Day: March 10, 2025

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Substituting NHS Doctors with Physician Associates is not Necessarily Safe

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Source: Pixabay CC0

Researchers say they can find no convincing evidence that physician associates add value in UK primary care or that anaesthetic associates add value in anaesthetics, and some evidence suggested that they do not.

In a special paper published by The BMJ, Professors Trisha Greenhalgh and Martin McKee say the absence of safety incidents in a handful of small studies “should not be taken as evidence that deployment of physician associates and anaesthetic associates is safe.”

New research is urgently needed “to explore staff concerns, examine safety incidents, and inform a national scope of practice for these relatively new and contested staff roles,” they add.

Physician associates and anaesthetic associates are being introduced in the UK to work alongside doctors and nurses. They are graduates – usually with a health or life sciences degree – who complete two years of extra training, but there has been much debate about the effectiveness and safety of these new roles.

As a result, the UK government has commissioned an independent review into the scope and safety of these roles in the NHS and their place in providing care to patients.

To inform this review, the researchers trawled three electronic research databases (PubMed, CINAHL, Cochrane Library) for any studies of physician associates and anaesthetic associates in UK healthcare published between 2015 and January 2025.

In all, 52 papers were eligible (48 on physician associates, 4 on anaesthetic associates), of which 29 (all from England) met their inclusion criteria of trustworthiness, generalisability, and relevance to current UK policy.

They found that the total number of physician associates studied was very small, especially in primary care, and no studies reported direct assessment of anaesthetic associates.

Only one study, of four physician associates, involved any assessment by a doctor of their clinical competence by direct observation, and no studies examined safety incidents.

Some studies among the 29 suggested that physician associates could support the work of ward based teams and work in emergency departments when appropriately deployed and supervised in low risk clinical settings, but the number of individuals and settings studied was small, so these findings should be considered preliminary.

However, studies reported that physician associates seemed to struggle in primary care because the role was more autonomous, the case mix was more diverse, decisions were more uncertain, institutional support was more limited, and supervision arrangements were more challenging.

Patients’ views of physician associates were mostly positive or neutral, whereas staff expressed concern about physician associates’ and anaesthetic associates’ competence to manage undifferentiated, clinically complex, or high dependency patients; order scans; or prescribe. Physician associates reported a range of experiences and desired a clear role within the team.

Overall, the researchers found no evidence that physician associates add value in primary care or that anaesthetic associates add value in anaesthetics and some evidence suggested that they do not.

They acknowledge some limitations, such as not including evidence on similar roles in other countries, and stress that their findings should be interpreted in the context of the wider international evidence base. But say their focus on UK based research, detailed search and analysis of the most influential papers, and identification of gaps in existing research, provide robust conclusions to help inform this policy review.

“Very few UK studies have assessed the clinical competence and safety of physician associates or anaesthetic associates,” they write. “Findings of apparent non-inferiority in non-randomised studies may obscure important unmeasured differences in quality of care.”

In a linked editorial, Professor Kieran Walshe at the University of Manchester, asks how did the NHS end up in this mess, and what should we do about it?

He points to massive underinvestment in research on the healthcare workforce, ambiguous and largely uncosted future plans for workforce expansion, and statutory arrangements for regulating the health professions that are not fit for purpose.

“It seems likely that a messy compromise will be found to resolve the debacle over physician associates and anaesthetic associates,” he writes. But says “we need to do these kinds of workforce reforms much better in the future—both for the safety of patients and for the wellbeing of staff.”

Source: The BMJ

Categories : Cancer Neurology New Compounds and TreatmentsTags : Leave a comment

Drug More than Doubles Survival Time for Glioblastoma Patients

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MRI scan showing brain cancer. Credit: Michelle Monje, MD, PhD, Stanford University

A drug developed at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) has been shown to extend survival for patients with glioblastoma, the most common primary brain tumour in adults.

Results of a trial led by the university and reported in Nature Communications revealed that a unique investigational drug formulation called Rhenium Obisbemeda (186RNL) more than doubled median survival and progression-free time, compared with standard median survival and progression rates, and with no dose-limiting toxic effects.

“As a disease with a pattern of recurrence, resistance to chemotherapies and difficulty to treat, glioblastoma has needed durable treatments that can directly target the tumour while sparing healthy tissue,” said lead author Andrew J. Brenner, MD, PhD, professor and chair of neuro-oncology research with Mays Cancer Center at UT Health San Antonio. “This trial provides hope, with a second trial under way and planned for completion by the end of this year.”

Brenner said that the median overall survival time for patients with glioblastoma after standard treatment fails with surgery, radiation and chemotherapy is only about 8 months. More than 90% of patients have a recurrence of the disease at its original location.

Rhenium Obisbemeda enables very high levels of a specific activity of rhenium-186 (186Re), a beta-emitting radioisotope, to be delivered by tiny liposomes, referring to artificial vesicles or sacs having at least one lipid bilayer. The researchers used a custom molecule known as BMEDA to chelate or attach 186Re and transport it into the interior of a liposome where it is irreversibly trapped.

In this trial, known as the phase 1 ReSPECT-GBM trial, scientists set out to determine the maximum tolerated dose of the drug, as well as safety, overall response rate, disease progression-free survival and overall survival.

After failing one to three therapies, 21 patients who were enrolled in the study between March 5, 2015, and April 22, 2021, were treated with the drug administered directly to the tumours using neuronavigation and convection catheters.

The researchers observed a significant improvement in survival compared with historical controls, especially in patients with the highest absorbed doses, with a median survival and progression-free time of 17 months and 6 months, respectively, for doses greater than 100Gy.

Importantly, they did not observe any dose-limiting toxic effects, with most adverse effects deemed unrelated to the study treatment.

“The combination of a novel nanoliposome radiotherapeutic delivered by convection-enhanced delivery, facilitated by neuronavigational tools, catheter design and imaging solutions, can successfully and safely provide high absorbed radiation doses to tumours with minimal toxicity and potential survival benefit,” Brenner concluded.

Source: University of Texas Health Science Center at San Antonio

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Scientists Upend the Current Understanding of How PARP Inhibitors Kill Cancer

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Breast cancer cells. Image by National Cancer Institute

Research by UMass Chan Medical School scientists poses a new explanation for how PARP inhibitor drugs attack and destroy BRCA1 and BRCA2 tumour cells. Published in Nature Cancer, this study illustrates how a small DNA nick – a break in one strand of the DNA – can expand into a large single-stranded DNA gap, killing BRCA mutant cancer cells, including drug-resistant breast cancer cells. These findings identify a novel vulnerability that may be a potential target for new therapeutics. 

Mutations in BRCA1 and BRCA2, tumour suppressor genes that play a crucial role in DNA repair, substantially increase the likelihood of cancer. These cancers are, however, quite sensitive to anticancer drugs such as poly (ADP-ribose) polymerase inhibitors (PARPi). When successful, these cancer treatments cause enough DNA damage to trigger cancer cell death. However, the array of different damages potentially induced by these drugs makes it difficult to pinpoint the exact cause of cell death. Additionally, PARPi resistance does occur, complicating treatment and leading to recurrent cancer.

“The conventional thinking has been that single-stranded DNA breaks from PARPi ultimately generated DNA double-strand breaks, and that was what was killing the BRCA mutant cancer cells,” said Sharon Cantor, PhD, professor of molecular, cell and cancer biology. “Yet, there wasn’t much in the literature that experimentally confirmed this belief. We decided to go back to the beginning and use genome engineering tools to see how these cells dealt with single-strand nicks to their DNA.” 

Using CRISPR technology, Cantor and Jenna M. Whalen, PhD, a postdoctoral researcher in the Cantor lab, introduced small, single strand breaks into several breast cancer cell lines, such as those with the BRCA1 and BRCA2 mutation, as well BRCA-proficient cells. They found that cells with BRCA1 or BRCA2 deficiency were uniquely sensitive to nicks. They also found that breast cancer cells that lose components of the complex that protects DNA from unnecessary DNA end cuts become resistant to chemotherapy drugs such as PARP inhibitors. However, restoring double strand DNA repair functions in breast cancer cells did not save the cells from dying, thus demonstrating that these repair functions are not critical for breast cancer cell survival. Instead, the cells become even more sensitive to single strand nicks, which then accumulate and form large gaps.  

“Our findings reveal that it is the resection of a nick into a single-stranded DNA gap that drives this cellular lethality,” said Whalen. “This highlights a distinct mechanism of cytotoxicity, where excessive resection, rather than failed DNA repair by homologous recombination, underpins the vulnerability of BRCA-deficient cells to nick-induced damage.” 

The findings suggest that PARPi may also work by generating nicks in BRCA1 and BRCA2 cancer cells, exploiting their inability to effectively process these lesions. For cancers that have developed PARPi-resistance, nick-inducing therapies provide a promising mechanism to bypass resistance and selectively target resection-dependent vulnerabilities.  

“Importantly, our findings suggest a path forward for treating PARPi-resistant cells that regained homologous recombination repair: to kill these cells, nicks could be induced such as through ionizing radiation,” said Cantor. “By targeting nicks in this way, therapies could effectively exploit the persistent vulnerabilities of these resistant cancer cells.”

Source: UMass Chan Medical School

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Low-carb Diet’s Colorectal Cancer Risk is Mediated by the Gut Microbiome

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Gut Microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health

Researchers from the University of Toronto have shown how a low-carbohydrate diet can worsen the DNA-damaging effects of some gut microbes to cause colorectal cancer.

The study, published in the journal Nature Microbiology, compared the effects of three different diets: normal, low-carb, or Western-style with high fat and high sugar, each in combination with specific gut bacteria on colorectal cancer development in mice.

They found that a unique strain of E. coli bacteria, when paired with a diet low in carbs and soluble fibre, drives the growth of polyps in the colon, which can be a precursor to cancer.

“Colorectal cancer has always been thought of as being caused by a number of different factors including diet, gut microbiome, environment and genetics,” says senior author Alberto Martin, a professor of immunology at U of T’.

“Our question was, does diet influence the ability of specific bacteria to cause cancer?”

To answer this question, the researchers, led by postdoctoral fellow Bhupesh Thakur, examined mice that were colonized with one of three bacterial species that had been previously linked to colorectal cancer and fed either a normal, low-carb or Western-style diet.

Only one combination, a low-carb diet paired with a strain of E. coli that produces the DNA-damaging compound colibactin, led to the development of colorectal cancer.

The researchers found that a diet deficient in fibre increased inflammation in the gut and altered the community of microbes that typically reside there, creating an environment that allowed the colibactin-producing E. coli to thrive.

They also showed that the mice fed a low-carb diet had a thinner layer of mucus separating the gut microbes from the colon epithelial cells. The mucus layer acts as a protective shield between the bacteria in the gut and the cells underneath. With a weakened barrier, more colibactin could reach the colon cells to cause genetic damage and drive tumour growth. These effects were especially strong in mice with genetic mutations in the mismatch repair pathway that hindered their ability to fix damaged DNA.

While both Thakur and Martin emphasize the need to confirm these findings in humans, they are also excited about the numerous ways in which their research can be applied to prevent cancer.

Defects in DNA mismatch repair are frequently found in colorectal cancer, which is the fourth most commonly diagnosed cancer in Canada. An estimated 15 per cent of these tumours having mutations in mismatch repair genes. Mutations in these genes also underlie Lynch syndrome, a genetic condition that significantly increases a person’s risk of developing certain cancers, including colorectal cancer.

“Can we identify which Lynch syndrome patients harbour these colibactin-producing microbes?” asks Martin. He notes that for these individuals, their findings suggest that avoiding a low-carb diet or taking a specific antibiotic treatment to get rid of the colibactin-producing bacteria could help reduce their risk of colorectal cancer.

Martin points out that a strain of E. coli called Nissle, which is commonly found in probiotics, also produces colibactin. Ongoing work in his lab is exploring whether long-term use of this probiotic is safe for people with Lynch syndrome or those who are on a low-carb diet.

Thakur is keen to follow up on an interesting result from their study showing that the addition of soluble fibre to the low-carb diet led to lower levels of the cancer-causing E. coli, less DNA damage and fewer tumours.

“We supplemented fibre and saw that it reduced the effects of the low-carb diet,” he says. “Now we are trying to find out which fibre sources are more beneficial, and which are less beneficial.”

To do this, Thakur and Martin are teaming up with Heather Armstrong, a researcher at the University of Alberta, to test whether supplementation with a soluble fibre called inulin can reduce colibactin-producing E. coli and improve gut health in high-risk individuals, like people with inflammatory bowel disease.

 “Our study highlights the potential dangers associated with long-term use of a low-carb, low-fibre diet, which is a common weight-reducing diet,” says Martin.

“More work is needed but we hope that it at least raises awareness.”

Source: University of Toronto

Categories : Implants and ProsthesesTags : Leave a comment

Prosthetic Hand ‘Knows’ What it’s Touching, Grasps Like a Human

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Sriramana Sankar/Johns Hopkins University.

Johns Hopkins University engineers have developed a pioneering prosthetic hand that can grip plush toys, water bottles, and other everyday objects like a human, carefully conforming and adjusting its grasp to avoid damaging or mishandling whatever it holds.

The system’s hybrid design is a first for robotic hands, which have typically been too rigid or too soft to replicate a human’s touch when handling objects of varying textures and materials. The innovation offers a promising solution for people with hand loss and could improve how robotic arms interact with their environment.

Details about the device appear in Science Advances.

“The goal from the beginning has been to create a prosthetic hand that we model based on the human hand’s physical and sensing capabilities—a more natural prosthetic that functions and feels like a lost limb,” said Sriramana Sankar, a Johns Hopkins PhD student in biomedical engineering who led the work. “We want to give people with upper-limb loss the ability to safely and freely interact with their environment, to feel and hold their loved ones without concern of hurting them.”

The device, developed by the same Neuroengineering and Biomedical Instrumentations Lab that in 2018 created the world’s first electronic “skin” with a humanlike sense of pain, features a multifinger system with rubberlike polymers and a rigid 3D-printed internal skeleton. Its three layers of tactile sensors, inspired by the layers of human skin, allow it to grasp and distinguish objects of various shapes and surface textures, rather than just detect touch. Each of its soft air-filled finger joints can be controlled with the forearm’s muscles, and machine learning algorithms focus the signals from the artificial touch receptors to create a realistic sense of touch, Sankar said.

“The sensory information from its fingers is translated into the language of nerves to provide naturalistic sensory feedback through electrical nerve stimulation,” Sankar said.

In the lab, the hand identified and manipulated 15 everyday objects, including delicate stuffed toys, dish sponges, and cardboard boxes, as well as pineapples, metal water bottles, and other sturdier items. In the experiments, the device achieved the best performance compared with the alternatives, successfully handling objects with 99.69% accuracy and adjusting its grip as needed to prevent mishaps. The best example was when it nimbly picked up a thin, fragile plastic cup filled with water, using only three fingers without denting it.

“We’re combining the strengths of both rigid and soft robotics to mimic the human hand,” Sankar said. “The human hand isn’t completely rigid or purely soft—it’s a hybrid system, with bones, soft joints, and tissue working together. That’s what we want our prosthetic hand to achieve. This is new territory for robotics and prosthetics, which haven’t fully embraced this hybrid technology before. It’s being able to give a firm handshake or pick up a soft object without fear of crushing it.”

To help amputees regain the ability to feel objects while grasping, prostheses will need three key components: sensors to detect the environment, a system to translate that data into nerve-like signals, and a way to stimulate nerves so the person can feel the sensation, said Nitish Thakor, a Johns Hopkins biomedical engineering professor who directed the work.

“The goal from the beginning has been to create a prosthetic hand that we model based on the human hand’s physical and sensing capabilities—a more natural prosthetic that functions and feels like a lost limb.”

Sriramana Sankar

PhD student, Biomedial engineering

The bioinspired technology allows the hand to function this way, using muscle signals from the forearm, like most hand prostheses. These signals bridge the brain and nerves, allowing the hand to flex, release, or react based on its sense of touch. The result is a robotic hand that intuitively “knows” what it’s touching, much like the nervous system does, Thakor said.

“If you’re holding a cup of coffee, how do you know you’re about to drop it? Your palm and fingertips send signals to your brain that the cup is slipping,” Thakor said. “Our system is neurally inspired—it models the hand’s touch receptors to produce nervelike messages so the prosthetics’ ‘brain,’ or its computer, understands if something is hot or cold, soft or hard, or slipping from the grip.”

While the research is an early breakthrough for hybrid robotic technology that could transform both prosthetics and robotics, more work is needed to refine the system, Thakor said. Future improvements could include stronger grip forces, additional sensors, and industrial-grade materials.

“This hybrid dexterity isn’t just essential for next-generation prostheses,” Thakor said. “It’s what the robotic hands of the future need because they won’t just be handling large, heavy objects. They’ll need to work with delicate materials such as glass, fabric, or soft toys. That’s why a hybrid robot, designed like the human hand, is so valuable—it combines soft and rigid structures, just like our skin, tissue, and bones.”