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COVID-19 Vaccine Surveillance- November update

COVID-19 Vaccine Surveillance- November update

Adverse effects of COVID-19 vaccines – what are they? Mass vaccinations against COVID-19 are being done around the globe. As of 3rd November 2021, over 7.1 billion doses of the COVID-19 vaccine have been administered throughout the world. Before their approval, these vaccines went through rigorous clinical trials and were found to be safe. Their administration to the general population on such a large scale has uncovered some adverse effects. However, most of the adverse effects are minor such as pain at the site of injection, headache, fatigue, and muscle pain. The major adverse effects are extremely rare which include anaphylaxis, vaccine‑induced immune thrombotic thrombocytopenia (VITT), myocarditis, and pericarditis. These latter disorders are by far the most important adverse effects caused by COVID-19 vaccines. Some other adverse effects include skin reactions, Bell’s palsy, rhabdomyolysis, vasculitis, pityriasis-rosea, reactivation of herpes simplex, varicella-zoster, reactivation of hepatitis C, ocular adverse effects, stroke, myelitis, and more. People with a history of chronic diseases and those who have previously been exposed to SARS-COV 2 are at greater risk to these reactions. Studies have also found that these adverse effects are slightly more prevalent in women. The exact type of adverse effect depends upon the medical history, age, and gender of the individual as well as the type and dose of the vaccine administered. The following are the developments in the understanding of some of the previously known adverse effects: Anaphylaxis Anaphylaxis is a potentially life-threatening allergic reaction that occurs minutes after receiving the COVID-19 vaccine. Anaphylaxis is one of the earliest reported adverse effects due to the COVID-19 vaccination. It is being hypothesized that anaphylaxis can occur due to the formation of a polyethylene glycol (PEG)-conjugated lipid derivative triggered by mRNA vaccines. This explains an observed trend that females are more susceptible to this allergic reaction. Hormonal differences can also be one of the contributing factors for the adverse reaction of anaphylaxis. Myocarditis Myocarditis is the inflammation of the walls of the heart. It is also one of the earliest reported adverse effects of COVID-19 vaccines. Myocarditis is more prevalent in males of younger age who received Pfizer/BioNTech, Moderna, or Janssen vaccine. According to a hypothesis, myocarditis is somehow associated with IFN-gamma and TNF-alpha. This hypothesis also explains the observed trend in terms of the age and gender of the affected individuals. Neurological Adverse Effects There are a variety of neurological adverse effects which occur following COVID-19 immunization. These include Guillain-Barre syndrome, Bell’s palsy, venous sinus thrombosis, and acute transverse myelitis. It is difficult to draw a causal association between such a wide spectrum of neurological adverse effects and COVID-19 vaccines, but identification of risk factors can reduce the incidence of these unwanted events. Patone et al. compared the risk of neurological disorders caused by the COVID-19 virus to the neurological adverse effects caused by the vaccines in an important review. The article reported that neurological complications of COVID-19 infection are much more prevalent than the adverse effects of the vaccines. This is an encouraging finding for the general population concerned about the devastating neurological adverse effects caused by COVID-19 vaccination. Recommendations regarding Vaccination Although the exact mechanisms of many of the adverse effects are still unknown, the epidemiological data can be used to understand certain patterns about these adverse effects which can help us prevent these events. Some recommendations are given below: People suffering from metabolic, musculoskeletal, immune system, and renal disorders should avoid inactivated virus-based COVID-19 vaccines. People suffering from diseases related to the vascular system should avoid mRNA-based vaccines. Studies have found that antibodies produced in response to the vaccination do cross the placental barrier and are also secreted in breast milk. Despite this, there were no significant adverse effects on the health of newborns. Therefore, it is safe for pregnant women to get the vaccination. CDC advises women younger than 50 years of age to be aware of the risk of TTS associated with Johnson & Johnson’s Janssen vaccine. Deaths after COVID-19 vaccine About 9,367 deaths following COVID-19 vaccination have been reported to the Vaccine Adverse Event Reporting System (VAERS). It is important to note that these deaths do not necessarily have a causal relationship with COVID-19 vaccination. They only have a temporal association with the administration of either the first or second dose of the vaccine. Schneider et al. performed an autopsy investigation on 18 individuals who died after receiving a shot of the COVID-19 vaccine. The authors reported that 13 of these 18 individuals died due to pre-existing diseases which were not related to the COVID-19 vaccine. CONCLUSION The benefits of COVID-19 vaccines clearly outweigh their potential risks. Mass vaccination is still the best way out of this pandemic. The transparency regarding the reporting of adverse effects of COVID-19 vaccines is essential to this mass vaccination strategy. It also allows to point out some general patterns so that at-risk individuals can take proper preventive measures. Written by: Numair Arshad

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COVID-19 Vaccines

COVID-19 Vaccines

Types of vaccines Vaccines can stimulate the body to produce a protective immune response. The vaccine itself can mimic natural infection, but it does not actually cause illness. If a pathogen infected the body after vaccination, the immune system would quickly prevent the pathogen from spreading in the body and causing disease. Vaccines can be divided into the 3 types: inactivated pathogen, recombinant protein-based, and genetic vaccine. In general, inactivated pathogen and recombinant protein-based vaccines induce humoral immunity (Th2-biased) via MHC II pathway. Genetic vaccine such as mRNA and DNA vaccine can induce both cellular and humoral immunity via MHC I and MHC II pathways. The emergence and rapid spread of a novel severe acute respiratory syndrome (SARS) like coronavirus SARS-CoV-2 is causing the global coronavirus disease 2019 (COVID-19) pandemic and destroying global health and economy. To date, SARS-CoV-2 has infected over 264 million people and caused more than 5.22 million deaths. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. Studies revealed that a virus surface spike protein mediates SARS-CoV-2 entry into cells by binding to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD). Therefore the spike protein is an excellent target for developing successful vaccine to protect from infection and curb the pandemic. To date, there are two mRNA vaccines (Pfizer-BioNTech and Moderna) and two virus vector-based vaccines (JNJ and AstraZeneca) have been approved in USA and Europe, two or three inactivated vaccines has also been approved in China and India. There are a few other vaccines still in clinical trial stages. We briefly discuss as follows: Genetic vaccines Vaccines from Pfizer-BioNTech, Moderna, and Johnson & Johnson are being administered in the U.S. The FDA has authorized—and the CDC has approved—booster shots for all three vaccines, along with a “mix-and-match” approach that would allow people to choose a different vaccine for their booster than the one they started with. They are all genetic vaccines. 1. mRNA vaccines Both Pfizer-BioNTech and Moderna vaccines are mRNA. Unlike vaccines that put a weakened or inactivated disease germ into the body, the mRNA vaccine delivers a tiny piece of genetic code from the SARS CoV-2 virus to host cells in the body, essentially giving those cells instructions, or blueprints, for making copies of spike proteins (the spikes you see sticking out of the coronavirus in pictures online and on TV). The spikes do the work of penetrating and infecting host cells. These proteins stimulate an immune response, producing antibodies (humoral immune response) and developing T cell and memory cell immune response that will recognize and respond if the body is infected with the actual virus. Both vaccines showed about 95% efficacy in Phase 3 clinical trials with two shots (21-28 days interval). This figure has changed over time. At six months after vaccination both Pfizer and Moderna still are considered highly effective, several recent studies showed Moderna to be more protective. One study published in The New England Journal of Medicine found Moderna vaccine to be 96.3% effective in preventing symptomatic illness in health care workers compared to 88.8% for Pfizer. Another, from the CDC, found Moderna’s effectiveness against hospitalization held steady over a four-month period, while Pfizer’s fell from 91% to 77%. This research is still limited and more data is needed to fully understand the differences between the two vaccines. Moderna reported that studies showed its vaccine is effective against the Beta, Delta, Eta, and Kappa variants, although it did show it to be about two times weaker against Delta than against the original virus. The Pfizer vaccine was found to be more than 95% effective against severe disease or death from the Alpha variant (first detected in the United Kingdom) and the Beta variant (first identified in South Africa) in two studies based on real-world vaccinations. 2. DNA vaccine INOVIO's DNA vaccine candidate (INO-4800) against SARS-CoV-2, is composed of a precisely designed DNA plasmid that is injected intradermally followed by electroporation using a proprietary smart device, which delivers the DNA plasmid directly into cells in the body and is intended to produce a well-tolerated immune response. As one of the only nucleic-acid based vaccines that is stable at room temperature for more than a year, at 37°C for more than a month, has a five-year projected shelf life at normal refrigeration temperature and does not need to be frozen during transport or storage, INO-4800 is anticipated to be well-positioned for a primary series immunization as well as a booster. Currently this DNA vaccine is under Phase 3 clinical trials in multiple countries in Latin America, Asia, and Africa. Regulatory authorization in India follows authorizations from health authorities in Brazil, Philippines, Mexico and Colombia. 3. Virus vector-based vaccine Johnson & Johnson and Oxford-AstraZeneca have developed similar virus vector-based COVID-19 vaccines. Unlike the mRNA vaccines, virus vector-based vaccines can be stored in normal refrigerator temperatures, and because it requires only a single shot, it is easier to distribute and administer. The virus vector-based vaccines use a different approach than the mRNA vaccines to instruct human cells to make the SARS CoV-2 spike protein. Scientists engineer a harmless adenovirus as a shell to carry genetic code on the spike proteins to the cells. The shell and the code cannot make you sick, but once the code is inside the cells, the cells produce a spike protein to train the body’s immune system, which creates antibodies and memory cells to protect against an actual SARS-CoV-2 infection. Both vaccines obtained similar overall efficacy (75%) and over 85% efficacy against moderate and severe disease. Johnson & Johnson reported in July 2021 that its vaccine is also effective against the Delta variant, showing only a small drop in potency compared with its efficacy against the original strain of the virus, although one recent study suggested that the J&J vaccine is less effective against Delta. Recombinant S protein-based or peptide vaccine 1. NovaVax NovaVax has developed a recombinant Spike protein vaccine which is highly effective in clinical trials. It is simpler to make than some of the other vaccines and can be stored in a refrigerator, making it easier to distribute. Unlike the mRNA and vector vaccines, the Novavax vaccine takes a different approach. It contains the spike protein of the coronavirus itself, but formulated as a nanoparticle, which cannot cause disease. When the vaccine is injected, this stimulates the immune system to produce antibodies and T-cell immune responses. Studies have shown 90% effectiveness against lab-confirmed, symptomatic infection and 100% against moderate and severe disease in Phase 3 trial results released in a company statement in June. The company says the vaccine was 91% protective of people in high-risk populations such as people older than 65, those with health conditions that increase risk of complication, and those in situations where they are frequently exposed to the virus. 2. Virus-like particles The company VBI has developed virus-like particle vaccine ( VBI-2900) that consists of three enveloped virus-like particle (eVLP) vaccine candidates: (1) VBI-2901, a trivalent pan-coronavirus vaccine expressing the SARS-CoV-2, SARS-CoV, and MERS-CoV spike proteins, (2) VBI-2902, a monovalent COVID-19-specific vaccine expressing the native SARS-CoV-2 spike protein, and (3) VBI-2905, a monovalent COVID-19-specific vaccine expressing the spike protein from the Beta variant (also known as B.1.351). The vaccine program has been developed through collaborations with the National Research Council of Canada (NRC), the Coalition for Epidemic Preparedness Innovations (CEPI), and the Government of Canada, through their Strategic Innovation Fund. In Phase 1 study, VBI-2902a induced neutralization titers in 100% of participants, with a GMT of 329, 4.3x the GMT of the convalescent serum panel, after two doses. After two doses, VBI-2902a also induced antibody binding titers in 100% of participants, with a GMT of 4,047 units/mL, 5.0x the GMT of the convalescent serum panel 3. Peptide vaccine Emergex announced approval to initiate Phase I clinical trial of its next generation COVID-19 vaccine candidate in November. This is a synthetic peptide vaccine designed to prime T-Cells to rapidly remove viral-infected cells from the body after infection. This vaccine may offer broad immunity against SARS-CoV-1 and all SARS-CoV-2 variants and provide long-lasting immunity that does not require seasonal booster vaccines. Emergex vaccines have been designed to be administered via the skin using micro needles and to be stable at ambient room temperature for more than three months, facilitating rapid and efficient distribution across the world and making administration of the vaccine more patient friendly. Inactivated virus vaccine Inactivated COVID-19 vaccines have also been approved in China (developed by Sino Biologics and Beijing Kexing) and in India (developed by Bharat Biotech). Written by: Feng Lin, M.D., Ph.D. References: Scudellari M. Nature, 2021, 595-640-644 Shang J, Wan Y, Luo C, et al. PNAS, 2020, 117:112-11734

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Immune Maps in the Brain Create Memory of Past Infections

Immune Maps in the Brain Create Memory of Past Infections

Implications for Psychosomatic Disorders Introduction Jack was severely allergic to pollen from flowers. His friends wanted to play a prank on him and decided to scare him by placing an artificial flower with no pollen in his backpack. As soon as Jack opened his backpack and saw this flower, he started showing symptoms similar to an actual allergic response, and soon developed a full-blown allergic response. Though this story is a figment of the writer’s imagination, this is what happened almost 150 years ago when Mackeszie and researchers studied the effects of an artificial flower on subjects allergic to pollen. This phenomenon is termed as a psychosomatic disorder. Cleveland Clinic defines psychosomatic disorder as “a psychological condition involving the occurrence of physical symptoms, usually lacking a medical explanation.” This suggests that a disorder may manifest without any apparent physical cause, solely due to “some unknown” effect of the nervous system. While there is no consensus about psychosomatic disorders and its underlying causes, a recently published study by researchers at Technion hints at a possible role of the brain in producing certain immune-related diseases. The Brain and The Immune System It has long been recognized that the immune system can affect the functioning of the brain, indirectly through immune mediators, and directly through the actions of immune cells on the nervous system. What this recent study shows is that the converse is true as well. The immune system is directly represented in certain areas of the brain and through these areas, the brain can regulate the immune system. The Study In the study that was published in a recent issue of Cell, Asya Rolls and her team of researchers from Technion – Israel Institute of Technology used a mouse model to induce inflammation in a part of the gut called the colon. In these mice, inflammation of the colon (colitis) was associated with an increase in the activity of neuronal cells. Specifically, an area of the brain called the insular cortex showed neuronal activation following colitis. This suggested that there was some correlation between colitis and brain activation. However, the key question was whether the reverse was true? To examine this, researchers artificially activated these same brain neurons in healthy mice. Surprisingly, they found that this led to inflammation that was restricted to the same region of the intestine but not to other areas of the body. This meant that the insular cortex region of the brain had formed a memory of the earlier inflammation and could stimulate the same response in the absence of any pathology in the intestine. Additionally, when these neurons were suppressed, it reduced the inflammation in the colon. So, the key takeaway from this study is that the insular cortex region of the brain can retain information related to immune signaling, similar to the way the brain retains memory. Further studies are essential to elucidate the mechanism involved in this communication between the nervous system and the immune system. Role of Insular Cortex The insular cortex region of the brain is also responsible for perception of sensations from inside the body, a process known as interoception. These are largely unconscious perceptions, and include perception of physical sensations in relation to organs such as heart beat, respiration, satiety, etc. It is interesting that the same brain area that is responsible for interoception is also involved in “remembering” the immune response. Conclusion This is a very important study which suggests that the brain may be programmed to store information about the immune system, similar to that of the sensory and motor systems. This may have implications for many immune-related disorders such as allergies, ulcerative colitis, Crohn’s disease, autoimmune disease, etc. Better understanding the mechanisms and pathways of neuroimmune signaling may help us manipulate it to manage related disorders. Written by: Sandeep Pingle, MD PhD

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PICK’S DISEASE

PICK’S DISEASE

Pick’s disease (PiD) was discovered by Arnold Pick in 1892. The meaning of the term “pick’s disease” has changed dramatically over the years. In the past, it was used to describe Frontotemporal dementia (FTD) but now it represents a histopathological (the study of tissues and cells under a microscope) subtype of FTD. FTD belongs to an even broader pathology called frontotemporal lobe degeneration (FTLD). FTD is any form of dementia in which frontal and temporal lobes of the brain degenerate. It is characterized by the presence of intraneuronal inclusions in the form of pick bodies and ballooned cells in the brain called pick cells. These inclusions contain aggregates of abnormal tau protein. Tau protein in PiD is 3-repeat, meaning the Tau protein exists in various isoforms and large amounts of 3-repeat have profound axonal transport defects and locomotor impairments. PiD is a primary tauopathy (deposition of abnormal levels of Tau protein). Healthy tau protein helps in the assembly of microtubules in the neurons. It is coded by the MAPT gene. Like all other types of dementia, it is a neurodegenerative disease. Atrophy in the PiD brain is limited to frontal and temporal lobes. This atrophy results in the formation of a characteristic knife-edge-like shape of the brain. Damage to the frontal lobe results in behavioral decline while damage to the temporal lobes results in language decline. The age of onset of PiD ranges from 40 to 75 years. PiD is more prevalent in men than in women. FTD is divided into clinical subtypes such as behavior called behavioral variant of Frontotemporal dementia (bvFTD) and diminished language skills called primary progressive aphasia (PPA). bvFTD presents the most common set of symptoms in PiD. Most cases of PiD have a sporadic origin. Characteristic symptoms of PiD include abrupt mood change, compulsive behavior, stereotypic and immoral behaviors, difficulty in speech, disinhibition, and apathy. Caregiving in PiD is particularly difficult due to the inappropriate behavior of patients towards caregivers. PiD patients show stereotypic, sexually inappropriate, and impulsive behavior. PiD patients also suffer from anomia; a condition in which a person has difficulty remembering the names of objects and places. Akinesia and rigidity may occur in the later stages of the disease. Diagnosis of living PiD patients is difficult because of the lack of specific biomarkers for pick bodies. Antibodies can be used in the diagnosis of PiD. Cognitive and behavioral tests are currently the best option for diagnosing PiD. Despite all these options, many PiD patients are misdiagnosed. Brain imaging can be used to visualize atrophy. Most patients suffering from PiD have mixed pathology in which other neurodegenerative diseases are also involved. Frontotemporal lobar atrophy is a prominent sign of PiD. Knife-edge-like cortical atrophy can be observed upon gross examination. The risk of PiD increases with age. High education, regular physical exercise, and a healthy diet can be effective in the prevention of all types of dementia including PiD. There are three stages of PiD. These are called initial, steady and terminal stages. Symptoms get worse with advancing stages. Males suffering from PiD show aggressive behavior. No treatment can slow down or reverse the progression of PiD. Different drugs can be used to manage the symptoms and the treatment is highly individualized. Cholinesterase inhibitors are used for the behavioral management of PiD. The drugs being used to manage symptoms of PiD are intended for symptomatic treatment of other disorders such as AD. Much work needs to be done to understand the pathophysiology of PiD in order to develop disease-modifying treatments. Written by: Numair Arshad & Lawrence D. Jones, Ph.D.

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Ebola Virus Disease

Ebola Virus Disease

What is Ebola Virus? Ebola is also called Ebola virus disease (EVD). EVD is a deadly disease with severe complications like Ebola hemorrhagic fever and organ failure in later stages of infection. EVD was earlier known as Ebola hemorrhagic fever or EHF, but since 2014, it was named EVD as it is not only limited to febrile illness. Historically, there have been several episodes of sporadic outbreak. The first of such outbreaks was documented in 1976, but the recent outbreak in Western Africa in 2013 – 2014 was notable due to the high incidence of outbreak. In 2014, the World Health Organization (WHO) declared the outbreak as a Public Health Emergency of International Concern (PHEIC). Further, WHO seeks enhanced efforts to combat this fatal disease. The name Ebola was taken from the Ebola River in Africa, where the earliest signs of outbreak occurred. EVD is a highly contagious disease caused by the Ebola virus where the virus easily spreads (transmissible) to people coming into contact with those infected by the virus. Symptoms The Ebola virus is an enveloped single-stranded RNA virus. EVD occurs in both primates and humans. In humans, it is caused by four Ebola virus species, namely Zaire Ebola virus, Sudan virus, Taï Forest virus, and Bundibugyo virus. It can infect 2 to 21 days of infection. The major early symptomatic manifestations of EVD are fever, muscle pain, fatigue, sore throat with headache. Subsequently, later symptoms may arise in the form of vomiting, diarrhea, skin rash, symptoms of impaired kidney and liver functions, low platelet counts with both internal and external bleeding. EVD begins typically with a febrile illness (high fever) followed by gastrointestinal problems. In patients with high viral loads, EVD infection progresses to a complicated fatal multiple organ dysfunction syndrome. Transmission The transmission of EVD is both zoonotic and anthroponotic, that is from animals to humans, and humans to humans, respectively. In zoonotic transmission, humans become infected while having physical contact with infected animals or while handling bushmeat. The human-to-human transmission was reported via contact with blood and/or body fluids from infected humans. Ebola virus can also transmit through the skin, even without bruises or cuts, bodily fluids, or fomites. Due to the severity of this and devastating socioeconomic effects, the Ebola virus is considered as a Category A Priority pathogen by the National Institute of Allergy and Infectious Diseases or NIAID. Furthermore, the Ebola virus is considered a Category A threat agent by the Centers for Disease Control and Prevention (CDC). Multi-organ failure is the primary cause for mortality in EVD while electrolyte imbalances may lead to cardiac rhythm problems or coma. Diagnosis Clinical misdiagnosis can occur in detecting EVD as the clinical manifestations are similar to diseases like meningitis, malaria, or typhoid fever. Even symptoms of pregnancy overlap with the clinical aspects of EVD. Thus, pregnant women should be tested rapidly if they suspect an Ebola virus infection. Laboratory-based diagnosis has a huge role to play in efforts related to rapid response to outbreaks. As a traditional as well as the gold standard of diagnosis, cell culture, and propagation of isolated virus in Vero E6 African green monkey’s kidney cells and examining it under biosafety level-4 containment or BSL-4 facility by electron microscopic techniques remains the standard. However, with the advent of modern technology and analyzing tools, there are quite a few diagnostic tests utilized to detect EVD. Such diagnoses depend on three basic techniques namely serology-based, antigen-based, and other molecular tests such as reverse transcriptase-polymerase chain reactions or RT-PCRs. However, none of the tests have proven to demonstrate the capability to detect the viral load before the onset of symptoms in patients, which is still a gap in the diagnosis protocol. An early point of care diagnosis is emphasized to detect cases under field settings. In acute symptomatic patients, viral proteins can be detected at optimal levels in antigen-based tests with better accuracy than antibody or serology-based tests. Also, the use of a rapid antigen detection test is further recommended under field settings. Associated risks There are increased risks of contracting the disease if an individual is suffering already from malnutrition as well as co-infections like malaria. Women as caregivers and pregnant women can carry the risk of passing on the fatal infection to its offspring. Adults between 35-44 years are more susceptible to Ebola virus infection. The strong risk of transmission of the Ebola virus from one human to another is determined via contact with infected bodily fluids like breast milk, saliva, semen, urine, aqueous humor, cerebrospinal fluid, and blood. In addition, rare sexual transmission of the Ebola virus can be another risk factor. Children were observed to have a higher risk of mortality than older populations, especially children below 5 years of age. Treatment and management has emphasized supportive care such as isolating patients and providing rehydration along with rapid diagnostic testing, monitoring of vital signs, ventilation, and symptomatic administration of therapeutics. Vaccines remain the promising approach to prevent cases of mortalities. Following the 2014 outbreak, several countries raise their concerns on implementation of precautionary measures in the form of vaccines. Only during the recent outbreak in the Democratic Republic of Congo (DRC), the vaccine Ervebo® has been recommended under compassionate use protocols. Ervebo® was approved by the U.S. Food and Drug Administration (FDA) on December 19, 2019, as the first vaccine for treating the deadliest strain of Ebola virus, Zaire Ebolavirus. Efficient control of an outbreak depends on the imposition of a set of interventions, which revolves around methodical case management, contact tracing, and surveillance, as well as the establishment of good laboratory services, safe burials, and maintenance of physical distancing and responsible communication. The establishment of strategic community engagement is an additional measure to successfully control and regulate outbreaks. These organizations help to disseminate awareness of risk factors, transmission and personal protective measures which are essential to reducing human-to-human transmission. At-risk healthcare workers are taught/provided with standard preventive measures that include maintenance of basic hand and respiratory hygiene, supply and implementation of personal protective equipment or PPE, safe injection as well as safe burial practices. Similarly, laboratory workers, who are at equal risk, are also provided protection and the protocols to maintain the highest level of biosafety precautions. The enormous number of mortalities, as well as affected health workers in the past episodes of EVD outbreak, has made it indispensable to analyze and research on both diagnostic and therapeutic aspects of EVD that are currently available along with formulating more efficient tactics to combat this virus. Currently, various novel immune therapies and drug therapies are being evaluated. On October 14, 2020, the FDA approved Inmazeb® (atoltivimab, maftivimab, and odesivimab-ebgn), a mixture of three monoclonal antibodies, as the first FDA-approved treatment for Zaire ebolavirus (Ebola virus) infection in adult and pediatric patients. While there is still some controversy, remdesivir, may also have a positive impact on reducing the effects of this deadly disease. Written By: Souvik Datta, Ph.D. & Lawrence D. Jones, Ph.D.

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DEMENTIA

DEMENTIA

What is Dementia Dementia is defined as a set of brain disorders that result in general cognitive decline. Dementia affects cognitive functions like memory, speech, judgment, reasoning, and visual perception. People suffering from dementia cannot live their life properly. They are dependent on others to perform even the most basic tasks. Dementia is the most common cause of disability among the older population of the world. The general symptoms of dementia can vary depending upon the cause of dementia. Life expectancy has increased in developed countries, and it continues to increase in underdeveloped countries due to better health measures such as vaccinations, availability of antibiotics, a healthy diet, and a clean environment. This increase in life expectancy has exposed the world population to age-related illnesses. Forms of Dementia Dementia is the most devastating of these age-related illnesses. It deprives people of their independence and makes the final stages of their life miserable. As the population ages, dementia will continue to have a greater impact on socioeconomic conditions. In this article, we have elaborated on the epidemiology, socioeconomic impacts, symptoms, and pathophysiology of major types of dementia. Alzheimer’s Disease Alzheimer’s Disease (AD) is the major form of dementia. The pathological processes responsible for AD begin decades before the onset of symptoms. The symptoms of AD include the most typical symptoms usually associated with dementia. These symptoms include a decline in short-term memory, judgment, and decision-making ability. So far, the best explanation of molecular processes leading to AD is given by the amyloid cascade hypothesis. Beta-amyloid (Aβ) produced from amyloid precursor protein (APP) accumulates within the neurons. Tau protein is also involved in AD. AD is considered a secondary tauopathy. The combined toxic effect of Aβ and hyperphosphorylated tau damages neurons and synapses in the brain. Currently, there is no disease-modifying treatment for AD; however, the symptoms can be managed individually using different drugs. Cholinesterase inhibitors are typically used for symptomatic management of AD and function to decrease the breakdown of acetylcholine. As a consequence, the relative increase in acetylcholine results in increased communication between nerve cells, which in turn, may temporarily improve or stabilize the symptoms of dementia. Vascular Dementia Vascular dementia (VD) occurs due to diminished blood supply to the brain. Stroke is the most common cause of this impaired blood supply to the brain. Symptoms of VD can vary depending on which part of the brain is receiving less than normal blood. Usually, frontal and temporal lobes are affected; therefore, the most common symptoms of VD are a decline in reasoning and decision-making abilities. The risk factors of VD include general risk factors of cardiovascular diseases. Lewy Body Dementia Lewy body dementia (LBD) is an umbrella term that includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). DLB is characterized by the presence of Lewy bodies in the limbic system, brain stem, and neocortical parts of the brain. Lewy bodies are composed of many proteins. α-Synuclein is the major protein in Lewy bodies. α-Synuclein is a small protein of only 140 amino acids. Visual hallucinations are strong in DLB and parkinsonian symptoms appear later in the disease. There is no disease-modifying treatment of DLB. The symptoms can be managed through appropriate drugs. Parkinson’s Disease Dementia Parkinson’s Disease Dementia (PDD) is characterized by the presence of early motor symptoms. Dementia symptoms appear later in the disease. α-Synuclein is also the major protein involved in the pathophysiology of PDD. Other proteins such as ubiquitin are also involved. Braak's hypothesis gives the best explanation of the origin and spread of PDD pathology. α-Synuclein pathology first originates in the peripheral nervous system and olfactory bulb and then propagates to substantia nigra. Frontotemporal Dementia Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by the degradation of the frontal and temporal lobes. A variety of proteins are involved in the pathophysiology of FTD. These proteins include Tau and TAR DNA-binding protein 43 (TDP-43). In the clinical setting, two major variants of FTD have been identified. These are Behavioral Frontotemporal (bvFTD) and Primary Progressive Aphasia (PPA). Emotional instability, inhibition, obsessive and compulsive behaviors, lack of motivation, change in eating habits, and lack of empathy are the major symptoms of FTD. Mixed Dementia Mixed dementia is the coexistence of different types of pathology in an individual. The coexisting pathologies often potentiate each other. AD and VD are most common in mixed dementia. Mixed dementia patients show symptoms of both AD and VD. These overlapping symptoms pose a challenge in identifying the correct diagnosis. Treatment of mixed dementia involves the management of contributing dementias separately. Written By: Numair Arshad & Lawrence D. Jones, Ph.D.

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Inflammatory Bowel Disease

Inflammatory Bowel Disease

What is Inflammatory Bowel Disease? Inflammatory bowel disease is an autoimmune disorder characterized by inflammation of the gastrointestinal tract (GIT). It is an idiopathic (of unknown cause) disease thought to be caused by a dysregulated mucosal immune response to gut microbiota. It includes Crohn’s disease (CD) and Ulcerative Colitis (UC). CD is the intermittent inflammation of three layers of any part of GIT while UC is the continuous inflammation of the mucosa of the colon and rectum. IBD occurs in genetically predisposed people but environmental factors are equally important. The most important environmental factor is diet. IBD is not life-threatening but it greatly affects the quality of life. Remission can be achieved through proper treatment but relapsing is common even in patients who have undergone surgery. IBD can retard growth in children. There is no cure for IBD, and the purpose of treatment is to restore normal life activities and growth in children. Epidemiology The incidence of IBD is greater in developed countries and according to some studies, it is increasing. Incidence varies a lot depending on region, ethnicity, and socioeconomic status. White and Jewish people are at greater risk of IBD. The prevalence of IBD is high due to its young-onset and chronic nature. Historically this disease has been more prevalent in North America and Europe and these places still lead in the number of patients but recently the incidence of IBD has been reported to increase in Asia owing to some improvement in the socioeconomic situation there. In general, it affects males and females equally. The chances of onset of IBD are greatest in the fourth decade of life. Pediatric patients account for as much as one-third of all patients. People with first-degree family members suffering from IBD are at five times greater risk of IBD and they tend to have an early onset of symptoms. Besides genetics, environment and diet are major risk factors of IBD and prevention mainly revolves around bringing dietary changes. Environmental factors include smoking, drugs, water pollution, geography, sleep, and stress. Symptoms Some common symptoms of CD and UC include diarrhea, abdominal pain, rectal bleeding, and weight loss. Symptoms of UC are limited to the colon and rectum but the symptoms of CD are diverse depending upon the exact site of inflammation. Abdominal pain, watery diarrhea, and weight loss are the characteristic symptoms of CD. Abdominal pain is sometimes so severe that patients might suspect they have appendicitis. Diarrhea is usually watery but rectal bleeding can occur in CD. Bloody diarrhea is more common in UC. Malnutrition can occur when the small intestine fails to absorb food properly, which causes weight loss and growth retardation in children. The characteristic symptoms of UC are blood in the stool with mucus, abdominal pain, frequent diarrhea, fever, loss of appetite, and tenesmus (a feeling that you need to pass stool even though your bowel is empty). Sometimes constipation can also occur accompanied by blood and mucus. Symptoms of IBD are not restricted to GIT. Endoscopy with multiple biopsies is the gold standard of diagnosis. Imaging and biomarkers are used for further evaluation. Ileocolonoscopy and chromoendoscopy are most often utilized. At least two biopsies should be taken from normal-appearing tissues of five sites including the ileum and rectum. Magnetic resonance elastography (MRE) is used to evaluate disease activity. IBD does not have a specific biomarker. Two biomarkers, C-reactive protein (CRP) and fecal calprotectin (FC) can give valuable information about disease activity but they cannot be used in diagnosis. Our gut harbors a vast population of microbes mostly bacteria which have a role in our overall health. Treatment Any change in the composition of this microbiota has far-reaching effects on our health. Pathogenesis of IBD involves disruption of gut microbiota in genetically predisposed individuals. Immune response to this disruption goes out of control in the presence of genetic mutations and begins damaging the healthy cells in the intestine. Treatment of IBD with biologics mostly targets the autoimmune aspect of pathogenesis. These include Immunomodulators, anti-TNF agents, aminosalicylates, corticosteroids, antibiotics, and anti-integrin agents. Originally used for the treatment of rheumatoid arthritis, oral 5-aminosalicylic acid (5-ASA) is effective in maintaining remission in IBD. Corticosteroids are commonly prescribed in IBD. Antibiotics can be used to restore balance in the microbiota population. mercaptopurine, azathioprine (AZA), and methotrexate (MTX) are commonly used immunomodulators in IBD. Anti-TNF agents work by blocking cytokines. Infliximab, adalimumab, certolizumab, and golimumab are the anti-TNF agents approved by the FDA for the treatment of IBD. If the patient does not show a response to anti-TNF therapy, then anti-integrin agents are used. Natalizumab and vedolizumab are anti-integrin agents approved by the FDA. Specific diets have been designed to achieve remission by helping the intestine heal faster. Exclusive enteral nutrition (EEN) is a commonly used nutritional approach to treat active CD. In a specific carbohydrate diet, the patient is given those carbohydrates which are easy to digest. CD exclusion diet (CDED) helps maintain healthy microbiota. Fecal microbiota transplantation (FMT) is the direct transplant of feces from a healthy person to an IBD patient to change the recipient's gut microbiota and stabilize its composition. This method of treatment is still in the developmental stages. Surgery is the last resort treatment in IBD. Despite the advent of advanced therapeutics, the rates of surgery have not declined. Surgery in IBD has evolved over the years. In the past, surgery was the only therapeutic option but biologic agents have helped delay surgery. There are several types of surgeries depending upon which specific part of the intestine is damaged. Inflammation can come back in CD after the surgery so postoperative care is important. There is a need for disease-modifying drugs for IBD. Novel therapeutic approaches are currently under investigation. New therapeutic strategies in inflammatory bowel disease (IBD) have shifted from symptom control towards treat-to-target algorithms in order to optimize treatment results. Written By: Numair Arshad & Lawrence D. Jones, Ph.D.

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Autoimmune myocarditis

Autoimmune myocarditis

Autoimmune myocarditis is an autoimmune disease resulting in damage to the myocardium of the heart. Autoimmune myocarditis is a genetic and rare disease according to the National Institute of Health (NIH). The development of autoimmune diseases is the result of a lack of “self-tolerance” of the immune system of the body. An autoimmune disorder occurs when the body's immune system attacks and destroys healthy body tissue by mistake. This disorder arises as a consequence of a defective function in immune system regulation and cells that comprise the immune system. Autoimmune myocarditis is an immune system attack on the heart resulting in aggravation and inflammation leading to damage of the myocardium (heart muscles). Generally, the clinical event of inflammation and myocardial damage in both general and autoimmune myocarditis is similar. Therefore, discussion on autoimmune myocarditis regarding symptoms and pathogenesis will be overlapping with myocarditis in general. Myocarditis is commonly regarded as a major public health concern due to sudden heart failures in young adults. Myocarditis was first coined in 1669 when physicians documented inflammation in the heart as a pathologic event. There are a number of factors affecting the development of autoimmunities such as having systemic autoimmune disease, exposures to toxins, or hypersensitivity to medications, and exposure to certain viruses. In virus-induced autoimmune myocarditis, an autoimmune reaction like antigen mimicry may be induced, where viral particles can mimic the body’s own molecules to elicit an antibody-based autoimmune mechanism leading to the self-destruction of the body’s own tissues and organs. A very specific and novel cause of autoimmune myocarditis is immune checkpoint inhibitor (ICI)-induced myocarditis, which is a result of drug therapy in cancers. Unfortunately, both innate and adaptive immune systems of the body are involved in the autoinflammatory processes of autoimmune myocarditis. Among the cardiomyopathies resulting from acute myocarditis, dilated cardiomyopathy or DCM is a clinically severe and fatal disease leading to cardiac arrest. Among the non-infectious myocarditis, there are three diseases namely rare giant cell myocarditis, eosinophilic necrotizing myocarditis, and immune checkpoint inhibitors or ICI-induced myocarditis. The latter is a result of an unchecked immune system and has a high associated rate of mortality. In the U.S., based on inpatient or hospital admitted patient sample data over the course of nine years, a gradual increase in the number of reported cases of myocarditis was observed from 95 per one million in 2005 to 144 per one million in 2014, of which the overall death was 4.43% of inpatients. In addition, past reports on ICI myocarditis, suggests that there may be up to 1–2% of ICI myocarditis with a significant mortality of 30%. While ICI therapy has been hailed as a useful therapy in the treatment of cancers, ICI myocarditis is considered a potential autoimmune side effect. Females are more affected than males. The etiology of autoimmune myocarditis may be viral or of a non-infectious cause such as the effect of cardiotoxins, hypersensitivity reactions within the body, radiation exposures, and systemic disorders such as systemic lupus erythematosus (SLE) and sarcoidosis. In addition, questions remain regarding the cardiovascular effects associated with severe acute respiratory syndrome related to SARS-CoV-2 infections. There are risk factors specific to the development of autoimmune myocarditis which may be systemic/local primary autoimmunity, viral infection, human leukocyte antigen (HLA) or host susceptibility factor and gender bias, exposure of cryptic antigens, antigen mimicry, and deficient thymic training induction. Symptoms range from chest pain to signs of acute cardiogenic shock. Diagnosis relies on preliminary clinical examination of patients and imaging followed by laboratory tests. Immunosuppressants are recommended therapeutics in autoimmune myocarditis along with other symptomatic treatments. Cardiac transplantation should be postponed in the acute phase of myocardial inflammation but may be considered for hemodynamically unstable patients with myocarditis if most of the intravenous drugs and mechanical assistance fail. Ventricular assist devices and oxygenation assist devices like ECMO may be required to provide medical assistance for cardiac transplant patients or recovery in case of cardiogenic shock. Patients with hemodynamically stable conditions, but having heart failure, should be treated with diuretics, angiotensin-converting enzyme inhibitor or angiotensin receptor blockers, and beta-adrenergic blockers to expel the undesired amount of water and salts from the body (via the urine) leading to lower blood pressure. In persistent heart failure despite the optimal management, additional treatment with aldosterone antagonists should be recommended. In addition, all types of physical activity or exercise should be avoided during myocarditis until full resolution. Specifically, in autoimmune myocarditis with common systemic disorders, high-dose intravenous immunoglobulin (IVIG) as a therapeutic, is a promising option. Proper follow-up should be maintained for every patient. Written by: Souvik Datta, Ph.D. & Lawrence D. Jones, Ph.D.

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GLIOBLASTOMA

GLIOBLASTOMA

What are brain tumors? Brain tumors are uncontrolled and abnormal cell growth in the brain or the spine (central nervous system or CNS), causing life-threatening complications, as well as damage to the brain. These may either be primary (one that starts in the brain) or secondary (one that starts in another part of the body and metastasizes to the brain). Primary tumors may be classified as glial tumors or gliomas (composed of glial cells) and non-glial tumors (developed on or in the structures of the brain, including nerves, blood vessels, and glands). About 80% of malignant brain tumors may be categorized as glioma. The highest-grade glioma or glioblastoma multiforme is one of the most lethal cancers in adults recording an annual incidence of 5.26 per 100,000 population and 17,000 new diagnoses per year. The incidence rate of glioblastomas is 1.58 times higher in men than in women in the United States. More than 80% of cases of malignant gliomas are glioblastomas and these are histologically characterized. Classification Glioblastomas are heterogeneous or pleomorphic because the cells in these tumors vary in size and shape and are derived different origins. This heterogeneous nature of glioblastomas poses a maximum hindrance in the development of an effective therapeutic approach with a uniform result. Radiation-induced glioblastomas have been observed after several years of therapeutic radiation indicated for another tumor or condition. Environmental exposure to vinyl chloride, pesticides, smoking, petroleum refining, and synthetic rubber manufacturing have been loosely associated with the development of gliomas. An increased risk of glioma development is seen in some specific genetic diseases, such as neurofibromatosis 1 and 2, tuberous sclerosis, Li-Fraumeni syndrome, retinoblastoma, and Turcot syndrome; however, less than 1% of glioma cases have been associated with a hereditary disease. According to the new 2016 WHO Classification of Tumors of the Central Nervous System, glioblastomas are now mainly classified according to the status of isocitrate dehydrogenase (IDH) mutation: IDH-wildtype (~90%) or IDH-mutant (~10%). Diagnosis and Treatment The diagnosis of brain tumors primarily depends on imaging techniques that can accurately pinpoint the location of brain tumors such as magnetic resonance imaging (MRI) and computed tomography (CT or CAT scan). A scan of the brain is followed by a biopsy. Depending on the location of the tumor, the biopsy and removal of the tumor may be performed at the same time. If doctors cannot perform a biopsy, then they determine a treatment plan based on the brain scan results. The mainstay of glioblastoma treatment is surgery, followed by radiation and chemotherapy. Surgery aims at removing the tumor as much as possible without injuring the surrounding normal brain tissue that is necessary for normal neurological function. However, glioblastomas are surrounded by migrating, infiltrating tumor cells that invade surrounding tissues, thus making it practically impossible to ever remove the entire tumor. The doctors thus perform the surgery to reduce the amount of solid tumor tissue within the brain, remove those cells in the center of the tumor that may be resistant to radiation and/or chemotherapy, and reduce intracranial pressure, which may aid to prolong the lives of some patients and improve the quality of remaining life. After the wound from surgery has healed properly, radiation therapy and chemotherapy are utilized. Radiation therapy is repeated for a total of 10 to 30 cycles depending on the type of tumor. The current standard of treatment for glioblastomas is chemotherapy with the drug temozolomide, which is administered every day during radiation therapy and then for six cycles after radiation during the maintenance phase. Tumor treating fields are another relatively new and different treatment modality that is introduced during the maintenance phase of radiation therapy. It creates alternating electrical fields, which prevents the growth and division of cancer cells. Lomustine (chemotherapy) and Bevacizumab (targeted therapy) are usually applied when the tumor progresses. Written By: Souvik Datta, Ph.D., Lawrence D. Jones, Ph.D.

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Human induced pluripotent stem cell (iPSC) -derived mesenchymal stem cells (MSCs)

Human induced pluripotent stem cell (iPSC) -derived mesenchymal stem cells (MSCs)

What is iPSCs? Induced pluripotent stem cells (iPSCs) are derived from donor skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state thus enabling the development of an unlimited source of any type of human cell needed for therapeutic purposes. For example, iPSC can be differentiated into beta islet cells to treat diabetes, blood cells to create new blood free of cancer cells for a leukemia patient, immune cells to treat cancers, or neurons to treat neurological disorders. In 2006, Dr. Sinya Yamanaka first discovered that intact mature cells could be reprogrammed to become immature stem cells (pluripotent stem cells) by introducing only a few genes. The resulting pluripotent stem cells are able to develop into all types of cells in the body. In 2012, Dr. Yamanaka and Dr. John Gurdon were awarded The Nobel Prize in Physiology or Medicine for the discovery that mature cells can be reprogrammed to become pluripotent cells (iPSCs). With this groundbreaking discovery, iPSC research has quickly become the foundation for new regenerative medicines. iPSC-derived mesenchymal stem cells (iPSC-MSCs) and therapeutic potential Mesenchymal stem cells (MSCs) are multipotent stromal cells derived from connective tissues, MSCs used in treatments show advantages over other approaches because they constitute a stem cell niche, support the growth of tissue-specific stem cells, and promote tissue regeneration. In addition, exogenous MSCs have shown immunomodulatory and regenerative potential in animal models of autoimmune and inflammatory diseases, as well as in clinical trials to treat these diseases such as Inflammatory Bowel Disease (IBD), COVID-19 related acute respiratory distress syndrome, via local delivery or systemic methods. Of note, MSCs are hypoimmunogenic, and the use of allogeneic MSCs is usually safe. This is because MSCs lack human leukocyte antigen class II antigen expression, which allows allogeneic administration without donor–recipient matching. Despite their promising therapeutic effects, tissue derived MSCs have several weaknesses, such as their limited expansion ability and variation across donors, production standardization difficulty, loss of differentiation capacity, and decreased therapeutic efficacy during expansion. iPSCs have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation. Human iPSCs can be induced to differentiate into MSCs following a clinically compliant protocol (see below diagram). These iPSC-derived MSCs, called iPSC-MSCs, show greater expandability and therefore offer potential for use in tissue repair therapies. The therapeutic potential of iPSC-MSCs have been shown in many animal models, for example in the models of IBD on mucosal healing. Human clinical trials of iPSC-derived cells have not previously been completed. For example, CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. a phase 1, open-label clinical trial (no. NCT02923375) was conducted in subjects with steroid refractory acute graft-versus-host disease (SR-aGvHD). CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. Overall response (OR), complete response (CR) and overall survival (OS) rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases. Written by: Feng Lin, M.D., Ph.D.

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ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD)

ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD)

Attention Deficit/Hyperactivity defined Attention Deficit/Hyperactivity Disorder (ADHD) was first described by Sir George F. Still (1902) as a condition persisting in children with a problem associated with “moral control”. The American Academy of Pediatrics (AAP, 1994) defines ADHD as a prevalent and debilitating disorder for which the diagnosis is based on persistent and developmentally inappropriate levels of over-activity, inattention, and impulsivity. The Diagnostic and Statistical Manual of Mental Disorders (DSM) – 5 version defines ADHD by clinical presentation before 12 years of age, with the symptoms of inattention and/or hyperactivity/impulsivity present in 2 or more settings that cannot be better explained by another condition. Prevalence ADHD imposes an enormous burden on society in terms of psychologic dysfunction, adverse vocational outcome, and stress on family members of the ADHD patients. A meta-analysis conducted in 2015 suggested there are approximately 129 million children (ages 5 – 19) suffering from ADHD. The Center for Disease Control and Prevention (CDC) provided statistics on ADHD for the year 2016 wherein it was reported that 6 out of 10 children were taking medication for ADHD (which represents 1 in 20 of all the children in the U.S.) for the age group 2 – 17 years. Of that number, 47% of ADHD patients received various behavioral treatments (within one year) and nearly 64% of ADHD patients had comorbidities such as conduct disorder, anxiety, depression, and Tourette syndrome. Etiopathogenesis ADHD has a complex etiology with multiple genetic and environmental factors, and the complex interactions between these factors create this spectrum of neurobiological lability. In recent years, the prefrontal cortex (PFC), caudate, and cerebellum areas of the brain have been identified as the primary areas where ADHD presents. The interrelationship among these regions is overly sensitive to the neurochemical environment, maintained by the neurotransmitters (NTs), dopamine (DA), and norepinephrine (NE). ADHD presents with a lower-than-normal density of DA. Most studies on ADHD report a reduction in size of the prefrontal and the precentral areas of the brain in these patients. In addition, in the temporal lobe, the cortical thickness differs significantly in ADHD patients, affecting language abilities, visual perception, multimodal sensory integration, and semantic memory processing. Delayed cortical maturation (at age 3 years, or later) has also been reported in children with ADHD as compared to typically developing children. Individuals with ADHD present with emotional dysregulation, that may arise as deficiencies in orienting towards, recognizing and/or allocating attention to emotional stimuli. ADHD is hypothesized to occur due to a mixture of dominant & recessive major genes with complex polygenic transmission patterns. Twin and family studies on ADHD report a strong heritability (60%-90%). Large, rare, chromosomal deletions and duplications called copy numbers are highly prevalent in ADHD. Polymorphisms of the genes that encode DAD4, DRD4, DAD5, SLC6A3, SNAP-25, HR1B, and DAT-1 receptors cause reduced functionality of the neurotransmitters in ADHD. Symptoms & Diagnosis The diagnosis of ADHD requires a psychiatrist/child psychiatrist, pediatrician, or other appropriately qualified, trained, and experienced specialists. The DSM-5 criteria require the symptoms to last for at least 6 months, with 6 or more symptoms, in 2 or more settings (home, school, workplace, extracurricular and/or social activities, etc.) that are inappropriate for the developmental level, and impair academic and/or social progression, and that cannot be better described in any other terminology relating to any other disease/disorder. An altered sensitivity to reward/punishment is also present in patients with ADHD. The symptoms of ADHD in adults include difficulty in concentration, procrastination, hyper-focalization, excessive distractibility, mind-wandering/daydreaming, easily overwhelmed with thoughts not necessarily negative (unlike anxiety). Impulsivity in adult-ADHD is prominent in the verbal sphere. Individuals with ADHD have difficulty with regulation of their emotions, which is prevalent throughout their lifespan. Emotional dysregulation may arise as deficits in orienting towards, recognizing and/or allocating attention to emotional stimuli. These deficits implicate a dysfunction within striato-amygdalo-medial prefrontal cortical network. A focus on this aspect of ADHD could guide novel therapeutics. The diagnosis of ADHD employs a clinical interview with the parents/family of the patient (who maybe a child/adult), that documents a detailed developmental history including medical or psychiatric antecedents (if any), information on family functioning, behavioral difficulties, and strengths of the patient in peer relationships, school/workplace, and leisure time. In this context, informant rating scales such as the Conner’s Rating Scales – 3rd edition, or the Strengths and Difficulties Questionnaire are useful. Neuroimaging is an adjunctive diagnostic tool for ADHD. Magnetic resonance imaging (MRI) gives a detailed insight into the brain microstructure including gray matter volume, density, cortical thickness, and white matter integrity. Functional MRI (fMRI) allows recording of physiologic parameters of a functioning brain through activation and connectivity measures with a high-spatial resolution. Studies have also identified several biomarkers for ADHD, in the areas of neurophysiology, neurochemistry, neuroimaging, and genetics. The differential diagnosis for ADHD includes disorders presenting with learning disabilities, speech problems, anxiety, vision and hearing problems, and oppositional defiant disorder (ODD). ADHD may co-exist with mood disorders, impulse control disorders, substance abuse disorders, and sleep disorders. Treatment Neuroimaging (MRI & fMRI), Intelligence Quotient (IQ) & other neuropsychologic tests, and Electroencephalogram (EEG) maybe used as adjunct diagnostic tools but are not recommended for routine use. Several national and international guidelines on management of ADHD exist. For pre-school aged children with ADHD, behavioral therapy is the first line of treatment, however, pharmacotherapy is the mainstay of treatment for older children and adults. The FDA-approved drugs for treating ADHD include stimulants – amphetamine & methylphenidate. Additionally, atomoxetine, α-2 agonists, and tricyclic antidepressants (TCAs) are used, off-label to treat ADHD. The non-pharmacologic treatment modalities have demonstrated a considerable success rate in the management of ADHD, especially in pre-school aged children. These comprise: Behavior management interventions (parent-training, classroom intervention, and peer-based intervention); Training interventions (cognitive behavioral therapy/CBT, neurofeedback, virtual- and augmented reality-based training educational games/programs, organizational & skills training); Physiologic interventions (physical exercise, and yoga); Integrative medicine (mindfulness, Tai Chi, hypnosis, dietary intervention, and meditation). Studies report a significant negative impact of ADHD on the quality of life in the affected individuals including both children and adults. However, benefits of early therapeutic intervention in children and pharmacotherapy in adults have been proven to improve the quality of life of ADHD patients. Written By: Manasa Tata, M.D.S. & Lawrence D. Jones, Ph.D

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Putting the “Informed” in Informed Consent

Putting the “Informed” in Informed Consent

“Informed consent is not a signed piece of paper bur, rather, the fluid, continuous process by which a researcher informs the subject in detail of what he or she proposes to do, why it is being proposed, and what possible consequences the experiment carries.” -Harriet Washington, Medical Aparthaid History of Informed Consent Up until the end of World War II, physicians and scientists were able to conduct research on patients without their permission, and sometimes even without their knowledge. Horrific medical experiments performed by researchers under the Nazi regime during World War II were captured and tried for their crimes during the Nuremberg Trials. The judges and doctors representing the prosecution produced the Nuremberg Code, a set of research ethics principles for human experimentation, which was adopted by the United Nations in 1948. The first of its kind, this document laid out the essential components of research involving human subjects, with its first point being “voluntary consent.” While the Nuremberg Code was a step in the right direction, it was never put into law or made a regulation by governing bodies, and unfortunately, this allowed some of the most infamous cases of research, without the consent of patients, to make their way into the history of clinical research. Researchers continued to escape punishment for their unethical research practices during this time by using marginalized groups such as African Americans, orphans, developmentally disabled individuals, mentally ill patients, and those in a class having the lowest social rank or standing due to low income, lack of skills or education. The people in these groups were often unable to decide whether they wanted to participate in certain “research trials”, and researchers justified their unethical behavior citing the work would be for the greater good of society. Additionally, people of a higher status and/or position of power generally did not care about these groups of people. Since the Nuremberg Code did not have legal authority, these individuals had no protections in place that are commonplace today. A Worst Case Scenario One of the most famous cases of clinical research, the Tuskegee syphilis study, actually began before the Nuremberg Code was published, and continued into 1972. This study recruited hundreds of African American men with syphilis, though they were not aware that what they had was syphilis. Indeed, they were told they had “bad blood.” The goal of the study was to study the progression of the disease without treatment, which was not very effective until the mid-1940s when penicillin became available. However, even when penicillin was promoted as the best-known treatment for syphilis, the researchers opted to continue to passively observe these men rather than treating them, which resulted in many men dying, going blind, or developing other health problems as their disease progressed. Had informed consent been a common and required practice for clinical research, these men would have been informed of their syphilis infection, saving their wives from contracting it and their children from being born with congenital syphilis. The researchers would also have been required to inform them that they now had a treatment, penicillin, sparing them from the agony of the disease progression. The study was finally shut down in 1972 after a journalist published an article about the study, prompting an advisory panel to look into it and deemed it “ethically unjustified.” Since then, the Belmont Report and the International Conference on Harmonization (ICH) have developed guidelines for human subjects research, and federal regulations have been established through the Food and Drug Administration (FDA) and the Department of Health and Human Services (HHS). Researchers now face legal complications and potential loss of their license to practice medicine and/or perform clinical research if they do not comply with these regulations. These regulations implemented practices such as Institutional Review Boards to oversee study protocols, financial disclosures for those involved in research, and informed consent. What Does Informed Consent Look Like? Even if someone has never been in a clinical research study, they have likely encountered the informed consent process during the course of regular medical care, as informed consent is required before undergoing procedures, even minimal risk procedures such as wisdom teeth removal. The consent will outline the procedure, its risks and benefits, and potential side effects. With the exception of emergencies, it is generally required that a patient sign a consent form before undergoing a procedure in the United States. While consent forms may be rather standardized for well-established medical procedures, consent forms can differ in many ways in the scope of clinical research due to the novel nature of research. For this reason, consent documents go through rigorous scrutiny before making their way into the hands of patients. The consent document itself must contain several points to truly be “informed.” These include describing the nature of the research, potential benefits and risks, alternative treatments, and letting the participant know how the research team will be involved with the patient’s care during the time of the project. Patients are to be given ample time to review a consent document and ask questions or raise concerns to the research team before signing the consent form and enrolling in a research project. For clarity no research procedures, even those as simple as getting a patient’s height and weight, should be performed before the consent is signed. Important Considerations Though informed consent is standard practice, it can look different depending on a number of factors. For example, someone who is unable to read or write will still be allowed to consent to a study but must have an impartial witness (someone not affiliated with the study or related to the patient) present to read the consent to them. Additionally, researchers and research sponsors have made strides to include demographics in their study that are representative of the overall population. They must include individuals from different racial and ethnic backgrounds, many of whom come from different cultural backgrounds and practices. Most institutions now have medical interpreters trained to assist patients in their medical care and research, but it is also vital to have staff familiar with the cultural factors that may come into play when consenting patients from a different background. This will help ensure that patients are not feeling coerced and that they understand the research being presented to them. One of the most common considerations in informed consent is whether or not a patient has the capacity to consent, which is an individual’s ability to understand and decide about participation. Capacity to consent can vary due to mental disorders (i.e. schizophrenia, dementia, developmental delays), neurological conditions (Alzheimer’s disease, stroke, head trauma), substance abuse, and even use of certain medications. In instances where researchers believe an individual does not have the capacity to consent, they will go through the informed consent with the patient’s legally authorized representative (LAR), who is someone related to or has a close relationship with the patient and can make decisions that are in the patient’s best interest and that are believed to be what the patient would want. LARs are critical in research, as they allow researchers to include patients who may not have the capacity to consent, so that progress can be made on understanding and/or treating their condition. Lastly, there exist situational factors that may influence someone’s willingness to participate in a research study. Many clinical trials include compensation that can vary from hundreds to thousands of dollars, and researchers must pay attention to a potential subject’s motive to participate to ensure that people are not just participating for the compensation. Scrutiny must also be given in terms of a patient’s situation and state of mind. For instance, someone who has just been diagnosed with an incurable disease may not be in the best state of mind to think through a consent form and commit to a clinical trial. Researchers must take account of all of these considerations and countless others. Looking Forward The past injustices resulting from a lack of informed consent from patients have shed light on the value and importance of informed consent . Modern clinical studies still have the same goal of advancing medical science for the benefit of human beings, but clinical researchers and patients are equal stakeholders in these studies. A thorough informed consent process is beneficial not just for patients, but for researchers as well. Patients who understand the research they’re participating in are also less likely to withdraw from the study, as some of the reasons participants withdraw include schedule conflicts, side effects, and a misunderstanding of expectations, which are topics that should be discussed during the informed consent process of a study. When patients understand the study and adhere to what they’re asked to do, the resulting data will likely be useful, clearer and more comprehensive. This in turn, will provide better care for patients and better science for researchers to continue to study disease and develop treatments. Written by Amanda Wilburn, BA

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Turner Syndrome

Turner Syndrome

Turner Syndrome.. What is it? Turner syndrome is a rare and random genetic disease afflicting only females. Turner syndrome affects multiple organs. There are 23 pairs of chromosomes (=46 chromosomes; 45, XX, or XY) within each cell of the body. In Turner syndrome, one chromosome in the form of a sex chromosome called the X chromosome is either missing completely (45, XO) or partially with loss of certain functions. Mosaicism is another event that leads to Turner syndrome. The prevalence of Turner syndrome is observed is approximately ranging from 1 birth in 2000 - 2500 live female births. Unfortunately, due to delayed diagnosis of the Turner syndrome, there has been an adverse impact on females as the age progresses. The patients show impaired sexual function, and almost half of the patients show sexual inactivity. In adolescent females, the disease often manifests with delayed puberty, secondary to premature ovarian failure. The typical feature is “Streak gonads”, which is a form of absence of cells in the tissue. Manifestations of Turner syndrome Turner syndrome was first defined and described by Oklahoma physician Henri Turner in 1938. The symptoms vary as the age progresses. Typically, in the female newborn, Turner syndrome can manifest with congenital lymphedema of the extremities of the body such as hands and feet, dysplasia of nail or presence of abnormalities within nail tissue, webbed neck, broad chest with widely spaced nipples, narrow and high-arched palate (a narrow, tall roof of the mouth or the hard palate), and short fourth metacarpals or metatarsals, hearing loss, kidney dysfunction, and eye or vision-related abnormalities are common associative manifestations of Turner syndrome. The prenatal diagnosis relies heavily on the sampling of chorionic-villus or amniocentesis. A karyotype analysis should be done with peripheral blood mononuclear cells first. Even if the initial karyotype testing does not indicate Turner syndrome, a second karyotype should be performed utilizing a different tissue such as skin, bladder epithelial cells, or buccal mucosa cells. Fluorescence in situ hybridization (FISH) study is an option in addition to the karyotype, which can detect abnormality in part of the DNA sequence or chromosomes regarding missing chromosomal matter. MRI, ultrasonography, and cardiovascular evaluation along with marker tests of AMH and TSH levels should be employed for confirmation of the disease. Turner syndrome complications and management Turner syndrome is usually not inheritable but is a random event during reproduction. During the formation of reproductive cells in a parent, a random event leads to improper segregation of the sex chromosome X in dividing cells to form gametes. Turner syndrome patients have an increased risk of complications and comorbidities such as cardiovascular malformations, diabetes, pulmonary or lung-related venous abnormalities, and coronary artery diseases. Patients with Turner syndrome also show an increase in death rate due to pneumonia, epilepsy, liver disease, as well as kidney disease. The management of Turner syndrome is symptomatic. Management comprises age-appropriate treatment of the symptoms, complicacies, and comorbidities of Turner syndrome, to improve the quality of life of the patients. Growth hormone therapy is the most promising therapy along with estrogen therapy in Turner syndrome. Patients' quality of life To maximize fertility preservation, all Turner syndrome women should be evaluated in childhood. Preservation is needed early in life as the majority of women will have their ovarian reserve exhausted before adulthood due to the disease. Growth hormone therapy can occasionally expose underlying scoliosis (a condition defining a one-sided curvature of the spine frequently diagnosed in adolescents). Hence, the patients should be monitored closely every six months, regarding the position of their spines during the treatment and if needed, they should consult an orthopedic surgeon for possible corrective surgery. Some other quality of life issues with patients taking necessary growth hormone therapy are adverse effects of intracranial hypertension, pancreatitis (inflammation of the pancreas), and slipped capital femoral epiphyses (a condition defining rearrangement of bones on hip joints during teens and pre-teens years of growth). If the patient needs further assistance for growth even after administration of growth hormone, oxandrolone may be administered, or pubertal induction can be presented. Patients' care Support groups recommend the use of Turner syndrome-specific transition tool kits such as the one improved by the Endocrine Society, Hormone Health Network, and Turner Syndrome Society of the US, specifically the American College of Physicians Pediatric to Adult Care Transitions toolkit. For best care, it is recommended that a dual-energy X-ray absorptiometry or DXA scans at least in 5 years along with continued estrogen supplementation until ordinary menopausal age should be done; it can also manage bone health in women with Turner syndrome. Adequate counseling in adult Turner syndrome clinics should be performed for psychosocial issues, career options and sustenance, sexual function, contraception, fertility options as well as interpersonal relationships. Multidimensional treatment and early diagnosis are needed to control the morbidities and further mortalities. The research needs to emphasize developing targeted therapeutics to help manage the disease in the future. Written by: Souvik Datta, Ph.D., Manasa Tata, M.D.S., & Lawrence D. Jones, Ph.D.

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Multiple Sclerosis

Multiple Sclerosis

What is Multiple Sclerosis (MS) Multiple sclerosis (MS) is the most common non-traumatic disabling disease that typically affects young adults. It is a chronic, autoimmune (disease caused by antibodies or lymphocytes produced against substances naturally present in the body), inflammatory, neurodegenerative (causing destruction/degeneration of the nerves) disease of the central nervous system (CNS). MS presents with progressive demyelination (damage to the protective covering, called the myelin sheath, present around the nerve fibers; a nerve fiber and its myelin sheath are comparable to an electric wire and its outer protective covering, respectively) and subsequent axonal (the long threadlike part of a nerve cell along which impulses are conducted from the cell body to other cells) degeneration. This disease has a huge impact on the quality of life of the affected individuals, both functionally and financially. Pooled Incidences The findings of the 3rd edition of the Atlas of MS (2020) that were derived from pooled incidence rates across 75 reporting countries, are as follows. The estimated number of people with MS worldwide increased from 2.3 million in 2013 to 2.8 million in 2020. The pooled incidence rate across 75 reporting countries was 2.1 per 100,000 persons/year. Recognition of pediatric-onset MS has increased substantially with ≥ 30,000 cases in individuals under the age of 18. Globally MS is twice more prevalent in females than males. Triggers of MS Development Vitamin D deficiency, diet, obesity in early life, and cigarette smoking have been reported to trigger the development of MS; low Vitamin D levels and cigarette smoking have a strong association with MS. MS may also be triggered by certain infections, such as, Epstein-Barr virus (EBV) infection. Carriers of the HLA DRB1*15 allele (an allele constitutes one of two or more versions of a gene, placed on the same chromosome) are 3 times more susceptible to MS than non-carriers. Additionally, IL2RA, IL7RA, CD58, TYK2, STAT3, and TNFRSF1A have been linked with MS. Although a few studies suggest that vaccination against yellow fever might increase the relapse rate of MS, the existing evidence is non-confirmatory of this association. The Pathophysiology of MS The pathophysiology (the course of development of a disease) of MS remains poorly understood although several explanatory mechanisms have been proposed. The most popular theory, proposed by Osterman et al. in 1975, states that partially demyelinated axons favor the ectopic generation of spontaneous nerve impulses which transversely spread to other axons within the nerve fiber tracts, ultimately manifesting as symptoms or attacks. Alternatively, an inflammatory component in MS has been proposed based on the favorable response to steroids in many reported cases. Furthermore, a third mechanism – ion channel dysfunction in partially demyelinated axons, has been proposed, which is supported by the proven high efficiency of acetazolamide and anti-epileptics (anti-seizure medicines) in reducing the frequency of MS attacks. However, these theories remain purely speculative, and a combination of these factors cannot be excluded either. Additionally, the possibility of other unknown phenomena leading to the development of MS, exists. Essentially, MS is a chronic neurodegenerative disease that is autoimmune in nature and targets the CNS. It is mediated by autoreactive lymphocytes that cross the blood-brain-barrier (BBB) and enter the CNS where they cause nerve demyelination, axonal damage, and subsequent neurological dysfunction due to the formation of multiple plaques or gliotic scarring (areas of the nerve fiber where the myelin is stripped-off) in the gray and white matter of the brain and the spinal cord; these processes comprise the hallmarks of the pathophysiology in MS. The plaques in MS are found mainly in the white matter around the brain-ventricles, optic nerve and its tract, corpus callosum, cerebellar peduncles, long tracts and the subpial region of the spinal cord and the brainstem. The Spectrum of MS The affected individuals, in most cases, present with an initial relapsing-remitting disease course that is followed by a progressive phase which lasts for several years. In pregnant women with MS, a transient improvement in MS relapse rate is seen in the 3rd trimester, which is followed by increased MS relapse rate, at around 3 months after delivery; studies have attributed this fluctuation to the natural immunomodulation brought about by sex hormones and the placental hormones in pregnant women. MS is divided into 4 subtypes based on the clinical disease pattern which appear to have dissimilar underlying pathophysiology – RRMS (Relapsing-Remitting MS), SPMS (Secondary Progressive MS), PPMS (Primary Progressive MS), and PRMS (Progressive Relapsing MS). This may be suggestive of MS being a heterogenous group of related diseases. MS is a spectrum of diseases ranging from less aggressive, treatable forms to highly aggressive fatal forms. MS Diagnosis The diagnosis of MS is based on the presence of CNS lesions that are disseminated in time and space (i.e., occur in different regions of the CNS, at least 3 months apart), with no better explanation for the disease process. Clinical presentation remains the gold standard for diagnosing MS, which is supported by the findings of investigations comprising neuroimaging (mainly magnetic resonance imaging – MRI), sensory evoked potential testing, cerebrospinal fluid (CSF - clear fluid that surrounds the brain and spinal cord) analysis, and serologic tests (examination of blood serum). The symptoms of MS depend primarily on the anatomic location of the plaques along the neural axis and include paraparesis (partial inability to move one’s legs) or paraplegia (paralysis of the legs and/or lower body), tremor, ataxia, aphasia, dysarthria (difficult/unclear speech), dysphagia (difficulty/discomfort in swallowing, as a symptom of disease), bladder and bowel problems, visual defects, and cognitive decline. Unfortunately, there is no cure for MS. The available therapies aim at improving the health-related quality of life (HRQoL) in affected individuals. The management comprises disease-modifying medications, symptomatic cure, and rehabilitation. The focus of research in MS is to understand its immunopathology, to identify new targets, and develop precision therapies to treat MS. Written by: Manasa Devi, M.D.S. & Lawrence D. Jones, Ph.D.

Funding announcement

CureScience announces patient centric support through Cureosyti program

Grant Opportunities $2,500-$25,000 CureScienceTM Institute is engaged in patient-centric research and development towards the discovery, development and production of novel medicines in a variety of therapeutic areas including but not limited to oncology, immunology and regenerative medicine. CureScienceTM, a 501(c)(3) nonprofit organization, focuses on research and development, patient development and the long term goal of providing quality health care products. CureScienceTM establishes and funds its own programs and also provides grants for other 501(c)(3) organizations engaged in patient care. CureScienceTM is seeking innovative patient engagement proposals that address patient care, patient support and/or patient education. Funding Amounts: Grants will be awarded in the amounts of $2,500-$25,000. The maximum funding amount for each patient engagement grant is up to $25,000. Grant information and applications available at [https://www.curescience.org/grants]

Team announcement

Dr. Boris Reznik of Biorasi and Venvalo Group joins CureScience as Advisor

Dr. Boris Reznik of Biorasi and Venvalo Group joins CureScience as Advisor

CureScienceTM Institute, a San Diego-based 501(c)(3) non-profit organization dedicated to accelerating novel curative therapies, announced today that Dr. Boris Reznik, has joined the organization's Advisory Board. Dr. Reznik is a veteran of multiple startups and has a strong track record of building companies across a diverse set of technologies-based industries with biomedical sciences being one of his primary focuses. Boris Reznik is the Chairman of Venvalo Group, venture value optimization firm. During his career, Dr. Reznik founded and built technology companies into market leaders and successfully dealt with both Fortune 500 and emerging companies as clients and partners. He has been a lead or co-investor in startups and mid-market firms and has participated in M&A transactions ranging from Millions to Billions. Dr. Reznik has a depth of experience in processes and systems – a unique perspective in the drug and device development world. As the Chairman of Biorasi, a global CRO, he led development of novel therapeutics, from filing IND to getting approved NDA, for companies ranging from startups to Big Pharma. "I am delighted to welcome Dr. Reznik to our Advisory Board," said Dr. Shashaanka Ashili, CEO of CureScienceTM Institute. "He brings a unique experience in accelerating drug and device development for life sciences companies. We at CureScienceTM look forward to benefiting from Dr. Reznik's counsel as we work towards developing personalized therapeutic approaches." "CureScienceTM is a nonprofit institute with a strong team of professionals and an agile approach to novel therapeutics development," said Dr. Reznik. "I am impressed by CureScienceTM 's unconventional methodologies to improving patients' lives. With the rapidly changing life sciences industry, partnerships and collaborations are key to advancing science and I look forward to working with the CureScienceTM team on this front." "Dr. Reznik's experience in novel therapeutics development will be valuable to the researchers at CureScienceTM as we navigate the complex world of translating innovations and discoveries into clinical applications," said Dr. Tom Ichim, Director, Clinical Sciences at CureScienceTM. The Institute is committed to developing a preemptive and personalized approaches based on the early diagnosis, immunology, and regenerative medicine. To this end, CureScienceTM is focused on accelerating research and development programs internally and through the establishment of strategic partnerships with academic and industry partners. More information on CureScience at [www.CureScience.org] More information on Boris Reznik at [www.venvalo.com] [https://www.prnewswire.com/news-releases/curescience-institute-names-dr-boris-reznik-as-advisory-board-member-301233633.html]

Product announcement

Advancing healthcare through co-creation

Advancing healthcare through co-creation

With a philosophy of “cocreate, not compete,” the Sorrento Valley-based nonprofit CureScience Institute is working to advance health care treatments that are more personalized to the patient. CureScience started with a focus on brain cancer research. It is now supporting work to develop curative therapies for cancer, immune and neurological disorders, in addition to using regenerative medicine to cure many different types of human health issues. “We expanded the mission and vision,” said Shashaanka Ashili, CureScience’s CEO. “Now we are looking to develop the framework where we can look into multiple disorders, multiple diseases.” He said a key component of that goal is developing a more holistic approach to putting vast quantities of data to use. “Google has some data, Apple has some data, Facebook has some data, some others have some data,” Ashili said. “Then you have the whole health care system which also has its own silos. Is it time to ask, can we put all these things together? And if so, how?” He added, “The resounding answer to that is yes. That time was yesterday.” The scope of CureScience’s work also includes COVID-19, which has killed more than 1 million people worldwide with vaccines still in development. “By March it struck us all that nobody’s escaping COVID,” Ashili said. “It’s going to disrupt every business and it’s going to change everything.” CureScience’s active mesenchymal stem cell research program could have implications for COVID-19 treatments, and could also yield insights into treating Alzheimer’s disease, which still has no effective treatments that can reverse symptoms. Other unmet patient needs that CureScience would like to address include noninvasive ways to diagnose and monitor the treatment of brain tumors. The institute is also supporting immunotherapy, in which the body’s immune system can be better deployed to fight cancer. The institute is also working in many other areas to bring about more “patient-driven” ways to improve health care. “In the next two years, we should have a framework where we can say this is what patient-driven health care looks like,” Ashili said, adding that the framework also has to showcase the value to patients. “Once we have that, the sky is the limit,” he continued. To help advance its work, CureScience is holding a virtual donor gala on Nov. 21. The event will feature an auction and guest speakers. The institute is located at 10225 Barnes Canyon Road. For more information, visit curescience.org [https://www.delmartimes.net/news/health-science/story/2020-10-27/curescience-ceo-wants-to-cocreate-not-compete-to-advance-health-care]

Team announcement

Dr. Marincola joins CureScience Advisory Board

Dr. Marincola joins CureScience Advisory Board

CureScience™ Institute, a San Diego-based 501(c)(3) non-profit institute dedicated to accelerating novel curative therapies, is pleased to announce that Francesco Marincola, M.D. will join the Advisory Board. "We're honored to have Dr. Francesco Marincola on the advisory board," said Dr. Shashaanka Ashili, CEO of CureScience™ Institute. "As a world leader in tumor immunology, tumor microenvironment, and translational research, Dr. Marincola's experience will be invaluable in advancing the CureScience™ mission and positively impacting patients' lives through development of personalized therapeutic approaches," said Dr. Feng Lin, Lead Immunology Scientist at the Institute. Dr. Marincola is currently Chief Scientific Officer and President at Refuge Biotech where he leads the development of a cell therapy platform. Prior to joining Refuge Biotech, he served as a distinguished research fellow and strategist for immune oncology discovery at AbbVie. In addition, Dr. Marincola developed and led a genetic research institute at Sidra Medical and Research Center in Qatar; and served as Chief of the Infectious Disease and Immunogenetics Section in the Department of Transfusion Medicine at the Clinical Center of the NIH in Bethesda. Dr. Marincola received his M.D. from the University of Milan, and completed his surgery training at Stanford University. He has published more than 600 original articles, reviews, editorials, and books. CureScience™ Institute is committed to developing a preemptive and personalized approach to medicine based on early diagnosis, immunology, and regenerative medicine. To this end, CureScience™ is focused on accelerating research and development programs internally and externally through the establishment of strategic partnerships with academic and industry partners. The addition of Dr. Marincola will particularly help drive the immunology program at CureScience™. "CureScience™ has a strong foundation in place with a talented and multidisciplinary team of scientists," said Dr. Marincola. "I'm excited to join as a member of the advisory board working with researchers to advance the clinical development of novel approaches." For more information at [www.CureScience.org] Media contact: Lawrence D. Jones, Ph.D. CureScience™ Institute (858) 800 CURE (2873) [https://www.prnewswire.com/news-releases/curescience-institute-announces-dr-franco-marincola-as-new-advisory-board-member-301123939.html]

Team announcement

The CureScience Institute appoints Gary Shields to Advisory Board

The CureScience Institute appoints Gary Shields to Advisory Board

Venture capitalist Gary Shields has been added to the Advisory Board of medical non-profit, The CureScience Institute. Mr. Shields brings expertise to help guide CureScience’s focus on providing therapies based on data- and patient-centric approaches, as well as a new need for COVID-19 treatments. "Data-centricity and patient-centricity are the core tenants of our mission and vision. Our three-pronged approach of bringing innovations, patient engagement, and care management is essential to realize the goals of precision medicine," said CureScience Interim CEO Dr. Shashaanka Ashili. "Gary brings decades of venture capital experience, and his insights would be instrumental in fostering relationships with innovators." Mr. Shields is the founder of venture capital company Avtech Ventures, and co-founder of investment bank Flemming Lessard & Shields. An experienced investment banker, he brings more than 30 years of experience in capitalization, investment and transactions. "The Institute's unique value of empowering the patients by making them the stakeholders within the ecosystem is very promising and exciting," said Mr. Shields. "Working with startups and building a translational ecosystem is critical to achieving the goals of precision medicine."

Other announcement

BCRI expands mission and vision

SAN DIEGO, July 16, 2020 /PRNewswire/ -- The CureScience™ Institute, a non-profit organization, focused on the acceleration of curative therapies for unmet needs, announced today a strategic expansion of its vision and mission. The Institute's initial focus was on translational research in oncology and neurological disorders. Based on recent successes, the Board of Directors has decided to strategically expand the Institute's vision to leverage early diagnostics, regenerative medicine, and immunotherapy to enable a new generation of precision medicines. The Institute is expanding research activities with a strategic focus on establishing transdisciplinary ThinkTanks to bring thought-provoking ideas to the forefront and to accelerate therapeutic and translational research by developing a collaborative ecosystem of academic, industry, and patient-centric stakeholders. The focus will be on exploring "out of the box" solutions to address the bottlenecks in clinical translation and unmet needs in the delivery of care. Crucially, the Institute will be the catalyst that is needed to establish feasibility and clinical implementation models of these new ideas. In addition to autoimmune and neurological disorders, different disorders will be adopted to explore solutions through transdisciplinary approaches. Strategically the Board of Directors chose to adopt COVID-19 as the current disorder theme due to its global impact. "I am proud to be part of this initiative, where the focus is on developing therapies through transdisciplinary approaches. The two key pieces, 'ThinkTanks' and 'Disorder themes,' are unique to our approach in addressing unmet needs," said Dr. Shashaanka Ashili. Regardingclinical implementation models, the Institute will engage patients and focus on developing patient engagement models to support the "disorder themes." As a core focus, the Institute will be working with startups and other corporate stakeholders. The goals of this initiative are to enable novel technologies to strengthen early diagnosis and build a pipeline of patient-centric therapeutic repositories. The Institute has already participated in enabling startups with a focus on establishing a pipeline of cancer therapeutics. To accomplish its mission, the Institute has expanded its Board of Advisors recruiting international scientists, including Dr. Jocopo Annese, founder of The Brain Observatory. "The Institute's approach of rapidly redirecting resources and orchestrating ThinkTanks towards priority focus areas is novel and unique in biomedical research. As a member of the Advisory Board, I am looking forward to contributing to this important challenge," said Dr. Jacopo Annese More information at www.CureScience.org [https://www.prnewswire.com/news-releases/curescience-institute-expands-vision-and-advisory-board-to-accelerate-innovation-301095253.html]

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