The Pathogen Problem

Candida auris is a fungus that can cause serious infections, particularly in patients who are immunocompromised, have pre-existing health conditions, are in long-term healthcare settings, or are undergoing treatment with invasive medical devices such as a catheter. Infection prevention and control is challenging because the fungus can grow on both dry and moist surfaces such as furniture, door handles, clothing, and medical equipment in healthcare facilities. It’s also shown resistance to many commonly used surface disinfectants and all three types of antifungal medicines. More than 1 in 3 patients with invasive C. auris infections — which can affect the blood, heart, or brain — dies.

What’s more, Nevada — one of six states with recently high burdens of C. auris — last year experienced outbreaks across multiple healthcare facilities and logged the most U.S. cases of the fungal infection. The Silver State experienced a 16-fold increase from just 24 cases in 2021 to 384 cases in 2022, according to the Centers for Disease Control and Prevention (CDC). Cases have also been reported in dozens of other countries.

What They Found

A research team led by Casey Barber, a UNLV School of Public Health doctoral student and Southern Nevada Water Authority (SNWA) graduate intern, recently published a study in the journal Environmental Science & Technology that analyzed 10 weeks’ worth of wastewater samples from seven Southern Nevada sewersheds.

The scientists detected the genetic material of C. auris in at least one untreated sewage sample from each Southern Nevada wastewater treatment facility and nearly 80% of all untreated sewage samples in the study. The sewersheds serving healthcare facilities involved in the outbreak also showed higher detection frequencies for the fungus. Researchers noted that no fungus was detected in untreated sewage samples from a wastewater treatment facility in Utah, an area with no known C. auris cases at the time. The fungus was not detected in the Las Vegas Wash, which contains treated wastewater effluent, nor in Lake Mead, indicating that there is no sign that C. auris poses a risk to drinking water.

“These results show that wastewater surveillance may help monitor the spread of C. auris and could serve as an early warning system for public health action,” Barber said.

Other Takeaways

The first human case of C. auris was reported in 2009, but it’s become more prevalent in recent years. The fungus is often spread via contaminated surfaces or skin-to-skin contact with infected individuals, including with those who are asymptomatic.

Scientists called the Southern Nevada fungus flare-up — which erupted in August 2021 and has now affected over 30 healthcare facilities — one of the largest recent outbreaks of healthcare-associated C. auris in the U.S. The research team formally launched C. auris-specific monitoring and data collection in late June 2022, as part of a larger ongoing UNLV wastewater surveillance collaboration with SNWA.

In addition to implications for large-scale C. auris detection and prevention, researchers said the study is groundbreaking in its progress towards helping establish new procedures for sewage sample processing, preparation, and analysis to look for C. auris.

Wastewater surveillance, they said, may provide a more accurate estimate of C. auris prevalence than traditional public health surveillance methods, in part because traditional methods may not accurately identify C. auris, leading to delays in targeted intervention measures. The team also anticipates that their previously established approach to monitoring COVID-19 levels in wastewater could be applied to watching for mutations and new strains of C. auris.

“Detection of Candida auris through wastewater surveillance has already prompted expanded screenings in Southern Nevada healthcare facilities in an effort to prevent larger outbreaks,” said SNWA principal research microbiologist Daniel Gerrity. “This demonstrates how wastewater surveillance can be applied to emerging public health threats beyond COVID-19.”

Catalyst materials accelerate chemical reactions without undergoing changes themselves. They are critical for refining petroleum products and for manufacturing pharmaceuticals, plastics, food additives, fertilizers, green fuels, industrial chemicals and much more.

Scientists and engineers have spent decades fine-tuning catalytic reactions — yet because it’s currently impossible to directly observe those reactions at the extreme temperatures and pressures often involved in industrial-scale catalysis, they haven’t known exactly what is taking place on the nano and atomic scales. This new research helps unravel that mystery with potentially major ramifications for industry.

In fact, just three catalytic reactions — steam-methane reforming to produce hydrogen, ammonia synthesis to produce fertilizer, and methanol synthesis — use close to 10% of the world’s energy.

“If you decrease the temperatures at which you have to run these reactions by only a few degrees, there will be an enormous decrease in the energy demand that we face as humanity today,” says Manos Mavrikakis, a professor of chemical and biological engineering at UW-Madison who led the research. “By decreasing the energy needs to run all these processes, you are also decreasing their environmental footprint.”

Mavrikakis and postdoctoral researchers Lang Xu and Konstantinos G. Papanikolaou along with graduate student Lisa Je published news of their advance in the April 7, 2023 issue of the journal Science.

In their research, the UW-Madison engineers develop and use powerful modeling techniques to simulate catalytic reactions at the atomic scale. For this study, they looked at reactions involving transition metal catalysts in nanoparticle form, which include elements like platinum, palladium, rhodium, copper, nickel, and others important in industry and green energy.

According to the current rigid-surface model of catalysis, the tightly packed atoms of transition metal catalysts provide a 2D surface that chemical reactants adhere to and participate in reactions. When enough pressure and heat or electricity is applied, the bonds between atoms in the chemical reactants break, allowing the fragments to recombine into new chemical products.

“The prevailing assumption is that these metal atoms are strongly bonded to each other and simply provide ‘landing spots’ for reactants. What everybody has assumed is that metal-metal bonds remain intact during the reactions they catalyze,” says Mavrikakis. “So here, for the first time, we asked the question, ‘Could the energy to break bonds in reactants be of similar amounts to the energy needed to disrupt bonds within the catalyst?'”

According to Mavrikakis’s modeling, the answer is yes. The energy provided for many catalytic processes to take place is enough to break bonds and allow single metal atoms (known as adatoms) to pop loose and start traveling on the surface of the catalyst. These adatoms combine into clusters, which serve as sites on the catalyst where chemical reactions can take place much easier than the original rigid surface of the catalyst.

Using a set of special calculations, the team looked at industrially important interactions of eight transition metal catalysts and 18 reactants, identifying energy levels and temperatures likely to form such small metal clusters, as well as the number of atoms in each cluster, which can also dramatically affect reaction rates.

Their experimental collaborators at the University of California, Berkeley, used atomically-resolved scanning tunneling microscopy to look at carbon monoxide adsorption on nickel (111), a stable, crystalline form of nickel useful in catalysis. Their experiments confirmed models that showed various defects in the structure of the catalyst can also influence how single metal atoms pop loose, as well as how reaction sites form.

Mavrikakis says the new framework is challenging the foundation of how researchers understand catalysis and how it takes place. It may apply to other non-metal catalysts as well, which he will investigate in future work. It is also relevant to understanding other important phenomena, including corrosion and tribology, or the interaction of surfaces in motion.

“We’re revisiting some very well-established assumptions in understanding how catalysts work and, more generally, how molecules interact with solids,” Mavrikakis says.

Manos Mavrikakis is Ernest Micek Distinguished Chair, James A. Dumesic Professor, and Vilas Distinguished Achievement Professor in Chemical and Biological Engineering at the University of Wisconsin-Madison.

Other authors include Barbara A.J. Lechner of the Technical University of Munich, and Gabor A. Somorjai and Miquel Salmeron of Lawrence Berkeley National Laboratory and the University of California, Berkeley.

The authors acknowledge support from the U.S. Department of Energy, Basic Energy Sciences, Division of Chemical Sciences, Catalysis Science Program, Grant DE-FG02-05ER15731; the Office of Basic Energy Sciences, Division of Materials Sciences and Engineering, of the U.S. Department of Energy under contract no. DE-AC02-05CH11231, through the Structure and Dynamics of Materials Interfaces program (FWP KC31SM).

Mavrikakis acknowledges financial support from the Miller Institute at UC Berkeley through a Visiting Miller Professorship with the Department of Chemistry.

The team also used the National Energy Research Scientific Computing Center, a DOE Office of Science User Facility supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231 using NERSC award BES- ERCAP0022773.

Part of the computational work was carried out using supercomputing resources at the Center for Nanoscale Materials, a DOE Office of Science User Facility located at Argonne National Laboratory, supported by DOE contract DE-AC02-06CH11357.

“This is a big step in providing actionable data for regulatory agencies and clinicians in terms of making sense of the state of the literature on this hugely important health topic. The results can be used by organizations like the Environmental Protection Agency, which is currently considering strengthening limits on PM2.5 exposure,” said lead author Marc Weisskopf, Cecil K. and Philip Drinker Professor of Environmental Epidemiology and Physiology. “Our findings support the public health importance of such a measure.”

The study is the first systematic review and meta-analysis to use the new Risk of Bias In Non-Randomized Studies of Exposure (ROBINS-E) tool, which addresses bias in environmental studies in greater detail than other assessment approaches. It also is the first to include newer studies that used “active case ascertainment,” a method that involved screening of entire study populations followed by in-person evaluation for dementia among individuals who did not have dementia at baseline.

The study will be published online April 5, 2023, in The BMJ.

More than 57 million people worldwide are currently living with dementia, and estimates suggest that number will increase to 153 million by 2050. Up to 40% of these cases are thought to be linked to potentially modifiable risk factors, such as exposure to air pollutants.

Weisskopf and his co-authors, Elissa Wilker, researcher in the Harvard Chan-NIEHS Center for Environmental Health, and Marwa Osman, a doctoral student in the Biological Science in Public Health program, scanned more than 2,000 studies and identified 51 that evaluated an association between ambient air pollution and clinical dementia, all published within the last 10 years. Those studies were assessed for bias using ROBINS-E, and 16 of them met the criteria for the meta-analysis. The majority of the research was about PM2.5, with nitrogen dioxide and nitrogen oxide being the next most common pollutants studied. Of the studies used in the meta-analysis, nine used active case ascertainment.

The researchers found consistent evidence of an association between PM2.5 and dementia, even when annual exposure was less than the current EPA annual standard of 12 micrograms per cubic meter of air (μg/m3). In particular, among the studies using active case ascertainment, the researchers found a 17% increase in risk for developing dementia for every 2 μg/m3 increase in average annual exposure to PM2.5. They also found evidence suggesting associations between dementia and nitrogen oxide (5% increase in risk for every 10 μg/m3 increase in annual exposure) and nitrogen dioxide (2% increase in risk for every 10 μg/m3 increase in annual exposure), though the data was more limited.

The researchers noted that air pollution’s estimated association with risk of dementia is smaller than that of other risk factors, such as education and smoking. However, because of the number of people exposed to air pollution, the population-level health implications could be substantial.

“Given the massive numbers of dementia cases, identifying actionable modifiable risk factors to reduce the burden of disease would have tremendous personal and societal impact,” Weisskopf said. “Exposure to PM2.5 and other air pollutants is modifiable to some extent by personal behaviors — but more importantly through regulation.”

Funding for the study came from Biogen and from National Institutes of Health grants P30 ES000002 and T32 HL007118.

Empowering survivors with the numbers

Despite the finding of excess mortality in survivors, the investigators found that patients’ health behaviors had an impact on their risk. Maintaining a healthy lifestyle (defined as having a healthy weight, not drinking more than moderate amount of alcohol, not smoking and exercising at or above the intensity recommended by the Centers for Disease Control guidelines) was associated with a 20% reduction in the risk of mortality, compared to those who did not.

“These findings provide important evidence that the high-risk for mortality that this population faces may be able to be reduced through changes in their health behaviors,” said senior author Greg Armstrong, M.D., M.S.C.E., St. Jude Department of Epidemiology and Cancer Control chair. “This is important because our goal is to extend the lifespan of survivors and to improve their healthspan as well.”

In addition to lifestyle, several major risk factors for heart disease and related issues were associated with mortality risk. Survivors with hypertension or diabetes had a significantly higher mortality rate than survivors without those conditions. However, these conditions are modifiable — patients can improve or prevent them, and physicians can provide treatments effective against these diseases.

“Much research has demonstrated that survivors are vulnerable to early onset of chronic disease and mortality,” said co-author Melissa Hudson, M.D., St. Jude Cancer Survivorship Division director. “The study highlights the importance of encouraging survivors to practice healthy behaviors and maintain good control of cardiovascular disease risk factors to improve their healthspan and lifespan.”

Excess mortality and cause of death in survivors

In addition to the importance of potentially modifiable risk factors, this report is the first to detail that the specific primary causes of death in long term survivors are similar to the leading causes of death in the U.S. population, occurring earlier in survivors.

“We identified that long-term survivors of childhood cancer are experiencing a large number of deaths in excess of what would be expected for the general, aging population,” said the first and corresponding author Stephanie Dixon, M.D., MPH, St. Jude Department of Oncology. “We were the first to find that decades after treatment, these excess deaths are predominantly due to the same leading causes of death as in the general population, including second cancers, heart disease, cerebrovascular disease/stroke, chronic liver and kidney disease and infectious causes of death, experienced at a younger age and higher rate, in childhood cancer survivors,” Dixon said.

Treatments for childhood cancers have improved to the point where over 85% of U.S. patients are effectively cured of their primary tumor after frontline treatment. As more patients survive their childhood cancer, there is a growing population of adult survivors. By comparing the CCSS cohort to the public, the researchers found that decades after treatment survivors still experience four times the expected risk of death.

The largest cancer survivor cohort feeds discovery

The researchers were able to understand the problems affecting survivors using detailed health data from thousands of CCSS participants. The CCSS is the largest cohort of cancer survivors in North America, representing an estimated 20% of all childhood cancer survivors in that region. The scientists were able to take this vast swath of data to statistically isolate variables affecting survivor mortality. The group showed that even when common confounders, such as sociodemographic features, were controlled for, the gap in mortality between survivors and the general public persisted, but so did the protective effects of a healthy life.

“What was most exciting to see was that, independent of prior treatment exposures and sociodemographic factors, a healthy lifestyle and absence of hypertension or diabetes were each associated with a reduced risk of health-related mortality,” Dixon said. “This suggests that while continued efforts to reduce treatment intensity while maintaining (or improving) 5-year survival are needed, future research should also focus on interventions for modifiable lifestyle and cardiovascular risk factors which may need to be specifically tailored to survivors with the goal of reducing chronic disease development and extending the lifespan of survivors of childhood cancer.”

Intensive treatments continue to tax childhood cancer survivors

Patients treated with more intensive therapies continued to experience higher mortality than other survivors. Much research has focused on minimizing the harms of therapy, but many survivors in the CCSS were treated before improved techniques were widely available. This study showed that physicians and researchers need to consider interventions that can decrease risk for the vulnerable population of survivors that were treated with aggressive therapies in their youth.

“The Childhood Cancer Survivors Study continues to provide important insights into the long-term outcomes of the growing number of children successfully treated for cancer,” said co-author Leslie Robison, emeritus St. Jude Department of Epidemiology and Cancer Control chair. “The findings from the current analysis further emphasize the need to expand our efforts to reduce acute, chronic and late-onset toxicities of treatment, particularly those toxicities that can directly or indirectly result in premature mortality.”

Approximately one in six people worldwide is affected by infertility, according to the World Health Organization, and one in every 22 children in Australia is born via assisted reproduction. With a 78% failure rate, each IVF cycle can be an emotional rollercoaster that often ends in heartbreak.

“Male infertility plays a role in around 30% of cases, due to problems such as low sperm count, reduced motility or movement or poor sperm quality,” says Professor Majid Warkiani from the School of Biomedical Engineering at the University of Technology Sydney (UTS).

“While much work has been done around selecting eggs and embryos to boost the success rates of IVF, sperm selection, an essential component in assisted reproduction, is by far the most neglected step in regard to technological innovation,” he says.

To tackle this problem, researchers from UTS and NeoGenix Biosciences, a UTS-born start-up, have created and tested a new microfluidic sperm selection device that provides a more reliable process for selecting high-quality sperm.

Traditional sperm selection methods, such as density gradient centrifugation and swim-up, can cause DNA fragmentation and cell death, leading to unsuccessful IVF cycles.

“This new technology is a 3D printed, biologically inspired microfluidic sperm selection device, which replicates the female reproductive tract and the natural sperm selection process, where only a small percentage of total sperm reach the egg,” Professor Warkiani said.

“We conducted extensive testing against conventional IVF selection methods, with the new method showing an 85% improvement in DNA integrity and an average 90% reduction in sperm cell death. The sperm selected by our method also demonstrated better recovery after freezing than traditional methods,” he said.

The study results were recently published in Nature: Microsystems & Nanoengineering.

The researchers have partnered with Monash University and Australian IVF clinics to implement the technology into clinical practice. They hope the device will provide help for those struggling with infertility and reduce the number of unsuccessful IVF cycles.