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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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In our experience, the vast majority of people are looking for a gentle re-volumisation of lips that may have thinned with the passage of time.


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Wrinkles can be successfully treated with a non-surgical aesthetic procedure. The toxin injected, reversibly weakens the muscles responsible for dynamic wrinkles which are lines that appear when you animate your face.
Know more: https://www.regentstreetclinic.co.uk/botox-london/

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  • Hydrocephalus is a chronic condition that occurs when excess cerebrospinal fluid (CSF) collects in your brain’s ventricles and increases pressure inside your head
  • Failure to treat the condition can lead to morbidity and death
  • First line therapy is the surgical insertion of a ventriculoperitoneal shunt (VPS) to restore your CSF circulation
  • A significant risk with the procedure is infection
  • To reduce infection manufacturers’ impregnate standard shunts with either silver or antibiotics and market the impregnated shunts at higher prices
  • Which VPS (standard, silver or antibiotic) provides patients with the most protection from infection?
  • Which VPS is most cost effective for healthcare systems?

 

Standard, silver or antibiotic?

 

It” affects people in all walks of life and from every socioeconomic background throughout the world. “It” is as common as Down's Syndrome and more common than Spina Bifida. One out of every 1,000 babies are born with “it”. “It” affects about 1m people in the US  and “it” is the most common reason for brain surgery in children.
 
It” is Hydrocephalus; a chronic condition that occurs when excess cerebrospinal fluid (CSF) collects in your brain’s ventricles, (fluid-filled areas). CSF disperses from your ventricles around your brain and spinal cord. Too much CSF may result in an accumulation of fluid, which can cause the pressure inside of your head to increase. In a child, this causes the bones of an immature skull to expand and separate to a larger-than-normal appearance.

There are no medical therapies to effectively treat hydrocephalus. The only viable treatment is surgical. The gold standard therapy is the insertion of a ventriculoperitoneal shunt (VPS), which is a common surgical procedure to restore your CSF circulation, regulate its flow and allow you to have a normal daily life. Notwithstanding, a significant challenge is infection at the site of the surgical wound, the shunt or in the cerebrospinal fluid itself (meningitis). This effects about 15% of hydrocephalus patients and may result in further surgeries, extended hospital stays, a reduction in your quality of life and a significant hike in healthcare costs.

To reduce potential infection manufacturers’ impregnate standard shunts with either silver (silver has benefits in reducing or preventing infection) or antibiotics and market the impregnated shunts at higher prices.
 
In this Commentary

 

This Commentary describes hydrocephalus and reports findings of a clinical study designed to determine, which ventriculoperitoneal shunt (standard, silver or antibiotic) provides patients with the most protection against infection and which type of shunt is most cost effective for healthcare systems. For completeness the Commentary briefly describes the causes of hydrocephalus, its signs and symptoms and how the condition is diagnosed.  Also, the Commentary briefly describes the procedure to insert a ventriculoperitoneal shunt.

 

Hydrocephalus
 
Hydrocephalus is a condition that occurs when excess CSF collects in your brain’s ventricles. CSF cushions your brain and protects it from injury inside your skull. Also, the fluid acts as a delivery system for nutrients that your brain needs and takes away waste products. Normally, CSF flows through these ventricles to the base of the brain. The fluid then bathes your brain and spinal cord before it is reabsorbed into your blood. When this normal flow is disrupted, the build-up of fluid can create harmful pressure on your brain’s tissues, which can damage your brain.
 
There are two principal classifications for hydrocephalus: (i) communicating and (ii) non-communicating hydrocephali. Both can be subdivided into congenital (present at birth) and acquired (occurs following birth). Communicating hydrocephalus can also be subdivided into normal pressure hydrocephalus (NPH) and hydrocephalus ex-vacuo, which occurs when there is damage to your brain caused by stroke or injury. It is generally understood that congenital hydrocephalus can be caused by genetic defects, which can be passed from one or both parents to a child, but the direct hereditary links are still being investigated. Notwithstanding, experts have found a connection between a rare genetic disorder called L1 syndrome and hydrocephalus. L1 syndrome is a group of conditions that mainly affects the nervous system and occurs almost exclusively in males.
 
Most babies born with hydrocephalus or who develop hydrocephalus as infants will have a normal lifespan, and approximately 40 to 50% will have normal intelligence. Seizure disorders have been diagnosed in about 10% of children with hydrocephalus and the mortality rate for infants is approximately 5%.
 
In the video below Sanj Bassi, a Consultant Neurosurgeon at King’s College Hospital, London and a member of the London Neurosurgery Partnership, describes hydrocephalus:

 

Causes
 
Some premature babies have bleeding in the brain, which can block the flow of CSF and cause hydrocephalus. Other possible causes of the condition include: X-linked hydrocephalus, which is caused by a mutation of the X chromosome and rare genetic disorders such as Dandy Walker malformation. This  is  a congenital (present at birth) defect, which affects the back part of the brain (the cerebellum) that controls movement, behaviour and cognitive ability. The most common cause of congenital hydrocephalus is an obstruction called aqueductal stenosis, which occurs when the long, narrow passageway between your third and fourth ventricles (the aqueduct of Sylvius) is narrowed or blocked, perhaps because of infection, haemorrhage, or a tumour. Other conditions, such as neural tube defects (like spina bifida), are also associated with hydrocephalus.

Signs and symptoms
 
Early signs of hydrocephalus in infants include bulging fontanel, which is the soft membranous gaps between the cranial bones on the surface of the infant skull; a rapid increase in head circumference; eyes that are fixed downward and poor feeding. In both infants and adults, symptoms include seizures; fuzzy vision, nausea, vomiting and excessive sleepiness. 

Diagnosing hydrocephalus
 
The diagnosis of hydrocephalus may be made before birth by an antenatal ultrasound. However, in many cases, hydrocephalus does not develop until the third trimester of a pregnancy and, therefore, may not be detected on an antenatal ultrasound. Congenital hydrocephalus may be diagnosed at birth. Important considerations include antenatal and birth history of your baby and whether there is a family history of hydrocephalus. Physical examination at birth can also detect hydrocephalus. A measurement of the circumference of your baby’s head is taken and compared to a graph that can identify normal and abnormal ranges for a baby’s age. Of interest to an early diagnosis for hydrocephalus are the developmental milestones in older babies since the condition may be associated with developmental delay, which might require further medical investigations for potential underlying problems. Other tests that may be performed to confirm a diagnosis of hydrocephalus include magnetic resonance imaging (MRI) and a computed tomography (CT) scan. MRI or CT images can reveal swellings of your brain or another condition that might be causing your symptoms, such as a tumour.
 
 In the video below Bassi describes how hydrocephalus is diagnosed:
 
 

 
 
Insertion of a ventriculoperitoneal shunt 
 
Although currently there is no known way to prevent or cure hydrocephalus, with early detection and appropriate intervention, the future for many patients with the condition is promising. The  gold standard treatment option available today is the surgical insertion of a ventriculoperitoneal shunt.

A shunt consists of two thin, long flexible hollow tubes, called catheters, with a valve that keeps fluid from your brain flowing in the right direction and at the proper rate and thereby reduces brain pressure to a safe level. To install a shunt a surgeon will make a small insertion behind your ear and also drill a small borehole in your scull. One catheter is then threaded into one of your brain’s ventricles through the hole in your scull, and the other is inserted behind your ear and threaded subcutaneously down to your chest and into your abdomen where excess CSF can drain safely, and your body can reabsorb it. Your surgeon may attach a tiny pump to both catheters and place it under the skin behind your ear. The pump will automatically activate to remove fluid when the pressure in your skull increases. Shunts can be programmable (externally adjustable by a magnetic device) to activate when the fluid increases to a certain volume, or non-programmable. Most surgeons tend to choose a programmable model, despite the fact that in clinical studies both types perform comparably.
 
In the video below Sanj Bassi describes both VPS therapy and some temporary treatment options for hydrocephalus. The latter includes medicines, which decrease the production of CFS, draining fluid from the spine via a lumbar puncture and draining fluid directly from your head into a bag via an external drainage system.

 
 
 
The Lancet study
 

To determine the relative clinical benefits and cost-effectiveness of the three different ventriculoperitoneal shunts (standard, silver or antibiotic) following their de novo insertions, the UK’s National Institute for Health Research funded a large prospective multi-centre randomised controlled clinical study - The British Antibiotic and Silver Impregnated Catheters for Ventriculoperitoneal Shunts Study - (BASICS). Findings were published in the September 2019 edition of The LancetThese concluded that shunts impregnated with antibiotics significantly reduce the risk of infection and also healthcare costs compared to both standard shunts and those impregnated with silver. Conor Mallucci, Consultant Paediatric Neurosurgeon at Alder Hey Children’s Hospital, Liverpool, UK, and lead author of the study, suggests that shunts impregnated with antibiotics should be, “the first choice for patients with hydrocephalus undergoing insertion of their first ventriculoperitoneal shunt”.

 

The Study’s clinical findings
 
Patient recruitment for the study took place between 2013 and 2017. Principal investigators assessed 3,505 patients and recruited 1,605 (children and adults) from 19 specialist neurosurgical centres across the UK & Ireland. Participants presented with hydrocephalus of any aetiology [including idiopathic intracranial hypertension (IIH), which is a condition with an unknown cause or causes and associated with raised fluid pressure around the brain]. All required an insertion of their first ventriculoperitoneal shunt.
 
All shunts used in the study were CE marked medical devices intended for the condition. Participants were randomly assigned to three groups: one group of 536 received a standard shunt, another of 531 received a silver impregnated shunt, and a third group of 538 received an antibiotic impregnated shunt. The minimum patient follow-up period was six months and the maximum two years. Six per cent of evaluable patients in both the standard and silver groups presented with infections and required a shunt revision. This compared to only 2% in the antibiotic impregnated shunt group that became infected and needed revising. The difference is significant.
 
The Study’s economic findings
 
The study’s clinical significance is enhanced by the fact that it provides the first health economic analysis of different VPS therapies from a UK perspective. Findings suggest that using an antibiotic impregnated VPS rather than either a standard shunt or those impregnated with silver, would result in annual savings to NHS England of approximately £135,753 (US$166,795) per infection avoided, which amounts to annual savings of some £7m (US$8.6m).
 
The research has a further significance because, despite the high medical costs of treating hydrocephalus, the annual spend  on hydrocephalus research is relatively low. For example, the US National Institutes of Health (NIH) invests less than US$8m per year in hydrocephalus research. This means that there is a dearth of clinical studies associated with the condition and no long-term follow-up research over the lifetime of patients.
 
Although BASICS is a significant study it should be mentioned that it is restricted by the relatively low proportion of patient-reported outcomes: 32, 31 and 12 reported infections after insertion of the standard, silver and antibiotic VPS’s respectively. 
 
Takeaways
 
This Commentary describes the findings of an important, well-conceived and well-executed clinical study of hydrocephalus. Its importance is derived from the fact that there’s a dearth of large prospective multi-centre randomised controlled clinical studies on hydrocephalus. The study’s findings are significant because they unequivocally suggest that, not only are antibiotic impregnated ventriculoperitoneal shunts more likely to deliver better clinical outcomes, but using them, instead of standard or silver impregnated ventriculoperitoneal shunts, would result in a substantial reduction in healthcare costs.
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  • CanRisk is a new online gene-based health-risk evaluation algorithm for detecting breast cancer
  • It identifies people with different levels of risk of breast cancer, not just those at high risk
  • As the infotech and biotech revolutions merge expect authority in medicine to be transferred to algorithms
  • CanRisk has the potential to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnosis before symptoms present
  • Breast cancer is the most common cancer in women worldwide and is the 5th most common cause of death from cancer in women
  • Currently mammography screening, which has a sensitivity between 72% and 87%, is the gold standard for preventing and controlling breast cancer
  • For every death from breast cancer that is prevented by screening, it is estimated there will be three false-positive cases that are detected and treated unnecessarily
  • Lack of resources do not support breast cancer screening in many regions of the world where the incidence rates of the disease are rapidly increasing
  • In the near-term expect interest in the CanRisk algorithm to increase
 
 A new comprehensive gene-based breast cancer prediction device

 
A new online gene-based health-risk evaluation device called CanRisk has the potential to identify women with different levels of risk of breast cancer; not just women who are at high risk. Predicated on a comprehensive algorithm, CanRisk is one of several innovations currently in development, which include novel methods for predicting the recurrence of breast cancer, a new class of molecules that aim to halt or destroy breast cancer, and liquid biopsies, which determine the presence and recurrent risk of the disease through the detection of tumour cells in peoples’ blood.
 
Although over the past two decades there have been significant improvements in the detection and treatment of breast cancer, the disease remains the most common cancer in women worldwide, with some 1.7m new cases diagnosed each year, which account for about 25% of all cancers in women and it is the fifth most common cause of death from cancer in women, with over 0.52m deaths each year.
 
Game changer for breast cancer
 
Findings of CanRisk were reported in the January 2019 edition of Genetics in Medicine. Findings of a less comprehensive version of the device’s algorithm were published in the July 2016 edition of the same journal. Commenting on the 2019 study, Antonis Antoniou, Professor of Cancer Risk Prediction at the University of Cambridge and lead author of the two studies said: "This is the first time that anyone has combined so many elements into one breast cancer prediction tool. It could be a game changer for breast cancer and help doctors to tailor the care they provide depending on their patients' level of risk”.
 
When fully developed and approved, CanRisk will be well positioned to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnostic test to detect breast cancer early in people with diverse levels of risk. This might be expected to provide an alternative to the current gold standard population-based mammography screening and assist in making a significant dent in the vast and escalating global burden of the disease.
 
In this Commentary
 
This Commentary describes the algorithm that drives CanRisk, which benefits from the increasing availability of vast and growing amounts of genomic and other personal data and significant advances in genomic sequencing technologies. The confluence of these two phenomena facilitates and enhances the quality and speed of data analysis and drives the development of new and innovative diagnostic and prognostic cancer technologies. The fact that CanRisk is based on UK data and its algorithm is available to researchers globally, presents a potential  opportunity for medical research organizations in emerging regions of the world where the burden of breast cancer is increasing. The Commentary briefly describes the heterogeneous nature of breast cancer and highlights some of its complexities and risk factors. Originally perceived as a Western disease, breast cancer is growing rapidly in Asia and other regions of the world where it tends to be detected late and managed less effectively. Developed economies prevent and manage breast cancer through well-established population-based mammography screening programs. Because of  the lack of resources,  such screening programs are not widely available in low to middle income countries (LMIC). As the infotech and biotech revolutions merge expect authority in medicine to be transferred to Big Data algorithms such as CanRisk. This not only could provide an alternative to gold standard mammography screening, but also provide a cheap and effective device for use in developing nations where the burden of breast cancer is significant and increasing.
 
CanRisk: a world first
 
CanRisk, developed by members of the Centre for Cancer Genetic Epidemiology at the University of Cambridge, UK, takes advantage of discoveries in both cancer genomics and epidemiology and aims to become a popular device used by primary care physicians, in consultation with their patients, to effectively assess patients’ diverse levels of risk of developing breast cancer. The device is predicated on an algorithm called BOADICEA (the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm). This is the world’s first polygenic breast cancer risk model and the only one to-date, which is available to the international research community. Also, it is the first breast cancer risk model to incorporate pathology data and population-specific cancer incidences in risk calculations. The algorithm accounts for over 300 genetic risk factors, including BRCA1, [BReast CAncer gene] BRCA2PALB2CHEK2, and ATM, which are genes that have been found to impact a person’s chances of developing breast cancer. The device uses a Polygenic Risk Score (PRS) based on 313 single-nucleotide polymorphisms (SNPs), [SNPs, pronounced ‘snips’, are the most common types of genetic variation in people. Each SNP represents a difference in a single DNA building block and is called a nucleotide] which explains 20% of breast cancer polygenic variance. CanRisk also includes a residual polygenic component, which accounts for other genetic/familial effects; known lifestyle/hormonal/reproductive risk factors and mammographic density [Dense breast tissue can make it harder to evaluate mammographic results and may also be associated with an increased risk of breast cancer].

 

Authority increasingly being transferred to algorithms
 
Over the past two decades we have increasingly learnt to accept the authority of Big Data algorithms. For example, without question we expect algorithms to give us directions, tell us what movies to watch, who to date, what clothes to wear, where to go on holiday, what flight to take, what hotel to stay in and where to eat. We are  comfortable with algorithms assigning us our credit rating, limiting our overdraft and capping our payments. Furthermore, we are beginning to accept the authority of algorithms in medicine. For example, we are gradually replacing the authority of primary care doctors with algorithms that can diagnose common diseases more accurately and more cost effectively.


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In December 2018, for the first time in history, the US FDA approved an algorithm to diagnose patients without a doctor’s interpretation. The algorithm, called IDx-DR, detects diabetic retinopathy by analysing images of the back of the eye. Indeed, we are living on the cusp of history when the twin revolutions of information technology and biotechnology are merging and providing the basis for us to transfer authority in medicine to algorithms. In the next two decades, it seems reasonable to assume that it will become common practice to accept the authority of algorithms such as CanRisk, which will inform us that we are suffering from a medical condition long before we present any signs or symptoms.
 
Increasing supply of data
 
CanRisk takes advantage of the fact that genetic and other risk factor data are becoming more easily available in clinical practice through electronic health records, biometric sensors that convert biological processes into electronic information, which computers can store and analyse, cost-effective high speed, high capacity genomic sequencing technologies, and efforts such as the 100,000 Genomes ProjectA UK Government sponsored initiative completed in December 2018, which collected, stored and analysed data from the genomes and medical records of 85,000 NHS England patients affected by cancer or rare disease. Genomics Englandwhich is wholly owned by the UK’s Department of Health, was set up in 2003 to deliver the project. Because CanRisk solely is based on UK population data, its findings are likely to be more applicable to similarly developed Western populations, and less so to populations in other regions of the world. This provides a potential opportunity for international organizations interested in early breast cancer diagnosis. 
 
International sequencing projects
 
The UK’s genomes project is part of a much larger rapidly growing and dynamic global genomics market comprised of data and gene sequencing technologies. 100,000 genomes have been the goal of several other nations interested in improving their healthcare - and lowering costs  - by carrying out precision medicine based on insights from sequencing data. Currently the global genomics market is estimated to be about US$19bn and projected to reach US$41bn by 2025. The market is driven by increasing government funding, the consequent rise  in the number of genomics projects, decreasing gene sequencing costs, growing application areas of genomics and the entry and fast growth of commercial players.

China has become the world’s leader in genomic sequencing. In 2010, the Beijing Genomics Institute (BGI) in Shenzhen was understood to be hosting a higher sequencing capacity than that of the entire US. While most government projects aim to sequence 100,000 genomes, China’s sequencing program is set to sequence 1m human genomes, which include subgroups of 50,000 people, each with specific conditions such as cancer or metabolic disease. The data will also include cohorts from different regions of China, which will facilitate “the analysis of different genetic backgrounds of subpopulations”.
 

Revolution in genome sequencing
 
The first human genome project began in 1990, took 13 years and about US$1bn to complete. The last two decades have seen a revolution in genome sequencing with dramatic increases in its speed and efficiency coupled with massive reductions in cost. Genomic sequencing has proved its usefulness as a diagnostic and prognostic tool. Today it is possible to get your genome sequenced for around US$1,000 in a few days and delivered by  post from firms such as Dante Labs and 24 Genetics in Europe, and Veritas Genetics and Sure Genomics in the US.
 
Breast cancer
 
Returning to breast cancer. It is important to note that the disease is not one, but  a group of conditions that manifest themselves with maladies in the same organ. Breasts are comprised of three main parts: lobules, which produce milk; ducts, which carry milk to the nipples; and fibrous and fatty connective tissue, which hold everything together. The type of breast cancer depends on which cells in the breast mutate, but most breast cancers begin in the ducts or lobules. Some mutated cells in the breast may never spread, however, most breast cancers tend to be invasive and may present with a number of different characteristics in terms of hardness and shape, which can provide some indication of their likely progression. Breast cancer can spread outside the breast through blood and lymph vessels. Further, there are significant differences in breast cancer at the genetic level. A study published in the April 2012 edition of Nature compared the genetic makeup of breast cancer tumour samples with their other characteristics for some 2,000 women, for whom information about the tumour characteristics had been meticulously recorded; and identified at least 10 distinct sub-types of breast cancer, each with its own unique characteristics. Although the study contributed to how breast cancer is diagnosed, classified and treated, in practice certain characteristics of these tumours were already known and tested for: most notably cellular receptors for estrogen, and progesterone, which are the two most significant steroid hormones responsible for various female characteristics. Their presence or absence generally suggests the potential utility of additional medication to accompany surgery, radiotherapy and chemotherapy.

 
Despite population screening and advanced therapies breast cancer remains a killer disease
 
Let us briefly consider breast cancer in the world’s most advanced and wealthiest nation: the US. Although there have been significant improvements in the detection and treatment of breast cancer in the US; still about 1 in 8 American women will develop an invasive type of the disease over the course of her lifetime. In 2019, an estimated 268,600 new cases of invasive breast cancer are expected to be diagnosed in the US, along with 62,930 new cases of non-invasive (in situ) breast cancer. Breast cancer death rates for women in the US are higher than those for any other cancer, besides lung cancer. As of January 2019, there were more than 3.1m women with a history of breast cancer in the US. Although breast cancer death rates in the US have been decreasing over the past three decades and women under 50 have experienced larger decreases, still some 41,760 are expected to die in 2019 from the disease. About 2,670 new cases of invasive breast cancer are expected to be diagnosed in men in the US in 2019 where a man’s lifetime risk of breast cancer is about 1 in 883.
 
Breast cancer challenges in Singapore
 
There are also breast cancer challenges in wealthy non-Western developed economies such as Singapore. Over the past four decades, the incidence of breast cancer in Singapore has more than doubled: from 25 to 65 per 100,000 women. Breast cancer is not just the most common cancer for Singaporean women, accounting for one in three cancers in women, but it is also the top killer. Data reported in the country’s Cancer Registry showed that 2,105 women died of the disease between 2011 and 2015. Notwithstanding, Singapore has extensive awareness-raising programs; population-wide mammography screening; excellent, multi-disciplinary primary and long-term care and improving palliative care, which have contributed to a significant increase in the survival rates of breast cancer patients. However, a substantial proportion of Singaporean women still appear to have a patchy knowledge of aspects of the disease, which leads to comparatively low participation rates in the nation’s breast cancer screening services, and this contributes to late presentation of the disease when it is more difficult to cure and more challenging to treat.

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Breast cancer growing rapidly in Asia
 
Breast cancer was once largely confined to developed Western countries and Australasia, but it has now become the most common cancer in Asia. Although Asian data on breast cancer are patchy, an Economist Intelligence Unit report, suggests that, “since the 1990s, increases in the incidence of breast cancer in Asia, as measured by age-standardised rates (ASRs), is four to eight times that of the global average”. Indeed, as younger cohorts of Asian women age and adopt Western diets and lifestyles (particularly fertility patterns, such as later first childbirth and shorter breast feeding), breast cancer incidence rates in Asia look set to converge with the much higher ones in the West.
 Further, in LMIC breast cancer is increasing at a more rapid rate than in the West and has become a significant healthcare challenge: 50% of breast cancer cases and 58% of deaths from the disease occur in LMIC.
 The significance of early detection
 
The good news is that if caught in its early stages, breast cancer can be treated effectively, with high survival rates. The average 5-year survival rate for women with invasive breast cancer is 90%. The average 10-year survival rate is 83%. If the cancer is located only in the breast, the 5-year survival rate of women with breast cancer is 99%. In all types of the disease early detection is the cornerstone of breast cancer control.
 
 Gold standard breast cancer mammography screening
 
The current gold standard for preventing and controlling breast cancer is population-based mammography screening. This is a non-invasive process that uses an x-ray of the breast to look for disease in women who do not have symptoms. The method has reasonable sensitivity (72%–87%) that increases with age and allows for the early detection of breast cancer, which helps increase survival, especially in women between 50 and 70. Notwithstanding, mammograms are not pleasant as the breast is squashed between two metal plates and further some women may find mammograms embarrassing.
 
Success of population-based mammography screening
 
Following a landmark Swedish study that began in 1977 mammography screening has been adopted in more than 26 developed countries worldwide. Findings of the study, reported in a 1989 edition of the Journal of Epidemiology and Community Health, suggested that mortality from breast cancer dropped 31% after screening of women aged 39 to 74. More recent findings of the UK screening program published in the June 2013 edition of the British Journal of Cancer, suggested mortality rates from breast cancer were reduced by 20% in the screened group compared to the unscreened group across all age groups. A study published in 2018 in Cancer, which tracked 52,438 Swedish women aged 40-69 from 1977 to 2015, suggested that regular mammograms contributed to a 60% decrease in breast cancer death during the first 10-years of diagnosis, and a 47% reduced risk within 20-years. Research has shown that mammography has relatively little benefit for women under 50.
 
Diverging views about mammography screening
 
Despite evidence to support the benefits of population-based mammography screening, there are diverging views among healthcare professionals about the impact of several decades of high levels of screening. Some argue that traditional mammography screening stretches finite resources and is not cost-effective because the majority of people who undergo screening do not have cancer and may never go on to develop it. Others suggest that there are significant uncertainties about the magnitude of the harms from mammography screening especially associated with false positives (a test result, which wrongly indicates that breast cancer is present).

Challenges of mammography screening
 
The sensitivity of mammography is between 72% and 87%, but is higher in women over 50 and in women with fatty rather than dense breasts. Dense breast tissue can make it harder to evaluate results of a mammogram. According to the Marmot review, for every death from breast cancer that is prevented by screening, it is estimated there will be three over-diagnosed or false-positive cases that are detected and treated unnecessarily. The chance of having a false positive result after one mammogram ranges from 7% to 12%, depending on age (younger women are more likely to have false positive results). After 10 yearly mammograms, the chance of having a false positive is about 50-60%. The more mammograms a woman has, the more likely it is she will have a false positive result. This makes it difficult for doctors to weigh and communicate the benefits and risks of mammography screening programs and fuels interest in innovations such as CanRisk.
 
Takeaways
 
Mammography screening for breast cancer is not 100% accurate. Further, knowhow, trained healthcare professionals and significant resources are required to effectively implement and manage a well-organized and sustainable breast cancer screening program that targets the right population group and ensures effective coordination and quality of actions across the whole continuum of care. These attributes tend to exist only in developed wealthy countries. CanRisk, and other innovative breast cancer early diagnostic devices under development, offer the potential for cheap, rapid, reliable and exquisitely accurate diagnosis that can be easily used in primary care settings throughout the world. In time, as authority in medicine passes to algorithms, expect these new and innovative devices to replace mammography screening in wealthy countries and quickly become devices of choice in developing economies and significantly dent the vast and rapidly growing global burden of breast cancer.
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