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The placebo problem

Leigh Frame, Ph.D., Master of Health Science, likes vitamin D. Executive director of the Office of Integrative Medicine and Health at George Washington School of Medicine and Health Sciences, she is especially interested in the role of vitamin D as an immune modulatory hormone.

She was starting a pilot study to determine the effectiveness of vitamin D supplementation via patch delivery (through the skin) versus pill delivery (via the gut) when the pandemic hit.

Vitamin D is a fat-soluble nutrient that also functions as a steroid hormone. Many of the body’s organs and tissues have receptors for vitamin D, which suggest important roles beyond what we currently know about its role in bone health.

Principles of research ethics

Respect for persons: Treat participants as autonomous; protect participants with decreased autonomy. Read more›››

Beneficence: First, do no harm; maximize benefits to participants; minimize risks to participants.

Justice: Fair recruitment of participants; participants asked to bear the risk should benefit from the research.

From “Ethical Concerns in Placebo-Controlled Supplementation Studies: How to Design a Rigorous Randomized Controlled Trial.” Permission from Leigh Frame.‹‹‹ Read less

“We had planned to bring 30 healthy subjects to the medical campus, who would otherwise not have needed to visit the campus,” Frame says. “Now, each visit would represent an added risk to them, which raises concerns in terms of the principles of beneficence and justice. Given that the benefit to these subjects is minimal as this study is not looking at potential therapeutic benefits, the risk of contracting COVID-19 through being on campus greatly outweighs the potential benefit to society. It would not have been ethical to proceed with this trial during the COVID-19 pandemic.”

 A SUDDEN HALT

The sudden emergence of COVID-19 meant clinical research was halted — or even terminated — in deference to the immediate needs of caring for patients and clinical trials focusing on the treatment and prevention of coronavirus infection were prioritized over studies focusing on other diseases. Once social distancing had been introduced by governments as a public health measure to prevent or slow the spread of disease, trial sponsors and investigators were required to determine whether ongoing trials should proceed. Several factors determined the fate of these trials, including trial location, the indication for the trial, the urgency of continuation, the safety of participants and staff, and risks to trial integrity.

The main question: Would it be ethical to continue?

“The field of research ethics has developed in response to research conducted without proper consideration for ethical issues or with blatant disregard for ethical concerns,” Frame wrote in a 2020 publication on ethical concerns in placebo-controlled supplementation studies. “The design of most research studies today involves more nuanced issues of research ethics relating to the Principles of Research Ethics.”

While Frame’s trial was put on hold, numerous studies were conducted on the potential of vitamin D to reduce risk of infection with COVID-19. Frame’s study looked at the efficacy of different supplementation methods: we already know that vitamin D supplementation can be beneficial, so investigating how this is best achieved fell short of the principle of beneficence. Using vitamin D as a preventative and potential adjunct treatment in COVID-19, however, was an unknown and potentially important in the fight against COVID-19.

“If you do a PubMed search for ‘vitamin D’ and ‘COVID,’ 936 results are returned from 2020 to 2021, plus 273 in 2022 as of June,” Frame says. “Those are substantial numbers, however if you restrict those results to clinical trials only, 30 results ranging from study protocols to completed results are returned from 2020 to Jun 2022. That is actually a very large number considering the extremely tight timeline from the emergence of COVID-19. Many of these studies, however, are observational in nature, meaning they are looking at vitamin D status in relation to COVID-19 infection and its progression and outcomes.”

ADDRESSING THE RISK

Observational studies are very low risk for the subjects, introducing very little additional risk to participants but offering potential benefit to society, though not the individual, Frame stresses. “Prioritizing this type of study during a pandemic makes sense ethically, not just due to the low risk, but because we have some evidence to inform a potential intervention that may prove beneficial. Vitamin D has known actions in viral infections and in the immune system more broadly. Therefore, it could be reasoned that vitamin D supplementation for prevention or as a potential adjunct therapy would be beneficial with minimal potential for harm.”

In these studies, the risk/benefit ratio is in favor of continuing. Keeping in mind the principles of beneficence and justice, it would be ethical to proceed.

“In fact, you could argue it would be unethical not to proceed,” Frame says. “Given the potential benefit to society, especially in a global pandemic, coupled with the potential benefit to the individual and the minimal risk they’d face. As this research would be done in those mostly likely to be affected by Covid-19, this bolsters the ethical nature of such studies. Plus, conducting research in those of greatest risk to morbidity and mortality from Covid-19 would further strengthen the justice component and could be used to improve health equity.”

Many of these studies found the same thing: insufficient blood levels of vitamin D were associated with increased risk of COVID-19 susceptibility, severity, and mortality.

Further research is still needed to determine the precise role and efficacy of vitamin D as a preventative or therapeutic measure in cases of COVID-19, but since vitamin D deficiency is common around the world, any link to its possibly helping surely justifies investigation.

Frame, and the principles of ethics in trial design, have concerns: One major concern with such studies is their use — or not — of placebo. Using a true placebo, an inert substance that participants believe is the therapeutic, has small positive effects in most cases, known as the placebo effect. However, this is likely smaller than an active control, in this case, a low dose vitamin D supplement.

Research is revealing that vitamin D has much broader effects than previously assumed, as it is an immune-modulating hormone. Vitamin D deficiency may lead to health issues involving infection, autoimmunity, cancer, chronic diseases such as cardiovascular disease, and even mental illness. Withholding vitamin D in clinical trials, therefore, may see harm done.

“As demonstrated in the Tuskegee Study of Untreated Syphilis, it is unethical to withhold treatment when there is a known, effective therapy,” Frame writes in Ethical Concerns in Placebo-Controlled Supplementation Studies. “This becomes less clear when talking about nutrition.”

COULD IT CAUSE HARM?

An individual may be found to have suboptimal or deficient stores of the nutrient in question. If they receive the therapy during the trial, their nutritional status should improve at least, even if the dose is insufficient to bring their levels to those required for the effect in question. If they are unfortunate enough to be placed in the control group, their nutritional status will not improve and may even worsen over the course of their treatment. This is the crux of the ethical issue, Frame says.

“Are we doing harm to these participants? That answer depends on many factors, but to be ethical we must maximize the benefits to participants and minimize the harm. I recommend using the current Recommended Dietary Allowance (RDA) as the active control in nutrition studies, which is the minimum amount most people need each day to avoid disease, but not to optimize health. A low dose of vitamin D would minimize risk, improving the risk/benefit ratio. However, this may make detecting differences between the groups more difficult by reducing the difference in effect sizes between the groups, requiring a larger sample size and increasing the cost of the study.”

As demonstrated in the Tuskegee Study of Untreated Syphilis, it is unethical to withhold treatment when there is a known, effective therapy.

– Leigh Frame

Above all, Frame advocates for weighing the risk/benefit ratio for each individual study during the study design process to optimize the potential for meaningful results from the study while protecting those participating:

“As a member of the research study team, it is your duty to protect your study participants and to ensure that your research is conducted ethically.”

Frame’s supplementation technique trial is still on hold. “We are hoping to start it very soon, as the risk of both contracting COVID-19 and the consequences of such infection have greatly decreased.”

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COVID was no barrier for UAE bird
enthusiasts

Research slowed during the pandemic for non-COVID matters as sputtering supply chains and closed labs made work difficult. But for a pair of amateur bird enthusiasts in the UAE, the skies were open and delivered an unexpected discovery.

The pair, then-chemistry teacher Oscar Campbell and physics teacher Simon Lloyd, made the outdoors their lab and discovered at an Abu Dhabi golf course a bird previously thought to be extinct and unknown in the UAE.

The steppe whimbrel is native to the Russian plains, remote areas of Kazakhstan and central Asia and is one of four whimbrel subspecies. It was declared extinct in 1994 and rediscovered in 1997, but its wintering grounds, in Mozambique, were not discovered until 2016. The UAE is a mid-way stop.

Campbell has been observing birds for many years, but spotting the juvenile steppe whimbrel was noteworthy.

We took hundreds of pictures. There are a bunch of features but the precise details of the underwing pattern are definitely the most diagnostic, critical ones

– Oscar Campbell

“It’s a significant finding,” Campbell says, because although there are an estimated 100 of them in existence, the fact that they found the young bird in the UAE means the species is continuing to breed.

Campbell and Lloyd had been doing monthly surveys of birds around the grounds of Saadiyat Beach Golf Club for about three years before they spotted the bird in August 2020. Campbell says the team at the golf club were excited about hosting such a rare bird.

Getting a look under the wing is crucial to identifying a steppe whimbrel. It was tricky, Campbell says.

“Part of the problem of course is most of the time you can’t see the underwings of a bird. And when you can see them, it’s flying so it’s moving fast. We took hundreds of pictures. There are a bunch of features but the precise details of the underwing pattern are definitely the most diagnostic, critical ones,” Campbell tells KUST Review.

The then-science teacher – now environmental scientist and ornithologist at Nautica Environmental Associates – regularly spent time out exploring and surveying birds as an amateur scientist for several other properties around the Emirates. He is currently working with a team on the third edition of Field Guide to Birds of the Middle East. The book is scheduled to be published in 2024.

Amateur scientists around the world are becoming more involved in research in a process growing in popularity known as citizen science. Amateurs work in collaboration with scientists to contribute data, analyze the data collaboratively or otherwise participate in projects.

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The bug named after a bug

The coronavirus left its mark on the world – and on a new species of insect found in the Western Balkans.

When Halil Ibrahimi and his team at the University of Prishtina discovered a new species of caddisfly – a flying insect similar to a moth whose eggs and larvae thrive in freshwater lakes, streams and ponds – they named it Potamophylax coronavirus.

The insect was discovered in Kosovo’s Bjeshket e Nemuna National Park before the pandemic, but the work of analyzing and describing it was done as the scientific world faced such challenges as lab lockdowns and difficulty accessing supplies.

The name is a good tool in increasing awareness for environmental protection.

– Halil Ibrahimi

This left Ibrahimi time to finish desktop research on previously started investigations. “Hence the name of the new species reflecting pandemia with all these obstacles,” Ibrahimi tells KUST Review.

But the name also has a second meaning.

It reflects “the hidden ‘pandemia,’ i.e. pollution and degradation of freshwater ecosystems in Kosovo and Western Balkans during the past two decades,” Ibrahimi says. “Many rare and important insect species, including the newly described Potamophylax coronavirus, are endangered by these activities.”

“The name is a good tool in increasing awareness for environmental protection,” he says.

Ibrahimi and the team published their results in Biodiversity Data Journal.

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Ask the experts: What have we learned
from the COVID-19 pandemic?

The worst of the pandemic seems to be behind us, but we’re just starting to get a better picture of how it affected the world. We asked experts in a variety of fields for their perspectives. Here’s what they said:

Pandemic is a reminder
of our duties to each other
Patricia M. Davidson

Calamities in history, such as war and pandemics, create an inflection point and a time for recalibration and focus across society. As well as causing much hardship, the COVID-19 pandemic has taught us many lessons.

Patricia M. Davidson

Prof. Patricia M. Davidson joined the University of Wollongong as vice-chancellor in May 2021. Prior to her current role, Davidson was dean of the Johns Hopkins School of Nursing in Baltimore in the United States. In 2021 she was the recipient of the Consortium of Universities for Global Health (CUGH) Distinguished Leader Award.

Firstly, we are all on this planet inextricably linked. Barriers and restrictions may have a short-term benefit in curtailing the spread of contagions, but they cause many unintended consequences, from loneliness to economic devastation.

We need international collaboration, and we need to support global governance.

Secondly, leadership is critically important at a global, national and local level.

People make a difference, and taking care of the most vulnerable should be a societal imperative and the responsibility of leaders.

Dealing with ambiguity and resilience has become the hallmark of modern leadership, and sometimes these lessons have been painfully learned.

And lastly, amidst the suffering and loss has emerged the emphasis on the power of science and the possibilities it generates.

The emergence of the importance of RNA and the rapid delivery of vaccines and antiviral therapies has been nothing short of remarkable and a life-saver.

Amidst the rhetoric of nationalism and populism has also been the extraordinary stories of local communities and global collaboration.

Critical lessons for me reflecting on the pandemic are: that we fail to take care of our planet at our peril; our people are important; leadership is critical; and the possibilities of science are endless.

To quote Joyce Lau (2022) in the Times Higher Education, universities can be “beacons of hope in undiplomatic times.”

Science and the quest for knowledge can be a global language and a source of common ground.

Leveraging the power of science and taking care of our people and planet can leverage possibilities for good. Failing to learn the lessons of this pandemic will be at our peril.

We owe it to the lives lost and immense suffering to strive to make our planet healthier and more equitable for all.

Supply chains must be
nimble and safeguarded
Ray O. Johnson

One of the standout lessons from the past two years is how fragile our global supply chains have become. Today’s world is a hyperconnected, interdependent ecosystem, a spider’s web of partners and relationships spun across all four corners of the globe. This vast network relies on so many variables that, in the face of COVID-19 were put under tremendous stress.

Ray O. Johnson

Dr. Ray O. Johnson is CEO of the Technology Innovation Institute and ASPIRE in Abu Dhabi.

Governments, businesses, and organizations everywhere had to adapt overnight to a “new normal.” That “normal” was ever-changing as the virus continued to mutate with scientists and medical professionals striving to keep up and keep us safe.

It is against this backdrop that the thinking of the renowned naturalist Charles Darwin seems appropriate. His research led to the conclusion that it is not the strongest of the species that survives, not the most intelligent that survives. It is the one that is the most adaptable to change. The ability to adapt in the face of adversity is the very characteristic that enabled the supply chain of vaccines and other necessities to flow around the world.

A report released mid-pandemic from DP World, a global leader in supply chains, highlighted that 83 percent of companies were reconfiguring their supply chains. The most interesting point, however, is that these reconfigurations were to diversify their supply chains, further increasing the number of countries with which they trade, adding yet more complexity to the system, as opposed to reversing globalization in favor of nationalism and localism.

While it remains vital that countries retain sovereign capabilities, particularly across critical sectors and national infrastructure, it is emboldening that off the back of the pandemic, organizations want to increase their number of trading partners rather than retreating.

To reward this positive mindset and deliver prosperity, we must work hard and continually develop technologies and systems to digitalize and safeguard our global supply chains and ensure the web of interconnectivity remains strong.

Increased screen time hampered child development
Binu George

The pandemic brought home the advantages of technology. From entertainment to food-delivery apps to even ongoing education for children that enabled distance learning, technology helped us bear the brunt of the quarantine and isolation brought by the pandemic. However, the very same technology also forced us into some parenting choices that are now being increasingly recognized as having caused more harm than good.

Binu George

Dr. Binu George is a developmental pediatrician and heads the Child Development Department at NMC Royal Hospital in Abu Dhabi. He also is an advisor to child-development activities for the Early Childhood Authority and the Department of Health in Abu Dhabi.

Specifically, we need to talk about the increasing “screen time” that kids were subjected to during this period. Given the extremely limited opportunities for socialization, recreation, and play activities available, families were more and more forced to entertain and occupy their kids through digital platforms of entertainment. This has had debilitating effects for all children but none more so than pre-schoolers.

The ages of 0 to 4 years are when brain growth and development are at their peak. It is at this age that social and play experiences help shape our skills and attitudes, which, if on track, are visible as developmental milestones and can be monitored.

Pediatricians around the world are finding an alarming increase in deficits in communication, language, attention and interaction skills of children who were at this age during the pandemic. A large percentage of these children were spending hours of the day sitting glued to entertainment channels, especially via streaming and media apps like YouTube.

This ensured that they not only missed out on the already meager opportunities to socialize and interact, thus developing social communication skills, but also preferentially started ignoring these for more “screen time.” This “screen addiction” is visible in every society in the world, and so is the increasing morbidity of developmental delays.

It is imperative that parents are educated about the unfettered use of devices to entertain their pre-school children and engage in more nurturing involvement to promote development.

We can’t blame the pandemic for supply-chain woes
Doug Munro

Supply chain is a term that few, outside of those who deal with them in their industry, had heard of before COVID. Now it seems like supply chain has become the whipping boy for all economic problems in a disruptive world.

Doug Munro

Doug Munro is a retired academic and automotive-industry executive. During his career, he worked in 10 countries. He holds a Ph.D. from Ohio State University.

Certainly, COVID created many challenges – population lockdowns, plant and office closures, and transportation disruptions, to name just a few. Inevitably, these events required producers, wholesalers, retailers, and the systems that moved products between those environments to scramble to adjust to a rapidly changing environment.

And since lockdowns, particularly in China, continue to impact economic activity in that country, the COVID hangover persisted into 2022.

But these are not the only factors that have impacted supply chains.

Manmade actions, including tariffs, the war in Ukraine, gas-pipeline shutdowns, OPEC output decisions, and increasing political tensions leading to trade restrictions, also play a major role. In addition, aging populations in developed countries, leading to a reduced labor force, created a worker shortage, which is often compounded by political opposition to immigration. Some of these events have been accentuated by COVID, but most would have arisen had there been no pandemic.

A perfect example of a manmade supply-chain disruption, independent of, but perhaps accentuated by, COVID, is Brexit.

Approved by UK voters in 2016 and implemented at the end of 2020, this political action essentially guaranteed that UK economic activity would be significantly disrupted.
The Brexiteer’s slogan was “Take Back Control.” Unfortunately, that ignored the complexities of an interconnected world.

A good case study is the vehicle industry.  Vehicles are the largest export from the UK by value, and more than half of those go to the EU. Brexit puts that in jeopardy.

The argument from Brexit supporters is that the UK’s newfound freedom will allow the country to expand globally. However, since all of the major auto manufacturers in the UK are foreign-owned, and all have well-established global distribution, it is unlikely that British exports will be allowed to go their own way.

Adding to the disruption, more than 50 percent of the content of UK-manufactured vehicles is imported, largely from the EU. The result will be that the sophisticated supply-chain processes that define the “just in time” assembly processes of large vehicle manufacturers will be disrupted by border checks, and exports will likely be subject to ongoing duties. Neither of these will work in the UK’s favor.

So, while the UK’s Society of Motor Manufacturers and Traders argues that “Automotive … has clearly been amongst the worst hit sectors” due to COVID and has driven “significant supply-chain disruption,” the fact is that COVID was a problem, but the big hit has been self-inflicted.

In 2015 the UK automotive trade group forecasted that UK vehicle production in 2020 would reach 2 million; the actual total was less than half that amount. Between 2019 and 2021, global vehicle production fell approximately 13 percent; UK vehicle production dropped 32 percent. It is difficult to blame COVID for the difference.

There is no question that COVID posed challenges around the world, but it is unfair to blame the pandemic for all that has gone wrong. The “freedom” Brexit brought to the UK shows only that we have learned ways to blame the virus for a lot that has gone wrong. As Janice Joplin elegantly sang, “Freedom’s just another word for nothin’ left to lose.” That may be the main lesson for the UK in a post-COVID world.

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Tech conceived during the pandemic
aims to calm a post-COVID world

A face mask developed during the pandemic to reduce stress and anxiety is evolving into a digital tool that can continue to serve its original purpose in a post-mask environment.

One of the winning teams of the 2022 Women to Impact venture of King Abdullah University of Science and Technology (KAUST) created a face mask called takeAbreath that monitors the wearer’s stress and anxiety levels. It then uses gaming technology to recommend breathing exercises to reduce any anxiety and stress identified.

The team – Anna-Maria Pappa, Sofia Dias and Leontios Hadjileontiadis of Khalifa University and Sahika Inal of KAUST – conceived the product during the height of the pandemic and are adapting the technology to offer relief for those who struggle with stress and anxiety.

Next generation
of face masks

People around the world wore masks in their daily lives during the pandemic to help prevent infection. Now, a new kind of mask might help diagnose illness. Read more›››

Engineers from MIT and Harvard say their new prototype can produce a COVID-19 test result in 90 minutes. The wearer breathes normally into the mask, and droplets produced by exhaling and coughing collect on a pad. The wearer then presses a button to activate the test. A small bit of water is released, flowing through the pad and rehydrating freeze-dried cells that react to the presence of coronavirus markers.After about 90 minutes, a colored line indicates whether the result is positive or negative. It looks like a pregnancy test. The team used a typical N95 mask and the results were published in Nature Biotechnology.This technology had been developed to detect other viruses such as Ebola. The MIT and Harvard teams have further plans for the technology. “We’ve demonstrated that we can freeze-dry a broad range of synthetic biology sensors to detect viral or bacterial nucleic acids, as well as toxic chemicals, including nerve toxins. We envision that this platform could enable next-generation wearable biosensors for first responders, health-care personnel and military personnel,” MIT researcher James Collins tells MIT news.Meanwhile, researchers at Khalifa University have been working on the NavaMASK, a sustainable and environmentally friendly mask made with a bio-based polymer that can be composted and integrated back into the ecosystem. “The NavaMASK not only addresses the pressing issue of mask waste but also highlights the importance of using renewable resources and minimizing environmental impact,” Shadi Hasan, director of KU’s Center for Membranes & Advanced Water Technology, tells KUST Review.‹‹‹ Read less

“In the end we do this to help people,” Pappa, who in 2019 was one of MIT Technology Review’s Innovators Under 35, tells KUST Review.

And now the team is adapting the technology into an app that, in its initial phase, begins with a simple breath into a phone and will eventually operate concurrently with wearable biosensors.

Users breathe into smartphone microphones, which capture the breath rate. The wearable biosensors read the wearers’ biological responses to stress. After the data is analyzed, the app recommends personalized breathing games to calm the heart rate and the wearer’s stress.

Breathing correctly, the team members say, is a skill people have to learn. They compare it to an athlete building endurance.

“Breathing in for seven seconds is not easy,” Dias says.

The team is working through some challenges around the many different brands of mobile devices and hopes to have a marketable product soon.

“Clearly, many development stages are on the horizon, yet we are hoping in one year to have the conceptualized idea transformed to a product. This will only happen with the intensive research efforts that we are currently undertaking, the support from Khalifa University and potential angel/venture funders,” Hadjileontiadis tells KUST Review.

The ultimate goal is for every breath to be a tool to “unlock our mindset toward stressless living,” Hadjileontiadis says.

According to the World Health Organization, stress and depression increased by 25 percent in the first year of the pandemic alone. It was so prevalent that it prompted 90 percent of countries surveyed to include mental health and psychosocial support in their COVID-19 response plans.