) and carries her back to his treetop home. As James and Harry search frantically for her, Jane tries to communicate with her captor, and over time she and Tarzan develop feelings for one another, but is love enough to keep them together, or will their differences ultimately force them apart?
Tarzan the Ape Man is a top-notch adventure movie; even before the title character hits the screen, there's excitement aplenty (while traveling down the river on makeshift rafts, Jane and her companions encounter angry hippos and hungry crocodiles; and a walk along the side of s sheer cliff nearly costs Jane her life). Once the Ape Man himself enters the picture, the action kicks into high gear, with Tarzan and his pet chimp Cheeta dodging a steady stream of ravenous jungle cats (director Van Dyke recruited a number of real animals for the film, though Tarzan's ape "family" was mostly men in suits).
Weissmuller may not have been the most charismatic actor ever to play Tarzan, but physically he was perfect for the role (a world-class swimmer, he won gold medals at both the 1924 and 1928 Olympics), and O'Sullivan delivers a spirited performance as Jane (carrying the scenes she shares with Weissmuller on her own). But as well-realized as these two characters are, even they take a back seat to the film's numerous action scenes, all of which are flawlessly staged (the final sequence, when Tarzan must save Jane and the others from a violent pygmy tribe, is as thrilling as it gets).
The first in what would be a long-running series (12 movies in all), Tarzan the Ape Man is arguably the best adventure film to come out of Hollywood during the pre-code era, and one of the greatest of all-time.
#2,329. Fire and Ice (1983)
#2,330. New Year's Evil (1980)
#2,331. Choke Canyon (1986)
#2,332. Weekend Pass (1984)
#2,333. Night Shift (1982)
#2,334. Ladyhawke (1985)
#2,335. The Final Destination (2009)
#2,336. The Wolf of Wall Street (2013)
#2,337. Terror in the Aisles (1984)
#2,338. The Last Days of Disco (1998)
#2,339. White Slave (1985)
#2,340. Lady Frankenstein (1971)
#2,341. The Adventure of Sherlock Holmes' Smarter ...
#2,343. Fairy Tales (1978)
#2,344. The Hearse (1980)
#2,345. The Blood of Dracula's Castle (1969)
#2,346. Tarzan and His Mate (1934)
#2,347. The Legend of Billie Jean (1985)
An Update, and an Explanation