What will stroke care look like in 2050?

 Who fucking cares? SURVIVORS WANT RECOVERY!   I've never heard a survivor ask for 'care'; I'd suggest you talk to survivors sometime; they all want recovery, and you are failing survivors!

What will stroke care look like in 2050?

By Tim TedeschiEmail TimEmail Tim513-556-5694

9 minute read October 23, 2025 For more than 40 years as a researcher and clinician, Joseph Broderick has actively contributed to improvements in stroke care, occupying a front row seat to seismic innovations: the clinical trials that proved tPA as the first effective treatment for acute ischemic stroke in the 1990s, the seminal trials leading to mechanical removal of clots within the artery in the 2000s and most recently the FASTEST trial today testing what could be the first treatment to slow bleeding for spontaneous acute intracerebral hemorrhage (ICH).

Looking back shows how far the field has come, but what does the future hold? Broderick sought to answer that question by making predictions for what stroke care will look like in 2050 in a new article published in the journal Stroke. The article is a follow-up to a 2003 article where Broderick made predictions about 2025 in the areas of acute treatment, stroke prevention and stroke recovery.“​​The last 50 years have been about advances in stroke prevention and acute treatment,” wrote Broderick, MD, professor in the University of Cincinnati’s College of Medicine, senior adviser at the UC Gardner Neuroscience Institute and director of the NIH StrokeNet National Coordinating Center.

Acute stroke

Past predictions

Until the mid-1990s, there was no scientifically proven treatment for acute stroke. By 2000, there were five proven scientific treatments or expanded indications, including the first medical treatment for ischemic stroke, t-PA. In 2003, Broderick predicted that novel mechanical devices would remove blood clots blocking brain arteries, with and without t-PA, improving outcomes by restoring blood flow to the brain. However, his prediction that neuroprotection techniques like rapid hypothermia would play a role during blood flow restoration has not yet come to fruition. “All these predictions proved to be pretty accurate, except for neuroprotection, which has been a very hard nut to crack and still has defied our best efforts,” wrote Broderick. “Regardless, we now have 20 scientifically proven treatments or expanded indications, including additional thrombolytic agents, various catheter devices, mobile stroke units, surgical treatment for selected patients with brain hemorrhage and drugs to slow bleeding in patients with brain hemorrhage. “The largest advance has been mechanical clot removal for ischemic stroke, first within six hours of onset and then out to 24 hours with appropriate imaging selection.”

 A vastly more useful intervention would be by just stopping the 5 causes of the neuronal cascade of death in the first week saving hundreds of millions to billions of neurons!

This is not going to be easy as Dr. Michael Tymianski, of the Toronto Western Hospital Research Institute in Canada states;  over the last half-century, there have been more than 1,000 drugs (So what are they?)aimed at preventing brain damage that have failed to work in people, even though they worked well in mice or rats. Because this? Rodent inflammation is not the same as human inflammation

In 2050?

Patient wearables will help begin stroke diagnosis at home, leading to specific treatments for ischemic and hemorrhagic stroke starting before arrival at the hospital for more patients. But treatment of ischemic stroke may reach the limits of biology and technology, as it has for myocardial infarction, which has not seen a major advance for a number of years.  Clot removal devices will become smaller and safer, and researchers will solve the challenge of neuroprotection that has not been solved yet. Treatment of ICH will continue to advance but remain the most challenging stroke to treat. “We are going to need larger global trials to find much smaller benefits as our success in acute stroke has dramatically increased,” Broderick said. “Artificial intelligence (AI) and telemedicine will play an even more important part in clinical decision-making worldwide and will help to deliver the best care to locations that currently lack expertise and resources. Finally, physiological time will remain the most important variable for success for all types of strokes.”

(Neuroprotection is a milquetoast term saying nothing! Should be correctly called the 

neuronal cascade of death!(From Rockefeller University- January 15, 2009 Signifying an immediate need to prevent that!)

Stroke prevention

Past predictions

In 1975, researchers had just identified the effectiveness of treating hypertension to prevent a first stroke and preventing a second stroke with aspirin. By 2000, the medical community had 14 proven primary and secondary prevention treatments. 

In 2003, Broderick predicted stroke would remain a great burden if at-risk behaviors and the high cost of therapies were not addressed and no treatments were available to delay or halt aging. Over the past years, the U.S. population has become much more obese.

Reductions in U.S. cigarette smoking rates and better managed hypertension have led to a decrease in the overall incidence of stroke in the Greater Cincinnati/Northern Kentucky region, but strokes have numerically increased among younger people. In 2025, we now have 35 proven prevention treatments and expanded indications.

“We know that the Mediterranean diet decreases the risk of recurrent stroke,” Broderick said of current stroke prevention advances. “We have four novel anticoagulants for primary and secondary prevention, primarily in patients with atrial fibrillation; more antiplatelet agents; genetic and medical treatments for sickle cell disease and other genetic diseases associated with stroke; stents for carotid arteries; mechanical devices to close holes between the upper chambers of the heart; and devices that close off chambers in the left atrium of the heart that can harbor blood clots for appropriately selected patients.

“The newest entrees for prevention have been GLP-1 and GIP receptor medications, which not only improve diabetic control and weight loss but also improve cardiovascular outcomes.”

Joseph Broderick has contributed to and witnessed major innovations in stroke care, but he said he believes the best is yet to come.

In 2050?

Lifestyle changes will remain the greatest challenge and opportunity for primary and secondary stroke prevention, particularly focused on diet, sleep, exercise, weight and blood pressure control, smoking cessation, and a patient’s metabolic state.“Weight control medications will be integral to primary and secondary stroke prevention and cardiovascular health as much as lipid medications. Biomarkers will provide greater precision for the use of antithrombotic drugs and devices, and we will have new treatments for genetic causes of stroke,” Broderick said. “But again, unless we have treatments that slow aging, the overall stroke burden will only decrease a little.”

Past predictions

With no scientifically proven treatments in 2003, Broderick predicted a number of approaches, including growth factors, stimulant medications and new physical therapy methods, could play a role in stroke recovery. In 2025, two treatments have been scientifically proven to be effective: modified constraint therapy and vagal nerve stimulation paired with modified constraint therapy.“Even more impressive is the AI revolution in understanding the neural code,” Broderick wrote. “Patients without the ability to move or to speak have been able with AI-driven brain-device interfaces to train their brains to move devices, to write words on the screen and even to speak. We've also developed techniques for decoding what the brain is visualizing.”Researchers like UC's Oluwole Awosika, MD, are using new technology and approaches to find more proven treatments to improve stroke recovery. Photo/Andrew Higley/UC Marketing + Brand.

In 2050?

Additional higher-intensity physical, occupational and speech therapies will be proven effective to enhance recovery. AI will accelerate connection between the brain and related organs with machines and the digital web to enhance daily function, though limited by cost.“Recovery approaches will be limited by the initial damage and physiological age of the recovering brain,” Broderick said. “Implanting new brain cells to replace damaged brain tissue that make new connections throughout the nervous system to enhance function may still require science beyond 2050.” Broderick said advances in stroke treatment, prevention and recovery have occurred primarily in developed countries with more economic resources, and even current treatments still need to be implemented worldwide in many regions of the world.  “The next century will be about advances in recovery and rehabilitation after stroke and addressing current global disparities in stroke incidence, outcomes and access to proven therapies,” Broderick said. “But until we solve aging, stroke will remain common and a tremendous societal and financial burden. We have made a significant dent in the burden of stroke over the past 50 years, and I think that the best is yet to come.”

Innovation Lives Here

The University of Cincinnati is leading public urban universities into a new era of innovation and impact. Our faculty, staff and students are saving lives, changing outcomes and bending the future in our city's direction. Next lives here. Featured photo at top of Dr. Broderick. Photo/Joseph Fuqua II/University of Cincinnati

Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke

These are all causes of the neuronal cascade of death. SOLVE THEM!  I don't care that there have been thousands of failures.

These failures of clinical trials have been known for years. WHOM  is cataloging and solving them to make the next ones better?

This is not going to be easy as Dr. Michael Tymianski, of the Toronto Western Hospital Research Institute in Canada states;  over the last half-century, there have been more than 1,000 drugs (So what are they?)aimed at preventing brain damage that have failed to work in people, even though they worked well in mice or rats.

The latest here:

Oxidative Stress in Ischemia/Reperfusion Injuries followingAcute Ischemic Stroke

Anamaria Jurcau 1,2,* and Adriana Ioana Ardelean 3,4 1 Department of Psycho-Neurosciences and Rehabilitation, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania 2 Department of Neurology, Clinical Municipal Hospital Oradea, Louis Pasteur Street nr 26, 410054 Oradea, Romania 3 Department of Preclinical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, Universitatii Street nr 1, 410087 Oradea, Romania; adriana_toadere@yahoo.com 4 Department of Cardiology, Clinical Emergency County Hospital Oradea, Gh. Doja Street nr 65, 410169 Oradea, Romania * Correspondence: anamaria.jurcau@gmail.com; Tel.: +40-744-600-833 

Abstract: 

Recanalization therapy is increasingly used in the treatment of acute ischemic stroke. However, in about one third of these patients, recanalization is followed by ischemia/reperfusion injuries, and clinically to worsening of the neurological status. Much research has focused on unraveling the involved mechanisms in order to prevent or efficiently treat these injuries. What we know so far is that oxidative stress and mitochondrial dysfunction are significantly involved in the pathogenesis of ischemia/reperfusion injury. However, despite promising results obtained in experimental research, clinical studies trying to interfere with the oxidative pathways have mostly failed. The current article discusses the main mechanisms leading to ischemia/reperfusion injuries, such as mitochondrial dysfunction, excitotoxicity, and oxidative stress, and reviews the clinical trials with antioxidant molecules highlighting recent developments and future strategies. 

Keywords: 

ischemic stroke; reactive oxygen species; mitochondria; oxidative stress; antioxidants; nanoparticles; stem cells 1. Introduction Although the proper management of vascular risk factors and increasing use of prophylactic measures between the 1970s and early 2000s resulted in an annual 1–1.5% decrease in stroke incidence in high income countries [1], stroke is still the main cause of disability in adults and the second leading cause of death worldwide. Moreover, the increasing prevalence of diabetes mellitus [2] and obesity [3], together with aging of the population, will probably increase the incidence of stroke [4]. The treatment of ischemic stroke entered a new era in 1995, with the release of the results of the National Institute of Neurological Disorders and Stroke trial with recombinant tissue plasminogen activator (r-tPA) [5], which showed that reestablishing blood flow in the first 3 h after stroke onset is able to salvage much of the hypoperfused cerebral tissue and improve patient outcome. Subsequent trials refined the recanalization methods by extending the time window to 4.5 h in certain subsets of patients [6], using intra-arterial thrombolysis [7], ultrasound-enhanced thrombolysis [8], or various devices for mechanical clot extraction [9] within 24 h from stroke onset [10]. However, still only 2–20% of acute ischemic stroke patients are eligible for recanalization treatments [11]. In addition, successful recanalization rates vary around 46% for intravenous thrombolysis, 63% for intra-arterial thrombolysis, or 83% for mechanical thrombectomy, and recanalization does not always translate into efficient reperfusion of the tissue at risk, leading to neurological worsening of the patient through cerebral edema, hemorrhagic transformation, or ischemia/reperfusion injuries (I/R injuries) [12]. Oxidative stress and neuroinflammation have been shown to significantly contribute to these complications. Thus, understanding the mechanisms of I/R injuries and finding ways to prevent them would significantly improve the outcome of ischemic stroke patients [13]. In the following sections we will review the literature on the pathophysiology of these injuries, focusing on oxidative stress, sources of reactive oxygen species (ROS), and neurotoxic oxidative and neuroprotective antioxidative pathways in the central nervous system (CNS). The second part reviews the studies done so far with antioxidants in ischemic stroke and discusses promising novel antioxidant approaches. 2. Oxidative Stress in the Pathophysiology of Ischemia/Reperfusion Injuries after Acute Ischemic Stroke Oxidative stress is an imbalance between the rate of generation of ROS and the biological system’s ability to clear these highly reactive molecules [14]. The cerebral tissue is particularly sensitive to oxidative stress due to a series of features, such as [15–18]: - It has the highest metabolic activity per unit weight compared to other organs; - It has low levels of antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, heme oxygenase-1; - Upon release, neurotransmitters contribute to cellular calcium overload and, through their metabolism, generate ROS; - Brain cells have a higher membrane surface/cytoplasmic volume ratio, and the plasmalemma is rich in cholesterol, is arranged in lipid rafts, has polyunsaturated fatty acids, and is very susceptible to oxidative damage; - The brain has lower levels of cytochrome c oxidase, leading to increased superoxide generation during adenosine triphosphate (ATP) generation; - Iron, released from damaged cerebral tissue, can catalyze the generation of free radicals. Restoration of blood supply to ischemic tissue, although necessary for restoration of aerobic metabolism, will also result in ROS production, which overwhelms the ability of cerebral tissue to neutralize these ROS and leads to increased oxidative stress. Research has shown that cerebral ischemia is accompanied by increased serum concentrations of markers of oxidative stress [19–21]. The main ROS are superoxide anions, (O2 −), hydroxyl radicals (OH−), and hydrogen peroxide (H2O2) [22], stemming from the activity of mitochondria, cyclooxygenases, lipoxygenases, nitric oxide synthases (NOSs), NADPH oxidase (NOX), and xanthine oxidase [23]. Once generated, ROS interact with various biological molecules: - ROS oxidize, degrade, or cleave proteins, leading to protein aggregation, modifications in ion channel activities, and enzyme inactivation [24]. - By attacking the carbon–carbon bonds of polyunsaturated fatty acids, ROS initiate lipid peroxidation, a self-propagating chain of events leading to the generation of unstable lipid radicals which further react with oxygen to form lipid peroxyl radicals [25]. Peroxidation of membrane lipids alters the bi-layer thickness, membrane fluidity, and membrane permeability. - ROS can directly damage deoxyribonucleic acids (DNA) by causing double strand breaks, structural changes, DNA mutations, or protein-DNA cross-links [26]. - They also regulate several apoptosis and necrosis signaling cascades. ROS can activate p53, a key molecule in ROS-induced cell death [27], which, in turn, upregulates PUMA (p53 upregulated modulator of apoptosis). ROS can open the mitochondrial permeability transition pore (MPTP), leading to mitochondrial swelling and cytochrome c release, thereby initiating apoptosis [28]. The MAPK (mitogen activated protein kinase) pathway, also triggered by ROS, has 3 main members: c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK 1/2), and p38 MAPK. While ERK 1/2 has a controversial role in cell death and appears to be rather neuroprotective against ischemia/reperfusion injuries [15], JNK and p38 MAPK, activated by ROS through ASK1 (apoptosis signal-regulating kinase 1), significantly contribute to apoptosis during reperfusion after an ischemic insult [29,30]. 2.1. Mitochondria as a Source of ROS and Their Implication in Cerebral Ischemia/Reperfusion Injuries Mitochondria, the powerhouse of the cell, generate over 90% of the ATP in the brain through beta-oxidation of fatty acids, the Krebs cycle, and oxidative phosphorylation (OxPhos) [31]. They also use pyruvate from cytosolic glycolysis to reduce flavin adenine dinucleotide and nicotinamide adenine dinucleotide, which serves in energy transfer to the electron transport chain (ETC) [32]. The mitochondrial electron transport chain (ETC) consists of a series of protein complexes situated in the inner mitochondrial membrane which use the electrons removed by reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) from the Krebs cycle to pump protons from the matrix into the intermembrane space, thereby generating a potential gradient across the inner mitochondrial membrane, which will be used in the final step of OxPhos to synthesize ATP [33]. NADH binds to NADH dehydrogenase (complex I), located on the inner mitochondrial membrane, and donates two electrons which will be passed down to ubiquinone to produce ubiquinol, a process coupled with the translocation of four protons from the matrix through the inner mitochondrial membrane [34]. Complex II, or succinate dehydrogenase, also participates in the Krebs cycle and contains FAD as a prosthetic group. It oxidizes succinate to fumarate and reduces ubiquinone [35]. Ubiquinol diffuses through the inner mitochondrial membrane and donates its electrons to cytochrome c reductase (complex III), which passes these electrons onto two molecules of cytochrome c while translocating two protons from the mitochondrial matrix and depositing an additional two protons in the intermembrane space [36]. At complex IV (cytochrome c oxidase), four cytochrome c molecules donate each one electron which will serve to form two H2O molecules from one O2 molecule, a process coupled with pumping of four protons from the matrix into the intermembrane space [37]. The final step is the synthesis of ATP from ADP and phosphate, achieved by ATP synthase (complex V), which uses the energy of the proton electrochemical gradient in a complex process, the elucidation of which led Boyer and Walker to achieve the 1997 Nobel Prize in Chemistry [38]. The transfer of protons from the mitochondrial matrix to the intermembrane space by the reactions of complexes I, III, and IV establishes a negative potential difference (∆Ψm) of 150–180 mV (with respect to the cytosol) across the inner mitochondrial membrane, which, together with the pH difference, drives complex V to generate ATP and cytosolic calcium ions to accumulate via the mitochondrial calcium uniporter in the matrix [32,39], where calcium stimulates the activity of dehydrogenases in the Krebs cycle and modulates the function of complexes IV and V [40]. As such, the balance between phosphorylation and dephosphorylation of the OxPhos complexes as well as intramitochondrial calcium concentrations maintain the cellular respiration rate and the ∆Ψm [41] by interfering with their electron transfer kinetics and allosteric regulation by ATP and ADP (adenosine diphosphate) [42]. Under normal conditions, more than 90% of oxygen is reduced to water, while about 2% of electrons may leak from complexes I and III and react with oxygen, generating superoxide anions [41]. During ischemia, the intramitochondrial calcium levels increase [42], activating mitochondrial phosphatases and leading to dephosphorylation of the OxPhos complexes, especially of cytochrome c and of cytochrome c oxidase [43], and ultimately to loss of allosteric inhibition by ATP [41]. Because oxygen as the final electron acceptor is lacking, OxPhos is maximally activated in a feed-forward mechanism. Upon restoration of oxygen supply, increased OxPhos activity restores ∆Ψm within 1 min and cellular levels of ATP within 15 min [44], after which it hyperpolarizes the mitochondrial membrane potential with dramatic effects on ROS production. Research has shown that a 10 mV increase in the ∆Ψm above 140 mV leads to a 70–90% increase in the generation of ROS [45].

 

More at link.

The nutraceutical potential of omega-3 alpha-linolenic acid in reducing the consequences of stroke

 You can't do anything with this until maybe 50 years from now when your doctor finally gets around to reading this research and creates protocols from it. Hope you aren't dead yet.

These failures of clinical trials have been known for years. WHOM  is cataloging and solving them to make the next ones better?

This is not going to be easy as Dr. Michael Tymianski, of the Toronto Western Hospital Research Institute in Canada states;  over the last half-century, there have been more than 1,000 drugs (So what are they?)aimed at preventing brain damage that have failed to work in people, even though they worked well in mice or rats.

The nutraceutical potential of omega-3 alpha-linolenic acid in reducing the consequences of stroke

Nicolas Blondeau  ¹

Affiliations

• PMID: 26092420
• DOI: 10.1016/j.biochi.2015.06.005

Abstract

Stroke is a worldwide major cause of mortality and morbidity. Preclinical studies have identified over 1000 molecules with brain-protective properties. More than 200 clinical trials have evaluated neuroprotective candidates for ischemic stroke yet, to date almost all failed, leading to a re-analysis of treatment strategies against stroke. An emerging view is to seek combinatory therapy, or discovering molecules able to stimulate multiple protective and regenerative mechanisms. A pertinent experimental approach to identify such candidates is the study of brain preconditioning, which refers to how the brain protects itself against ischemia and others stress-inducing stimuli. The recent discovery that nutrients like alpha-linolenic acid (ALA is an essential omega-3 polyunsaturated fatty acid required as part of our daily diet), may be an efficient brain preconditionner against stroke fosters the novel concept of brain preconditioning by nutraceuticals. This review stresses the underestimated role of nutrition in preventing and combating stroke. Although there is a consensus that increased consumption of salt, fatty foods and alcoholic beverages may promote pathologies like hypertension, obesity and alcoholism - all of which are well known risk factors of stroke - few risk factors are attributed to a deficiency in an essential nutrient in the diet. The ALA deficiency observed in the Western modern diets may itself constitute a risk factor. This review outlines how ALA supplementation by modification of the daily diet prevented mortality and cerebral damage in a rodent model of ischemic stroke. It also describes the pleiotropic ability of ALA to trigger responses that are multicellular, mechanistically diverse, resulting in neuronal protection, stimulation of neuroplasticity, and brain artery vasodilation. Overall, this review proposes a promising therapeutic opportunity by integrating a nutritional-based approach focusing on enriching the daily diet in ALA to prevent the devastating damage caused by stroke.

Keywords: Brain preconditioning; Functional food; Ischemia; Neurogenesis; Neuroprotection; Synaptogenesis.

Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

 

Rehabilitation is Initiated Early After Stroke, but Most Motor Rehabilitation Trials Are Not: A Systematic Review

It is good for you to know that absolutely nothing in stroke recovery is known.  Your doctor and therapists only know guidelines.  So start planning your own recovery protocols Then ask your doctor why you are paying them for ignorance. 

Rehabilitation is Initiated Early After Stroke, but Most Motor Rehabilitation Trials Are Not: A Systematic Review

 

1 Stroke is the third most common cause of death and the most common cause of acquired adult disability in developed countries.1 Motor impairment is common after stroke, and a critical factor influencing the patient’s ability to live independently.2,3 The neurobiological mechanisms of plasticity and spontaneous recovery during the initial days and weeks after stroke have been reasonably well characterized using animal models.4,5 These mechanisms include cell genesis, functional plasticity, and structural adaptations, such as axonal sprouting and synaptogenesis. The nature and time course of these mechanisms map onto the trajectory of motor recovery observed in human patients, most of whom reach their recovery plateau within 3 months of stroke.6,7 Rehabilitation is primarily delivered in this time period, to capitalize on the unique physiological conditions that prevail, and shape the spontaneous recovery process for the patient’s benefit. Recovery of function is likely to be enhanced by novel treatments that interact with and facilitate the underlying mechanisms of spontaneous recovery.A variety of neurorehabilitation techniques aimed at improving motor recovery after stroke have been developed and trialed over the past 3 decades. These include repetitive task training, biofeedback, constraint-induced movement therapy, robotics, virtual reality, motor imagery, noninvasive brain stimulation, and pharmacological agents.8,9 However, despite almost 1000 randomized control trials (RCTs) in stroke rehabilitation,10 there is very little translation of this evidence base into clinical practice.11,12 Research efforts to develop the evidence base are challenged by difficulties in recruiting patients, resulting in small sample sizes; the heterogeneity of impairments after stroke and the complexity of their interactions with factors affecting recovery; and limited collaboration between scientists, clinicians, patient groups, and industry.11(So you want to give up just because research is hard? Try recovering from a stroke with NO useful medical guidance.) Even when the research evidence base supports the development of clinical guidelines, significant barriers to implementation remain.10,13Reviews of stroke rehabilitation commonly identify the need to perform research in real-world clinical settings9,11; however, they do not routinely report the timing of RCTs with respect to stroke onset. Similarly, Cochrane reviews typically draw conclusions about the efficacy of an intervention based on RCTs performed at any time after stroke.14–19 These conclusions are then used to develop guidelines that recommend initiating rehabilitation as soon as safely possible after stroke.20–24 A misalignment between the timing of RCTs and the real-world delivery of stroke rehabilitation may be an important aspect of the evidence base that limits its translation to clinical practice.The first 30 days after stroke represent a critical time period for treatment initiation.25 Delays in RCT initiation may reduce the efficacy of the new treatment being tested, in the same way that delays in initiating rehabilitation lead to worse outcomes.26–28 The evidence base for new treatments initiated within the first month after stroke has not been evaluated. Rehabilitation of motor function is a common goal after stroke, and RCTs in this area are likely to be fairly representative of the stroke rehabilitation evidence base. The aim of this review was to determine the percentage of motor rehabilitation RCTs initiated within 30 days of stroke, and characterize these studies.

Four steps to building an innovation culture in pharma

Now do our fucking failures of stroke associations have enough functioning brain cells to follow this? Or do stroke addled survivors have to step in and do the job? 

Four steps to building an innovation culture in pharma

The quest for innovation is a major driving force in pharma. From the discovery of therapeutic biologicals in the 1920s, such as Salvarsan and insulin, to the blockbuster drugs birthed in the 1990s, such as Lipitor and Humira, pharma has always been on a quest for novel, groundbreaking drug development.

However, advancements in technology are constantly transforming how industries and thought leaders operate. Even though the desire for innovation is still at the core of pharma, the industry is still struggling with slower and less efficient traditional R&D models – and is consequently lagging behind in optimizing the benefits of new models of innovation. In order to remain competitive, pharmaceutical companies must learn to foster a culture of innovation at every level of their organization and at every stage of drug development.

Here are four things pharma companies can do to build a dynamic culture of innovation.

1) Be honest about failure(Exactly what has been learned from Dr. Michael Tymianski of the Toronto Western Hospital Research Institute in Canada referencing 1000+ failed neuroprotective clinical trials?)

Most researchers want to learn from failure, but only a few are publicly transparent about failure. When a clinical trial fails to achieve the intended results, newer studies can benefit from the lessons learned in that failure. However, the researchers involved in the failed trial are not usually incentivised to share their mistakes or the lessons that they learned in the process.

Model predictions and studies such as 2016’s ‘Learning from successes and failures in pharmaceutical R&D’ in the Journal of Evolutionary Economics have clearly demonstrated that both successes and failures can contribute to pharmaceutical R&D department investment decisions. Consequently, there should be no shame in being honest about failure. In fact, the faster that pharma companies learn from their failures, the more successful they will be in bringing innovative drugs to market.

On average, it takes 12 years for drugs to go from pre-clinical testing to FDA approval, and it takes seven years for medical devices to go through the process. The journey to approval is too long and the increasing complexity of traditional clinical trials has contributed to the high cost of failure in drug development. Too much time passes before researchers have an opportunity to learn from failure, and the stakes are high.

In an article by Chorus, the authors contrast the traditional drug development model with an alternative model they call ‘quick win, fast fail’ and which places a greater focus on reaching proof-of-concept faster. Consequently, there are more chances to be successful, even when there are many failures along the way. In other words, failing fast (and more often) is a big catalyst for success.

In addition to failing fast, pharma firms need to find more efficient ways to create failure through experiments. According to Amy Edmondson, the Novartis professor of leadership and management at the Harvard Business School, one of the skills that company leaders should have is the ability to create failure through experiments.

But how can the pharma industry as a whole learn from these failures? It starts with companies being willing to incentivise the open sharing of lessons learned from failure. When a drug fails in research or in clinical trials, companies should incentivise researchers to publicise the failure so that others can learn from it. Individual researchers within the same company should not be territorial about their research but should share lessons learned from failure with one another. In an ideal world, this sharing of failures should also take place between different companies, though they would have to make a concerted effort to embrace this level of transparency.

2) Build data analysis as a core competency(We need that complete database of all stroke research in the last 300 years, back to when bloodletting was a therapy. We need to stop these fucking meta-analyses, they should never be necessary.)

In the past, the core competencies of pharmaceutical companies were research and marketing. Recently, data analysis has become a forerunner on the list of core competencies.

In order to be increasingly innovative in the discovery of novel drugs, pharma companies must be empowered to elevate their data analysis capacities. They need to exercise control over their own data analytics and not merely rely on an external organisation to help them leverage their own data. That’s why we don’t simply sell a product or service – we sell an ecosystem that empowers in-house analytics teams to work faster and smarter.

In-house data science teams with advanced analytics capabilities are becoming increasingly common in pharma. As with any new competency, learning quickly will support the effectiveness of these capabilities. Pharma will need to learn to reduce the time-lag in data analysis, emulating other industries that work with real time data and insights.

Companies must become competent with not just extracting the data points and sets available to them, but also with explaining the relationships and connections between disparate data points and indicating smart ways to use the data. This is no easy task, but there is a recent emergence of tools, such as our iPlexus platform, that empower data analytics within a company to find these relationships and relevant insights.

Pharma companies must also become adept at network analysis. We are now in the age of the algorithm, precision medicine and data-driven analysis. Pharma firms need to take advantage of these new technologies. They must learn to parse data in new ways. For instance, the use of ‘low-code’ (designing and developing new software by relying on libraries, APIs and third-party infrastructure) can help pharma companies meet their needs faster. With low-code, they would be able to create something new without coding from scratch. One of the benefits low-code can give pharma companies is ensuring that they bring drugs to the market faster.

Additionally, to catalyse innovation, pharma firms need to use tools such as AI and machine learning to make sense of complex data and inform decision making. Clinical researchers know that accuracy, repeatability, and reproducibility are important in bringing a drug to market, however pharma companies still rely heavily on human input to achieve high-volume tasks. Low-code can be used together with robotic process automation (RPA) and artificial intelligence (AI) to leverage data and create innovative products.

3) Encourage cross-functional collaboration(I see no collaboration with survivors at all.
This just proves once again what Amy Farber has to say.
For the past five years Farber has been battling not only her own disease but also the wall of resistance erected by those who believe that a patient can make about as much of a meaningful contribution to the process of scientific discovery as a laboratory rat.)

Data silos and lack of open data are big challenges in pharma. Pharma companies should incentivise researchers to share insights with one another and to collaborate on projects.

They need to engage more in new open innovation models that encourage sharing of data without the risk of losing intellectual property. Examples of open innovation models are open sourcing, crowdsourcing, public-private partnerships (PPPs), collaborations with academic centers and outsourcing to virtual R&Ds.

Let’s briefly identify the roles each of these models play in achieving innovation in pharma:

• Open sourcing allows pharma to gain knowledge from the public, especially in drug development for neglected diseases
• Crowdsourcing is similar to open sourcing, but instead of getting ideas from the general public, crowdsourcing solicits the skills of experts in the field
• PPPs allows companies to combine resources and share risks
• Recruiting experts from academic centers can help solve complex problems
• Virtualisation of R&Ds helps companies keep their focus on core technologies while partnering with virtual firms that help them pursue under-utilised tasks.

Due to these open innovation models, traditional R&D models are progressing from internally-driven to externally-driven prototypes. Although this transition has caused major pharma companies such as Merck, AstraZeneca and Pfizer to downsize their internal R&D departments, open innovation has produced measurable benefits for pharma in terms of innovation. In a recent Bain & Company survey, 91% of surveyed executives recognised that they need to increase their company’s capacity for innovation because it is “critical to creating future competitive advantage and earning profits”.

4) Automate lower-level cognitive tasks

To focus on creativity and innovation, researchers in pharma need to spend less time performing lower-level cognitive tasks, such as administrative work and collecting, cleaning, and organising data. Performing these tasks limits thinking outside the box. Researchers need a larger brain bandwidth to achieve ‘Aha!’ moments.

Research by McKinsey and Company shows that about 45% of tasks people are paid for can be automated using technology. Examples of automation technologies within pharma and healthcare include IBM’s Watson and Innoplexus’ iPlexus platform.

Using automated systems allows researchers and pharma companies to focus on higher-end creative tasks. It can yield more meaningful work and, in turn, can catalyse innovation.

By taking steps towards incentivising the sharing of failure, building data as a core competency, encouraging cross-functional collaboration, and automating lower-level tasks, pharma companies can build the culture of innovation that they need to remain competitive in this dynamic field.

Chapter 20 – Animal Models of Ischemic Stroke Versus Clinical Stroke: Comparison of Infarct Size, Cause, Location, Study Design, and Efficacy of Experimental Therapies

You'll have to ask your doctor if this analysis covered Dr. Michael Tymianski of the Toronto Western Hospital Research Institute in Canada referencing 1000+ failed neuroprotective clinical trials. 

Chapter 20 – Animal Models of Ischemic Stroke Versus Clinical Stroke: Comparison of Infarct Size, Cause, Location, Study Design, and Efficacy of Experimental Therapies

• Victoria E. O’Collins^*,
• Geoffrey A. Donnan^*,
• Malcolm R. Macleod^**,
• David W. Howells^{*, †}

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https://doi.org/10.1016/B978-0-12-809468-6.00020-6

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Abstract

A quantitative and qualitative comparison of contemporary neuroprotection and thrombolytic stroke trials and their preclinical animal counterparts has been undertaken, with metaanalysis [DerSimonian, R., Laird, N., 1986. Metaanalysis in clinical trials. Control. Clin. Trials 7 (3), 177–188.] used to evaluate imaging and histological outcomes.

Results from 35 clinical trials including 5,532 patients were compared with data from 3,145 preclinical acute-stroke experiments in 45,476 animals. While clinical trials tended to be of higher methodological quality and have larger sample sizes than animal experiments (71 patients vs. 7 animals per group), both were similarly underpowered owing to the greater variability in human stroke (average standard deviation of mean in humans 99% vs. 30% in animals). Proportionally, animal infarcts were almost 4 times larger than human infarcts in untreated control groups (27% vs. 8% of the hemisphere) although there was considerable variability in size owing to comorbidities and stroke type. Eighty-six percent of animal studies and 54% of clinical trials reported smaller infarcts in groups receiving treatment, with 41% of clinical trials reporting an improvement in the prespecified hypothesis. Animal experiments were not effective in predicting individual trial results, nor the level of neuroprotection, however, there was a fair agreement between the direction of the animal and clinical outcomes when looking at the overall direction of drug outcome. As a drug-screening tool, experimental stroke studies need refinement. Rational frameworks for translational research will help.

Keywords

• animal models;
• cerebral ischemia;
• focal ischemia;
• infarct size;
• metaanalysis;
• neuroprotection;
• stroke;
• thrombolysis

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Your New Medical Team: Algorithms and Physicians

This is absolutely necessary for stroke. Our fucking failures of stroke associations seem to have NO strategy on how to address all the failures in stroke and where to direct stroke research. Dr. Watson should easily be able to take the 1000+ failed neuroprotection trials and figure out why they failed and recommend a course of action. But this is going to require our stroke associations to acknowledge their complete failure and turn it over to someone who can lead them to success.
http://www.nytimes.com/2015/12/08/upshot/your-new-medical-team-algorithms-and-physicians.html?ribbon-ad-idx=14&rref=science&_r=0

What is new in stroke research? - An update from the 1st European Stroke Organisation Conference.

Rather appalling that there is little talk on stopping the neuronal cascade of death. The same statement on 1000 failed neuroprotective drug candidates was made by Dr. Michael Tymianski, of the Toronto Western Hospital Research Institute in Canada years ago. So what are those 1000+ failed candidates and why did they fail?
What is new in stroke research? - An update from the 1st European Stroke Organisation Conference.

A Phase III Failure at Eli Lilly. Yes, Again.

We need an analysis like this for stroke drugs.
From Derek Lowe at blog.
There are 1000 stroke failures that Dr. Michael Tymianski has referred to that need this type of analysis. A great stroke association would already have a database of all the failures and use that to create a forward looking plan to get to success. But we have crap for stroke survivor support and prevention of disability.
A Phase III Failure at Eli Lilly. Yes, Again.

Why Animal Experimentation Doesn't Work -- Reason 2: Animals Don't Get Human Diseases

This neurologist lists 3 strikes as to why stroke testing in animals doesn't work. She missed the most important strike.

The rodent model in inflammation is not the same as humans.
there have been more than 1,000 drugs (So what are they?)aimed at preventing brain damage that have failed to work in people, even though they worked well in mice or rats, said study researcher Dr. Michael Tymianski, of the Toronto Western Hospital Research Institute in Canada.
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Reason 1 is here;
Why Animal Experimentation Doesn't Work -- Reason 1: Stressed Animals Yield Poor Data
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Reason 2 is here;
Why Animal Experimentation Doesn't Work -- Reason 2: Animals Don't Get Human Diseases

Selected paragraphs are here:
Let's take a look at stroke experiments in animals to examine how they strike out. In humans, stroke is usually caused by the gradual narrowing of a blood vessel to the brain by atherosclerosis or by a blood clot that developed in another part of the body. Animals in labs don't naturally get strokes. Experimenters artificially induce strokes by methods such as clamping off major blood vessels in animals' brains or artificially inserting clots into their vessels. Here are the problems with this:

Strike 1: Artificially inducing stroke in animals does not recreate the complex physiology that causes the natural disease in humans, which may develop over decades.

Diseases are diseases in context. In humans, stroke is usually linked to pre-disposing conditions such atherosclerosis, high blood pressure, and diabetes.

Strike 2: Animal stroke models don't usually include the underlying conditions, which contribute to human stroke.

Experimenters try to recreate the underlying human conditions such as diabetes in animals. However, these underlying conditions are usually also artificially induced in animals, and as we saw with diabetes, are often wrong anyway.

Strike 3: Artificially inducing in animals the underlying conditions that lead to human stroke does not replicate the processes that occur in humans.

Recognition of each difference between animal models and human diseases leads to renewed efforts to eliminate these differences. But in trying to recreate the complex physiology behind the human diseases, experimenters try to reproduce the complex physiology of the underlying conditions, which are just as difficult to accomplish. Thus animal experimenters are continuously going around in circles.
Stroke is probably one of the easiest human diseases to try to recreate in animals. Yet, over 150 stroke drugs found effective in animal stroke models failed in humans (1).
1. Macleod M. What can systematic review and meta-analysis tell us about the experimental data supporting stroke drug development? Int J Neuroprot Neuroregener 2005; 1: 201

Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly

What does your doctor think of this?
Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly

Abstract

Stroke is a major cause of both death and disability. However, there are no pharmacological treatments used in most countries other than recombinant tissue plasminogen activator, a thrombolytic, and this is only used in about 4% of patients presenting after an acute ischaemic stroke. One novel thrombolytic (desmoteplase) has just been reported to have failed in a Phase IIb/III trial, but other thrombolytics and reperfusion agents remain in development. The picture with neuroprotectant agents, that is compounds that act to preserve neurones following an acute cerebral ischaemic insult, is even more bleak. Despite the development of over 1000 compounds, many proving effective in animal models of stroke, none has demonstrated efficacy in patients in the over 100 clinical trials conducted. This includes NXY-059, which was developed in accordance with the guidelines proposed by an academic-industry roundtable group (STAIR). This review examines the available data on compounds currently in development. It also proposes that the failure of translation between efficacy in preclinical models and patients is likely to terminate most current neuroprotective drug development. It is suggested that animal models must be made more representative of the patient condition (with other co-morbid conditions) and suggests that since stroke is primarily a cardiovascular disease with a neurological outcome, more research on the neurovascular unit would be valuable. New approaches on neuroinflammation, neurorestoration and neurorepair are also likely to gain prominence in the search for new drugs to treat this major clinical problem.

AN INFLAMMATORY FINDING Mice Aren’t Men

This is probably why the 1000 studies that worked in rodents but failed in humans, as Dr. Tymianski noted years ago. Inflammation is extremely important to figure out in the stroke aftermath.

AN INFLAMMATORY FINDING Mice Aren’t Men

A recent paper coauthored by associate professor of pediatrics H. Shaw Warren does just that. In a study that involved collaboration among more than a dozen institutions, Warren, an expert in sepsis (see below), asked whether the bodies of mice react to burns, blunt trauma, and infection the same way that human bodies do. Examining the genetic signatures of response to such assaults, the scientists found very little similarity between the two species.
The finding is stunning because mice have long been considered a model organism for researching drugs for use in people. The study authors estimate that 150 potential treatments for severe inflammation have been tested in people after being found to work in mice—and in the human trials, not a single one worked.

Full article at the link.

Discovery of 'executioner' protein opens door to new options for stroke ALS, spinal cord injury

So ask your researchers to go back over the 1000 failed hyperacute therapies and see if  this new knowledge could require new clinical trials.
Discovery of 'executioner' protein opens door to new options for stroke ALS, spinal cord injury

Oxidative stress turns a protein that normally protects healthy cells into their executioner, according to a study released today in the Proceedings of the National Academy of Sciences journal.
Alvaro Estevez, an associate professor at the University of Central Florida's College of Medicine, led the multi-university team that made the discovery, which could eventually help scientists develop new therapies to combat a host of conditions from stroke to Lou Gehrig's disease
Researchers have long known that oxidative stress damages cells and results in neurodegeneration, inflammation and aging. It was commonly believed that oxidation made a "crude," demolition-like attack on cells, causing them to crumble like a building in an earthquake, Estevez said. However, the latest findings show that oxidation results in a much more targeted attack to specific parts of the cell. Oxidative stress damages a specific "chaperone" cell protein called Hsp90. It plays a role in up to 200 different cell functions. But when a form of oxidative stress called tyrosine nitration modifies that protein, it turns into the cell "executioner" shutting it down.
"The concept that a protein that is normally protective and indispensable for cell survival and growth can turn into a killing machine, and just because of one specific oxidative modification, is amazing," said Maria C. Franco, a postdoctoral associate at UCF's Burnett School of Biomedical Sciences. She co-wrote the study. "Considering that this modified protein is present in a vast number of pathologies, it gives us hopes on finding new therapeutics approaches for several different diseases."
For example, researchers could devise a drug that stroke patients could take at the onset of their symptoms to prevent more healthy cells from dying, thus limiting the damage of the stroke. Because oxidation is linked to inflammation, researchers believe tyrosine nitration could also be related to other health problems including heart disease, cancer, aging and chronic pain.
"These are very exciting results and could begin a major shift in medicine," said Joseph Beckman, from Oregon State University Environmental Health Sciences Center, a collaborator on the study. "Preventing this process of tyrosine nitration may protect against a wide range of degenerative diseases."
"Most people think of things like heart disease, cancer, aging, liver disease, even the damage from spinal injury as completely different medical issues," Beckman said. "To the extent they can often be traced back to inflammatory processes that are caused by oxidative attack and cellular damage, they can be more similar than different. It could be possible to develop therapies with value against many seemingly different health problems."