The study was published in Nature Microbiology.

Human body temperature is one of the natural barriers against fungal infections, as most strains cannot survive above 95 °F. For this reason, the emergence of thermotolerant fungi is a public health challenge.

The study’s authors are part of a consortium of health centers in China which, since 2009, has been isolating fungi found in the bloodstream of hospitalized patients.

The initiative began with 12 hospitals and now includes more than 100. The species in question was found circulating in the blood of two elderly men from different cities at different times.

In a mouse infection model, the researchers showed that R. fluvialis became more virulent after treatment with two antifungal drugs from two of the three classes most commonly used in the clinic.

However, this was only the case when it was grown at a mammal’s average body temperature of 98.6 °F.

When treated with Amphotericin B, a drug normally used to fight strains resistant to other classes, it was found that the number of mutations generated by the temperature also created resistance to the drug.

To identify the genetic basis of the resistance, the two fungus strains were sequenced, revealing a duplication of the ERG11 gene, which codes for the target protein of drugs such as fluconazole.

This duplication has already been reported in other fungi resistant to the same class of drugs, the azoles.

However, when researchers deleted the extra copy of the gene, the resistance remained unchanged. What’s more, when they expressed the gene in another species that was susceptible to the drugs, it became highly resistant.

The dangers of high temperatures

Invasive pathogenic fungi are a major cause of morbidity and mortality, particularly in individuals with compromised immune systems, resulting in approximately 3.7 million deaths annually, wrote the authors.

“Considering the high diversity of fungi, with recent estimates of 2.2 million to 3.8 million species on Earth, it is believed that the danger and importance of new pathogens is seriously underestimated,” the researchers warn.

In a statement published in the same journal, researchers not involved in the study say the observations challenge current drug susceptibility testing protocols, which are designed to predict the rapid emergence of resistance, as well as doctors’ interpretations of the results.

“As global temperatures rise, not only will thermotolerance be selected for by fungi, but the pool of potential human pathogens will also increase,” write Michael J. Bottery and David W. Denning from the University of Manchester’s School of Biology, Medicine and Health in the UK.

“High temperatures can also lead to increased mutation rates, thereby increasing the genomic adaptability of these microorganisms,” they explain.

The good news is that the authors of the study have found an antimicrobial peptide that is active against R. fluvialis, with no evolution of resistance observed even at high temperatures.

The finding suggests that similar peptides could become an alternative treatment in the future.

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Applying research findings to health services and systems is in everyone’s best interest: researchers, funding agencies, and society. However, it is not yet a simple task.

Since the 1970s, with advances in evidence-based medicine, researchers from various parts of the world have been looking into ways to incorporate research findings into not only clinical decision-making but also into the development, improvement, and implementation of health programs and policies.

A particularly strong movement has come out of Canada and has set the tone for our expectations in relation to knowledge translation, a concept recognized beyond the dissemination of research findings, as a dynamic, interactive, and iterative process that involves knowledge production, synthesis, contextualization, dissemination, and ethical application, for the good of the population.

Currently, the World Health Organization (WHO) has been hard at work in this area, and in 2021 released a guide on evidence-informed decision-making (EIDM) titled Evidence, Policy, Impact.

This guide details the entire knowledge translation cycle, which includes:

• Interaction among researchers and decision-makers;
• Prioritize health problems;
• Produce knowledge through evidence synthesis or primary studies.

Additionally, this knowledge is contextualized to the specific environment where it will be applied, democratized, and implemented.

It is important to emphasize that everything is governed within the framework of equity, so that research findings do not magnify inequalities and vulnerabilities within the population, but rather promote the sustainable use of scientific evidence.

The issue is so important that WHO has been developing a research agenda for knowledge translation and evidence-informed decision-making.

Incorporating findings

In Brazil, processes for incorporating findings are also being pursued. In the latest public calls for research in the health field issued by the National Council for Scientific and Technological Development (CNPq), all proposals must include a knowledge translation plan.

In other words, researchers’ applications must detail how they intend to present their findings so that they can be incorporated by various government sectors.

This has encouraged the scientific community to reflect on the purpose of the research they are conducting, particularly when funded by the government.

In São Paulo, the São Paulo Research Foundation (FAPESP) has also been requiring researchers responding to public calls to include information about the incorporation of research findings, as required in their Research in Public Policies Program (PPPP), for example.

Another good example of this movement is the Research Program for the Unified Health System (PPSUS), a research initiative developed by the Brazilian Ministry of Health that, since 2004, has supported research whose findings can be applied to improve the health system.

This program is innovative in several respects. There are 27 programs, one in each state, and each program must involve key players from the state in a shared approach to managing the program. Some of the funding comes from the Ministry of Health and some comes from the Research Funding Agencies (FAP) in each state.

The goal is to fund research related to high-priority health and health sector management issues at a local level, which can help provide solutions to the major health problems faced by the population, as well as issues related to systems and services, which must be addressed through scientific knowledge.

As such, each state defines its priorities, evaluates and commissions the projects using its own resources, and monitors the call for proposals and research findings.

To this end, in addition to the FAP, representatives from Brazil’s State Health Secretariats (SES) are recruited to help define research priorities, evaluate and monitor research initiatives, and incorporate their findings into the health systems, services, and policies at a local level.

Benefits for the health system

In the state of São Paulo, the PPSUS has already issued eight public calls since 2004, with over 250 studies conducted and an investment of more than 41 million reais. The São Paulo State Health Secretariat (SES-SP) has been represented by the Health Institute since 2006.

The program has achieved quite impressive results:

• Developing lines of care;
• Drafting policies;
• Implementing programs;
• Suggesting processes for evaluating the health system and training programs for SUS personnel;
• Developing products and social innovations, among other actions.

The program has achieved such significant success because all PPSUS managers have ensured that it is conducted in an aligned manner. Additionally, the scientific community has understood the program and is dedicated to presenting proposals with the potential to benefit the health system.

However, this was not a simple process, nor was it immediately adopted from the first edition.

This culture of developing research projects with the possibility of incorporating the findings into services or the health system has evolved through actions that have been implemented to increasingly integrate knowledge translation and the PPSUS.

An example of this is the attempt to create closer ties between public players such as researchers and managers involved in project development. This has been encouraged since designing the project that would forge a partnership between academia and an institution under the SUS umbrella.

Another example of this is the presence of state and municipal managers and public oversight representatives at program events, in which the researchers present their findings, and dialogue on implementation is encouraged.

Recently, two meetings were held to define the priorities for the next PPSUS public call.

The first was to survey the state’s main health issues and concerns and was attended only by the State Health Secretariat’s Coordinating Offices.

The second, larger meeting was attended by over a hundred people, including researchers, managers, and community representatives, who came up with 14 lines of research for the new call for proposals.

This exercise was deemed a successful first step in bringing these public players together. The next step will be issuing the call for proposals, which should occur shortly. The PPSUS expects to receive proposals that can truly seek answers to the issues identified.

There are still many challenges to incorporating research findings into services and the health system. However, applying knowledge translation processes has been fundamental to reducing the gap between research and management.

An example of this is the PPSUS in São Paulo, which has successfully demonstrated that this is possible.

Maritsa Carla de Bortoli has a Bachelor’s degree in Nutrition (UFPR), a Master’s degree in Applied Human Nutrition (USP), and is a researcher and director at the Center for SUS/SP Health Technology for the São Paulo State Health Secretariat’s Health Institute, where she coordinates the Evidence Center¾affiliated with the Evidence-Informed Policy Network (EVIPNet).

Opinion articles do not necessarily reflect the views of Science Arena and Hospital Israelita Albert Einstein.

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These very warnings have been ignored and have led to extreme events, such as the tragedy that devastated residents of Rio Grande do Sul.

In an interview with Science Arena, biologist Antonia Maria Ramos Franco Pereira, who has a PhD in cellular and molecular biology, discusses the risk of climate change leading to future epidemics.

“When you change the environment, you also change the temperature and the winds, the humidity, the soil, and much more, including diseases transmitted by insects,” explains Pereira, a researcher at the National Institute of Amazonian Research (INPA), an organization she directed from 2018 to 2023. She was the first woman to direct the INPA in more than 70 years since the institution was founded.

During the interview, Pereira also commented on the challenges of being a female researcher and institution director in the Amazon region.

Science Arena – How does climate change lead to extreme events, such as the incident in Rio Grande do Sul?

Antonia Pereira – The scientific community—including us at INPA, through the Large-Scale Biosphere-Atmosphere Experiment in Amazonia (LBA) and Amazon-Face—has already been indicating that these changes would occur, including the savannization of the Amazon region. The disasters caused by heavy rainfall and rising temperatures also have a lot to do with urban infrastructure.

Amazon-Face is a long-term scientific research project conducted in partnership with the University of Campinas (UNICAMP) and the UK government. It seeks to provide answers to a major uncertainty regarding the future of the Amazon: understanding how the increase in atmospheric carbon dioxide (CO₂) impacts the rainforest, biodiversity, and so-called ecosystem services.

Brazil has experienced other extreme weather events in recent years, including the drought in the North region. How do such events affect the epidemiology of tropical diseases?

When you change the environment, you also change the temperature and the winds, the humidity, the soil, and much more, including diseases transmitted by insects. There is a risk that various pathogens and insect vectors themselves will adapt to the new environmental conditions.

Some may be unable to survive and will be eliminated. But some adapt and could lead to extreme conditions with regard to the incidence of diseases, including the emergence of new epidemics.

Due to the flooding in hundreds of cities in Rio Grande do Sul, there has been a huge jump in cases of diarrhea, hepatitis A, dengue fever, and leptospirosis. With the current situation, what are the most potentially effective health measures?

In cases of flooding, such as what we have seen in Rio Grande do Sul, contaminants result from the presence of microorganisms and bacteria. Leptospirosis is caused by a bacteria found in urine from rats and other animals. Action in the midst of disaster is complicated. Residents need medication and emergency treatment. Precautions involve avoiding contamination by sewage.

Sanitation measures are needed, with a focus on host animals, which are the sources of infection. In addition to leptospirosis, residents are at risk of cholera and severe diarrhea. We must examine people and diagnose cases in these regions. We need ongoing actions that are not merely palliative, as we often see in emergencies.

At the Leishmaniasis and Chagas Disease Laboratory (LLDC), under your coordination at the INPA, what progress has been made in understanding parasitic diseases in order to characterize and define the different types of illnesses?

The laboratory has a history of eco-epidemiological studies, focused on geographical distribution and diversity, as the Amazon provides our country with an enormous biodiversity of species, vectors, and pathogens.

Leishmaniasis, especially in the state of Amazonas, presents as tegumentary [causing ulcers on the mucus membranes and skin]. In Santarém, in the state of Pará, the disease is visceral [affecting the internal organs, such as the liver, spleen, and bone marrow], which can lead to death.

How is your laboratory using new approaches to diagnose and treat Leishmaniasis and other diseases based on in vitro studies or clinical research?

We are focusing on diagnosis, isolation, biochemical and molecular characterization of the pathogens, and the infection process of the vectors. In the laboratory, we study the pathogen’s resistance to drugs, such as Glucantime, which is offered by Brazil’s Unified Health System (SUS) to treat tegumentary leishmaniasis.

People who live on secondary roads [perpendicular to Amazonian highways] have difficulty even accessing transportation to Basic Healthcare Units (UBS). Can you imagine going to a UBS to get an intramuscular injection or to receive intravenous treatment daily?

With the aim of developing a topical treatment (a cream or ointment), we have been studying, since 2003, the use of natural products. We have tested many plant samples. We work with nanoparticles, because if the disease affects the skin, it is important that the treatment can pass through the skin and reach the parasite, which is located in the dermal region.

We have discovered a natural product from a plant found in the North and Northeast regions of Brazil, with anti-inflammatory properties. We already have the patent. We fractionated the material and isolated substances. From twenty substances, we found that two performed very well.

In animal models, the results were also effective. We are now advancing to a phase 1 clinical trial, in which we will evaluate how to make the microemulsion and observe whether it causes dermal and allergic reactions in healthy people, who have never come into contact with the pathogen.

When it comes to neglected tropical diseases, actions are often palliative. Which social determinants should we pay more attention to? What needs to be done to prevent outbreaks and epidemics?

As professor [Carlos Medicis] Morel [doctor, biophysicist, researcher, and member of the Brazilian Academy of Sciences] says, when we talk about neglected tropical diseases, we are actually dealing with people who are neglected. People on the lower end when it comes to quality of life, in terms of health infrastructure and housing.

When I was teaching, I always talked about children with ringworm who didn’t have shoes. Because they didn’t have shoes, they would wear plastic bags on their feet, so they didn’t touch the soil. Especially in the North, where we have a lack of filtered water and open sewer systems.

People need a better quality of life in terms of their environment and food. If we fail to care for our cities and those who live in them, we will experience more incidents like those of Rio Grande do Sul.

What were the consequences, in Brazil, of experiencing a pandemic while the federal government promoted environmental destruction and attacks on science, as well as the dissemination of fake news about vaccines and other health issues?

Many countries were generally unprepared for a pandemic. In terms of science, vaccine production was possible due to advanced prior knowledge and production. I don’t really like to discuss politics. I don’t pick sides. I’m a neutral person. So, it’s not up to me to judge one or the other. Ultimately, some people found it difficult to believe in science, mainly the vaccine.

In general, people still do not know how an immunization is produced. The media needs to show how a vaccine is made, how it affects the body, and how it prevents diseases. People need to think, be careful, and potentially use social media in a more educational, objective, and helpful way, without making things too complicated.

During the pandemic, all eyes were on COVID-19 and this affected the epidemiological control of other diseases. Was this an additional challenge for you, as the first woman to direct the INPA?

Being a woman in charge of the INPA, which has only been run by men for over 70 years, has certainly been challenging. And I like challenges. I had already been approved for a grant from the Coordination for the Improvement of Higher Education (CAPES) to go to Washington, in the United States, to participate in a year-long postdoctoral fellowship. However, I decided to take on the challenge of managing the INPA. Firstly, because no woman had ever gone through the selection process for this role at INPA.

And, to a certain extent, in a region like the Amazon, as well as the entire North region of Brazil, a woman’s presence is always challenging in high-ranking positions.

I am from Rio de Janeiro and I have become an Amazonian. I love this land. This land that so desperately needs development, growth, improvements, and particular care for the Indigenous and riverside communities. We can’t always do everything we want, because we butt up against legislation and bureaucracy.

Scientists also have their challenges, because they disagree with each other, which is healthy. Disagreement brings with it new opportunities. Even with shifting budgets in Science and Technology, the exchanges I have had with ministers Marcos Pontes, Paulo Alvim, and, more recently, Luciana Santos have been positive. I have nothing critical to say about any of them. And, in face of all the challenges, I would like to say that I had an excellent team of colleagues and support from my husband and family. I am grateful for each and every one of them. And I can’t forget my friends and the LLDC team at the INPA, which I direct, and who have held the line when I was away on institutional management duties.

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The book Empire of Pain: The Secret History of the Sackler Dynasty (Doubleday, 2021), by American journalist Patrick Radden Keefe.

WHY IS IT WORTH READING?

Since its publication in 2021, the book Empire of Pain has become increasingly prominent on the shelves of bookstores and libraries around the world, receiving an avalanche of positive reviews.

Written by the acclaimed author Patrick Radden Keefe, this meticulously researched and engaging book is a must-read for those seeking to uncover the secret history of the Sackler family—often referred to as “the most evil family in America”—and to understand how they may be responsible for triggering one of the worst public health crises ever faced in the United States.

The Sackler family, known for their love of the arts and their philanthropy in the 1930s and 1940s, have a dark side that few knew about, but which is very well addressed in the book. During their years in medical school, the Sackler brothers became adept at shock therapy and began using it to treat their psychiatric patients and even patients without symptoms.

Unfortunately, these treatments often resulted in patients being subjected to inhumane conditions, which led to many of them dying. At a crucial time in the history of medicine, in the 1960s, the Sackler brothers bought a small pharmaceutical company that would later become Purdue Pharma.

At the time, they were already amassing fortunes selling highly addictive anxiolytics. When the patent for these drugs expired, the Sackler brothers needed a replacement.

Keefe delves into the central theme of his book, which deals with how the pharmaceutical company Purdue Pharma produced the highly addictive painkiller called Oxycontin. Every detail is thoroughly explored by the author, including the unlawful filing of documents to the Food and Drug Administration (FDA), the regulatory agency for drugs in the United States, to regulate drug sales.

After its approval, Oxycontin became the best-selling drug in the United States, overtaking Viagra. The business practices adopted by Purdue Pharma are highly controversial and include excessive and inappropriate prescriptions for the drug, as well as the manipulation of documents and protocols that mitigated the impact of Oxycontin on patients’ health.

Additionally, the company used aggressive marketing tactics to boost drug sales, such as advertisements posted in doctors’ offices that include images of people with the phrase “I got my life back,” and even financial incentives for doctors who prescribed Oxycontin frequently.

The pharmaceutical company even paid other doctors to convince colleagues of the supposed benefits of Oxycontin, even though the drug is more potent than morphine and highly addictive.

Unfortunately, Oxycontin has played a major role in the opioid epidemic that has hit several countries, particularly the United States, leading to an alarming number of overdose deaths—around 500,000 people in the last 20 years.

Although the crisis was officially recognized in the 1990s, we can clearly see how the Sackler family’s questionable business practices were responsible for this calamity.

In 2007, Purdue Pharma and some of its executives pleaded guilty to criminal charges related to promoting Oxycontin. They were fined US$634 million and sentenced to provide community service.

However, the Sackler family did not face any serious criminal charges for their actions and retained ownership of the company. In 2019, the company filed for bankruptcy after facing thousands of lawsuits filed by local and state governments in the United States and victims of the opioid crisis.

The Sackler family agreed to pay US$225 million in a settlement with the courts to resolve civil charges related to Oxycontin.

With its engaging and unbiased approach, the book is a valuable resource for anyone interested in understanding the causes and consequences of the opioid epidemic that affects so many people and communities throughout the United States. In fact, the book has become a reference point for scholars, health professionals, researchers, and the general public seeking to better understand this complex issue.

Overall, Empire of Pain is an extremely important and provocative book, which sheds light on the opioid epidemic, the pharmaceutical industry, and the way that wealth and power can be used to shield individuals and companies from their responsibilities.

Opinion articles do not necessarily reflect the views of Science Arena or Hospital Israelita Albert Einstein.

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