“Timely identification of infants at highest risk of RSV-related morbidity is key to prevention,” said lead author Brittney M. Snyder, PhD, assistant professor, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center. “Our personalized risk prediction tool may have applications in allocating expensive and/or limited immunoprophylaxis (immunization with nirsevimab or palivizumab) to achieve the greatest benefit and in promoting RSV prevention among families with high-risk infants.”

More than half of RSV LRTIs are among healthy, term infants who are generally considered low risk. These infants are, in fact, at risk for requiring intensive care unit -level care, and some may die from their illness. Early immunization with nirsevimab is recommended for all infants by the Centers for Disease Control & Prevention, yet in October 2023 nirsevimab was in short supply and the CDC recommended giving it only to high-risk infants who weren’t eligible for immunization with palivizumab.Both products, which prevent RSV LRTI in newborns and young children, are monoclonal antibodies (nirsevimab is long-acting and only requires one dose, while palivizumab is short-acting and requires monthly injections during RSV season).

In the population-based study by Dr. Snyder and colleagues including children insured by the Tennessee Medicaid Program, the researchers assessed infants who did not receive RSV immunoprophylaxis in the first year of life. They gathered demographic and clinical data from administrative health care encounters and linked birth certificates. “To predict whether these infants developed severe RSV LRTI requiring ICU admission during the first year of life, we developed a multivariable logistic regression model. The model includes demographic and clinical variables collected at or shortly after birth-19 variables in all, such as prenatal smoking, delivery method, maternal age and assisted breathing (ventilation) during birth hospitalization,” said lead biostatistician Tebeb Gebretsadik, MPH, Department of Biostatistics, Vanderbilt University Medical Center.

Among 429,365 infants in the study, 713 had severe RSV LRTI requiring ICU admission. The tool had good predictive accuracy and internal validation that indicated a good fit.

“Our objective was to develop a personalized tool for use in all newborns using readily available birth and postnatal data to predict risk of RSV LRTI requiring ICU admission, useful for prioritizing RSV prevention products with limited availability,” said Principal Investigator Tina V. Hartert, MD, MPH, professor of medicine and pediatrics at Vanderbilt University Medical Center. Even though the recent nirsevimab shortage has, fortunately, eased up, it is not known whether shortages will occur in the future. “This tool may be particularly helpful in prioritizing which infants should be immunized during times of limited availability of RSV prevention medicines. Using the tool to identify if their infant is at high risk for RSV infection requiring ICU care may also persuade vaccine-hesitant families to accept RSV immunoprophylaxis, by showing them their newborn is at high risk,” she added.

“To ensure compatibility with nirsevimab and maternal vaccination, our tool was developed for use in all infants,” concluded co-author Niek Achten, MD, postdoctoral fellow in pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands, who imagined the need for such a tool. “In addition to use in the United States during times of limited availability, our tool may prove useful in countries with budgetary constraints needing to prioritize administration to the highest risk infants.”

The authors note that next steps to ensure optimal usefulness include validation of the tool in external populations, further cost-effectiveness analyses and decision curve analyses.

For the first time, a team of researchers from the National Park Service, U.S. Geological Survey, the University of California, Davis, and other institutions have documented and sampled some of the impaired waters, pinpointing 75 locations across a Texas-sized area of northern Alaska’s Brooks Range.

These degraded rivers and streams could have significant implications for drinking water and fisheries in Arctic watersheds as the climate changes, the researchers said.

“The more we flew around, we started noticing more and more orange rivers and streams,” said lead author Jon O’Donnell, an ecologist for the NPS’ Arctic Inventory and Monitoring Network. “There are certain sites that look almost like a milky orange juice.

Those orange streams can be problematic both in terms of being toxic but might also prevent migration of fish to spawning areas.”

Visible from space

O’Donnell first noticed an issue when he visited a river in 2018 that appeared rusty despite having been clear the year prior. He began asking around and compiling locations while grabbing water samples when possible in the remote region, where helicopters are generally the only way to access the rivers and streams.

“The stained rivers are so big we can see them from space,” said Brett Poulin, an assistant professor of environmental toxicology at UC Davis who was a principal investigator in the research. “These have to be stained a lot to pick them up from space.”

Poulin, whose expertise is in water chemistry, thought the staining looked similar to what happens with acid mine drainage, except no mines are near any of the impaired rivers, including along the famed Salmon River and other federally protected waters.

One hypothesis is that the permafrost, which is essentially frozen ground, stores minerals and as the climate warmed, the metal ores that were once locked up were exposed to water and oxygen, resulting in the release of acid and metals.

“Chemistry tells us minerals are weathering,” Poulin said. “Understanding what’s in the water is a fingerprint as to what occurred.”

The impacted rivers are on federal lands managed by Bureau of Land Management, Fish and Wildlife Service and NPS, including Gates of the Arctic and Kobuk Valley national parks.

Poulin and Ph.D. candidate Taylor Evinger analyzed initial samples, then collected their own on a trip last August, while others took samples in June and July. This year, they will take three trips during the summer to collect additional samples.

Acidic water releasing metals

Some samples from the impaired waters have a pH of 2.3 compared to the average pH of 8 for these rivers. This means the sulfide minerals are weathering, resulting in highly acidic and corrosive conditions that release additional metals. Elevated or high levels of iron, zinc, nickel, copper and cadmium have been measured.

“We see a lot of different types of metals in these waters,” Evinger said. “One of the most dominant metals is iron. That’s what is causing the color change.”

While O’Donnell first noticed a change in 2018, satellite images have turned up stained waters dating back to 2008.

“The issue is slowly propagating from small headwaters into bigger rivers over time,” he said. “When emergent issues or threats come about, we need to be able to understand them.”

Understanding risk

The researchers are in the second year of a three-year grant aimed at understanding what is happening in the water, modeling what other areas may be at risk and assessing implications for drinking water and fishing stocks.

The problem is growing and affecting habitat, water quality and other ecological systems, turning healthy areas into degraded habitats with fewer fish and invertebrates. If rural communities rely on these rivers for drinking water, they could require treatment eventually, and the fishing stocks that feed local residents could be affected.

“There’s a lot of implications,” O’Donnell said. “As the climate continues to warm, we would expect permafrost to continue to thaw and so wherever there are these types of minerals, there’s potential for streams to be turning orange and becoming degraded in terms of water quality.”

More work is needed to better understand the problem and whether rivers and streams can rebound, perhaps after cold weather promotes permafrost recovery.

“I think there will be a lot more detailed work to follow up to address some of the uncertainties that we currently have,” O’Donnell said.

Scientists from Alaska Pacific University, Colorado State University, University of Alaska Anchorage and UC Riverside also contributed to the research.

The research was funded by U.S. Geological Survey-NPS Water Quality Partnership program, the U.S. Geological Survey Changing Arctic Ecosystem Initiative and the NPS Arctic Inventory and Monitoring Program.

The research, published today in Clinical Cancer Research by a team from King’s College London and funded by Breast Cancer Now, marks a new method in cancer treatment.

The discovery is particular to triple negative breast cancer, which makes up 15% of all diagnosed breast cancer. This type of breast cancer is typically aggressive, resistant to chemotherapy, has a lower survival rate and is more common in women under 40.

Usual treatment involves surgery, chemotherapy and radiotherapy, however this type of cancer can evade the drugs and return to spread again.

The scientists conducted data analysis using over 6000 breast cancer samples to investigate the properties of breast cancer cells that are associated with aggressive and chemotherapy-resistant cancers.

They studied the cancer’s biology, what is expressed in the tumour and the cell surface, and the cell’s insides to understand how the cancer cells escape from cancer drugs. They established the presence of the cancer cell surface marker EGFR along with oncogenic molecules cyclin-dependent kinases (CDK), which are responsible for cell division and proliferation.

They used this knowledge against the cancer cells to link cetuximab, a tumour-selective antibody that targets the EGFR protein expressed in this type of cancer, with a CDK-blocking drug to create a tailored drug for breast cancer. Because the antibody drug conjugate specifically targets the cancer cell, it may be possible to administer a lower inhibitor dose than usual which means it’s less toxic for the patient.

Lead author Professor Sophia Karagiannis, from King’s College London, said: “We were on the hunt for cancer’s vulnerabilities and now we’ve found out how we can guide our therapies to one of these. We combined these two drugs to create a tailored antibody drug conjugate for patients with this aggressive cancer. The antibody guides the toxic drug directly to the cancer cell which offers the possibility for a lower dose and less adverse side effects to be experienced.

“More work needs to be done before this therapy can reach the clinic, but we expect that this can offer new treatment options for cancers with unfavourable prognosis. Beyond this antibody drug conjugate, we hope that our concept will lead the way for new antibody drug conjugates of this type to be tailored to patient groups likely to benefit.”

Lead research scientist Dr Anthony Cheung from King’s College London said: ”Triple negative breast cancer represents a molecularly and clinically diverse disease. By exploiting EGFR overexpression and dysregulated cell cycle molecules in selected patient groups, the antibody drug conjugate, but not the antibody alone, could stop the cancer cell from dividing and engender cytotoxic functions specifically against the cancer cells.”

Dr Simon Vincent, director of services, support and influencing at Breast Cancer Now, which funded this research, said: “Each year, around 8,000 women in the UK are diagnosed with triple negative breast cancer, which is typically more aggressive than other breast cancers and more likely to return or spread following treatment.

“This exciting research has not only improved our understanding of the properties of aggressive breast cancer cells that are resistant to chemotherapy but has also brought us closer to developing a targeted therapy that destroys these cancer cells while minimising side effects for patients.

“While further research is needed before this treatment can be used in people, this is an exciting step forward in developing targeted therapies for triple negative breast cancer, and we look forward to seeing how these findings could lead to new and effective ways of tackling this devastating disease.”