The Duffy-null phenotype results in relatively lower levels of white blood cells called neutrophils when measured in the blood. This is not because they have less neutrophils overall, but because they are more frequently located in other body tissues. Tests that restrict clinical trial eligibility to patients with certain blood levels of neutrophils may therefore be unfairly discriminating against patients who could potentially benefit from trial therapies.

The failure to account for Duffy-null phenotype also means that recommendations for many standard cancer drugs inappropriately call for less-effective doses for some individuals, researchers say.

Tests that count neutrophils in a blood sample are performed to ensure that patients can safely be treated with chemotherapy or other anti-cancer drugs. Levels of neutrophils, white blood cells that kill bacteria and other foreign microbes, are often reduced by cancer drugs, potentially raising the risk of infection. For patients to qualify for a clinical trial or a standard dose of many cancer drugs, their neutrophil levels need to be above a certain threshold to ensure they will retain enough of these cells following treatment.

The threshold was established by studies conducted primarily in patients of European descent who rarely have the Duffy-null phenotype. Many healthy people with the Duffy-null phenotype (mostly people of African and Middle Eastern ancestry), however, normally have lower levels of neutrophils in their blood and relatively higher levels in their other tissues.

“Natural variation in neutrophil counts between people of different ancestry has been historically described by the inaccurate and now-outdated diagnosis ‘benign ethnic neutropenia,'” says Stephen Hibbs of Queen Mary University of London, who led the study, published today by JAMA Network Open, and for which Dana-Farber’s Andrew Hantel, MD is senior author. “But since this variation was discovered to be caused by the Duffy null phenotype, we need to re-examine the ways in which neutrophil count misinterpretation can affect patient care.”

“People with the Duffy-null phenotype are equally able to fight off infections compared to others,” Hantel says. “The concern is that they’ve been excluded from clinical trials because the neutrophil blood levels that are normal for them can fall below the cut-off points for trial participation. In this study, we explored the extent to which this occurs.”

The researchers examined participation criteria for 289 major phase III trials of drugs for the five most prevalent cancers in the United States and United Kingdom: prostate, breast, colorectal, and lung cancer, and melanoma. The drugs included chemotherapy agents, targeted therapies, and hormonal therapies (which generally don’t decrease neutrophil levels).

They found that 76.5% of the trials excluded patients whose blood neutrophil counts were in the normal range for people with the Duffy-null phenotype. The trials with the highest exclusion rate — 86.4% — were for patients with colorectal cancer. Even trials of hormonal cancer therapies — which generally don’t decrease neutrophil levels — had a significant exclusion rate.

The researchers also examined the extent to which clinical trial protocols require that drug doses be modified for patients with lower neutrophil counts.

“The treatment guidelines set by the National Comprehensive Cancer Network, or NCCN, are based on the clinical trials in which those drugs were tested,” Hantel explains. “If a trial stipulates that the dosage should be lowered or delayed if a patient’s blood neutrophil count is below a certain level, doctors often use those modifications once the drug is approved as standard therapy. We know that in many cases, survival rates are lower for patients who receive lowered or delayed doses.”

The researchers reviewed 71 clinical trials that led to NCCN recommended treatment regimens. They found that more than half required reducing the drug dose, delaying its administration, or stopping it if a participant’s neutrophil count fell below a level that was still normal for people with the Duffy null phenotype. When they looked at recommended changed based on individual Food and Drug Administration labels for each therapy used, a similar rate of dose changes was seen.

“The effect of these recommendations is to inappropriately reduce the intensity of treatment for patients who would likely tolerate regular doses,” Hantel says.

Based on their findings, the researchers recommend that clinical trials of cancer drugs allow entry to patients with lower, but normal-for-them neutrophil counts. “Everyone being screened for trial entry should be tested for the Duffy-null phenotype. If they are Duffy-null and their counts are in the reference range for that group, they should be admitted,” Hantel remarks.

For current and future trials, the same principle should be used in determining whether trial participants require lower or delayed doses: people with Duffy-null phenotype whose neutrophils are in their healthy range should be eligible for full doses of the study drug. For trials that have already been completed, follow-up studies are needed to determine if administering full doses to people with Duffy-null phenotype and lower neutrophils counts are safe and effective, researchers say.

“Health inequity in cancer treatment and research has many causes, and some are more difficult to address than others. Neutrophil criteria for clinical trials and dose modifications are a hidden contributor to inequity that can be rectified. Now, action to amend these criteria is needed to ensure Duffy-null patients are not disadvantaged,” said Hibbs.

The study was funded by the National Institutes of Health, the American Society for Clinical Oncology, and the Wellcome Trust.

In what the researchers say in Scientific Reports is the first time for a non-human animal to be demonstrated to possess some mental states (e.g., mental body image, standards, intentions, goals) which are elements of private self-awareness, bluestreak cleaner wrasse (Labroides dimidiatus) checked their body size in a mirror before choosing whether to attack fish that were slightly larger or smaller than themselves.

The team of OMU Graduate School of Science student Taiga Kobayashi, Specially Appointed Professor Masanori Kohda, Professor Satoshi Awata, and Specially Appointed Researcher Shumpei Sogawa, and Professor Redouan Bshary of Switzerland’s University of Neuchâtel, were among the group that last year reported the cleaner wrasse could identify photographs of itself as itself, based on its face through mirror self-recognition.

This time, the cleaner wrasse’s behavior of going to look in the mirror installed in a tank when necessary indicated the possibility that the fish were using the mirror to check their own body size against that of other fish and predict the outcome of fights.

“The results that fish can use the mirror as a tool can help clarify the similarities between human and non-human animal self-awareness and provide important clues to elucidate how self-awareness has evolved,” doctoral candidate Kobayashi declared.

This study was financially supported by JST SPRING (JPMJSP2139 to T.K.), JSPS KAKENHI (23KJ1829 to T.K., 19F19713 and 20K20630 to M.K., 22H02703 to S.A., and 20K20154 to S.S.), Swiss Science Foundation (310030_192673 to R.B.), and an OCU Strategic Research Grant 2018-2019 (to M.K. and S.A.).

Pathogens can be airborne, but little is known about the diversity of microbes that can survive at very high altitudes, where the conditions are harsh. “We know that above a certain point in the troposphere (called the planetary boundary layer), certain materials can be transported over long distances because the air in that region is isolated from the surface and there is less friction. But we did not suspect that viable microorganisms could be there also,” says Xavier Rodó, ICREA researcher at ISGlobal.

“Our study is unique in that we performed 10 tropospheric flights to examine microbial diversity at high altitudes, while most studies have been performed only a few metres above the ground or the ocean,” he adds.

Airborne microbes high above Japan

Using a Cessna aircraft, Rodó and an international team of colleagues conducted ten air surveys between 1,000 and 3,000 metres above Japan, starting from Chofu airport near Tokyo. All flights were planned to follow wind currents coming from mainland Asia in what are known as tropospheric bridges, which connect air from distant regions of the world; in this case, air that uplifts in mainland China and then descends over Tokyo due to typical winter weather conditions. For comparison, samples were also collected on the ground at Chofu. A total of 22 aerosol filter samples, collected during two periods (February and April, 2014), were analysed for their chemical and biological composition.

DNA sequencing allowed the research team to identify over 266 fungal and 305 bacterial genera associated with the aerosols, some of which are potentially pathogenic for humans, other animals or plants. For instance, bacterial species such as Escherichia coli, Serratia marcescens, Clostridium difficile, Clostridium botulinum, Haemophillus parainfluenzae, Acinetobacter baumannii and several Staphylococcus species were identified, as well as fungal species from genera such as Candida, Cladosporium and Malassezia, capable of causing disease in susceptible and immunocompromised individuals.

By culturing some of the samples, the researchers showed that bacteria collected from the air remained viable, and that some were resistant to commonly used antibiotics. “Surprisingly, the Micrococcus luteus strain isolated was resistant to multiple drugs, including carbapenems, glycopeptides, ciprofloxacin, and trimethoprim-sulfamethoxazole. Our findings suggest that antimicrobial resistance could spread over long distances via this previously unrecognised route,” says Sofya Podzniakova, co-first author of the study.

Travelling thousands of kilometres

The association of these aerosols with certain elements such as zinc sulfate and potassium, commonly used in fertilizers and pesticides, suggests an agricultural origin, consistent with intensively farmed croplands in northeast China.

Finally, during the days sampled, flight and ground samples were very similar in terms of microbial diversity, which can be explained by air descending from high altitudes to the ground. The particle transport models, simulated by Roger Curcoll -currently a researcher at the Universitat Politècnica de Catalunya — BarcelonaTech (UPC)- have corroborated both the possible transport of these particles from northeast China and the decline of tropospheric air masses to land in Japan.

“Our findings uncover a rich and unprecedented diversity of microbes that are dispersed by wind currents thousands of kilometres away from their sources by intense tunnels of wind that form high in the troposphere,” says Rodó. “They represent a paradigm shift in our understanding of how human health can be affected by pathogens thriving in the environment, particularly in the air.”

While the study does not prove a causal link between the presence of known human pathogens in aerosols and health effects, it does emphasise the need to further explore the spread of different microbial pathogens over long distances.

The study was presented by Dr Anne Vejen Hansen from the department of respiratory medicine at Copenhagen University Hospital, Denmark.

She said: “Asthma is common in women of reproductive age. Previous studies have shown that it takes women with asthma longer to get pregnant than those without asthma when undergoing fertility treatment, and that asthmatic women who succeed in getting pregnant have more often had fertility treatment than non-asthmatic women. But most existing studies are on women who have actually got pregnant, so we wanted to examine fertility outcomes on a national scale, to also include those that might not become pregnant at all.”

The team analysed reproductive outcomes for all Danish women born from 1976 to 1999, following them from 1994 to 2017. In total, 769,880 women were included and followed; anyone who took anti-asthma medication on a regular basis was classified as asthmatic.

They found that women with asthma experienced a higher degree of foetal loss compared to women without asthma (17.0% vs. 15.7%) and more use of fertility treatment (5.6% vs. 5.0%). However, the proportion who subsequently gave birth was 77% in women with and without asthma, suggesting that asthma does not seem to affect the number of live births.

Dr Vejen Hansen said: “We found that women fulfilling the definition of asthma had a higher rate of foetal loss and an increased use of fertility treatment. The more severe the asthma and the more flare ups the women experienced, the more likely they were to need fertility treatment. Why this is, is not clear. It might be related to systemic inflammation throughout the body, including women’s reproductive organs.

“But the numbers also show that these same women who redeem asthma medication still have as many live births in the end as women who don’t. This suggests that most women with asthma probably do manage to become pregnant and have babies in the end.

“We also plan to investigate the possible effect of male asthma on fertility, and, therefore, have another similar registry-based study in the pipeline.”

Professor Lena Uller is Chair of the ERS group on Airway Pharmacology and Treatment and Head of the Respiratory Immunopharmacology research group at Lund University, Sweden, and was not involved in the research. She said: “It’s reassuring that women seem to have the same live birth rate regardless of their asthma. However, the results also indicate that women with asthma should take into consideration potential reproductive challenges in their family planning. If women with asthma are worried about their fertility, they should speak to their doctor.

“The results of this study also underscore the importance of managing asthma in reproductive-aged women. The fact that the more severe the asthma, the more the problems with fertility, suggests that uncontrolled asthma is the problem and we should be helping women to get their asthma under control.”

Inflammatory bowel diseases (IBD) have become more common in both humans and animals. IBD is now a fairly common disease also in horses, causing serious welfare challenges such as weight loss, decreased performance, and pain-related behaviors. Symptoms can lead to premature retirement and even euthanasia of the horse. IBD is usually diagnosed by observing general symptoms and ultimately by endoscopy and examining a biopsy taken from the intestinal wall.

“Diagnosing IBD is also expensive for the owner and stressful for the horse, as it requires fasting, endoscopy and usually transportation to a horse hospital,” explains Academy Research Fellow Silva Uusi-Heikkilä from the University of Jyväskylä. Furthermore, endoscopy is challenging because an adult horse has a long gastrointestinal tract and most of it remains unexplored during endoscopy for practical reasons.

Microbiota Composition Studied from Horse Fecal Samples

Researchers at the University of Jyväskylä explored the opportunities to use the composition of the bacterial community, or microbiota, in horse fecal samples as a non-invasive diagnostic tool for IBD. Studies in other species, such as humans, have shown that the gut microbiota composition can be used to detect IBD and the progression of the disease. Based on this knowledge, researchers analyzed the microbiota composition of horse fecal samples to determine if that can indicate the presence of IBD.

“We observed differences in the composition of the gut microbiota between horses with IBD and healthy horses, explains Uusi-Heikkilä. The relative abundances of certain bacterial groups were found to either increase or decrease in horses with IBD,” she adds.

Artificial Intelligence Utilized in the Research

Using microbiota composition assessments, the researchers developed a machine learning model to predict IBD based on the microbiota species composition in fecal samples.

“This AI-based neural network model predicted IBD in the test samples with 100% accuracy,” says Postdoctoral Researcher Tiina Sävilammifrom the University of Jyväskylä. The next step is to further test the model and to improve its performance with more samples, she adds.

Benefits of the New Diagnostic Method for Humans and Animals

The researchers’ promising results suggest that in the future, analyzing the species composition of microbiota in fecal samples could become an accurate, cost-effective, and non-invasive method to support screening IBD in horses. This advancement could reduce the stress and financial burden associated with current diagnostic methods, benefiting both horses and their owners.

Acinetobacter baumannii (or A. baumannii) is a bacterial species commonly found in environmental settings such as water and soil. It is a known opportunistic pathogen that can cause serious infections, particularly in the bloodstream, urinary tract, lungs (resulting in pneumonia), or open wounds, especially in hospitalized or immunocompromised patients.

A. baumannii has been named as one of the top priority pathogens by the World Health Organization (WHO) and is the cause of most prevalent multi-drug resistant infections in healthcare settings. A. baumannii persists in hostile environments by readily forming biofilms — clusters of microorganisms that stick to non-biological surfaces — and utilising multiple resistance mechanisms to overcome exposure to antimicrobial agents and other environmental toxins. These properties have facilitated the global emergence of multiple drug-resistant and extremely drug-resistant phenotypes.

Described in a new study published in Antimicrobial Agents and Chemotherapy, the researchers have created the mutant strains using molecular engineering to insert various resistance motifs into A. baumannii bacteria.

The strains will facilitate the study of the pharmacodynamics and efficacy of anti-Acinetobacter compounds. This experimental platform is potentially useful for global preparedness to combat the ever-evolving threat of multi-and extremely drug-resistant A. baumannii infections.

Corresponding author Dr Vineet Dubey, Postdoctoral Research Associate at the University of Liverpool said: “This innovative approach offers a powerful tool to study the pharmacodynamics of novel therapeutics against A. baumannii. Our molecular constructs have demonstrated both stability and virulence in experimental models, ensuring robust and reliable data. The modularity of our system enables the exploration of emerging resistance mechanisms, including the ability to express multiple resistance genes, thereby facilitating the study of complex resistance networks in A. baumannii.”