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Pharmaceutical Companies Racing Together to Find a Cure for COVID-19
Reporter: Irina Robu, PhD
The global outbreak has put pressure on companies and the Food and Drug Administration (FDA) to act quickly to make medications available to patients. Several companies are working together to find solutions to treat those infected by the virus and prevent it from spreading.
AstraZeneca is responding to the COVID-19 (novel coronavirus) outbreak to accelerate the development of its di diagnostic testing capabilities to scale-up screening and is also working in partnership with governments on existing screening programs to supplement testing. In addition, AstraZeneca is working to identify monoclonal antibodies to progress towards clinical trial evaluation as a treatment to prevent COVID-19.
Bayer, German multinational pharmaceutical and life sciences company is donating malaria drug, Resochin to the US government for possible use to treat COVID-19. Resochin, made of chloroquine phosphate is a current approve treatment for malaria. China is evaluating it for potential use of COVID-19 and presented decent effects against the first SARS virus in 2003. Doctors consider it a promising treatment for seriously ill coronavirus patients.
AbbVie is research-driven biopharmaceutical company dedicated to developing innovative advanced therapies for four primary therapeutic areas: immunology, oncology, virology and neuroscience. The company declared plans to evaluate HIV medicine as COVID-19 treatment and go into partnerships with health authorities in various countries to explore the efficacy and antiviral activity of the medication.
Boehringer Ingelheim, research driven company is collaborating with the German Center for Infectious Research to develop therapies and diagnostic tools for COVID-19. Their research teams are screening their entire molecule library with more than one million compounds to identify novel small molecules with activity against the virus.
EMD Serono is the biopharmaceutical business of Merck KGaA, Germany donated interferon beta-1a to French Institute of National Health and Medical Research to use for a clinical trial. Interferon beta-1a is presently in use to treat multiple sclerosis and is under investigation as potential treatment for people with COVID-19 coronavirus disease caused by the SARS-nCoV-2 virus. When confronted with the virus, each cell shoots an emergency flare of interferon to tell the immune system to strengthen its defenses. The interferon beta1a cytokine activates macrophages that engulf antigens and natural killer cells, which are integral to innate immune system. The trial is subsidized by INSERM and its start has been announced by the French Health authorities on March 11. To date, Merck interferon beta-1a is not approved by any regulatory authority for the treatment of COVID-19 or for use as an antiviral agent.
GLAXOSMITHKLINE (GSK) has been working to make vaccine using its established pandemic vaccine adjuvant platform technology available. Sanofi and GSK announced on April 14, 2020 they will collaborate to develop an adjuvanted vaccine for COVID-19, using innovative technology from both companies. Sanofi will donate its S-protein COVID-19 antigen, which is based on recombinant DNA technology. This technology gives an exact genetic match to proteins found on the surface of the virus and the DNA sequence encoding this antigen has been combined into the DNA of the baculovirus expression platform, the basis of Sanofi’s licensed recombinant influenza product in the US.GSK will contribute its proven pandemic adjuvant technology to the collaboration, since it may reduce the amount of vaccine protein required per dose, letting more vaccine doses to be produced and consequently contributing to protect more people.
JOHNSON & JOHNSON has started research into a vaccine, leveraging the same innovative technology used for Ebola vaccine. Janssen, the pharmaceutical arm of J&J has donated medicines for use in laboratory-based investigations to support efforts in finding a resolution against COVID-19.
Eli Lilly entered into an agreement with AbCellera to co-develop antibody products for the treatment and prevention of COVID-19. The collaboration will leverage AbCellera’s rapid pandemic response platform, established under the DARPA Pandemic Prevention Platform Program, along with Lilly’s global capabilities for rapid development, manufacturing and distribution of therapeutic antibodies. Eli Lilly has also entered an agreement with NIH, NIAID to study baricitinib as an arm in NIAID’s Adaptive COVID-19 treatment trial. Baricitinib, an oral JAK1/JAK2 inhibitor is accepted in more than 65 countries as a treatment for adults with moderately to severely active rheumatoid arthritis. Because of the inflammatory cascade in COVID-19, baricitinib’s anti-inflammatory activity has been hypothesized to have a potential beneficial effect in COVID-19 and needs further study in patients with this infection. Eli Lilly is also using an investigational selective monoclonal antibody against Angiopoientin-2 to Phase 2 testing in pneumonia patients hospitalized with COVID-19 who are at higher risk of delveoping acute respiratory distress syndrome. The company will look whether inhibiting the effects of Angiopoientin-2 with monoclonal antibody which can reduce the progression of acute respiratory distress syndrome. The trial will start in April 2020.
Pfizer and BioNTech work together to develop a potential COVID-19 vaccine which aims to accelerate development of BioNTech’s potential first-in-class COVID-19 mRNA vaccine program, BNT162 . A clinical study is expected to start by the end of April 2020. The collaboration is a continuation of the original agreement in 2019 between the two companies to develop mRNA-based vaccines for prevention of influenza.
Roche, Canada has been designated as a participant in a Phase III clinical trial evaluating the safety and efficacy of one of Roche’s portfolio medicines in hospitalized adult patients with severe COVID-19 pneumonia. The company announced the future launch of its Elecsys Anti-SARS-CoV-2 serology test to detect antibodies in people who have been exposed to SARS-CoV-2 that causes the COVID-19 disease. Antibody testing is vital to help detect people who have been infected by the virus, particularly those who may have been infected but did not display symptoms. Furthermore, the test can support priority screening of high-risk groups who might by now have advanced a certain level of immunity and can continue serving and/or return to work.
Takeda Pharmaceutical Company is initiating the development of an anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG) to treat high-risk individuals with COVID-19, although also investigating whether Takeda’s currently marketed products may be effective treatments for infected patients. Hyperimmune globulins are plasma derived-therapies that have been effective in the treatment of severe acute viral respiratory infections and could be a treatment option for COVID-19. Takeda has the research expertise to develop and manufacture a potential anti-SARS-CoV-2 polyclonal H-IG.
Takeda is presently in discussions with multiple national health and regulatory agencies and health care partners in the US, Asia, and Europe to expeditiously move the research into anti-SARS-CoV-2 polyclonal H-IG forward. The research requires access to source plasma from people who have efficaciously recovered from COVID-19. The donors have developed antibodies to the virus that could possibly alleviate severity of illness in COVID-19 patients and perhaps prevent it. By transferring the antibodies to a new patient, it may help that person’s immune system respond to the infection and increase their chance of recovery. These efforts to find a vaccine are at an early stage nevertheless being given a high priority within the company.
Some COVID-19 Pneumonia Cases Are Like Acute Respiratory Distress Syndrome
Reporter: Irina Robu, PhD
Doctors around the world are still learning about the novel coronavirus (COVID-19), but it’s obvious that the most serious cases include severe respiratory symptoms that can damage a person’s lungs. The COVID-19 can cause pneumonia which can lead to a more severe condition called acute respiratory distress syndrome (ARDS). Fluid buildup in the lungs prevents them from filling with air, decreasing the amount of oxygen that reaches the bloodstream.
At the start, COVID-19 pneumonia presents with the resulting characteristics such as low elastance (the amount of gas in the lung), low ventilation-to-perfusion, low lung weight and low lung recruit ability (amount of non-aerated tissue). When the coronavirus reaches the lungs, it causes viral pneumonia. The lungs can then become filled with fluid. The COVID-19 disease can be mild, but more severe cases may require hospitalization. The infections associated with the disease can escalate to the point a patient develops ARDS. The higher mortality rate for COVID-19 patients who develop ARDS may be attributable to other symptoms of the coronavirus.
Like many viruses, the respiratory droplets related with COVID-19 attach to the back of a person’s throat or nose, then move through the respiratory tract. The human body replies to viruses by trying to fight them off, which causes inflammation. Some scientists also suggested that pneumonia that presents in COVID-19 tends to be bilateral, meaning it affects both lungs. Fluid buildup in the lungs prevents them from filling with air, decreasing the amount of oxygen that reaches the bloodstream.
Medical experts are correspondingly trying to determine if pneumonia caused by the coronavirus is more likely to become severe and cause ARDS. The limited number of tests performed on COVID-19 patients makes it impossible to say at this time. Doctors may prescribe antiviral medication to treat pneumonia caused by the flu. It’s unclear if any medicines are reliable for patients diagnosed with the coronavirus.
Pneumonia caused by a virus tends to show up on CT scans as hazy white patches known as ground-glass opacities. The doctors at Mount Sinai Health System in New York City who studied CT scans from COVID-19 patients noticed those hazy patches tended to cluster around the edge of both lungs.
Imaging the lungs in a patient who may have COVID-19 can be problematic, since imaging machines necessitate thorough disinfecting after they’re used to take an X-ray or CT scan of a patient suspected of having the coronavirus.
Personalized Medicine, Omics, and Health Disparities in Cancer: Can Personalized Medicine Help Reduce the Disparity Problem?
Curator: Stephen J. Williams, PhD
In a Science Perspectives article by Timothy Rebbeck, health disparities, specifically cancer disparities existing in the sub-Saharan African (SSA) nations, highlighting the cancer incidence disparities which exist compared with cancer incidence in high income areas of the world [1]. The sub-Saharan African nations display a much higher incidence of prostate, breast, and cervix cancer and these cancers are predicted to double within the next twenty years, according to IARC[2]. Most importantly,
the histopathologic and demographic features of these tumors differ from those in high-income countries
meaning that the differences seen in incidence may reflect a true health disparity as increases rates in these cancers are not seen in high income countries (HIC).
Most frequent male cancers in SSA include prostate, lung, liver, leukemia, non-Hodgkin’s lymphoma, and Kaposi’s sarcoma (a cancer frequently seen in HIV infected patients [3]). In SSA women, breast and cervical cancer are the most common and these display higher rates than seen in high income countries. In fact, liver cancer is seen in SSA females at twice the rate, and in SSA males almost three times the rate as in high income countries.
Reasons for cancer disparity in SSA
Patients with cancer are often diagnosed at a late stage in SSA countries. This contrasts with patients from high income countries, which have their cancers usually diagnosed at an earlier stage, and with many cancers, like breast[4], ovarian[5, 6], and colon, detecting the tumor in the early stages is critical for a favorable outcome and prognosis[7-10]. In addition, late diagnosis also limits many therapeutic options for the cancer patient and diseases at later stages are much harder to manage, especially with respect to unresponsiveness and/or resistance of many therapies. In addition, treatments have to be performed in low-resource settings in SSA, and availability of clinical lab work and imaging technologies may be limited.
Molecular differences in SSA versus HIC cancers which may account for disparities
Emerging evidence suggests that there are distinct molecular signatures with SSA tumors with respect to histotype and pathology. For example Dr. Rebbeck mentions that Nigerian breast cancers were defined by increased mutational signatures associated with deficiency of the homologous recombination DNA repair pathway, pervasive mutations in the tumor suppressor gene TP53, mutations in GATA binding protein 3 (GATA3), and greater mutational burden, compared with breast tumors from African Americans or Caucasians[11]. However more research will be required to understand the etiology and causal factors related to this molecular distinction in mutational spectra.
It is believed that there is a higher rate of hereditary cancers in SSA. And many SSA cancers exhibit the more aggressive phenotype than in other parts of the world. For example breast tumors in SSA black cases are twice as likely than SSA Caucasian cases to be of the triple negative phenotype, which is generally more aggressive and tougher to detect and treat, as triple negative cancers are HER2 negative and therefore are not a candidate for Herceptin. Also BRCA1/2 mutations are more frequent in black SSA cases than in Caucasian SSA cases [12, 13].
Initiatives to Combat Health Disparities in SSA
Multiple initiatives are being proposed or in action to bring personalized medicine to the sub-Saharan African nations. These include:
H3Africa empowers African researchers to be competitive in genomic sciences, establishes and nurtures effective collaborations among African researchers on the African continent, and generates unique data that could be used to improve both African and global health.
There is currently a global effort to apply genomic science and associated technologies to further the understanding of health and disease in diverse populations. These efforts work to identify individuals and populations who are at risk for developing specific diseases, and to better understand underlying genetic and environmental contributions to that risk. Given the large amount of genetic diversity on the African continent, there exists an enormous opportunity to utilize such approaches to benefit African populations and to inform global health.
The Human Heredity and Health in Africa (H3Africa) consortium facilitates fundamental research into diseases on the African continent while also developing infrastructure, resources, training, and ethical guidelines to support a sustainable African research enterprise – led by African scientists, for the African people. The initiative consists of 51 African projects that include population-based genomic studies of common, non-communicable disorders such as heart and renal disease, as well as communicable diseases such as tuberculosis. These studies are led by African scientists and use genetic, clinical, and epidemiologic methods to identify hereditary and environmental contributions to health and disease. To establish a foundation for African scientists to continue this essential work into the future work, the consortium also supports many crucial capacity building elements, such as: ethical, legal, and social implications research; training and capacity building for bioinformatics; capacity for biobanking; and coordination and networking.
Advancing precision medicine in a way that is equitable and beneficial to society means ensuring that healthcare systems can adopt the most scientifically and technologically appropriate approaches to a more targeted and personalized way of diagnosing and treating disease. In certain instances, countries or institutions may be able to bypass, or “leapfrog”, legacy systems or approaches that prevail in developed country contexts.
The World Economic Forum’s Leapfrogging with Precision Medicine project will develop a set of tools and case studies demonstrating how a precision medicine approach in countries with greenfield policy spaces can potentially transform their healthcare delivery and outcomes. Policies and governance mechanisms that enable leapfrogging will be iterated and scaled up to other projects.
Successes in personalized genomic research in SSA
As Dr. Rebbeck states:
Because of the underlying genetic and genomic relationships between Africans and members of the African diaspora (primarily in North America and Europe), knowledge gained from research in SSA can be used to address health disparities that are prevalent in members of the African diaspora.
For example members of the West African heritage and genomic ancestry has been reported to confer the highest genomic risk for prostate cancer in any worldwide population [14].
Science 03 Jan 2020:
Vol. 367, Issue 6473, pp. 27-28
DOI: 10.1126/science.aay474
Summary/Abstract
Cancer is an increasing global public health burden. This is especially the case in sub-Saharan Africa (SSA); high rates of cancer—particularly of the prostate, breast, and cervix—characterize cancer in most countries in SSA. The number of these cancers in SSA is predicted to more than double in the next 20 years (1). Both the explanations for these increasing rates and the solutions to address this cancer epidemic require SSA-specific data and approaches. The histopathologic and demographic features of these tumors differ from those in high-income countries (HICs). Basic knowledge of the epidemiology, clinical features, and molecular characteristics of cancers in SSA is needed to build prevention and treatment tools that will address the future cancer burden. The distinct distribution and determinants of cancer in SSA provide an opportunity to generate knowledge about cancer risk factors, genomics, and opportunities for prevention and treatment globally, not only in Africa.
Parkin DM, Ferlay J, Jemal A, Borok M, Manraj S, N’Da G, Ogunbiyi F, Liu B, Bray F: Cancer in Sub-Saharan Africa: International Agency for Research on Cancer; 2018.
Chinula L, Moses A, Gopal S: HIV-associated malignancies in sub-Saharan Africa: progress, challenges, and opportunities. Current opinion in HIV and AIDS 2017, 12(1):89-95.
Colditz GA: Epidemiology of breast cancer. Findings from the nurses’ health study. Cancer 1993, 71(4 Suppl):1480-1489.
Hamilton TC, Penault-Llorca F, Dauplat J: [Natural history of ovarian adenocarcinomas: from epidemiology to experimentation]. Contracept Fertil Sex 1998, 26(11):800-804.
Garner EI: Advances in the early detection of ovarian carcinoma. J Reprod Med 2005, 50(6):447-453.
Brockbank EC, Harry V, Kolomainen D, Mukhopadhyay D, Sohaib A, Bridges JE, Nobbenhuis MA, Shepherd JH, Ind TE, Barton DP: Laparoscopic staging for apparent early stage ovarian or fallopian tube cancer. First case series from a UK cancer centre and systematic literature review. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2013, 39(8):912-917.
Kolligs FT: Diagnostics and Epidemiology of Colorectal Cancer. Visceral medicine 2016, 32(3):158-164.
Rocken C, Neumann U, Ebert MP: [New approaches to early detection, estimation of prognosis and therapy for malignant tumours of the gastrointestinal tract]. Zeitschrift fur Gastroenterologie 2008, 46(2):216-222.
Srivastava S, Verma M, Henson DE: Biomarkers for early detection of colon cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 2001, 7(5):1118-1126.
Pitt JJ, Riester M, Zheng Y, Yoshimatsu TF, Sanni A, Oluwasola O, Veloso A, Labrot E, Wang S, Odetunde A et al: Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features. Nature communications 2018, 9(1):4181.
Zheng Y, Walsh T, Gulsuner S, Casadei S, Lee MK, Ogundiran TO, Ademola A, Falusi AG, Adebamowo CA, Oluwasola AO et al: Inherited Breast Cancer in Nigerian Women. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018, 36(28):2820-2825.
Rebbeck TR, Friebel TM, Friedman E, Hamann U, Huo D, Kwong A, Olah E, Olopade OI, Solano AR, Teo SH et al: Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Human mutation 2018, 39(5):593-620.
Lachance J, Berens AJ, Hansen MEB, Teng AK, Tishkoff SA, Rebbeck TR: Genetic Hitchhiking and Population Bottlenecks Contribute to Prostate Cancer Disparities in Men of African Descent. Cancer research 2018, 78(9):2432-2443.
Other articles on Cancer Health Disparities and Genomics on this Online Open Access Journal Include:
Article ID #274: My Memories Tell a Story to Share by Larry Howard Bernstein, MD, FCAP. Published 4/19/2020
WordCloud Image Produced by Adam Tubman
Updated on 6/2/2020
In preparation for a PODCAST with Dr. Larry, we prepared the following content:
For many years, he was the Chief Scientific Officer and Member of the Board of Leaders in Pharmaceutical Business Intelligence (LPBI) Group, a Pharmaceutical Media Venture with several Cloud Based products: (1) an Open Access Online Scientific Journal
PharmaceuticalIntelligence.com, (2) a BioMed e-Series of 16 volumes in Medicine (3) A Real Time Press Coverage of Biotech and Medical Conferences (4) a Podcast Library of Interviews with Key Opinion Leaders (4) A Platform with Composition of Methods and (5) a Team of Experts, Authors, Writers.
Dr. Bernstein had contributed 1,400 curated articles to LPBI’s Journal, mentioned above and served as Editor and Content Consultant to each of the 16 volumes in LPBI’s BioMed e-Series.
Examples of the TOP articles in the Journal by e-Readers Views shows the cardinal positioning of Dr. Bernstein’s publications.
Top Posts for all days ending 2020-06-02 (Summarized)
Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?
17,117
Larry H. Bernstein, MD, FACP
Investigator Initiated Research
Recent comprehensive review on the role of ultrasound in breast cancer management
14,242
Dr. D. Nir
Commission by Aviva Lev-Ari, PhD, RN
Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) and PRADAXA (dabigatran)
13,839
Dr. Pearlman, MD, PhD, FACC & Aviva Lev-Ari, PhD, RN
Commission by Aviva Lev-Ari, PhD, RN
Paclitaxel vs Abraxane (albumin-bound paclitaxel)
13,709
Tilda Barliya, PhD
Investigator Initiated Research
Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications
8,230
Aviva Lev-Ari, PhD, RN
Investigator Initiated Research
Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care
7,903
Dr. Pearlman, MD, PhD, FACC & Aviva Lev-Ari, PhD, RN
Investigator Initiated Research
Mesothelin: An early detection biomarker for cancer (By Jack Andraka)
6,540
Tilda Barliya, PhD
Investigator Initiated Research
Our TEAM
6,505
Internet Access
Tabulation
Biochemistry of the Coagulation Cascade and Platelet Aggregation: Nitric Oxide: Platelets, Circulatory Disorders, and Coagulation Effects
5,221
Larry H. Bernstein, MD, FACP
Investigator Initiated Research
Interaction of enzymes and hormones
4,901
Larry H. Bernstein, MD, FACP
Commission by Aviva Lev-Ari, PhD, RN
Akt inhibition for cancer treatment, where do we stand today?
4,852
Ziv Raviv, PhD
Investigator Initiated Research
AstraZeneca’s WEE1 protein inhibitor AZD1775 Shows Success Against Tumors with a SETD2 mutation
4,535
Stephen J. Williams, PhD
Investigator Initiated Research
The History and Creators of Total Parenteral Nutrition
4,511
Larry H. Bernstein, MD, FACP
Commission by Aviva Lev-Ari, PhD, RN
Newer Treatments for Depression: Monoamine, Neurotrophic Factor & Pharmacokinetic Hypotheses
4,365
Zohi Sternberg, PhD
Investigator Initiated Research
FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules
4,188
Stephen J. Williams, PhD
Investigator Initiated Research
The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets
4,038
Dr. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD, FACP & Aviva Lev-Ari, PhD, RN
Commission by Aviva Lev-Ari, PhD, RN
Founder
3,895
Aviva Lev-Ari, PhD, RN
Investigator Initiated Research
That small sample from a universe of 1,400 articles reflects just a glimpse of the topics that he had covered in his writing.
In addition, in 2020 the Journal ontology has 700 Categories of Research, more than 50% were create by Dr. Bernstein for allowing a precise classification of the wide range of topics his life body of research had covered, chiefly: Cancer, Genomics, Pathology, Coagulation, Cardiovascular, Nutrition, Cell Biology and Biochemistry Processes, at large.
Dr. Bernstein served on the Board of Director of NAACLS and the American Library Association Commission on Accreditation and he is listed in the America’s Top Physicians.
He has three patents:
1. Measuring Lactate Dehydrogenase Isoenzymes by differential inhibition of heart and muscle enzymes using the inhibition by a triplex formed by pyruvate – NAD+ and LDH.
2. Measuring the mitochondrial Malate Dehydrogenase using the inhibition of mMDH by a triplex formed by OAA – NAD+ – and mMDH in the laboratory of Nathan Oren Kaplan (NAS).
3. Measuring a cancer modified MDH by loss of mMDH inhibition with Prof. Johannes Everse. In addition, only a provisional patent was filed for Converting Hematology Based Data into an Inferential Interpretation under the direction of Prof. Ronald Raphael Coifman (NAS). No patent was filed for the statistical determination of myocardial infarct using two assays for creatine kinase MB. No patent was filed for the diagnosis of myaocardial infarct using a neural network under the supervision of Izaak Mayzlin, eminent mathematician from former Soviet Union; No patent was filed for the determination of myocardial infarct using Kullback Entropy.
My lab was the only one to get down to reliable measurements of transthyretin of 20 mg/L. I co-chaired the First International Transthyretin Congress in Strasbourg, at the invitation of Yves Ingenbleek, MD, PhD, Professor of Pharmacology, University Louis Pasteur, Strasbourg.
I chaired the 14th and was an invited participant in the 17th Ross Roundtable on Nutrition, Organized and Chaired the Beckman Roundtable on Pre-albumin in Los Angeles, was responsible for the AACC first document of Standards of Clinical Laboratory Practice with Lawrence Kaplan, and was recipient of the Labbe/Garry award of the Nutrition Division of AACC).
Other projects in normalizing the NT-proBNP for age and estimated glomerular filtration rate (eGFR), were successful, but widespread implementation is even more gradual than was TTR.
Could you tell us about the research project that had the most significance in your career?
You worked with two noted researchers – Gil David and Yale University’s Chairman of the Mathematics Department Ronald Coifman – to develop a software system which is today’s equivalent of electronic health records that gathers medical information, generates metrics and analyzes data in real-time, providing a health diagnosis for an individual’s medical condition.
4/19/2020
The Schwartz and Auslander Families
I was born a triplet to David and Lillian Bernstein on December 28, 1941, the first set of triplets born in Highland Park Hospital in some 20 years, but on graduation from Mumford High School, Detroit, Michigan in 1960, we were one of three sets of triplets. We were Larry, Leslie and Linda, who were preceded by Sharon, a sister two years older, also a December baby. Our parents were middle class and our father was a dental technician, so a family with four children was not easy to bring up. We always lived in a household of two families, with my uncle Irving and aunt Elsie Bernstein, living in the lower level, having two children, Barbara, who was our age, and Richard, who was the older brother. When we were born, under the circumstance of my grandmother, Bobby Mulvin (Mulvina in Hungarian), three calls were made in successive days to inform the family in Cleveland, Ohio, of our birth. My mother’s father and mother were Julius and Mulvina Schwartz, from the Hungarian edge of Austria on the Raba River, who moved the family to Cleveland as the intentions of Hitler became clear. My mother had two older brothers and a younger sister, David, Herman and Bernice. David had already been a United States citizen when the Schwartz family moved to the United States in 1931, and Herman was a third year medical student in Budapest after completing a year in Vienna, having been valedictorian of his high school class after special arrangement of his local catholic priest. But Herman had to move from Hungary months prior to graduation because immigration would close. Lillian was 18 years age when she brought her 11 year old sister to America. Julius and David worked in the dry cleaning business in Cleveland. There was also a Mulvina cousin, Biederman, who was a jeweler in Vienna who moved to Cleveland, but his father did not escape the Nazis. Their children were Alan and Marvin, Lois, Robert and Barbara (Liss), Lucille and Janice. Another two generations have passed. Robert was a merit scholar in upstate New York, became a reporter on the Miami Herald, and had three children. He died too young of leukemia. Barbara married and had 3 Wolfe children, two boys and a girl.
I have described the Cleveland side of the family. My mother worked making ties in Cleveland for a friend of my father’s family. She helped bring him to Detroit and married my mother. My father came from Czeckoslovakia, his father having a tree farm on the Carpathian mountains, near the border with Poland. He became a Schochet (kosher chicken). He had a sister, Rivka. Rivka married a cantor after her husband died. My grandmother was in the Auslander family. Auslander means out of the land. A rabbi brought his family out of Spain and changed the family name to Auslander. My grandfather was Meyer and grandmother was Rachel (Bobby Rochel). They lived two streets from the elementary school, so we had lunch at the grandparents house. My grandmother had sisters Esther, Edna, Katie, Jeanette. We go to a next generation rich in talent. This family lived in the city of Detroit, which has an interesting history.
The Jewish Community
Grandfather Meyer was very orthodox, but he shaved, and attended the Gelitzioner Shul, but our mother objected to her children going to an orthodox yeshiva school that was too rigid. Our mother read a lot to become knowledgable and also fluent in the English language. Our father read the Detroit Free Press and the business section daily. Some of our family went to the reform synagogue, Temple Israel, that did not use rigorous Hebrew in prayer. We attended the Bnai Moshe synagogue, which had Rabbi Moses Lehrman, whose daughter became an English teacher at our school. There was a cantor, and there was a superb reader of the Torah (Baal Koreh). The president of the Bnai Moshe was the founder of a salami that was the equal to that in New York.
Detroit
Detroit was a city on the Detroit River that was once known as Fort Ponchartrain at the time of the Revolutionary War with the British. There were Indians at the edge of the Upper Peninsula. The Upper Peninsula was obtained by Governor Lewis Cass from Wisconsin an a trade that made Toledo a part of Ohio. Detroit and the Detroit River became a crossing point for Negroes at the time of flight from the Southern states during the Civil War. Windsor, Ontario was a point of transfer of liquor from Winsor, Ontario. Detroit became important when Henry Ford brought automation into auto manufacturing, and it was followed by Dodge/Crysler and General Motors. Neighboring Dearborn, Michigan became a city where there was later a Ford Museum, and it was known to be only for whites and non-jews. There was also before my arrival an anti-Semitic priest, Father Coughlin. In addition, Henry Ford was known to disseminate “The Elders of Zion. So the city was somewhat divided, as perhaps other cities – like New York. Philadelphia, Chicago, and Los Angeles – that had distinctly jewish and black neighborhoods that one might consider ghettos. The city of Highland Park, within Detroit, was Polish. The jewish neighborhood migrated from Chicago Boulevard toward Livernois, and beyond to beyond Seven Mile Road, and eventually beyond Eight Mile Road, the Detroit border.
My early childhood was on Sturtevant, between Linwood and Dexter. Linwood extended to middle Detroit, where there was an automobile convention center. There was a theater at the corner of Linwood and Livernois. There was an upper middle class neighborhood adjacent to Oak Park, and a zoo on Woodward Avenue. The synagogue my family attended was on Dexter, and there was a butcher shop, a bakery, and the Dexter Davison Market. My aunt Edna had an ice cream parlor a short distance from the synagogue on Dexter. She had two sons and one became a doctor and the other a professor. The McCullough elementary school and across the street a United Hebrew School were walking distance from where my family lived, with many children on our street. Milk was delivered to a milkbox, and an alternative way of entering the home was through the milkbox. The next door neighbor had a dog named Blackie. He was child friendly. There were many children in the neighborhood. My best friend in elementary school was an Armenian boy, Michael Michalian.
High School and College
We moved from the old neighborhood at the time were to attend High School. My brother and I joined the chess club and learned from Peter Wolf, who excelled at it. Mumford High School chess club won the city championship over Redford High School, taking the cup four years in succession. I also found a friend in high school a grade ahead, Fred Baskin, who was extremely bright and very social. The triplets graduated from high school and entered WSU in 1960. When we finished high school we all went to Wayne State University (WSU), where I majored in chemistry, and was a premedical student. Fred had a Merit Scholarship. I prepared myself sufficiently so that if I were not to qualify for medical school, I could follow a suitable career. My older sister, Sharon, was a very fine pianist and she entered WSU with a General Motors Scholarship three years earlier. She excelled in mathematics. She has taught piano for years and still does so at 80 years age. Fred went on to graduate school in biochemistry at University of California, Berkeley and I went on to medical school at Wayne State University upon graduation. My sister Linda did graduate work and obtained a Master degree in biology at Wayne State, married a psychiatry graduate, and they moved to California and raised two boys. I shared the same room as Leslie, but I did not see changes in him that lead to attempted suicide and admittance to the hospital. The three of us spent a summer at the NIH in a study of Schizophrenia. Leslie went to San Diego to be near Linda.
I worked very hard in my first two years of medical school. I engaged in a graduate study in embryology under Harry Maisel in the Anatomy Department, studying the evolution of the proteins of the lens of the eye (crystallins) under Prof. Harry Maisel, but I also studied the changes in the isoenzymes of lactate dehydrogenase (LD). He was an inspiring scientist, but I also had the opportunity to learn electron microscopy under Maurice Bernstein in the same department. When I finished the Master degree I returned to finish the last two years of medical school. This was a valuable experience under two inspiring mentors. In the study of the evolution of the LD isoenzymes I became extremely interested in the work of Nathan Kaplan at the Graduate University of Biochemistry in Boston, and the work of one of his graduate students who looked at the changes in the wings of avians, depending on flight characterics. I chose to go to the University of Kansas Medical School for residency and PhD in pathology. When I arrived in 1968, the pathologist whose work interested me had left to carry on the chairmanship elsewhere, but I was fortunate to meet Masahiro Chiga, who had left an Acting Chairman of Biochemistry to return to pathology. He was an inspiration. I finished less than a year when he recommended that I go to the University of California, San Diego to work with Nathan Kaplan. He modestly said that he had worked with the muscle enzyme of adenylate kinase (myokinase) that is different than the liver enzyme, but he hadn’t had the insight that Kaplan had. I stayed in touch with him until his death. My mother developed gastric cancer, quite rare then, and I visited her several times before she died. I also dated an old Mumford schoolmate, Audrey Mellon, who I married before going to San Diego.
University of Calfornia, San Diego
I found myself in a completely different environment in San Diego. One part of it was the enormous scientific environment, not only with Kaplan’s laboratory his two competent two assistants, and his several postdoctoral students, but also my engagement with several staff biochemists. There were presentations in the hallway next to Prof. Kaplan’s office, and some were from outside research institutions. It was amazing how when the medical school was opened, it had drawn talents from all of the best institutions. An unintended benefit was the beautiful ocean, the nearby La Jolla, and nearby other research centers. Dr. Kaplan was the Editor, and he cofounded Methods in Enzymology with Sidney Colowick, who had worked with Carl and Gerty Cori (Nobel Laureates) in St. Louis. They had both worked with Fritz Lippman in the discovery of Coenzyme A , the cofactor that acts as an acyl carrier, and either activates the acyl group for group transfer or electrophilic attack, or increases the acidity of the protons adjacent to the carbonyl group. He shared the Nobel Prize in Physiology in 1945 with Hans Krebs, who elucidated the Krebs cycle. Kaplan’s role in the discovery was significant. Interestingly, Hans Krebs work was related to work carried out in the laboratory of Otto Warburg (Nobel Laureate, 1937)), whose work pioneered the study of mitochondrial impairment if cancer.
My own work was not with lactate dehydrogenase, but with Malate dehydrogenase, a critical enzyme linked to mitochondrial function. While LDH catalyze the conversion of pyruvate to lactate with NADH as cofactor and the transfer of a proton, the reverse reaction was inhibited by a ternary complex formed by LDH-NAD- and lactate, but this reaction was weak with the muscle type LDH compared to the heart type LDH. In a similar manner the malate dehydrogenase had a mitochondrial and cytoplasmic isoenzyme, the mitochondrial MDH forming a ternary complex, but not the cytoplasmic enzyme. I spent many months purifying the mitochondrial enzyme from 50 lb of chicken hearts with first an ammonium sulfate precipitation, then a column separation, and dialysis. A study of the mitochondrial malate dehydrogenase was followed by stopped flow analysis and that showed the inhibition by transfer of the hydrogen to form a ternary complex.
I returned to residency in pathology at UCSD under an NIH fellowship with Averill Liebow in the next year. Liebow was an internationally known expert in pulmonary pathology. He was also very amazing. A resident from Yale referred to Liebow noticing him sleeping in the back row and the professor called his name, the son of so and so, you can’t sleep in my class. His car was the first in the lot, until I came. Then when I went to the VA Hospital and parked on the other side, he noted that I parked around the corner. The chief of chemistry at the VA was an outstanding teacher and biochemist who subsequently took a position at Beckman-Coulter. I set up an assay in a study of swimming rats with Liebow. My first daughter was born during my residency and it was fascinating watching her learn to stand up. I took her to the San Diego zoo on weekends and she would stand up in her crib and say zoo, zoo. It was at this time that I collected urine specimens for a study of adenylate kinase with Percy Russell, and also took serum specimens from a study of creatine kinase MB in myocardial infarction that was done by the cardiologist Burton Sobel for my own study that was published.
At the end of my residency I had to give two years for my time deferred from the Vietnam War. Liebow called the Armed Forces Institute of Pathology in Washington to give me the best placement. I then spent the next two years working in orthopedic pathology with Lent C. Johnson, who was quite a genius. He determined the normal ratio of bone forming to bone removing cells, and did pioneering work in bone cancer. Liebow wanted me to return after the two years, but he had a stroke. At the end of two years I took a pathology position at the University of South Florida, Tampa, under Herschel Sidransky.
Herschel was an outstanding researcher from University of Pittsburg Medical School. He had several outstanding researchers in his department. I returned to my studies of malate dehydrogenase and in particular, the mitochondrial malate dehydrogenase in hepatic cancer from Herschel Sidransky’s animals. I had a grant from the Cancer Society. I also had the support in statistics from a mathematician.
Herschel became the Chairman of Pathology at George Washington University, Washington, DC. Several faculty went with him, but I received a substantial salary increase and a supportive offer from the University of South Alabama, Mobile, with a very enthusiastic pathology chairman. Just prior to leaving Florida, Naomi was born. I took on a role with the Medical Technology Program, and I also participated in program reviews, and some time later was on the National Committee for Clinical Laboratory Standards. The Chairman was a capable and enthusiastic neuropathologist who intended to build a good department, but it was not long after that the Chair of Medicine, also the Dean, set up a clinical laboratory for his own interest, without merit. I submitted a cancer grant proposal that was approvingly reviewed by the Chairman of Physiology. It was approved by the NIH without funding, with suggestions to consider. That was a point that I chose to move, and after two years, I moved the family to Des Moines, Iowa to work at the Iowa Methodist Medical Center, the second largest after University Hospital. The President of the hospital sent me a high school student and we completed a project on fetal lung maturity that we published. However, the move was not a good match, as the Chairman’s main concern was outside laboratory work and there was also a laboratory manager who was manipulative.
After two years we moved to Binghamton, New York to a position with Gustavo Reynoso, who came from Rochester, New York and was a very respected pathologist. There was a consolidation of hospitals that led to Dr. Reynoso taking the chairmanship of pathology at Norwalk Hospital, in Norwalk, Connecticut, and he procured a position for me at Bridgeport Hospital, in Bridgeport, CT. The move was very good with an excellent staff in pathology, and I was the director of chemistry and blood bank. This time I stayed for 20 years, and developed a very good relationship with the medical staff, the Chairman of Pathology, Dr. Marguerite Pinto, and particularly with my supervisors in Blood Bank and Chemistry. My Blood Bank supervisor married and moved to Greece and eventually was in charge of the Athens Blood Program.
My relationship with the residents in medicine and cardiology was very collaborative. When I was in the hospital recovering from a femoral fracture, I received a call from I.J. Good, Chairman and Editor of a mathematics journal to whom I had sent cardiac enzyme data some years before. He had finished and validated a program “Diagnosis of acute myocardial infarction from two measurements of creatine kinase isoenzyme MB with use of nonparametric probability estimation”, and they successfully ran the data. We published the paper in Clinical Chemistry. The President of the College of American Pathologist complimented the work at a national meeting. I also met another pathologist, Rosser Rudolph, at a pathology meeting and he had developed a powerful mathematical program that determined the entropy of diagnostic data. We collaborated for many years. In addition, I was really privileged to work with the father of my daughter’s classmate, Isaac Mayzlin, who was an important mathematician at Moscow University. We developed an neural network algorithm for myocardial infarction.
I had a very long, satisfying role in collaboration with Dr. Walter Pleban, who was the surgeon in charge of the only burn unit in Connecticut. I had been engaged in the nutritional support program with Dr. Pleban for some years because of my work on transthyretin. Unfortunately, the criteria using decrease in serum albumin that was in use was very inadequate for early recognition. Transthyretin is a plasma protein that binds to vitamin A and declines very early in protein malnutrition. A decline in transthyretin results in impairment of methionine metabolism. I also had a longstanding relationship with Prof. Yves Ingenbleek at University Louis Pasteur, Strasbourg, in this work. When Stanley Dudrick became the Chairman of Surgery, it was a fortunate circumstance. Stanley was the pioneer in developing intravenous nutrition and was nominated for the Nobel Prize for his work.
A year after Yale University took charge of the Bridgeport Pathology Department, I took a position as Chief of Clinical Chemistry and Blood Bank at the Methodist Hospital of Brooklyn. I had a very good relationship with surgery and medicine, and had superb projects with the residents, but also had excellent high school and college students work on projects. I was 65 years old five years later, and returned to work at Norwalk Hospital in charge of the Blood Bank while the position was recruited. After finishing my work there, I went to Yale University and developed a project with Ronald R. Coifman, the retired Chairman of Mathematics and his graduate student. It lead to the development of a powerful algorithm for interpreting the hemogram that we published. There is a substantial body of research being published of a similar nature, but it is not at all clear whether or how this will be incorporated into the electronic medical record. It reminds me of the support I had at Bridgeport Hospital using a laboratory system designed by Dr. Perry Seamonds that eliminated nonessential examination of peripheral smears by rules criteria. This laboratory system also alleviated the volume of laboratory testing to relieve the burden on the physicians. A different problem I later noticed was that the Hospital Systems that were later introduced had the laboratory, but did not include the Blood Bank! However, as the electronic medical record has evolved it has taken an enormous physician, nursing, and provider time that does not justify a reduction in staff.
After I had been done with my Yale project, I developed a visual problem and stopped driving. I had problems I would later realize. I had had two incidents in a few years that I drove my car off the road because of sleep apnea. I was walking in my neighborhood and had to stop and hold on to a tree for balance. In the case of sleep apnea, it was diagnosed earlier in a sleep apnea study in Brooklyn. I had a study at Yale that brought to my realization that I had thyroid cancer, for which I had thyroidectomy. However, I had diplopia after surgery which disappeared some time later. We moved to Northampton, Massachusetts when our daughter, Naomi and her husband Daniel with grandson Joseph moved, Naomi taking a teaching position at Holyoke Community College, and Daniel working as a neurologist at the VA hospital.
Prior to moving I was contacted by Aviva Lev-Ari, PhD, RN who was building an online medical forum known as Leaders in Pharmaceutical Business Intelligence (LPBI) Group,and I became the Chief Scientific Officer (CSO). Over the decade I wrote many articles (1,390) in the Open Access Online Scientific Journal http://pharmaceuticalintelligence.comthat were included in 16 organized e-Books in Medicine. Dr. Lev-Ari’s accomplishment is quite impressive. The e-Books are all available on Amazon.com
I stopped contributing two years ago, but a graduate student had read my work and wanted my academic guidance (in Canada). She finished her thesis and graduated a year ago. It was a privilege to work with her. Since moving to Northampton, we has been in a very good community at Lathrup.
AAAS Science Podcast: Why some diseases are seasonal and some are not: Coronaviruses and more
Reporter: Stephen J. Williams, PhD
The following podcast from the American Association for Advancement of Science (AAAS) discusses the seasonality of some viruses while other viruses are able to manifest themselves in different seasons over the globe.
The Impact Of The Coronavirus Crisis On Mergers And Acquisitions
Reporter – Dr. Joel T. Shertok
The Impact Of The Coronavirus Crisis On Mergers And Acquisitions
By Richard D. Harroch, David A. Lipkin, and Richard V. Smith
Forbes – April 17, 2020
The coronavirus (COVID-19) crisis is having and will continue to have a material global impact on mergers and acquisitions (“M&A”). On a massive scale and in a very short period of time, hundreds of thousands of businesses have shuttered or cut back their operations significantly, millions of workers have been laid off or furloughed, consumer spending has been drastically reduced, supply chains have been disrupted, and demand for oil and other energy sources has plummeted.
The M&A world has endured and recovered from past economic crises, including the burst of the dot-com bubble in 2000-2002 and the Great Recession of 2007-2009. As in past financial and economic crises, uncertainties in the business and capital markets have already contributed to buyers delaying or cutting back on their acquisition plans. But this time things are different—the impact of the pandemic is not just on the financial system generally, the valuation of sellers, and the appetite of buyers to get deals done in the short term, but on a multitude of other factors affecting M&A deals.
These include deal terms themselves, new due diligence issues that have arisen, the manner in which due diligence is conducted, the availability, pricing and other terms of deal financing, and the time it will take to obtain necessary regulatory and other third-party approvals for transactions.
Moreover, unlike in past crises that have affected M&A deals and activity, this time there has also been a sea change in the manner in which M&A transactions are developed and negotiated. With all of the principal players working remotely, the effective use of new and creative collaborative tools, technologies and techniques have become more critical as buyers, sellers, providers of M&A financing, and all of their respective legal and financial advisors adjust to the changed environment.
In this article, we will discuss how the foregoing factors and others have already impacted M&A dealmaking and will likely continue to impact the M&A world for some time to come, including how buyers and sellers can each adjust to the changed circumstances to help minimize their exposure to the business risks resulting from the pandemic.
1. M&A Deal Activity
Global mergers and acquisitions have already plummeted as result of the coronavirus crisis, and by the end of March 2020 had reached a near standstill. M&A levels in the United States fell by more than 50% in the first quarter to $253 billion compared to 2019, but most of those transactions were entered into or closed earlier in the quarter before the crisis spread worldwide.
Among other things, executives of companies that would typically have been strategic buyers have been forced to redirect the focus and energy of their teams toward the immediate health of their own companies and away from longer term goals that include pursuing growth through acquisition strategies. Similarly, private equity sponsors have spent an increasing amount of time on efforts to strengthen or save their existing portfolio companies, at the expense of new deal activity.
Parties to pending M&A transactions are also abandoning significant deals that were pending, such as Xerox recently dropping its $34 billion offer for HP, after having postponed meetings with HP shareholders to focus on coping with the coronavirus pandemic. SoftBank has terminated its $3 billion tender offer for WeWork shares, citing the coronavirus impact together with the failure of a number of closing conditions. Bed Bath & Beyond has initiated litigation in Delaware with respect to delays in the pending sale of one of its divisions to 1-800-Flowers for $250 million. Boeing suppliers Hexcel and Woodward have called off their pending $6.4 billion merger of equals transaction noting the “unprecedented challenges” caused by the pandemic. Investment bankers report that most new sell-side assignments are being put on hold until things stabilize.
Of course, certain industries that have been disproportionately affected by the pandemic, such as travel and leisure, transportation, and oil and gas, may see upticks in M&A activity in 2020 as buyers see opportunities for bargains in these sectors. The existing M&A pipeline is thin, and the percentage of transactions involving rescue deals, restructurings, and distressed sellers will likely increase, both in dollar terms and as a percentage of overall M&A activity.
2. Timing and Delay in M&A Deals
For both existing M&A deals that survive the pandemic and new deals entered into during the pandemic, it is expected that deal timelines will be significantly extended. Each stage of a typical transaction, including preliminary discussions between the parties, the negotiation of letter of intent or term sheet, the negotiation of a definitive acquisition agreement, and the pre-closing period, will likely take longer to accomplish. These delays will result from a number of pandemic-related factors, including the following:
Negotiations will take longer: the overused adage of “getting everyone in the room” to get a deal agreed is not currently possible.
Due diligence will take longer, and new M&A due diligence issues will need to be addressed.
Third-party consents (such as from landlords, customers, and intellectual property licensors) will take longer to obtain.
There will be delays in obtaining any necessary antitrust or other regulatory approvals. The Department of Justice has asked firms involved in mergers and acquisitions to add 30 days to their deal timing agreements, and European competition regulators have suspended investigations of a number of proposed deals.
Buyers and their boards of directors are going to be much more cautious, and internal justifications for dealmaking in this environment will need to be more compelling.
M&A agreement terms will take longer to negotiate as buyers will want to shift more closing risk and (where applicable) indemnity risk to sellers, and sellers will seek comfort that the persistence of the pandemic will not permit buyers to walk away from deals based on “buyer’s remorse.”
Buyers will have concerns about their ability to properly value a seller in this environment. Valuations from comparable transactions, even those entered into very recently, will likely be no longer applicable.
Buyers requiring financing will encounter delays resulting from the unsettled state of debt markets and available liquidity, and M&A lenders may seek closing conditions that are even more stringent than those sought by buyers, increasing closing risk for both buyers and sellers.
3. Impact on Letters of Intent
Letters of intent, term sheets, memoranda of understanding, and the like are a common feature of the M&A landscape. Before investing heavily in due diligence and negotiating detailed transaction documents, buyers and sellers typically employ these preliminary, largely non-binding documents to memorialize their mutual understanding of all or some of the material deal terms. Further, since a grant of exclusivity by the seller (which frequently accompanies the execution of a letter of intent or completion of a term sheet) shifts negotiating leverage considerably in favor of the buyer, the seller will desire to nail down as many major deal terms as possible at this stage of the M&A process. Of course, it also is not unusual for a negotiated letter of intent or term sheet to address the purchase price and little else.
In light of the coronavirus pandemic, we expect to see buyers and sellers alike refraining from entering into (or even negotiating) a traditional letter of intent until the buyer first has performed incremental due diligence on the degree to which COVID-19 has adversely affected the seller’s business, results of operations, financial condition, customers, suppliers, workforce, and business prospects. The length of this period of incremental due diligence will depend upon the seller’s circumstances and the parties’ relative bargaining power. A buyer can expect the seller to push hard for a short period while resisting concurrent exclusivity.
Once the letter of intent negotiation begins, buyers should expect sellers (in the context of the pandemic) to attempt to include in the letter of intent provisions relating to closing conditions (including the scope of the material adverse effect definition), pre-closing covenants and drop dead dates (which are discussed in more detail below). For most letters of intent, these are unusual provisions. But during the pandemic, thoughtful sellers will want to take advantage of any bargaining leverage they have to address closing risk and closing certainty.
Buyers will feel justified in seeking longer periods of exclusivity than in the recent past since the pandemic poses new due diligence challenges. Until now, sellers—especially in the technology sector—in many instances had been successful in keeping exclusivity periods to 30-45 days or so (and sometimes even less). Now, it will be more common to see buyers insisting upon at least 60-75 days, with the ability to extend, in anticipation of coronavirus fallout interfering with or delaying the buyer’s due diligence investigation. In turn, well-advised sellers will seek provisions terminating exclusivity at the first sign that the buyer may be unwilling to proceed with the transaction on the terms set forth in the letter of intent or term sheet.
4. Availability and Terms of Debt Financing to Fund Acquisitions
Traditionally, a significant percentage of M&A deals are financed partially through debt, particularly in the private equity space. The volatility in the financing markets brought about by the coronavirus crisis has created challenges for transactions that depend on third-party debt financing, including injecting a fair amount of uncertainty about the availability and terms of such debt financing. The new financing-related questions and challenges facing buyers/borrowers will include the following:
Will lenders underwrite new financing commitments?
Will the buyer’s committed debt financing actually be available when the time comes to close the acquisition?
Will lead lenders whose commitments are conditioned on spreading the risk among a group of lenders have greater difficulty in syndicating the debt?
Will lenders be willing to conform their closing conditions to the closing conditions in the acquisition agreement, or will they insist on more stringent terms (such as the ability to declare a “material adverse effect” even if the buyer is willing to proceed with the transaction)?
Will the lenders increase pricing due to the risks of the coronavirus crisis, and insist on tighter financial covenants, increasing the risk of future events of default?
Will the amount of debt leverage available be decreased from the levels that had been customary in recent times, requiring private equity buyers to inject more equity into buyouts?
What additional due diligence will a lender insist upon, and how much delay will that involve?
How marginally risk averse will lenders be in acquisitions involving industries particularly hard hit by the crisis?
What obligations will buyers have in the event they cannot close a deal if debt markets become illiquid and lenders are unable to lend, and what remedies will sellers have in this circumstance? Will we see an increase in buyers seeking to use “reverse financing termination fees” in private company transactions to limit their financial exposure for broken deals?
Will lenders have a renewed focus on the “outside date” in their financing commitments and loan agreements, and potentially require increased payments for any commitment extension?
5. Effect on Dealmaking and Deal Terms
Invariably, when there is significant economic or other uncertainty in the world of M&A dealmaking, leverage shifts toward buyers and away from sellers. This was certainly the case with respect to dealmaking in the context of the burst of the dot-com bubble and dealmaking in the context of the Great Recession.
There is no reason to believe that it will be any different this time, in the context of the coronavirus pandemic. While strategic and private equity buyers are of course facing their own business and operational challenges, many continue to be “cash-rich” and generally can afford to bide their time to find the right acquisition targets at the right price.
Although public stock valuations have declined significantly since the end of February 2020, and the number of deals using all-stock or part-stock consideration had increased in the last few years, cash continues to be king in the dealmaking world. Many buyers continue to have plenty of “dry powder,” and the immediate slowdown in dealmaking as the crisis took hold in March 2020 will only serve to increase the relative leverage of buyers as the crisis continues to unfold.
Of course, some buyers may conclude that some of the cash that they would otherwise have used for M&A should be used for other obligations, including financing their own operating costs and replacing their own revenue lost as a result from the crisis.
Inevitably, as in past crises, the effect on deal pricing will not be uniform—sellers in industries that have been more significantly impacted by the pandemic (including retail, hospitality, travel, coworking spaces, and automobile and aircraft production) will be more significantly impacted than others (such as cloud computing, software, videoconferencing, other online technologies, biotech, food delivery, and online shopping) that have either been less impacted or have even thrived during the crisis.
To be sure, an increase in leverage for buyers in M&A dealmaking generally should not be misconstrued as suggesting that buyers will now be more likely to prevail in negotiating each individual deal term. Sellers will strenuously pursue deal terms that protect them from closing uncertainty, arguing that buyers in future deals will have had their “eyes open” about the pandemic and its consequences when they enter into acquisition agreements. While the pandemic (at least in the United States) was arguably not “foreseeable” when deals were entered into prior to March 2020, it certainly has become not only foreseeable, but the most significant factor in dealmaking since then.
In contrast, with respect to deals signed before the crisis unfolded that have not yet closed, buyers may have a degree of leverage to seek to terminate and walk away from deals, or renegotiate deal terms because of the effect of the pandemic on the ability of the seller to perform its pre-closing covenants and satisfy the buyer’s closing conditions.
The following is a summary of a number of M&A deal terms that have already been implicated by the coronavirus crisis, or with respect to which deal negotiations will likely be impacted by the crisis:
“Material Adverse Effect” Provisions.In most M&A transactions, the acquisition agreement has traditionally included a term commonly known as the “material adverse effect” (“MAE”) or “material adverse change” definition. The most important use of this definition is in the closing conditions—the buyer is not obligated to close the acquisition if the seller has suffered an MAE since the signing of the acquisition agreement (or the date of the seller’s most recent financial statements). The MAE provision seeks to allocate between the parties the risk of certain negative circumstances occurring or existing during the relevant period.
The question of whether a significant event such as the coronavirus pandemic constitutes an MAE depends on the specific contractual language used in the clause, as well as the current (or reasonably anticipated) impact of the pandemic on the seller’s business. There is a good deal of variation among MAE clauses, but they typically include these two components:
First, MAE clauses frequently include a number of “carve outs,” which the parties agree in advance will not constitute an MAE. Some common examples include conditions affecting the industry in which the seller operates, the U.S. economy or financial markets or any foreign markets or any foreign economy or financial markets in any location where the seller has material operations or sales, and acts of God, calamities, acts of war or terrorism, or national or international political or social conditions.
Second, they often include an exception to certain carve-out provisions, providing that the carve out only applies to the extent that the adverse effect of the identified matter (e.g., an act of God) does not “disproportionately” adversely affect the seller compared to other companies in the same industry.
Prior to the outbreak of COVID-19, if an MAE provision had included a carve out specifically referencing an “outbreak,” “epidemic,” “pandemic,” or other similar medical event, then the coronavirus pandemic would pretty clearly not constitute an MAE with respect to such transaction (although the “disproportionality” clause could enable a buyer to still declare an MAE if the seller has been affected more than its competitors by the pandemic). However, historically only a relatively small percentage of acquisition agreements have included terms that specifically reference such dangers to public health.
Courts have traditionally construed MAE clauses very narrowly, and few buyers have successfully terminated M&A transactions on the basis of such provisions. In Delaware, for example, an event will only constitute an MAE if it “substantially threaten[s] the overall earnings potential of the target in a durationally-significant manner.” Thus, the question of whether the effects of the COVID-19 pandemic may constitute an MAE (where it is not specifically carved out from the definition) may depend on the ultimate duration of the crisis and the persistence of its effect on the seller in question.
In future deals, some buyers will likely seek to include specific contractual language, providing that the COVID-19 pandemic is itself an MAE, or at least seeking to exclude it from the carve outs. But just as surely, sellers will take the position that the pandemic represents a known risk that the buyer should fairly have taken into account in valuing the seller’s business and proceeding with the transaction. Certainly, at a minimum, buyers will likely insist on the inclusion of the disproportionality clause, so that they are protected against adverse pandemic-related developments that ultimately are not industry-wide but rather limited to (or with greater impact on) the particular seller.
Pre-Closing Business Covenants.M&A transactions that require regulatory approvals or third-party consents usually provide for a period of time between signing and closing during which such approvals and consents are pursued and obtained. During this period, the seller is required to continue to operate in the ordinary course of business, and to comply with a number of other business covenants. These obligations may be absolute, or the seller may be required only to use commercially reasonable efforts to comply with them. There are commonly permitted deviations from the covenants in order for the seller to comply with applicable law, to comply with the acquisition agreement, to carry out a directive from the buyer, or to take actions that have been pre-approved by the buyer.
One of the closing conditions is invariably that the seller has complied (or complied in all material respects) with these pre-closing covenants. Moreover, in private company deals where the buyer is entitled to post-closing indemnification, a breach of the pre-closing business covenants likely will be one of the indemnifiable matters.
The rationale for requiring these covenants is solid: the buyer wants the seller to protect and maintain the business being acquired, and thus wants the right to veto any actions or decisions by the seller that may threaten the value of the business. The seller, on the other hand, wants to continue to control the business in the manner that it sees fit (particularly given that the transaction may ultimately not be consummated), and minimize the likelihood that closing conditions may not be satisfied. For deals with purchase price adjustment provisions (based on closing working capital or other financial metrics), the seller also wants to run the business in a manner that minimizes the risk of a negative purchase price adjustment.
In the case of transactions entered into before the COVID-19 pandemic became generally known, the pandemic may result in the seller being incapable of complying with one or more of these covenants, including restrictions on workforce reductions, restrictions on capital or other expenditures, prohibitions on material changes to personnel policies, and prohibitions on changes in compensation or benefits. Where there is an exception for matters “required by law,” the seller may be able to argue that shelter in place orders and similar governmental edicts permit it to deviate from these covenants.
For new transactions, the extent to which the performance of the seller’s pre-closing covenants may be excused by the effects or consequences of the pandemic will be a hotly contested topic. The seller will want comfort that reasonable (or required) steps it takes in response to the pandemic are not breaches of the acquisition agreement. Sellers will want to be able to respond quickly and decisively to the pandemic, without fear of breaching the acquisition agreement. In contrast, the buyer may argue that notwithstanding this, it should not ultimately be required to acquire a seller whose business and prospects at the time of closing have significantly deteriorated, whatever the cause. Having the buyer pre-approve the seller’s contingency plans in response to the pandemic could help avoid misunderstandings and disagreements on these topics.
“Drop-Dead” Dates and Termination Provisions.Another common feature of an M&A transaction with a delayed closing is the inclusion of a “drop-dead” date in the acquisition agreement. This is a particular date, typically several weeks (or months in the case of deals with potential regulatory issues) after the intended closing date, after which either party may terminate the agreement without consequence as a result of an unforeseen delay. If, for example, the closing of the deal has been unforeseeably delayed by the failure to obtain required antitrust or other regulatory approvals, or third-party consents, either party may terminate the transaction after the drop-dead date, provided that its own breach has not caused the delay.
The coronavirus crisis will cause both buyers and sellers to reconsider (and likely extend) the period of time between signing and the drop-dead date. Federal, state, and foreign governments have seen their operations, including their ability to complete M&A regulatory analyses, significantly impacted by the pandemic, delaying the turnaround times for such reviews and deal approvals.
With respect to transactions where the acquisition agreement was entered into before the COVID-19 pandemic but the transaction has not closed, the passage of the drop-dead date may provide an opportunity for a buyer with second thoughts about the deal to freely terminate the transaction. While the seller might believe it is unfair for the buyer to benefit from the unforeseen regulatory delay, the fact is that the possibility of such a delay is why the drop-dead provision was included in the first place.
Working Capital and Other Price Adjustment Provisions. Many private company M&A transactions include purchase price adjustment provisions based on the amount of the seller’s cash and indebtedness at closing. There is also typically a purchase price adjustment based on a comparison of the level of the seller’s working capital at closing to a target amount of “normalized” working capital. For transactions that were already signed (but not closed) before the coronavirus crisis, such adjustment provisions may result in reductions at closing to the net purchase price that the seller had previously expected to receive. For transactions yet to be signed, the COVID-19 pandemic will undoubtedly result in changes to practices associated with these provisions.
The question of what level of working capital is appropriate will likely be subject to new levels of scrutiny by buyers in light of the pandemic. Buyers may seek greater levels of normalized working capital (to help assure there will be sufficient working capital for the continued operations of the acquired business following the transaction in light of reduced revenues and new categories of expenditures). Sellers that become illiquid as a result of the crisis may also come under pressure from buyers to leave behind a portion of the purchase price credit they would otherwise have received for their closing cash balances.
The desire to avoid such price reductions may lead sellers to propose that the working capital-based price adjustment provisions be “collared” so that there is a band (above and below the agreed level of normalized working capital) within which the price reduction does not kick in, but buyers may be reluctant to accommodate such requests. The need to negotiate these types of new and more complex provisions may further delay transactions.
Alternative Forms of Consideration.The financial crisis associated with the COVID-19 pandemic will likely result in both downward pressures on deal values and a greater focus on the possible use of stock consideration in lieu of (or supplemental to) the buyer’s cash, as well as pricing structures involving earnouts or milestone payments.
These alternative forms of consideration traditionally become more prominent whenever, as a result of a financial crisis, there is a reduction in equity values that creates a fundamental disconnect between the price expectations of buyers and sellers. In the case of public buyers that have seen the pandemic reduce their market capitalizations, the use of their stock as acquisition consideration (where the seller has also lost value) may help to bring the parties together from a valuation perspective. Similarly, earnout and milestone structures, notwithstanding their complexities and flaws, could help enable buyers and sellers that cannot agree on valuation to reach an understanding that enables each party to feel that it is fairly sharing in the risks and uncertainties, and possible benefits, of the seller’s future performance.
Antitrust and Other Regulatory Approvals. Like other participants in M&A transactions, for the duration of the crisis it appears that most regulators will be working remotely, and paper filings will be discouraged or prohibited. This and other factors have severely disrupted the ordinary procedures for reviewing and approving transactions. For example, the Department of Justice and the Federal Trade Commission (FTC), after implementing an e-filing system for deal notifications under the Hart-Scott-Rodino Act, initially suspended the practice of granting early termination of the 30-day waiting period. The FTC has announced delays of several months in a number of high-profile administrative antitrust merger challenges, citing disruptions caused by the coronavirus outbreak. The speed at which regulators are able to adapt to the new environment and make continued changes in their procedures will be an important factor in dealmaking for buyers, sellers, and their legal and financial advisors.
Subsequently, the U.S. antitrust agencies announced that they would begin to allow early terminations on a limited basis, but also made clear that they would resolve any doubts in favor of not granting early termination. However, parties to transactions that do have antitrust implications may continue to expect routine clearance at the end of such period. It also can be expected that the agencies more frequently will ask parties to pull and refile notifications in order to give the agencies an additional 30 days to complete their review. International competition authorities, particularly in the European Union, have also significantly altered their deal review procedures in light of the pandemic.
For transactions that receive “second requests” from U.S. antitrust authorities, parties should expect that the crisis will add an additional two to three months to the already lengthy process of responding and resolving the regulatory concerns. Already several significant M&A transactions, including a generics merger between Pfizer’s Upjohn unit and Mylan, and a $63 billion merger of AbbVie and Allergan, have been delayed or postponed as a result of these regulatory developments.
For sensitive transactions involving foreign investment that must be cleared by the inter-agency committee known as the Committee on Foreign Investment in the United States (CFIUS), the relevant agencies are struggling with their caseload due to work-at-home requirements. The percentage of M&A transactions requiring CFIUS reviews has increased significantly as a result of the expansion of the scope of CFIUS coverage since 2018. One unique and critical challenge is that government officials are not permitted to access classified information from home or other remote locations. As a consequence of this and other related factors, in certain cases such agencies simply have not been commencing official CFIUS reviews during this period, and for deals where the official review has commenced, lengthy delays in obtaining clearance can be expected.
Representations and Warranties.The pandemic will lead to a demand by buyers for a number of additional focused representations and warranties from the seller, and associated disclosures, including with respect to the following areas:
The effects and consequences of the pandemic on the financial condition, results of operations, and prospects of the seller;
The seller’s compliance with applicable laws and governmental orders relating to the pandemic and development of contingency plans and processes to ensure business continuity;
The effect of the pandemic on the seller’s workforce, supply chain, inventory, accounts receivable, ability to perform material contracts, and solvency;
The potential availability to the seller of loans and other financial assistance associated with the pandemic;
Full or partial business closures (whether mandated by the government or as a result of changes in demand for the seller’s goods and services); and
The ability of the seller to adjust its business practices to minimize the short-term and long-term effect of the pandemic on its business.
The purpose of such enhanced representations and warranties, from the standpoint of the buyer, is to give the buyer a potential right to walk away from the deal if it were to learn before closing that such representations and warranties were untrue when made or have become untrue with the passage of time, and (in private company transactions) to enhance the buyer’s post-closing indemnification remedies associated with inaccuracies in the seller’s representations and warranties.
Of course such enhanced disclosures also serve to assist the buyer in effectively integrating the seller’s operations with its own, which will now include the new challenge of understanding the manner in which the seller has responded to the pandemic so that its response can be effectively melded with the buyer’s own response as quickly as possible following the closing.
Indemnity and Escrow Provisions; Representation and Warranty Insurance.In private company acquisitions, it is expected that the coronavirus crisis will put upward pressure on the size (typically expressed as a percentage of deal value) of indemnity escrows or holdbacks. This may be particularly the case in transactions where a seller has been successful in maintaining its expected top-line price notwithstanding the pandemic. In return for agreeing to such a “high” value, the buyer it is expected that the buyer may attempt to shift to the seller more of the risk of any breach by the seller of the acquisition agreement. In addition, it is expected that buyers will be less reticent to ask for “special indemnities” when they identify a particular risk in the seller’s business, and the post-closing consequences of such risk are less foreseeable or predictable as a result of the pandemic.
For private company acquisitions (primarily those involving private equity buyers) where representation and warranty insurance has become more prevalent in recent years, it is important to understand that insurers have been developing new underwriting policies and procedures to address the business risks of the pandemic. In certain cases, these new policies may exclude coverage for representations and warranties focused on pandemic-related topics. Insurers may also be increasingly reluctant to cover certain categories of buyer losses, including business interruptions and other consequences of the pandemic, consistent with their long-standing practice of seeking to exclude “known risks” from policy coverage. Predictably, representation and warranty insurers, just like buyers, will also likely insist on enhanced or extended diligence before underwriting policies.
If buyers that would otherwise rely solely or primarily on representations and warranty insurance start to perceive that they are not receiving appropriate coverage for deal-related risks, they may bring pressure on sellers to contribute increasing amounts to indemnity escrows or holdbacks as a backup to the insurance. Premiums also may increase as a result of these developments, which could contribute to an increasing percentage of deals where parties choose to utilize traditional escrow and holdback arrangements, rather than turning to insurance.
6. New M&A Due Diligence Issues
Acquirers are undertaking significant additional due diligence to assess the effect of the coronavirus crisis on the seller’s business. The expanded due diligence issues include the following:
In a world where physical contact is next to impossible, what strategies should the buyer implement to get to know the seller’s management and key employees? What can the buyer do to get comfortable without a physical visit/inspection?
What is the seller’s cash position? Does it have enough liquidity to fund its near-term obligations?
Are the seller’s revised financial projections reasonable and believable?
How has the seller’s workforce been impacted by the coronavirus? Does the seller have enough employees and third-party contractors to successfully continue its business?
Has the seller complied with federal and state laws in connection with furloughs and layoffs?
What is the cost to the seller of continuing to provide health care benefits to furloughed workers?
Has the seller defaulted on key contracts and/or leases?
Who are the counterparties to the seller’s key contracts and are they performing under those contracts?
What are the termination rights under key contracts? Do the seller’s contracts include “force majeure” clauses that may enable it or the counterparty to terminate the agreement or suspend performance or payment?
Is the seller in compliance with financial covenants and other terms of debt instruments?
Has the seller been able to work with landlords to defer rent payments? Has the seller started to search for alternative, lower cost space to rent?
Is the seller overly dependent on suppliers in certain geographic regions hard hit by the coronavirus?
What is the financial condition of the seller’s key customers?
What are the risks on collectability of accounts receivable?
What insurance (including business interruption insurance) does the seller have available to cushion losses? Are those losses insured if they are consequences of the coronavirus pandemic, or are they subject to policy exceptions? Have claims been made to the insurers?
What long-term liabilities does the seller have and will the seller be able to satisfy them?
Are there solvency or going concern risks?
Are there sufficient business continuity plans and crisis management procedures?
Who are the key employees? What happens to the seller’s business (and its value to the buyer) if they succumb to COVID-19?
What is the seller’s ability to control or reduce operating expenses? What contracts is the seller attempting to renegotiate to lower expenses?
What is the effect of “working from home” for employees (e.g., data privacy and privacy breaches)? What expenses is the seller incurring to provide equipment to employees working from home?
What IT, cybersecurity, and data breach issues has the seller encountered? Has the seller had problems with hackers interfering with video conferences or taken steps to prevent that risk?
Is the seller at risk of having insufficient inventory or parts?
Is the seller able to take advantage of the favorable loans under the Coronavirus Aid, Relief, and Economic Security (CARES) Act? If so, what are the terms of these loans and how do they affect the buyer’s plans and expectations going forward?
Is the seller in compliance with federal, state, and local orders related to the pandemic?
Is the seller in compliance with health and safety laws with respect to its workplaces and employees in light of the danger posed by the pandemic?
If all or a portion of the seller’s workforce is unionized, what is the state of relations between the union(s) and the seller? Is there a strike or walk-out risk?
7. The WARN Act and Consequences of Layoffs and Furloughs
The coronavirus crisis has led a significant number of employers across the country to seek to control costs through massive workforce reductions and furloughs. Over 20 million new applications for unemployment payments have been filed just within the last few weeks. Companies considering these reductions and furloughs must consider the impact of the Worker Adjustment and Retraining Notification (WARN) Act, and careful compliance with relevant federal and state laws impacting employment will be particularly critical for sellers considering participating in M&A in the near future. The WARN Act generally requires employers to provide written notice at least 60 days in advance of significant layoffs or other covered activities (such as plant closures), or pay in lieu of such notice.
Layoffs of less than six months in duration do not constitute a mass layoff under the WARN Act. But since coronavirus-related reductions in force may, at least initially, be of uncertain duration, sellers will need to be careful to comply as soon as practicable if a delay in reactivating a furloughed workforce brings the WARN Act into effect.
The Warn Act sets forth certain exceptions that may affect its applicability to sellers that would otherwise be covered by its terms in the context of the coronavirus crisis. There is an “unforeseeable business circumstances exception” that applies to reductions in force that are made based on changes in the business environment that were not reasonably foreseeable at the time when the written notice would otherwise have been required to be given, such as circumstances “caused by some sudden, dramatic, and unexpected action or condition outside the employer’s control.” There is also a “natural disaster exception” that covers “floods, earthquakes, droughts, storms, tidal waves or tsunamis and similar effects of nature.”
Employers that would otherwise be covered by the WARN Act could potentially take the position that the pandemic qualifies for one or both of these exceptions. However, the safer course of action, particularly for a company involved or likely to be involved as a seller in an M&A transaction, is to simply comply with the WARN Act, as the buyer in the transaction may predictably not wish to run the risk that a claim of an exception might be challenged by the government for affected employees following the closing. Compliance with employee-related laws and regulations will clearly be an area of increased due diligence by buyers in the new business environment.
Each sheet in the workbook is separated by current COVID-19 vaccine trials, currents COVID-19 trials with the IL6R (interleukin 6 receptor) antagonist tocilizumab, and all COVID related trials. The Excel spreadsheet also contains links to more information about the trials.
As of April 15, 2020 the number of listed trials are as follows:
clinicaltrials.gov search terms
Number of results
Number of completed trials
Number of trials currently recruiting
COVID-19 or SARS-CoV-2
410
5 completed
5 withdrawn
192
1st row terms + vaccine
28
0
15
1st row terms + tocilizumab
16
0
10
1st row terms + hydroxychloroquine
61
1
22
A few highlights of the COVID related trials on clinicaltrials.gov
This is an open label, randomized, controlled, pilot clinical study in patients with COVID-19, to obtain preliminary biologic, physiologic, and clinical data in patients with COVID-19 treated with rhACE2 or control patients, to help determine whether a subsequent Phase 2B trial is warranted.
Condition or disease
Intervention/treatment
Phase
COVID-19
Drug: Recombinant human angiotensin-converting enzyme 2 (rhACE2)
Not Applicable
Detailed Description:
This is a small pilot study investigating whether there is any efficacy signal that warrants a larger Phase 2B trial, or any harm that suggests that such a trial should not be done. It is not expected to produce statistically significant results in the major endpoints. The investigators will examine all of the biologic, physiological, and clinical data to determine whether a Phase 2B trial is warranted.
Primary efficacy analysis will be carried only on patients receiving at least 4 doses of active drug. Safety analysis will be carried out on all patients receiving at least one dose of active drug.
It is planned to enroll more than or equal to 24 subjects with COVID-19. It is expected to have at least 12 evaluable patients in each group.
Experimental group: 0.4 mg/kg rhACE2 IV BID and standard of care Control group: standard of care
Intervention duration: up to 7 days of therapy
No planned interim analysis.
Study was withdrawn before participants were enrolled.
Gut dysbiosis co-exists in patients with coronavirus pneumonia. Some of these patients would develop secondary bacterial infections and antibiotic-associated diarrhea (AAD). The recent study on using washed microbiota transplantation (WMT) as rescue therapy in critically ill patients with AAD demonstrated the important clinical benefits and safety of WMT. This clinical trial aims to evaluate the outcome of WMT combining with standard therapy for patients with 2019-novel coronavirus pneumonia, especially for those patients with dysbiosis-related conditions.
Detailed Description:
An ongoing outbreak of 2019 novel coronavirus was reported in Wuhan, China. 2019-nCoV has caused a cluster of pneumonia cases, and posed continuing epidemic threat to China and even global health. Unfortunately, there is currently no specific effective treatment for the viral infection and the related serious complications. It is in urgent need to find a new specific effective treatment for the 2019-nCoV infection. According to Declaration of Helsinki and International Ethical Guidelines for Health-related Research Involving Humans, the desperately ill patients with 2019-nCov infection during disease outbreaks have a moral right to try unvalidated medical interventions (UMIs) and that it is therefore unethical to restrict access to UMIs to the clinical trial context.
There is a vital link between the intestinal tract and respiratory tract, which was exemplified by intestinal complications during respiratory disease and vice versa. Some of these patients can develop secondary bacterial infections and antibiotic-associated diarrhea (AAD). The recent study on using washed microbiota transplantation (WMT) as rescue therapy in critically ill patients with AAD demonstrated the important clinical benefits and safety of WMT. Additionally, the recent animal study provided direct evidence supporting that antibiotics could decrease gut microbiota and the lung stromal interferon signature and facilitate early influenza virus replication in lung epithelia. Importantly, the above antibiotics caused negative effects can be reversed by fecal microbiota transplantation (FMT) which suggested that FMT might be able to induce a significant improvement in the respiratory virus infection. Another evidence is that the microbiota could confer protection against certain virus infection such as influenza virus and respiratory syncytial virus by priming the immune response to viral evasion. The above results suggested that FMT might be a new therapeutic option for the treatment of virus-related pneumonia. The methodology of FMT recently was coined as WMT, which is dependent on the automatic facilities and washing process in a laboratory room. Patients underwent WMT with the decreased rate of adverse events and unchanged clinical efficacy in ulcerative colitis and Crohn’s disease. This clinical trial aims to evaluate the outcome of WMT combining with standard therapy for patients with novel coronavirus pneumonia, especially for those patients with dysbiosis-related conditions.
Responsible Party:
Faming Zhang, Director of Medical Center for Digestive Diseases, The Second Hospital of Nanjing Medical University
The 2019 novel coronavirus pneumonia outbroken in Wuhan, China, which spread quickly to 26 countries worldwide and presented a serious threat to public health. It is mainly characterized by fever, dry cough, shortness of breath and breathing difficulties. Some patients may develop into rapid and deadly respiratory system injury with overwhelming inflammation in the lung. Currently, there is no effective treatment in clinical practice. The present clinical trial is to explore the safety and efficacy of Human Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) therapy for novel coronavirus pneumonia patients.
Detailed Description:
Since late December 2019, human pneumonia cases infected by a novel coronavirus (2019-nCoV) were firstly identified in Wuhan, China. As the virus is contagious and of great epidemic, more and more cases have found in other areas of China and abroad. Up to February 24, a total of 77, 779 confirmed cases were reported in China. At present, there is no effective treatment for patients identified with novel coronavirus pneumonia. Therefore, it’s urgent to explore more active therapeutic methods to cure the patients.
Recently, some clinical researches about the 2019 novel coronavirus pneumonia published in The Lancet and The New England Journal of Medicine suggested that massive inflammatory cell infiltration and inflammatory cytokines secretion were found in patients’ lungs, alveolar epithelial cells and capillary endothelial cells were damaged, causing acute lung injury. It seems that the key to cure the pneumonia is to inhibit the inflammatory response, resulting to reduce the damage of alveolar epithelial cells and endothelial cells and repair the function of the lung.
Mesenchymal stem cells (MSCs) are widely used in basic research and clinical application. They are proved to migrate to damaged tissues, exert anti-inflammatory and immunoregulatory functions, promote the regeneration of damaged tissues and inhibit tissue fibrosis. Studies have shown that MSCs can significantly reduce acute lung injury in mice caused by H9N2 and H5N1 viruses by reducing the levels of proinflammatory cytokines and the recruitment of inflammatory cells into the lungs. Compared with MSCs from other sources, human umbilical cord-derived MSCs (UC-MSCs) have been widely applied to various diseases due to their convenient collection, no ethical controversy, low immunogenicity, and rapid proliferation rate. In our recent research, we confirmed that UC-MSCs can significantly reduce inflammatory cell infiltration and inflammatory factors expression in lung tissue, and significantly protect lung tissue from endotoxin (LPS) -induced acute lung injury in mice.
The purpose of this clinical study is to investigate safety and efficiency of UC-MSCs in treating pneumonia patients infected by 2019-nCoV. The investigators planned to recruit 48 patients aged from 18 to 75 years old and had no severe underlying diseases. In the cell treatment group, 24 patients received 0.5*10E6 UC-MSCs /kg body weight intravenously treatment 4 times every other day besides conventional treatment. In the control group, other 24 patients received conventional treatment plus 4 times of placebo intravenously. The lung CT, blood biochemical examination, lymphocyte subsets, inflammatory factors, 28-days mortality, etc will be evaluated within 24h and 1, 2, 4, 8 weeks after UC-MSCs treatment.
Sponsor:
Puren Hospital Affiliated to Wuhan University of Science and Technology
Collaborator:
Wuhan Hamilton Bio-technology Co., Ltd
Study was withdrawn before participants were enrolled.
There are currently no clinical studies reporting clinical characteristics difference between the hypertension patients with and without ACEI treatment when suffered with novel coronavirus infection in China
Detailed Description:
At present, the outbreak of the new coronavirus (2019-nCoV) infection in Wuhan and Hubei provinces has attracted great attention from the medical community across the country. Both 2019-nCoV and SARS viruses are coronaviruses, and they have a large homology.
Published laboratory studies have suggested that SARS virus infection and its lung injury are related to angiotensin-converting enzyme 2 (ACE2) in lung tissue. And ACE and ACE2 in the renin-angiotensin system (RAS) are vital central links to maintain hemodynamic stability and normal heart and kidney function in vivo.
A large amount of evidence-based medical evidence shows that ACE inhibitors are the basic therapeutic drugs for maintaining hypertension, reducing the risk of cardiovascular, cerebrovascular, and renal adverse events, improving quality of life, and prolonging life in patients with hypertension. Recent experimental studies suggest that treatment with ACE inhibitors can significantly reduce pulmonary inflammation and cytokine release caused by coronavirus infection.
ACEI treatment
hypertension patients with ACEI treatment when suffered with novel coronavirus infection in China
Control
hypertension patients without ACEI treatment when suffered with novel coronavirus infection in China
Locations
China
The First Affiliated Hospital of Chongqing Medical University Chongqing, China
Sponsors and Collaborators Chongqing Medical University
Responsible PI:
Dongying Zhang, Associate Professor, Chongqing Medical University
Withdrawn (Similar projects have been registered, and it needs to be withdrawn.)
April 16, 2020 – Report on the Ongoing SARS-CoV-2 Pandemic causing the COVID-19 Disease
Reporter and Curator: Mr. Srinjoy Chakraborty (Junior Research Fellow) and Dr. Sudipta Saha, Ph.D.
Introduction:
In December 2019, several cases of viral pneumonia of unknown origin were reported in the city of Wuhan, China. Further investigation by the national regulatory authorities revealed that many of the registered cases had links to the Huanan wholesale seafood market. A novel corona virus was identified after broncho-alveolar lavage fluid from patients with pneumonia of unknown origin was inoculated in human airway epithelial cells and Vero E6 and Huh7 cell lines. A few days later, the whole genome sequence of this novel virus was published, and it was named as the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses because of its close resemblance to the SARS-CoV, which had infected approximately 8000 individuals worldwide.
The first SARS-CoV-2-related death was reported on the 11th of January, 2020. Today, having spread to approximately 213 countries and territories and claiming a total of 1,30,885 lives worldwide (as of 16th April 2020), the SARS-CoV-2 pandemic has left several leading economies in ruins.
Genome and Phylogenetics:
The novel SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus that belongs to the broad family of viruses known as coronaviridae. The viruses belonging to this family are further divided into four genera: Alpha-, Beta-, Gamma-, and Delta-coronavirus. Other viruses belonging to this family are known to cause illnesses ranging from the common cold to more severe diseases such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS).
The SARS-Cov-2 is the seventh known coronavirus to infect people, after 229E, NL63, OC43, HKU1, MERS-CoV and the original SARS-CoV. With a diameter of approximately 65–125 nm, the genome of the coronavirus is approximately 30 kb-long. The four important structural components of the virus are the envelope protein (E) membrane protein (M) spike protein (S) and nucleocapsid protein (N).
Phylogenetic analysis of SARS-CoV-2 that were isolated from patients in Wuhan revealed that it was closely related to a SARS-like (SL) CoV, RaTG13, which was obtained from infected Rhinolophus sinicus in a cave in Yunnan, China, in 2013. These two viruses share approximately 96% of nucleotide sequence identities, thus confirming it to be of zoonotic origin
Biochemistry and mechanism of infection:
Biochemical and structural studies have revealed that the SARS-CoV-2 utilizes a densely glycosylated spike (S) protein to enter host cells. The two functional domains of the S protein are a receptor binding domain and a domain that mediates fusion of the viral and cell membranes. A furin like cleavage site in the S protein results in the cleavage of the protein, thus mediating fusion of the viral and cell membranes.
The receptor binding domain (RBD) of the S protein binds to angiotensin-converting enzyme 2 (ACE2) in host cells with higher affinity compared to severe acute respiratory syndrome (SARS)-CoV. ACE2 is a membrane-associated aminopeptidase that is expressed in vascular endothelia, renal and cardiovascular tissue, and epithelia of the small intestine and testes. Several studies have demonstrated that overexpression of ACE2 enhanced the severity of the disease in mouse, human and other animal models. It has been reported that the epithelial cells that line the respiratory tract, especially the lung epithelia and the alveolar epithelial type 2 cells, are more susceptible to infection by the virus and that these cells act as reservoirs for viral invasion. These viruses cause acute lung injury and acute respiratory disease syndrome.
India and SARS-CoV-2:
With a steady increase in the number of patients who are testing positive for SARS-CoV-19, national and international regulatory bodies are taking crucial and radical steps to curb and reduce the number of cases. On the 14th of April, the Indian government extended the ongoing lockdown till the 3rd of May, 2020. Social distancing has been the most effective way of avoiding the spread of this disease. Various organisations in the private and public sectors are engaged in developing diagnostic kits and possible therapies for tackling this pandemic.
Based on the reports and protocols in China, the Indian Council of Medical Research (ICMR) started screening passengers arriving from China and other countries from the 18th of January. Several citizens who were evacuated from the pandemic hit areas across the globe were screened upon their arrival to the country. Samples were first sent to the National Institute of Virology for screening. After genome sequence of the SARS-CoV-2 virus was published in China, candidate diagnostic real-time reverse transcription-polymerase chain reaction (rRTPCR) assays were designed and made available in the public domain for researchers. This method targeted the SARS-CoV-2-specific E gene. Confirmatory assays targeted the ‘RdRp gene’, ‘N gene’ and ‘ORF-1b’. An optimized method of the same assay was developed by the ICMR-National Institute of Virology to detect various genomic regions of the SARS-Cov-2. Recently, the ICMR also approved a diagnostic kit for detecting antibodies in blood samples. This kit detects IgM and IgG antibodies in blood samples. This method is not only a cheaper alternative but also a rapid test. However, as of 13th April, 2020, this testing is yet to begin in India as the country is currently awaits the import of rapid test kits. Housing the country’s only biosafety level 4 laboratory, scientists at the NIV recently published an electron micrograph image of the SARS-CoV-2 viral particle.
Although much is known about the physiology and the mode of action of SARS-CoV-2, we are still far away from developing a vaccine or a treatment. Several promising vaccine candidates against SARS-Cov-2 include live viruses, recombinant protein subunits, and nucleic acids. Several pharmaceutical organizations and universities are now attempting to fast track ways of developing a vaccine as soon as possible.
Social distancing and mass awareness continue to be the most effective way in tackling the spread of this disease. We must also consider the fact that COViD-19 is the 3rd pandemic caused by a virus belonging to the coronavirus family in the last 20 years; SARS in 2002, MERS in 2012, and now COVID-19. Therefore stockpiling and developing vaccines, testing kits, personal protective equipment, as well as identifying international funding mechanisms to support the development, manufacture, and storage of vaccines and therapeutic alternatives is of utmost priority today.
Nitric oxide is an important molecule playing a key role in a broad range of biological process such as neurotransmission, vasodilatation and immune responses. While the anti-microbiological properties of nitric oxide-derived reactive nitrogen intermediates (RNI) such as peroxynitrite, are known, the mechanism of these effects are as yet poorly studied. Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) belongs to the family Coronaviridae, was first identified during 2002-2003. Mortality in SARS patients ranges from between 6 to 55%. We have previously shown that nitric oxide inhibits the replication cycle of SARS-CoV in vitro by an unknown mechanism. In this study, we have further investigated the mechanism of the inhibition process of nitric oxide against SARS-CoV. We found that peroxynitrite, an intermediate product of nitric oxide in solution formed by the reaction of NO with superoxide, has no effect on the replication cycle of SARS-CoV, suggesting that the inhibition is either directly effected by NO or a derivative other than peroxynitrite. Most interestingly, we found that NO inhibits the replication of SARS-CoV by two distinct mechanisms.
Firstly, NO or its derivatives cause a reduction in the palmitoylation of nascently expressed spike (S) protein which affects the fusion between the S protein and its cognate receptor, angiotensin converting enzyme 2.
Secondly, NO or its derivatives cause a reduction in viral RNA production in the early steps of viral replication, and this could possibly be due to an effect on one or both of the cysteine proteases encoded in Orf1a of SARS-CoV.
A Possible Explanation for the COVID-19 Racial Disparity
— And a possible solution
by Jason Kidde MS, MPAS, PA-CApril 18, 2020
While the pathophysiology of hypertension is complex and multifaceted, there are notable racial differences. In the context of COVID-19, the most suspicious difference is a comparative deficiency of L-arginine and subsequently nitric oxide (NO). In this lies a potential explanation for the COVID-19 race disparity
NO is a gas synthesized by our cells and has multiple roles, but perhaps is best known for vascular dilation. In short, NO facilitates relaxation of vascular smooth muscle allowing vessel dilation and increased blood flow.
This on its own has potential implications in acute respiratory distress syndrome (ARDS), a condition that results from severe COVID-19 infection. By improving blood flow across the entire lung, this theoretically results in improved gas exchange and oxygenation of the blood. In fact, there is research that inhaled NO improved oxygenation and other clinical outcomes in SARS-1 patients, and current research in COVID-19 coronavirus (SARS-CoV-2) supports this previously demonstrated efficacy.
Additionally, abnormal blood clotting is an increasingly recognized complication of this disease, both systemically and within the pulmonary circulation. In fact, one of the greatest predictors of death is a serum blood test that indicates elevated clotting activity. Most recently, some physicians have suggested that small clots within the lungs are central to pathogenesis and have administered clot busting drugs known as thrombolytics which abruptly improve oxygenation, albeit transiently, as the medication effect weans and the predisposition to clot formation persists. NO inhibits clot formation, and deficiency may contribute to a prothrombotic state. In fact, it has been shown that inhaled NO decreases the propensity of clotting in ARDS.
However, perhaps the most convincing role of nitric oxide in this disease is its antiviral properties. SARS-CoV-2 infects cells by attaching to a receptor on the lining of the airways called angiotensin-converting enzyme 2 (ACE2). This is the same mechanism by which SAR-1 infects cells. NO specifically alters a surface protein on SARS-1, known as the spike protein, such that it cannot attach to the ACE2 receptor. This results in blocking viral entry into the cell as well as the subsequent replication of the virus. Since SARS-CoV-2 shares the same mechanism of cell entry, we can relatively confidently assume that NO would have a similar effect regarding this novel virus.
Knowing that NO deficiency is common in African Americans and that this population is disproportionately dying from an infection that can be blocked by this gas, augmenting NO seems like a reasonable therapeutic target. While NO is being used as an inhaled gas via mechanical ventilation, this is only suitable for someone ill enough to require mechanical ventilation.
A better way to increase nitric oxide in the minimally ill or even uninfected is to augment the body’s ability to create it. There are many pharmacologic ways to do this; however, potentially the most effective, cheapest, and lowest risk is to supplement with the precursor amino-acids L-arginine and L-citrulline. We already know these nutritional supplements result in this very effect and that there seems to be a more potent effect of supplementation on NO production in L-arginine-deficient African Americans.
Therefore, a reasonable action is to expedite clinical trials to further investigate this theory. At a minimum, we need to start a conversation to improve our understanding of the role of nitric oxide deficiency as a risk factor for disease severity. It is my strong belief that augmenting NO via L-arginine and L-citrulline not only has potential for treatment and reducing progression to severe illness, but given the safety profile, it may be most valuable as a preventative measure.
It could save many lives at a minimal cost.
Jason Kidde, MS, MPAS, is a physician assistant at University of Utah Health in Salt Lake City.
ummary: A new clinical trial is enrolling patients with severe COVID-19 symptoms to assess the effect of nitric oxide in treating the virus. Previous research found nitric oxide has antiviral properties against coronaviruses. The effect was tested and demonstrated during the SARS outbreak in the early 2000s.
Source: University of Alabama at Birmingham
The University of Alabama at Birmingham has been selected to begin enrolling patients in an international study assessing the use of inhaled nitric oxide (iNO) to improve outcomes for COVID-19 patients with severely damaged lungs.
iNO has been used for the treatment of failing lungs, but it was also found to have antiviral properties against coronaviruses
“In humans, nitric oxide is generated within the blood vessels and regulates blood pressure, and prevents formation of clots and also destroys potential toxins,” Arora said.
The UAB team says this pandemic has led to an extraordinary unifying response by the medical community, including ICU physicians, nurses, respiratory therapists, clinical trial specialists, reviewers and medical administrators, allowing for faster than normal approvals for potentially lifesaving research studies.
“The fact that we are able to get this trial started quickly was due to collaborations across specialties and fields of expertise at UAB with the common goal of providing the highest quality of scientifically proven care for our COVID-19 patients,” Arora said. “We are all trying to fight this together, and I hope, with our resilience, we shall overcome these difficult times.”
SOURCE
Source: University of Alabama at Birmingham Media Contacts:
Adam Pope – University of Alabama at Birmingham Image Source:
The image is credited to University of Alabama at Birmingham.
Other related articles published in this Open Access Online Scientific Journal include the following:
Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use of iNO in the Institutional Market, Therapy Demand and Cost of Care vs. Existing Supply Solutions
Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms. On com since 6/21/2013 https://lnkd.in/8DANfq
Cardiovascular Diseases, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation. On com since 11/30/2015 https://lnkd.in/ekbuNZ3
Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics. On com since 11/29/2015 https://lnkd.in/ecp5mrA
Cardiovascular Diseases, Volume Four: Regenerative and Translational Medicine: The Therapeutics Promise for Cardiovascular Diseases. On com since 12/26/2015 https://lnkd.in/dwqM3K3
Cardiovascular Diseases, Volume Five: Pharmacological Agents in Treatment of Cardiovascular Diseases. On com since 12/23/2018 https://lnkd.in/e3r87cQ
Cardiovascular Diseases, Volume Six: Interventional Cardiology for Disease Diagnosis and Cardiac Surgery for Condition Treatment. On com since 12/24/2018 https://lnkd.in/e_CTb4R
Cardiovascular Diseases, Volume One: Perspectives on Nitric Oxide in Disease Mechanisms. On Amazon.com since 6/21/2013
Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients
Reporter: Aviva Lev-Ari, PhD, RN
Emergency room doctor, near death with coronavirus, saved with experimental treatment
Soon after being admitted to his own hospital with a fever, cough and difficulty breathing, he was placed on a ventilator. Five days after that, his lungs and kidneys were failing, his heart was in trouble, and doctors figured he had a day or so to live.
He owes his survival to an elite team of doctors who tried an experimental treatment pioneered in China and used on the sickest of all COVID-19 patients.
Lessons from his dramatic recovery could help doctors worldwide treat other extremely ill COVID-19 patients.
Based on the astronomical level of inflammation in his body and reports written by Chinese and Italian physicians who had treated the sickest COVID-19 patients, the doctors came to believe that it was not the disease itself killing him but his own immune system.
It had gone haywire and began to attack itself — a syndrome known as a “cytokine storm.”
The immune system normally uses proteins called cytokines as weapons in fighting a disease. For unknown reasons in some COVID-19 patients, the immune system first fails to respond quickly enough and then floods the body with cytokines, destroying blood vessels and filling the lungs with fluid.
Dr. Matt Hartman, a cardiologist, said that after four days on the immunosuppressive drug, supplemented by high-dose vitamin C and other therapies, the level of oxygen in Padgett’s blood improved dramatically. On March 23, doctors were able to take him off life support.
Four days later, they removed his breathing tube. He slowly came out of his sedated coma, at first imagining that he was in the top floor of the Space Needle converted to a COVID ward.