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Wednesday, April 22, 2020

COVID 19 : A structural insight.

       Understand the problem, give it a thought ..and act accordingly to find a solution towards it..


This holds very much true in case of the recent 
pandemic COVID-19.What started off as a unusual respiratory  infection, in late 2019 reported from Wuhan,China..has come on to affect 2,627,630 to date. The source of the infection identified as a novel coronavirus has emerged related to Severe Acute Respiratory Syndrome ( SARS ).  
                                                                              
Similar to other coronaviruses, SARS-CoV-2 particles have a spherical structure and have proteins which have spike like structure protruding from their surfaces. Mechanism of action involves the protein spike like structures attach onto human cells, then undergo a structural changes that enables the viral membrane to fuse. And similar to any other virus, this new configuration enables the viruses to multiply. These spikes bind to receptors on the human cell surface called angiotensin-converting enzyme 2 ( ACE2 ).

Cryo electron microscopy method was used to image these biological molecules ( Zhou et al, 2020). The researchers found that the bond between SARS-CoV2 and ACE2 has a profound similarity to the pattern of virus that had caused the 2003 SARS outbreak. However, the difference lies with the amino acids which bind these two molecules. The importance of these bonds and the difference in the structural configuration somehow impacts its transmission. Although SARS causing viruses focused on upper respiratory tract infections, the SARS-CoV2 shows its lethal power by interaction with other receptor cells as well.



The very structural configuration of SARS-CoV 2 and its interaction with the human cells project the key and lock which needs to be understood for anti-viral drugs production. As most anti-virals focus on halting this very interaction, so that targeted viral entry can be avoided. 



SARS-CoV-2 spike proteinAtomic-level structure of the SARS-CoV-2 spike protein. The receptor binding domain, the part of the spike that binds to the host cell, is colored green. UT Austin, McLellan Lab


PiCo Vacc ?


A study funded by NIH's National Institute of Allergy and Infectious Diseases (NIAID) published the atomic- level structure of the SARS- CoV 2. It was found the SARS- CoV 2 spike was 10-20 times more likely to bind ACE2 on human cells than the spike from the SARS virus from 2002. Which might be a potential cause for its easier spread than the earlier virus.

It was also reported that antibodies used for 2002 SARS could not successfully bind to the SARS-CoV 2 spike proteins, suggesting a more targeted study for the potential vaccine and antibody-based strategy which has to be unique to the new structural configuration of the virus.

What seems to be a recent advancement towards the drug discovery against this novel virus, which has led to potential disruption of the mankind comes in the form of a inactivated vaccine PiCo Vacc putforth by  Qiang Gao et al, 2020. The authors concluded that a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc) confers complete protection in non-human primates against SARS-CoV-2 strains circulating worldwide by eliciting potent humoral responses devoid of immunopathology.



Use of convalescent plasma? Antiviral drug/steroid ?


With novel coronavirus, the degree of illness varies, ranging from asymptomatic to fulminant and fatal. What seems to be the way in regards to this illness, involves sepsis, acute respiratory distress syndrome (ARDS), and/or multiple organ failure which are not unique to coronavirus.
 This host response to infection has been well described and involves a complex interaction of cytokine storm, inflammation, endothelial dysfunction, and pathologic coagulation.

The pathway is common to multiple inciting events and has been the target of treatment for years, with therapeutic plasma exchange uniquely offering benefit on multiple levels by removing inflammatory cytokines, stabilizing endothelial membranes, and resetting the hypercoagulable state. 
Convalescent plasma therapy for SARS-CoV-2 has been brought into effect considering the effectiveness of plasma therapy.

THERE IS NO SINGLE ANSWER RATHER A COMPLEX SYNERGISTIC EFFECT MIGHT BE FRUITFUL..

The targets of COVID-19 treatment should be largely divided into two categories. First, it is aimed at the virus itself. The first thing you can think of is destroying the body of the virus. However, destroying the virus itself is a concept of disinfection and is too dangerous for humans to apply. As a therapeutic agent, there are drugs that inhibit RNA-dependent RNA polymerase by inhibiting the replication of viruses (e.g., remdesivir), or drugs that inhibit protease (e.g., lopinavir/ritonavir).





Another target is angiotensin converting enzyme 2 (ACE2), a gatekeeper and receptor for viruses to enter human cells. By raising the intracellular pH, glycosylation of ACE2 can be prevented to block the entry of the virus (e.g., chloroquine) or it can be prevented from binding to ACE2 in advance by sticking to the spike protein of the virus.

Considering the above treatment mechanisms, it can be seen that it is difficult to succeed with only one mechanism to treat COVID-19. Blocking a virus with antibodies is not enough to win the battle. We must also suppress the replication of the virus, and prepare for a cytokine storm that occurs during treatment.

 In conclusion, it makes no sense as to which of these treatment methods was a decisive factor in the successful treatment. Rather, it is necessary to combine all of these to engage in treatment.


It’s hard for people to focus on other people’s problems when we have our own fears — that’s human nature — but that’s exactly the opportunity to show human greatness in these moments. Until then, lets just prepare ourselves and take care of each other. 



Sources - as mentioned



Sources :

Convalescent Plasma Therapy for Corona Virus Disease 2019: a Long Way to Go but Worth Trying

A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19

A New Study Indicates Asymptomatic People are Still Highly Contagious 

The convalescent sera option for containing COVID-19

WHO

coronavirus.jhu.edu

Tuesday, October 8, 2019

Nobel Prize in Medicine Won For Profound Discovery of How Cells Sense Oxygen


The Nobel Prize in physiology or medicine was awarded Monday to three physician-scientists from the United States and Britain - William G. Kaelin Jr., Peter J. Ratcliffe and Gregg L. Semenza - "for their discoveries of how cells sense and adapt to oxygen availability.

"The discoveries by the trio illuminated what the Nobel Committee called "one of life's most essential adaptive processes," answering profound questions about how the body works and providing potential new therapeutic avenues to treat cancer and other diseases.
The three scientists, working independently, revealed the cascade of molecular events that allow cells to detect and respond to different levels of oxygen. That allows the human body to adapt to thinner air at high altitude by generating more red blood cells to carry oxygen.
But it can also go awry in disease, providing new targets for treatment: Cancer cells exploit these molecular switches to thrive, for example, and increasing cells' tolerance for low oxygen could offer a way to treat heart attacks and strokes.
"If you think of the main causes of death in the US, three out of five are related to lack of oxygen," including heart attack, stroke and respiratory diseases, said Isha Jain, a scientist at the University of California at San Francisco who was partially inspired to enter the field by the work being honored by the Nobel. "Understanding how the body senses and responds to low oxygen is pretty fundamental to all these diseases," she said.The predawn phone call from Stockholm announcing the award is the induction to a very exclusive club, and it kicked off a frenzied day of media interviews, standing ovations and requests to take selfies for scientists more accustomed to spending time in the lab than in the limelight. Semenza, a professor of genetic medicine at Johns Hopkins University, told a packed auditorium of colleagues and students that his scientific inspiration was a remarkable high school biology teacher, Rose Nelson, who is now deceased.
"She used to say to us, 'When you win your Nobel Prize, I don't want you to forget that you learned that here.' She just assumed that one of us was going to do that," Semenza said. "She was my inspiration, and I think that is the importance of teachers, to serve as that kind of spark."
Kaelin, a scientist at Dana-Farber Cancer Institute in Boston, said in a telephone interview that he awoke to the 5 a.m. phone call from Stockholm, wondering at first if it was a dream.
"My heart was racing in disbelief," Kaelin said.
Ratcliffe, director of clinical research at the Francis Crick Institute in London, was writing a grant proposal when he received the call.
The work began in the 1990s, when Semenza identified genes that turned on when oxygen levels were low to increase levels of erythropoietin (EPO), a protein that increases the production of oxygen-carrying red blood cells. (This is the same basic idea behind doping, in which endurance athletes try to increase their supply of oxygen-carrying red blood cells.)
An anemia drug that increases red blood cells by targeting this basic mechanism was recently approved in China.
Semenza's scientific paper describing the protein that responds to low oxygen has now been cited thousands of times, but he recalled that it was rejected from numerous top journals - a reminder that science builds on itself over time, and blockbuster discoveries that transform understanding are not instantly apparent, even to other scientists.
"We submitted to these so-called top-tier journals. They didn't find it to be of sufficient interest to warrant publication," Semenza said.
Today, some of the most exciting applications of the research are in cancer. The cells at the center of a tumor are able to thrive in an oxygen-deprived environment, far from blood vessels that carry nourishing oxygen.
Traditional chemotherapy or radiation treatments mostly kill the tumor cells on the periphery, not the ones at the center that have adapted to a low-oxygen environment, said Qing Zhang, a scientist at the University of Texas Southwestern Medical Center, who previously worked in Kaelin's laboratory. Those hardy cells that survive can metastasize to seed new cancers, one of the biggest challenges facing patients and oncologists.
Randall Johnson, a member of the Nobel Assembly, compared the molecular machinery the scientists discovered to a switch that ensures that the body always has the right level of oxygen.
"The prize is for this … rheostat or thermostat of the oxygen levels - a damper that you'd have on your furnace to let in more or less oxygen at any given time so that it's just right, so that the flame burns just right," Johnson said.
Although it has become clear that this line of research has medical applications, Kaelin said that the prize underscores the importance of doing research to follow curiosity and unravel basic biology. He and the other scientists hoped, but did not know, that unraveling how cells sense oxygen could spark ideas for new approaches for human diseases, including stroke and cancer. Kaelin and Semenza both received funding from the National Institutes of Health.
"This kind of research is increasingly under threat. It's much easier for fundraisers and policymakers to say we will support scientists, but … tell us how it will improve outcomes in five years," Kaelin said. "When you're doing real science, you have to be prepared to take the road where it takes you - and if you're doing science, it's hard to predict where the road is going to take you."
The three scientists will split the award, worth about US$900,000, equally.
2019 © The Washington Post
This article was originally published by The Washington Post.

Monday, October 7, 2019

$14m invested to create vaccine for debilitating periodontal gum disease

Denteric launch
Melbourne Dental School Head of School Mike Morgan, CSL Senior Vice President of Research Andrew Nash, University of Melbourne Vice-President (Enterprise) Doron Ben-Meir, COHR CEO & Director of Research Eric Reynolds, Member for Higgins Katie Allen and Brandon Capital Investment Manager Ingmar Wahlqvist at the launch of Denteric.
A vaccine for periodontal gum disease, which affects a third of all adults globally, is in development following a $14 million investment into newly-formed biotech company Denteric Pty Ltd.
The company was set-up to develop and commercialise the research outputs of a long-running programme originating from the University of Melbourne working in collaboration with CSL.
The announcement was made at the official launch of the University’s Centre for Oral Health Research (COHR).
The Series A investment comes from the Medical Research Commercialisation Fund’s (MRCF) Biomedical Translation Fund, a Commonwealth-backed fund managed by Brandon Capital Partners, CSL Ltd., Australia’s largest biotechnology company, and the University of Melbourne.
Denteric will focus on developing a therapeutic vaccine for treating periodontal disease, a debilitating and painful form of gum disease which affects one in three people globally. The disease damages periodontal soft tissue and alveolar bones, which support teeth, due to an accumulation of bacteria.
Moderate to severe periodontitis affects more than 50 per cent of Australians over the age of 65 and is associated with diabetes, heart disease, rheumatoid arthritis, dementia and certain cancers. Poor oral hygiene is the leading cause of periodontitis but there are currently no cures available.
University of Melbourne Professor Eric Reynolds, founder and CEO of the Oral Health CRC, now COHR, said the creation of Denteric is the perfect example of public-private collaboration within the thriving Melbourne Biomedical Precinct.
“My team has been developing this critical treatment for periodontal disease over many years at the University of Melbourne,” Professor Reynolds said. “Today, in a true partnership with the Australian Government and private capital, we have launched a company which will bring a Melbourne-developed gum disease therapy to market.”
MRCF CEO Dr Chris Nave said a treatment for periodontal disease is much-needed as the condition is highly prevalent and affects millions of people globally.
“Current methods for treating periodontal disease are archaic and painful. Looking at the science and market opportunity for Denteric, the Porphyromonas gingivalis (Pg) vaccine research program has great promise and the vaccine would be a blockbuster if it comes to market,” Dr Nave said.
CSL Limited Senior Vice President of Research Dr Andrew Nash said it’s exciting to see the treatment progress to the next stage of development.
“We’ve seen significant potential in this treatment from the early days and we are pleased to continue our support for the program through Series A investment into Denteric. The potential to address unmet medical needs with a new vaccine is very important.”
University of Melbourne Deputy Vice-Chancellor (Research) Professor Jim McCluskey said: “We welcome the significant investment in this critical research, which has the potential to change the lives of people around the world.”
The Series A investment will go towards progressing the Pg vaccine research program. It was a lead program at the Oral Health CRC, which was funded under the Australian Government’s Cooperative Research Centres (CRC) Program from 2003 to 2018.
The Oral Health CRC, which has long been supported by funding from the Victorian Government, Australian Government, CSL and the University of Melbourne, is no longer part of the CRC Program. As part of a new agreement, the CRC has been transformed into the University of Melbourne’s Centre for Oral Health Research, which will come under the Melbourne Dental School.
Those who worked on the Pg vaccine research program as part of the Oral Health CRC will continue to support the established collaborative research and commercialisation relationship with Denteric.
The company is looking to commence its first clinical trial in humans in the next two to three years.


SOURCE 

Friday, September 27, 2019

Keep looking up…there may be a rainbow waiting for you.

Nearly 450 million people worldwide are currently living with a mental illness, yet nearly two thirds of people with a known mental illness never seek treatment. 




Due to the stigma associated with mental illness, a lack of awareness, and limited access to professional help, only 10-12% of these sufferers will seek help.

Support, judgement, fear
The study revealed three broad segments of people based on their attitudes towards mental illness.


People’s understanding of mental health
The study showed that while 87% of the respondents showed some awareness of mental illness, 71% also used terms associated with stigma.


This shows that stigma and awareness are two separate issues although interlinked.
They need to be addressed in parallel in order to tackle the burden of mental illness in India. If individuals continue to view mental illness with apprehension and resistance, it will remain difficult for people with mental health concerns to seek the support they require due to the fear of being labelled or judged.
People's attitudes towards those affected


Social inclusion
A majority of respondents appreciate the importance of social support for people with mental illness, but while 68% agree that we have a responsibility to provide the best possible care for sufferers, the number of people who believe no one has the right to exclude people with mental illness from their neighbourhoods is comparatively lower (57%).


What people feel about sufferers
Respondents were asked about their feelings towards people with mental illness. While there exists widespread sympathy towards sufferers, with more than 75% of participants stating they would always feel sympathetic towards them, they also exhibit feelings of fear (14% would always be fearful), hatred (28% feel hatred sometimes or always), and anger (43% feel angry sometimes or always) towards people with mental illness. More than a quarter admitted that they would always be ‘indifferent’ towards people with mental illness.
This admission of the general public to their feelings towards people with mental illness again indicates the prevalent stigma in society.


Next steps
The need of the hour is to sensitize and educate individuals about the signs and symptoms of mental illness while normalizing the idea of seeking support for themselves and their loved ones.
There needs to be more open discussion and dialogue with the general public, and not just experts on this subject, which will in turn help create a more inclusive environment for people with mental illness.




Although it may seem bizzare to some, it does come to light..how much of our life we spend worrying about stuff that doesnt matter. The best way to fight and sail through would be to  life into put  perspective and see what matters.


Source :

YOUR LIFE YOUR VOICE
The Live Love Laugh Foundation

Wednesday, October 4, 2017

Indian doctor becomes WHO’s Deputy Director General

The World Health Organization has an Indian doctor for its new Deputy Director General for Programmes. Dr. Soumya Swaminathan, the director general of the Indian Council of Medical Research has been appointed as the same.
A paediatrician by trade, Swaminathan is famous for her research in tuberculosis. The position she now adorns in the WHO is the second highest position in the global organization. It comes only below the Director General. Dr. Tedros Adhanom Ghebreyesus, who took the post in July is the Director General.
Swaminathan's is also the highest position adorned by an Indian in WHO’s history.
DOCTOR RESPONSIBLE FOR RAISING INDIA’S FOCUS ON TB RESEARCH
The doctor comes with over 30 years of experience in clinical research. She used to be the director of the National Institute of Research in Tuberculosis, Chennai.
She has been largely responsible for heightening the focus on tuberculosis research in India. To this end, she even created a consortium called “India TB Research and Development Corporation.” The organization aimed to bring under the same umbrella all the leading national and international stakeholders to develop new tools that could combat TB including diagnostics, vaccines and drugs.
In a related statement, the WHO said that the new team includes people from 14 different nations. It “includes former ministers of health, some of the world’s leading physicians, scientists and researchers, and programmatic experts in universal health coverage, health emergencies, communicable and non-communicable diseases, climate and environmental health, and women’s, adolescents’ and children’s health.”
“The team represents 14 countries, including all WHO regions, and is more than 60% women, reflecting my deep-held belief that we need top talent, gender equity and a geographically diverse set of perspectives to fulfil our mission to keep the world safe,” said Dr Tedros.
Dr. Sowmya Swaminathan hails from Tamil Nadu and her father is the legendary MS Swaminathan- considered as the pioneer of the Green Revolution in India. 

Wednesday, August 9, 2017

Why the ‘gold standard’ of medical research is no longer enough ?

R
andomized controlled trials have long been held up as the “gold standard” of clinical research. There’s no doubt that well-designed trials are effective tools for testing a new drug, device, or other intervention. Yet much of modern medical care — perhaps most of it — is not based on randomized controlled trials and likely never will be. In this “dark matter” of clinical medicine, past practices and anecdotes all too often rule. We need to look beyond trials to improve medical care in these areas.
In a randomized controlled trial (RCT), participants are randomly assigned to receive either the treatment under investigation or, as a control, a placebo or the current standard treatment. The randomization process helps ensure that the various groups in the study are virtually identical in age, gender, socioeconomic status, and other variables. This minimizes the potential for bias and the influence of confounding factors.
Despite their strengths, RCTs have substantial limitations. They can be very expensive to run. They can take many years to complete, and even then may not last long enough to assess the long-term effect of an intervention such as vaccine immunity, or to detect rare or long-term adverse effects. Findings from RCTs may not be valid beyond the study population — a trial that included a high-risk population in order to maximize the possibility of detecting an effect, for example, may not be relevant to a low-risk population. RCTs may not be practical for population-wide interventions and often aren’t relevant for urgent health issues such as infectious disease outbreaks, for which public health decisions must be made quickly.
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As I write this week in the New England Journal of Medicine, several other study types can generate data that are at least as effective as RCTs, or may be even more effective, at generating evidence for action, especially related to population-wide interventions.
The effectiveness of the nasal spray flu vaccine (also called the live attenuated vaccine) is a dramatic illustration of the limitations of RCTs. Trials suggested that the nasal spray vaccine was superior to flu shots, at least for some populations. In subsequent years, however, observational studies, including case-control studies, documented that, for reasons which are still unclear, the nasal spray wasn’teffective against the flu. That led the Advisory Committee on Immunization Practices to recommend, and the CDC to accept the recommendation, that the nasal spray flu vaccine not be used in the 2016-2017 flu season.
For some public health issues, it isn’t ethical to conduct an RCT. Take sudden infant death syndrome (SIDS). Early case-control studies suggested, but didn’t prove, that babies who sleep on their stomachs are more likely to die of SIDS than babies who sleep on their backs. It wouldn’t have been ethical to randomize some babies to stomach sleeping. A public program to implement putting children to sleep on their backs proved that this measure reduced the incidence of SIDS.
It would be difficult, if not impossible, to do an RCT of community-wide tobacco control measures. But analyses of the results of implementing tobacco control policies, such as taxes, smoke-free laws, and advertising bans, have generated robust evidence of effectiveness that could not have been accomplished through an RCT-style study.
For the several thousand rare diseases, RCTs are unlikely to be conducted due to the small number of people who have them and other logistical constraints. Detailed case studies, registries that collect information about specific conditions and diseases, and other study types can enhance understanding of a particular disease and its treatment to improve the health of affected patients.

The emerging use of “big data,” including information from electronic health records and expanded patient registries, presents new opportunities to conduct large-scale studies with many of the benefits of RCTs but without the expense. One such study used data from the Veterans Health Administration and Medicare to examine outcomes of treatment for type 2 diabetes. This study was many times larger, with much longer follow-up and lower cost, than previous RCTs comparing the effectiveness of different diabetes drugs. It clearly showed that one class of drug, the thiazolidinediones, was much more effective than another class, the sulfonylureas, in reducing hospitalization and death.
Clinical and public health decisions are almost always made with imperfect data. There is no single, best approach to obtain better information about health interventions. Evidence grading systems, policy makers, and researchers must embrace other study types in addition to RCTs. Essential steps in interpreting findings and identifying data for action include promoting transparency in study methods, ensuring standardized data collection for key outcomes, and using new approaches to improve data synthesis.
Despite the global evidence base, around the world there are often claims that “there is no evidence tobacco harms health here” or that “soda isn’t proven to drive obesity in this country.” In part, such claims can be made because some formal systems of analyzing evidence give undue weight to RCTs and inappropriately discount other types of rigorously developed evidence.
A valid ideal is “evidence-based practice,” which means implementing in clinical care and public policy interventions that are proven to work. But it’s also important, and perhaps more so, to develop “practice-based evidence,” — that is, to implement programs and rigorously document whether or not they work. That would both save lives and expand the evidence base of effective interventions.



SOURCE : https://www.statnews.com/2017/08/02/randomized-controlled-trials-medical-research/

COVID 19 : A structural insight.

        Understand the problem, give it a thought ..and act accordingly to find a solution towards it.. This holds very much true in...