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Why Aroa is pushing ahead with its IPO despite pandemic – The Australian Financial Review

Posted: June 23, 2020 at 5:54 pm

"When COVID came along we really weren't sure how things would pan out ... but we were less impacted than we thought we'd be ... in that sense there is ongoing demand, but we will have some lumpiness."

Aroa filed its prospectus to list this week, intending to start trading on July 30. The float is being managed by brokers Wilsons and Bell Potter.

We've been able to provide a leading biologic that's 20-60 per cent less expensive.

Brian Ward, Aroa Biosurgery CEO

The New Zealand company has created a biological scaffold from sheep forestomachs, which helps the body to grow new tissue that's been lost due to disease or injury.

The business gets access to the forestomachs from sheep that have been killed for food and the product would have otherwise gone to waste.

Its Endoform products are already in use in more than 600 hospitals and have been used in 4 million surgeries to date.

At the moment the company has scaffolds on the market that can be used to help heal diabetic ulcers, hernias and wounds.

In the year to March 31, the business recorded $NZ25 million ($23.4 million) of revenue and a loss after tax of $NZ6 million.

Mr Ward said the product's advantage over other biological scaffolds on the market was that they were cheaper but just as effective, if not more.

"We have a very efficient large-scale process that's able to produce the material very cost-effectively and in doing that, it's also just a really high-quality product," he said.

Mr Ward says Aroa's biological scaffolds are cheaper and at least as effective as any others on the market.

"We purify it in a gentle way that preserves the biology of the material, having invested significant time and resource into that process in the past 11 years.

"To date, other biologic materials have been limited because they're very expensive, but we've been able to provide a leading biologic that's 20-60 per cent less expensive, letting more patients get access to it."

To date the company has raised about $NZ30 million from venture capitalists and wealthy investors in New Zealand and Australia.

As part of the float, the company will issue 40 million new shares at 75 a share, raising $30 million, while existing shareholders will sell $15 million worth of shares.

After the float, Mr Ward will retain an 11 per cent stake.

Mr Ward started his career as a veterinary surgeon before moving into the life sciences sector, taking on roles with Baxter and SmithKline Beecham. He has also managed investments into New Zealand technology companies for the Foundation for Research Science and Technology.

After becoming interested in regenerative medicine, Mr Ward spent eight years developing the Endoform product before launching commercially in 2016.

Its products have been peer-reviewed and have regulatory approval in 37 countries. Its biggest market is the US, where it sells its products directly as well as through NASDAQ-listed TELA Bio.

The total addressable market for its current products is estimated to be $US1.5 billion ($2.2 billion), but it has more products in its pipeline targeted at things such as complex wounds and breast surgery that it expects will grow this by an additional $US1 billion.

Aroa competes with fellow ASX-listed biotech company PolyNovo, which in early 2019 traded at only 60, but now fetches about $2.45 a share and has a market capitalisation of $1.6 billion.

Mr Ward said the capital raised through the IPO would help it expand its commercial team in the US.

"We see a great opportunity for us to really develop a leadership position at the advanced end of this market," he said. "We believe we can be the leading regenerative medicine company."

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BrainStorm Cell Therapeutics to Join the Russell 2000 Index and Russell 3000 Index – Yahoo Finance

Posted: June 23, 2020 at 5:54 pm

NEW YORK, June 23, 2020 /PRNewswire/ --BrainStorm Cell Therapeutics Inc. (NasdaqCM: BCLI), a leading developer of adult stem cell therapies for neurodegenerative diseases, today announced that its shares will join the Russell 2000 Index and the broad-market Russell 3000 Index at the conclusion of the 2020 Russell indexes annual reconstitution, effective after the US stock market opens on June 29, 2020.

Annual Russell indexes reconstitution captures the 4,000 largest US stocks as of May 8, ranking them by total market capitalization. Membership in the US all-cap Russell 3000 Index, which remains in place for one year, means automatic inclusion in the large-cap Russell 1000 Index or small-cap Russell 2000 Index as well as the appropriate growth and value style indexes. FTSE Russell determines membership for its Russell indexes primarily by objective, market-capitalization rankings and style attributes.

Russell indexes are widely used by investment managers and institutional investors for index funds and as benchmarks for active investment strategies. Approximately $9 trillion in assets are benchmarked against Russell's US indexes. Russell indexes are part of FTSE Russell, a leading global index provider.

For more information on the Russell 3000 Index and the Russell indexes reconstitution, go to the "Russell Reconstitution" section on the FTSE Russell website.

About FTSE Russell

FTSE Russell is a leading global index provider creating and managing a wide range of indexes, data and analytic solutions to meet client needs across asset classes, style and strategies. Covering 98% of the investable market, FTSE Russell indexes offer a true picture of global markets, combined with the specialist knowledge gained from developing local benchmarks around the world.

FTSE Russell index expertise and products are used extensively by institutional and retail investors globally. Approximately $16 trillion is currently benchmarked to FTSE Russell indexes. For over 30 years, leading asset owners, asset managers, ETF providers and investment banks have chosen FTSE Russell indexes to benchmark their investment performance and create investment funds, ETFs, structured products and index-based derivatives. FTSE Russell indexes also provide clients with tools for asset allocation, investment strategy analysis and risk management.

A core set of universal principles guides FTSE Russell index design and management: a transparent rules-based methodology is informed by independent committees of leading market participants. FTSE Russell is focused on index innovation and customer partnership applying the highest industry standards and embracing the IOSCO Principles. FTSE Russell is wholly owned by London Stock Exchange Group. For more information, visit http://www.ftserussell.com/.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug status designation from the U.S. Food and Drug Administration (U.S. FDA) and the European Medicines Agency (EMA) in ALS. BrainStorm has fully enrolled a Phase 3 pivotal trial in ALS (NCT03280056), investigating repeat-administration of autologous MSC-NTF cells at six U.S. sites supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). The pivotal study is intended to support a filing for U.S. FDA approval of autologous MSC-NTF cells in ALS. BrainStorm also recently received U.S. FDA clearance to initiate a Phase 2 open-label multicenter trial in progressive Multiple Sclerosis. The Phase 2 study of autologous MSC-NTF cells in patients with progressive MS (NCT03799718) started enrollment in March 2019.

Story continues

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may", "should", "would", "could", "will", "expect", "likely", "believe", "plan", "estimate", "predict", "potential", and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, regulatory approval of BrainStorm's NurOwn treatment candidate, the success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation,; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available at http://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

CONTACTS

Investor Relations:Michael RiceLifeSci Advisors, LLCPhone: +1 646 889 1200mrice@lifesciadvisors.com

Public Relations:Paul TyhalaSmithSolve973.442.1555paul.tyahla@smithsolve.com

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SOURCE Brainstorm Cell Therapeutics Inc

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Biologics Safety Testing Market Is Projected to Expanding at a CAGR of 12.13% By The End of 2025 (Study With Impact of COVID-19 on Global Market) -…

Posted: June 23, 2020 at 5:54 pm

The global Biologics Safety Testing Market was valued at USD 2.18 billion in 2016 and is projected to reach USD 6.10billion by 2025, growing at a CAGR of 12.13% from 2017 to 2025.

Stability or Safety Testing can be used to demonstrate short and long term stability of a drug substance/product after exposure to a variety of environmental factors including temperature, humidity and light.It can be used to determine the genetic disorders, health conditions, Testing of Vaccines before public launch.

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X-Ray Detectors MarketBiometric MarketCybersecurity MarketBYOD And Enterprise Mobility MarketSalmon MarketSmart Home MarketU.S. Financial Services Cyber Security MarketResearch Antibodies MarketMedical Devices Packaging MarketLaboratory Filtration MarketGlucometer MarketCompetent Cells Market Collagen And Gelatin Market For Regenerative Medicine MarketBiologics Safety Testing MarketBiobanking Market

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Market Dynamics:1. Market Drivers1.1 Increasing investments in Biotechnology and pharmaceutical companies1.2 Positive developments in R&D sector1.3 Growing Drug Discoveries1.4 Prevalence of chronic diseases

2. Market Restraints2.1 Dearth of IT Professionals

Market Segmentation:1. Global Biologics Safety Testing Market, by Test Type:1.1 Endotoxin Tests1.2 Sterility Tests1.3 Cell Line Authentication and Characterization Tests1.4 Bioburden Tests1.5 Residual Host Contaminant Detection Tests1.6 Adventitious Agent Detection Tests1.7 Other Tests

2.Global Biologics Safety Testing Market, by Products and Services:2.1 Kits & Reagents2.2 Services2.3 Instruments

3. Global Biologics Safety Testing Market, by Application:3.1 Vaccine & Therapeutics Development3.2 Blood and Blood-Related Products Testing3.3 Cellular and Gene Therapy3.4 Tissue and Tissue-Related Products Testing3.5 Stem Cell Research

4. Global Biologics Safety Testing Market, by Region:4.1 North America (U.S., Canada, Mexico)4.2 Europe (Germany, UK, France, Rest of Europe)4.3 Asia Pacific (China, India, Japan, Rest of Asia Pacific)4.4 Latin America (Brazil, Argentina, Rest of Latin America)4.5 Middle East & Africa

Competitive Landscape:The major players in the market are as follows:1. Charles River Laboratories International, Inc.2. Merck KGaA3. Lonza Group Ltd.4. SGS S.A.5. Thermo Fisher Scientific Inc.6. Wuxi Apptec7. Sartorius AG8. Cytovance Biologics, Inc.9. Pace Analytical Services Inc.10. Toxikon Corporation11. Eurofins Scientific Se12. Avance Biosciences Inc.13. Source BioscienceThese major players have adopted various organic as well as inorganic growth strategies such as mergers & acquisitions, new product launches, expansions, agreements, joint ventures, partnerships, and others to strengthen their position in this market.

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Pfizer and Sangamo report positive data from hemophilia A therapy trial – Clinical Trials Arena

Posted: June 23, 2020 at 5:54 pm

Giroctocogene fitelparvovec is being developed as part of an agreement between Sangamo and Pfizer for the global development of gene therapies for hemophilia A. Credit: Coolcaesar.

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Pfizer and Sangamo Therapeutics have reported positive follow-up data from the Phase I/II Alta study of giroctocogene fitelparvovec (PF-07055480) to treat patients with severe hemophilia A.

The investigational gene therapy Giroctocogene fitelparvovec consists of a recombinant adeno-associated virus serotype 6 vector (AAV6) encoding the complementary deoxyribonucleic acid for B domain deleted human FVIII.

The open-label, dose-ranging, multi-centre Alta clinical trial has been designed to assess the safety and tolerability of the therapy in severe hemophilia A patients.

Across four dose cohorts, the mean age of the 11 patients assessed is 30 years and all are male.

All five patients with severe hemophilia A were given the 3e13 vg/kg dose and they showed sustained factor VIII (FVIII) activity levels, with a median of 64.2% via chromogenic assay.

No patients experienced bleeding events or required FVIII infusions during the trial.

Pfizer Rare Disease Research Unit senior vice-president and chief scientific officer Seng Cheng said: We are excited that these data affirm previous findings from this Phase I/II study, and that all five patients have sustained levels of factor VIII activity with no bleeding events or use of factor replacement therapy.

The Phase III lead in study is ongoing, and we look forward to dosing patients with this investigational gene therapy in the pivotal Phase III trial later this year.

Giroctocogene fitelparvovec received orphan drug, fast track, and regenerative medicine advanced therapy (RMAT) designations from the US Food and Drug Administration and Orphan Medicinal Product designation from the European Medicines Agency.

The therapy is being developed as part of a collaboration agreement between Sangamo and Pfizer for the global development and commercialisation of gene therapies for hemophilia A.

Sangamo chief medical officer Bettina Cockroft said: These follow-up data indicate that treatment with giroctocogene fitelparvovec resulted in sustained factor levels up to 14 months following treatment and suggests the potential of this investigational gene therapy to alleviate the treatment burden of current hemophilia disease management.

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Pfizer and Sangamo report positive data from hemophilia A therapy trial - Clinical Trials Arena

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Global Cell Expansion Supporting Equipment Market Research with COVID-19 After Effects – Cole of Duty

Posted: June 23, 2020 at 5:54 pm

Researchstore.biz has published an exclusive report named Global Cell Expansion Supporting Equipment Market 2020 by Manufacturers, Regions, Type and Application, Forecast to 2025 which consists of overall market scenario with prevalent and future growth prospects. The report delivers the analytical elaboration and other industry-linked information in an aim to supply specific and reliable analysis on the global Cell Expansion Supporting Equipment market. The report focuses on market dynamics, growth-driving factors, restraints, and limitations this market is currently facing and is expected to face in the coming years (2020-2025). The report is further divided by company, by country, and by application/types for the competitive landscape analysis. It estimates production chain, manufacturing capacity, sales volume, and revenue.

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New Preclinical Data Demonstrates Immune-Enhancing Effects of Triple I/O Combination Therapy with BeyondSpring’s Plinabulin – BioSpace

Posted: June 23, 2020 at 5:51 pm

Research Presented at 2020 AACR Virtual Annual Meeting

The Triple I/O Combination of Plinabulin, Anti-PD-1 and Radiation Achieved a 100 Percent Complete Response in Anti-PD-1 Non-responsive Animal Model

Triple I/O Combination to Be Administered to Patients Who Failed I/O in Second Half of 2020

NEW YORK, June 23, 2020 (GLOBE NEWSWIRE) -- BeyondSpring Inc. (the Company or BeyondSpring) (NASDAQ: BYSI), a global biopharmaceutical company focused on the development of innovative immuno-oncology (I/O) therapies, today announced new preclinical research findings that indicate BeyondSprings lead asset, Plinabulin, enhances immuno-radiotherapy for cancer patients. The results of this preclinical study was highlighted in a poster presentation titled, Plinabulin, a microtubule destabilizing agent, improves tumor control by enhancing dendritic cell maturation and CD8 T cell infiltration in combination with immunoradiotherapy, at this years American Association for Cancer Research (AACR) Virtual Annual Meeting on June 22, 2020.

Based on these preclinical findings, including a 100% complete response of the triple I/O combination of Plinabulin, anti-PD-1, and radiation in a PD-1 antibody non-responsive model, the compound is being advanced toward a Phase 1 clinical trial in patients who failed or progressed on PD-1 / PD-L1 antibody treatments. Principal investigator Steven H. Lin,M.D., Ph.D., associate professor of radiation oncology at The University of Texas MD Anderson Cancer Center, presented the research data.

The experiments from my lab demonstrated that Plinabulin treatment in murine cancer models leads to activation of antigen-presenting dendritic cells, said Dr. Lin. The combination therapy with Plinabulin, anti-PD-1 therapy and radiation therapy further activated the immune system, resulting in increased T-cell activation, which is associated with increased tumor regressions.

Additional data highlights include:

The above data presentation is available on the Posters page of the BeyondSprings website at: https://www.beyondspringpharma.com/conferences/list.aspx?lcid=3.

Peer-reviewed 2019 publications in Chem and Cell Reports demonstrated that Plinabulin is differentiated from all other tubulin-targeted agents through its binding site and kinetics and is among the most potent agents that induce dendritic cell maturation. Dendritic cells are key immune cell types in the activation of the immune system against cancer cells, but currently approved immuno-oncology agents, such as antibodies to PD-1, only take the brakes off of T-cells without activating antigen-presenting cells that stimulate T-cells to attack foreign proteins expressed by cancer cells.

We believe that the activation of dendritic cells is a key to unlocking the next boost to the efficacy of immuno-oncology agents, said Dr. James Tonra, BeyondSprings Chief Scientific Officer. Activated dendritic cells present foreign tumor antigens to T-cells to induce cancer-directed immune attacks. Thus, adding this critical step of dendritic cell activation in the immune cascade to the established effects of immune checkpoint inhibition therapies is expected to increase overall anti-cancer efficacy in the clinic. Our anti-cancer strategy was to activate dendritic cells and T-cells, in combination with checkpoint inhibition and to add onto the benefits of neoantigen generation and immune activation from radiotherapy, as Plinabulin serves as the key to reverse the tumor non-response to PD-1/PD-L1 antibodies. The data strongly indicates that this triple combination has enough potential to move into clinical testing to help patients who failed or had progressed on anti-PD-1/PD-L1 targeted therapy, a severely unmet medical need.

About BeyondSpringBeyondSpring is a global, clinical-stage biopharmaceutical company focused on the development of innovative immuno-oncology cancer therapies. BeyondSprings lead asset, first-in-class agent Plinabulin as an immune and stem cell modulator, is in a Phase 3 global clinical trial as a direct anticancer agent in the treatment of non-small cell lung cancer (NSCLC) and two Phase 3 clinical programs in the prevention of chemotherapy-induced neutropenia (CIN). BeyondSpring has strong R&D capabilities with a robust pipeline in addition to Plinabulin, including three immuno-oncology assets and a drug discovery platform using the ubiquitination degradation pathway. The Company also has a seasoned management team with many years of experience bringing drugs to the global market.

About PlinabulinPlinabulin, BeyondSprings lead asset, is a differentiated immune and stem cell modulator. Plinabulin is currently in late-stage clinical development to increase overall survival in cancer patients, as well as to alleviate chemotherapy-induced neutropenia (CIN). The durable anticancer benefits of Plinabulin have been associated with its effect as a potent antigen-presenting cell (APC) inducer (through dendritic cell maturation) and T-cell activation (Chem and Cell Reports, 2019). Plinabulins CIN data highlights the ability to boost the number of hematopoietic stem / progenitor cells (HSPCs), or lineage-/cKit+/Sca1+ (LSK) cells in mice. Effects on HSPCs could explain the ability of Plinabulin to not only treat CIN but also to reduce chemotherapy-induced thrombocytopenia and increase circulating CD34+ cells in patients.

Cautionary Note Regarding Forward-Looking StatementsThis press release includes forward-looking statements that are not historical facts. Words such as "will," "expect," "anticipate," "plan," "believe," "design," "may," "future," "estimate," "predict," "objective," "goal," or variations thereof and variations of such words and similar expressions are intended to identify such forward-looking statements. Forward-looking statements are based on BeyondSpring's current knowledge and its present beliefs and expectations regarding possible future events and are subject to risks, uncertainties and assumptions. Actual results and the timing of events could differ materially from those anticipated in these forward-looking statements as a result of several factors including, but not limited to, difficulties raising the anticipated amount needed to finance the Company's future operations on terms acceptable to the Company, if at all, unexpected results of clinical trials, delays or denial in regulatory approval process, results that do not meet our expectations regarding the potential safety, the ultimate efficacy or clinical utility of our product candidates, increased competition in the market, and other risks described in BeyondSprings most recent Form 20-F on file with the U.S. Securities and Exchange Commission. All forward-looking statements made herein speak only as of the date of this release and BeyondSpring undertakes no obligation to update publicly such forward-looking statements to reflect subsequent events or circumstances, except as otherwise required by law.

Media ContactsCaitlin Kasunich / Raquel ConaKCSA Strategic Communications212.896.1241 / 212.896.1276ckasunich@kcsa.com / rcona@kcsa.com

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New Preclinical Data Demonstrates Immune-Enhancing Effects of Triple I/O Combination Therapy with BeyondSpring's Plinabulin - BioSpace

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Tau: Why Alzheimer’s Worsens Fast in Some, Slowly in Others – Alzforum

Posted: June 23, 2020 at 5:51 pm

22 Jun 2020

Why do some people with AD slide rapidly into severe dementia, while others decline gradually over more than a decade? Part of the answer could come down to which biochemical forms of tau inhabit a persons brain, suggests a study published June 22 in Nature Medicine. Among postmortem brain samples from people with advanced AD, Bradley Hyman at Massachusetts General Hospital in Charlestown and colleagues found a striking variability in taus ability to seed aggregation. The scientists tied aggregation-prone forms of tau in the postmortem brain to a more rapid course of disease during life. They pegged large, soluble tau oligomersphosphorylated on specific residuesas the most hazardous species. Antibodies trained against these types of tau stopped its aggregation. The findings cast taus behavior as a major prognostic determinant for AD, and support the concept of targeting these troublesome forms of the protein with therapeutics.

This is a well-designed study underlining once more the importance of the soluble tau oligomeric assemblies over long tau filaments in Alzheimers disease, as well as heterogeneity in tau oligomers, commented Rakez Kayed of the University of Texas Medical Branch in Galveston.

The study clearly highlights the complexity and heterogeneity of tau proteins in people with AD, noted Hilal Lashuel of cole Polytechnique Fdrale de Lausanne in Switzerland. The complexity calls for cautious interpretation of the findings, Lashuel added, noting that enigmatic tau oligomers are in dynamic equilibrium that can be influenced by disease stage and all manner of other factors. It would be very difficult to identify a specific oligomer species that consistently correlates with tau propagation or disease progression, he said.

Throughout the course of AD, neurofibrillary tangles of tau overtake the brain in a stereotypical sequence (Braak and Braak, 1991). Fueled at least in part by a templated misfolding mechanism, the propagation of tau tangles throughout the brain is tied closely to clinical progression of the disease (Jan 2020 news; May 2019 news;Jun 2019 news).

But even among people with the typical, amnestic form of AD, how aggressively their clinical disease gets worse varies strikingly from one person to the next (Komarova et al., 2011). This not only creates uncertainty for patients and their families, but also poses a risk for clinical trials, whose success depends on being able to measure a treatment effect within a set time, typically six months for Phase 2. Too many slow progressors in a trial cohort can sink a study even if the drug did what it was intended to do. Might molecular variations in tau speciesparticularly those that influence its propagationexplain this clinical heterogeneity?

Diversity of Decline. CDR-SOB scores worsened (increased) at vastly different rates in people who ultimately died with advanced AD. Some never reached the maximum score before they died. [Courtesy of Dujardin et al., Nature Medicine, 2020.]

First author Simon Dujardin and colleagues addressed this question by probing myriad aspects of tau taken from the postmortem brains of 32 people who had died in the advanced stages of AD. At the time of death, each had extensive tau tangles in the brain, at Braak stage V/VI. However, their clinical trajectories had been remarkably variable. Their age at onset ranged from 45 to 81, and the time between symptom onset and when they died ranged from five to 19 years. Their rates of cognitive decline, as gauged by serial tests on the clinical dementia rating scale sum of boxes (CDR-SOB), also varied widely.

The researchers started by measuring the capacity of tau to seed aggregation in biosensor cell lines. Equipped with a tau fragment tagged with fluorescent donor and acceptor molecules, these cells light up when potent seeds spark aggregation (Oct 2014 news). Although the researchers normalized the amount of tau used from each brain, they found wide variation in seeding activity. It ranged by an order of magnitude across samples. Notably, the three samples with the highest seeding activity came from people who carried two copies of ApoE4, suggesting the risk factor influences tau propagation.

Seed Span. When added to biosensor cell lines (left), soluble tau proteins extracted from the brains of people with AD were strikingly heterogeneous in a seeding assay. [Courtesy of Dujardin et al., Nature Medicine, 2020.]

The physiological relevance of this cell-based biosensor assay has been challenged recently (May 2020 news). So as not to rely entirely on this assay as a proxy for taus propagation potential, the researchers also conducted a series of alternative seeding experiments with a subset of the samples deemed low, intermediate, or high seeders based on the biosensor assay. Whether treating primary neuron cultures with these extracts or injecting the extracts directly into the brains of mice expressing P301S tau, the researchers observed similar relative trends in seeding activity among the samples. This suggested that the cell-based biosensor assay provided a meaningful gauge of the relative potency of tau seeds in each sample.

Planting the Seed. Tau extracted from human brain samples with low, moderate, or high seeding activity on biosensor assays triggered similar trends of tau aggregation when injected into the P301S mouse brain. [Courtesy of Dujardin et al., Nature Medicine, 2020.]

To figure out what about tau determines its seeding potency, the researchers subjected tau in the brain extracts to a barrage of biochemical assays and cross-referenced the results with the seeding activity gleaned from biosensor assays. They report that seeding activity correlated not with a persons amount of total tau, but with levels of oligomeric, hyperphosphorylated tau in each sample. Compared with intermediate or low "seeders," high seeders had an abundance of soluble, high-molecular-weight tau oligomers.

Using mass spectrometry, the researchers mapped the phosphorylation landscape of tau across samples, noting that tau doubly phosphorylated on Thr231 and Ser235, or singly phosphorylated on Ser262, correlated with seeding activity. Curiously, neither ptau-181 nor ptau-217the species that rise in the cerebrospinal fluid in the preclinical stages of ADwere significantly tied to seeding activity (Mar 2020 news; Apr 2020 conference news).

Does tau seeding activity, or any of its biochemical correlates, relate to a patients clinical progression? Indeed, the researchers found that the higher the tau seeding activity, the steeper the persons rate of decline on the CDR-SOB, and the younger his or her age at symptom onset. The abundance of oligomeric, hyperphosphorylated species of tau also correlated with disease progression, as did levels of the same phospho-tau species that associated with seeding activity.

Collectively, tau seeding activity accounted for about 25 percent of the clinical heterogeneity among people with typical AD, the researchers reported. This suggests that tau antibodies that block tau seeding might also stem clinical progression of the disease. To identify antibodies that might do the trick, the researchers used a panel of seven antibodies trained against different parts of the tau protein, or against specific phospho-residues, to deplete tau from the brain extracts, then tested the remaining seeding activity. They found that some antibodies quashed seeding more effectively than others, and that there was significant variability between samples. Overall, antibodies such as AT8 and PHF1, which bind to pathological forms of tau, inhibited seeding most consistently across samples.

At first glance, the heterogeneity in taus seeding capacity and biochemical forms across AD brains may seem at odds with cryo-electron microscopy studies, which identified two predominant conformations of tau fibrils in people with AD (Jul 2017 news). Thats not the case, Dujardin noted. Soluble tau oligomersnot fibrilsare the source of taus biochemical variability in this postmortem study. He said it would be fascinating to examine tau oligomers via cryo-EM.

Lashuel noted that the researchers did not analyze insoluble fractions of tau in their assays, biasing them to zero in on soluble species. He suggested that attention be paid to understanding the near-total lack of seeding activity in the "low seeders," who still ultimately developed AD. Perhaps more answers would be found in insoluble fractions, he said.

Why is one persons tau not like anothers? Dujardin suspects genetic differences that influence cellular processes such as degradation and autophagy, which may selectively degrade certain forms of tau. Though microglial function theoretically influences these pathways, Dujardin noted that inflammatory markers in the 32 brains did not correlate with seeding activity, at least at this end stage of disease. Individual differences in kinase activity could also influence which phosphorylations tau accumulates over a persons lifetime.

How might researchers leverage the findings to inform a persons prognosis? Dujardin noted several possibilities. A handful of studies have managed to detect seeding activity in tau derived from CSF, though Dujardin noted that these assays need to become more sensitive (Takeda et al., 2016). In lieu of directly measuring seeding activity, perhaps quantification of tau oligomers, and/or specific phospho-tau species associated with seeding activity, could serve the same purpose.Jessica Shugart

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Scholarly Perspectives on COVID-19, Part 1: This Was Only a Matter of Time – Southern Newsroom

Posted: June 23, 2020 at 5:51 pm

In retrospect, December 2019 seems like an altogether different era now. For most of the U.S. population, at least, those were the halcyon days when students were doggedly completing final exams and papers, teachers were grading and looking forward to winter break, shoppers were checking off gift lists online and in stores, the faithful were making pilgrimages to holy sites, families were crisscrossing states and oceans to visit loved ones, football fans were celebrating the NFL playoffs, tourists were crowding into theaters on and off Broadway, crafters were selling their wares at holiday bazaars, farmers were repairing their equipment, and friends were meeting up for peppermint and eggnog latts.

On New Years Eve, meanwhile, the China Country Office of the World Health Organization (WHO) received reports that a cluster of pneumonia cases had presented in the city of Wuhan, in Hubei Provinceplace names that have since become ominously familiar but were then still unknown to many Americans. Six days later, the cause of the illness was still obscure, but by January 7, 2020, scientists in China had already isolated the pathogen and shared its full genetic sequence with the global scientific community. They identified it as a novel coronavirus (2019-nCoV).

Combining visual metaphor and perhaps not a little irony, coronaviruses are named for their crown- or halo-like appearance when peered at through an electron microscope; corona in Latin denotes an honorific garland worn on the head or else a halo encircling a celestial body, such as the sun. The pathogens, of which there are currently four main types known to affect humans, were first characterized in 1965 and are the source of mild to serious upper respiratory syndromes; some coronaviruses, for example, are known to cause the common cold (as do more than 200 other viruses, such as rhinoviruses). This newest coronavirus, however, had within a week caused 44 patients to seek in-hospital care, with 11 reported as severely ill.

Back in Georgetown, Texas, microbiologist Martn Gonzalez was just one Southwestern scientist who was carefully following updates on the epidemic as news emerged each day in the popular media and within the scholarly community. A novel virus is always cause for keen interest among researchers and healthcare practitioners alike, certainly, but its not necessarily a source of surprise. After all, in reflecting on the long history of human disease, researchers started predicting a pandemic like COVID-19 decades ago and more recently in articles such as The Next Plague Is Coming; Is America Ready? by science journalist Ed Yong and in the 2020 Netflix documentary series Pandemic: How to Prevent an Outbreak (whose first episode, Gonzalez says, is the one to watch if you want an accessible explanation of how a global disease affects communities, how researchers and healthcare providers approach them, and how difficult it is to develop vaccines).

With all the past epidemics and pandemics that weve seen, this was only a matter of time, Gonzalez says. I think most people in the sciences realized this was the case.

Gonzalez was teaching microbiology in January. On the first day of class, he posed the same question he asks at the beginning of every lecture: Has anybody heard anything going on in science? That day, he received a lot of blank stares; his students, like most people across the nation, had not yet started paying attention to the 2019-nCoV coverage, blissfully unaware of how the virus and the disease it causes would soon take center stage during classroom discussions and, of course, disrupt their very lives. But Gonzalez knew that the virus was one to watch: the first case of a 2019-nCoV infection in the U.S. was confirmed on January 20, in Snohomish County, Washington; by the end of the same month, the infected were numbering nearly 10,000 in at least 21 countries, and the WHO had declared a public health emergency of international concern. So he asked his students to start sharing the latest information at the top of each class meeting.

It didnt take long, he says, for students to start realizing that this was going to be much bigger than we originally thought.

Transmission electron microscopic image of an isolate from the first U.S. case of COVID-19. The spherical viral particles, colorized blue, contain a cross-section through the viral genome, seen as black dots. Credit: CDC Image Library, ID# 23354.

On February 11, 2020, the International Committee on Taxonomy of Viruses (ICTV) announced that, given the genetic relationship between the novel coronavirus and the coronavirus responsible for the 2003 outbreak of SARS, the new pathogen would be named severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2. The same day, the WHO christened the disease caused by SARS-CoV-2 coronavirus disease 2019, or COVID-19.

Meanwhile, Gonzalez and his students discussed how viruses, the smallest of all microbes, consist of DNA or RNA surrounded by a protein coat called a capsid and sometimes, as with SARS-CoV-2, by a lipid envelope that can be dissolved with soap, thereby destroying the entire particle (TL;DR? wash those hands!). They knew how viruses attach to the plasma membranes of living host cells and hack the cells mechanisms to replicate before detaching and invading other cells, usually destroying those cells, damaging tissues, and sickening or even killing the host organism. They discussed how viruses spread through the human population in many ways. For example, some can be passed on by skin-to-skin contact. Others can be transmitted via contaminated surfaces (disinfect those countertops!). They can spread through exposure to others bodily fluids and secretions, such as through sharing needles, sexual contact, or coughing and sneezing (again, wash those hands! but also wear masks to keep from infecting others!). And viruses can be carried by vectors, or disease-bearing organisms, such as mosquitoes, fleas, or bats, the last of which may have served as a reservoir for SARS-CoV-2 before it jumped to an intermediate host and then eventually infected humanswho are also possible vectors.

It was a great learning experience, Gonzalez reflects.

But he noticed that as the days went by, his students began expressing frustration about the governmental and public responses to the outbreak. By late February, the number of confirmed cases of COVID-19 had topped approximately 84,000 in at least 56 countries, and the death toll had climbed to 3,900, but many nations, including the U.S., were slow to react and failed to implement a unified, strategic approach to testing and prevention based on classic epidemiological models.

Gonzalezs students wanted to know why. And I told them, We can talk about politics, but I have no idea why were approaching this the way we are, he remembers.

They also wondered aloud whether the novel coronavirus was something to be worried about considering comparisons that were being drawn between COVID-19 and seasonal influenza. Gonzalezs response was to remind them of the flus grave statistics: the Centers for Disease Control and Prevention (CDC), for example, estimates that in the U.S. in 20162017 alone, 29 million people contracted symptoms of the seasonal flu, with 14 million seeking medical care, 500,000 requiring hospitalization, and 38,000 dying. Moreover, many people worldwide have developed immunity to seasonal flu strains, and flu vaccines exist to combat infection. By contrast, although mortality rates are impossible to confirm while an epidemic or pandemic is ongoing, the risk of death from COVID-19 appears to be higher than that from the flu. In addition, it remains unclear even now whether those who have survived COVID-19 have developed immunity, how long that immunity lasts, when a safe vaccine will be available, and when a large enough swathe of the global population will be inoculated to develop herd immunity.

Gonzalez says that his students became more educated in all this. They became aware of the power of knowledge. And they became aware of the stress of knowledge.

Given the store of knowledge scientists have developed based on previous epidemics, including the more recent outbreaks of coronavirus-caused diseases such as SARS (in 2003) and MERS (Middle East respiratory syndrome, in 2012), you would think that we would have been more prepared and known how to respond more quickly. And countries such as Taiwan, New Zealand, Costa Rica, Iceland, Norway, and Denmark have been highly successful in limiting both infection and mortality because they relied on science, prioritized public health, coordinated responses among institutions, acted swiftly, and garnered the trust and cooperation of its citizens.

But elsewhere, as in the U.S., Gonzalez says, its been clear we havent learned the lessons of past outbreaks. A significant etiology of the chaotic and ineffective response has been misinformation, and he believes that platforms such as Nextdoor, Facebook, Twitter are just some of the vectors to blame for the spread of false or misleading information. One of the things that concerns me is were very much a social-media society now, he explains. Social media can be an incredible tool to get your message out, but if your message is filled with misinformation, its devastating to the cause . Lives are at stake here.

Social media can be an incredible tool to get your message out, but if your message is filled with misinformation, its devastating to the cause . Lives are at stake here.

Ironically, one flagrant inaccuracy Gonzalez saw floating about was a comment about vaccines in which the poster opined that scientists were lying. Understandably, Gonzalez had to refrain from responding, and he now limits his media diet to reporting by the CDC and the BBC, the British news channel. I havent checked it recently, but I can imagine my blood pressure is up a little bit, he laughs.

In the absence of accurate and clear communicationnot to mention the lack of other standard epidemiological strategies, including widespread reliable testing, quick diagnosis and quarantine, and contact tracing and isolationthe U.S. federal response to the disaster has been, well, disastrous. The most glaring symptom of this failure is that the countrys tally of infections and deaths far surpasses that of any other country: on May 24, the U.S. exceeded 1.6 million confirmed cases and 100,000 deaths, and at the time of this publication, a day shy of one month later, that death toll has risen to 120,225, with well more than 2.29 million confirmed cases. Another complication of the U.S.s messy response has been a host of avoidable draconian interventions with wide-ranging impacts on human behavior and the economy, such as social distancing, stay-at-home mandates, and school and business closuressacrifices that became necessary to flatten the curve (i.e., reduce the number of infections to prevent overburdening the healthcare system) but would also lead to upheaval in the lives and learning of Southwesterns own staff, faculty, and students.

But one other adverse effect of the lack of a coordinated national response has been a shortage of life-saving medical supplies. States, for example, were left to compete for ventilators, and healthcare providers were forced to reuse or go without personal protective equipment (PPE), jeopardizing the lives of the very people who can actually treat the disease. I think what is most frustrating is were putting people on the frontlines of this pandemic in danger, Gonzalez shares. He felt so strongly about the supply crisis, in fact, that he broached to his colleagues in the Biology Department a way they could help. I said, We have all these gloves were not going to be using because were not having labs or classes, and we have a good stock, so we can donate them! he recalls. The biology faculty consulted with Southwesterns administration, and their colleagues in the Chemistry Department volunteered to donate their equipment as well. Its one of those things where youre saying, I shouldnt have to be doing this, but were doing it, Gonzalez adds.

Despite his and his students deep concerns about the way the COVID-19 pandemic has been handled, Gonzalez saw some glimmers of positivity and hope when stay-at-home orders were in effectfrom the community wanting to support local restaurants by ordering takeout and neighbors offering to pick up items from the grocery store to help protect those who are greater risk of developing serious illness, such as those 65 years and older or those with underlying medical conditions, such as diabetes, heart disease, or compromised immunity. From that standpoint, its been very uplifting for me, he says. Some of the community is wanting to make a difference and looking to help.

He also celebrates the many breakthroughs of his STEM colleagues around the world, who have worked tirelessly in the past few months to advance knowledge of COVID-19 and over the years and decades to improve our learning about infectious diseases more broadly. He loves seeing publications such as Nature encouraging scientists to share their latest findings to expand our understanding and build this knowledge base. And he looks forward to discoveries that might be just around the corner, such as a universal vaccine that provides long-term immunization against all influenza types or a platform vaccine, long advocated by National Institute of Allergy and Infectious Diseases Director Anthony Fauci, which would enable researchers to begin the first phase of clinical trials for new vaccines within months rather than years. You have no idea how much pride I had when it was less than two weeks after [the COVID-19 pandemic] started rolling that the global scientific community came out with a genetic sequence for [SARS-CoV-2], he says excitedly. Thats why I fell in love with science: its truly a community. When we publish papers, we police each other by doing peer review, and people will try to reproduce some of your results. Weve been doing this for a long time, and its worked. Ive been really happy with that.

You have no idea how much pride I had when it was less than two weeks after [the COVID-19 pandemic] started rolling that the global scientific community came out with a genetic sequence for [SARS-CoV-2].

Gonzalez says that we still have much to learn about SARS-CoV-2 and COVID-19, but even after the current pandemic ends, we cannot be complacent going forward; instead, we must apply the lessons of yesterday and today. We can look at some of the earliest Old World infectious diseasesthings like dengue fever, yellow fever, and malaria. It took something like 300 years for those three diseases to be found on most places on this planet, he explains. And then you look at the global society we are now and look at some of these new emerging infectious diseases, such as West Nile virus, Zika virus, and Chinkungunya virus. Its taken them less than 16 years to be found pretty much on a very large percentage of this Earth.

Moreover, Gonzalez adds, we have yet to fully comprehend the many twists and turns of infectious disease. For example, how might climate change accelerate or exacerbate the spread of such illnesses? When will the next single mutation in a known virus enable the sudden transmission of the pathogen from animals to humans, as was the case of SARS-Co-V-2? We were fortunate that the coronavirus that causes MERS, a disease with a 35% casefatality rate, did not easily transfer between human beings, but what if a more robust MERS-CoV-2 were to emerge? And what if Ebolaa fast-spreading disease with quickly manifesting symptoms and a shocking mortality rate as high as 90% in some WHO estimateswere suddenly contagious when carriers were asymptomatic (i.e., not exhibiting symptoms)?

We need to be prepared for this, he asserts. This is not something where we can sit there and say, As soon as this starts happening, well jump. We need to be working at this right now.

However, scientific discovery and innovation require opportunity and resourcesincluding both money and time. The medias pursuit of big stories and eye-catching headlines might suggest that scientific progress happens by leaps and bounds within days or weeks; the anxious public may be impatient for answers about a public-health crisis that is shaping individual lives. Nevertheless, good science requires time: time for research and development, time for experimentation and failure, time for correcting errors and replicating results, and time for collaboration and peer review. Yes, [scientists] can figure it out, but it takes time, Gonzalez says. Science is not do one experiment and have a result. It just didnt work that way. I wish it did! he laughs.

And with the COVID-19 pandemic, that scientific progress is actually happening fairly quickly, regardless of what naysayers might think or say. But because of the relatively rapid pace of research on SARS-CoV-2 and COVID-19, scientific findings and recommendations shared with the public can change, sometimes in the course of just weeks. After all, scientists are constantly expanding on previous work, discovering new phenomena, and drawing conclusions from the latest evidence. Their work can also be misinterpreted and misreportedaccidentally or intentionallyby journalists, pundits, and social-media frequenters. And in a heightened atmosphere characterized by fear of the unknown and suspicion of the very science we should be relying on, Gonzalez knows moving forward will require a lot of education.

As Ive always said, trust the science, he says. The science will police itself and will let you know if theres something you shouldnt be listening to.

Gonzalez will continue urging his students to use the communication skills theyve gained at Southwestern to share their scientific knowledge with their families, friends, and communities.

In the meantime, Gonzalez will continue urging his students to use the communication skills theyve gained at Southwestern to share their scientific knowledge with their families, friends, and communities. Its a practice that he hopes will prevent his students from caving to fear, will keep their circle of connections informed, and will ensure the health and safety of their loved ones. Says Gonzalez, Thats the one thing Ive really told my students: Whether this [pandemic] was going on or not, youre going to be part of a community, and there are times when a community requires a voice of reason. Your job is to go out there, use what youve learned, and bring that voice. I hope they do it; I really do.

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Online game looks to stoke interest in regenerative medicine – The Union Leader

Posted: June 23, 2020 at 5:50 pm

An online game that lets students learn about stem cells and tissue engineering also offered them information about high school and college internship programs to further spur their interest in regenerative medicine.

Through the game, aimed mainly at seventh graders through high school seniors, students competed in daily challenges to win swag and the chance to meet inventor Dean Kamen (virtually in this pandemic age).

The vision is to help inform young people about all the really cool things that are happening in this space, said Alexander Titus, the freshly minted chief strategy officer at the Advanced Regenerative Manufacturing Institute in Manchesters Millyard.

The game helps to inspire students as they choose their classes, their elective classes in high school and particularly majors in college, Titus said last week.

Nearly 100 students took part in the game, which ended Friday. The content about regenerative medicine will remain online through June.

ARMI, which is working to manufacture human tissue commercially, is working on recruiting tomorrows workforce one cool video at a time.

I think the timing of this couldnt be any better, said Julie Demers, executive director of the New Hampshire Tech Alliance. The pandemic has limited in-person, work-based learning opportunities and interactions with industry professionals. Interactive opportunities to get students interested in and thinking about career opportunities are critical.

Titus said a chief goal is to build a pipeline of future workers.

Its all tied together in attracting students while theyre young to understand the process of what to study along the way to get to college and a job when theyre done, said Titus, who earned a Ph.D. in quantitative biomedical sciences at Dartmouth.

Titus said he expects the game to help ARMI officials learn what draws the interest of students so they can develop other programming they know will garner student interest, he said.

The ARMI challenge, called TEMPtation, featured profiles of businesses from more than a dozen states as well as universities and colleges interested in regenerative medicine.

Arizona State University holds summer camps for middle and high school students that are interested in learning more about science and mathematics, read one profile.

From Georgia Tech in Atlanta: Georgia Tech has a Center for Career Discovery & Development, which offers internships, co-ops, and career services that give students the resources they need to support their search for employment following their graduation.

Formerly employed at the U.S. Department of Defense, Titus returned to New Hampshire to join ARMI.

The mission, he said, is marrying science and manufacturing.

Bring the science to the stage where we can automate it and market the new technologies we couldnt make before, said Titus, previously assistant director for biotechnology within the Office of the Under Secretary of Defense for Research & Engineering.

ARMI features more than 150 partners and more than $300 million in government and private investment committed.

If we want to be able to produce a replacement heart for people who have heart disease, what are the components that go into that? Titus said.

He hopes ARMI can attract startups in the Manchester area, allowing for ARMI to mentor them until they are viable companies.

The idea is for companies to move into New Hampshire and move into our ecosystem if you will, Titus said.

I think especially given now, where were seeing so many people in the cities during COVID have a hard time social distancing, I expect well see some shifting of people out of the cities, said Titus, who speculated some could settle in New Hampshire.

Whats Working, a series exploring solutions for New Hampshires workforce needs, is sponsored by the New Hampshire Solutions Journalism Lab at the Nackey S. Loeb School of Communications and is funded by Eversource, the New Hampshire Charitable Foundation, Dartmouth-Hitchcock Medical Center, the New Hampshire College & University Council, Northeast Delta Dental and the New Hampshire Coalition for Business and Education. Contact reporter Michael Cousineau at mcousineau@unionleader.com. To read stories in the series, visit unionleader.com/whatsworking.

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Maryland University of Integrative Health Announces Educational Partnership with the Maryland Naturopathic Doctors Association – Reported Times

Posted: June 23, 2020 at 12:51 am

Jun 22, 2020 1:00 PM ET

iCrowd Newswire Jun 22, 2020

Laurel, Md. Maryland University of Integrative Health (MUIH) has entered a new educational partnership with the Maryland Naturopathic Doctors Association (MNDA). MUIH and MNDA share the joint goal of promoting the use of holistic and natural approaches to promote well-being for our clients. This partnership expands MUIHs role in supporting the health and wellness of Marylands residents through naturopathic medicine.

MUIHs Professional and Continuing Education (PCE) program is proud to welcome MNDA as a new partner to spotlight the field of integrative health through mission-driven collaborations. Through our evidence-based, continuing education opportunities, PCE aims to support naturopathic doctors in their professional development goals, empowering them to add to their knowledge and credentials to further support their clients and patients health and wellbeing with a whole-person approach, said Beth Romanski, director of professional and continuing education at MUIH.

In its continued effort to provide educational resources to our members, the MNDA is happy to announce a new partnership with MUIH. We will now offer MUIH PCE courses at discounts to our members so that they may continue to advance and update their knowledge in the areas of nutrition, botanical medicine, stress resilience, and general well-being, said Dr. Cristine Ehly, ND, Past President, Maryland Naturopathic Doctors Association.

Naturopathic doctors have been licensed in Maryland since 2016. MUIH is pleased to count naturopathic doctors among its faculty and to offer naturopathic medicine services in its Natural Care Center, which is open to the public. For more information about MUIH Professional and Continuing Education offerings, visit http://www.muih.edu/ce.

About Maryland University of Integrative Health (MUIH)

Maryland University of Integrative Health (MUIH) is a leading academic institution focused on the study and practice of integrative health and wellness and one of the few universities in the U.S. dedicated solely to such practices. Deeply rooted in a holistic philosophy, its model for integrative health and wellness is grounded in whole-person, relationship-centered, evidence-informed care.

Since 1974, MUIH has been a values-driven community educating practitioners and professionals to become future health and wellness leaders through transformative programs grounded in traditional wisdom and contemporary science. MUIH has more than 20 progressive graduate degree programs in a wide range of disciplines, offered on-campus and online. For more information visit http://www.muih.edu.

About Maryland Naturopathic Doctors Association (MNDA)

The Maryland Naturopathic Doctors Association (MNDA) is the professional organization of Naturopathic Doctors and the voice of Naturopathic medicine in Maryland. The MNDA is a leader in 21st-century healthcare and believes that the ability to heal resides in all of us and that conventional medicine and complementary care do not exist in opposition. The MNDA is committed to creating a greater state of health in Maryland, working with the state government to promote access to high-quality Naturopathic healthcare for all Marylanders. It is also an advocate for naturopathic doctors; offering continuing education, professional development opportunities, and professional community and support.

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Kionne S. Johnson Communications Manager [emailprotected]

Keywords:Health, Wellness, Naturopathic Medicine, Doctors, Maryland, Medicine

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