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Hendford Dental Practice Yeovil

Hendford Dental Practice Yeovil
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Hendford Dental Practice has been providing patients throughout Yeovil and the surrounding areas with a range of high-quality dental services for a number of years now. Our small and friendly dental practice offers a range of comprehensive preventative and cosmetic dentistry, including teething whitening, to both new and existing patients. For all your dental care and needs, be sure to book a dentist appointment with your local dentist in Yeovil at Hendford Dental Practice.

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https://hendforddentalpractice.co.uk

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30 Hendford, Yeovil, Somerset, South West, BA20 1TG

Phone Number:
01935 433337


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Our mission is to deliver the best possible dental care for infants, children, teens and kids with special healthcare needs.


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Dr. Christina Casado

Alma Community - World Of Wellness

Health & wellness Center Miami - Dr. Christina M. Casado A.P. is a Florida-Licensed acupuncture.Physician and Certified Chinese Medical Herbalist. She is a student of Japanese acupuncture master Kiiko Matsumoto and travels annually to Japan and China to hone her skills and learn new techniques.Her credentials include a B.S. in Environmental Science from Tufts University in Boston, Massachusetts; an M.S. in biology from the University of Missouri at St. Louis; and an M.B.A. from Florida International University. Christina is also certified in injection therapy for pain management and detoxification.


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Deepak kumar

Dental clinic in Coimbatore

Crown Dental Clinic is a speciality Dental Clinic for family & child/kids offers best dental treatment & centrally situated in Trichy road, Sungam, Near Race Cource, Coimbatore . Our Dental clinic is built up by expert dental specialist, and authorized dental implant specialist whose focus is prepared to give worldwide standard of dental consideration to the patients. We believe in giving utmost care to our patients which is supported by our top-notch dental technologies. Our Dental Clinic in Ramanathapuram,Coimbatore (Sungam, Race Course, Singanallur) ensure enhanced patient experience, understanding of the requirement and providing efficient results.


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Dr. Susan Fox

Fox Vein & Laser Experts

Dr. Susan Fox is an expert in varicose vein treatment. She is Board Certified in Internal Medicine, Vascular Medicine and Phlebology (the treatment of veins). She was one of the first physicians in the United States to be Board Certified in the treatment of veins.


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Carlos Burnett

Plastic Surgeon

Burnett Plastic Surgery in Westfield, NJ, is led by Dr. Carlos Burnett, an experienced and board-certified plastic surgeon who offers face, body, and breast procedures for women and men seeking to gain confidence in their appearance. The practice also offers nonsurgical skincare solutions to smooth out wrinkles, change facial contours, and more. Dr. Burnett prefers a patient-centered approach, working with each person who comes to him as an individual with unique desires-which leads to customized, natural-looking results. Consultations are long and detail oriented so he can truly get to know each patient before recommending a course of action.


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  • Prime editing devised by researchers at the Broad Institute led by David Liu is a significant advance of the original CRISPR gene editing tool discovered in 2012
  • CRISPR can cut and edit your DNA to correct defects inside your body’s cells to prevent and heal a range of incurable diseases and has revolutionized biomedicine
  • The original CRISPR is fraught with inaccuracies referred to as off target effects
  • Prime editing substantially reduces CRISPR’s off target effects and has the potential to correct up to 89% of known disease-causing genetic variations
  • CRISPR also has the capacity to edit genes in an embryo in such a way that the change is heritable
  • In 2018 Chinese researcher He Jiankui “created” the world’s first CRISPR babies
  • This triggered international criticism from scientists and bioethicists
  • A principal concern is that CRISPR is easy-to-use, cheap, regularly used in thousands of laboratories throughout the world and there is no internationally agreed and enforceable regulatory framework for its use
 
For better or worse we all now live in CRISPR’s world
 
In 2012 the world of biomedicine changed when a revolutionary gene editing technology known as CRISPR-Cas9 (an acronym for Clustered Regularly Interspaced Short Palindromic Repeats) was discovered. The technology harnesses your body’s naturally occurring immune system that bacteria use to fight-off viruses and has the potential to forever change the fundamental nature of humanity. Since its discovery CRISPR has been developing at lightning speed primarily because it is simple and affordable and today is used in thousands of laboratories throughout the world.
 
In this Commentary
 
In this Commentary we describe prime editing, which is the latest advance of the CRISPR's tool box, devised bya team of researchers, led by Andrew Anzalone, a Jane Coffin Childs postdoctoral fellow from the Broad Institute of MIT and Harvard and published in the October 2019 edition of Nature. Prime editing is significant because it provides a means to eliminate the unintentional consequences of CRISPR and therefore bring the technique closer for use in clinics. But this is still a long way off.
 
We also review a case where an ambitious scientist “created” the first CRISPR babies. This immediately triggered international criticism and a call for tighter regulatory control of the technology. Scientists and bioethicists are concerned that CRISPR can easily be used to create heritable DNA changes, which ultimately could lead to ‘designer babies’.
 
These two accounts of CRISPR might seem “opposites” and not sit well together in a single Commentary. Notwithstanding, what prompted putting them together was John Travis, the News Managing Editor of the well-known scientific journal Science, who soon after CRISPR’s discovery in 2012  said, “For better or worse we all now live in CRISPR’s world”
 
CRISPR and your DNA

CRISPR is different to traditional gene therapy, which uses viruses to insert new genes into cells to try and treat diseases and has caused some safety challenges. CRISPR, which avoids the use of viruses, was conceived in 2007 when a yogurt company identified an unexpected defence mechanism that its bacteria used to fight off viruses. Subsequent research made a surprising observation that bacteria could remember viruses. CRISPR has been likened to a pair of microscopic scissors that can cut and edit your DNA to correct defects inside your body’s cells to prevent and heal a range of intractable diseases. The standard picture of DNA is a double helix, which looks similar to a ladder that has been twisted. The steps in this twisted ladder are DNA base pairs. The fundamental building blocks of DNA are the four bases adenine (A), cytosine (C), guanine (G) and thymine (T). They are commonly known by their respective letters, A, C, G and T. Three billion of these letters form the complete manual for building and maintaining  your body, but tiny errors can cause disease.  For example, a mutation that turned one specific A into a T results in the most common form of sickle cell disease.
 
The original CRISPR
 
The original CRISPR tool, which is the first and most popular gene editing system, uses a guide RNA (principally a messenger carrying instructions from your DNA for controlling the synthesis of proteins) to locate a mutated gene plus an enzyme, like Cas9, to cut the double-stranded gene helix and create space for functioning genes to be inserted. However, a concern about CRISPR is that the editing could go awry and cause unintended changes in DNA that could trigger health problems. Findings of a study published in the July 2018 edition of  the journal Nature Biotechnology found that such inaccuracies, referred to as off-target effects, were substantially higher than originally reported and some were thought to silence genes that should be active and activate genes that should be silent. These off-target effects, such as random insertions, deletions, translocations, or other base-to-base conversions, pose significant challenges for developing policy associated with the technology.

Subsequently however, the paper was retracted, and an error correction was posted on a scientific website. Contrary to their original findings, the authors of the Nature Biotechnology paper restated that the CRISPR-Cas9 gene editing approach, "can precisely edit the genome at the organismal level and may not introduce numerous, unintended, off-target mutations".

 
Base editing

Notwithstanding, researchers remained concerned about CRISPR’s off target effects and several devised a technique, referred to as base editing, to reduce these. Base editing is described in three research papers published in 2017: one in the November edition of the journalProtein and Cell’, another in the October edition ofSciencethe and a third by researchers from the Broad Institute, in the October edition of the journal Nature’. Base editing takes the original CRISPR-Cas9 and fuses it to proteins that can make four precise DNA changes: it can change the letters C-to-T, T-to-C, A-to-G and G-to-A. The technique genetically transforms base pairs at a target position in the genome of living cells with more than 50% efficiency and virtually no detectable off-target effects. Despite its success, there remained  other types of point mutations that scientists wanted to target for diseases.

 

Prime editing
 
Prime editing is different to previous gene editing systems in that it uses RNA to direct the insertion of new DNA sequences in human cells. According to David Liu,  the senior author of the 2019 Nature paper and a world renowned authority on genetics and next-generation therapeutics, “a major aspiration in the molecular life sciences is the ability to precisely make any change to the genome in any location. We think prime editing brings us closer to that goal”.  Because prime editing provides a means to be more precise and more efficient in editing human cells in a versatile way, which eliminates many of CRISPR’s unintentional errors, it significantly expands the scope of gene editing for biological and therapeutic research.
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There are around 75,000 different mutations that can cause disease in people and prime editing has the potential to correct up to 89% of known disease-causing genetic variations. According to Liu, "Prime editing is the beginning, rather than the end, of a long-standing aspiration in the molecular life-sciences to be able to make any DNA change in any position of a living cell or organism, including potentially human patients with genetic diseases". Liu’s team at the Broad Institute intends to continue optimizing prime editing. In their October 2019 Nature paper researchers reported that they can precisely correct mutant genes, which cause sickle cell anaemia and Tay Sachs disease.
 

Sickle cell anaemia and Tay Sachs
 
Sickle cell anaemia is an inherited form of anaemia. This is when there are not enough healthy red blood cells  (haemoglobin) to carry adequate oxygen throughout your body. The condition is the most common inherited blood disorder in the US, affecting 70,000 to 80,000 and further it is estimated  each year some 300,000 babies are born with the disorder worldwide. Tay-Sachs disease is a rare and fatal nerve condition often caused by the addition of four extra letters of code.  Although anyone can be a carrier of  the disease it is much more common among people of Ashkenazi (Eastern European) Jewish descent. In the Ashkenazi Jewish population, the disease incidence is about 1 in every 3,500 new-borns and the carrier frequency is 1 in every 29 individuals.

 
Some moral and ethical implications of CRISPR
 
Being able to modify your DNA with CRISPR tools has transformed scientific research and is revolutionising medicine although it will be some time before the technology is regularly used in clinics. In addition to its potential benefits there are significant moral and ethical challenges associated with the technology, especially when it is used for germline engineering, which is the process by which your genome is edited in such a way that the change is heritable. Inappropriate use of germline editing could dent the progress of the CRISPR technology.
 
The first CRISPR babies
 
One well publicized  inappropriate use of CRISPR is a team in China, led by He Jiankui of the Southern University of Science and Technology in Shenzhen, which in November 2018 “created” the first gene edited twins, known by their pseudonyms Lulu and Nana. He edited the twins’ cells to be immune to HIV infection when they were embryos, therefore ensuring that every cell in their bodies were changed, including their reproductive ones, which means their edited genomes can be passed on to their children and grandchildren, despite the fact that scientists cannot be sure what the long term effects of such lasting modifications might be. The twins are the first CRISPR babies and the first humans to have every cell in their body genetically modified using the technology.
 
In 2015 Chinese researchers were the first to edit the genes of a human embryo in a laboratory dish. Although the embryos did not go to term, the experiment triggered an international outcry from bioethicists, who argued that CRISPR should not be used to make babies. Notwithstanding, He Jiankui did just this.
 
He  employed CRISPR to alter a gene in IVF embryos to disable the production of an immune cell surface protein, CCR5, which HIV uses to establish an infection before insemination. CCR5 is a well-studied genetic mutation, and there is scientific and medical value in understanding how CRISPR can be used to disable and prevent HIV/AIDS. He believed that the use of CRISPR technology was medically appropriate and expected his experiment, “to produce an IVF baby naturally immunized against AIDS”. But more contentiously, He created twins who could pass the protective mutation to future generations. It is CRISPR’s ability to easily and cheaply edit human embryos, eggs, or sperm in order to create irrevocable changes and the potential for designer babies, which raises concerns.  
 
He defended his work at a Hong Kong genomics conference in late November 2018, but there was immediate and significant international criticism about the scientific and ethical legitimacy of his experiments, which broached China’s guidelines as well as international ethical and regulatory norms. A Chinese government investigation found He to have violated state law in pursuit of “personal fame and fortune”.  His endeavours cost him his university position and the leadership of a biotech company he founded, which had successfully raised US$43m start-up capital and was advised by Craig Melloprofessor  of the University of Massachusetts Medical School and Nobel Laureate for medicine in 2006 for his genetics research.
 
Opacity and scientific competition
 
Some scientists are reluctant to be critical of He and suggest his studies, which resulted in the first CRISPR babies,  simply signal the “next chapter in the technology’s story”. He Jiankui appears to be an ambitious scientist desperate to become the first to conduct the gene editing experiment on humans, but who made some significant errors of judgement by initiating his study prematurely and by withholding information from regulatory authorities and his university. A generous interpretation might suggest that He was motivated by science and humanity. Through a Beijing-based organization, which helps Chinese people with HIV, he recruited couples for his experiment where only the fathers were living with HIV infections, which they managed by antiviral drugs. Eight couples agreed to participate, although one subsequently withdrew.
 
Since He’s statement at the Hong Kong conference he has disappeared, but the background to his studies has been well documented. In late 2017, He, who specialized in sequencing DNA, began his efforts to produce human babies from gene edited embryos and before and during his study it is reported that he sought advice from international experts in the field and communicated openly with international colleagues about his plans. Notwithstanding, it is alleged that He faked a blood test for one of the fathers in the study, aware that in China the HIV status of the father would disqualify him from participating in fertility treatments. Also, He failed to appropriately inform the hospital where the twins were edited and implanted of the status of his experiments.

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Fierce competition among scientists is not uncommon and competition fuels opacity among scientists in their battle to become the first to make a discovery. Indeed, it is not uncommon for scientists to shield their ideas and research. This does not condone He’s actions, but it might help to explain them. Generally speaking, scientific opacity is not created by ambitious scientists alone, but it is partly created by scientific funding bodies and research institutions. Such opacity is a significant obstacle to open collaboration. In addition to wanting to be the first, He’s intentions might also have been an attempt to spare children of parents with HIV/AIDS  from inheriting the disease.
CRISPR is not yet safe
 
Be that as it may, many scientists agree that CRISPR is not yet safe and precise enough to be used in human embryos. In the March 2019 edition of Nature a group of 18 prominent CRISPR scientists and bioethicists from seven countries called for a global moratorium on heritable genome editing until the establishment of an international framework that would compel countries to establish both scientific safety and broad societal agreement before allowing the technology to progress.  "We call for a global moratorium on all clinical uses of human germline editing; that is, changing heritable DNA (in sperm, eggs or embryos) to make genetically modified children" , the scientists wrote.

Opposition to germline editing is mixed
 
However, opposition to germline editing is mixed. In February 2017 the US National Academies of Sciences, Engineering, and Medicine (NASEM) published a report, which did not call for an international ban of germline editing, but instead suggested that it "might be permitted" if strict criteria were met. In July 2018, the UK’s Nuffield Council of Bioethics published a report on heritable genome editing and suggested that under certain circumstances it could be morally permissible, even in cases of human enhancement. 

Given that CRISPR is cheap, easy-to-use and already an effective tool in thousands of laboratories throughout the world, it seems reasonable to assume that standards and laws are unlikely to prevent a determined scientist and desperate patients from using the technology prematurely. Indeed, science and medicine have a history of researchers attracting public criticism for undertaking experiments prematurely only to have those experiments become common medical practices: in-vitro fertilization  (IVF) is one such example. Although IVF has a chequered history today it accounts for millions of births worldwide and  1% to 3% of all births every year in the US and Europe.
 
Germline engineering and somatic genetic modification
 
Here we describe the difference between germline and somatic adjustments. The former uses CRISPR to modify DNA in such a way that the change is heritable. The latter uses CRISPR to modify the DNA of people with incurable diseases in a way that such modifications are limited to the people treated and not passed on to future generations. Broadly speaking, your body has two kinds of cells: somatic and germ cells. The vast majority are somatic. These cells make up your body and are responsible for forming all your familiar structures: such as your skin, blood, muscles and organs etc. Your somatic cells die when you die so there is no chance of them creating a new organism. However, germ cells are different. Early in your development your germ cells  are sequestered: they divide more slowly and under restricted circumstances. Germ cells cannot become a physical feature such as an ear or a finger, but they do make the only bits of you, which can form a new person: your eggs and your sperm. Every cell in your body holds your DNA in an unbroken lineage stretching back millions of years and thousands of generations, but only the germline has a chance to go forward. Human germline modification means deliberately changing the genes passed on to children and future generations and thereby creating genetically modified people. Somatic genetic modification is different. It adds, cuts, or changes the genes in some of your cells, typically to alleviate a medical condition. The use of human genome editing to make edits in somatic cells for purposes of treating genetically inherited diseases is already in clinical studies. If perfected, somatic gene editing (gene therapy) holds promise for helping people who are sick, affecting only an individual consenting patient. With the exception of He’s studies, human clinical studies with CRISPR have been limited to somatic cells. In effect, this renders CRISPR no more consequential than any other experimental drug or treatment. Any CRISPR-made somatic cell changes are a genetic dead-end and are not heritable. However, germline cells have the possibility of immortality, with the potential to affect thousands of people over the course of several generations. Tampering with germline cells is therefore a much more serious proposition.
 
Clinical studies of gene therapies
 
Gene therapy is primarily available in a research setting. The US Food and Drug Administration (FDA) has approved only a limited number of gene therapy products for sale in the US.According to the US National Institutes of Health, which serves as a clearinghouse for biomedical research worldwide, there are over 800 clinical studies currently underway to test gene therapy as a treatment for genetic conditions. The list includes a relatively small number of CRISPR studies as a treatment for cancers of the lung, bladder, cervix and prostate, the majority of which are in China where doctors appear to be leading the race to treat cancer by editing genes. For the past two decades China has been investing heavily in biomedicine. It is one way that China is able to compete with the West and demonstrate its technological prowess in the 21st century. Also, it is important for China to keep its vast population healthy in the 21st century. Given the somewhat ambiguous state of CRISPR technology it seems reasonable to assume that the first therapeutic applications of CRISPR will be in diseases where cells can be taken out of your body, edited, checked to ensure they are safe and then reintroduced. This suggests blood disorders such as sickle cell or thalassemia.
 
Takeaways
 
Bioethicist Henry T (Hank) Greely, professor at Stanford University, California, US, compares CRISPR to the Model T Ford, which was not the first automobile, but because of its simplicity of production, dependability and affordability it transformed society. CRISPR is not the first gene editing technology, but it is cheap and easy to use and is on the cusp of transforming biomedicine. A significant challenge is getting CRISPR tools, which are capable of performing gene edits, into the right place and to ensure they are safe. Prime editing is a smart, innovative and a substantial step forward in achieving this. Indeed, David Liu and his colleagues from the Broad Institute  have expanded the gene editing toolbox to facilitate ever-more precise editing ability and efficiency. Significantly, the overwhelming majority of human genetic disorders are due to the types of mutation that prime editing is able to correct, which stands the technique in good stead to be useful in therapies for intractable diseases. Notwithstanding, it is one thing to cut out sequences of DNA that cause genetic diseases and another to make genetic changes that are passed down to all later generations. Because CRISPR is cheap, easy-to-use, in the hands of scientists throughout the world, and already has been used to create babies with heritable traits, the technology provokes deep ethical and societal debate about what is, and what is not acceptable in efforts to prevent disease. Given that CRISPR has the potential to change the nature of humanity, it is incumbent on all citizens, not just scientists, bioethicists and regulators, to call for open and inclusive processes associated with all aspects of CRISPR.
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  • Diabetic foot ulcers (DFUs) are a result of diabetes complications and can lead to amputations and death
  • Scientists and clinicians struggle to reduce the vast and escalating burden of DFUs
  • In wealthy countries like the UK there are specialist multidisciplinary diabetic foot clinics
  • New and innovative therapies are beginning to emerge, which accelerates the rate of complete wound closure for DFUs
  • Notwithstanding new products coming to market, the best therapy is prevention
  
The vast and rapidly growing burden of diabetic foot ulcers and amniotic tissue
 
This Commentary discusses diabetic foot ulcers (DFUs) within the context of chronic wounds. Although chronic wounds tend to be an overlooked area of medicine and do not feature prominently in the popular media; NHS England, spends £5bn a year treating 2m patients with chronic wounds. The incidence rates of people affected with wounds are rising fast and some experts suggest that nearly 60% of all wounds become chronic. According to Una Adderley, a wound expert and Director of NHS England’s National Wound Care Strategy Programme, therapy in England for chronic wounds is patchy and suboptimal, “leading to non-healing or delayed healing (which) increases the number of people living with chronic wounds. Too many people are receiving care for which there is little evidence that it works and too few are receiving care for which there is strong evidence that it works”.
 
According to a 2019 report by the consulting firm MarketsandMarkets the global wound care market in 2019 is estimated to be US$20bn and projected to reach US$25bn by 2024. Market drivers include the vast and fast-growing incidence rates of hard-to-heal chronic wounds, a large proportion of which are associated with diabetes, increasing R&D spending, technological developments, the growing use of regenerative medicine in wound care, recent advances in molecular data that have contributed to genome sequencing, and the increasing use of AI in the management of wound care solutions. The chronic wound care markets of North America and Europe are expected to grow at a CAGR of ~4.5% for the next 5 years, but the highest CAGR is expected in Asia where the vast pool of patients is increasing significantly, and favourable reimbursement policies are expected to persist in the region for the next decade. 

When accompanied by an underlying condition such as diabetes, chronic wounds in the form of DFUs, are challenging to heal and have a deleterious effect on your quality of life: you experience pain, suffering, disfigurement, anxiety impaired mobility, malodour and social isolation. Because the prevalence of diabetes is increasing worldwide, DFUs have become a large, severe and growing public health issue as described in two research papers published in 2019.
 
One, published in the May 2019 edition of Diabetic Medicine, reports findings of an 18 year study of DFUs, and suggests that although current therapies in the UK result in better than previously reported survival in persons < 65 years (10 year survival is 85%), treatments fail to, “reduce recurrent incidence (of DFUs and) cumulative prevalence of all ulcers continues to increase”; from 20.7 to 33.1 per 1,000 persons between 2003 to 2017. The second paper, published in the January-March 2019 edition of the International Journal of Applied Basic Research, report sfindings of a prospective Indian study of 63 patients >18 with DFUs and shows the increase in the severity of DFUs and the consequent increase in the rate of hospital readmissions, amputations and mortality.
 
In this Commentary
 
This Commentary briefly describes the increasing prevalence of diabetes and its complications, the causes and symptoms of DFUs, which benefit from specialist multidisciplinary clinics and strategies to prevent them deteriorating to the point where the only therapy is amputation. We complete the Commentary by briefly mentioning how human amniotic membrane is being used in the current standard of care as a therapy for DFUs and describe the findings of two amniotic membrane studies. Notwithstanding these and other new product offerings coming to market, which accelerate the closure of DFUs, the most efficacious therapy for DFUs is prevention.
 
Diabetes and DFUs
 
Diabetes is a chronic disease that occurs either when your pancreas does not produce enough insulin or when your body cannot effectively use the insulin it produces. Insulin is a hormone that regulates your blood sugar level. High blood sugar levels (hyperglycaemia) is a common effect of uncontrolled diabetes and can lead to serious complications, which include blindness, kidney failure, heart attacks, stroke, diabetic foot ulcers (DFUs), and lower limb amputations. According to the World Health Organization, the global prevalence of diabetes among people >18 has risen from 4.7% in 1980 to 8.5% in 2014. Today, some 422m people worldwide have diabetes, which has increased from 108m in 1980. There is expected to be some 642m people >18 living with diabetes by 2040.
 
If you have diabetes you are prone to ulcers because your increased blood sugar levels create thick, sticky blood, which can lead to  peripheral artery disease (PAD), neuropathy (a loss of sensation due to nerve damage), and/or problems with circulation due to damage to your small blood vessels, which reduce your body’s ability to heal injuries.
 
Signs and symptoms of DFUs include numbness in your toes and a loss of feeling in your feet, painful tingling sensations, blisters, minor abrasions and cuts without pain that do not heal, skin discoloration and temperature changes  With a loss of sensation, a minor injury to your foot can go unnoticed and untreated, and quickly lead to an ulcer. If you are living with diabetes, ulceration is an ongoing challenge. Only about 66% of DFUs eventually heal without surgery. If you have had a foot ulcer you are at increased risk of further ulceration. Studies suggest that around 25% of people living with diabetes who become ulcer-free have developed new ulcers within 3 months, and 34% to 41% within 12 months. Some foot ulcers are painful, and treatment often requires that you spend a significant amount of time visiting clinics to frequently change your wound dressings. The poor prognosis of DFUs is often attributed to other complications of diabetes such as peripheral neuropathy, peripheral vascular disease and persistent hyperglycaemia. Managing diabetic foot ulcers is a major challenge for healthcare systems globally and the main cause of more than half of nontraumatic lower limb amputations: every 30 seconds in the world, a lower limb is amputated due to diabetes. Amputations have life-altering repercussions for patients and represent a significant burden for the healthcare industry as a whole. Between 0.03% and 1.5% of people with DFUs require an amputation and most amputations start with ulcers.

 
Major amputations and mortality rates
 
For major amputations, the prognosis is poor because your other limb is at risk.  Research suggests that only around 50% of patients survive for two years after major diabetes related amputations. The one-year mortality rate has been estimated at 32.7% after major amputation and 18.3% after minor amputation if you have diabetes. Five-year cumulative mortality for patients with diabetes undergoing a first major amputation has been estimated at 68% to 78.7%. Thus, if you have diabetes and a DFU you have almost a 50% chance of being dead within five years, which is significantly higher than for people with either breast (18%) or prostate (8%) cancers.

 
The UK
 
In the UK some 70,000 to 90,000 people living with diabetes have DFUs at any one time. If you have diabetes you are about 23 times more likely to experience an amputation than someone without diabetes. In England, diabetes leads to more than 9,000 lower limb amputations each year. Each week in England some 169 people undergo an amputation procedure as a result of diabetes. Analysis by the charity Diabetes UK found that between 2014 and 2017, 26,378 people had lower limb amputations linked to diabetes, which represented a 19% rise from 2010 to 2013. Diabetes affects almost 3.7m people in the UK. In 2017 NHS England launched a special transformation fund aimed at improving patients with diabetes access to specialist multidiscipline foot care clinics to help avoid amputations.

 
Specialist multidisciplinary treatment centres
 
In the video below Hisham Rashid, Consultant Vascular Surgeon at King’s College Hospital, London, describes a DFU and explains why they benefit from specialist multidisciplinary treatment centres. “DFUs have similar features to other ulcers, and often present in the toes and heal areas of the foot with the loss of skin and an exposed base with infection and necrosis. The significant difference is that a DFU usually comes with multiple pathologies, which, in addition to infection, include neuropathy and peripheral vascular disease. DFUs do not heal quickly and often require vascular surgeons working closely with radiologists, orthopaedic surgeons to correct any deformity and a microbiology unit to manage infection,” says Rashid.

 
What are diabetic foot ulcers?
 
Why does therapy for diabetic foot ulcers complications require a special center?

Rashid also explains that different therapies are used to heal DFUs. “If the patient has peripheral artery disease (ischaemia) then this has to be treated first with an angioplasty or a bypass or both to improve blood circulation into the foot. Once this is achieved, the ulcer is debrided and dressed. There are different dressings, which include negative pressure dressing, which sucks the blood into the tissues and thereby promotes healing. Sometimes skin graphs are necessary to get the tissue to heal faster. This can be done as a day surgery using local anaesthetic,” says Rashid.
 

How do diabetic foot ulcers heal?

Prevention of DFUs
 
Given the severity of DFUs and their vast and rapidly increasing burden on individuals with diabetes and healthcare systems, increasing attention is being devoted to prevention,  which involves adequate glycaemic control and modification of risk factors. While education is an obligation of healthcare professionals, it is crucial that people living with diabetes themselves increase their awareness and understanding of the condition and integrate regular feet examination and care into their daily lives.  In the video below, Roni Sharvanu Saha, Consultant in Acute Medicine, Diabetes and Endocrinology, St George’s Hospital, London, suggests that, “We’re getting better at understanding why DFUs occur, and better at examining peoples’ feet. In England, if you have diabetes you are entitled to a clinical examination of your feet at least twice a year. Checks include whether you have any minor abrasions, or whether you can distinguish hot and cold water with your feet, and  signs that you might have problems with your circulation and nervous system. Ensuring that people living with diabetes receive regular checks means that if you have reduced or poor circulation, you’re referred to the correct specialty team in order to protect you from developing DFUs. Prevention is better that cure. If we can get better at examining feet, outcomes will improve. If diabetes is not controlled complications will occur”.
 
 
New therapies and amniotic membrane
 
With the well-being of millions of people living with diabetes at stake, there is a pressing need for therapies that bring DFUs to closure as quickly as possible. The current standard of care (SOC) regimen for DFUs involves maintaining a moist wound environment, debriding nonviable tissue, relieving pressure with an offloading boot and preventing or managing wound infection. Even with a good SOC, DFUs are notoriously slow to close, creating a demand for new and innovative medicines and techniques to enhance closure. Increasingly, there are advanced therapies to facilitate healing DFUs when traditional approaches fail.
 
An example of a relatively new product to help close DFUs is human amniotic membrane.  Amniotic membrane has been used for wound healing purposes since the early 20th century, but it represents a relatively recent and promising advanced therapy to accelerate healing in DFUs. Amniotic membrane is derived from the human placental sac that supports the foetus by forming the inner lining of the amniotic cavity. Functions of amniotic membrane include the exchange of water-soluble molecules and the production of cytokines and growth factors  to facilitate the development of the foetes. The anatomic makeup of amniotic membrane dictates its functionality, and a significant characteristic is its ability to produce a wide variety of regenerative growth factors that facilitate foetal development. These growth factors, in combination with various other cytokines, have substantial potential benefits in wound healing, which include creating a structural scaffold for tissue proliferation, modulating the immune response, reducing inflammation, stimulating angiogenesis and facilitating tissue re-modelling.

 
Two studies of human amniotic membrane products used in wound healing

Two small but significant prospective cohort studies on the effectiveness of human amniotic tissue to treat DFUs were reported in the journal Wounds. One in the March 2016 edition and another in the November 2017 edition. The first is a prospective, randomized, multicentre, controlled study and the second a retrospective cohort study of 20 patients. In both studies amniotic membrane is used in combination with SOC, including debridement, well-controlled offloading, management of bacterial burden, and adequate perfusion.
 
Both studies suggested that the use of amniotic membrane is more likely to: (i) lead to complete wound closure, (ii) accelerate the rate of wound closure, and (iii) present no additional safety risks when compared to SOC alone in the treatment of DFUs. The first study demonstrated a statistically significant advantage of an amniotic membrane as compared to SOC in facilitating closure of chronic DFUs. 45% of participants achieved complete wound closure, while 0% of SOC participants alone achieved complete wound closure within 6 weeks. Further, there appears to be no increased rate of adverse events associated with the use of amniotic membrane in these wounds. The second study was a retrospective cohort study using a human amniotic membrane on 20 patients presenting with DFUs and venous leg ulcers. Patients underwent a 2-week ‘run-in’ period with good SOC; and if upon their return the ulcer had closed ≥ 30% in area, the subject was excluded from participation in the study. All wounds were effectively closed in approximately 10 weeks, DFUs in 12 weeks and venous leg ulcers in 9 weeks, and no adverse events were noted, suggesting that the therapy using human amniotic membrane is safe.
 
Discussion
 
The most significant limitation of both studies is their small sample size, which decreases the generalizability of their findings. Notwithstanding, the studies suggest that amniotic tissue products are efficacious options for DFUs when used in conjunction with the current SOC, which includes aggressive sharp debridement, adequate offloading and the application of sterile dressings. Further, amniotic membrane, like most biologic tissue products, requires significant processing and therefore its cost is relatively high: on average between US$500 to US$1,000 per application. Notwithstanding, these costs are significantly less than the average annual therapy cost of US$28,000 per patient for SOC for a DFU. And therefore, using amniotic tissue in the therapy for DFUs could result in significant savings for healthcare systems. Tissue storage as well as the time and skill required to apply amniotic membranes also represent challenges inherent to these products.
 
Takeaways
 
Millions of people are living with diabetes, which, if not managed appropriately can lead to life-changing complications. A DFU is one such complication, which often starts with a minor abrasion on your ankle or toe that you do not feel and therefore tend not to perceive to be important, until that is, it quickly escalates into a chronic wound that does not heal and eventually leads to a lower limb amputation. In most wealthy nations, health providers are aware of the dangers of DFUs and have set up multi-disciplinary diabetic foot clinics to treat and manage the condition. However, access to such clinics is patchy and the prevalence of DFUs continues to increase, and the eye-watering costs of treating and managing DFUs continue to escalate. In recent years, the therapy for DFUs has been improved by technological advances. We describe one of these: the use of amniotic tissue in conjunction with standard of care protocols. Recent research findings suggest that the use of amniotic tissue holds out the possibility not only of significant therapeutic benefits, but also of substantial cost savings for healthcare systems. Notwithstanding, perhaps the most efficacious therapy for DFUs is prevention. This means investing in effective education and awareness programs, good glycaemic control and appropriate footwear; encouraging people living with diabetes to participate in regular foot examinations and screening for peripheral neuropathy and peripheral arterial disease, and insisting that early telltale signs of foot wounds, no matter how minor, should be immediately referred to a specialist clinic.
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