Day: September 17, 2024

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Ignore Antifungal Resistance at Your Peril, Scientists Warn

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Candida Auris

Without immediate action, humanity will potentially face further escalation in resistance in fungal disease, a renowned group of scientists from the across the world has warned. The commentary – published in ‘The Lancet’ this week – 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 Organization – 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.

Devastating health impacts

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 coordinated the comment with Professor Ferry Hagen from the University of Amsterdam and the Westerdijk Institute in the Netherlands.

Dr van Rhijn 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.

Back to square one

Professor Ferry Hagen 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.

Source: Universiteit van Amsterdam

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Can a Cancer Diagnosis Cause Mental Health and Cardiovascular Problems in Family Members?

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Study’s findings reveal increased risks, indicating the need for interventions to reduce stress for patients and their relatives.

Photo by Alex Green on Pexels

New research suggests that a family member’s cancer diagnosis may increase first-degree relatives’ and spouses’ risks of developing psychological and cardiovascular illnesses. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

Having a family member diagnosed with cancer can be a stressful and traumatic experience for the entire family. Because stress influences not only mental health but also cardiovascular health, investigators explored whether a cancer diagnosis contributes to negative psychological and cardiovascular outcomes in family members.

Using data from the Utah Population Database, the researchers identified 77 938 first-degree relatives and spouses of 49 284 individuals diagnosed with genitourinary cancer between 1990 and 2015, and they compared them with 81 022 relatives and spouses of 246 775 individuals not diagnosed with cancer.

The team found that 7.1% of relatives and spouses were diagnosed with a psychological illness within 5 years of a family member’s cancer diagnosis, and 7.6% were diagnosed with a cardiovascular illness. Compared with controls, they had 10%, 5%, and 4% higher risks of developing a psychological condition at 1, 3, and 5 years after a family member’s cancer diagnosis. They also had 28%, 16%, and 14% higher risks of developing cardiovascular disease at 1, 3, and 5 years.

Parents of children with cancer experienced the highest risks of developing negative health outcomes – a nearly 4-times increased risk at 1-year compared with other relatives. Also, a diagnosis of kidney or bladder cancer appeared to be the most stressful among genitourinary cancer types, while testis cancer was the least.

“A diagnosis of cancer is a life-changing event for patients and their families. With our group’s unique access to the Utah Population Database, we were able to create multi-generational networks highlighting the impact of a cancer diagnosis on families,” said lead author Mouneeb Choudry, MD, of the Mayo Clinic, in Phoenix, Arizona. “As health care professionals, we should take a multidisciplinary approach to addressing the stress of a cancer diagnosis by helping mitigate financial toxicity, treatment burden, and emotional impact on both the patient and their family.”

Source: Wiley

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A Cuffless Smartphone App that Can Measure Blood Pressure

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Photo by Ivan Samkov on Pexels

Researchers at the University of Pittsburgh are pioneering a new approach to blood pressure monitoring, using the devices we carry 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 the sensors readily available in smartphones and figure out how to detect blood pressure with them. 

“The most significant thing you can do to reduce your risk of cardiovascular disease is to lower high blood pressure through lifestyle changes, but in underserved populations, many people don’t have access to blood pressure cuffs, regular doctor’s appointments, or even know it’s a problem,” Mukkamala said. “But they do have smartphones.”

Mukkamala’s team harnessed tools already built into most smartphones, like motion-sensing accelerometers, front cameras, and touch sensors to build an Android smartphone application that can measure an individual’s pulse pressure. The user performs a hand-raising motion while holding the smartphone to make a measurement. The results of the project, published in Scientific Reports, demonstrate a promising new technology that could uniquely help reduce the burden of systolic hypertension globally, particularly in underserved populations. 

Designing blood pressure technology for a touchscreen 

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. 

By pairing this hand-raising motion with guided thumb maneuvers on the smartphone, the team was able to calculate each participant’s pulse pressure, the difference between systolic and diastolic numbers. For example, an individual with a BP measurement of 120/80 has a pulse pressure of 40. For Sanjeev Shroff, collaborator and bioengineering department chair, this publication is a promising advancement for blood pressure measurement devices. 

“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,” Shroff said. “The research work reported in this publication is an important step in the right direction, and is also encouraging for additional work aimed at obtaining systolic, diastolic, and mean pressures.”

Although pulse pressure isn’t typically used in cardiovascular disease monitoring, the study revealed its significance as a metric for detecting hypertension, according to Céderick Landry, assistant professor at the University of Sherbrooke and former postdoctoral researcher in the lab. 

“Guidelines typically require doctors to measure both systolic and diastolic blood pressure, and pulse pressure is just the difference between the two.” Landry said. “We showed that if you only have access to pulse pressure, it’s still very correlated with hypertension, so part of our challenge now is changing the mentality on how to best measure things.”

Hypertension management within reach

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 innovation is especially promising for managing hypertension, which can often be lowered through lifestyle changes such as reducing salt intake, quitting smoking and exercising regularly. 

“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.” 

“The research is here – we just need some help making the technology better.” Landry said. “This is the first method of its kind, and even better, it’s something that we can start implementing right now.”

Source: University of Pittsburgh

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Anaesthesia Experiment Hints at Consciousness Arising from Quantum Effects

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Photo by Bruce Christianson on Unsplash

For decades, one of the most fundamental and vexing questions in neuroscience has been: what is the physical basis of consciousness in the brain? Most researchers favour classical models, based on classical physics, while a minority have argued that consciousness must be quantum in nature, and that its brain basis is a collective quantum vibration of ‘microtubule’ proteins inside neurons.

New research from Wellesley College published in eNeuro has yielded important experimental results relevant to this debate, by examining how anaesthesia affects the brain of rat models. Volatile anaesthetics are currently believed to cause unconsciousness by acting on one or more molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins.

Anaesthetic gases including isoflurane bind to cytoskeletal microtubules (MTs) and dampen their quantum optical effects, potentially contributing to causing unconsciousness. This idea is supported by the observation that taxane chemotherapy, consisting of MT-stabilising drugs, reduces anaesthesia effectiveness during surgery in human cancer patients.

Lead researcher professor Mike Wiest and his research team found that when they gave rats the brain-penetrant MT–stabilising drug epothilone B (epoB), it took the rats significantly longer (69s) to fall unconscious under 4% isoflurane, as measured by loss of righting reflex (LORR).

The effect could not be accounted for by tolerance from repeated exposure to isoflurane.

Their results suggest that binding of the anesthetic gas isoflurane to MTs causes unconsciousness and loss of purposeful behaviour in rats (and presumably humans and other animals). This supports the idea that consciousness is a quantum state tied to MTs.

“Since we don’t know of another (ie, classical) way that anesthetic binding to microtubules would generally reduce brain activity and cause unconsciousness,” Wiest says, “this finding supports the quantum model of consciousness.”

It’s hard to overstate the significance of the classical/quantum debate about consciousness, says Wiest, an associate professor of neuroscience at Wellesley. “When it becomes accepted that the mind is a quantum phenomenon, we will have entered a new era in our understanding of what we are,” he says. The new approach “would lead to improved understanding of how anaesthesia works, and it would shape our thinking about a wide variety of related questions, such as whether coma patients or non-human animals are conscious, how mysterious drugs like lithium modulate conscious experience to stabilize mood, how diseases like Alzheimer’s or schizophrenia affect perception and memory, and so on.”

More broadly, a quantum understanding of consciousness “gives us a world picture in which we can be connected to the universe in a more natural and holistic way,” Wiest says. Wiest plans to pursue future research in this field, and hopes to explain and explore the quantum consciousness theory in a book for a general audience.

Source: Wellesley College

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Gene Therapy for Inherited Blindness Results in 100-fold Vision Improvement

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Photo by Victor Freitas on Pexels

People with a rare genetic mutation that causes significant vision loss early in childhood experienced a 100-fold improvement in vision after receiving a corrective gene therapy. Some patients even experienced a 10 000-fold improvement in their vision after receiving the highest dose of the therapy, according to researchers from the Perelman School of Medicine at the University of Pennsylvania who co-led the clinical trial published in The Lancet.

“That 10 000-fold improvement is the same as a patient being able to see their surroundings on a moonlit night outdoors as opposed to requiring bright indoor lighting before treatment,” said the study’s lead author, Artur Cideciyan, PhD, a research professor of Ophthalmology and co-director of the Center for Hereditary Retinal Degenerations. “One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”

A total of 15 people participated in the Phase 1/2 trial, including three paediatric patients. Each patient had Leber congenital amaurosis as the result of mutations in the GUCY2D gene, which is essential to producing proteins critical for vision. This specific condition, which affects less than 100 000 people worldwide and is abbreviated as LCA1, causes significant amount of vision loss as early as infancy.

All subjects had severe vision loss with their best measure of vision being equal or worse than 20/80 – meaning if a typically-sighted person could see an object clearly at 80 feet (24m), these patients would have to move up to at least 20 feet (6m) to see it. Glasses provide limited benefit to these patients because they correct abnormalities in the optical focusing ability of the eye, and are unable to address medical causes of vision loss, such as genetic retinal diseases like LCA1.

The trial tested different dosage levels of the gene therapy, ATSN-101, which was adapted from the AAV5 microorganism and was surgically injected under the retina. For the first part of the study, cohorts of three adults each received either a low, mid, ore high dose. Evaluations were held between each level of dosage to ensure that they were safe before upping the dosage for the next cohort. A second phase of the study involved only administering the high dosage levels to both an adult cohort of three and a paediatric cohort of three, again after safety reviews of the previous cohorts.

Improvements were noticed quickly, often within the first month, after the therapy was applied and lasted for at least 12 months. Observations of participating patients are also ongoing. Three of six high-dosage patients who were tested to navigate a mobility course in varying levels of light achieved the maximum-possible score. Other tests used eye charts or measured the dimmest flashes of light patients perceived in a dark environment.

Of the nine patients who received the maximum dosage, two had the 10 000-fold improvement in vision.

“Even though we previously predicted a large vision improvement potential in LCA1, we did not know how receptive patients’ photoreceptors would be to treatment after decades of blindness,” said Cideciyan. “It is very satisfying to see a successful multi-center trial that shows gene therapy can be dramatically efficacious.”

Primarily, the study sought to determine the safety of the gene therapy and its varying dosage levels. Researchers did find some patients had side effects, but the overwhelming majority were related to the surgical procedure itself. The most common side effect was conjunctival haemorrhage, the breakage of small blood vessels underneath the clear surface of the eye, which healed. Two patients had eye inflammation that was reversed with a course of steroids. No serious side effects were related to the study drug.

This work comes on the heels of another successful ophthalmological trial at Penn restoring sight in patients with a different form of LCA. Earlier in 2024, CRISPR-Cas9 gene editing was used to improve the sight of many patients with a form of LCA tied to mutations in the CEP290 gene. Co-led by one of the new paper’s co-authors, Tomas S. Aleman, MD, professor in ophthalmology and co-director with Cideciyan of the Center for Hereditary Retinal Degenerations, the study used similar tests and was the first time children were involved in any gene editing work.

“The treatment success in our most recent clinical trials together with our earlier experience brings hope for a viable treatment for about 20 percent of infantile blindness caused by inherited retinal degenerations,” Aleman said. “The focus now is on perfecting the treatments and treating earlier manifestations of these conditions once safety is confirmed. We hope similar approaches will lead to equally positive outcomes in other forms of congenital retinal blindness.”

Moving forward, approval of this experimental medicine for clinical use requires a randomised controlled trial.

Source: University of Pennsylvania School of Medicine