StemCell Therapy

LAFAYETTE, Ind. Dr. Sarah Hallberg, the medical director at Virta Health, was recently awarded the Sagamore of the Wabash award for her work in diabetes research.

The Sagamore of the Wabash first started in 1946 with then-Indiana Gov. Ralph Gates. Gates was on his way to a conference of Kentucky, Indiana and Ohio officials when he learned that the then-Kentucky governor, Simeon S. Willis,planned to award gates the Kentucky Colonel, the state's highest honor.

Not to be outdone by Kentucky, Gates named Willis the first recipient of the Sagamore of the Wabash. Since then, thousandsof people have received this honor, including David Letterman, Muhammed Ali, and now, Dr. Hallberg.

According to its description, TheSagamore of the Wabash is the "highest honor, which the governor of Indiana bestows. It is a personal tribute usually given to those who have rendered a distinguished service to the state or to the governor."

"Among these who have received Sagamores have been astronauts, presidents, ambassadors, artists, musicians, politicians, and ordinary citizens who have contributed greatly to our Hoosier heritage."

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There is no official record of how many have been presented with this honor, as each governor has kept their choicesdocumented using different methods.

"I was just floored," Hallberg said about she show felt when she won the award. "I'm so lucky to have had this career where I can really help people improve their lives, and be a real patient advocate."

Before joining Virta Health, Hallberg worked at IU Health Arnett Hospital where she founded the Supervised Weight Loss Program.This clinic served as the host for Virta's clinical trials.

"What I came across was carbohydrate restriction," Hallberg said, "and we opened the clinic as a carbohydrate-restricted clinic. That was the nutrition intervention that we were using. What we were seeing in patients was just remarkable. When we were putting them on a therapeutic, carbohydrate-restrictive diet, their diabetes was going away."

These clinics took place about a decade ago, according to Hallberg, and up until thatpoint, Type 2 Diabetes was seen as a chronic and progressive disease. Seeing the effects a carb-restricted diet has on patients motivated Hallberg to expand her research to beyond her clinic in central Indiana.

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Dr. Stephen D. Phinney, the chief innovation officer and co-founder of Virta Health, and Hallberg have worked and continue to work on a number of published papers together to help get the news of reversible diabetes through carb-restriction out there.

"The biggest thing is that this study, in central Indiana, changed the American Diabetes Association guidelines," Hallberg said. "We did this research that impacted the guidelines that haveimpacted so many Americans. And that happened here in central Indiana."

Four years ago, Hallberg was diagnosed with advanced lung cancer. She explained howher diagnosis and her work experience being a patient advocate both affected her.

"Being a patient advocate for so long and just wantingto empower and teach them (the patients) with the science," Hallberg said, "really came into play for me four years ago when I became a patient myself. So all the advocacy I've done for my patients, I was really fortunate in that I could turn that into being an advocate for myself with an advanced cancer diagnosis."

Margaret Troupis a reporter for the Journal & Courier. Email herat mtroup@jconline.com and follow heron Twitter@MargaretTroup2

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Hallberg given Sagamore of the Wabash for work in diabetes research - Journal & Courier

When blood vessels that feed the heart become blocked, damage to the heart muscle can occur and this can affect cardiac function. By stimulating the formation of new blood vessels, a new stem-cell-carrying gel helps mice overcome this condition called myocardial Infarction. The stem cell delivery system was developed by scientists from Kansai University, Japan. It is published in Science and Technology of Advanced Materials.

The hydrogel acts like a scaffold to hold the stem cells in place at injection site and keep them alive longer. The stem cells release cytokines, which stimulate the formation blood vessels and help the heart to recover. The gel is biodegradable so that it eventually dissolves and can be discarded by the body. Image credit: Kansai University

In their application, the team used stem cells from fat tissue. These stem cells, also known as adipose derived stem cells, have been used in the treatment of damaged cardiac tissue due to reduced blood flow. This is called myocardial Ischemia. Once injected into damaged tissue, the stem cells are supposed to release stimulants that can help regenerate blood vessels. However, they are not able to be retained in the tissue or survive long enough. Scientists have also found that injecting biodegradable hydrogels, which are cell-free, into damaged heart tissue can help partial recovery.

They first created hydrogels that could hold stem cells in place longer at the site where there is tissue damage. They are best used at room temperature. This allows you to easily mix the stem cells. The solution reacts with the body to heat and transforms into a gel when it is injected into the organ.

One hydrogel was particularly good at keeping its gel state. It was made from a mixture of molecules called tri-PCG with acrolyl group attached. The tri-PCG-acryl mixture was then combined with a polythiol derivative.

The team also added stem cells from adipose tissue to the hydrogel. They then observed how long they lived in petri dishes as well as the production of different genes and substances.

The stem cells were able to survive in our injectable hydrogel and released molecules that stimulate blood vessel formation, improving heart function and making it effective for treatment of ischemic heart.

Yuichi Ohya, Bioengineer, Kansai University

After confirming safety, the team plans to next test the therapy on larger animals and then conduct clinical trials in humans. They plan to use their injectable hydrogel for immune cells to treat cancer and in vaccines against viral infections.

Source:

Journal reference:

Yoshizaki, Y.,et al.(2021) Cellular therapy for myocardial ischemia using a temperature-responsive biodegradable injectable polymer system with adipose-derived stem cells.Science and Technology of Advanced Materials.doi.org/10.1080/14686996.2021.1938212.

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New Stem cell conveying hydrogel could assist the heart with recuperating myocardial ischemia - Microbioz India

Aclinical trial testing a novel gene therapy for a rare neurological disease has been put on hold after one of the participants in a Phase 3 trial developed a bone marrow disorder that can lead to cancer. The pause, announced Monday by the trials sponsor, bluebird bio, and mandated by the US Food and Drug Administration (FDA), was taken out of an abundance of caution, the companys president of rare genetic diseases, Andrew Obenshain, said in a recent quarterly call.

The therapy targets cerebral adrenoleukodystrophy, which is caused by a mutation in the gene for an enzyme called adrenoleukodystrophy protein (ALDP) that breaks down fats. The mutation causes fat to build up in the brain, where it breaks down the insulating myelin that allows neurons to communicate with one another. Because the gene is on the X chromosome, women typically have a least one good copy, so the disease primarily strikes men. Left untreated, it causes damage to hearing, vision, cognition, and coordination. It is often fatal.

Bluebirds gene therapy uses an engineered lentivirus to correct the mutation associated with the disease. Lentiviruses belong to the same family as HIVretrovirusesand have been widely used in gene therapies and other medical applications for many years. While other virus-based platforms using retroviruses had previously been linked to cancer among patients, it is only recently that a lentivirus has been implicated in such an outcome: in February of this year, bluebird bio paused another trial, one for a blood disorder, after two patients developed leukemia-like cancer, Sciencereports, although it was later determined that the virus was likely not the cause, and the trial resumed.

Most in the field were hoping that we would not see such an event with lentiviral vectors, Harry Malech, a gene therapy researcher at the National Institutes of Health, tells Science, adding, I dont think anybodys been . . . saying this couldnt happen.

The cerebral adrenoleukodystrophy therapy involves taking samples of a patients bone marrow and treating the stem cells therein with the modified virus that contains a corrected copy of the gene that encodes ALDP. After a round of chemotherapy to reduce the persons bone marrow cells, the treated cells are infused back into the patient. Thereafter, the patients stem cells produce healthy blood cells with a functional copy of the gene for ALDP. The therapy entered the market in Europe last month following a previous safety and efficacy trial that included 32 patients. A second trial, the one that has now been paused, was set to finish in 2024.

Speaking on the call, bluebird bios Chief Scientific Officer Philip Gregory said that one patient in the second trial developed myelodysplastic syndrome (MDS), a blood disorder that sometimes leads to leukemia, and another two had abnormal bone marrow cells that could progress to MDS. When scientists examined their cells, they found lentiviral DNA inserted at a site in the genome that has previously been linked to MDS in retrovirus-based therapies, suggesting that the virus may have caused the changes.

Specifically, Gregory said the issue is likely caused by the virus promoter, the DNA sequence that turns on the therapeutic copy of the gene. To ensure the gene produces enough ALDP in the brain to be an effective treatment, the researchers needed a strong promoter, but as a consequence, the promoter had off-target effects, turning on other genes in the area around the mutation, including cancer genes, Gregory speculated.

Donald Kohn, a gene therapy researcher at the University of California, Los Angeles, who helped design the viral vector, tells Sciencethat in the time since bluebird bio first began developing the therapy, researchers have identified other promoters that might be able to do the job with a lower risk of causing cancer. He adds that this particular incident shouldnt preclude scientists from pursuing other lentivirus treatments, as the issue seems to come down to design, and Kohn doesnt know of any other lentivirus therapies that use the same type of promoter.

Panam Malik, a hematologist at Cincinnati Childrens Hospital who was not involved in the work, similarly tells Science that virus-based platforms should be highlighted for the good they have done. This is a severe adverse event, she says, but adds, we should never lose sight of the fact that so many patients . . . have been helped. Despite this rare incident, the findings could help scientists and researchers design safer and better vectors for the future.

Continued here:
Participants Diagnosis Halts Gene Therapy Clinical Trial - The Scientist

AUGUST 11, 2021

FOR THE ARCHITECTURAL HISTORIAN and critic Reyner Banham, the bag of potato chips (or crisps as he, an Englishman, put it) was a remarkable technological innovation. But it was an emotional object rather than a practical one. The sound of the bag crinkling and tearing as you ripped it open and consumed every greasy chip and then the shards at the bottom, expressed the temper of the late 20th century: Its the first and most familiar of Total-Destructo products and probably sublimates more aggression per annum than any quantity of dramaturgical catharsis, Banham wrote in his short essay The Crisp at the Crossroads (1970). Banham speculated about the possibilities for flavored chips: not just cheese-and-onion or barbecued bacon, but toad in the hole, crme de menthe, and more, all of them flavor stations along the expanding snacking frontier. But flavor seemed to interest him less than form. The relationship between chip and bag seemed to him almost vernacular: the bag of chips was like some survivor from a lost golden age of peasant technologies that have matured long in the wood and hand: the oar, the axe, the rolling pin. The chip glows golden when you hold it up to the light but it is unlike the oar, axe, or rolling pin, because its vernacular quality stems from the way it pairs with its packaging, the proper use of both involving a crinkling burst. The chip is an impractical food if the task is to get the most nutrition possible out of the potato; but if the task is to pleasurably wreck something, then the chip-and-bag is very good design indeed.

Fifty years later, the chip retains its basic shape, although some chips are now chili mango flavored. And the world of snacking R-and-D has not run out of steam. Entrepreneurs, working to transform food through technology, seem to promise new innovations every day, not all of them intended as mere snacks. There are pea protein puffs, and new kinds of plant-based burgers, and bunches of kale leaves grown hydroponically in vertical farms. The most ambitious of them all, the dream of growing meat in labs, hovers at the horizon, gaining headline coverage as companies promise to produce it soon but cultured meat never quite arrives in the supermarkets. The entrepreneurs call all these things innovations. But what if the best metaphor for describing new food-tech products was not innovation but involution? That latter term stems from the Latin involutio and carries the meaning of curling inwards (as a chip curls) but has more common meanings, which the OED provides: the state of being complicated; the shrinkage of old or inactive tissue in the body; a mathematical function, transformation, or operator that is equal to its inverse, or in other words, that continues to be itself when applied to itself. This should sound counterintuitive, for we are used to thinking of technological changes as introducing novelty into a system, perhaps changing that system fundamentally, rather than causing it to curl in on itself. In any case, involution may seem like a lofty term to apply to crunchy protein bars made with cricket flour, ersatz meat made by extruding pea protein, or powdered algae, but I will argue for the terms explanatory power bite by bite.

In his 1936 essay Loose Ends of a Theory on the Individual Pattern and Involution in Primitive Society, the anthropologist Alexander A. Goldenweiser put involution on anthropologys map. While meditating on the relationship between individual expression and cultural patterns, Goldenweiser used involution to describe an enduring condition in which patterns both in the sense of physical symbols but also forms of social behavior run through every aspect of a human communitys life, providing both a fabric of meaning and a limiting, even restrictive force. In primitive societies, Goldenweiser wrote, pattern is particularly conspicuous in rituals and the forms of religious objects, where the tenacity of pattern is enhanced by social inertia or a sacred halo. Pattern limits development, and Goldenweiser seemed to imply that an intimate relation with pattern was part of what kept primitive societies primitive. It inhibited the technical, social, and intellectual developments that could eventually lead to modernization.

But patterns also set limits in a more positive sense, as a canvas edge or a frame establishes the boundary for a painting. Thus Goldenweiser characterized the traditional art of the Maori, in which simple units of design recombine in multiple ways within a delimited space: The inevitable result is progressive complication, variety within uniformity, virtuosity within monotony. This, too, is involution. Involution wasnt limited to primitive contexts; Goldenweiser also found its inward curling in late Gothic art, whose structures and component parts may be fixed but still express play and creativity in elaborations on basic themes. But Goldenweiser saw involutions limits as ultimately negative:

Expansive creativeness having dried up at the source, a special kind of virtuosity takes its place, a sort of technical hairsplitting. No longer capable of genuine procreation, art here, like a seedless orange, breeds within itself, crowding its inner structure with the pale specters of unborn generations.

Like a seedless orange? Or like a protein bar made with cricket flour, its basic design already set by the architects of snacking, but filled with the bodies of insects? Crunch! Complexity. Crunch! Sameness.

Larissa Zimberoff, in her admirably skeptical book Technically Food: Inside Silicon Valleys Mission to Change What We Eat, describes the contemporary food-tech nexus, surveying a wide range of startup companies, mostly based in the San Francisco Bay Area. She interviews dozens of entrepreneurs, encountering them at tech conferences or in the warehouses and labs where they try to grow the future. She hears their pitches and then examines those pitches to see if they survive close scrutiny. Many of Zimberoffs entrepreneurs claim that their products will replace existing foods that are environmentally unsustainable or cruel to nonhuman animals. Their mission, then, is one of supersession. What if you could eliminate animal agriculture, with its massive environmental footprint and relatively inefficient transformation of plants into animal protein? Sensitive to concerns about the environment, and about animal cruelty, Zimberoff keeps human health at the books center: are these new foods really going to be better for us, especially given that so many of them are ultra-processed, a category linked to bad health outcomes? How about the well-known plant-based Impossible and Beyond Meat burgers? They are far more fatty and caloric than, say, a meal of chickpeas. Coconut oil, a key ingredient used in most plant-based meat, is about 90 percent saturated fat. Memorably, Zimberoff compares the creation of these burgers to fabricating a Slim Jim, which is made from chicken scraps through the same technique, extrusion. Are these different products? Yes. Are they similarly made? Yes. Zimberoffs book is marbled with detail, and performs a useful analytic service for readers trying to understand new tech foods: while many novel food companies claim to break out of the paradigms set by Big Food (those huge international companies that fill the central aisles of grocery stores with processed stuff ), Zimberoff shows that many of their founders hope to sell ingredients to Big Food, and use processing techniques that Big Food perfected or they may plan to sell the whole company to Big Food, lock, stock, and bioreactors.

As I followed Zimberoffs journey from one warehouse-based company to another, from algae to fungi, from pea protein to vegan milk and eggs, from plant-based burgers to vertical farming, and all the way to cultured meat, I found myself thinking back to Goldenweisers essay. How can we tell if a given novel food technology represents innovation, the change that changes everything, or if it represents involution, a change that ultimately changes nothing within enduring cultural, economic, and social patterns? Disclosure: I appear briefly in Technically Food as an expert on cultured meat, the subject of my own 2019 book, Meat Planet: Artificial Flesh and the Future of Food; Zimberoff spoke with me several times during her research. I spent years conducting fieldwork with tissue engineers and other scientists, as well as with entrepreneurs and futures consultants, who hope to grow animal muscle and fat, consumable as meat, from biopsies of cells, obviating the need for industrial animal agriculture. Hypothetically, cultured meat would require vastly fewer natural resources, and cause no cruelty to animals at all. We could visit a pig on a farm, eat meat grown from a biopsy of its cells, and then play with that same pig. If this effort succeeds, I believe it will constitute the largest and fastest shift in human subsistence strategies in history. Watch your step. That initial if is a doozy.

Innovation or involution? Form is the first clue. The wonder foods in Zimberoffs book mostly imitate familiar foods like chips, puffs, bars, shakes, and burgers. They may be made of new materials, but those materials do not dictate their shape. A plant-based sausage, with its arbitrary relationship between form and material, is in fact a skeuomorph, a Greek term which more or less means vessel-form. Its shape is like a container that used to be filled with other stuff, stuff that dictated the original form of the container consider those lintels of ancient Greek temples that rendered, in stone, the ends of protruding wood beams. Where pig intestines once gave sausage its shape, cultural expectation now dictates a cylinder, tapered where the traditional length of intestine was tied off at the ends. The compass in a smartphone doesnt work the way a magnetized needle does, but the digital representation of the compass on the phones screen is familiar, expected. The shapes of meat surrogate products, whether they are based on plant or animal cells, now come not from the bodies of animals, nor from the inspiration of corporate sculptors (should such a professional category exist outside my fantasy life), but from the imagined desires of consumers: burgers, sausages, chicken nuggets. Formally speaking, then, there is something involuted about the new food products Zimberoff documents. Apparently, when you ask consumers to think of plants as meat, you first must make the plants meat-shaped. And in the process you realize that meat, in our era of industrial mass-produced cheapness, has taken on arbitrary shapes. Nuggets do not appear on the bodies of chickens, at least not healthy ones.

Theres a great deal of repetition at the food-tech nexus. Soylent, the well-known meal replacement shake, closely resembles SlimFast, the diet drink targeted at women from 1977 onward. When the company Hampton Creek, which now calls itself Eat Just, released a vegan mayonnaise product, it was nearly identical to another 1977 product (odd coincidence) called Vegenaise, resembling it so closely that the creators of Vegenaise were shocked. Some of this repetition is probably conscious; Follow Your Heart, the maker of Vegenaise, has been around for a long time. And some of it may stem from entrepreneurs simply following a common pattern of thinking, according to which the problem with our food system is not our eating habits, but the nature of our food itself. Why not keep mayonnaise but make it vegan? Why not keep drinking milk, or eating ice cream, but make it from milk proteins we grow in a lab? What if we could get our artificial dyes, not to mention our protein powder, from algae? Some companies are making mycelium steaks, working with the fungus, related to mushrooms, that looks a bit like an underground network of threads. If you abstracted mycelium from the earth in which it lives, it might look like a mystical fairy network. From the standpoint of the anthropology of food, it is fascinating to notice that entrepreneurs first instinct was not to work with the natural form of those mycelium threads, to see what kind of food product might follow from that form, but instead to ask if mycelium could become an ingredient in something perceived as marketable. Throughout my research into cultured meat, I was bemused by the striking combination of inventiveness in the lab, as scientists adapted tissue culture techniques, widely used in medical research, to food production and the topological sameness of the burgers, hot dogs, and chicken nuggets that entrepreneurs hoped to produce. Theres a lot of copycat innovation not a lot of real innovation, says one of Zimberoffs interviewees, the CEO of a fungi-based meat company. Again, I recall Goldenweiser: The inevitable result is progressive complication, variety within uniformity, virtuosity within monotony.

Does all this count as involution? Taking stock, we are looking at an intense mimetic tendency, with food makers producing products that resemble each other, even if they differ in surprising ways in their raw ingredients or how they are processed. We have consistency within the pattern of seeking ever more clever ways to process foods in pursuit of value (because the greatest profit lies, as the work of food scholar Marion Nestle has shown, in processed foods). We have entrepreneurs seeking to change our products rather than the way we consume them. We have sector-wide ideological agreement that our food systems problems must be essentially technical, perhaps because technical solutions are the ones we can imagine using (and getting funded). In Meat Planet, I argue that this represents a form of imaginative closure, in which the economic, social, and ultimately political character of our food system gets obscured, because of the appeal of technological tools. This does not mean that technologies wont change our food system (indeed, if cultured meat works, it really could change everything) but that what makes the whole system of food-tech entrepreneurship work, imaginatively speaking, is the idea that technology, plus the workings of the consumer market, can provide all the change human civilization needs. Another way to express this imaginative closure may be in terms of involution. I must consider a straightforward objection to such claims. Goldenweiser thought that involution means that pattern checks creativity and development. But much of the work done at the food-tech nexus is mightily creative, and sometimes involves new ways of solving problems having to do with texture and flavor. Innovation surely describes this. Snackland is not bereft of ideas. A fair view of involution and innovation at the food-tech nexus might be that the nexus displays both traits at once. And yet involution always seems to win, because the creativity and inventiveness of food scientists takes place within economic systems they cannot contest, and usually do not want to. The nature of involution, for Goldenweiser, is that we cannot see outside a pattern, and here the salient pattern is a model of production, consumption, and value seeking that we often shorthand to capitalism.

In his 2006 book Meals to Come: A History of the Future of Food, historian Warren Belasco chronicles a set of long-running debates about the future of food, debates that have run through universities, think tanks, and into the public realm of journalism. A few major schools of thought have dominated those debates. There are Malthusians, who believe that increases in agricultural yields (due to technological progress, perhaps) tend to fall behind increases in population, because the former rises arithmetically and the latter geometrically. This means that the poorest members of any society will be exposed to malnutrition and that we have compelling reasons to impose artificial limits on population growth. There are Cornucopians who believe that technological progress will in fact outpace population growth, producing enough for all, possibly without limit. Then there is a third group, more equality-minded, who believe that the solution to problems in the food system is not a matter of managing supply and demand, but achieving more equal distribution of what we produce through better governance. The debate between the three positions began in the late 18th century, and while Malthusianism has always been influential it helped shape the food policy of the British Empire, since Thomas Robert Malthus himself taught at the school run by the British East India Company it is in Cornucopianisms belly that we effectively live and work today, getting slowly ceviched by its digestive juices. Those who work at the food-tech nexus are trying to keep Cornucopianism alive (although they may not identify with that term at all) in a new millennium, as the pressures of environmental crisis loom large. Cornucopians dream of a world with nothing but upside we save the environment and our market economies, predicated on growth, all at once. I was reminded of this when one of the companies trying to make cultured meat, previously called Memphis Meats (but based in Berkeley) rebranded as UPSIDE Foods. If you uncase a Pringles Wavy Potato Crisp and examine it from the right angle, it looks like a smiley face.

Cultured meat displays involution and innovation at once. Its researchers display great creativity in their technical efforts to take animal muscle stem cells, as well as fat cells, and induce them to grow in vitro, adapting a technique called tissue culture, which itself dates back to the early 20th century, to food production. They play with scaffolds on which animal cells can grow; they search for ideal growth media to feed their cells; they ask if it might be advantageous to combine the cells of different species in a single piece of meat, because one speciess cell line seems to produce better fat, the other better muscle, under laboratory conditions. And yet this work unfolds within a set of assumptions about the shape of meat, and appetites for meat, not to mention the assumptions that the combined powers of technology and the market will solve our human problems. In 2019, a chemical engineer named Dave Humbird was hired to conduct a feasibility study for cultured meat. I spoke with Humbird as he pursued his research and wrote his report. While other researchers have conducted feasibility studies and lifecycle analyses for cultured meat, Humbirds was the first by a scientist with no material or ideological investment in the proposition of cultured meat. His conclusions were not encouraging for anyone who hopes that cultured meat will work at scale, its costs eventually decreasing enough that it undercuts and supersedes conventional meat. Humbird found challenges both economic and technical some of the latter derived from the kinds of physical stresses on cells grown in very large bioreactors, and some of the former derived from the costs of raw ingredients. Both strongly suggest that cultured meat might never scale effectively. But I was also intrigued by Humbirds observation, relayed to me conversationally, that very few people involved with the nascent cultured meat industry either as entrepreneurs or as investors contacted him about his study, or spoke openly about his findings, even to challenge them. This fit a pattern I had long observed during my fieldwork, namely that despite the considerable hype around cultured meat, there is relatively little balanced public discussion of its technical feasibility. This could be because the startups would find no strategic advantage in such discussion, or because they simply do not have the time or resources for it.

The anthropologist Clifford Geertz turned Goldenweisers involution into agricultural involution in a 1963 book of that title, Agricultural Involution: The Process of Ecological Change in Indonesia. That book, vastly better known than Goldenweisers original essay (and challenged by many critics over the years), applies involution to Indonesian rice paddy farming from the 19th century into the 20th, with Geertz observing how Javanese peasants tried to adapt themselves to a Dutch colonial system that sought to extract value from their land and labor. According to Geertz, agricultural involution happens when farming technology and technique remain at a standstill, even as more labor flows into the system, ultimately yielding ever more complex social arrangements around work. The result is a kind of shared poverty as more and more laborers subdivide the available work. Social arrangements become Byzantine. Where Goldenweiser focused on ritual and aesthetic examples of involution, Geertz used the concept to describe how one kind of innovation, namely shifting social arrangements between peasant workers and landowners, unfolded within the limitations of Javanese agricultures technological standstill. The food-tech nexus that Zimberoff charts displays a different style of involution: technological innovation, to the point of virtuosity, within a larger limiting pattern. Call that pattern our collective difficulty recognizing the political and social character of the food system itself.

Involution is a capacious metaphor. In the work of the anthropologist Xiang Biao, involution (neijuan) describes the predicament of contemporary Chinese society, in which the middle classes and elites are locked in a struggle to pass wealth and advantage on to the next generation: only certain jobs can facilitate this process, and only certain paths of training and accomplishment lead to those jobs. Here the frame or pattern in which involution curls into complexity is determined by the narrow set of conditions for an acceptable life. The social, psychological, and material costs of failure of falling off the social treadmill are very high. Xiang Biaos version of involution shares, with Geertz and Goldenweiser, a sense of stuckness. Every story about involution implicitly conjures a form of change or progress that involution blocks. In Zimberoffs Technically Food, food-tech entrepreneurs pursue value in niches and crevasses that Big Food previously ignored, but rather than progress, their work seems like a desperate effort to keep food habits, forms, and economies afloat as climate change diminishes our available farmland and water. Every strategy in food futurism is a form of imaginative closure. The question facing us in food technology is how to tell innovation from involution and recognize how the two modes feed upon each other.

I have been saving the hardest part for last: when I say that a new food technology counts as innovation or involution, I am making a value claim, just as Goldenweiser and then Geertz and then Xiang Biao have done. But food systems are complex and social things, and political too; an individuals value claim does next to nothing. The challenge is to establish conversations about what human communities find valuable in food. Agreeing about norms is often harder than agreeing about facts. Some approaches to the future of food try to advance individual human health; others try to feed as many as possible, based on their assumptions about what counts as a sufficient diet; others presume that there are natural limits to how many of us can share the planet at once. Why not end with a question: was Reyner Banhams bag of chips a case of innovation or involution? The brilliance of his short essay was to show that the vernacular meaning of industrial foods the curling chip; the bursting, crinkling bag escapes our designs.

Benjamin Aldes Wurgaft is the author of Meat Planet: Artificial Flesh and the Future of Food.

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The Involuted Palate, or the Savage Crinkle of Future Snacks - lareviewofbooks

Sushi-loving diners in Callie will soon be partaking of test-tube salmon, compliments of San Francisco-based firm Wildtype. The company touts itself as Building a better food system by pioneering cellular agriculture to grow delicious cuts of our favorite seafood no fishing or fish farming required. I know, just when you think life cant get any weirder.

The companys website hypes its cutting-edge efforts as reinventing seafood, with a clever emphasis on inventing, since the entire process has come about through lab experimentation on handpicked cells of salmon, in the vein of stem cell exploration.

The seeds of Wildtypes chunks seed money has already been gotten aplenty comes via the choicest cells of the finest wild salmon, including king salmon, the finest and fattiest known. Once cells have been adroitly procured, the cellular growing process is on, as the meat of the matter is grown upon a type of organic plant-based scaffolding until done or ripe or something.

The plant-based scaffolding we provide for the cells to grow on, along with all the necessary nutrients like sugars, amino acids, and fats we deliver in solution, allows for the formation of the complex textures that were able to create for all types of sushi products spanning sashimi, nigiri and maki rolls, explains the companys cofounder Ary Elfenbein, a cardiologist and molecular biologist.

Wildtypes test-tube salmon is rather frighteningly identical to the real swimming thing, with a fat composition like the donor fish, including levels of healthy omega-3 fatty acids, but none of the heavy metals, microplastics, parasites, or antibiotics found in most salmon, per the companys website.

One of this methods claims to fame is how it might reduce the need for environmentally suspect fish farming.

Net pens used in fish farming pollute sensitive coastal waterways with concentrated excrement. Many farms have had escape events, introducing invasive species into sensitive ecosystems that compete with local fish populations, company cofounder Justin Kolbeck recently told Forbes magazine.

It should be emphasized this grown-in-house fish product is not even remotely related to soy-based imitation seafood and meats. The end products DNA makeup is salmon all the way; theres simply no energy wasted on the little things, like growing skeletons, scales, internal organs or brains.

Anyone remember the sci-fi thriller The Blob? Just asking for no particular reason.

To buttress Kolbecks point about escape, its profoundly unlikely that a chunk of Wildtype salmon will ooze out of the lab, leaving behind a telltale slime trail along the escape route before seeping seaward to freedom. Of course, should that happen, it would be quite a hook-up sight for any angler reeling in a big chunk of raw salmon meat. Anyone know how to clean this thing? Oh, wait, now that I think about it

OK, should we buy into this New Age salmon meat when it hits close to home? It will hit select market by next month or so, after which the company hopes to eventually produce tons and tons of its highly salmonesque stuff. Also, reports indicate other companies are champing at the test tube to get in on cellular seafood.

Personally, I somewhat prefer my seafood has seen the sea. That said, there is no doubt lab-grown seafood could be a healthy alternative to our overfishing of the worlds oceans. I can even foresee both wild-caught salmon and the beaker-based variety being served at a meal and folks clearly preferring the Wildtype offering, calling the natural too gamey.

As to the early taste tests of freshly picked/harvested Wildtype salmon, even educated buds are giving it flying colors speaking of which, the color of Wildtype salmon is identical to the donor fishs flesh color since it is the exact same fish again with the DNA thing.

For you travelers, if youre out San Fran way, the Wildtype company is all but begging folks to stop on in.

Wildtype wants to establish a high standard of education, trust, and transparency with our customers and the public. We want to show people where their food comes from and how its made, offer the owners.

Ill wax snarky by wondering if it might not be best to place test-tube salmon making in the same realm as, say, scrapple making. Philly folks get my dont ask/dont tell drift.

By the by, there have been some unique growing pains to developing a better bodiless salmon. For some unknown cell binding reason, the first chunks did not take at all well to cooking. The meat broke into what might be called individual component parts hundreds of tiny undefinable pieces of salmon essence. I cant imagine what that would have looked like and I would surely have been the only one in the lab laughing my ass off.

The last I heard, the creative minds of the company are tweaking the growing process so we can someday buy San Fran salmon for more than just sashimi, sushi and sausages.

I will absolutely be among the early-on buyers of salmon a la lab. One problem I see is naming the stuff with full disclosure in tow. There must be a distinct, immediately recognizable terminology. Ill be the first to admit that test-tube salmon would be off-putting. Less so would be manmade salmon or sea-free salmon. The company itself might run with cellular salmon, based on its self-hype that Wildtype is pioneering cellular agriculture to grow delicious cuts of our favorite seafood no fishing or fish farming required.

ECO-UGLY ABANDONMENT: I need to combine two tales in one since both have to do with mankind unloosing nonindigenous species into our delicate Pinelands environment.

The more recent of the two comes via a jungle-ish find by Division of Fish and Wildlife conservation officers. While on patrol, the officers came across your everyday boa constrictor crossing a dirt road. Yes, its everyday if you live in frickin Central America!

The 4-footer was found in a state Wildlife Management Area. Id safely venture to say it was not simply taking in the sights of our outback before making the long slither back to some tropical rainforest.

Forgoing the other minuscule possibility that the boas owner had simply been out walking it only to have his minion slip its leash, this was an all too familiar case of someone ignobly abandoning a faithful critter even after it had dedicated its entire life to being a family-member pet.

OK, that might sound a bit overemotional, but such dump-offs are a lousy trick by incompetent-as-s*** pet owners.

As to what would have become of the tropical snake had it not come back to the road looking for its human buddy, I believe it was Jack London who morbidly suggested that freezing to death isnt the worst way to go. Winter would have ended the snakes unwanted flirtation with untamed freedom.

There was no chance the lone boa could have led to the Pinelands becoming a covey of constrictors even if the captured boa wore a boa, meaning it was a female.

That tale roundaboutly leads to a twinish tale of the time piranhas swam about in Stafford Forge Lake.

It was July 2007 when I got word of weird fish being caught in the historic lake, former home to a forge and cranberry bogs. As I wrote back then, A number of piranhas were recently taken by an angler using Bass Stoppers, a favorite freshwater rig. And these werent minor models of this highly nonindigenous species. One piranha was way hefty.

I recall my well-founded disbelief upon seeing the first photo of the landing. At mere first glance, I knew this hookup was a member of a world-renowned fish family that includes piranha, pacu and oscars. To me, it was clearly a piranha.

So, what in bloody hell was such a species doing in the tannin-laced, temperate zone waters of the Forge?

The answer was all too obvious: Some numbnut had released it after it had outgrown its aquarium and its welcome. Such dumpings, while displaying a touch of compassion when compared to a toilet flush-down, are quite common. In fact, many state waters are now plagued by introduced carp, the leave-behinds from anglers using cheap so-called feeder goldfish to live-line for largemouth bass and pickerel.

The sacrificial goldfish, small carp in essence, either get off the hook or are poured into lakes at the end of a fishing session. They grow rapidly into immense vegetation bottom feeders. Once established, they create such a bottom stir that it can muck up the water, impacting gamefish, which feed by sight. They also inadvertently mosey over bass and sunfish nests hollows in the sand inadvertently sucking up eggs and newborns.

As to the Forge piranhas, the hookups led to an utterly surprising finding that they had surely been there more than just one season. The hardy little devils were showing signs of prospering, likely going into a torpor state when the lake froze in winter. Fears arose as to what they were thriving upon, assuredly indigenous species.

The realization that piranhas were making themselves at home in a New Jersey lake led to fear regarding the many people and pets commonly wading right where the fish were caught. Such frets were a bit unfounded. While packs of piranhas can go gruesomely gonzo over the smell of blood and raw flesh, Ive seen naked native children in Brazil freely swim among them, with nary a single natural bris being reported. Nonetheless, N.J. Fish and Wildlife folks went on one weird-ass search-and-destroy mission by electrocuting the lake. The method shocked the hell out of the lakes inhabitants, causing them to rise woozily to the surface, where any species non grata could be removed and apologies offered to acceptable lake occupants, which quickly recovered from the buzz, all wondering What the hell was that all about?!

RUNDOWN: Weirdly, the blowfish are back in town, mainly the far west side of Barnegat Bay where they had been, then left, only to be replaced by a ton of all new puffers moving in from waters to our north. It is once again possible to best a hundred or more per chumming session.

There are also small weaks and kingfish entering the chum slick.

Weirdest chum-related hookup was a massive black drum estimated by Paul P. at 50 pounds. It was almost landed, net hovering above, before the tiny hook gave way. That is pretty far north for Barnegat Bay black drum.

Speaking of drum, its about time for red drum to make beachline passes. The state record remains at 55 pounds, a fish taken in Great Bay by Daniel Yanino in 1985.

This is an amazing time of year to chum with grass shrimp in places like Myers Hole and surely some deeper waters toward Little Egg Inlet. Such panfishing often offers as great a variety of fish species as youll ever hook during one Jersey sitting.

Considering most of the fish drawn to a shrimp chum will be juveniles, you must use circle hooks and unhook undersized fish as quickly and gently as possible. Best bet is to not even bring them aboard. A nice series of photos can be taken without fish having to pass over the gunnel.

Surfside fluking is fair. Its best when waters are at least a bit roiled. Calm, crystal-clear water periods seem to knock down the flattie action. Every now and again there is a sudsy doormat taken.

Stingrays have glided a bit north, though a few are still quite obvious along the clear-water shoreline. Ive gotten two emails regarding ways to cook ray wings. Ill give them a try. If my taste buds salute, Ill pass them on.

Triggerfish are making their typical late-summer presence known. Some nice-sized ones mixed in, way larger than they usually show down south, re-begging the question of whether these fish go back to the Deep South or move off shore for the winter. The average sheepshead size up here dwarfs the typical sheepsheads in places like the Indian and Banana rivers in Florida.

Please do not try to fillet triggers. Too much meat is utterly wasted. After gutting, simply cook them whole. Once done and they bake very quickly with skin still on pull off the now easily removed skin and dine on the delicate white meat within. Of note, there are some filefish being labeled triggerfish. They are different to a degree, but are surprisingly similar in taste.

jaymann@thesandpaper.net

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Time to Go Sushi With Cellular Salmon; When Pet Owners Tire of Their Minions - The SandPaper

This article was originally published here

Transfus Med. 2021 Aug 15. doi: 10.1111/tme.12805. Online ahead of print.

ABSTRACT

BACKGROUND: Haematopoietic stem cells (HSC) may act as a source of infection for the recipient due to manipulation at multiple levels from collection to infusion. Due to the high risk of contamination cultures are usually taken during multiple steps. The clinical significance of microbial contamination of HSC on the post-transplant course and the role of prophylactic antibiotics is relatively unknown.

AIMS AND METHODS: The aim of our study is to investigate the incidence of microbial contamination of haematopoietic stem cell and to assess its impact on the post-transplant febrile neutropenia, engraftment kinetics, hospitalisation and day 100 mortality. Details of all patients admitted in the bone marrow transplantation unit of a tertiary care centre in India between January 2014 and December 2018 were collected from case records.

RESULTS: Of the 1306 stem cell harvests from 503 patients sent for culture, 17 harvests (1.3%) were found to have a culture positive report. Sixteen patients had undergone autologous transplant. Multiple myeloma was most common indication of HSC transplant followed by Non-Hodgkin Lymphoma (NHL). Twelve of 17 HSC cultures were positive at the time of infusion and five were positive at the time of harvest. The five HSC that were culture positive at the time of harvest were culture negative at the time of infusion. Gram-positive organisms were isolated in six cultures and gram-negative in rest. All patients developed febrile neutropenia post-transplantation between day 1 and day 7. The median time of onset of fever was day +5 (1-7), the median duration of fever was 4 days (2-7), the median duration of antibiotic use was 11 days (9-16). Median day for neutrophil engraftment was 11 days (9-16), the median day for platelet engraftment was 14 days (10-25) and median duration of hospitalisation was 15 days (12-78). All patients were alive at day 100 of transplant.

CONCLUSION: This study shows that there appears to be minimal impact of culture positive HSC on transplant related outcomes in terms of engraftment kinetics, duration of hospitalisation and day 100 mortality. Discarding of contaminated HSC may not be required, though on development of febrile neutropenia appropriate antibiotics should be administered based on sensitivity pattern of HSC culture. Larger prospective studies are needed to determine the clinical relevance of such contaminations. Emphasis should be laid on better infection control practices to minimise contamination rates.

PMID:34396610 | DOI:10.1111/tme.12805

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Impact of microbial contamination of haematopoietic stem cells on post-transplant outcomes: A retrospective study from tertiary care centre in India -...

Longeveron Inc. (LGVN, Financial) is an emerging clinical-stage biotechnology player that utilizes stem cell research. It is working towards developing regenerative medication via allogeneic mesenchymal stem cells. It is in the progress of building a number of cellular therapies at its facility, utilizing healthy bone marrow of adult donors to develop treatments for aging and aging-related diseases like Alzheimers Disease.

The companys lead candidate is a therapy known as Lomecel-B, an allogeneic product containing medicinal signaling cells from the adult donor bone marrow (from an 18 to 45 age group) and culture expanded in the companys cell processing facility. They identify and use cells with regenerative properties to build a therapy that could carry out various functions, including tissue repair and organ maintenance.

Longeveron has been in the news recently as it released the data of the Phase 2b aging frailty trials for Lomecel-B. The results did not live up to expectations, causing the stock to plunge. However, the long-term prospects of the company have not changed, in my opinion, which could mean now is a great opportunity to buy the dip.

The Phase 2b trial data

Longeveron carried out a multi-center study to assess the effect of its lead candidate Lomecel-B therapy on 148 random subjects. Its trial was partially funded by an SBIR (Small Business Innovation Research) grant from the National Institute of Aging. The company carried out a single peripheral intravenous infusion of the lead candidate in various quantities ranging from 25 million to 200 million cells. It kept the subjects under observation for 52 weeks to evaluate the efficacy and safety of the therapy. The management performed a six-minute walk test on the subjects to assess their exercise tolerance and endurance in order to evaluate the impact of the treatment. This test also analyzed gait speed, short physical performance battery, grip strength, performance-oriented mobility assessment, sexual function, cognition, depression and other factors associated with the subjects in their daily lives.

Longeveron did not see statistically significant results compared to the placebo after 180 days, which is what has disappointed investors and led to the recent selloff. However, the management saw a significant difference from placebo after 270 days of the treatment. Moreover, Lomecel-B continues to demonstrate a high level of safety as no patients showed signs of any severe adverse conditions.

The information is sufficient for Longeveron to continue pursuing their research aggressively, not just in the U.S. but in other countries as well. The management aims to initiate the Phase 2 Japanese Aging Frailty trial this year while waiting for the results of Phase 1/2 HERA trial data. The 'HERA' trial data is expected to evaluate the effects of Lomecel-B on the immune response to influenza vaccination in Aging Frailty subjects.

The importance of aging and frailty research

Aging Frailty-oriented research is gaining a very high amount of importance because of its substantial addressable market. Most patients who suffer from it show symptoms like muscle loss and decreased strength, low-level activity, slow walking, poor energy level and endurance, weight loss, nutritional deficiencies and fatigue. It has a negative impact on muscle and bone tissue health. Apart from muscles and bones, aging and frailty also negatively affects the cardiovascular system, immune system and cognition.

Stem cell treatments for aging-associated diseases are a crucial area of research given the ageing population. However, there are no FDA approved stem cell treatments in the U.S. within this domain. The potential addressable market for aging and frailty is rising sharply due to the gradual increase in average life expectancy as well as declining birth rates. Longeveron is one of the key movers in this domain and has shown significant results through their Lomecel-B therapy trials.

While the trials may not have shown a statistically significant result in a 180-day period, the 270-day data is extremely encouraging for the companys future. Furthermore, if the Lomecel-B trials continue to show success in the upcoming quarters, Longeveron could become a top candidate for a large pharma acquisition.

Is the crash justified?

Longeverons stock crashed after the companys Phase 2b press release came out, but is this crash justified? The trial results may not have been positive for a 180-day time horizon as hoped, but the 270-day results have been encouraging. Moreover, given the fact that the safety of Lomecel-B has been unquestionable, this implies that the company can go ahead with other trials (including the Phase 2 trial for aging and frailty in the Japanese market) with great confidence.

There is also a huge upside potential with respect to the future prospects of Lomecel-Bs application in Alzheimers Disease and other ageing-related diseases. Last but not the least, the company has sufficient cash to go through with multiple trials across different geographies. Thus, I believe that the recent crash in Longeverons stock price is no reason for investors to panic. Moreover, biotech microcap investors with a high risk appetite could see this drop as an investment opportunity.

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Longeveron: Time to Buy the Di - GuruFocus.com

The Department of Education is sending letters to the governors of Texas and Florida, as well as Florida school district superintendents, amid an escalating battle between the White House and state officials over school mask guidance as the Delta variant surges.

In a new letter Friday, Education Secretary Miguel Cardona wrote to Republican Gov. Ron DeSantis of Florida that he is deeply concerned by the states executive order restricting the implementation of school mask mandates. Cardona also took aim at the recent threat from the governors office that the state board of education could move towithhold the salariesof superintendents and school board members who disregard his executive order.

Cardona sent a similar warning to Texas Republican Gov. Greg Abbott and the states education commissioner Mike Morath, underscoring how Texass recent actions to block school districts from voluntarily adopting science-based strategies for preventing the spread of COVID-19 that are aligned with the guidance from the Centers for Disease Control and Prevention (CDC) puts these goals at risk and may infringe upon a school districts authority to adopt policies to protect students and educators as they develop their safe return to in-person instruction plans required by Federal law.

This follows statements from White House press secretary Jen Psaki earlier this week, whotold reportersthat the White House and federal government are continuing to look for ways to support local school districts and educators in Florida, as they try to follow the science do the right thing and save lives.

Psaki said later that paying for salaries could be a part of that, and the Department of Education is looking at options. Withholding funds is not the intention, she said.

Previously, Biden and members of his administration havespecificallytargetedthe governors of Florida and Texas for standing in the way of mask and vaccine requirements, pointing to the extraordinary amount of Covid-19 cases and hospitalizations in their states.

In Fridays letter to DeSantis and Corcoran, Cardona pointed to how Florida school districts can use funds from federal Covid relief for educators salaries, noting that any threat by Florida to withhold salaries from superintendents and school board members who are working to protect students and educators (or to levy other financial penalties) can be addressed using ESSER funds at the sole and complete discretion of Florida school districts.

In the letter to Florida school district superintendents, Cardona further emphasized the administrations support, saying, I want you to know that the U.S. Department of Education stands with you. Your decisions are vital to safely reopen schools and maintain safe in-person instruction, and they are undoubtedly in the best interest of your students.

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The latest on the Covid-19 pandemic in the US: Live updates - CNN

Vitali Voskoboiniks bright blue eyes sparkled behind his glasses as he sat in his sunny Pacifica apartment. At 79, the Holocaust refugee looked full of life; he laughed and smiled, introducing himself first in Russian, then in Hebrew, and then in English.

One would never guess that just a few months ago he was bedridden, unable to breathe independently or speak, and on the brink of death from a severe case of Covid-19.

To me, this is a miracle, said Lena Asadov, who helped care for Voskoboinik as administrator of South San Franciscos Angel Palliative Care and Hospice, Inc.

Asadov said when she had last seen him, Voskoboinik could barely sit on the edge of his bed without collapsing, his body and lungs extremely weakened from months of illness. On July 26, he stood to greet her, and he later walked down to the garden of his home at Terrace Senior Housing two accomplishments that no one was sure he would be able to achieve.

While Voskoboinik is not yet able to resume his two-mile walks to the Pacifica pier, he has made a remarkable recovery a feat Asadov credits to Voskoboiniks fighting spirit and his daughters perseverance.

Voskoboinik was born in 1941, on a train headed to Uzbekistan as his mother was escaping Nazi-occupied Ukraine. He never met his soldier father and only knew him through a series of letters his parents exchanged before his father was killed in the war. Voskoboinik grew up in the Soviet Union, where he met his wife, and together they moved to Israel. They lived there for 20 years before coming to America in 2014.

Voskoboinik passed down his fighting spirit to his only daughter, Yulia Nedzvetski, who advocated day and night for her father after he got sick in January.

Voskoboiniks symptoms began with a cough and difficulty breathing. His condition worsened rapidly, and after six days on antibiotics Voskoboinik was rushed to the ICU at Sutter Healths Mills-Peninsula Medical Center.

Once they had stabilized him, doctors estimated he had only months to live, Nedzvetski said. She refused to accept that prognosis. She had over 30 years of nursing experience in Ukraine, Russia, Israel and the U.S., as well as education in health care management and administration from Ariel University. But she also had something even more powerful: determination to get her father well again.

I knew he would get better, said Nedzvetski, who admitted to being so focused on his recovery she refused to accept that he was in critical condition.

Strict Covid safety precautions prevented her from seeing her father, except for a few times when she came to meet with doctors after she was vaccinated, but this did not stop her from dedicating her time and energy to his care. She left her job as a case manager at the VA and, with her two sons who live in Israel, set to work researching possible treatment options once doctors told her they had done everything they could, she said.

One treatment Nedzvetski suggested was proning, a process of carefully turning a patient in respiratory distress from their back to their stomach to help improve oxygen flow. Another was to use an ECMO machine, which pumps and oxygenates a patients blood outside the body, allowing the heart and lungs to rest. But Nedzvetski said she was told it was only for patients under 65.

I came with three, four, five different treatment options and everything was a no, said Nedzvetski. Its not something we do in the U.S., its not something we do for older people.

Eventually she became so frustrated and desperate she began demonstrating outside the hospital, at one point holding a sign that read Sutter, let the Holocaust survivor get the FDA approved medicine. Although she was able to meet with the ICU director and speak with a roundtable of doctors and nurses, she said they would not approve the treatments she suggested.

Nedzvetski believes that families must advocate even more than usual for their loved ones, with hospitals overwhelmed with Covid patients and visitation restricted. She said such limited access has had a negative impact on patient care.

J. asked Sutter Health about Voskoboiniks case but the hospital declined to comment.

Nedzvetski decided it was time to move her father back home and care for him there with help. But his condition was so dire he was under sedation, on a ventilator and under constant medical watch that as far as the hospital was concerned, he could not be discharged home safely.

Hospitals are and were dealing with a lot during this time, and Yulia did her best finding every possible solution, said Traci Dobronravova, director of Seniors At Home, one of the senior care services through Jewish Family and Childrens Services.

Nedzvetski utilized the help of Brigit Jacoby, Russian bilingual senior care manager at JFCS, who connected her with chaplain Bruce D. Feldstein of Jewish Chaplaincy Services at Stanford Medicine. He helped communicate with the hospital and contacted dozens of agencies about caring for Voskoboinik at home, but almost all saw his medical condition as a costly liability.

When you get into the world of experimental treatments there are a lot of protocols you have to follow, and his case fell outside of that, Feldstein. It really looked like he would not have made it, [and] it is heart-wrenching when theres a situation where you believe they should be able to help but they cant.

Then Nedzvetski found a compassionate ear at Angel Palliative Care and Hospice. I really felt for them, Asadov said. As a Jewish person who was also born in Ukraine, I just knew I needed to do everything I could to help.

Asadov said the transition from the ICU to home was extremely difficult, and that moving a patient on a ventilator to home hospice is not common. Nedzvetski said Sutter agreed to discharge her father home under the condition that she get instruction at the hospital on how to use all of the necessary medical equipment.

Asadov and the Angel Palliative Care and Hospice team helped Nedzvetski turn her home into a makeshift ICU room, complete with a hospital bed, ventilator, feeding tube and other medical supports. Nedzvetski said the agency was there whenever she needed assistance, and that one nurse, Lora Lemenov, even left her own birthday celebration to come help.

Once home, Voskoboinik was given stem cell treatment by a private physician and three days later, according to Nedzvetski, her father began to recover.

Within the month, Voskoboinik was breathing independently. As his condition improved, Angel Palliative Care and Hospice recognized that his care goals had changed and he was in need of rehabilitation services. They were able to safely graduate him from home hospice to a rehabilitation plan with Pacifica Nursing and Rehab Center. He was discharged back home in mid-July.

Asadov hopes that Voskoboiniks story will help change the stigma around hospice care, and make people aware that the goal is to provide comfort and improve patients quality of life, even if it turns out to be their final moments.

Everyone is scared of the word hospice. They hear that and think thats it, this is the end. said Asadov. But for him, hospice wasnt the end of his life. It was a new beginning.

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How this Holocaust refugee beat Covid-19 against all odds J. - The Jewish News of Northern California

Significance

Plant vascular systems play a central role in global water and carbon cycles and drought resistance. These vascular systems perform multiple functions that affect the fitness of plants, and trade-offs are present among these functions. Some trade-offs are well established, but studies have not examined the full suite of functions of these complex systems. Here, we used a powerful multivariate method, structural equation modeling, to test hypotheses about the trade-offs that govern this vital and globally important tissue. We show that xylem traits are broadly governed by trade-offs related to transport, mechanical support, and storage, which are rooted in cellular structure, and that the level of dehydration experienced by plants in the field exerts a strong influence over these relationships.

The xylem in plants is specialized to transport water, mechanically support the plant body, and store water and carbohydrates. Balancing these functions leads to trade-offs that are linked to xylem structure. We proposed a multivariate hypothesis regarding the main xylem functions and tested it using structural equation modeling. We sampled 29 native shrub species from field sites in semiarid Southern California. We quantified xylem water transport (embolism resistance and transport efficiency), mechanical strength, storage of water (capacitance) and starch, minimum hydrostatic pressures (Pmin), and proportions of fibers, vessels, and parenchyma, which were treated as a latent variable representing cellular trade-offs. We found that xylem functions (transport, mechanical support, water storage, and starch storage) were independent, a result driven by Pmin. Pmin was strongly and directly or indirectly associated with all xylem functions as a hub trait. More negative Pmin was associated with increased embolism resistance and tissue strength and reduced capacitance and starch storage. We found strong support for a trade-off between embolism resistance and transport efficiency. Tissue strength was not directly associated with embolism resistance or transport efficiency, and any associations were indirect involving Pmin. With Pmin removed from the model, cellular trade-offs were central and related to all other traits. We conclude that xylem traits are broadly governed by functional trade-offs and that the Pmin experienced by plants in the field exerts a strong influence over these relationships. Angiosperm xylem contains different cell types that contribute to different functions and that underpin trade-offs.

From cells to ecosystems, biological systems are complex and span multiple scales. To fully understand such systems, multivariate analytical methods are a powerful tool (1), yet it is most common to analyze variables separately or descriptively ordinate them. One powerful multivariate analytical framework is structural equation modeling (SEM) (2, 3). Plant vascular systems represent a complex multivariate system, where many traits determine functions in direct and indirect ways and interact with one another. There is much interest in understanding xylem in a systems context (46); however, using SEM to test hypotheses of the full range of xylem function in a single model has yet to be done. A positive development is that several recent studies that have applied SEM to understanding some xylem functions and traits (79).

Xylem functions include transport of water, mechanical support, and storage of water and carbohydrates (reviewed in ref. 6). These functions are interrelated, and associations among traits arise due to mechanistic links between structure and function. This can lead to trade-offs where prowess in one trait necessarily diminishes that of another (10). Traits may also be associated for at least two other reasons: shared ancestry, or when ecological conditions select for a suite of adaptive traits in different lineages in a process called concerted convergence (11).

We present relationships among xylem traits as a multivariate hypothesis in a path diagram (Fig. 1). The path model depicts the multiple variables, and the arrows (paths) represent connections between variables that can be direct (a direct arrow from one to another) or indirect (a direct arrow to a trait that has a direct path to a second trait), where indirect effects can be as important as direct ones. There are two central elements to our hypothesized model. First, that there are different cell types that are specialized to perform xylem functions: vessels conduct water; fibers provide support; and parenchyma stores carbohydrates (see also ref. 12). The division of cellular labor mitigates some direct functional trade-offs found in species with tracheid-based vascular systems (13); nevertheless, trade-offs may arise based on the amount of tissue volume allocated to different cells (4, 14). We examined this trade-off as a latent variable in our SEM model where cellular trade-off is represented by the proportions of different cell types in cross section (Fig. 1). The second centerpiece in our hypothesis is that the hydrostatic pressure potential experienced by plants during droughts or dry periods (Pmin) exerts a mechanical strain giving rise to direct and indirect effects on all other traits (11, 15, 16). This trait is affected by the environment (amount and timing of rainfall, temperature, and soil water content and conductance), and plant traits such as water use and hydraulic conductance, with additional links to many other traits (11).

Hypothesized relationships among the various xylem functions. The arrows represent pathways between two variables. Traits may have direct effects on another trait represented by an arrow directly connecting two traits, and traits may also exert indirect effects when they are connected through an intermediate trait. Latent variables are connected to their measured traits by gray arrows. Cellular trade-off is a latent variable represented by measured fiber, parenchyma, and vessel area in cross section. Tissue strength is represented by xylem density. Omitted are any double-headed arrows for variables with correlated errors (SI Appendix).

We hypothesized that Pmin is directly associated with embolism resistance and indirectly affects hydraulic transport efficiency (Fig. 1). Emboli are gas bubbles that form in conduits that block transport during drought or following freezethaw events (4). Species have evolved broad differences in embolism resistance (xylem safety) that is under strong selection by drought when negative pressures in the xylem exceed safety thresholds, leading to dieback and mortality (1719); moreover, xylem safety is strongly associated with Pmin (20, 21).

Increased embolism resistance is directly linked to reduced hydraulic transport efficiency in a well-studied trade-off (9, 22). Efficiency of xylem refers to the mass flow rate of water for a given pressure gradient and area of tissue (xylem-specific conductivity, Ks). No species has xylem that is simultaneously highly resistant to embolism (very safe) and highly efficient (23). One reason for this is because of the pits and pit membranes that connect conduits. These cellulosic membranes have nanoscopic pores, and the smaller these pores, the more resistant they are to embolism spread; however, smaller pores and thicker membranes reduce transport efficiency (22, 24). The arrangement and connections of the network of vessels in a vascular system is also an important factor (25). Globally and across angiosperm and gymnosperm lineages, a safetyefficiency trade-off has not been supported (16); however, within a specific lineage, community, or growth form, this trade-off can occur, and understanding this context is a research priority (9, 10). Pmin and efficiency are additionally predicted to be directly related because of an effect of Pmin on vessel diameters. Larger-diameter vessels are associated with greater efficiency (26), and such vessels can take longer to develop (27). If water is limited when vessels are developing, then the diminished turgor will limit vessel size (28).

Cellular trade-offs and tissue strength may be directly affected by Pmin because extreme pressures can strain conduits to the point of buckling damage or collapse (29). This threat is minimized by thicker cell walls between conduits, smaller conduit diameters, and an extensive and supportive fiber matrix (13, 30, 31), all of which create a series of direct and indirect paths (Fig. 1). First, these factors should lead to direct associations between Pmin and tissue strength (4, 29, 32) and with cellular trade-offs. A cellular trade-off affects tissue strength because more fibers promote strength at the expense of parenchyma and vessels (6). The association between tissue strength and Pmin creates four indirect paths from tissue strength (Fig. 1). These pathways lead to associations with embolism resistance and efficiency and that are hypothesized to arise because the more negative Pmin a plant experiences, the greater the need for vessels to resist embolism (30). Additionally, efficiency is reduced because smaller-diameter vessels better resist implosion (29), and stronger vessel walls are thicker and create deeper and longer pit chambers (24). Another indirect association is between tissue strength and water storage capacity. For nonsucculent woody species, most water is stored in the lumens of fibers and stronger tissues with thick-walled fibers, and narrow lumens have lower water storage (33). A final indirect association is predicted between tissue strength and Pmin through its effect on water storage, which leads to a feedback loop among these three traits.

Storage of carbohydrates in xylem allows plants to cope with variable and uncertain environments (34). Their diverse functional roles are an area of active research (34), and they are important to understand in the context of trade-offs (6, 8). Stored carbohydrates are found in parenchyma, thus increased storage capacity requires an increase in these cells [living fibers can also be important (35, 36)], which links cellular trade-offs to carbohydrate storage. Parenchyma may be structurally diverse, but they are generally thin-walled living cells that provide the least support to vessels in resisting implosion and mechanical strains contributing to the link between cellular trade-off and tissue strength and embolism resistance (30, 37). Pmin is hypothesized to be directly linked to starch storage because species that experience more negative Pmin osmoregulate by hydrolyzing starch to simple sugars (34, 38), which should create a negative association between Pmin and starch storage.

Two other direct trade-offs are predicted between cellular trade-offs and transport efficiency and embolism resistance. Previous work has found an association between the proportion of vessels in xylem (vessel area) and transport efficiency (32) or the proportion of vessel lumen area (39). We also predicted a direct relationship between cellular trade-offs and embolism resistance. This association could arise due to direct associations between proportions of cellular traits and their importance in resisting the strain of negative pressures, or this may simply be indirect through a direct effect on tissue strength. These associations also create the potential for indirect associations of Pmin with transport efficiency and embolism resistance through association with cellular trade-offs.

We used an SEM approach to test our model and hypotheses (represented in Fig. 1). Both cellular trade-offs and Pmin were predicted to affect all other traits directly or indirectly. Evaluating both simultaneously is informative, but to understand how they affected one another, we created an additional model with Pmin removed. Our hypotheses determined the paths in the diagram and the direction of their effects; however, other formulations are possible and are discussed. We measured variables representing different xylem functions and Pmin in 29 species of chaparral shrubs from Southern California. All species were growing at field sites with a semiarid Mediterranean-type climate. This system has a protracted dry season that places considerable strain on vascular transport traits (40); moreover, the values for xylem traits found among chaparral shrubs, even co-occurring ones, span a wide range, providing abundant trait variation (21, 36). All species were sampled in the same laboratory and using the same methods, thus minimizing errors due to methods differences.

Shrub species (n = 29) were measured at four field sites in Southern California (SI Appendix, Table S1). At all sites, n = 6 different individuals were tagged for sampling for each species at that site. Our goal was to study many independent species, thus sites were selected that contained diverse species (mixed chaparral). We also selected those of a similar community type and that contained abundant individuals of the indicator species chamise (Adenostoma fasciculatum). In chaparral classification, these sites would be mixed/chamise-type chaparral (40). Sites had not experienced a burn in at least 30 y, so they contained mature shrubs. All sites have a Mediterranean-type climate with hot dry summers and cool moist winters. Precipitation is almost entirely rainfall that occurs between November and May each year, with a protracted rainless season occurring in the Summer and Fall months. For more details on the sites, see ref. 36. Most of the samples and data were collected in 2009 and 2010. The phylogeny of the sampled species was reconstructed using the phylomatic database, and it was fine-tuned using a molecular phylogeny (see ref. 36 for additional details).

We measured a suite of traits to represent xylem functions with an aim to include them in a structural equation model. In many cases, there are multiple traits that could represent a function. Because our goal was to present a simple model, we did not include all the measured traits in our model because it was overly complicated and impractical. In the following sections, we highlight the care that we took to compare methods and measures to ensure the traits we chose represented a particular xylem function. The target sample size for all measurements was n = 6 different individuals per species, and the same individuals were used throughout the study to minimize intraspecific error variation. The mean of these six samples was the unit of analysis for species. For all measured traits, we sampled healthy branches that were similarly sized (about 6 mm in diameter) and located in the sunny south side of the outer canopy to minimize branch-to-branch variation. We measured multiple variables on the same stems when possible, which included hydraulic measurements, xylem density, and anatomy. Methods are fully described for most traits. Starch storage and measures of xylem cellular proportions have been previously published (36), and methods for these traits are only briefly described with the relevant publications referenced.

Resistance to embolism of distal branches was measured using a centrifuge method. Samples were brought back to the laboratory and flushed prior to sampling (see next paragraph). This method exposes stems to increasingly negative xylem pressures and measures hydraulic conductivity (Kh) declines in response. The resistance to embolism is expressed as the negative pressure for a given percentage loss of Kh. It is common to use the pressure potential at a loss of 50% of maximum Kh (P50). Here, we used the pressure potential at a 75% loss in Kh (P75). The P50 and P75 were strongly correlated (r = 0.91, P << 0.001), so this choice did not alter the analyses. The sampling protocol followed methods that have been previously published and extensively compared to reference methods (e.g., ref. 41).

Hydraulic efficiency was measured on the same stems as used for P75. Stems were 14 cm long and were flushed for 60 min at 100 kPa with an ultrafiltered (0.01-m pore) and degassed 20 mM KCl solution. The flushing treatment removed emboli from the stem xylem. The stems were then connected to a tubing system with a pressure head of 2 to 3 kPa, and flow through the stem was collected on a four-point balance. The flow rate (kg/ s) was divided by the pressure gradient (MPa/ m) to compute the Kh of the stems. This was divided by the sapwood area to compute the xylem-specific Kh (Ks), which is a trait commonly used to represent transport efficiency. Another trait that can represent efficiency is vessel diameter. We compared our Ks data to vessel diameter to validate them. The Ks was strongly and positively correlated to vessel diameter (r = 0.78, P << 0.001).

The minimum seasonal water potential was measured on distal branchlets at the end of the Fall dry season in 2009 using a pressure chamber (Model 2000, PMS Instrument Co.). Not all sites could be sampled before rains fell in 2009, so additional sampling was completed in Fall 2010. Samples were taken at predawn and midday. In theory, the predawn values equilibrate with soil water potential, and all the organs of the plant are in equilibrium including the stem xylem pressure potential (P). The predawn and midday values were strongly correlated (r = 0.95, P << 0.001), and we report midday values as Pmin. The Pmin values can be challenging to assess in long-lived species. In chaparral systems, because of the predictable and protracted Summer/Fall dry season, it is not that difficult. The Pmin that a species experiences during a typical dry season has been found to be strongly correlated to the Pmin during high-intensity drought (r = 0.87 in ref. 21).

Xylem strength was measured in two ways. One simple estimate of tissue strength is xylem density. This was measured on the same stems used for P75 measures using Archimedes principle. Stems were debarked and depithed and saturated with water. The xylem was submerged in water on a four-point balance. The mass of water displaced, the temperature of the water, and the density of water were used to convert the displaced water mass to a volume. The xylem was then oven dried at 70 C for >3 d, and the dry mass was measured. Xylem density was expressed as tissue dry mass per volume. Modulus of rupture (MOR) of stems was measured using a mechanical properties tester (Model 3342, Instron) following the methods of ref. 30. Xylem density and MOR were strongly correlated (SI Appendix, Fig. S1), thus we chose to use xylem density for simplicity.

Water storage of xylem (capacitance) was measured by generating pressurevolume curves on debarked and depithed samples that were about 1 cm long and 6 mm diameter. This size was necessary so samples would fit into psychrometers (Model C30, Wescor Corp.). Samples were saturated with water and weighed on a four-point balance. They were then placed into psychrometers for >2 h to allow them to equilibrate. The water potential of the psychrometers was measured with a datalogger (Model CR7, Campbell Scientific). Following equilibration, the samples were removed from the chamber, and the masses of the samples were weighed and recorded. The mean mass was taken pre- and postmeasurement and the average used to represent the mass at a water potential. Samples were then air dehydrated for 1 to 5 min and resealed in the psychrometers. This process was repeated between 8 and 16 times until the water potentials were about 6 MPa (the lower limit of these psychrometers). We used an array of 18 psychrometers and, to improve accuracy, psychrometers were calibrated with four to five salt solutions each time a species was sampled. Calibrations were done at three different cooling times, which we found was valuable to measure the most negative water potentials (the longest cooling time) and to get precise readings for more hydrated samples (shorter cooling times). To determine capacitance, curves were generated plotting relative water content (RWC; fresh weight dry weight/saturated weight dry weight) on the y-axis and in response to water potential (SI Appendix, Fig. S2). Capacitance was calculated as the slope (RWC/MPa) of the linear portion of the curve between about 0.3 and 1.5 MPa.

Starch content of xylem was measured using an enzymatic method for samples collected in Fall 2009. Fall was selected because this is the seasonal point when starch storage should be close to its seasonal maximum. Stems were debarked and depithed, and the remaining xylem was ground using a ball mill, consequently, only xylem starch content was measured, which was appropriate for our focus on xylem trade-offs. The starch data we used can be found in another study where our methods are fully described (36).

The proportions of difference cell types, fibers, parenchyma, and vessels were measured in cross sections of the same stems sampled for the same stems in which hydraulic traits were measured (n = 3 to 6 stems/species). Thin sections were made using a microtome and mounted in glycerol. Samples were examined at 200 magnification with a microscope (36).

We used an SEM approach to test our multivariate hypothesis (Fig. 1). We had two latent variables in our model: cellular trade-off and tissue strength. Cellular trade-off was represented by the area of fibers, vessels, and parenchyma measured in cross section, and tissue strength was represented by xylem density. Strength of xylem can be measured in many ways and at different scales (cell to tissue), thus it made conceptual sense to treat is as a latent variable (8); however, we did not statistically analyze it as a latent variable (SI Appendix, Fig. S3). Representing cellular trade-off in this way consistently led to an impossible negative error for fiber area in our models. The negative value was always very small (0.001 to 0.006). Thus, we set fiber error to zero, which has little effect on parameter estimates when the error is very close to zero (42).

The modeling approach consisted of two parts. The first was to develop a path diagram that represented the hypothesized multivariate relationships among xylem traits (Fig. 1). In the second step, we examined if the model provided an adequate fit of the data. Prior to analysis, the data were examined in the context of parametric statistical assumptions. The data were transformed using natural log for all traits except for xylem density and water storage because the transformed relationships were less linear. The absolute value of Pmin and P75 were used (SI Appendix, Table S2). The unstandardized coefficients that we report are transformed and scaled (SI Appendix, Fig. S3). All SEM tests were run using R (R version 4.0.5) package lavaan 0.6 to 8 (43).

Statisticians recommend a larger sample size than we used for SEM models that are relatively complex; however, there are reasons why we did not collect more samples. Our data set consisted of 29 species and six replicates for most variables, so we collected 174 data points for each of the nice measured factors, all of which are time consuming to measure. Another option would be to combine available data to form a larger data set, but this is not presently possible due to lack of data for the full suite of variables that we measured.

Because of our small sample size, we adjusted our model selection criteria in some ways. The goodness of fit of the SEM model was determined by a 2 test that compared the fit of the model to a model with all predictor variables. The null hypothesis was that the tested model would not differ from the fully parameterized model, thus indication of a good model fit is P > 0.05. We report model tests from standard and BollenStine bootstrapped values that are recommended for small sample sizes (3). We also report the comparative fit index and the TuckerLewis index (TLI), where values of >0.95 suggest good model fit. After testing our hypothesized model, we found that it fit the data reasonably well, but there were some paths in the model that were not significantly supported. We ran additional models with these paths removed. We compared these models to our initial hypothesized full model using information theoretic tests (Akaike information criterion [AIC] and Bayesian information criterion [BIC]), with an emphasis on the corrected AIC (AICc), which is adjusted for small sample size. These statistics evaluate the goodness of fit of a model and parsimony. The best-fit models have lower values of AIC and BIC, and values of >|2| are better fitting models.

In additional to analyzing raw trait values, we also ran analyses on phylogenetic independent contrasts (PICs). These were calculated for all traits using branch lengths set to 1 (Mesquite version 3.61). The same processes were followed and models run using PICs.

Additional analyses included assessing the variation across our sites for the nine traits we measured. This was done using boxplots and violin plots (R package ggplot2) and by partitioning the variance of the measured traits among species nested within each site, across the different sites, and within each species (intraspecific; R package lme4 for mixed-effect models). We also analyzed the bivariate relationships among all traits using simple Pearson correlations. We conducted a network analysis that shows correlations among traits in a correlogram. We included a strength analysis that assesses the importance of a trait in a network in the context of how strongly it is correlated with the other variables. The last analysis we conducted was a principal components analysis to describe the multivariate relationships among traits (princomp function in base R and plotted with package ggbiplot). We used a scree plot to determine that two components adequately explained the variation among our traits.

We observed large differences in trait values among the 29 shrub species we analyzed. These values spanned a large proportion of the observed variation across the globe for woody species (9, 38). Sampling many different species across different field sites leads to different sources of variation (SI Appendix, Table S1). We analyzed variation within sites, across sites, and intraspecifically. The general finding was that variation among traits was wide for species sampled within each site, indicating that sites were unlikely to be exerting unique effects on the measured traits (SI Appendix, Fig. S4). This is also supported by the large proportion of overall variance contributed by species nested within site (SI Appendix, Fig. S5). One exception was for Pmin and P75, which at one site (Phantom site) did not have species with values as extremely negative as found at the other sites (SI Appendix, Fig. S4); however, this likely occurred because we did not randomly sample species within a site and instead chose unique species. The Phantom site was established last, and the site contained species that experience highly negative Pmin values, but we elected to not sample them because they were already in our data set from other sites. Moreover, this site receives the second-lowest average rainfall among the four sampled, and it also experiences hot temperatures, suggesting it is not a mesic site in our study (see ref. 36).

Significant and strong bivariate correlations were observed among many of the measured traits (Fig. 2). The extremes were Pmin, which was significantly correlated with all variables except parenchyma area, and parenchyma area, which was only correlated with one other trait (Fig. 2). Not only was Pmin correlated to most variables, it also had many strong associations (SI Appendix, Fig. S6). Fiber area was another trait with many significant and strong associations with other traits (Fig. 2 and SI Appendix, Fig. S6). Making these same comparisons with PICs generally showed the same patterns (SI Appendix, Fig. S7).

Bivariate correlations among all the traits with associated r-values and significance (*** < 0.001; ** < 0.01, * < 0.05, . < 0.10) for raw trait values, and those for PICs are in the supplemental figures (SI Appendix, Fig. S7). Cap. refers to capacitance or water storage, and Par. is short for parenchyma. P75 represents the water potential at 75% loss of hydraulic conductivity and estimates embolism resistance, and Ks is xylem specific conductivity and represents transport efficiency. Details about other traits are described in Materials and Methods.

Summarizing the multivariate relationships among these traits using principal component (PC) analysis showed clear patterns where PC1 captured the inverse relationships between safety and efficiency, tissue strength and starch storage, and vessels and fibers (SI Appendix, Fig. S8). PC2 described the inverse relationship between water storage and xylem density and parenchyma and fibers. The same patterns were apparent when analyzed using PICs (SI Appendix, Fig. S8).

The analyzed SEM model produces different types of variables and coefficients. The coefficients shown along the paths (predictors) represent the relationship between variables (Fig. 3). They are standardized and represent the change expected (positive or negative) if a predictor variable is varied by one SD. In cases where there are multiple predictors for a single trait (embolism resistance, transport efficiency, tissue strength, and starch storage), the coefficients represent partial regression coefficients. We include both standardized coefficients (Fig. 3) and unstandardized coefficients in the transformed units of the measured traits (SI Appendix, Fig. S3 and Table S2).

Results from our analyzed SEM model for raw trait values (A) and PICs (B). The weights of the solid arrows correspond to P values where the thickest is <0.001, intermediate <0.01, and thinnest is <0.05. The dotted arrows correspond to P > 0.05. The values shown along paths are standardized coefficients and SEs in parentheses (SI Appendix, Fig. S3 shows unstandardized coefficients). The variance explained (R2) is shown for each trait. Latent variables are connected to their measured traits by gray arrows. Values are not shown for xylem density because this trait is included within the tissue strength variable, and the values there apply to xylem density.

The overall hypothesized model (Fig. 1) was a good fit of the data [i.e., the fit was not significantly different from a saturated model where all the possible paths were included (Fig. 3A and SI Appendix, Fig. S3 and Table 1)]. The same was true for the model using PICs (Fig. 3B and SI Appendix, Fig. S3 and Table 1). Although the model provided adequate support for covariation among the traits, there were six paths in the model that had high P values (Fig. 3 and Table 1); moreover, the TLI was <0.95. To investigate, we created models with these paths removed and compared the effect on model fit (Table 1). For the six paths with large P values, we proceeded by removing variables with the largest P values, rerunning the model, and evaluating the effect on the P values and model fit. In all cases, removing the paths had little effect on the large P values and model fit, so we removed them all (Table 1). We found that the best-fit model was the full model minus six paths with high P values (Fig. 4 and Table 1). The path between water storage and Pmin was also not significant (P = 0.198); however, removing this path led to a poorer-fitting model (Table 1).

Model fit statistics comparing the fit of different models to our hypothesized model (full model, Fig. 2)

The best-fitting SEM models for raw trait values (A) and PICs (B). The weights of the solid arrows correspond to P values where the thickest is <0.001, intermediate <0.01, and thinnest is <0.05. The dotted arrows correspond to P = 0.198 (A) and 0.220 (B). The values shown along paths are standardized coefficients and SEs in parentheses (SI Appendix, Fig. S3 shows unstandardized coefficients). The variance explained (R2) is shown for each trait. Latent variables are connected to their measured traits by gray arrows. Values are not shown for xylem density because this trait is included within the tissue strength variable, and the values there apply to xylem density.

Among the relationships that were predicted based on our hypotheses, many were not supported by the model. The model showed that transport, tissue strength, and starch storage functions were independent of one another. An important result is that a cellular trade-off was associated with Pmin and was independent of tissue strength. This trade-off was directly linked to starch storage, but it was not associated with any other traits. A network analysis shows Pmin to be a hub trait due to the number and strength of the associations (SI Appendix, Fig. S6). Another direct predicted relationship supported was the inverse relationship (trade-off) between safety from embolism and efficiency.

The results for the raw traits and PICs were virtually identical, thus we focus on raw trait values for simplicity. The direct relationships that were not supported were those between Pmin and efficiency, tissue strength and efficiency and embolism resistance, cellular trade-off and embolism resistance, efficiency, and tissue strength. Pmin and efficiency were associated through a shared relationship with embolism resistance. Tissue strength was not directly related to either embolism resistance or efficiency, thus any relationship it has with these traits is through Pmin and possibly water storage. These indirect relationships highlight Pmin as a central parameter underlying xylem trait relationships.

To explore the influence of Pmin on trait relationships further, we created models with Pmin removed (SI Appendix, Figs. S9S11). The best-fit model was produced from three candidate models (SI Appendix, Table S3). An important result is that cellular trade-offs take on a central role, directly or indirectly affecting all other traits when Pmin is removed (SI Appendix, Figs. S9S11). A good example of how Pmin is exerting influence is between cellular trade-off and tissue strength, both of which have direct paths from Pmin (Fig. 4). In the full model with Pmin this path is insignificant, and the partial standardized regression coefficient is 0.16 (Fig. 3A), thus for every SD increase in cellular trade-off, there is a 0.16 decline in tissue strength (a result of the inverse relationship between vessel area and xylem density). In the model without Pmin, the coefficient goes to 0.47 and it is significant, a result almost entirely due to the absence of Pmin. This analysis did not support a direct association between tissue strength and embolism resistance (SI Appendix, Table S3 and Figs. S9S11).

We proposed a multivariate hypothesis regarding trade-offs in xylem function that predicted how key functional traits were interrelated. These trade-offs have been mostly evaluated individually (5, 6, 8, 37); however, none have done so as part of a multivariate testable model. Such models allow for the identification of direct and indirect relationships, as well as the dependence of traits on one another. Results using PICs were the same as those with raw trait values, suggesting that shared ancestry cannot explain the associations among our sampled traits.

We found that the xylem functions (transport, strength, water storage, and carbohydrate storage) were independent of one another, and the only trait linked to all of them was Pmin. Bivariate relationships indicated significant associations between tissue strength and embolism resistance and cellular trade-offs, but these were not supported by our final SEM model. A key reason for this result is the presence of Pmin in the model and its strong associations with nearly all traits. To explore this, we created a model with Pmin removed. In this model, a cellular trade-off was found to directly affect embolism resistance, tissue strength, and starch storage and indirectly affect efficiency and water storage (all traits in the model). This supports one of our main hypotheses that the balance between the different cell types is a central structural factor affecting xylem function; moreover, it suggests that the cellular functional divisions and the range of different cellular sizes, shapes, and wall thicknesses cannot fully overcome trade-offs (6, 31).

Taken as a whole, the effect of cellular trade-offs and tissue strength is not independent of Pmin. The relationships between embolism resistance and tissue strength and cellular trade-offs are hypothesized to occur because of the need to reinforce vessels against implosion (29, 30), which is more of a threat in species that experience more negative hydrostatic pressures and that are highly resistant to embolism. Thus, the hypothesis that predicts these relationships also predicts a lack of independence among these traits, as we found. One aspect of cellular strength not included here is direct estimate of implosion resistance of individual vessels or vessel pairs (29), which if independent of bulk tissue strength, could affect model results.

Our results highlight the central importance of Pmin as an explanatory variable (11). In the context of a trait network, Pmin is a hub trait (1). Pmin represents the level of dehydration a plant experiences, and within a similar environment and measured at midday, it integrates many plant traits such as rooting patterns (44), stomatal responses (11, 45), leaf turgor and hydraulic conductance (11), and hydraulic conductance of the plant and soil system. The hub effect of Pmin in our model of xylem traits likely occurs because it captures variability in many fundamental aspects of plant function that are associated with xylem function in an example of concerted convergence. A strong relationship between Pmin and embolism resistance is well established (20), but our study shows that tissue strength and embolism resistance and cellular trade-offs are not related independent of Pmin and that Pmin is linked to cellular trade-offs.

The association between Pmin and cellular trade-offs may arise for structural and storage reasons. A shift to containing less fibers and more parenchyma may destabilize the xylem, creating a risk of vessel implosion (30). If so, then more negative Pmin would be associated with more fiber area and reduced parenchyma and vessel area, which was supported as seen among bivariate correlations [note, parenchyma is not significant; ref. 46]. These ideas suggest a link between cellular trade-offs and tissue strength, a relationship not independent of Pmin. Shifting from less fibers to more parenchyma is also associated with greater starch storage (6, 8, 35), and starch storage is strongly associated with Pmin (36). Expressing cellular trade-offs as a latent variable described by all cell types helped to identify important relationships; however, parenchyma performs important functions beyond storage such as defense, radial transport, and refilling of tracheary elements, and these additional functions warrant further study (12, 31, 47). Different types of parenchyma cells and arrangements (axial, ray, paratracheal, contact, isolation, etc.) may associate differently with different functions and predictors (12, 31), which is likely due to functional differences among these parenchyma types (8).

Storage of xylem starch and carbohydrates is an important trait related to drought tolerance and growth (48) and plays a role in xylem refilling (49). We hypothesized that Pmin drives starch storage because starch is hydrolyzed to osmoregulate in dehydration tolerant species that experience highly negative Pmin (38, 50), and this was consistent with our data. The connection between starch storage and Pmin may drive the association between starch storage and embolism resistance (36). Understanding the dynamics of carbohydrates, including its transport, is an important area of active research (34, 50).

Water storage is the only trait in our model that affects Pmin, which gives it the potential to play a critical role in overall xylem function (50). Water storage indirectly links tissue strength to the transport functions through Pmin. Xylem density (tissue strength) correlates with many different xylem traits and ecological and life history traits (51), and its effects on water storage and Pmin are likely important in this context. One caveat is that the association between water storage and Pmin was in the best-fitting model, but it was not strongly supported (P > 0.05 for the path connecting water storage to Pmin). This is mainly due to the hypothesized complex relationship between Pmin, tissue strength, and water storage. This relationship is modeled as nonrecursive (a loop) where water storage indirectly affects itself through its effect on Pmin, which in turn affects tissue strength, then back to water storage. Feedback loops are likely important in the context of selection for and relationships among traits affecting Pmin and are an important area for further study.

Other well-supported relationships in our model are the link between Pmin and embolism resistance and the trade-off between safety from embolism and efficiency. Species widely differ in the Pmin they experience, and Pmin is correlated to drought resistance and embolism resistance (18, 52). This is consistent with the hypothesis that embolism resistance is an important trait associated with plant dehydration avoidance/tolerance strategy. Our results are also consistent with the well-studied trade-off between safety from embolism and efficiency (9). At the global scale, this relationship is weak (23), and it has been argued that the multiple traits affecting this trade-off over diverse selective environments has uncoupled these traits (16). Our study is in a semiarid ecosystem, where strong water limitation likely constrains the range of responses.

Hydraulic efficiency was only strongly and significantly associated with embolism resistance. Bivariate relationships showed some significant relationships, including an association with Pmin and cellular trade-offs (fiber area), yet none of our models suggested direct associations with hydraulic efficiency. Efficiency is indirectly associated with Pmin through a direct path between Pmin and embolism resistance, and in models without Pmin, it is similarly indirectly associated with cellular trade-offs. Pmin could directly affect efficiency if expansion of large vessels was limited by turgor pressure, especially if wider vessels take longer to develop (27); however, chaparral shrubs do not have very large vessels globally speaking (53), thus during a typical hydrological year, interspecific differences may be unlikely. Nevertheless, during a drought, there will certainly be a reduction in xylem growth increment and vessel diameter, which may be driven by Pmin.

We also did not find a direct connection between tissue strength and transport efficiency. This path was predicted to arise because of the need for denser tissues in response to Pmin. The denser tissues were hypothesized to compromise efficiency between vessels with narrower diameters and thicker walls because thicker walls increase the path length through the pits where sap flows in between vessels, and this would decrease hydraulic efficiency (24). Tissue strength is driven by fiber traits (fiber abundance and wall thickness), so angiosperms can adjust their tissue strength independent of transport. However, these relationships may manifest in lineages where the developmental connection between fiber and vessel walls is strong (24).

The ecological context for our study is likely important to understand relationships with transport efficiency. Efficient transport of xylem is broadly associated with fast acquisition and use of resources, competitive ability, and has been linked to greater photosynthetic capacity and may lead to lower construction costs of stems (23). Our study focused on shrubs in a semiarid ecosystem where xylem efficiency may be unlikely to be the primary trait affecting fitness. By contrast, limited water is a likely a primary selective force for traits associated with drought survival. As such, embolism resistance may be under stronger selection than xylem efficiency (18, 52). In ecosystems with greater resources and dominated by trees, the arrows between efficiency to other traits may reverse, whereby it becomes a predictor instead of a response variable. We tried this in the present study, and when we reversed the path between efficiency and embolism resistance in the best-fit model (Table 1), the resulting model fit was poor (2 = 37.77, df = 25, P = 0.049). Direct manipulative tests to examine questions about adaptive significance of xylem traits is an area where more research is needed.

Hypotheses underpinning trait relationships with starch storage may change when carbon gain is limited over a long period by an unfavorable environment. It is well documented that when plants are carbohydrate limited, they produce less-dense tissues (54). Thus, when carbon gain is marginal relative to carbon expenses and phloem transport is impaired (55), starch availability to cambia may be limited and drive reduced tissue density and strength (56, 57). Under such conditions, a direct link between tissue strength and embolism resistance may be important as mechanically weak vessels become vulnerable to collapse (54, 56).

We conclude that xylem traits are broadly governed by trade-offs among cellular traits related to transport, mechanical support, and storage and that the Pmin experienced by plants in the field exerts a strong influence over these relationships. While angiosperms have evolved different cell types that have different functions within the xylem, and there are important functional trade-offs associated with the relative proportions of these different cell types. The important effects of Pmin on xylem traits likely arises because it places a direct mechanical strain on tissues that requires reinforcement to avoid cellular implosion; nevertheless, Pmin can affect xylem function by other pathways and traits not considered in our model because it integrates many functional attributes of plants.

All study data are included in the article and/or SI Appendix. Previously published data were used for this work [some data were previously published in a very different format in Pratt et al. (36)].

We thank Paul Smith, Michael Clem, Christine Hayes, Evan D. MacKinnon, and Hayden Toschi, who helped collect data. This study was supported by the NSF under Grant No. IOS-0845125 to R.B.P. and NSF HRD-1547784 to R.B.P. and A.L.J. Thanks to M. Witter, K. VinZant, and M. Lardner for help with permitting field sites. Two reviewers are thanked for their helpful comments.

Author contributions: R.B.P., A.L.J., and M.F.T. designed research; R.B.P., A.L.J., M.I.P., M.E.D.G., C.A.T., and M.F.T. performed research; R.B.P., A.L.J., and M.F.T. analyzed data; and R.B.P., A.L.J., M.I.P., M.E.D.G., C.A.T., and M.F.T. wrote the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2104336118/-/DCSupplemental.

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Trade-offs among transport, support, and storage in xylem from shrubs in a semiarid chaparral environment tested with structural equation modeling -...

Originally known as Neuropathy Treatment Centers of PGH, Tri-State Neuropathy Centers was established in 2013 by Dr. Shawn Richey and served patients only from their Wexford office until 2015 when expansions began. There are now five locations with three of those located in Pennsylvania (Monroeville, Washington, and Wexford), one in Poland, Ohio, and one in Weirton, West Virginia.

Approximately 30 million Americans suffer from peripheral neuropathy and its debilitating symptoms of painful cramping, burning and tingling, numbness in the feet, legs and/or hands, difficulty walking and even interruption of sleep. Tri-State Neuropathys program has had a phenomenal satisfaction rate and has seen thousands of patients suffering with peripheral neuropathy who have tried everything including potentially harmful medications and other painful testing and treatments. This can leave patients still struggling and wandering down the long road of endless disappointment.

With Tri-State Neuropathy Centers innovative treatments, patients now have hope and can have the pain associated with peripheral neuropathy addressed. We have treated over 8,000 patients with a 90% satisfaction rate, and we are confident that we can help improve most anyones life who has been affected by this devastating disease, said Dr. Shawn Richey, CEO, Tri-State Neuropathy Centers.

Tri-State Neuropathy Centers are 100% focused on helping people obtain relief from neuropathy, said Dr. Richey. Our proven treatment protocol is a PAINLESS, NON-INVASIVE AND DRUG-FREE therapy that utilizes advanced technology to reverse the horrible symptoms of peripheral neuropathy. It was once thought that there was no hope for neuropathy sufferers, and now there is.

Paula Connelly sought help in 2020 when her foot became numb after surgery. I was getting very depressed as my foot was numb on the side of the incision and it was affecting my life.I decided to meet with Tri State Neuropathy Centers for a free consultation. I have completed the program I am pain free and 90 percent better. I am 68 and a Grammy of 6 grandchildren.The treatment has helped me walk without a cane and be more active with my active family as my balance has improved tremendously.

Janine Caddys pain was progressing to the point where she couldnt walk. It seems like it became noticeable about 20 years ago. At first my feet would ache from time to time, then my feet would ache so bad that I had to limit my time standing or walking. I could no longer go hiking with my husband or just take a walk. I knew it was just a matter of time before I would need a wheelchair. I heard about Tri-State Neuropathy Centers and went for my free consultation to see if I was a candidate. To date, I see a significant improvement. I can take short walks, cook and I have even been gardening. It feels like a miracle.

Frank Smitts foot condition preventing him from enjoying his usual activities. Ten years ago I hurt my foot and it continued to get worse over the years. It got to the point that my feet were so sore and cold all the time. Outdoor activities are very important to me and I was losing the ability to do them. I felt there was no hope. A friend of mine learned of Tri StateNeuropathy Centers and I made an appointment. The results have been unbelievable. I have no more pain and my feet are no longer cold. My range of motion is so much better, and my balance is back. I am now enjoying all the outdoor activities I use to and am nearly 100% better.

If you are suffering with peripheral neuropathy, you may want to consult Tri-State Neuropathy Centers for a free evaluation. We offer the first initial consultation, examination and first treatment for FREE. We qualify patients to make sure they are candidates for our treatments, and of the over 8,000 patients we have qualified, we have an outstanding success rate, said Dr. Richey.

Patients can call 724-940-9000 to schedule an initial, no-cost consultation to determine if they qualify for the Tri-State Neuropathy Centers treatment program. Additionally, a free confidential online survey is available for patients on the Tri-State Neuropathy website (www.marydancedin.com). Each survey is reviewed by a doctor.

Sponsored content brought to you byTri-State Neuropathy Centers.

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Expanding at 5.9% CAGR, Peripheral Neuropathy to Cement Dominance in Diabetic Neuropathy Treatment Market

The diabetic neuropathy market study by Fact.MR offers compelling insights into key growth drivers and restraints impacting the market through 2031. The survey offers diabetic neuropathy demand outlook and studies opportunities existing in key segments, including type and end user. It also highlights key strategies adopted by market players to increase diabetic neuropathy sales.

Fact.MR A Market Research and Competitive Intelligence Provider: As per the insights by Fact.MR, the global market for diabetic neuropathy is anticipated to rise at a CAGR of 5.6% over the forecast period 2021-2031.

Increasing prevalence of diabetes as a result of changing lifestyles and imbalanced diets is a primary factor, supporting the growth of the diabetic neuropathy market. In 2019, it was found that over 1/10th of the worlds population suffered from diabetes.

Considering this, leading manufacturers are increasingly focusing on incorporating anti-diabetic formulations within their diversified portfolio. For instance, Janssen Global Services LLC, a leading pharmaceutical company offers a wide range of drugs including NUCYNTA, NUCYNTA ER, Duragesic and INVOKANA.

These drugs include tapentadol and canagliflozin, which help in regulating the blood sugar levels. Several other leading pharmaceutical companies are expected to join the bandwagon, while expanding their portfolio. These factors will contribute towards the growth of the diabetic neuropathy market.

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Among various types of disorders, peripheral neuropathy segment is gaining traction and exhibiting a higher sales of diabetic neuropathy formulations. As per the Fact.MR, demand outlook for peripheral neuropathy remains optimistic and it is set to expand at a CAGR of 5.9% over the upcoming years.

Besides these, hospitals have emerged as dominant end users owing to the availability of advanced infrastructure and healthcare expertise. Also higher footfall patients will continue supporting growth in demand across hospitals.

According to the study, North America is dominating the market for diabetic neuropathy, accounting for nearly 2/5 of the market revenue across the globe. Owing to factors such as increasing number of patients for getting treatment along with rising investment in research for the development of new drugs, the market in the region is expected to expand considerably over the forecast period 2021-2031.

Increasing emphasis on research and development pursuits along with innovations in drug combinations for fulfilling the dual purpose of providing symptomatic pain relief and preventing the progression of neuropathic processes will bolster future growth prospects, says a Fact.MR analyst.

Key Takeaways from Diabetic Neuropathy Market Survey

Key Drivers

Key Restraints

To learn more about Diabetic Neuropathy Market, you can get in touch with our Analyst at:

https://www.factmr.com/connectus/sample?flag=AE&rep_id=4698

Competitive Landscape

Diabetic neuropathy manufacturers are focusing on receiving certifications from international organizations for their new product launches.

In 2017, Pfizer announced that the U.S. Food and Drug Administration (FDA) approves STEGLATRO(ertugliflozin) tablets, an oral sodium-glucose cotransporter 2 (SGLT2)inhibitor, and the fixed-dose combination STEGLUJAN (ertugliflozin and sitagliptin) tablets

For instance, in 2020, Lupin Pharmaceuticals Inc, received tentative approval from U.S. health regulator to market type 2 diabetes drugs namely Empagliflozin and Linagliptin tablets.

Some of the leading players operating in the diabetic neuropathy market profiled by Fact.MR are:

More Valuable Insights on Diabetic Neuropathy Market

Fact.MR, in its new report, offers an unbiased analysis of the global diabetic neuropathy market, analysing forecast statistics through 2021 and beyond. The survey reveals growth projections on diabetic neuropathy market with detailed segmentation:

Key Questions Covered in the Diabetic Neuropathy Market Report

Explore Fact.MRs Coverage on the Healthcare Domain

Diabetes Diagnostics Market- The demand for diabetes diagnostics is predicted to increase as a result of the COVID-19 outbreak, which has resulted in an increase in hospitalizations. Diabetes test strips are in high demand as a result of studies that show diabetics are at a higher risk of becoming seriously ill if infected with the virus. Government investment for hospitals will help to expand the market overall by making healthcare more accessible in remote areas. The diabetes diagnostics industry will see further growth as the prevalence of obesity rises. Through 2030, the global diabetes diagnostics market will be dominated by players from North America, Asia Pacific, and Europe.

Diabetes Management Software Market- The rising prevalence of type 1 and type 2 diabetes is one of the factors driving the growth of the diabetes management software industry. Diabetes patients are growing as a result of unhealthy lifestyles, poor diets, and rising stress and tensions. As a result, in recent years, the adoption of diabetes management software has increased, resulting in a favourable impact on the diabetes management software market. Another factor driving the growth of the diabetes management software market is technological advancements. One of the most important elements driving the remarkable development in the use of diabetes management software is the increasing number of younger diabetics.

OTC Analgesics Market- Over the last few years, there has been an increase in the use of off-label medications, which are inexpensive and unapproved but effective in treating ailments. Off-label medications such as tricyclic antidepressants, antihistamines, anticonvulsants, selective serotonin reuptake inhibitors, anti-anxiety medicines, and steroids are increasingly being used to treat pain sensations. Because of the widespread availability of over-the-counter analgesics, which are administered with approved medications as maintenance therapy, symptom management linked with pain has become convenient and straightforward. The market for over-the-counter analgesics has shown to have a lot of potential all over the world.

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Out of Every Ten Diabetic Patient, At least Seven are Identified with Diabetic Neuropathy - BioSpace

New research, released by a team based in Turkey, Qatar, and the United Kingdom, has indicated that a specialised eye exam can be used to identify long COVID.

Published in the British Journal of Ophthalmology, the research found that corneal confocal microscopy (CCM) a non-invasive eye test that conducts real-time imaging of corneal nerve fibres can also potentially be used to confirm suspected cases of long COVID by identifying specific nerve damage.

CCM is also used to identify other conditions, such as diabetic neuropathy, Parkinsons disease, multiple sclerosis, and dementia.

THE LARGER CONTEXT

Penned by researchers from Turkeys Necmettin Erbakan University, Weill Cornell Medicine-Qatar (WCM-Q), and the UKs University of Manchester, the study stated that CCM identifies corneal small nerve fibre loss and increased DCs [dendritic cells] in patients with long COVID, especially those with neurological symptoms.

As a result, CCM could be used to objectively identify patients with long COVID.

The paper added: Long COVID is characterised by a range of potentially debilitating symptoms which develop in at least 10% of people who have recovered from acute SARS-CoV-2 infection.

Symptoms of long COVID include headache, tingling and/or numbness, neuropathic pain, a loss or change in the senses of taste and smell, and so called brain fog.

WHY IT MATTERS

According to a statement by WCM-Q, nerve damage observed in the corneas using CCM can be reliably used as an indicator of nerve damage in other parts of the body.

CCMs value as a diagnostic tool is increased by a number of important factors: the test takes only a few minutes, is completely non-invasive, causes almost no discomfort for patients, utilises existing and widely available ophthalmic equipment, and can be done in the clinic.

ON THE RECORD

The predominance of neurologic symptoms in people with long COVID prompted us to investigate whether CCM could be used to objectively identify nerve damage in patients with the disease, said Rayaz Malik, professor of medicine and assistant dean for clinical investigations at WCM-Q. We are the first group in the world to report a very strong association between nerve damage observed using CCM and long COVID.

Although the majority of people had mild COVID, patients with more severe disease had evidence of greater corneal nerve damage, suggesting that the severity of nerve damage may be related to the severity of disease at presentation.

We believe CCM has the potential to serve as an extremely valuable tool to be used by physicians to help diagnose and assess the evolution of long COVID and to determine the severity in individual cases. The identification of underlying nerve damage also allows us to think about this condition as a neurodegenerative disease, which may be amenable to treatment.

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CCM can identify nerve damage in patients with long COVID, new study finds - Mobihealth News

Introduction

Entrapment mononeuropathies are common and contribute to considerable morbidity in the community. The most common entrapment is carpal tunnel syndrome, with an estimated incidence of 197 per 100,000 women,1,2 and much higher rates among employees in certain industries (eg, up to 42% prevalence in poultry workers).3,4 Early diagnosis is essential in entrapment mononeuropathy, to limit nerve injury and associated morbidity. Unfortunately, electrodiagnostic studies (EDX) are frequently non-localising in entrapment neuropathy, and this is the most frequent indication for nerve ultrasound in clinical practice.5 In addition, a significant proportion of EDX are non-diagnostic, between 10% and 25% in CTS for instance, depending on the severity of presentation and EDX protocol used.6,7

Separately, peripheral neuropathy (PN) represents a major cause of morbidity globally,8 and its prevalence is increasing. This has been attributed to the ageing population, an increased prevalence of diabetes and use of neurotoxic drugs such as chemotherapeutics and antiretrovirals.914 The assessment of PN has traditionally relied on neurological assessment, close review of comorbidities and EDX testing. EDX enables neuropathy to be diagnosed, providing information on the pattern of involvement, severity, distinction between axonal and demyelinating pathologies, as well as allowing prognostication and monitoring.15 The clinical and EDX assessment has several limitations however, including a lack of precise anatomical information,15 difficulty diagnosing proximal demyelinating PN,16 and difficulty in distinguishing hereditary from acquired demyelinating PN.17,18 Consequently, there is a need for newer techniques to better diagnose and monitor patients with PN.

Ultrasound using modern, high-frequency probes and image processing provides excellent visualisation of the peripheral nerve, with good spatial resolution and the ability to assess vascularisation with power Doppler. Ultrasound has the further advantage of being able to assess the entire nerve course in real time, whilst being quick, painless, non-invasive, free of radiation and relatively cheap. Ultrasound therefore provides the ideal tool for assessing PN, entrapment mononeuropathy and complements the clinical and EDX assessment. Given the rapid uptake of ultrasound by clinicians, the present review is designed as a practical resource to promote an understanding of the basics of peripheral nerve ultrasound as well as current and emerging applications of ultrasound in the diagnosis of neurological disease.

An ultrasound system uses a transducer to convert electrical current into ultrasound waves via the piezoelectric effect. These waves travel through tissue and are either reflected, refracted, scattered, or absorbed. The amount of resistance an ultrasound beam experiences as it travels through a tissue is referred to as acoustic impedance and is dependent on tissue density. The degree of ultrasound reflection is dependent on the relative differences in tissue densities at a tissue interface, as well as the angle of insonation. Reflected waves are recorded by the transducer and converted into electrical energy which is used to generate our image. The brightness of this image is labelled echointensity (EI) and is proportional to the amount of reflection. This signal is amplified (gain), which can be adjusted. Anisotropy is the loss of echogenicity when an ultrasound beam is not perpendicular to the structure imaged and can be exploited to distinguish peripheral nerves (low anisotropy) from adjacent structures such as tendons (high anisotropy).

The ultrasound image resolution is determined largely by the frequency of the waves, recorded in megahertz (MHz). Higher frequencies allow for greater image resolution, and frequencies greater than 12 MHz are typically utilised for peripheral nerve imaging. In contrast, higher frequencies undergo greater attenuation at increasing depths, and therefore lower frequency ultrasound with better penetration is preferable when imaging deeper structures such as muscle. Consequently, ultrasound imaging is a trade-off between resolution and penetrance, which is achieved in neuromuscular ultrasound by using a transducer with a range of frequencies, for example, 186 MHz. Linear array transducers are typically used in neuromuscular diagnosis, providing a narrower field of view but better resolution at the edges of an image than curvilinear transducers. A smaller footprint probe is sometimes desirable when imaging structures where only limited contact between a probe and the body surface is possible, for instance the hands and feet.

The appearance of peripheral nerves on ultrasound correlates with the microscopic and macroscopic anatomy.19 When viewed longitudinally nerves appear as linear hypoechoic fascicles surrounded by hyperechoic perineurial connective tissue, both enclosed by the bright epineurial connective tissue layer (Figure 1). In cross section, nerves take on a honeycomb appearance of rounded hypoechoic fascicles surrounded by hyperechoic connective tissue (Figure 1). The size and fascicular pattern of healthy nerves can vary depending on location. More proximal nerve segments are typically larger in cross-sectional area (CSA) with fewer or no fascicles, meaning they appear more hypoechoic. This is the result of densely packed fascicles with less connective tissue.20 This process also occurs at fibro-osseous boundaries, for instance the ulnar nerve at the level of the medial epicondyle also appears relatively more hypoechoic even in normal limbs21 (Figure 2D).

Figure 1 Ultrasound appearance of normal nerves. Ulnar nerve imaged in axial/cross-sectional view with honeycomb pattern (A) and longitudinal view with tram track pattern (B).

Figure 2 Normal ulnar nerve and ulnar artery (artery denoted *) in cross section at the wrist (A) in Guyons canal. Ulnar nerve in cross section in the forearm (B), cubital tunnel between two heads of flexor carpi ulnaris (FCU) muscle (C) and between the medial epicondyle (**) and olecranon at the elbow (D).

When differentiating nerves from other structures the following key features can be utilised. Firstly, nerves are surrounded by a hyperechoic rim due to epineurial connective tissue. Secondly, they are more anisotropic than muscle and tendons, meaning tilting the transducer will markedly change the echointensity of these other structures when compared to nerves. Thirdly, unlike blood vessels they are non-compressible, with no pulsatile movement or Doppler flow.

There are several characteristic sonographic features in peripheral nerve injury, including changes in nerve size, echointensity, fascicle dimensions, epineurial boundaries and Doppler signal. Peripheral nerve size increases focally with entrapment and more diffusely in some patients with PN. The cross-sectional area (CSA), measured by tracing inside the hyperechoic epineurium, has a high inter and intraobserver reliability and is highly reproducible.22 The CSA has been widely used to quantify PN, by reference to established normal values for several key peripheral nerves and the brachial plexus.2326 It is important to adjust CSA for normal variability seen across age, sex, height, and BMI.23,24

Echointensity is typically reduced in nerve injury and is usually assessed qualitatively and is usually associated with loss of the normal fascicular architecture described above. Nerve echogenicity can be measured quantitatively using mean gray-scale analysis.21,27,28 Quantitative measures are specific to the individual ultrasound machine used to establish the normative data, limiting their broader application, unless values are normalized using standardized phantoms.

Improvements in ultrasound technology has facilitated measurement of individual nerve fascicles,29 for instance ultra-high frequency ultrasound can identify increased fascicular diameter in immune-mediated PN.30 Fascicular architecture varies from person to person, nerve to nerve and from one anatomical location to another, and there is more work needed to characterise this metric in health and disease.

The Doppler effect is a change in ultrasound frequency reflected from an object, such as a red blood cell, moving toward or away from the transducer. This can be used to demonstrate changes in vascularity of peripheral nerves and surrounding structures. Normal nerve does not have any detectable blood flow. Hence, the presence of Doppler flow is abnormal in peripheral nerves and indicates hypervascularity, which has been described in compressive and inflammatory and some axonal neuropathies.3133

Elastography is a technique used to determine the elasticity of tissue. This is in the form of either strain elastography, in which tissue displacement from extrinsic compression or ambient tissue oscillations is used, or shear wave elastography (SWE), produced by acoustic radiation force impulses generated by the ultrasound probe. Peripheral nerve injury involves the destruction of myelin, which is more compliant, and a proliferation of stiff connective tissue.34 This results in increased stiffness on elastography. There are now several studies supporting the role of both strain and shear wave elastography in diagnosing carpal tunnel syndrome, ulnar neuropathy at the elbow, diabetic PN and even optic neuropathy.35 Further research is ongoing to assess the ability of elastography to diagnose nerve injury in preclinical neuropathy, and to evaluate elastography as a monitoring tool for longitudinal assessment.

Peripheral nerve compression results in nerve enlargement proximal /or distal to the entrapment site on cross-sectional imaging and can appear as an hourglass configuration on longitudinal views (Figure 3).5,36,37 The entrapped nerve may also appear flattened, hypoechoic, immobile and hypervascular.3739 Importantly, up to 42% of mononeuropathy cases studied with ultrasound detect a pathology that alters diagnosis or management, for instance nerve strictures, ganglion cysts or other intraneural or extraneural lesions.40

Figure 3 Normal median nerve and flexor tendons (*) in cross section (A) and longitudinal view (B). Normal median nerve in the forearm (C) superficial to flexor digitorum profundus (FDP) and deep to flexor digitorum superficialis (FDS) muscles. Abnormal median nerve at the wrist (D) with hourglass constriction (white arrows) with swelling proximally at the carpal tunnel entrance (**).

Interestingly, a Sonographic Tinel sign may be present, with clinical symptoms elicited by mechanical pressure from the ultrasound probe at a compression site. Of further interest, chronic nerve compression may result in neurogenic changes to the muscle supplied, such as hyperechogenic and eventually atrophied muscle with fasciculations. The sonographic findings for specific mononeuropathies are summarised below and in Table 1.

Table 1 Diagnostic Sonographic Findings in Compressive Mononeuropathies

The median nerve is optimally studied with the patient seated or lying with the palm facing upward. Imaging can begin at the distal wrist crease, with a cross-sectional view of the median nerve at the entry to the carpal tunnel. The nerve can then be traced proximally as it dives between the flexor digitorum superficialis and profundus in the forearm, and then between the two heads of the pronator teres (another potential site of entrapment).41,42 At the elbow, it runs with the brachial artery, and it can be traced with the artery up to the axilla.

Carpal tunnel syndrome (CTS) results in increased median nerve CSA at the wrist (Figure 3). The ratio of CSA between the wrist and forearm (12 cm proximal to the distal wrist crease), known as wrist to forearm ratio (WFR) will also be increased (Table 1). The median nerve may also be swollen distally at the carpal tunnel outlet, and scanning this region increases the diagnostic sensitivity by 15%20%.43,44 The presence of an immobile, hypoechoic or hypervascular median nerve at the wrist also aids in diagnosis.39 There are several clinical and EDX mimics for CTS, such as benign tumours (neuroma, schwannoma, hamartomas), ganglion cysts, thrombosed vessels or tenosynovitis.45 These are easily diagnosed with ultrasound.45,46 A bifid median nerve can also be identified, which is more prevalent in patients with CTS.47 Ultrasound is useful to assess persistent symptoms post-surgical carpal tunnel release, where it can detect a compressive post-operative scar, a residual anatomical constriction point suggesting incomplete release or an alternative cause for neuropathy.48

In addition, ultrasound can localise a proximal median nerve injury and may help establish a cause, such as entrapment by the ligament of Struthers,49 pronator teres muscle,50 or an accessory palmaris longus muscle,51 as well as vascular pathology52 and iatrogenic injury.53

The ulnar nerve is ideally studied with the elbow flexed at 90 degrees, palm facing upwards and the patient either seated or supine. The Ulnar nerve can be easily located at the elbow in the groove between the olecranon and the medial epicondyle of the humerus (Figure 2C). The nerve can be traced proximally as it runs between the biceps brachii and medial head of triceps brachii en route to join the axillary artery. The nerve can then be traced from the elbow distally as it travels between the two heads of the flexor carpi ulnaris muscle (forming the cubital tunnel) (Figure 2C), before travelling between the flexor digitorum profundus and superficialis as it approaches the ulnar artery (Figure 2B). The ulnar nerve together with the ulnar artery enter the hand superficially via the guyons canal (Figure 2A).

Approximately 76% of ulnar neuropathies are localised to the olecranon groove54 and are typically caused by extrinsic compression or stretch of the nerve resulting in focal demyelination. Focal increase in the ulnar nerve CSA at or above the olecranon is diagnostic.55 The next most common site for injury is at the cubital tunnel due to ulnar nerve entrapment, referred to as cubital tunnel syndrome. Ultrasound demonstrating focal nerve constriction at the entry to the tunnel with proximal swelling is diagnostic. Longitudinal views can aid in localising compression. Both the degree of swelling and hypervascularity are markers of severity56 and axonal loss.57,58 It is important to differentiate cubital tunnel entrapment from compression in the olecranon groove because the former is amenable to surgical release.59 Less common aetiology of ulnar nerve injury can also be identified with ultrasound, including Struthers arcade compression in the upper arm,60 ganglion at the elbow, benign tumours, abscess or anomalous muscles (anconeus epitrochlearis).55 Dynamic ultrasound can also detect a subluxing ulnar nerve, which refers to the migration of the ulnar nerve to the medial epicondyle tip with elbow flexion. Studies assessing the causative role of this abnormality in ulnar neuropathy are conflicting.6163 An elegant study by Omejec et al demonstrated higher rates of ulnar nerve subluxation in patients without a clinical neuropathy, especially those with subclinical ulnar nerve changes on EDX.64

A common dilemma when assessing ulnar neuropathy electrodiagnostically is the inability to localise the dysfunction, and between 14% and 25% of EDX studies are non-localising.65,66 Importantly, the majority of these electrodiagnostically non-localising ulnar neuropathies can be localised with ultrasound.65,66 In addition, ultrasound can readily diagnose ulnar nerve injury at Guyons canal for example due to cycling-related wrist compression,67 intraneural ganglion cyst68 or ulnar artery thrombosis.69

The radial nerve is best imaged with the elbow flexed and the dorsal upper arm directed toward the examiner, so that the posterior course of the nerve above the elbow can be easily traced. The nerve is readily identified in the lateral antecubital fossa, lying above the brachialis and beneath the brachioradialis muscles (Figure 4A). At this location, the nerve starts to divide into the superficial and deep branches. The radial nerve can be traced proximally as it wraps behind the humerus. The radial nerve is then followed up to the spiral groove, between the medial and lateral heads of the triceps brachii muscle (Figure 4B). The nerve can be traced from the antecubital fossa distally as it divides. The superficial branch travels laterally, beneath the brachioradialis and next to the radial artery, before perforating the extensor facia in the distal forearm to reach the anatomical snuff box and provides sensation to the dorsolateral hand and dorsal aspect of digits 13. The deep branch travels medially and dives through the arcade of Frohse (a fibrous arch extending from supinator muscle to lateral epicondyle) as it pierces the supinator muscle (Figure 4C). The nerve then becomes the posterior interosseus nerve travelling over the interosseus membrane and supplying the extensor compartment of the forearm.

Figure 4 Posterior interosseus nerve (PIN) and Superficial radial nerve (SRN) branches of the radial nerve in the cubital fossa (A). Radial nerve branches deep to brachioradialis and superficial to brachialis muscles. Cross section of normal radial nerve in the spiral groove between the triceps muscle and humerus bone (B). Posterior interosseus nerve travelling between the two heads of supinator muscle (*) overlying the proximal radius bone (C). Cross section of abnormal enlarged radial nerve in spiral groove with CSA measuring 35 mm2 (D).

The commonest cause of radial neuropathy is compression at the spiral groove due to extrinsic pressure, known as the Saturday night palsy because it may be associated with sleeping awkwardly when sedated. Ultrasound will show focally increased radial nerve CSA in the spiral groove (Figure 4D). This can be based on absolute increase in CSA or side-to-side comparison (Table 1). Swelling in the radial groove also has prognostic value and predicts a worse clinical outcome at 3 months then radial palsy with normal nerve calibre.70 Another common cause for proximal radial neuropathy is a humeral shaft fracture. Nerve injury secondary to fracture is readily diagnosed with ultrasound.71 The deep motor branch, the posterior interosseus nerve, can be injured at the arcade of Frohse. Causes of this Posterior Interosseus Syndrome may be diagnosed with ultrasound including iatrogenic injury,72 ganglion cysts,73,74 vascular abnormalities,75 tumours76 and entrapment from other structures.77 The superficial radial sensory nerve is susceptible to injury from extrinsic compression, trauma, or mass lesions7880 which may be seen on ultrasound.

The fibular nerve can be identified on ultrasound by first imaging the sciatic nerve in the proximal popliteal fossa (Figure 5A) and tracing it distally as it bifurcates into the fibular (lateral) and tibial (medial) nerves (Figure 5B). The common fibular nerve can then be traced around the head of the fibular bone (Figure 5C). An enlarged and hypoechoic nerve at the fibular head support a diagnosis of compression,24,8183 although care must be taken to not image the nerve obliquely at this location. The deep and superficial fibular nerve branches are more difficult to visualise distally due to their small size and depth, although the deep fibular nerve is readily identified in the anterior ankle. The most common cause for fibular nerve injury at the fibular head is stretch or contusion,84 often associated with significant weight loss, sustained immobility and excessive leg crossing.85,86 However, in one series, as many as 18% of patients presenting with foot drop, have an intraneural ganglion of the fibular nerve identifiable with ultrasound.87 Entrapment of the fibular nerve in the fibular tunnel is a rare cause of fibular neuropathy,88 but this can be seen on ultrasound as a focal stricture of the nerve just prior to the fibular (Figure 5). It is critical to image patients with fibular neuropathy to exclude entrapment and intraneural ganglion, as these patients require surgical decompression whereas non-operative management is indicated for other causes.

Figure 5 Cross-sectional view of the normal sciatic nerve in the distal thigh (A), fibular and tibial nerves in the popliteal fossa (B), fibular nerve at the fibular head (C) and tibial nerve just above the ankle, * denote the ulnar artery (D).

The tibial nerve can also be identified in the popliteal fossa (Figure 5B) before it dives between the heads of the gastrocnemius muscle. The patient is usually examined in the prone position. The tibial is more difficult to identify when running deep in the calf due to the overlying gastrocnemius and soleus muscles but the nerve can be imaged distally as it travels behind the medial epicondyle of the ankle, beneath the flexor reticulum (also known as the tarsal tunnel), in the company of the posterior tibial vessels, tibialis posterior, flexor digitorum longus and flexor hallucis longus tendons. The tibial nerve then branches into the medial and lateral plantar nerves to innervate the sole of the foot.

Ultrasound can identify a cause for distal tibial neuropathy in up to 94% of presentations.89 In one series of 81 ultrasound cases the most prevalent causes were varicose plantar veins, static foot disorders, epineurial ganglion cysts, neuropathies, and iatrogenic injuries. Tarsal tunnel syndrome is a rare compressive mononeuropathy which may be diagnosed on ultrasound by demonstrating an enlarged tibial nerve CSA within the tunnel (Table 1). Ultrasound may also detect a cause in proximal tibial neuropathies, such as bakers cyst90 or soleus arcade/sling.91,92

After significant nerve trauma we may see axonotmesis with interruption of axons but intact connective tissue which acts to guide axonal regrowth. If severe axonotmesis occurs, axonal regrowth occurs proximal to distal at a rate of 1 mm per day. Alternatively, nerve trauma may result in neurotmesis with interruption of both axon and connective tissue. In this circumstance, axonal regeneration is precluded by scar tissue.93 There are several limitations to clinical and EDX evaluation of traumatic peripheral nerve injury. EDX in the acute setting cannot differentiate between a nerve with damaged axons but intact connective tissue and a complete nerve transection.94 This is crucial, however, because complete transection can improve with time-critical surgical intervention. In addition, without imaging one cannot identify other specific anatomical lesions that may require surgery, for instance a painful chronic neuroma,95 or ongoing nerve injury from bone spurs, haematoma, or surgical hardware.96

Importantly, ultrasound can assist in diagnosing and localising a traumatic peripheral nerve injury.95,96 This is visualised by focal swelling and reduced echogenicity, altered fascicular architecture, discontinuity97 or neuroma formation.95 In addition, ultrasound allows the detection of muscle hyperintensity and atrophy secondary to nerve trauma, which often precedes other sonographic and EDX changes.98 In addition, ultrasound can be used to assess whether surgical intervention is required in the setting of nerve discontinuity,96 neuromas99 or bony entrapment.100,101 It is worth noting that ultrasound will not differentiate between severe axonal injury with and without intact epineurium.

Ultrasound also plays a role in surgical planning, by identifying the exact location and length of nerve injury as well as associated structures.20,96,102 Intraoperative high-resolution nerve ultrasound monitoring can also be used103 as it matches closely with intraoperative neurophysiological and neuropathological findings. Following surgical peripheral nerve repair104 ultrasound has a role in identification of partial discontinuity, neuroma formation and compression by overlying scars that may require surgical re-exploration. In a retrospective series of 143 consecutively imaged traumatic peripheral nerve injuries96 ultrasound was 90% sensitive for any nerve injury. The most common abnormalities seen were nerve swelling, followed by neuroma, scar tissue, and discontinuity. Complete nerve transections were infrequent, but readily identified by swollen nerve stumps proximally and distally. The degree of nerve swelling did not correlate with severity of motor dysfunction on EDX.

Thus, ultrasound is an important tool in diagnosing and localising nerve trauma, grading injury, determining the need for surgery and provides useful information in the intra and post-operative setting. In concert with improvements in ultrasound, MRI techniques to visualize the peripheral nervous system such as Diffusion tensor imaging (DTI) have undergone rapid development. DTI with tractography uses water diffusion anisotropy along longitudinal fibre tracts to image nerve pathways.105 DTI has the capability to image nerve injury not identified using EDX or standard imaging techniques.93 In addition, DTI can identify axonal regeneration following traumatic nerve injury with the potential to guide the need for surgical intervention.106

Generalised peripheral neuropathy may be associated with changes on nerve ultrasound. The most prominent changes are identified in demyelinating neuropathies where nerve enlargement is characteristic. Axonal neuropathies are perhaps surprisingly only infrequently associated with reduction of nerve size. The role for ultrasound in diagnosing PN is increasing, and it has the potential to streamline diagnostic algorithms, reduce the need for expensive or invasive investigations and even rationalise costly immunomodulatory and genetic therapies. The following section explores the current ultrasound findings in hereditary, immune mediated and axonal PN.

CIDP is an immune-mediated process typified by multifocal demyelinating nerve pathology in proximal and distal limbs, leading to weakness, sensory loss and reduced deep tendon reflexes. The presentation of CIDP is variable and includes atypical forms such as pure motor or pure sensory CIDP, multifocal acquired demyelinating sensory motor neuropathy (MADSAM) and distal acquired demyelinating sensory (DADS) neuropathy. Abnormal nerve morphology is identified on ultrasound in 6487% of patients.107109Typical sonographic findings are increased nerve CSA in a multifocal pattern, affecting proximal and distal segments and non-entrapment sites110 (Figure 6). Like clinical features, ultrasound findings are similarly variable, with some patients even demonstrating normal nerve size on ultrasound.107

Figure 6 Abnormal median nerve in the forearm in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), demonstrating multifocal nerve enlargement in longitudinal views (A). Heterogeneous hypo and hyperechoic fascicular enlargement seen of the same nerve in cross section (B) with CSA measuring 68 mm2. Cross sectional view of enlarged median nerve in the forearm with uniform fascicular enlargement seen in Charcot Marie Tooth Type 1A (C) with CSA measuring 62 mm2.

MADSAM is an asymmetric CIDP variant with a more asymmetrical, multifocal pattern of nerve enlargement on ultrasound.111,112 Enlarged hypoechoic fascicles are typically seen in segments with past or present conduction block112,113 and seem to reduce in response to treatment.114

Several distinct ultrasound patterns in CIDP have been identified which correlate with disease duration. Three ultrasound classes were described by Padua et al108 based on CSA and echogenicity. Large hypoechoic nerves (class 1) were associated with the shortest disease duration (04 years) when compared to normal size nerve with hyperechoic changes (class 3) (711 years duration). Large nerves with heterogeneous hypo- and hyperechoic fascicles (class 2) were also heterogenous regards disease duration (0.516 years).

Ultrasound can increase diagnostic accuracy in CIDP, especially when proximal segments and the brachial plexus are imaged.115 This is important because misdiagnosis is common in CIDP, especially in the atypical variants.116 One prospective study assessed 100 suspected chronic immune mediated polyneuropathy referrals with EDX and ultrasound.115 Enlargement in the proximal median nerve or C5 root (referred to as the Short Ultrasound Protocol) was diagnostic with a sensitivity of 84.696.4% and specificity of 44.972.8% depending on the reference standard. Importantly, 25% (11/44) of the those ultimately diagnosed as CIDP/MMN had normal EDX but abnormal ultrasound and were responsive to immunotherapy.

Ultrasound has also been researched as a tool to differentiate between hereditary demyelinating neuropathies, CIDP and other immune mediated PN (Table 2). Various schema has been proposed to quantify these differences. CMT1A is typically associated with the largest nerves, which are homogeneously/diffusely enlarged.107,117 The pattern of enlargement is more variable and to a lesser degree in CIDP. Normal nerve calibre, focal and diffuse enlargement resembling CMT have all been described in CIDP.23,107,109,118 Mild, regional, asymmetrical or heterogenous enlargement all point towards atypical CIDP, MMN, or GBS.23,107 Various imaging protocols and scoring systems have been proposed eg, the homogeneity score and the regional nerve enlargement index.119 The more focal pattern of nerve enlargement seen in inflammatory neuropathies can also be quantified using the intranerve variability (maximum CSA/minimum CSA for a given nerve) and the internerve variability (maximum intranerve variability/minimum intranerve variability for a given patient).120 However, these patterns and scores are predominantly based on relatively small retrospective cohorts, and larger prospective studies are required to define the optimal ultrasound protocols to differentiate these disorders.119

Table 2 Diagnostic Sonographic Findings in Peripheral Neuropathies

Ultrasound provides surrogate markers for disease severity in CIDP, such as hypervascularity, number of nerves involved and cervical nerve root CSA.121,122 Larger nerve CSA has been correlated with slower conduction velocities on EDX testing in many123,124 but not all studies.125 Nerve enlargement has also been associated with clinical weakness and disability.124,125 Additionally, ultrasound provides prognostic information in CIDP, with both decreasing intra-nerve CSA variability and normal or decreasing nerve calibre predicting treatment responsiveness.126

Furthermore, ultrasound has potential as an outcome measure in CIDP. A study of 23 consecutive patients with CIDP followed with serial ultrasound measurements over 3-years, noted CSA increased in 51% of nerve segments, and was associated with increased functional disability and decreased motor nerve amplitudes on EDX.124

GBS is an acute immune mediated generalised polyneuropathy, characterised by ascending sensory disturbance and areflexic weakness, with both demyelinating (acute inflammatory demyelinating polyneuropathy AIDP) and axonal forms (acute motor/sensory axonal neuropathy AMAN/AMSAN). The nadir is typically reached by 6 weeks, and diagnosis is clinical, supported by EDX and cerebrospinal fluid studies.

Proximal nerve and nerve root enlargement has been reported on ultrasound, although the degree and frequency are less then CMT1A and CIDP.23,107 For example, mild enlargement was reported in 8/17 upper limb nerves in one cohort,23 and 5/6 patients in another cohort, although this involved only 9% of the studied nerve segments.127 Importantly, nerve enlargement can be seen as early as day 13 of symptoms,23,128 before EDX changes are apparent.23 The presence of enlarged cervical nerve roots and vagus nerves, together with normal nerve calibre elsewhere can differentiate GBS from CIDP with a positive predictive value > 85%.117 Vagal nerve enlargement on ultrasound has also been correlated with autonomic dysfunction in AIDP.128,129

Some studies have suggested ultrasound can be used to distinguish demyelinating and axonal variants of GBS,130 while other studies have found no difference.131 Mori et al demonstrated enlarged cervical and proximal nerve segments in 6 patients with AIDP, contrasting to enlarged distal nerve segments (forearm, wrist and ankle) in 9 patients with AMAN/AMSAN.130

Miller Fisher Syndrome (MFS) is a rare GBS variant characterised by the triad of ophthalmalgia, ataxia and areflexia, and is often associated with bilateral facial weakness. Hsueh et al132 reported significantly enlarged facial but normal limb nerves in MFS.

Ultrasound has been proposed as an outcome measure for treatment in GBS.129,131 Grimm and colleagues assessed 27 patients with GBS and 31 controls with ultrasound at baseline and 6 months follow up.129 Cervical spinal, medial and vagus nerves were significantly larger in GBS at baseline, but returned to normal at 6 months, except for the vagus nerve which remained enlarged in those patients with significant autonomic dysfunction.

MMN is a rare upper limb predominant demyelinating polyneuropathy characterised by slowly progressive weakness and response to treatment with intravenous immunoglobulin.133135 In practice, MMN can be difficult to distinguish from certain ALS variants.136 Sonographically mild multifocal nerve enlargement, typically in proximal sites and the brachial plexus, is seen in up to 90% MMN patients.137 Ultrasound enlargement can also occur in clinically and electrophysiologically unaffected nerve segments.137

Importantly, nerve and nerve root enlargement on ultrasound can differentiate MMN from ALS. Grimm and colleagues demonstrated that 4 enlarged nerves/nerve roots had a 87.5% sensitivity and 94.1% specificity for distinguishing MMN from ALS in their cohort.138 Others have found that ultrasound is better at distinguishing MMN from ALS then standard EDX assessments.139,140 Ultrasound can occasionally aid in the distinction of MMN from CIDP by the presence of milder, asymmetric nerve enlargement with greater side-to-side intranerve variability, although considerable overlap exists.141

Multiple studies have demonstrated a variable association between ultrasound findings and clinical weakness, disability and EDX abnormalities.139,141,142 Rattay et al demonstrated that the nerve enlargement reduced in parallel with disability after 612 months of treatment in MMN, although baseline nerve enlargement did not correlate with clinical or EDX markers of severity.143 Thus, nerve ultrasound can not only improve diagnosis but also disease monitoring in MMN.

Anti-MAG is an immune mediated demyelinating neuropathy with distally predominant symmetrical sensorimotor impairment and prolonged distal motor latencies on EDX. Despite this the ultrasound abnormalities tend to be proximal144 and there are no reports of distal nerve enlargement. Segmental nerve enlargement has been described in cervical nerve roots, brachial plexus, and proximal nerve segments145 with considerable inter-nerve variability.146 Nerve ultrasound has been used to distinguish anti-MAG neuropathy from similar pathologies. Specifically, nerve size is greater in MAG positive than MAG-negative paraproteinaemic neuropathy.146 Some cohorts found nerve calibre in MAG to be smaller than CIDP.146

POEMS is a rare paraneoplastic multisystem plasma cell disorder causing a mixed axonal and demyelinating polyneuropathy that can mimic CIDP. Pathogenesis is attributed to increased vascular endothelial growth factor leading to neovascularisation and peripheral nerve oedema.147 It is somewhat surprising then, that peripheral nerve ultrasound studies have demonstrated nerve enlargement at entrapment sites only.148 Indeed, the lack of diffuse/multifocal enlargement has been offered as a means of distinguishing POEMS from CIDP.148 However, the published cases describe nerve ultrasound in the subacute setting, after significant secondary axonal degeneration has occurred, and thus the ultrasound findings in early disease remain to be defined.

Brachial neuritis is an idiopathic monophasic inflammatory condition affecting the branches of the brachial plexus. The typical presentation is with severe pain followed by unilateral upper limb weakness. Imaging with ultrasound and other modalities, combined with surgical exploration, have led to greater pathological understanding of this condition. It is now hypothesized that a sequence of nerve enlargement, fascicular adhesion and constriction contributes to ongoing nerve injury.149 Rotational movements of the upper limb are then thought to cause the adhered nerve to tort, with fascicular entwinement and further constriction which has been associated with poor recovery.149 The most common finding on ultrasound, seen in 74% of cases, is unilateral focal nerve enlargement, often affecting the median, radial, anterior, or posterior interosseus nerves.150,151 Other findings include partial nerve constriction, fascicular entwinement or complete nerve constriction with an hourglass morphology, described in up to 50% of cases.152 Early imaging with ultrasound can potentially identify those cases with partial or complete constriction who may benefit from surgical intervention.149,151 Diaphragmatic ultrasound can be used to diagnose phrenic nerve involvement in this condition.

Mononeuritis multiplex is the characteristic pattern of peripheral nerve vasculitis both in isolated nerve and systemic vasculitic disorders. This is reflected on nerve ultrasound by focal, asymmetrically enlarged nerves, in proximal segments without extension to the brachial plexus.153155 Enlargement is described in most EDX affected nerve segments, and prominently in the tibial and fibular nerves.154,156,157 Importantly, nerve enlargement is seen in almost half of all clinically and EDX unaffected nerves.155 Hypervascularity can support a diagnosis of vasculitis PN and is reported in 19% of cases.155 The presence of an axonal neuropathy, with multifocal nerve enlargement proximal to compression sites without plexus involvement is argued to be 94% sensitive and 88% specific for vasculitis.155 Nerve enlargement might reduce with treatment, although this is based on a single case study only.153 Nerve ultrasound has also been suggested as a tool to guide nerve biopsy. Hence, ultrasound can improve diagnosis in PN vasculitis and has the potential to guide biopsy sites and support treatment monitoring.

Hereditary neuropathies are among the most studied conditions in the field of neuromuscular ultrasound. The disorders discussed below are just some of the hereditary conditions that have been studied. There are many others where no data exists.

CMT1A is the most common form of CMT, caused by an autosomal dominant duplication of the peripheral myelin protein 22 gene, resulting in a demyelinating PN. Ultrasound in CMT1A demonstrates diffuse symmetrical nerve CSA increase in 89100% of patients158160 (Figure 6C). This occurs from the brachial plexus and proximal nerve segments to the small sensory nerves such as the sural and auricular nerves.158 Nerve enlargement is detectable from as young as 19 months of age,161 and as such ultrasound is an ideal non-invasive diagnostic aid in young children. Larger CSA has been associated with more severe disease, measured with the CMT neuropathy score.158,162 In addition, a number of studies have demonstrated a correlation between the degree of nerve enlargement and neurophysiological dysfunction,158,162 although this has not been a universal finding.159

CMT1B is another demyelinating form of CMT, due to Myelin Protein Zero mutations. Ultrasound in CMT1B demonstrates nerve enlargement proximally,163,164 but reduced CSA in the lower limbs, helping to distinguish it from CMT1A.164 CMT1X is an X linked mutation of the gap junction associated protein and demonstrates symmetrically enlarged CSA in proximal segments and lower limbs on ultrasound.165 Finally, CMT2 is a heterogenous collection of variably inherited axonal polyneuropathies, with similarly variable findings on ultrasound.100,166

Research into nerve ultrasound as a longitudinal biomarker in CMT has been limited to date. A small study of 15 adults with CMT1A over 5 years failed to demonstrate a change in nerve calibre when assessing the sural and median nerves.167

Although outside the scope of this review, muscle ultrasound in a cohort with CMT has demonstrated reduced thickness and increased echointensity of the first dorsal interossei and tibialis anterior muscles.168 This was more pronounced in CMT1A compared to CMTX1 and CMT2A patients, and correlate with degree of muscle weakness. Consequently, nerve and possibly muscle ultrasound can improve diagnosis and assessments of severity in CMT.

HNPP is caused by an autosomal recessive deletion of the PMP22 gene, leading to multiple painless entrapment mononeuropathies. The classical ultrasound finding in HNPP is multiple areas of nerve enlargement at entrapment sites,169,170 but enlargement at non entrapment sites have also been described.171 Sonographic findings such as CSA do not correlate with neurophysiological parameters, such as the distal motor latency.172

Variant or hereditary transthyretin amyloidosis is an autosomal dominant disorder, where point mutations in the transthyretin gene results in an axonal sensorimotor and autonomic neuropathy. The recent development of disease modifying therapy has prompted great interest in diagnostic and treatment biomarkers. Ultrasound studies in vATTR Amyloidosis have reported increased nerve CSA at entrapment sites, proximal nerve segments and the brachial plexus when compared to healthy controls.100,173 CSA is also greater in symptomatic vATTR then asymptomatic carriers100 and in those with abnormal motor conduction studies.174 While carpal tunnel syndrome is common in vATTR, the median nerve CSA at the wrist is smaller than in idiopathic CTS and is discordant with EDX severity.175 This has been suggested as an early clinical clue for vATTR in patients presenting with CTS.

CANVAS is an adult-onset disorder caused by mutation in the RFC1 gene. A sensory neuronopathy is universally seen in patients with CANVAS,176 and can be detected on ultrasound as a reduction in CSA of the median, ulnar, tibial, and sural nerves.177 A reduced median and ulnar nerve CSA < 5 mm2 in the mid-forearm or mid-humerus demonstrate a sensitivity of 7993%, specificity 100% and area under the curve (AUC) of 0.970.99178 for distinguishing CANVAS from healthy controls.

SCA 2 is an autosomal dominant CAG triplet repeat mutation in the Ataxin 2 gene, resulting in cerebellar ataxia, sensory motor neuropathy, pyramidal and extrapyramidal dysfunction.179 Reduced nerve CSA on ultrasound is seen in the majority (74%) of patients and correlates with the presence of a sensory neuronopathy.177

Friedrich Ataxia is an autosomal dominant GAA triplet repeat disorder affecting the Frataxin gene, leading to cerebellar ataxia, cardiomyopathy and sensory neuropathy/neuronopathy. Interestingly, upper limb nerve CSA is enlarged in Friedrich ataxia, attributed to dysmyelintation and perineurial connective tissue proliferation,180 while lower limb nerve CSA is normal.

The utility of ultrasound in axonal PN is less well characterised. It was hypothesized initially that nerve calibre would be reduced in axonal neuropathies. However, ultrasound has revealed that nerves are typically either normal or slightly enlarged.23,119 The potential application of nerve ultrasound to many forms of axonal neuropathy, eg, toxic, metabolic, inflammatory aetiology remains to be defined by future research.

DPN is characterised sonographically by mild hypoechoic nerve enlargement, notably at compression sites. Several studies have reported enlarged CSA for the median and tibial nerves of Type 1 and Type 2 Diabetics with PN when compared to healthy controls.181184 Nerve enlargement can also predate clinical neuropathy,185 and increases further once DPN develops.186 In addition, the degree of enlargement and vascularity are biomarkers of severity, and correlate with clinical and EDX parameters.182,184,185 Further, in type 2 diabetics nerve ultrasound can demonstrate enlarged fascicles and marked hypoechogenicity when compared to controls, and this to correlates with EDX abnormalities.184,185 Type 2 diabetics with metabolic syndrome also demonstrate larger nerves and more severe neuropathy then diabetics without metabolic syndrome.187 Furthermore, increased tibial nerve stiffness on shear wave elastography is 90% sensitive and 85% specific for diabetes and increases with the development of DPN.188

Chemotherapy-associated PN demonstrates mild, often asymptomatic nerve enlargement at compression sites in 69% of patients and may point to nerve vulnerability to mechanical stress.188 In contrast, Lycan et al studied 20 patients with breast cancer exposed to taxane-based chemotherapy and reported reduced sural nerve calibre on ultrasound.190 Nerve size was further correlated with older age, longer time since exposure and intraepidermal nerve fibre density on skin biopsy.

Leprosy secondary to infection with Mycobacterium leprae is a prevalent cause for PN outside the western world191 and has been well studied with peripheral nerve ultrasound. Leprosy is characterised by both axonal and segmentally demyelinating PN with palpably thickened nerves and skin changes. Leprosy typically manifests with recurrent immune reactions referred to as active leprosy. Ultrasound studies have reported multiple asymmetric nerve enlargement with epineurial thickening.32,192195 Active leprosy is associated with nerve hypervascularisation in 5571% of patients and decreases to 2.75.9% with treatment.193,195 Thus, peripheral nerve ultrasound has potential as both a diagnostic and monitoring tool in Leprosy.193

EDX in children is challenging. EDX testing is potentially painful, with pain more frequently experienced when EMG is performed, when greater than one muscle and proximal muscles are tested.196 It is unsurprising therefore that younger age, especially under 3 years, is associated with inadequate and incomplete EDX in paediatric cohorts.196 Furthermore, EMG relies on active muscle recruitment and patient participation which is limited in the very young.197 Nerve imaging with MRI in children is also challenging due to the need to lie still for prolonged periods which may necessitate sedation. Nerve ultrasound on the other hand is painless, quick, adaptable, cost effective and well tolerated in paediatric patients.198 It seems natural therefore to see a recent growth in paediatric neuromuscular ultrasound research.107,199

Peripheral nerves increase in size as we age, meaning children with enlarged nerves may be incorrectly interpreted as normal if adult references values are applied. Therefore, the accurate interpretation of abnormal nerve CSA is reliant on the ongoing expansion age-specific normative ultrasound data.200,201 Zaidman et al23 examined 40 healthy children aged 217, among a larger cohort of 90 adults and children, and reported a range of normal CSA values. Of interest, an association between height and nerve CSA was seen, and was stronger in children (r =0.9, P < 0.001) than adults (r = 0.5, P < 0.001). Cartwright et al202 recorded peripheral nerve CSA in a further 43 children aged 3 months to 16 years as well 160 adults. Age was the strongest predictor of nerve CSA, although height and BMI were also predictive. Druzhinin et al201 systematically collected ultrasound CSA measurements in an children and young adults, scanning 72 healthy subjects aged 230 years. Their data suggest that nerve CSA is independently associated with age and weight but not height, differing from previous studies by Zaidman23 and Cartwright.201 Zaidman and Cartwright analysed for associations using pooled CSA values from all nerve measurements while Druzhinin analysed each nerve measurement individually, and this may explain their different findings. All three studies found nerve size plateaued at 1214 years leading the authors to conclude that paediatric specific normative values are essential to interpret imaging in subjects below this cut off. The intra and inter-nerve variability was measured in Zaidman and Druzhinins populations and interestingly did not differ significantly with age.23,201 This may be a potential age-independent measure to use where normative data is limited.

Entrapment mononeuropathies are uncommon in children, and when they do occur ultrasound can detect unusual causes such as mucopolysaccharidosis.203,204 Research in adult populations has been used to argue for supplementation or even replacement of standard EDX assessments with neuromuscular ultrasound in certain focal mononeuropathies such as carpal tunnel syndrome.46,205,206 A similar argument could be made for children with mononeuropathies but will require further studies to evaluate.

Polyneuropathies on the other hand are common in children and sonographic nerve changes are detectable in certain hereditary neuropathies such as CMT from a very young age.107,161 Further, nerve CSA in children with CMT1A correlates with disease severity, as well as age, height and weight.161 Furthermore, ultrasound can aid in the distinction between hereditary and acquired inflammatory polyneuropathies in this age group.107,119 Zaidman et al performed nerve ultrasound in 128 adults and children with a range of hereditary and acquired peripheral neuropathies. Thirty-five CMT1 patients age 271 years were examined and 8 out of 9 children with CMT demonstrated diffuse sonographic nerve enlargement.

Ultrasound has also been used to assess neonatal brachial plexopathy, which occurs in up to 3 in 1000 live births.207 The current standard is a 3-month period of observation for spontaneous recovery followed by surgical exploration where recovery is poor.208 In 2015, Somashekar et all compared preoperative US to surgical exploration in the detection of traction neuromas in 33 children.209 Of their cohort, 31 of the 33 surgically identified neuromas were detectable on US. Furthermore, muscle atrophy was identified in 11 children and guided spinal accessory and supra scapular nerve transfers in 8 of those patients.

Another advantage of ultrasound is its potential to limit the amount of EDX testing required to achieve a diagnosis. Rardin et al210 compared retrospective data from 21 children who were assessed by ultrasound prior to EDX with 84 aged-matched control subjects who had EDX assessment alone. Those subjects investigated with ultrasound first required less EDX tests, with fewer nerve stimulations and fewer muscles sampled by EMG. This led the authors to conclude an ultrasound first approach should be considered in paediatric patients to limit EDX testing.

Therefore, ultrasound has a number of distinct advantages in paediatric neuromuscular assessment and its role is likely to grow in this population. Further studies are needed to better define normal nerve size, as well as more detailed structural assessment such as fascicle measurements, echotexture and elastography.

Disorders of the motor neuron include Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA) and Spinal Bulbar Muscular Atrophy (SBMA or Kennedys disease) and Poliomyelitis. Diagnostic delay is a significant issue in these disorders, for instance in ALS the median time to diagnosis is 11.5 months after onset of symptoms.210 In SMA, the emergence of disease modifying therapy has generated the need for accessible, accurate, responsive, and reliable outcome measures. Hence, ultrasound has clear potential to improve the diagnosis and monitoring of motor neuron disease, and there is a growing body of literature supporting its use in ALS and SMA.

ALS is a fatal neurodegenerative disorder affecting the motor neuron, with a median survival of 35 years,212214 characterised by dysfunction of both upper and lower motor neurons (UMN and LMN) as well as cognition.213 Clinical heterogeneity exists, and there is an absence of pathognomonic investigations, leading to significant diagnostic delay.215 To better define the investigations of ALS and to promote recruitment of patients to clinical trials, the El Escorial and revised El Escorial (rEEC) were developed incorporating the presence of upper (UMN) and lower motor neuron (LMN) signs.216218 It was argued that the rEEC, although specific, was lacking in sensitivity, particularly in the early stages of disease, and consequently the Awaji criteria and more recently the Gold Coast criteria were developed.220224 These included the identification of fasciculations on EMG as an LMN sign and have contributed to the increased sensitivity in diagnosing ALS.216,224226 Neuromuscular ultrasound offers greater sensitivity then EMG in the detection of fasciculations especially in bulbar structures and thus has the potential to further improve the diagnostic sensitivity of the criteria.228 Further, muscle ultrasound in ALS can improve diagnosis through the detection of reduced muscle thickness and increased muscle echointensity98,227229 (Figure 7). Furthermore, quantitative measures of muscle echotexture have been used as diagnostic biomarkers and responsive outcome measures in ALS.230,231

Figure 7 Cross-sectional image of a normal tibialis anterior muscle (A) and quadriceps muscles (C) in a healthy individual. Cross-sectional image of abnormal tibialis anterior muscle (B) and vastus intermedius muscle and to a lesser extent rectus femoris muscle (D) in a person with amyotrophic lateral sclerosis. Note in the abnormal muscles there is atrophy with increased brightness or echointensity with a loss of the underlying bone reflection (*).

A reduction in motor nerve and cervical nerve root calibre with a sparing of sensory nerves has been consistently described in ALS232235 and is likely to reflect motor axon loss. This occurs in both clinically affected and unaffected regions.233 Nerve ultrasound can distinguish ALS from mimic disorders such as MMN and peripheral nerve hyperexcitability syndromes.236 Specifically an increased distal:proximal CSA ratio of the median nerve can distinguish ALS and reflects the relative density of motor fibres in the proximal portion of the nerve.236 Additionally, nerve ultrasound is abnormal in preclinical ALS where axonal degeneration is compensated and thus muscle wasting/weakness not yet apparent.233,237 Detecting the submillimetre nerve CSA changes in this preclinical state will likely improve as higher frequency ultrasound probes are developed and in wider use.237,238 One current limitation of nerve ultrasound is its insensitivity as a tool to monitor disease progression.238 Furthermore, nerve ultrasound measurements are not consistently correlated with disease severity on clinical and EDX measures, in part due to the confounding effect of UMN dysfunction.235

Bulbar motor neuron dysfunction, associated with dysphagia, is common in ALS, and can be measured by ultrasound in several ways. Video ultrasonography, a technique to dynamically assess tongue position and morphotexture during attempted swallow, is an early and sensitive measure of dysphagia in ALS.239 Further, ultrasound measures of tongue thickness are reduced in ALS, and this is most marked in those patients with bulbar onset disease and lower BMI.240 Furthermore, tongue thickness decreases with disease progression and may be used to monitor dysphagia and potentially guide timing of nutritional interventions such as parenteral feeding which are associated with improved survival in ALS.241,242 Lastly, minimal change in tongue thickness during swallowing, measured as a reduced thickness ratio is a specific marker of UMN bulbar dysfunction.243 Thus, dynamic tongue ultrasound has potential as a diagnostic and prognostic biomarker of bulbar dysfunction in ALS.

Respiratory dysfunction is universal in ALS as the disease progresses.244 Monitoring respiratory dysfunction, traditionally with spirometry, is essential to guide institution of non-invasive ventilation which can improve survival and quality of life.244246 A major limitation of spirometry in ALS is its poor reliability in the setting of bulbar and facial weakness as well as cognitive impairment. Dynamic diaphragmatic ultrasound thickness, measured as inspiration:expiration thickness or thickening ratio, offers an alternative measure in such patients. Ultrasound diaphragm thickness and thickening ratio are reliable in ALS,247 and correlate with vital capacity, hypercapnia, hypoventilation and motor disability more broadly.247 Thus, diaphragmatic ultrasound represents an important diagnostic biomarker for respiratory dysfunction in ALS,248 although at this stage it remains experimental and is not a substitute for standard measurements.

SMA is an autosomal recessive disorder of spinal lower motor neurons, caused by the mutation in the survival motor neuron (SMN1) gene. This ranges in severity from the severe type 1 SMA with onset before 6 months of age to Type 4 SMA with adult onset. There is considerable interest in biomarkers for diagnosis and disease progression in SMA due to the emergence of disease modifying therapy in the form of antisense oligonucleotides (Nusinersen and Risdiplan) and the gene replacement therapy (onasemnogene abeparvovec-xioi). Nerve ultrasound can distinguish adult onset SMA from mimicking disorders such as CIDP and MMNCB, based on reduced proximal nerve and nerve root CSA in SMA.249

In addition, high-frequency nerve ultrasound may provide prognostic information. This was suggested in a pilot study of 3 SMA patients using ultra high-frequency median nerve imaging.250 A reduced median nerve CSA and fascicle number was seen in the most severely affected subject (SMA I) relative to controls. Further, quantitative muscle ultrasound echo intensity, expressed as a Luminosity ratio, was increased in a cohort of SMA II and III subjects compared to healthy controls.251 Luminosity ratio was higher in more severe disease (SMA II) and correlated with dynamometry measures of strength. This suggests the diagnostic and monitoring potential for muscle ultrasound in SMA. Further research is needed to assess the role of nerve and muscle ultrasound in SMA.

The use of ultrasound to assess peripheral nerves in routine clinical practice is increasing due to its safety, accessibility, and dynamic quality. Current ultrasound technology provides excellent resolution of peripheral nerves and the flexibility of point of care machines allow easy integration into neuromuscular and electrodiagnostic clinics. Ultrasound adds critical structural information to compliment clinical and EDX assessments, contributing to improved diagnosis and pathophysiological understanding of peripheral nerve disorders. While nerve ultrasound is most frequently used to diagnose focal compressive mononeuropathy, its application has grown to include traumatic nerve injury, generalised peripheral neuropathy, motor neuron diseases and a range of other neuromuscular conditions in both adult and paediatric populations. Despite the operator-dependant nature of ultrasound, further development of quantitative measures, standardised protocols and consensus scoring frameworks will allow wider application and lead to improved diagnosis of peripheral nerve disease.

Funding support from the National Health and Medical Research Council of Australia is gratefully acknowledged.

Professor Matthew C Kiernan reports grants from NHMRC, is the Editor-in-Chief of Journal of Neurology, Neurosurgery & Psychiatry, during the conduct of the study. The authors report no conflicts of interest in this work. There are no financial interests or other conflicts of interest to declare.

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9. Simmons Z, Feldman EL. Update on diabetic neuropathy. Curr Opin Neurol. 2002;15(5):595603. doi:10.1097/00019052-200210000-00010

10. Kandula T, Farrar MA, Cohn RJ, et al. Chemotherapy-induced peripheral neuropathy in long-term survivors of childhood cancer: clinical, neurophysiological, functional, and patient-reported outcomes. JAMA Neurol. 2018;75(8):980988. doi:10.1001/jamaneurol.2018.0963

See the original post here:
Spotlight on ultrasonography in the diagnosis of PND | IJGM - Dove Medical Press

(StudyFinds.org) Long COVID continues to confound doctors as patients still struggle with debilitating symptoms months after first being infected. A new study now suggests that COVID patients who could be long-haulers could be diagnosed by taking a close look at their eyes. Nerve fiber loss and an increase in key immune cells on the surface of the eye may be a way of identifying the long term impact of the virus, say scientists.

The changes are particularly evident among those with neurological symptoms, such asloss of taste and smell,headache, dizziness, numbness, and neuropathic pain. Doctors at Weill Cornell Medicine-Qatar say long COVID ischaracterized by a range of symptomswhich continue for more than four weeks after the acute phase of the infection has passed, and which arent explained by an alternative diagnosis.

CCM has been used to identify nerve damage and inflammatory changes attributable to diabetic neuropathy,multiple sclerosis, and fibromyalgia..

Forty people who had recovered from confirmed COVID-19 infection between one and six months earlier completed a National Institute of Health and Clinical Excellence (NICE) questionnaire. Data was used to find out if they had long Covid, with a total score ranging from zero to 28. Neurological symptoms were present at four and 12 weeks in 22 out of 40 patients (55 percent) and 13 out of 29 (45 percent), respectively, according to the findings published in theBritish Journal of Ophthalmology.

The participants corneas were then scanned using CCM to look for small nerve fiber damage and the density of dendritic cells. These have a key role in the primaryimmune system responseby capturing and presenting antigens from invading organisms.

The corneal scans were compared with those of 30 healthy people who hadnt been infected by COVID.

Results show that 55 percent of theCOVID patientshad no clinical signs of pneumonia. Twenty-eight percent had clinical signs of pneumonia not requiring oxygen therapy. Ten percent had been admitted to hospital with pneumonia and received oxygen therapy, and 8 percentt with pneumonia had been admitted to the intensive care.

The corneal scans revealed that patients with neurological symptoms for four weeks after they had recovered from acute COVID-19 had greater corneal nerve fiber damage and loss, with higher numbers of dendritic cells, than those who hadnt been infected by the virus. Those without neurological symptoms had comparable numbers of corneal nerve fibers as those who hadnt been infected with COVID, but higher numbers of dendritic cells.

The questionnaire responses indicative oflong COVID symptomscorrelated strongly with corneal nerve fiber loss, says study author Professor Rayaz Malik in astatement.

He notes that it was an observational study, and as such, cant establish cause, and only a small number of participants were involved.

To the best of our knowledge, this is the first study reporting corneal nerve loss and an increase in [dendritic cell] densityin patients who have recoveredfrom COVID-19, especially in subjects with persisting symptoms consistent with long COVID, he adds. We show that patients with long COVID have evidence of small nerve fiber damage which relates to the severity of long COVID and neuropathic as well as musculoskeletal symptoms. Corneal confocal microscopy may have clinical utility as a rapid objective ophthalmic test to evaluate patients with long COVID.

South West News Service writer Stephen Beech contributed to this report.

Continue reading here:
Eye scan could determine whether COVID patients will be long haulers - WGNO New Orleans

The Diabetic Neuropathy Treatment Market is expected to account for a robust CAGR of 5.6% during the forecast period of 2021-27. The market held a CAGR of xx % in 2021 and xx USD billion in terms of revenue.

Once the immediate and direct impact of COVID-19 has passed in a given geographic area, the consequences of delaying care will almost certainly generate new issues for individuals and the healthcare system, potentially raising annual expenses globally. The pandemic has created an everlasting impact on the market and the healthcare industry.

The scope of our market report is to provide you with top-notch information on the market. The report consists of pie diagrams, bar diagrams, line diagrams, and other infographics to give a holistic and scrutinized view of the dynamic environment of the market. This reports analysis aids players in the business in comprehending shifting market dynamics through time.

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Top key players: Abbott, Roche, Eli Lilly, Johnson and Johnson, GlaxoSmithKline, Lupin, Glenmark, Depomed, Astellas, and Pfizer

Segmentation of Diabetic Neuropathy Treatment Market:

Product Type Coverage

Peripheral Neuropathy

Autonomic Neuropathy

Proximal Neuropathy

Focal Neuropathy

Application Coverage

Hospitals

Clinics

Others

The main goal for the dissemination of this information is to give a descriptive analysis of how the trends could potentially affect the upcoming future of Diabetic Neuropathy Treatment Market during the forecast period. This markets competitive manufactures and the upcoming manufactures are studied with their detailed research. Revenue, production, price, market share of these players is mentioned with precise information.

Diabetic Neuropathy Treatment Market: Regional Segment Analysis

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The report includes six parts, dealing with:1.) Basic information;2.) The Asia Diabetic Neuropathy Treatment Market;3.) The North American Diabetic Neuropathy Treatment Market;4.) The European Diabetic Neuropathy Treatment Market;5.) Market entry and investment feasibility;6.) The report conclusion.

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Diabetic Neuropathy Treatment Market Trends and Forecast to 2027 Players are Abbott, Roche, Eli Lilly - The Manomet Current

For Jess Guilln, pain is a feather touch and a constant companion. To illustrate, Guilln, who has been living with HIV since 1985, moves one elegant hand, bending at the wrist to mimic running a feather gently along skin.

I just start doing this over and over and over, he says. I tell people, This is a feather. But what do you feel if I keep doing this for 30 minutes, or for an hour?

Usually, folks push him away, irritated at the sensation. Thats one of the ways Guilln describes the chronic pain that sometimes keeps him in bed until noon and can make every step hurt. But thats not the only way he describes it. Theres the feeling of a nail or a thorn from a rose pressed nonstop against skin. And then, theres the pain that wakes him up in the middle of the night and consumes his thoughts, like a knife stabbing him over and over again. For Guilln, chronic pain is a lack of sensation, then, all at once, too much sensationand a sensation he cant escape.

It never stops. [People with chronic pain] dont get used to it, but we manage somehow, he says. We still want to experience life in some way.

Guilln is far from alone. Studies have found that between 25% and 85% of people living with HIV experience chronic pain, compared with estimates of 11% to 20% of the general population. Often, this is neuropathic painpain that starts in the brain but is usually experienced as numbness, tingling, burning or stabbing in the limbs, hands and feet.

Despite the high rates of pain, some research suggests that people living with HIV are less likely to be prescribed opioid pain treatment than their HIV-negative peers. The additional challenge of coexisting substance use disorders can render even that form of pain relief elusive for some people with HIV. But the opioid epidemic has led to new research on pain and how to address it at its core, including specifically for people living with HIV.

What We Know About Pain and HIV

Jessica Robinson-Papp, MD, had just come off a general medicine internship at St. Vincents hospital in New York City, where she fell in love with working with HIV-positive people, when she began training in neurology. Luckily for her, she was able to combine her passions. Today, shes a clinical neurologist at New York Citys Mount Sinai Hospital, serving people with HIV who have a variety of pain syndromes.

The more people with HIV she saw, the more Robinson-Papp realized that peripheral neuropathy was usually just one of a litany of pain complaints her patients had.

Youll start talking about neuropathic pain, she says. And then theyll say, Oh, but then, theres back pain, and Theres pain radiating down, and Theres pain over here, and Then, there are headaches.

What shes learned, and what the science of pain in general has revealed, is that there is no one cause of pain, or, if there is, science hasnt discovered it yet. Its not even clear whether people living with HIV really experience more pain than people without HIV, Robinson-Papp says.

We dont even really know that, she says. Understanding the [source] of pain is very much in its infancy.

We manage somehow. We still want to experience life.

What researchers do know is that pain is more likely a syndromea constellation of symptomsthan one disease with a single cause that can be cured. In fact, each kind of pain could have a different cause.

For instance, neuropathy is often a side effect of older HIV medications or chemotherapy for AIDS-defining illnesses. It could also be due to accelerated aging in people with HIV. Then theres degenerative joint diseasethat is, joint pain due to osteoarthritis or avascular necrosis, which often necessitate joint replacements. For people who menstruate, menopause can come with its own kinds of pain. HIV-associated chronic inflammation is another likely contributor to pain, Robinson-Papp says.

Whats more, people with one pain syndrome, such as HIV-associated peripheral neuropathy, are more likely to have another, like migraines or joint pain from osteoarthritisor even multiple other pain syndromes. Scientists dont know why that is either, says Robinson-Papp.

Plus, some factors may amplify ones perception of pain. For instance, its possible that some HIV viral proteins themselves may enhance pain. Pain is also associated with other health conditions, such as depression, anxiety or posttraumatic stress disorder, most of which can be part of whats known as AIDS Survivor Syndrome, a cluster of symptoms resulting from trauma endured during the early years of the epidemic.

Then there are factors that can make it easier to focus on pain, like the social isolation that can accompany aging. Moreover, certain behaviors, such as lack of exercise, can increase pain, and conditions such as insomnia or drug misuse or addiction (which can be an attempt to self-medicate) can complicate how individuals cope with pain.

All of this can impact the ability to take HIV meds as prescribed, which can deprive people with uncontrolled pain of the health benefits of having an undetectable viral load.

So when Robinson-Papp talks to patients about options to alleviate pain, the first step is to see if theres a physical reason for it, like diabetes, autoimmune diseases, infections such as hepatitis B or C or malnutrition associated with alcoholism.

But once Robinson-Papp has helped patients address those problems, there are only a few proven solutions she can offer people to help manage their pain or at least cope with it. These include physical therapy, massage, acupuncture, mindfulness-based stress reduction, cognitive behavioral therapy, exercise, non-opioid pain relievers and cortisone injections (for joint pain). Some data show that cannabis and capsaicin (derived from chili peppers) alleviated some pain in people with HIV, according to a systematic review published in a recent special issue of the journal AIDS Care on the topic of HIV and chronic pain that Robinson-Papp coedited. But the quality of the data were low, and more work is needed to confirm their effectiveness, researchers wrote.

That leaves one last option. Sometimes people are on opioids, she says. Thats a fact of life.

Guilln knows this all too well. Its taken years to find the right mix of meds, one that keeps the pain to a manageable level but doesnt wallop him with brain fog or fatigue. He rattles off the list of meds hes tried for pain: Cymbalta, morphine, medicines for depression, even schizophrenia drugs.

For five years, hes been on a regimen that works for him: a base of 20 milligrams of OxyContin (oxycodone hydrochloride) twice a day, with Norco (a combination of hydrocodone and acetaminophen) as needed but no more than one pill every four hours. He augments these with over-the-counter pain patches, hot and cold compresses, a device to deliver nerve stimulation to muscles and massagers.

Temperature, movement, vibrationthese are all different elements that affect whatever youre feeling, he says. But this is not a formula or a recipe. It is a lot of work, sadly, to find whatever works for you.

Opioid Epidemic Leads to Innovations

Sciences understanding of HIV and pain may be about to change, however. In the HIV and chronic pain issue of AIDS Care, a global task force of HIV experts began to lay out a research agenda for studying pain in people with HIV. (Their preference: Start with what causes it.) The issue includes new data showing that many HIV-positive people cant separate their chronic pain from their experience of having the virus.

The HIV Global Pain Task Force, of which Robinson-Papp is a member, is now soliciting recommendations for the HIV pain research agenda from people living with HIV.

Another effort is more wide-ranging. The National Institutes of Health (NIH) launched the Helping to End Addiction Long-term (HEAL) Initiative in 2018 and has so far funded it with $1.5 billion to back experimental research and the development of medical devices that might treat opioid use disorder or address or prevent pain.

The funding also supports the Pain Management Effectiveness Research Network, which is testing existing non-opioid drugs against pain, and the Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing as well as new research paths for interventions that could treat pain without requiring opioids.

Thats where Marco Loggia, PhD, associate director of Massachusetts General Hospitals Center for Integrative Pain NeuroImaging, comes in.

Loggia isnt an HIV researcher. But he has dedicated his career to studying what pain of all sorts looks like in the brain using PET and MRI scans.

Neuroinflammation is what brought him to HIV. Chronic HIV infection can lead to persistent immune activation and inflammation even among people on effective antiretroviral treatment who have an undetectable viral load.

Loggias lab was the first to show that in people with chronic pain a protein in the brain called translocator protein (TSPO) is present in unusually high numbers in the thalamus, the part of the brain that perceives pain and other stimuli. If his theory is correct and the presence of TSPO in people with chronic pain isnt just a coincidence but actually an objective marker of how much pain people are in, lowering TSPO might also reduce how much pain a person feels, without the need for opioids. Drugmakers could then develop medications that target and reduce TSPO and therefore reduce the pain itself.

HIV is a perfect storm of neuroinflammation, he says. We wanted to knowabove and beyond the inflammation associated with the viruswhy some people with HIV have pain and some dont.

In short, if all people with HIV have neuroinflammation, why dont they all also have pain? And does neuroinflammation look different in the brains of HIV-positive and HIV-negative people with chronic pain?

Loggias current study is recruiting participants in the Boston area to be part of an imaging study to look at just this. It divides participants into three categories: 30 people living with HIV without chronic pain, 30 people with HIV and chronic pain who engaged in opioid pain management and 30 people with HIV with chronic pain not taking opioids. Thats because of another complication of opioid use: Scientists think ongoing opioid use could actually increase inflammation, and maybe TSPO, in the brain.

The HEAL Initiative gives Robinson-Papp hope for the future of pain treatment for people living with HIV.

The HEAL Initiative has really brought together the addiction world and the pain world, which I think is extraordinarily beneficial, particularly for the pain world, because there are ways addiction medicine conceptualizes care that would be really lovely for us as well, she says, noting addiction cares focus on harm reduction. You have to think about the whole personwhere they live, what the context of their pain is.

Jess GuillnAngela DeCenzo

Reclaiming Joy

One of Guillns early memories as a child was dancing with his aunts. One aunt would take him by the hand, and another aunt would grab his sister. They would teach the kids salsa and other dances. When Guilln remembers it, he beams with adoration for his aunts, one of whom recently died.

In the years since, his experience in his body is, like pain, never just one thing. The breathtaking rush of a first kiss and first touch with another man linger with memories of the burning under his skin that came with his HIV diagnosis. The horror of the feel of bald patches on his scalp from the stress of being closeted and living with HIV in 1985 coexist with the youthful energy of nights spent at discos, dancing until dawn. Theres the mix of adrenaline and the great vibration in his chest from standing in front of a crowd and singing. Now, at 60, in chronic pain and with a hip replacement, Guilln is proud of the fact that these days, when he does dance, he can still break it down all the way to the ground.

Sometimes, when every step on the sidewalk feels like stabbing, he imagines hes walking on a bed of Jell-O. It takes him out of his current body, this painful body that nevertheless he loves.

He can still access the joy he felt dancing as a child. It will cost him in energy and recovery later, but for five or 10 minutes, his feet move in that familiar way, in concert with his shoulders, hips leading, weight shifting from balls of feet to heels, shoulders shifting to compensate. For those minutes, he is that child again, dancing in the kitchen with his aunt.

Some days, thats just a fantasy. But he can escape into that memory and know what its been like to be a whole person in a currently painful body.

Even if were sitting down, we can have those wonderful memories of movement, he says, as his hands come up in front of his chest and his shoulders shimmy. And even with just the hands, or the hands right here, we are in our brains really doing the twist. And it might help.

Read more:
The Feather and the Knife: Navigating Life With Chronic Pain - POZ

Financing strengthens balance sheet, furthers financial and operational flexibility and lowers overall cost of capital

No financial covenants and no warrants issued in connection with non-dilutive financing

Full drawdown expected to extend cash runway to support key value-creating milestones including availability of Phase 1/2 GAN data from the highest dose cohort as well as regulatory guidance on registration pathway for GAN, data readouts in GM2 gangliosidosis, Rett syndrome, CLN1 disease, and SURF1-associated Leigh syndrome and, importantly, a potential regulatory approval for TSHA-120 in GAN without the need for additional financing

DALLAS, August 16, 2021--(BUSINESS WIRE)--Taysha Gene Therapies, Inc. (Nasdaq: TSHA), a patient-centric gene therapy company focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the central nervous system in both rare and large patient populations, today announced that it has entered into a loan and security agreement with Silicon Valley Bank (SVB) that provides Taysha with up to $100 million of borrowing capacity.

"Access to this non-dilutive financing at an attractive cost of capital, along with the current cash on hand, will provide Taysha with operational and financial flexibility to achieve numerous value-generating milestones including a potential regulatory approval for TSHA-120 in giant axonal neuropathy, or GAN," said RA Session II, Chief Executive Officer of Taysha. "Additional milestones include the release of Phase 1/2 data in the highest dose cohort in GAN, and Phase 1/2 data in GM2 gangliosidosis, Rett syndrome, CLN1 disease and SURF1-associated Leigh syndrome. We are pleased to partner with SVB as we continue to execute on our ambitious business plan."

This non-dilutive financing provides Taysha with up to $100 million, with $40 million available at closing of which Taysha has drawn $30.0 million. The Company has the option to draw down the remaining tranches, subject to certain conditions. The interest rate is the greater of 7.0% or the WSJ Prime Rate plus 3.75%. There are no financial covenants and no warrants associated with the term loan.

Story continues

"Our financial commitment to Taysha speaks to our confidence in its core strategies and is consistent with our support of innovative life sciences businesses," said Michael White, Head of Business Development, Life Science & Healthcare, Silicon Valley Bank. "We are delighted to provide additional capital for the Company to further advance its robust development pipeline and achieve key value-generating milestones in the years to come."

"In the last 12 months, we have quickly made the transition from a private to public company and from preclinical to clinical to pivotal-stage," said Kamran Alam, Chief Financial Officer of Taysha. "Building upon this momentum, we expect this non-dilutive financing to enable us to be well positioned to maximize long-term stockholder value."

About Taysha Gene Therapies

Taysha Gene Therapies (Nasdaq: TSHA) is on a mission to eradicate monogenic CNS disease. With a singular focus on developing curative medicines, we aim to rapidly translate our treatments from bench to bedside. We have combined our teams proven experience in gene therapy drug development and commercialization with the world-class UT Southwestern Gene Therapy Program to build an extensive, AAV gene therapy pipeline focused on both rare and large-market indications. Together, we leverage our fully integrated platforman engine for potential new cureswith a goal of dramatically improving patients lives. More information is available at http://www.tayshagtx.com.

About Silicon Valley Bank

For nearly 40 years, Silicon Valley Bank (SVB) has helped innovative companies and their investors move bold ideas forward, fast. SVB provides targeted financial services and expertise through its offices in innovation centers around the world. With commercial, international and private banking services, SVB helps address the unique needs of innovators. Learn more at svb.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "anticipates," "believes," "expects," "intends," "projects," and "future" or similar expressions are intended to identify forward-looking statements. Forward-looking statements include statements concerning or implying the potential of our product candidates to positively impact quality of life and alter the course of disease in the patients we seek to treat, our research, development and regulatory plans for our product candidates, the anticipated use of proceeds from borrowings under the loan and security agreement, our ability to access the full $100 million potentially available under the loan and security agreement and our ability to fund operations into the second half of 2023. Forward-looking statements are based on managements current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission ("SEC") filings, including in our Annual Report on Form 10-K for the year ended December 31, 2020 and our Quarterly Report on Form 10-Q for the quarter ended June 30, 2021, both of which are available on the SECs website at http://www.sec.gov. Additional information will be made available in other filings that we make from time to time with the SEC. Such risks may be amplified by the impacts of the COVID-19 pandemic. These forward-looking statements speak only as of the date hereof, and we disclaim any obligation to update these statements except as may be required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210816005185/en/

Contacts

Company Contact: Kimberly Lee, D.O.SVP, Corporate Communications and Investor RelationsTaysha Gene Therapiesklee@tayshagtx.com

Media Contact: Carolyn HawleyCanale Communicationscarolyn.hawley@canalecomm.com

Read more here:
Taysha Gene Therapies Secures up to $100 Million Non-Dilutive Term Loan Financing - Yahoo Finance

Sonnet BioTherapeutics Provides Fiscal Year 2021 Third Quarter Business and Earnings Update

Expanded F H AB Intellectual Property Portfolio

Completed $15.9 million At-The-Market Financing

SON-1010 and SON-080 on track for IND submissions by calendar year end

PRINCETON, NJ / ACCESSWIRE / August 16, 2021 / Sonnet BioTherapeutics Holdings, Inc. (NASDAQ:SONN) ("Sonnet" or the "Company"), a biopharmaceutical company developing innovative targeted biologic drugs, announced today its financial results for the three months ended June 30th , 2021 and provided a business update.

"Throughout the quarter, we've continued to make several advancements towards the clinic with our proprietary Fully Human Albumin Binding (F H AB) pipeline assets, and our partnered product" commented Pankaj Mohan, Ph.D., Founder and CEO. "We are progressing our SON-1010 (F H AB-IL12) and SON-080 (Low-dose IL-6) programs, with IND applications on track to be filed with the FDA for both before the end of 2021, with an additional IND for SON-1210 (IL12-F H AB-IL15) during the first half of 2022. We remain confident that the ability to deliver a therapeutic payload in a more targeted manner than traditional, wild-type cytokines has the potential to result in greater efficacy with an improved toxicity profile."

"We are pleased with our ongoing financing strategy, which is designed to provide the company with the funding necessary to advance our R&D activities and to grow the company beyond 2021," commented Jay Cross, CFO.

FY 2021 Third Quarter and Recent Corporate Updates

Sonnet provided the following corporate updates:

In May 2021, Sonnet entered into a license agreement with New Life Therapeutics, granting exclusive licenses to develop and commercialize SON-080 for the prevention, treatment, or palliation of diabetic peripheral neuropathy in certain territories in Asia.

In June 2021, the United States Patent and Trademark Office issued U.S. Patent No. 11,028,166 entitled "Albumin Domain Fusion Proteins" that covers Sonnet's F H AB technology. The patent also includes therapeutic fusion proteins that utilize F H AB for tumor targeting and retention, thereby providing extended pharmacokinetics.

Story continues

In June 2021, Sonnet executed its final issuance of shares of its common stock under the At-the-Market Sales Agreement, pursuant to which the Company executed issuances of an aggregate of 7,454,238 Shares for aggregate gross proceeds of $15,874,999.

FY 2021 Third Quarter Ended June 30, 2021 Financial Results

As of June 30, 2021, Sonnet had $6.0 million cash on hand.

Research and development expenses were $3.9 million for the three months ended June 30, 2021, compared to $2.5 million for the three months ended June 30, 2020. The increase of $1.4 million was primarily due to increased expenditures for the development of the cell line for IL12-FHAB and IL12-FHAB-IL15 and increased costs for research and development activities due to the acquisition of Relief and an increase in payroll and share-based compensation expense as operations are expanded.

General and administrative expenses were $2.4 million for the three months ended June 30, 2021, compared to $2.5 million for the three months ended June 30, 2020. The decrease of $0.1 million was primarily due to a $0.9 million decrease in professional fees and transaction-related fees associated with the closing of the merger, offset by an increase in payroll and share-based compensation expense of $0.7 million to support expanded operations.

About Sonnet BioTherapeutics Holdings, Inc.

Sonnet BioTherapeutics is an oncology-focused biotechnology company with a proprietary platform for innovating biologic drugs of single or bispecific action. Known as F H AB (Fully Human Albumin Binding), the technology utilizes a fully human single chain antibody fragment (scFv) that binds to and "hitch-hikes" on human serum albumin (HSA) for transport to target tissues. F H AB is the foundation of a modular, plug-and-play construct for potentiating a range of large molecule therapeutic classes, including cytokines, peptides, antibodies and vaccines.

Forward-Looking Statements

This press release contains certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and Private Securities Litigation Reform Act, as amended, including those relating to the Company's product development, clinical and regulatory timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statements that are predictive in nature. These forward-looking statements are based on current expectations, estimates, forecasts and projections about the industry and markets in which the Company operates and management's current beliefs and assumptions.

These statements may be identified by the use of forward-looking expressions, including, but not limited to, "expect," "anticipate," "intend," "plan," "believe," "estimate," "potential, "predict," "project," "should," "would" and similar expressions and the negatives of those terms. These statements relate to future events or the Company's financial performance and involve known and unknown risks, uncertainties, and other factors which may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Such factors include those set forth in the Company's filings with the Securities and Exchange Commission. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this press release. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Sonnet Biotherapeutics Investor Contact

Michael V. Morabito, Ph.D.Solebury Trout917-936-8430mmorabito@soleburytrout.com

Sonnet BioTherapeutics Holdings, Inc.Consolidated Balance Sheets(unaudited)

June 30,

September 30,

2021

2020

Assets

Current assets:

Cash

$

6,038,190

$

7,349,903

Prepaid expenses and other current assets

934,213

287,738

Total current assets

6,972,403

7,637,641

Property and equipment, net

58,644

67,889

Operating lease right-of-use asset

144,787

205,919

Other assets

-

82,959

Total assets

$

7,175,834

$

7,994,408

Liabilities and stockholders' equity

Current liabilities:

Related-party notes

$

748

$

21,184

Accounts payable

2,150,791

2,057,559

Accrued expenses

2,508,956

2,063,678

Operating lease liability

91,239

82,060

Deferred income

1,000,000

500,000

Total current liabilities

5,751,734

4,724,481

Note payable

-

124,878

Operating lease liability

55,464

125,132

Total liabilities

5,807,198

4,974,491

Stockholders' equity:

Preferred stock; $0.0001 par value: 5,000,000 shares authorized. No shares issued or outstanding

-

-

Common stock; $0.0001 par value: 125,000,000 shares authorized; 24,757,847 and 14,724,105 issued and outstanding at June 30, 2021 and September 30, 2020, respectively

2,475

1,472

Additional paid-in capital

56,103,306

39,723,702

Accumulated deficit

(54,737,145

)

Excerpt from:
Sonnet BioTherapeutics Provides Fiscal Year 2021 Third Quarter Business and Earnings Update - Yahoo Finance

Most of us learn pretty earlywhether it's via an ice cream headache or pizza-party hangoverthat it is indeed possible to get too much of a good thing. Unfortunately, as health-conscious adults, many of us are slow to realize the same lesson still applies. When it comes to vitamins and supplements, more doesn't mean better. Taking too many vitamins can have unpleasant or serious side effects, and some vitamins shouldn't be taken in supplement form at all. Read on to find out moreand to ensure your health and the health of others, don't miss these Sure Signs You Have "Long" COVID and May Not Even Know It.

The first sign that you've taken too many vitamins or supplements is usually gastrointestinal. You might experience nausea, vomiting or diarrhea. It might mean you've taken a vitamin on an empty stomach that you'd better tolerate with foodor that you're taking more supplements than your body should handle. To be safe, it's always a good idea to talk with your doctor before beginning a new vitamin or supplement regimen.

This is one of the side effects associated with taking too much vitamin A, which is a fat-soluble vitamin. Unlike water-soluble vitaminsof which the body eliminates any excess in the urinefat-soluble vitamins are stored in body fat. If you take too many, that can result in toxicity. The other fat-soluble vitamins are D, E and K, and you should take care not to exceed the recommended daily dosage of each.

RELATED: What Taking a Vitamin Every Day Does to Your Body

Yikes. But indeed, that's what research has indicated about taking supplements of beta-carotene or vitamin E, or excessive amounts of biotin. Last spring, the United States Preventive Services Task Force (USPSTF) officially recommended against taking vitamin E or beta-carotene supplements, saying they may increase the risk of cancer or poor outcomes from heart disease. Another study found that men had an increased risk of lung cancer after taking megadoses of biotin (5 mg to 10 mg daily).

RELATED: The #1 Best Supplement to Take For Immunity

Taking too much of certain vitamins, such as vitamin B6, can result in nerve issues, such as neuropathy (numbness) or tingling. To avoid this, never take more than the recommended daily allowance.

RELATED: Signs You're Getting One of the "Most Deadly" Cancers

Another potentially dangerous vitamin or multivitamin ingredient is vitamin E. "Unless you have a reason to take vitamin E, you shouldn't be taking it as a random supplement," says Kathryn Boling, MD, a family medicine doctor with Mercy Medical Center in Baltimore. "We used to think it was good to take because it's an antioxidant, but it turns out the risk is higher than the benefit." That risk: Vitamin E thins the blood, which could turn minor injuries into serious bleeding episodes.And to get through this pandemic at your healthiest, don't miss these 35 Places You're Most Likely to Catch COVID.

Original post:
Ugly Side Effects of Too Many Vitamins - Eat This Not That - Eat This, Not That