Medical Bulletin 14/ September/ 2024

Researchers at the University of Pittsburgh pioneered a new approach to blood pressure monitoring by using the devices we carried with us every day.

Ramakrishna Mukkamala, professor of bioengineering at Pitt’s Swanson School of Engineering, is passionate about developing accessible blood pressure (BP) detection tools. Instead of designing a new medical device to monitor BP, Mukkamala decided to take advantage of what is in nearly everyone’s pockets smartphones and figure out how to detect blood pressure using sensors already built into them.

Mukkamala’s team harnessed tools already built into most smartphones, like motion-sensing accelerometers, front cameras, and touch sensors to build a smartphone application on an Android that can measure an individual’s pulse pressure. The user performs a hand-raising motion while holding the smartphone to make a measurement.

The findings published in Scientific Reports, demonstrate a promising new technology that could uniquely help reduce the burden of systolic hypertension globally, particularly in underserved populations.

Turning a smartphone into a monitoring device is no easy task, as Vishaal Dhamotharan, graduate student in the Cardiovascular Health Tech Laboratory, found out through multiple iterations of app development. Because smartphones don’t have force sensing tools, a crucial element of the project was figuring out how to replicate the effects of a traditional blood pressure exam using only a cell phone, which the team solved by using a familiar force — gravity.

“Because of gravity, there’s a hydrostatic pressure change in your thumb when you raise your hands up above your heart, and using the phone’s accelerometer, you’re able to convert that into the relative change in pressure,” Dhamotharan said.

“Development of a cuffless blood pressure measurement device that does not require any external calibration is the holy grail such a device currently does not exist,” said Sanjeev Shroff, collaborator and bioengineering department chair.

Systolic hypertension, or high blood pressure is the leading modifiable risk factor for cardiovascular disease, the top cause of death globally. This app could bring blood pressure monitoring software to any smartphone owner, enabling consistent self-monitoring and easy sharing of results with healthcare providers.

“This app would be really useful in low-income settings where people may not even have existing access to blood pressure tools,” Dhamotharan said. “Being able to measure blood pressure more frequently would allow an individual to track any significant changes in blood pressure, monitor for hypertension, and be able to manage their conditions with that knowledge.”

Reference: Landry, C., Dhamotharan, V., Freithaler, M. et al. A smartphone application toward detection of systolic hypertension in underserved populations. Sci Rep 14, 15410 (2024). https://doi.org/10.1038/s41598-024-65269-w

In a study of 12 participants, researchers at Beth Israel Deaconess Medical Center (BIDMC) have demonstrated that a cocktail of three broadly neutralizing antibodies (bNAb) successfully suppressed the virus in people living with HIV.

A subset of participants also demonstrated long-term control of the virus months after antibody levels declined to low or undetectable. The findings were published in Nature Medicine.

“Our data suggest that the triple broadly neutralizing antibodies (bNAb) cocktail can lead to virologic control for a prolonged period of time in most people living with HIV following ART discontinuation,” said co-corresponding author Dan H. Barouch, MD, PhD, director of the Center for Virology and Vaccine Research at BIDMC. “Larger studies are planned based on these results.”

HIV remains a global public health challenge. While ART a combination of drugs typically taken daily has transformed HIV from a fatal illness into a manageable long-term condition, it does not eliminate the virus. The antibody cocktail tested in this study could offer an alternative that reduces reliance on daily medication.

To evaluate the safety, tolerability and antiviral effect of the combination of three broadly neutralizing antibodies, Barouch and colleagues enrolled 12 volunteers living with HIV to receive three monthly infusions of the triple-antibody cocktail, with the option of receiving three more as long as participants remained virologically suppressed. Participants discontinued ART two days after their first antibody infusion.

“Overall, our study showed that three anti-HIV antibodies with significant breadth of neutralization were actually able to maintain virological suppression in the absence of ART at least during the dosing period in a majority of the participants,” said co-corresponding author Boris Juelg, MD, PhD, a principal investigator at the Ragon Institute of MGH, MIT, and Harvard. “In a smaller subset, this control was maintained up to week 44 even when the antibodies had reached very low levels in the blood. Future studies are now needed to determine the exact mechanisms of control and how long it can last.”

Reference: Julg, B., Walker-Sperling, V.E.K., Wagh, K. et al. Safety and antiviral effect of a triple combination of HIV-1 broadly neutralizing antibodies: a phase 1/2a trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03247-5

Researchers have found that a history of repeated antibiotic use causes defects in the normally protective mucus barrier of the gut, due to antibiotic-driven alterations in the microbiota. In a further study, the researchers found a bacteria-independent mechanism through which antibiotics can damage the mucus barrier directly.

The results have been published in the scientific journals Gut Microbes and Science Advances.

“Together, these two studies suggest that antibiotics can damage the mucus layer through at least two independent mechanisms and that they may have long-lasting effects through an altered gut bacteria. This further supports the notion that antibiotics should be administered in a responsible manner,” says Björn Schröder, Docent in Infection Biology in the Department of Molecular Biology at Umeå University.

Previous research has shown the consequences of short-term antibiotic treatments on the intestinal environment, but it is less clear how repeated antibiotic use in past years can affect our guts.

To address this question, Björn Schröder and his group at Umeå University teamed up with a research group at Tartu University in Estonia, who have built a deeply characterised cohort of individuals that provided stool samples and health records.

The researchers selected individuals who had taken at least five courses of antibiotics in the past, but not within six months before the stool collection, and compared their microbiota composition to individuals who had not taken any antibiotics within the last ten years.

“The analysis revealed changes to the gut bacteria composition, even though the antibiotics were taken a long time ago. These results indicate that repeated antibiotic use has a lasting effect on gut bacteria composition that can persist at least months after the last treatment,” says Kertu-Liis Krigul, PhD student at Tartu University.

After transplantation of the human microbiota into mice and using specialised methods to analyse the mucus function in the gut, the researchers found that the function of the mucus layer was disrupted in mice transplanted with bacteria from humans with a history of repeated antibiotic use. Expansion of the mucus was reduced, and the mucus layer became penetrable, allowing bacteria to move closer to the intestinal lining.

“Looking at the bacteria present in the gut in more detail, we could see that bacteria known to feed on the mucus layer were present at higher levels in these mice. This further supports a role for the gut bacteria in determining how well the mucus barrier can function,” says Rachel Feeney, PhD student at the Department of Molecular Biology at Umeå University.

Reference: Jasmin Sawaed, Lilach Zelik, Yehonatan Levin, Rachel Feeney, Maria Naama, Ateret Gordon, Mor Zigdon, Elad Rubin, Shahar Telpaz, Sonia Modilevsky, Shira Ben-Simon, Aya Awad, Sarina Harshuk-Shabso, Meital Nuriel-Ohayon, Michal Werbner, Bjoern O. Schroeder, Amir Erez, Shai Bel. Antibiotics damage the colonic mucus barrier in a microbiota-independent manner. Science Advances, 2024; 10 (37) DOI: 10.1126/sciadv.adp4119

While being overweight increases the risk of developing lifestyle-related diseases, there is a phenomenon known as the obesity paradox where a decreased risk of death has been seen during cancer therapy.

However, that paradox might not be the trend for all cancer therapies, an Osaka Metropolitan University team reports in JAMA Network Open, a publication of the American Medical Association.

The researchers used a Japanese administrative claims database of more than 500,000 lung cancer patients and examined the relation between body mass index (BMI) and the risk of mortality during immunotherapy and conventional chemotherapy.

Focusing only on patients with advanced non-small cell lung cancer, the team found that the higher the BMI, the lower the risk of mortality when undergoing both immunotherapy and chemotherapy, though it does a U-turn around a BMI of 24. Patients with a BMI under 28 showed lower risk of mortality when undergoing immunotherapy compared to conventional chemotherapy, but for those at or over that figure, the risk increases with immunotherapy while it continues to get lower with chemotherapy.

“Immunotherapy might not always be the optimal treatment method for obese patients with advanced non-small cell lung cancer, so the use of conventional chemotherapy should also be considered,” stated Mr Yasutaka Ihara of the Graduate School of Medicine’s Department of Medical Statistics, who led the study. “In addition to BMI, age, hormones, and gut microbiota have been reported as factors that influence the effectiveness of immunotherapy. Evaluation of whether immunotherapy or conventional chemotherapy improves survival in the presence of these factors is expected to contribute to the development of precision medicine.”

Reference: Ihara Y, Sawa K, Imai T, et al. Immunotherapy and Overall Survival Among Patients With Advanced Non–Small Cell Lung Cancer and Obesity. JAMA Netw Open. 2024;7(8):e2425363. doi:10.1001/jamanetworkopen.2024.25363

Without immediate action, humanity will potentially face further escalation in resistance in fungal disease, a renowned group of scientists from across the world has warned. The commentary – published in The Lancet – was coordinated by scientists at The University of Manchester, the Westerdijk Institute and the University of Amsterdam. According to the scientists most fungal pathogens identified by the World Health Organisation – accounting for around 3.8 million deaths a year – are either already resistant or rapidly acquiring resistance to antifungal drugs.

The authors argue that the currently narrow focus on bacteria will not fully combat antimicrobial resistance (AMR). September’s United Nations meeting on antimicrobial resistance (AMR) must, they demand, include resistance developed in many fungal pathogens.

Resistance is nowadays the rule rather than the exception for the four currently available antifungal classes, making it difficult – if not impossible – to treat many invasive fungal infections. Fungicide resistant infections include Aspergillus, Candida, Nakaseomyces glabratus, and Trichophyton indotineae, all of which can have devastating health impacts on older or immunocompromised people.

Dr Norman van Rhijn from The University of Manchester who coordinated the comment said: “Most people agree that resistant bacterial infections constitute a significant part of the AMR problem. However many drug resistance problems over the past decades have also been the result of invasive fungal diseases largely underrecognized by scientists, governments, clinicians and pharmaceutical companies. The threat of fungal pathogens and antifungal resistance, even though it is a growing global issue, is being left out of the debate.”

Unlike bacteria, the close similarities between fungal and human cells which, say the experts, means it is hard to find treatments that selectively inhibit fungi with minimal toxicity to patients.

Professor Ferry Hagen from the University of Amsterdam and the Westerdijk Institute in the Netherlands added: “Despite the huge difficulties in developing them, several promising new agents including entirely new classes of molecules, have entered clinical trials in recent years. But even before they reach the market after years of development, fungicides with similar modes of action are developed by the agrochemical industry resulting in cross-resistance. That sets us back to square one again. It is true many essential crops are affected by fungi, so antifungal protection is required for food security. But the question is, at what price?”

The scientists recommend:

Worldwide agreement on restricting the use of certain classes of antifungal molecules for specific applications.

Collaboration on solutions and regulations that ensure food security and universal health for animals, plants, and humans.

Adding priority to AMR to fungal infections at the UN’s meeting in September.

Reference: van Rhijna, N., Arikan-Akdaglib, S., Beardsley, J., Bongo, F., Chakrabarti, A., Chen, S.-C. A., Chiller, T., Lopes Colombo, A., Govender, N. P., Alastruey-Izquierdo, A., Kidd, S. E., Lackner, M., Li, R., & Hagen, F. (2024). Beyond bacteria: The growing threat of antifungal resistance. The Lancet, 404(10457), 1017–1018. https://doi.org/10.1016/S0140-6736(24)00739-3