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  • The CoVID-19 pandemic created an unprecedented global shock and killed hundreds of thousands
  • Nations responded by closing their borders, implementing stringent lockdowns and saying the  world is at war with a common invisible adversary
  • Responses to the outbreak diverged in the different regions of the world
  • Asian countries responded rapidly and effectively
  • The US and UK responded slowly and ineffectively
  • Observers suggested that the divergent responses to CoVID-19 signal a shift in power and influence from West to East
  • National responses alone are insufficient to effectively deal with the coronavirus
  • Only by embracing effective international cooperation will governments protect their citizens and safely exit the CoVID-19 crisis
 
National leaders have described the coronavirus CoVID-19 pandemic as “the enemy”. In attempts to protect their citizens, nations turned inwards and closed their borders, implemented stringent lockdown restrictions and suggested that the world is at war with a common adversary it cannot see. The speed and effectiveness of national responses to the new coronavirus crisis differed, but not even the wealthiest, most advanced nations were able to protect their citizens. The global coronavirus crisis made millions seriously ill, killed hundreds of thousands, destroyed industries, bankrupted thousands of companies, caused economies to nose-dive and threw societies into turmoil. Only by avoiding nationalist policies and embracing effective international cooperation will governments protect their citizens and safely exit the CoVID-19 crisis.
 
Viruses are notoriously difficult to treat and cure

CoVID-19 has rapidly spread throughout the world with a scale and a severity not witnessed since the devastating Spanish Flu in 1918. So-called because Spain was neutral during WW1 and was one of the few countries where journalists were free to report on the outbreak. In an era before antibiotics and vaccines, the Spanish Flu claimed the lives of nearly 0.68m Americans, 0.25m Britons and between 50 to 100m people worldwide. Adjusting for population growth, that is equivalent to between 200 and 425m today.
 
At the time of writing - June 2020 - neither an adequate therapy nor a vaccine has been developed and CoVID-19 remains prevalent in populations throughout the world. Even with today’s scientific advances, infectious diseases are notoriously challenging to either treat or cure: an Ebola vaccine was more than two decades in the making; despite the first cases of the human immunodeficiency virus (HIV) presenting in 1983, we still do not have a therapeutic preventative vaccine for the disease; nor do we have a vaccine for severe acute respiratory syndrome (SARS), a killer coronavirus, which also originated in China and was unknown before its outbreak in 2002.
 
Recovery will neither be straightforward nor quick

Notwithstanding, governments have lifted lockdown restrictions in order to get their economies working again. V, U, W and L are letters of the alphabet used to describe the shape of a recovery following the economic crisis caused by CoVID-19. Stringent lockdowns forced economies into unprecedented cold storage, and no one knows what shape a recovery will take since professional forecasters have never encountered anything like the sheer magnitude of the current economic crisis.
 
The Bank of England’s Monetary Policy Report published in May 2020, warned that the coronavirus has caused the worst economic crisis in 300 years. So, emerging from this is unlikely to be either straightforward or quick. National responses to the coronavirus outbreak were mixed. Although it is too soon to know the longer-term effects of the virus, China, Singapore and South Korea are among the countries that responded early and effectively, while the US and UK, together with other Western European countries, responded late and less effectively. As of June 1, China, with a population of 1.4bn, had 83,017 confirmed cases and 4,634 deaths; South Korea with a population of 52m, had 11,537 cases and 270 deaths,  and Singapore with a population of 5.7m, had 34,884 confirmed cases and 23 deaths.
 
In this Commentary

This Commentary describes the divergent national responses to the CoVID-19 pandemic; in particular that of China, Singapore, South Korea, the US and UK. China’s more effective response might have been because Beijing benefitted from the lessons it learned after the SARS epidemic in 2002. Governments also differed in their approaches to lifting restrictions. China’s approach was slower than that of the US and more determined to make some of the unexpected benefits thrown up by the crisis permanent. Some observers perceive such variances as a difference between liberal and illiberal nations. Others view the divergences as a shift in power and influence from West to East. We suggest that the divergent responses and outcomes are a product of the capacity and legal authority of different states and reveal different mindsets and competing views about solutions. We also contend that the devastation created by the pandemic will only be resolved with effective international cooperation. However, it is difficult to see this happening in the near term as the pandemic has become a theatre for a wider political disagreement between the US and China, in which other nation states are being forced to take sides.
 
Asian nations won the battle against CoVID-19

China, Singapore and South Korea leveraged the collectivists mindset of their citizens, their centralised authority and digital infrastructures to quickly implement the gold standard “test-trace-and-isolate” strategy to reduce and control the virus. The reason for such prompt actions and the subsequent relatively low number of cases and deaths in these Asian countries is described by  Byung-Chul Han, a South Korean-born German Professor of Philosophy at the Universität der Künste in Berlin. In an article published on May 22, in the Spanish newspaper El Pais, Han suggests that Asian nations won the battle against the CoVID-19 outbreak because their citizens, “have a collectivists mindset, which comes from their cultural tradition of Confucianism. Asians are less rebellious and more obedient than people in the West. They trust the state more. Daily life is much more organised, and Asians are strongly committed to digital surveillance. The epidemics in Asia are fought not only by virologists and epidemiologists but also by computer scientists and big data specialists”.
 
Confucian mindset rather than authoritarianism

Given Iran’s response to CoVID-19 has been less effective, it seems reasonable to suggest that the Confucian mindset, rather than authoritarianism, appears to provide at least a short-term advantage. In early March, at the Shia Muslim Masumeh shrine in the holy city of Qom, pilgrims licked and kissed its gates. Qom experienced Iran’s first outbreak of the coronavirus and became the country's worst-hit city. Shortly afterwards the government closed all major Shia shrines across the Islamic republic and reopened them again in late May. As of June 1, Iran with a population of 81m, had confirmed 154,000 cases of CoVID-19 and 7,878 deaths.  

 

Smaller democracies appear to cope well

Small democracies such as New Zealand and Greece seem to raise some doubt about Han’s thesis because they too have effectively responded to the outbreak. As of June 1, New Zealand, with a population of 5m, had confirmed 1,154 cases and 22 deaths and Greece, with a population of 11m, had a total of 2,917 cases and 175 deaths.
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Notwithstanding, New Zealand’s lockdown only occurred after significant pressure was applied by civil society that suggested the government needed to change track. Both New Zealand and Greece have concentrations of political power, access for vested interest, a lack of public participation in politics and weak media. Further, Greece had no choice but to act swiftly and robustly to the coronavirus outbreak because the country has been in an almost constant state of austerity management since 2008, which has significantly reduced its resources to tackle an outbreak of this magnitude. In both countries the effect of stringent nation-wide lockdowns could further weaken already fragile civil societies, media and parliamentary systems by concentrating power in political leaders, curtailing civil liberties, adjourning parliaments and restricting the normal operations of the media.
 
The Swedish exception

By contrast to all other developed countries, Sweden exercised a radical laissez faire no-lockdown approach to the CoVID-19 outbreak. The architect of this was the Swedish State Epidemiologist Anders Tegnell, who argued that, “nothing [to do with lockdowns] has any scientific basis”, particularly decisions to close schools because there is no evidence that children are a major cause of coronavirus transmission. In Sweden, primary and secondary schools, day care centres, restaurants, bars, cafés, cinemas, theatres, shops and places of work all remained open as normal, with Swedish health authorities relying on voluntary social distancing and people choosing to work from home. Schools for over-16s and universities were closed, and gatherings of more than 50 people were banned. As of June 1, as the death toll has fallen substantially in other European countries, 4,403 people had died from CoVID-19 in Sweden, a country with a population of 10m. Its neighbours, Denmark, Finland and Norway - each with populations of about 5m - have recorded death tolls of 574, 320 and 236, respectively.
 
Not only does Sweden’s no-lockdown approach enjoy significant support among its citizens, it also has the backing of Jonathan Sumption, an historian and a former Justice of the Supreme Court of the UK. Writing in The Times of London Sumption suggests that, “The lesson of CoVID-19 is brutally simply. . . . . . Free people make mistakes and willingly take risks. If we hold politicians responsible for everything that goes wrong, they will take away our liberty so that nothing can go wrong. They will do this not for our protection against risk, but for their own protection against criticism”.
 
At the beginning of June, Tegnell conceded that Sweden should have imposed more restrictions to avoid having such a high death toll. 
 
The US and UK mindset

Compared to the responses described above, the US and UK were slow to implement testing, late to acquire essential equipment, gave confusing public health messages and delayed introducing stringent lockdowns and social distancing. For example, in mid-March, when borders were being closed and mass quarantines enforced across Europe, the US government was failing to establish a clear and focused response to the outbreak. By the time the US President declared a national emergency, several states had introduced lockdowns, universities had shifted to online learning and churches had begun to close. At the same time, schools in England largely remained open and the UK government was pursuing a strategy of exposing its population to the coronavirus in the expectation that citizens would develop a “herd immunity”. As of May 31, the US with a population of 328m, had confirmed 1.83m cases and 106,000 deaths, and the UK with a population of 67m, had 276,000 cases and 39,045 deaths.
 
Signs of danger ignored

Neither the US nor the UK government appeared to have been influenced by well publicised signals of pending dangers, which included: (i) CoVID-19 being a highly contagious ‘novel’ coronavirus without either a therapy or a cure, (ii) around January 23, after the discovery of the outbreak and before the lockdown of Wuhan, the city in China where the virus originated, some 5m people left the city and were potential super spreaders, (iii) by February 4, the coronavirus had spread to 24 countries, (iv) also on February 4, China had opened the first of two mega hospitals in Wuhan, both built from scratch in a couple of weeks specifically to cater for patients affected by the fast-spreading coronavirus. Together, the two hospitals had a 2,600-bed capacity and were staffed with over 3,000 health professionals.
 
Mixed messages

Inside the US messages about CoVID-19 were mixed. Main media outlets reported the acceleration of the virus internationally and state governors independently started to take emergency actions. Notwithstanding, on February 26, at a White House briefing, President Trump urged Americans to take the same precautions for coronavirus as they would for normal flu, and US Health and Human Services Secretary Alex Azar advised that the coronavirus only posed a low risk to the American public. On February 25, the Centers for Disease Control and Prevention (CDC) confirmed that there were 60 CoVID-19 cases in the US and warned Americans that “it's a question of when, not if” the virus, which had killed thousands, would spread within the US.
 
Convinced of a rapid V-shaped recovery

In late February, in tune with White House messaging, many US business leaders from sectors not seriously affected by CoVID-19, were convinced that the coronavirus outbreak would be a relatively short-lived regional issue, concentrated in China with some limited transmission through supply chains to other parts of Asia, Europe and the US. They believed the outbreak would only have a temporary impact on global GDP and trade and weigh modestly on US business activities in Q1 2020. Although it might be difficult to contemplate now, in late February some US business leaders were suggesting that their companies and the American economy would bounce back in Q2 2020 after a modest V-shaped dip.
 
Such optimism might have been influenced by the SARS outbreak, which also originated from China, spread to 37 countries, infected more than 8,000 people and killed about 800. The impact SARS was to reduce China’s GDP growth by about 1% and it only had a limited effect on world GDP and trade. Although the SARS epidemic did not register much with US business leaders, it prompted Beijing to overhaul its healthcare system and prepare China for another potential virus epidemic. After SARS China invested in systems for disease surveillance and reporting, as well as epidemic prevention and control. Centres for disease control were built across the country and public insurance programmes were expanded to provide affordable care for the rural population. Arguably, this strengthened China’s preparedness for its response to CoVID-19.
 
By contrast, the US and UK did not appear to perceive a threat of a pandemic as serious. In May 2018, President Trump disbanded the US Global Health Security and Biodefense unit responsible for pandemic preparedness, which was established in 2015 by Barack Obama’s National Security Advisor. The UK did something similar. According to Professor Sir Ian Boyd, the UK’s Chief Scientific Adviser between 2012 and 2019, the nation’s biological security strategy, which Boyd partly wrote and published in 2018 to address the threat of a pandemic, was not properly implemented because of a lack of resources.
 
Commercial impact

As a consequence, on March 11, when the World Health Organization (WHO) declared the coronavirus CoVID-19 as a pandemic the US and UK were unprepared. The WHO pointed to Europe as the “epicentre” of the outbreak and, by the end of March, the outbreak had a significant effect on most industries in the developed world. Transportation, manufacturing and wholesale trade sectors were substantially affected by disrupted supply chains and travel restrictions. In many countries retail and hospitality sectors experienced sharp falls in demand and were closed. However, sectors differed in their ability to respond flexibly to supply disruptions and falls in demand. For example, business as usual continued for many professional services if their employees were able to work from home.
 
Impact on healthcare

The impact on healthcare was mixed. Demands on hospitals increased significantly as they shifted their resources and efforts to treating CoVID-19 patients. Policy responses were aimed at managing the increased capacity demands on hospitals by ‘flattening the curve’ of infection. The impact of the coronavirus outbreak on the MedTech sector was bifurcated. The vast and increased demand for critical care devices and personal protective equipment (PPE) significantly advantaged some manufacturers, while others, particularly orthopaedics, were disadvantaged as hospitals dedicated capacity to treating infected coronavirus patients and deferred non urgent surgeries. Sector forecasts suggested a reduction in medical device use in the Q1 and Q2, and a moderate recovery in the second half of 2020. But this hinged on successful efforts to halt the virus' spread. The global economic slowdown and the shift in healthcare resources toward fighting CoVID-19 dented MedTech sales and triggered a hit to their stock valuations.

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CoVID-19 weakens the ‘Western brand

Some commentators perceive the CoVID-19 crisis as a test of the competing claims of liberal and illiberal states to better manage significant social and economic shocks. According to Stephen Walt, Professor of international affairs at Harvard University's John F. Kennedy School of Government, the slow and diffident responses to the outbreak from US, UK and some other European governments could potentially weaken the dominance of the Western brand, and “accelerate the shift of power and influence from west to east”.
China building on the response to SARS

Despite China’s endeavours to be ready for a pandemic after the SARS outbreak, CoVID-19 exposed cracks in China’s preparedness, which Beijing swiftly sought to fix. This included enhancing the nation’s healthcare system’s cost management by further centralizing procurement, purchasing drugs in bulk and implementing a two-invoice policy to eliminate layers of bureaucracy in the nation’s distribution channels. Beijing also encouraged product innovation from local and foreign companies by fast-tracking approvals for medicines and medical devices. And, like many other countries, China increased its digitalization strategies by accelerating the integration of big data, artificial intelligence, telemedicine, online pharma retail and more. The coronavirus impact in China and elsewhere in the world prompted a massive shift in patients and doctors using Internet-based options for diagnosis and treatment. This shift to digital necessitated by the coronavirus outbreak is well positioned to become the ‘new normal’, which could help healthcare providers, hospitals, health systems and clinicians optimise their use of resources.
 
G7’s response to CoVID-19

Between March and April, G7 nations (Canada, France, Germany, Italy, Japan, the UK and the US) injected US$2.5tn of new money into financial markets through quantitative easing and liquidity programmes to help nations recover from the economic crisis caused by CoVID-19. Notwithstanding, only about US$1 in US$10 lent by British banks went to non-financial service companies. Most of the new credit supported financial trading. A similar pattern occurred in other G7 countries. As these nations navigate their way out of the crisis, there is little evidence of any industrial strategy being linked the CoVID-19 shock. For economies to recover, they will need financial markets to do something similar to what they did following WWII when banks worked closely with governments and used the increased liquidity for committed long-term financing that created jobs, enhanced productivity and stimulated innovation.

Interestingly, on May 30, President Trump said he will postpone the G7 meeting planned for August at the White House. He called the current group’s format , “very outdated”, suggested that it does not properly represent "what's going on in the world" and said its membership should include Russia, Australia, South Korea and India.
 
The pandemic is not over

Compared with G7 nations, China has opted for a more strategic approach to its recovery from the pandemic. Beijing has put the prevention and control of the CoVID-19 crisis as the keystone of a national strategy. Significantly, Premier Li Keqiang, did not use his annual report to China’s National Legislature on May 29 to claim victory over CoVID-19. Instead he stressed that, “The pandemic is not over” and outlined Beijing’s plans for continued vigilance against the coronavirus, which, Li said, “is a core thread in determining everything from macro-level strategy to micro-level policy for the foreseeable future in China”. Beijing committed a ¥1tn (US$138bn) rise in its fiscal deficit and ¥1tn of special governments bonds to its CoVID-19 recovery strategy, which is dedicated to: (i) securing jobs, (ii) maintaining and increasing people’s livelihoods, (iii) developing businesses, (iv) securing food and energy, (v) developing and maintaining stable industrial and supply chains, and (vi) reducing government red tape.
 
CoVID-19 strengthens the US$

Beijing’s coronavirus recovery strategy does not guarantee that China will evolve stronger than the US from the crisis. Indeed, the US may surface in better shape than analysts suggest. This is because of the strength of the US$, which remains the world’s reserve currency and is perceived as a relatively safe asset in times of crisis. The CoVID-19 crisis reinforced the US$’s strength and therefore it seems reasonable to suggest that the coronavirus outbreak may not do as much damage to the US economy as some observers suggest. Walt’s prediction, mentioned above, that CoVID-19 will accelerate the shift of power and influence from West to East will depend on whether: (i) the US successfully restarts its economy and avoids a resurgence of the coronavirus, and (ii) the US maintains its ‘America first’ approach to the pandemic or changes to its natural global leadership position, which it assumed after WWII.
 
US suspends payment to the WHO

On March 26, after a virtual G20 summit, there were encouraging signs when a joint statement said that, “Combatting this pandemic calls for a transparent, robust, coordinated, large-scale and science-based global response in the spirit of solidarity. We are strongly committed to presenting a united front against this common threat”. Despite this pledge to cooperate, little cooperation followed, and the pandemic became a theatre for a wider disagreement between the US and China. On April 20, President Trump suspended US payments to the WHO in protest at what he regards as the body’s China-centric approach, reflected, by what he suggests is the WHO’s failure to challenge China sufficiently over the origins of the CoVID-19 outbreak. On May 29, Trump said, “We will be today terminating our relationship with the World Health Organization and redirecting those funds to other worldwide and deserving urgent global public health needs”. In the near-term, before the US presidential election in November, it does not look that the US will change its ‘America first’ strategy.
 
Takeaways

CoVID-19 has created an unprecedented global crisis. Governments throughout the world responded to the crisis by closing their boarders, implementing stringent lockdown restrictions and used wartime rhetoric to rally their citizens. While this temporarily lowered the rate of infection it is not a permanent solution. Two significant takeaways from the coronavirus crisis are: (i) not even the riches and most technologically advanced nations with state-of-the-art healthcare systems were able to protect their populations and (ii) only by turning outwards and embracing effective international cooperation will nations protect their citizens and safely exit the CoVID-19 crisis.

#coronavirus #coVID-19 #pandemic #coVID-19outbreak #lockdown
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The HealthPad team extends Ramadan Mubarak to all our friends, family members and colleagues who are participating in the Holy Month of Ramadan. We very much would like to share with you a short video by DrSufyan Hussain, Consultant Physician in Diabetes and Endocrinology at Guy's and St Thomas' NHS Foundation Trust, London, UK, which we made to specifically help those who are living with diabetes and fasting.
During these unprecedented challenging times caused by the coronavirus CoVID-19 pandemic, we trust that you all stay safe and well and let the spirit of Ramadan remain in your hearts and light up your souls from within.
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The HealthPad team extends its sincerest best wishes to you, your families and loved ones during these unprecedented times caused by the coronavirus CoVID-19 pandemic. We trust that you all stay safe and well.

To everyone working long and stressful hours on the frontline of healthcare; thank you for the sacrifices you’re making every day to help others in their moments of need. Your dedication, commitment and courage have our deepest gratitude and admiration.

Also, our heartfelt thanks go to all key workers who are unselfishly providing essential services, which are helping all of us through this coronavirus outbreak. Your resolution and mettle make a huge difference to our daily lives and we hold you in the highest esteem.

 

#coronavirus #CoVID-19  #frontlinehealthcareworkers #keyworkers #healthcare

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  • The coronavirus CoVID-19 has created the greatest health-cum-economic-cum-societal crisis in history and put unprecedented pressure on overstretched and unprepared healthcare systems
  • Before the coronavirus outbreak, primary care in England already was in crisis, fuelled by an aging population, a large and increasing demand for its services and a shrinking supply of health professionals
  • In 2019, before the outbreak, 75% of primary care doctors (GPs) across 540 clinics in England were over the age of 55 and nearing retirement and a large percentage of newly trained GPs were seeking employment abroad
  • Patients who could not get GP appointments used A&E departments as convenient drop-in clinics for minor ailments, which significantly increased healthcare costs and burden
  • For decades successive UK governments have tried in vain to transform the nation’s primary care services predicated upon face-to-face patient-doctor consultations
  • Several well-funded long-term national plans advocated increased digitization of some routine primary care services
  • But before the coronavirus outbreak only 1% of all primary care consultations were online
  • What these national plans could not achieve in decades appears to have been achieved in days by the UK’s NHS’s response to the coronavirus outbreak
  • Today, millions of patients in England are having face-to-face appointments with their GPs replaced by telephone or video consultations
  • Could CoVID-19 transform the UK’s traditional primary care model?

 

Introduction
 
The UK’s National Health Service’s (NHS) response to the coronavirus CoVID-19 outbreak might improve the nation’s crisis ridden primary care service. This became evident in March 2020, when the UK government ordered all citizens except key workers to stay at home. At the same time, NHS England announced its ‘battle plan’ for CoVID-19, which recommended that England’s 7,000 primary care clinics start conducting as many remote consultations as soon as possible.  In a matter of days, millions of patients had face-to-face appointments with their GP replaced by telephone or video consultations. If this shift to online consultations becomes permanent then the NHS’s response to the coronavirus would have achieved in days what well-funded national healthcare plans, such as the NHS Digital First Primary Care drive, could not achieve in decades.
 
Future healthcare is digital
 
For years, the benefits of online doctor-patient consultations have been advocated by  Devi Shetty, a world-renowned heart surgeon and  founder and chairman of Narayana Health, one India’s largest hospital groups.  According to Shetty, “The next biggest thing in healthcare is not going to be a ‘magic’ pill, a faster scanner or a new operation but information technology (IT). IT will dramatically change the way a health professional will interact with a patient. Every step of patient care will be informed by a protocol embedded in a smartphone. This will make healthcare safer for the patient and remove a lot of traditional dace-to-face healthcare activities and shift healthcare away from the clinic and into the home. Doctors and patients don't need to be together; they could be in their respective homes and effective consultations could take place online.” (see video below)
 
The next ‘big thing’ in healthcare
 
The coronavirus CoVID-19
 
In December 2019, initial reports of a new coronavirus - CoVID-19 - emerged  when patients from Wuhan, the sprawling capital city of China’s Hubei province, which has a population of some 11m, presented with pneumonia of unknown origin. By December 2019 the virus had spread to other countries and on 11th March 2020, the World Health Organization characterised the outbreak as a pandemic. CoVID-19 is an illness caused by a member of the coronavirus family that has never been encountered before but is believed to come from animals.There have been other coronaviruses. For example, severe acute respiratory syndrome (Sars) and Middle Eastern respiratory syndrome (Mers) are both caused by coronaviruses that came from animals. In 2002, Sars spread virtually unchecked to 37 countries, causing global panic, infecting more than 8,000 people and killing about 800, but it soon ran itself out. Mers first emerged in 2012, cases of which have been occurring sporadically since. Mers appears to be less easily passed from human to human, but has greater lethality, killing 35% of about 2,500 people who were infected. CoVID-19 is different to Sars and Mers in that the spectrum of disease is broader, with around 80% of cases leading to a mild infection. There may also be many people carrying the disease and displaying no symptoms, making it even harder to control. CoVID-19 affects your lungs and airways and can cause pneumonia. So, people with an  inflammatory lung disease that causes obstructed airflow from the lungs, such as asthma and chronic obstructive pulmonary disease (COPD), are particularly vulnerable; as are people with weak immune systems, which make them susceptible to infections that might be more severe or harder to treat. In January 2020, China’s national health commission confirmed human-to-human transmission of CoVID-19, and there have been such transmissions in countries throughout the world. Those who have fallen ill are reported to suffer a general feeling of being unwell, fever, dry cough, tiredness, breathing difficulties and a loss of taste and smell. In roughly 14% of cases the virus causes severe disease, including pneumonia and shortness of breath. In about 5% of patients it is critical, leading to respiratory failure, septic shock and multiple organ failure. As this is viral pneumonia, antibiotics are of no use. The antiviral drugs we have against flu will not work. Recovery depends on the strength of your immune system. Many of those who have died were already in poor health. Initially, scientists were challenged to accurately assess how dangerous CoVID-19 was because there were inadequate data. A challenge  to  collecting data was because of a shortage of tests and also because people who had contracted the coronavirus were emitting, or “shedding,” infectious viruses early in the progression of the illness; sometimes before they develop symptoms.

The 1918 Spanish Influenza 
remains the most devastating virus in modern history. The disease swept around the globe and is estimated to have caused between 50m and 100m deaths. A cousin of the same virus was also behind the 2009 swine flu outbreak, thought to have killed as many as 0.58m. Other major viral outbreaks include the Asian flu in 1957, which led to roughly 2m deaths and the Hong Kong flu, which killed 1m people 11 years later. 

 
In this Commentary
 
This Commentary is produced by HealthPad, which is an online health solutions company. (see below). We begin the Commentary by briefly describing the underlying reasons for the UK’s primary care crisis, which include: (i)  the changing and aging population and the consequent increased demand for healthcare, (ii) the shrinking supply of health professionals, and (iii) failing national initiatives to improve the provision of primary care. We then draw attention to some well funded national plans, whose intentions have been to harness the power of information and digital strategies to reform and improve primary care services in England. We also cite research, which suggests that these plans have failed. The Commentary briefly describes a number of innovative online healthcare solution companies, (HealthPad is one).  The majority of these are private initiatives, which have taken advantage of the UK’s high smartphone penetration rates and advanced wireless networks to enter the UK’s healthcare market with an intention to transform the sector. Notwithstanding, to-date the overall impact of these companies has been marginal, due in part, to the general resistance of private enterprises playing a significant role in England’s public NHS, which offers free healthcare to all citizens at the point of care. However, they represent a nascent UK online healthcare solutions market, which is well positioned to benefit from the nation’s response to the coronavirus outbreak, which has forced more primary care services to be delivered online. To increase their footprint these companies, which are largely driven by technology, will need to become more strategic and consolidate. And this will take time. We conclude the Commentary by looking to China and WeDoctor to understand the potential that online services can make to the delivery of healthcare in England. WeDoctor is a Chinese mobile app launched in 2010 to help patients book doctor appointments. Over the past decade it has added more functions to help unclog China’s fragmented and bureaucratic healthcare system and has become a US$5.5bn healthcare company, which connects some 210m registered users with 360,000 doctors.
 
UK’s primary care crisis
 
There are three drivers to the UK’s primary care crisis: (i) the changing and aging population, which increases the demand for healthcare, (ii)  the shrinking supply of healthcare professionals to a point where GP workloads are becoming unsafe, and (iii) failing national initiatives to improve the provision of primary care. Let us briefly describe these.
 
Changing and aging population
 
The UK’s population is changing and aging, which is fuelled by improvements in life expectancy and a decrease in fertility. According to the UK’s Office of National Statistics, in 2016, there were 12m UK residents aged 65 years and over, representing 18% of the total population. 25 years before, in 1991, there were 9m, accounting for 16% of the population. By 2040, it is projected that there will be an additional 8m people aged 65 years and over in the UK: a population roughly the size of present-day London, which will account for 25% of the total population.
 
A report by Deloitte,  a consultancy, suggests that as people age so their propensity for illness increases and more than a quarter of the UK’s population of some 66m have long-term chronic illnesses. This places a significant extra burden on the nation’s overstretched primary care services by utilizing about half of all GP appointments. Deloitte’s analysis is supported by a British Medical Association’s 2019 GP Patient Survey, which found that GP clinics are now caring for 0.72m more patients than they were in 2018. Findings of a 2016 report by the UK’s Royal College of General Practitioners (RGCP), suggest that GPs see 1.3m patients a day and do more than 370m consultations annually: 60m more than in 2010. A research study on GP productivity carried out by the King’s Fund and also published in 2016, suggested that between 2010 and 2015 the total number of telephone consultations increased by 15%, but still only accounted for 1% of all patient-doctor consultations.
 
Shrinking supply of GPs
 
As the UK’s population has grown and aged and the consequent demand for healthcare has increased, so there has been a sustained fall in the number of GPs. This  dynamic is described in a Nuffield Trust report published in May 2019, which confirms the findings of a joint report from the Institute of Fiscal Studies and the Health Foundation for the NHS Confederation, which concluded that, “The fall in GPs per person reflects insufficient numbers previously being trained and going on to join NHS England, failure to recruit enough from abroad and more GPs leaving for early retirement”. As to the future, a  2019 report by three leading think tanks - the Nuffield Trust, the Health Foundation and the King's Fund - predicts that GP shortages in England will almost triple to 7,000 by 2024. According to NHS Statistics, Facts and Figures, currently there are just over 42,000 GPs working in England, down by nearly 1,500 since 2016.
 
Failure to stop or slow these trends means today, primary care services in England struggle with staff shortages and a rising demand for care. A 2019 Pulse Magazine survey found that  GPs in England are seeing more patients than is safe. A probe undertaken by The Times in 2019 suggested that the  national shortage of GPs has left some surgeries with one permanent doctor caring for as many as 11,000 patients and one in 10 GPs are seeing up to 60 patients a day, double the number considered safe.
 
GPs across the UK work an average 11-hour day. In that time, they typically see patients for 8 hours and spend the other 3 on administrative tasks such as checking test results and reading letters sent by hospitals.  A 2019 British Medical Association survey found that more than 80% of GPs said the pressure to attend to multiple tasks at once meant they were unable to guarantee safe care, while 91% said excessive workload was the main reason the NHS was struggling to recruit enough staff. The situation has resulted in patients having to wait longer - up to three weeks - for a GP consultation. It seems reasonable to suggest that GPs with too many patients and using traditional face-to-face delivery methods will fail in their duty of care, which obliges them to inform patients about their health and reach shared clinical decisions about treatments. This requires that patients understand their condition/s and are well informed. In many cases, a 10-minute  face-to-face GP consultation might not be the best way to achieve this.
 
Failing national initiatives to improve primary care
 
Subsequent UK governments have struggled to reduce the primary care crisis with well funded national plans. In 2019, the British Medical Journal published findings of a survey to report UK GPs’ views and experience of national healthcare initiatives introduced in England to address the workforce crisis in general practice. The survey was conducted in the same region as a similar survey undertaken in 2014. This allows for a comparative analysis to see how GPs’ views have changed over time. Findings confirm that primary care in England remains in crisis and suggest that numerous national initiatives to improve general practice are perceived by GPs as, “reactive in approach”. To reduce the primary care crisis, respondents suggested, “more GPs and better education of the public". 
 
The UK’s NHS
 
Healthcare in the UK is mainly provided by the National Health Service (NHS), which is a vast public institution funded largely from general taxation to the tune of some £134bn (US$161bn) a year. Created in 1948, the NHS  provides free health services at the point of care for everyone living in the UK and has become the largest single payer health system in the world, and the biggest employer in the UK with 1.2m full time equivalent (FTE) workers, which is the fifth-largest workforce in the world. NHS England is a vast bureaucratic and fragmented organisation, which has proven difficult to change. Private provision of NHS services has always been controversial, even though some services, such as dentistry, optical care and pharmacy, have been provided by the private sector to the NHS for decades and most GP practices are private partnerships. It is challenging to determine how much the NHS spends each year on the private sector because central bodies do not hold detailed information on individual contracts with service providers, especially where these contracts may cover relatively small amounts of activity and spending. Notwithstanding, estimates suggest the share of the NHS’s total revenue budget that is spent on private providers is about 7.3%. 

National plans to improve the NHS
 
The planning and authorising of NHS services is the responsibility of regional Clinical Commissioning Groups (CCGs). Although CCGs are constantly changing because of mergers, as of 2019, there were 191 CCGs in England supporting about 7,000 primary care clinics, some 42,000 GPs and about 15,800 FTE nurses who work in GP clinics, and 1,257 hospitals, which include NHS Trust-managed hospitals and private hospitals that provide services to the NHS. In total, the NHS employs around 150,000 doctors  and over 320,000 nurses and midwives.
 
Successive UK governments have been aware of the impact of technological advances, changing healthcare needs and societal developments on healthcare and have introduced a succession of well-funded national plans to change and improve the NHS. For example, in June 2018, the UK’s Prime Minister announced a new five-year funding settlement for the NHS that amounted to an extra £20.5bn (US$25.2bn) between 2019 and 2024, which represents a 3.4% real average annual increase.
 
NHS long term plan to transform primary care
 
To unlock the funding, national bodies were asked to develop a long-term plan to help the NHS cut costs and improve services. The suggested plan articulated the need to integrate care in order to meet the needs of a changing population and was in line with the Forward View, a planning document published in 2014 and the General practice forward view,which was first published in 2016 and updated in subsequent years. The long-term plan committed the government to an extra £2.4bn (US$3bn) a year to speed up the transformation of primary care and suggested GP clinics join together to form networks typically covering 30,000 to 50,000 patients and provide them with multidisciplinary integrated care. The plan also suggested ‘significant changes’ in the existing performance management and payment of NHS GPs [the Quality and Outcomes Framework (QOF)] in order to encourage more personalised care.
 
NHS long term plans and private online healthcare solution companies have delivered little change
 
Three of five principal objectives of the latest NHS long term plan are to: (i) “give people more control over their own health and the care they receive”;  (ii) “increase the contribution to tackling some of the most significant causes of ill health, including new action to help people stop smoking, overcome drinking problems and avoid Type 2 diabetes”, and (iii) “provide more convenient access to services and health information for patients”.

The plan emphasises the importance of developing digital services, and recommends that within five years, all patients should be able to access GP consultations via a telephone or online. This goal is supported by NHS Digital, which is the national information and technology partner to the UK’s health and social care system. Its mission is to harness the power of information and technology to improve healthcare. Over the past decade there has been an increasing number of innovative online private  healthcare solutions companies entering the market. (see below). Notwithstanding, these and the NHS’s well-funded national plans, have failed to dent the primary care crisis by slowing the vast and escalating demand for healthcare and reversing the shrinking supply of healthcare professionals. So, for the past two decades at least, the NHS has tended to operate on the cusp of a crisis.
 
The death of distance
 
According to Deloitte, the UK has more than 90% smartphone penetration. The main driver of high smartphone adoption rates is the take-up among older age groups. By 2023 smartphone ownership among 55-to-75-year-olds will reach 85% in the UK, and the difference in smartphone penetration by age will disappear. Further, the UK’s smartphone market has seen a greater variety of choice of models and the introduction of faster and more reliable wireless networks. This has benefited the online private healthcare solution companies, which have entered the UK market to provide varying degrees of qualified online healthcare information, consultations, networking opportunities, triage and Q&A. According to Shetty, “A doctor only needs to touch a patient if s/he is going to operate on that patient. If a doctor doesn’t need to operate, a doctor-patient consultation can take place remotely. For a patient-doctor communication distance doesn’t matter.” (see video below)
 

 A doctor only needs to touch a patient if s/he is going to operate on that patient
 
Innovative online healthcare solution enterprises
 
The new online healthcare solution enterprises are a combination of private, public and charitable initiatives, which are well positioned to contribute to the transformation of the UK’s traditional primary care model and include: Babylon Health, which provides remote consultations with doctors and healthcare professionals via text and video; BioBeatsa workplace wellbeing platform designed to empower and improve mental health; Docly, a digital messaging healthcare service, which is a spin-off of Min Doktor; Doctorlink, which partners with payers, healthcare professionals and pharmacists to provide a 24-7 platform for NHS patients to assess symptoms; DrDoctor, a patient engagement platform, which enables patients to book, change and cancel their appointments; EggPlant, a software testing and monitoring company, which helps to streamline patient activities; Dr Fox, an online primary care clinic and pharmacy service; Gogodoc, an online GP video consultation service with possible follow-up home visits; Healthcare Communications UK, which provides appointment management software and patient experience surveys; HealthPad, an online platform that manages and distributes healthcare video information between health providers and patients in order to improve outcomes and cut costs, and has accrued a proprietary content library of over 6,000 short videos contributed by leading clinicians that address peoples FAQs across some 30 therapeutic pathways, (HealthPad is the publisher of this Commentary).  HealthTalksOnline, an events and community portal for health; HealthUnlocked, a social networking service that offers peer support to help people manage their health; Healum provides healthcare professionals with a software, which enables them to support and motivate their patients to better manage their conditions; LIVI, provides GP video consultations; Medshra platform for medical professionals to discover, discuss and share clinical cases and medical images; Microtest Health, a health informatics company that provides practice management systems for NHS GP surgeries. MSKnote Limited creates clinical applications for healthcare professionals and patients with a focus on musculoskeletal conditions; MyWay Digital Health provides advice and solutions to help patients better manage diabetes; NHS.uk/conditions provides online text-based information and advice about medical conditions; NHS 111, a free-to-call medical helpline; the Now Healthcare Group, a GP video consultation platform and tele-pharmacy; Patient Access, which started by enabling patients to book GP appointments online and order repeat prescriptions and has evolved to allow patients to connect with their GPs remotely and access their medical records online; Patientinfo provides patients and health professionals with online health information. PatientAccess and Patientinfo are subsidiaries of EMIS Health, a leading supplier of  software used by NHS England; Patients Know Best, a social enterprise, which provides patients with access to their medical records and information about treatments; PatientsLikeMe, an online service that helps patients find people with similar health conditions in order to take actions that are expected to improve outcomes; Push Doctor, an online video consultation service; SaySo Medical is a digital communications agency, which connects people in order to improve their health; SystmOne, a centrally hosted computer system that provides primary care professionals with electronic patient health records in real time at the point of care; uMotif, a platform that captures electronic patient-reported outcomes data across a range of conditions and works with pharmaceutical companies to measure patient’s health, outcomes and experience; Unminda workplace mental health platform designed to  empower organisations and employees to improve their mental wellbeing; Visiba Care, a digital solutions company, which provides communication and administration software for healthcare practices; VisionHealth provides NHS primary care professionals with software solutions; VisualDX provides clinical decision support systems to enhance diagnoses and therapeutic decisions in order to improve patient safety; WebMD, an online publisher of healthcare news and information, and Zava, an online GP and pharmacy service.
 
 Technologically heavy and strategically light
 
Despite a significant number of online healthcare solution enterprises entering the market and the fact that some provide services to millions of people in the UK, this market segment is in its infancy and fragmented. All the initiatives mentioned above have been advantaged by the NHS’s response to the coronavirus outbreak. Notwithstanding, to permanently increase their footprint and significantly influence primary care in England, barriers to private enterprises and to online services will need to be reduced; and private companies in this segment will need to act more strategically and consolidate.
 
Most of these online healthcare service providers are technologically heavy and strategically light. For private companies in this market to grow and increase their influence on the NHS they will need to increase their focus on profitability and scale, which will require them to become more strategic and develop merger-integration skills. To become a dominant player, a company will have to successfully consolidate. Speed and merger competence are paramount. Companies that capture critical ground early and move up the consolidation curve the fastest will be successful. Enterprises that are slow to consolidate will become acquisition targets and disappear. Companies that stay out of the consolidation contest altogether will not survive.

A Chinese example
 
History has shown that many short-term emergency measures have a tendency to  become permanent fixtures. Thus, the UK’s response to the coronavirus CoVID-19 outbreak might permanently reduce the barriers to moving routine primary care tasks to innovative private online enterprises.
 
In an attempt to fully appreciate the potential of increasing online primary healthcare services in England, consider WeDoctor, a Chinese mobile app launched in 2010 by artificial intelligence expert Jerry Liao. Originally called Guahao (Mandarin for “booking”), WeDoctor started as a simple booking platform that made it easier for patients to make appointments with doctors. From these humble beginnings WeDoctor grew by adding extra functions such as reminders for regular medical checks, screening, prescriptions and online diagnoses and consultations. This helped to unclog China’s fragmented and bureaucratic healthcare system and made quality healthcare more accessible to the average person.
 
WeDoctor secured backing from Tencent Holdings, a Chinese multinational conglomerate, Sequoia Capital, the Goldman Sachs Group and the insurer AIA Group. In 2018, the company raised US$0.5bn in a private financing round at a valuation of US$5.5bn. Today, WeDoctor has more than 210m registered users mainly in China for its online appointment booking, prescription and diagnosis services and is linked to about 3,200 hospitals and 360,000 doctors. In March 2020, at the height of the CoVID-19 pandemic, it was reported that, in the latter half of 2020, WeDoctor intends to raise HK$1bn in an IPO on the Hong Kong Stock Exchange at a valuation of HK$10bn.
 
Although NHS England is much smaller than China’s healthcare provision, it is similarly fragmented and bureaucratic. The UK online solutions enterprises described in this Commentary have significant potential simply by helping to reduce GPs large and increasing burden of administration while increasing the connectivity between patients and GPs. This will help GPs to concentrate on what they have been trained to do and improve healthcare for people in most need.
 
Takeaways
 
Over the past two decades, legacy primary care systems and attitudes in the UK have slowed the uptake of online healthcare solutions. Notwithstanding, the NHS’s response to the coronavirus CoVID-19 outbreak might prove to have helped to transform the UK’s traditional face-to-face primary care model by making GPs deliver some of their services online. In a recent interview with the New York Times, Dr Bruce Aylward, Assistant Director-General of the World Health Organization, stressed how the Chinese had responded to the coronavirus outbreak by significantly increasing the amount of medical care the nation provides online.  In light of the discussion in this Commentary, be minded that in Mandarin the word “crisis” is denoted by two characters: 危机, one means ‘disaster’ and the other means ‘opportunity’.
 
 
#coronavirus #coVID-19 #NHSEngland #NHS #pandemic #primarycarecrisis #ChinaWeDoctor #WeDoctor #DigitalHealthcare 
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  • The burden of breast cancer throughout the world is significant and increasing
  • Research has shown that a cheap pill (anastrozole) halves postmenopausal women’s risk of breast cancer and continues to be effective seven years after women stop taking the drug
  • Anastrozole has fewer side-effects and is more effective than comparable treatments
  • Government watchdogs both in the UK and US recommend anastrozole
  • But the uptake of the drug in the UK is relatively low
  • Doctors are not prescribing anastrozole and women are not availing themselves of the drug
  • The UK’s NHS should employ new behavioural techniques to influence and change doctors’ and patients’ decisions and increase the uptake of anastrozole to reduce the burden of breast cancer

Will behavioural techniques improve breast cancer outcomes?
 
Being a woman and growing older are two unavoidable risk factors for breast cancer. Indeed, most breast cancers are found in women who are 50 years or older. Despite significant advances in diagnoses and treatments, breast cancer is one of the rapidly increasing cancers among women and a significant cause of cancer-related morbidity and mortality worldwide.  Breast cancer alone accounts for 30% of all new cancer diagnoses among females and has become a major 21st century health challenge.
 
Study shows long term benefits of a cheap breast cancer pill

Research findings reported in the December 2019 edition of The Lancet and also presented at the  December 2019 San Antonio Breast Cancer Symposium in Texas, show that a cheap pill, anastrozole,  if taken once a day for 5 years, not only halves postmenopausal women’s risk of breast cancer, but continues to be effective seven years after stopping treatment, which for the first time, suggests a long-term benefit.
 
Relatively low uptake
 
The UK’s NHS watchdog, the National Institute for Health and Care Excellence (NICE), suggests that hundreds of thousands of healthy older women should take anastrozole to cut their risk of breast cancer and recommends that the drug is offered to postmenopausal women at moderate to high risk of breast cancer unless they have severe osteoporosis. However, evidence suggests that some doctors in the UK are not prescribing anastrozole and some women are not availing themselves of the drug despite its demonstrated clinical benefits and the fact that anastrozole is supported by NICE.
 
Jack Cuzick, the lead author of The Lancet 2019 paper, who is Professor of Epidemiology and the Director of the Wolfson Institute of Preventive Medicine at Queen Mary UniversityLondon, is concerned because although anastrozole is, “An agent that looks really effective with minimal side-effects and is available on the NHS in the UK; its uptake has been quite low with only a tenth of eligible women receiving it”. Cuzick’s concerns are echoed by Delyth Jane Morgan, Chief Executive of the charity Breast Cancer Now, who said: "It is worrying to hear that anastrozole may not be being offered to all that could benefit. We need to understand the extent of this potential issue. It's essential that we raise awareness of this option among doctors and patients".
 
 In this Commentary
 
Part 1 of this Commentary explores some of the reasons for the relatively low uptake of anastrozole. Part 2 describes new behavioural techniques, which could be cheaply and easily employed by health systems to increase the uptake of anastrozole and dent the burden of breast cancer. Also the Commentary: (i) describes breast cancer, (ii) provides some epidemiological facts of the disease, (iii) estimates the cost to treat breast cancer in the UK, (iv) describes hormone receptor positive breast cancer, (v) explains how anastrozole works and (vi) reports the findings of The Lancet 2019 study.

 
Part 1
 
 
Breast cancer
 
Cancer is a group of diseases that cause cells in your body to change and spread out of control. Most types of cancer cells eventually form a lump or mass called a tumour and are named after the part of your body where the tumour originates.

 

Breast cancer is characterized by the presence of cancer cells in the tissue or ducts of your breast. Most breast cancers begin either in the breast tissue made up of glands for milk production, called lobules, or in the ducts that connect the lobules to the nipple. The remainder of the breast is made up of fatty, connective and lymphatic tissues. Advanced breast cancer refers to cancer that has spread outside of your breast to lymph nodes and/or distant locations in your body, often invading your vital organs.
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Epidemiology of breast cancer
 
Breast cancer is a common malignancy. Although more and more women are surviving the disease, each year in the UK there are over 55,000 new breast cancer cases: which equates to over 1,000 diagnosed each week. In the US, there are some 250,000 new breast cancer cases diagnosed each year: nearly 5,000 a week. Between 1993 and 2016 the incidence of breast cancer in the UK increased by 24%. Over a similar period, breast cancer incidence in the US declined, but an increasing trend of some 1.1% was observed among American Asians. In China, between 2000 to 2013, breast cancer increased at an annual rate of around 3.5%. Breast cancer rates in China are higher in urban areas than in rural areas: the higher the population density, the higher the rate. It is not altogether clear why breast cancer incidence is increasing. Experts suggest that breast cancer is a complicated disease with a variety of causes. Most cases of the disease are not linked to a family history. Around 5% of people diagnosed with breast cancer have inherited a faulty BRCA1 or BRCA2 gene. However, if you have a faulty gene, it does not mean that you will automatically develop breast cancer, but you are at higher risk. Out of every 100 women with a faulty gene, between 40 and 85 will develop breast cancer in their lifetime. Optimal therapy for breast cancer often requires several different treatment modalities including surgery, radiation, chemotherapy and hormone therapy (see below).
 
Cost of breast cancer treatment in the UK
 
The cost of treating breast cancer in the UK is significant and rising. Findings of research on the treatment costs of breast cancer published in the August 1999 edition of The Breast estimated that the average cost per case of breast cancer in the UK to be £7,247 (US$9,418).  Although the estimate is dated, it provides a guide. With 55,000 new cases of breast cancer diagnosed each year, the annual cost of treating the newly diagnosed alone, would be about £0.4bn (US$0.52bn). According to the UK charity Breast Cancer Now, an estimated 840,000  women  living in the UK have been diagnosed with breast cancer and the charity predicts that this figure will increase to 1.2m over the next decade. Thus, ceteris paribus, we can assume that the current annual cost  of treating breast cancer in the UK is significantly higher than £0.4bn and this figure is expected to increase substantially by 2030.
 
 
Hormones and hormone therapy
 
Hormones are chemical messengers secreted directly into your bloodstream, which carry them to organs and tissues of your body to exercise their functions.  Oestrogen and progesterone are steroid hormones produced by the ovaries in premenopausal women and by some other tissues, including fat and skin, in both premenopausal and postmenopausal women. These hormones play a critical role in regulating reproduction. Oestrogen promotes the development and maintenance of female sex characteristics and the growth of long bones. Progesterone plays a role in the menstrual cycle and pregnancy.
 
Similar hormones are produced artificially either for use in oral contraceptives or to treat menopausal and menstrual disorders. Oestrogen and progesterone also promote the growth of some breast cancers, which are called hormone-sensitive (or hormone-dependent) breast cancers. Hormone-sensitive breast cancer cells contain proteins called hormone receptors, which become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes that can stimulate cell growth.
 
Anastrozole is a hormone therapy (also called hormonal therapy and endocrine therapy), which slows or stops the growth of hormone-sensitive tumours by either blocking the body’s ability to produce hormones or by interfering with the effects of hormones on breast cancer cells. Anastrozole blocks a process called aromatisation, which changes sex hormones called androgens into oestrogen. This happens mainly in the fatty tissues, muscle and the skin and needs a particular enzyme called aromatase.
 
 Prescribing anastrozole
 
Anastrozole belongs to a group of drugs called aromatase inhibitors, which are specifically designed to treat postmenopausal women diagnosed with hormone-receptor-positive, early-stage breast cancer.  It is most often prescribed as an adjuvant therapy (after surgery) to decrease the risk of your cancer returning but can also be used in the neoadjuvant setting (prior to surgery) to decrease the size of your cancer in the breast. Hormone blocking therapy is also used to treat breast cancer that has recurred or spread. Most hormone blocking therapy drugs such as anastrozole are taken daily in pill form.
 
Anastrozole also may be given to reduce the risk of breast cancer in women who have not had breast cancer but have an increased risk of developing it because of their family history. Most experts suggest that your breast cancer risk should be higher than average for you to consider taking anastrozole as a preventative strategy. If your cancer is hormone receptor negative, then anastrozole will not be of any benefit, because these cancers do not need oestrogen to grow and usually such cancer cells do not stop growing when treated with hormones that block oestrogen from binding.
 
Reasons for the relatively low uptake of anastrozole
 
There are at least three probably reasons for the relatively low uptake of anastrozole. These include: (i) doctors becoming so used to prescribing the gold standard tamoxifen as an adjuvant hormone therapy, (ii) doctors wanting to be convinced about anastrozole’s long term benefits, and (iii) doctors wanting assurance about anastrozole’s minimal side effects.
  
Tamoxifen
 
Tamoxifen is the oldest and most-prescribed aromatase inhibitor and for the past three decades has become the standard of care as the adjuvant treatment of postmenopausal women with hormone-responsive early breast cancer. The drug reduces the risk of breast cancer returning by 40% to 50% in postmenopausal women and by 30% to 50% in premenopausal women. Notwithstanding, over the past two decades a new generation of aromatase inhibitors have been developed, and anastrozole is one of these. How does anastrozole compare with the gold standard tamoxifen?

Tamoxifen and anastrozole compared
 
Findings of two long-term comparative clinical studies undertaken in North America and Europe involving over 1,000 women with oestrogen receptor positive advanced breast cancer, showed that anastrozole is better than tamoxifen for: (i) increasing the time before the cancer returns in those who experience recurrence, (ii) reducing the risk of the cancer spreading to other parts of the body and (iii) reducing the risk of a new cancer developing in the other breast.

Significantly, studies have shown that anastrozole avoids two of tamoxifen's more serious side-effects: an increased risk of developing a blood-clotting disease and an increased risk of developing womb cancer.  Anastrozole can make bones weaker and so it is not recommended for women with osteoporosis and also it can cause stiff joints, hot flushes and vaginal dryness, which clinicians need to recognize and manage. But overall, the benefits of anastrozole over tamoxifen were maintained without a detrimental impact on quality of life. However, anastrozole is not a therapy for  premenopausal women because it blocks the hormone oestrogen and in effect creates a drug-induced menopause.


Part 2

Increasing the uptake of anastrozole
 
For healthcare systems to function effectively and efficiently we expect doctors and patients to behave rationally and make effective and efficient decisions. Traditionally, the rational choice model, which is predicated upon the belief that all human beings (including doctors and patients) act rationally in their own self-interest, has been used to influence people to behave in desirable ways. However, evidence suggests that, despite the well-founded theory and sound evidence to support it, the rational choice approach does not appear to work that well in practice.



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Behavioral scientists not doctors will prevent CVD

 A newer theory to explain peoples’ choices and behaviours
 
A newer approach to influencing behaviour, which builds on decades of research by Nobel prize-winning psychologist Daniel Kahneman, and described in a book published in 2008 entitled Nudge, by Nobel Prize winning economist Richard Thaler and Harvard Law School professor Cass Sunstein, suggests that no choice is ever presented in a neutral way and people - including doctors and patients - are susceptible to biases that can lead them to make suboptimal decisions. The authors suggest that many decisions and consequent behaviours are made automatically rather than after a considered rational decision. And this applies to decisions about your health.
Policymakers have been quick to latch onto the possibilities of these new behavioural techniques. Following the publication of Thaler and Sunstein’s book in 2008, President Obama set up a “Nudge Unit” in the White House and the UK Government, under Prime Minister David Cameron, set up the Behavioural Insights Team, popularly known as the Nudge Unit, in 10 Downing Street, and other governments around the world have since followed suit.

Nudges
 
Nudges are particular types of interventions, which are used to change peoples’ behaviour and improve outcomes at lower cost than traditional tools across a range of policy areas. Nudge techniques have been used in healthcare to influence behaviour and decision making to improve patient outcomes. For instance, the behavioural analysis of the decision-making that leads to a patient taking one drug instead of another. A research paper published in 2015 by the UK’s Health Foundation entitled “Behavioural insights in healthcare” suggests that health messages are often inconsistent and confusing to patients and framing them using social comparison via descriptive social norms (pointing out what is commonly done) or using injunctive norms (pointing out what is approved of) has been demonstrated to change patients’ behaviour and thereby have the potential to improve patient outcomes.
 
Information design
 
Behavioural techniques suggest that more attention should be given to the design of health information because the design and the way information is presented can influence and change doctors' and patients’ behaviour. Clinical guidelines, patients’ checklists and decision aids can all be improved in terms of text and language (e.g. the use of “plain English” and behaviourally specific, concrete statements and presentation of risk) and appearance (e.g. colour, visual stimuli, images etc).
 
HealthPad advocates that health information can have significantly more influence on the choices that doctors and patients make and on their  behaviour simply by presenting critical information in a video format. Over the past few decades people have moved away from consuming information in written and audio formats to consuming information predominantly in a visual format.  
 
Shift to consuming information in video format
 
Consider the following as being indicative of this shift. 82% of Twitter’s 330m average monthly users consume information in video format. The video channel You Tube has over a billion users and more than 500m hours of video are watched on the channel each day. 72 hours of video are uploaded to You Tube every 60 seconds, and more video content is uploaded onto the channel in 30 days than the major US television networks have created in 30 years. To further put things into perspective, in 2017, 56 exabytes (equivalent to 1bn gigabytes) of internet video content was consumed on a monthly basis, and this figure is expected to more than quadruple to 240 exabytes per month by 2022.

Today, almost all industries,  with the exception of healthcare, use video formats to communicate and the overwhelming majority of people who have consumed information in video format say it has influenced their choices and changed their behaviour. With video becoming the most significant influence on consumer decisions, it seems reasonable to suggest that more health information needs to be communicated in a video format if it is to influence and change doctors’ and patients’ behaviours in order to improve medical outcomes, increase the quality of care and slow and prevent chronic lifetime diseases.
 
Prompts cues reminders and audits
 
Prompts, cues and reminders have been demonstrated to be generally effective “nudges” that can successfully change the behaviour of healthcare providers and consumers, as well as being relatively inexpensive and easy to administer. Audit and feedback “nudges” are also effective. A set of best practices derived from systematic review evidence suggests that various nudge-type interventions (notably information design and presentation) may offer new ways to enhance choices and change behaviour.
  
Takeaways
 
The burden of breast cancer is huge and increasing globally. Research has demonstrated that a cheap pill, anastrozole, halves postmenopausal women’s risk of the disease and continues to be effective seven years after women stop taking the drug. We suggest that healthcare systems should consider using new behavioural techniques to influence and change doctors' and patients’ decisions to increase the uptake of anastrozole to help reduce the burden of breast cancer. Evidence suggests that nudge-type interventions, if suitably applied, can influence and change the behaviour of doctors and patients and thereby contribute to the reduction of the burden of breast cancer. However, given the newness of these techniques the quality of evidence available about their impact is relatively thin and patchy. Notwithstanding, this suggests a need for more quality evaluation and synthesised evidence of nudge-type interventions, their behaviour change potential and their impact on reducing the burden of breast cancer and other chronic lifetime diseases.
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  • Bioengineers throughout the world are competing to achieve the Holy Grail: an affordable, point-of-care blood test - liquid biopsy - that detects cancer before any symptoms present
  • Success in achieving this will save millions of lives, substantially reduce healthcare costs and make investors, researchers and organisations billions
  • Despite significant advances no one has yet achieved the Holy Grail and there remains a substantial gap between researchers’ aspirations and reality
  • How close are we?

 
 

Finding the Holy Grail: early detection tests for cancer
 

 

“It’s too soon to even claim that the research is promising," commented Paul Pharoah, a professor at Cambridge University’s Centre for Cancer Genetic Epidemiology, on the research findings of  Daniyah Alfattani, a PhD student in the Centre of Excellence for Autoimmunity in Cancer (CEAC) at Nottingham University’s School of Medicine in the UK.
 
Alfattani was presenting research findings of a small study at the National Cancer Research Institute’s (NCRI) conference in Glasgow, Scotland, in November 2019, which is an international forum for showcasing cancer advances.
 
A September 2019 HealthPad Commentary described another early detection test for breast cancer called CanRisk, which has been developed by researchers from Cambridge University’s Centre for Cancer Genetic Epidemiology and  has the potential to identify women with different levels of risk of breast cancer.
 
Alfattani and bioengineers from the universities of Nottingham and Cambridge are players in a vast and rapidly evolving international army of researchers engaged in an intensely competitive global race to develop an affordable, point-of-care, early detection test (EDT) for cancer based upon a liquid biopsy and next generation sequencing technologies. The Holy Grail is for such a test to detect cancer cells in an asymptomatic patient, locate the tissue of origin and give that person an early diagnosis when treatment is more likely to be successful; and to do all this with 100% accuracy. 

Although Alfattani’s research study is modest, her findings are potentially clinically relevant because they are on the Holy Grail therapeutic pathway, and her preliminary findings suggest that a simple, cheap and easy-to-use blood test - liquid biopsy - could detect breast cancer five years before any symptoms present. If demonstrated to be exquisitely accurate, safe and efficient by a larger study, which already is underway at Nottingham University’s CEAC, Alfattani’s research could be a key to saving thousands of lives and substantial amounts of money.

 


Gold standard breast cancer screening
 
Currently, mammography screening is the gold standard for preventing and controlling breast cancer, which is costly to administer and only has a sensitivity between 72% and 87%.  For every death from breast cancer that is prevented by mammography screening, it is estimated there are three false-positive cases detected and treated unnecessarily. Further, nearly half of all cancer sufferers are diagnosed late, when their tumours have already metastasized. It is estimated that 30% to 40% of cancer deaths could be prevented by early detection and treatment.
 
In this Commentary
 
This Commentary provides a partial update of some bioengineering initiatives described in a 2016 HealthPad Commentary, to speed up and improve liquid biopsies, which can simultaneously detect cancer early and identify its tissue of origin. Although there have been significant developments, the challenge for liquid biopsy assays still remains the level of their positive predictive values. This Commentary provides a brief and partial epidemiology of breast cancer, describes Alfattani’s research and its findings and briefly mentions some similar research that is underway. We describe categories of biomarkers employed by researchers and indicate some advances in EDTs made by some giant biopharma companies as well as briefly describing another innovative university-based development. We conclude by suggesting that: (i) despite significant and well supported research endeavours over the past decade to develop EDTs, there still remains a gap between scientific aspirations and reality; and (ii) there appears to be a gap opening between commercially available personalised cancer therapies, which are by-products of EDT research and standard oncological therapies.
 
Partial epidemiology of breast cancer
 
Despite significant advances in the awareness, diagnosis and treatment of breast cancer, it still remains the most common cancer in women worldwide, contributing 25.4% of the total number of new cases of cancer diagnosed in 2018. Each year, more than 0.5m women throughout the world die from the condition.  In the US each year, over 268,000 new cases of invasive breast cancer are diagnosed in women, and over 41,000 women die from breast cancer. Between 1989 and 2016, death rates from female breast cancer in the US dropped by 40%. Over the past decade, death rates from breast cancer in older women in the US continued to decrease but remained steady in women under 50. Such decreases are attributed to increased awareness of the condition, earlier detection through screening and improved treatments. In the UK, there are over 55,000 new breast cancer cases diagnosed each year. In contrast to the US, since the early 1990s, breast cancer incidence rates in the UK have increased by around 19%, but death rates have fallen because of greater awareness, earlier detection and enhanced therapies. Notwithstanding, each year more than 11,000 women in the UK die from breast cancer. Furthermore, each year in the US, there are over 1.7m new diagnoses of all cancers, while in the UK there are over 360,000 new cases. Although recent advances in EDTs have the potential to decrease cancer deaths, as yet there is not a simple and cheap liquid biopsy, which can be used routinely  in clinics to diagnose a range of cancers early. .
 
Alfattani’s research
 
The research pursued by Alfattani and her Nottingham colleagues is predicated upon the fact that cancer cells produce proteins called antigens, which trigger the body to make antibodies against them. These are called “autoantibodies”. Researchers discovered that these tumour-associated antigens (TAAs) are good indicators (biomarkers) of cancer. Alfattani and her colleagues developed panels of TAAs, which are known to be linked with breast cancer as a technique to detect whether or not there are autoantibodies against them in blood samples taken from patients.

The Nottingham researchers took blood samples from 90 breast cancer patients at the time they were diagnosed with the disease and matched them with samples taken from 90 patients without breast cancer (the control group). Researchers employed technology (protein microarray), which allowed them to screen the blood samples for the presence of autoantibodies against 40 TAAs associated with breast cancer and also 27 TAAs not known to be linked with the disease. The accuracy of the test improved in the panels that contained more TAAs.

Findings

A panel of five TAAs correctly detected breast cancer in 29% of the samples from the cancer patients and correctly identified 84% of the control group as being cancer-free. A panel of seven TAAs was able to detect disease in 35% of cases with breast cancer and rule out 79% of patients in the control group. The most successful technique was a panel of nine antigens, which correctly identified the disease in 37% of cancer samples and no cancer in 79% of the controls. “The results of our study showed that breast cancer does induce autoantibodies against panels of specific tumour-associated antigens. . . . . The results are encouraging and indicate that it is possible to detect a signal for early breast cancer. Once we have improved the accuracy of the test, then it opens the possibility of using a simple blood test to improve early detection of the disease”, said Alfattani.

David Crosby, head of early detection at the Cancer Research UK charitysaid, “Diagnosing cancer at the earliest stages before it grows or spreads gives patients the best chance that their treatment will be successful. So, the potential to detect markers in the blood before other signs appear is promising”.
 
Similar studies
 
Nottingham University’s CEAC is also working on similar tests to that used by Alfattani for pancreatic, colorectal and liver cancers. Solid tumours like these, as well as lung and breast cancer, represent around 70% of all cancers. Further, a similar test for lung cancer is currently being tested in a randomised controlled clinical study in Scotland, which is believed to be the largest trial of its kind in the world, involving 12,000 people at high risk of developing lung cancer because they smoke.
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Participants in the study have been randomly assigned to two groups: one is given an autoantibody blood test and the other (the control group ) is not. Participants who test positive for the autoantibodies are then followed up with a CT scan every two years in order to detect lung cancer in its early stages when it is easier to treat. Findings suggest that the test detects lung cancer four years or more before standard clinical diagnosis. In the UK about 85% of lung cancer patients are left undiagnosed until the disease has spread to other parts of the body.

 


Liquid biopsies

 
Liquid biopsies require biomarkers, which are substances, structures, or processes in your body that can be analysed in order to explain the pathogenesis of cancer and other disease states, and thereby inform diagnosis, predict onset and suggest appropriate therapies. Notwithstanding, the multiple types of biomarkers have varying degrees of reliability. Initially, the principal focus of research into EDTs was largely focussed on circulating tumour cells (CTC) and DNA. More recently however, additional biomarkers have become an important focus for such research. Antibodies are just one type of molecular biomarker. Because antibodies function by binding specific antigens, attempts to identify antibody biomarkers have involved using antigens to capture antibodies that are overproduced in cancer. Identifying relevant antigens is critical for discovering antibody biomarkers. Array-based approaches employed by Alfattani and her colleagues depend on exposing serum samples from patients to an ordered array of putative antigens, capturing those antibodies that bind antigens on the arrays and measuring their levels. Antibodies that are present at significantly higher levels in the serum of patients with breast cancer, (compared to control serums from healthy patients) are candidate biomarkers. 
 
Because of the unreliability of such biomarkers, new liquid biopsy tests tend to be predicated upon the levels of cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and exosomes. These also pose challenges because of the varying physiological levels of the different biomarker fragments in your bloodstream.
cfDNA refers to DNA molecules that circulate in your blood after cell death. The amount of cfDNA varies significantly depending on the location, type and stage of your cancer. Concentrations of cfDNA can range from 1 to 100,000 fragments per ml of blood.

ctDNA refers to DNA that comes from cancerous cells and is present in your bloodstream. As a tumour grows, your cells die and are replaced by new cells. Your dead cells decompose and their contents, including DNA, are released into your bloodstream. So, ctDNA are small fragments of DNA, the quantity of which varies between individuals and the location, type and stage of your cancerous tumour. Detection of single mutations in ctDNA requires a large volume of blood. The principal challenge of research predicated upon ctDNA is their relatively low abundance in your bloodstream. As a consequence, scientists cannot rely solely on ctDNA, and are forced to search for other genetic and epigenetic mutations in your blood.
Exosomes is another class of biomarker. Cancer related exosomes are nano-size membrane vesicles that play important roles in tumour microenvironment. A 2007 paper in Nature Cell Biology 
suggested that exosomes can load unique cargoes, including proteins and nucleic acids that reflect the condition of a tumour. Since the 2007 Nature paper, research into exosomes has increased and they are now being used as diagnostic and prognostic biomarkers for various cancers. 

 
CancerSEEK

 
An innovative liquid biopsy called CancerSEEK, which has been developed by researchers from the Johns Hopkins Kimmel Cancer Center, in Baltimore, USA, is expected to make early cancer detection a part of routine medical care. Significantly, the test screens for eight common cancers, which account for more than 60% of all cancer deaths in the US. Currently, five of the cancers covered by the test have no screening test. CancerSEEK combines cutting-edge liquid biopsy technology with a machine learning engine, which is expected to improve the test’s accuracy with every person it screens. Findings of a retrospective study of multiple cancer types published in the February 2018 edition of the journal Science suggested that CancerSEEK has a sensitivity between 69% and 98% for ovarian, liver, stomach, pancreatic and oesophageal cancers, a specificity of 99%. Further, the study suggested that the test  has a false-positive rate of less than 1%. In 2019, CancerSEEK received Breakthrough Device designation from the US Food and Drug Administration (FDA) for the detection of genetic mutations and proteins associated with pancreatic and ovarian cancers, and also raised US$110m to launch a start-up company to develop the technology further.
 
FDA approval for a liquid biopsy developed by Roche
 
In June 2016, Roche, a global biopharma, became the first company to receive FDA approval of a liquid biopsy test to detect mutations associated with non-small cell lung cancers (NSCLC). Notwithstanding, the biopsy is not a universal test to detect the presence of NSCLC, but rather a test, which is being used in people with lung cancer to enhance personalised targeted therapies, and to monitor progression of the cancer. Some patients may benefit from the test's accompanying drug erlotinib (Tarceva), which treats NSCLC.
 
In September 2019, Genentech, a member of the Roche Group, announced positive results from the first prospective phase II/III clinical study to use a liquid biopsy and next generation sequencing to select treatment for people with NSCLC, without the need for a tissue biopsy. Next-generation sequencing facilitates the analysis of minute quantities of cfDNA circulating in the blood. In addition, Genentech is using machine learning algorithms on large data sets to characterize the molecular signatures of various cancer types.
 
Guardant and GRAIL
 
Previous HealthPad Commentaries have described research endeavours by Guardant Health  and GRAILwhich are “betting-on” liquid biopsies. Here briefly we update the developments of these two giant biopharma companies.

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In 2014 Guardant launched a next generation sequencing cfDNA assay called Guardant360 for treatment selection in a number of solid tumour cancers. In December 2018, the company launched an assay referred to as LUNAR to detect a range of early stage and recurrent cancers. LUNAR is based on data that Guardant collected from 80,000 advanced cancer patients using its 360 technology. In October 2019, the company launched ECLIPSE, a 10,000-patient clinical study to evaluate the performance of a second generation LUNAR blood test to detect colorectal cancer (CRC) in average-risk adults. The study is intended to improve CRC screening rates by offering a simpler liquid biopsy that overcomes challenges associated with current testing methods described above.
GRAIL has developed a prototype cfDNA sequencing assay to detect a range of cancers, many of which are not screened today and often present at late stages. Significantly, GRAIL has developed a prospective, observational, longitudinal clinical study called the Circulating Cell-free Genome Atlas (CCGA). The study has 15,000 participants across 142 sites in the US and Canada and has been designed to characterize the landscape of genomic cancer biomarkers of people with and without cancer. The company’s STRIVE study is fully enrolled with approximately 115,000 women and another study called SUMMIT also is fully enrolled with approximately 50,000 men and women aged 50 and older who do not have a cancer diagnosis at the time of enrolment.
 
Despite advancing technologies, FDA approvals, ongoing clinical studies and large and increasing investments in the development of liquid biopsies, (see a paper published in the June 2019 edition of Clinical and Translational Science entitled, “The Labyrinth of Product Development and Regulatory Approvals in Liquid Biopsy Diagnostics”) there remains a substantial gap between scientific aspirations and reality. Liquid biopsies still do not provide physicians with a reliable, point-of-care means to detect cancer early and become a reliable substitute for the more invasive and more expensive gold standard tissue biopsy.
 
Takeaways
 
Liquid biopsies represent a large and rapidly evolving area of bioengineering. There are hundreds of research papers published in peer reviewed medical journals, which describe findings of the latest research in this area. Oncologists involved in EDT research are familiar with genomics, the molecular properties of cancer tumours and commercially available innovative therapies, which are by-products of EDT research, but many oncologists are not. This difference of knowhow seems to be creating another gap  between certain personalised cancer therapies advocated by research oncologists and standard cancer management provided in many clinics. Closing these gaps is partly contingent upon continued and open EDT research and more effective education.
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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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  • 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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China’s rising MedTech industry and the dilemma facing Western companies

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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