Despite strenuous control efforts, hospital-acquired infections still occur – the most common of which is caused by the bacterium Clostridioides difficile, which creates lingering spores and resists alcohol-based hand sanitisers. Surprising findings from a new study in Nature Medicine suggest that the burden of C. diff infection may be less a matter of hospital transmission and more a result of characteristics associated with the patients themselves.
The study team, led by Evan Snitkin, PhD; Vincent Young, MD, PhD; and Mary Hayden, MD, leveraged ongoing epidemiological studies focused on hospital-acquired infections that enabled them to analyse daily faecal samples from every patient within the intensive care unit at Rush University Medical Center over a nine-month period.
Arianna Miles-Jay, a postdoctoral fellow in Dr Snitkin’s lab, analysed 1141 eligible patients, and found that a little over 9% were colonised with C. diff. Using whole genome sequencing at U-M of 425 C. difficile strains isolated from nearly 4000 faecal specimens, she compared the strains to each other to analyse spread. But she found that, based on the genomics, there was very little transmission.
Essentially, there was very little evidence that the strains of C. diff from one patient to the next were the same, which would imply in-hospital acquisition. In fact, there were only six genomically supported transmissions over the study period. Instead, people who were already colonised were at greater risk of transitioning to infection.
“Something happened to these patients that we still don’t understand to trigger the transition from C. diff hanging out in the gut to the organism causing diarrhoea and the other complications resulting from infection,” said Snitkin.
Hayden notes this doesn’t mean hospital infection prevention measures are not needed. In fact, the measures in place in the Rush ICU at the time of the study – high rates of compliance with hand hygiene among healthcare personnel, routine environmental disinfection with an agent active against C. diff, and single patient rooms were likely responsible for the low transmission rate. The current study highlights, though that more steps are needed to identify patients who are colonised and try to prevent infection in them.
Where did the C. diff come from? “They are sort of all around us,” said Young. “C. diff creates spores, which are quite resistant to environmental stresses including exposure to oxygen and dehydration…for example, they are impervious to alcohol-based hand sanitiser.”
However, only about 5% of the population outside of a healthcare setting has C. diff in their gut – where it typically causes no issues.
“We need to figure out ways to prevent patients from developing an infection when we give them tube feedings, antibiotics, proton pump inhibitors – all things which predispose people to getting an actual infection with C. diff that causes damage to the intestines or worse,” said Young.
The team next hopes to build on work on AI prediction for patients at risk of C. diff infection to identify patients more likely to be colonised and who could benefit from more focused intervention.
Said Snitkin, “A lot of resources are put into gaining further improvements in preventing the spread of infections, when there is increasing support to redirect some of these resources to optimise the use of antibiotics and identify other triggers that lead patients harbouring C. diff and other healthcare pathogens to develop serious infections.”
Graduates and third year students are encouraged to apply for the new Postgraduate Diploma to drive business ownership and job creation.
The University of the Witwatersrand (Wits) announced its Postgraduate Diploma in Innovation and Entrepreneurship. The diploma aims for graduates and third-year students in engineering, science, and health sciences to become catalysts for business ownership and job creation. Apply for the PG Dip in Innovation and Entrepreneurship before 30 November 2023.
Professor Christo Doherty, the course coordinator says: “We particularly encourage candidates who are contemplating pursuing a Master’s or PhD in any of these fields, so they can embark on advanced degrees armed with the knowledge of how to commercialise their research. Graduates of this programme will have a wealth of career opportunities. Equipped with the aptitude and mindset for innovation and creation, they represent the future generation of entrepreneurs and job creators. They will not merely seek jobs; they will create them.”
The programme was developed and is led by the Wits Innovation Centre, and will bridge the gap between academic research and real-world innovation. It will empower students to translate their research into tangible solutions that drive meaningful change in society. The Diploma seeks to harness the entrepreneurial spirit of young scientists and engineers to ensure that their research outcomes do not languish on dusty shelves but ignite the flames of practical application. Professor Nithaya Chetty, the Dean of the Wits Faculty of Science says: “South African universities must now give attention to both discovery research and innovation. This is a novel diploma that will combine collaborative teaching and learning to fast-track researchers into careers as innovators and entrepreneurs”.
The PGDip in Innovation and Entrepreneurship is a multi-faculty initiative characterised by a hands-on approach, with a year-long research project at its core. Students will collaborate closely with an interdisciplinary team of lecturers, gaining invaluable insights and guidance throughout their journey. The curriculum covers critical subjects such as The Fundamentals of Business for Innovators, Innovation and the Commercialization of Research, Creating Ventures for Innovators, and Applying Design Thinking to Innovation. The programme’s objective is to expedite the transformation of students’ research and ideas into commercially viable endeavours or solutions with significant societal impact.
From 2025, the programme will expand to include humanities, commerce and other faculties.
The percentage of people living with HIV receiving a three to six-month supply of ARVs at a time in the Free State has dropped from 13% last year to 3% this year, making the province the worst performer in multi-month dispensing of ARVs in the country. This while in Mpumalanga, 64% of people living with HIV receive a three to six-month refill as per national guidelines.
This is according to the latest figures from community-led clinic monitoring group, Ritshidze. In its third Free State report, released on 30 August, the group notes several challenges faced by people living with HIV, key populations that include men who have sex with men and sex workers, among others, and other public healthcare users in the province. Among these are a lack of multi-month dispensing of ARVs and long waiting times at clinics, two factors that can make it harder to take treatment as prescribed.
The report notes that multi-month dispensing often allows people living with HIV to collect their treatment at pick-up points situated at healthcare facilities or externally in the community, making it quicker and easier to collect ARVs. Yet the monitoring data shows that 41% of people using facility pick-up points said they still have to collect files, take vitals, and see a clinician before getting their parcel, which adds to unnecessary delays. “Overall, these shortcomings contribute to slow progress towards getting everyone to start and stay on HIV treatment,” the report states.
Monitoring for the new report was done in April and May this year at 21 facilities and included interviews with 1 095 public healthcare users across four districts in the province. Of the public healthcare users interviewed, 47% (516) were people living with HIV (PLHIV) and 16% (180) were younger than 25.
The recommendations
The report stresses that multi-month dispensing of antiretroviral treatment is just one of several ways to help reduce the burden on the healthcare system, and to reduce the pressure manifesting in long waiting times, overcrowded clinics, and overworked clinic staff. Ritshidze recommends – as it did in its two previous Free State reports – that “the department extends and implements refills up to three months by end of December 2023, and six months by end of September 2024”. It is also recommended that the department, “Ensures that all people living with HIV are offered a range of repeat prescription collection strategy options”, “that facility pick-up points are one-stop very quick ART collection-only, that clinic visits are under 30 minutes and there is no need to go to the clinic registry, collect folders, and to see a clinician.
“Multi-month dispensing and repeat prescription collection strategies can simplify and adapt HIV services across the cascade in ways that both serve the needs of people living with HIV better and reduce unnecessary burdens on the health system,” the report notes.
As people living with HIV often report that healthcare workers send them to the back of the queue when they miss appointments, Ritshidze recommends that staff acknowledge and understand the importance of ART continuity, that it is normal to miss appointments, and that no person living with HIV should be sent to the back of the queue if they miss an appointment as per the welcome back campaign strategy. Ritshidze also recommends that clinics must not require transfer letters to restart or continue with ART and any reports where treatment is delayed by healthcare workers requiring a transfer letter should be urgently investigated and disciplinary action taken where appropriate.
The value of multi-month dispensing
The value of multi-month dispensing is well established. Study findings on the HIV programme in Ethiopia released in May this year, for example, stressed that multi-month dispensing of antiretroviral therapy is “an integral component of differentiated HIV service delivery for people living with HIV”. Ethiopia was the first African country to implement six-month dispensing at scale.
The benefits cited by study participants included “time and cost-savings, fewer work disruptions, reduced stigma due to fewer clinic visits, better medication adherence, and improved overall health”. The perceived health system-level benefits included “improved quality of care, decongested facilities, reduced provider workloads, and improved record-keeping”.
According to Clinical Director at the Southern African HIV Clinicians Society, Camilla Wattrus, requiring people to visit healthcare facilities monthly to collect routine medication, can place a huge strain on the available resources in these facilities.
“Multi-month dispensing for eligible, stable patients on chronic medications, including ARVs can help to alleviate some of this burden, easing up the staff’s available time towards those with acute conditions and unstable patients, says Wattrus.
She says multi-month dispensing is also one way to increase access for stable patients to their medication by reducing potential adherence barriers leading to poor health and loss of income due to transport costs and time away from work – all factors identified by Ritshidze through its monitoring. External pick-up points can also help alleviate congestion at facilities and reduce waiting times.
When asked what the Free State health department can do to improve its performance on multi-month dispensing, Wattrus says establishing clear eligibility criteria will work because not all patients may be suitable. She says that patient education is vital so that they understand the importance of adherence.
“Knowing how to take and store medication, knowing where and when to collect medication, when to return for appointments, and understanding that they can return to the facility at any time they feel unwell or in the case of an emergency is very important. Adequate supply chain management to ensure an uninterrupted supply of medication along with accurate record-keeping and communication is vital,” she says. “Pharmacists, prescribers, and other staff members involved must also be adequately trained on how to deliver multi-month dispensing.”
Wattrus says in order for the Free State to do well, there needs to be an improved supply chain management system, adequate training for all involved staff, and a well-functioning pick-up point system implemented.
The reality on the ground
However, founder of the lesbian, gay, bisexual, and transgender (LGBT) organisation, Free State Rainbow Seeds, Thabiso Chaka says the Free State can do better in expanding external pickup points. “Once a person has shown interest and is also adhering to their medication, it is a bonus to say now you don’t have to come to the facility every month and every day. You can come after every three to six months. “I believe it is a good strategy to ensure that people adhere to their treatment. The reason why the Free State is doing poorly is because there is also not enough treatment viral load literacy and this creates a serious challenge and the level of care is often compromised because facilities are congested,” says Chaka.
“As the Free State Rainbow seed, we also want to become a CCMD point where we can be able to issue three to six months because by so doing our people will be comfortable.” CCMD (Central Chronic Medicines Dispensing and Distribution) is a government programme that enables stable patients to collect chronic medicines dispensed centrally from designated pick-up points. Chaka says multi-month dispensing of ARVs “is a good approach to limit issues of defaulting because the stigma attached to HIV-positive people is still there”.
According to Judy Mokoena from the Treatment Action Campaign (TAC) in the Free State, there are many reasons why the provincial department is struggling with multi-month dispensing of ARVs.
“The first one is that most facility managers and pharmacists order medication too late. Another reason is that they do not have an actual database of people living with HIV who come to their facilities. What I have noticed is that most people in the province still receive their medication inside the facilities. As TAC, we have been emphasising the issue of giving patients a supply of three to six months, but they are failing dismally,” she says. “Every year we ask the same questions when it comes to the multi-month dispensing, but there has not been a clear answer from government.”
“ARV shortage and ARV theft also play a role and could be another reason why the government is struggling to provide three to six months’ supply,” says Mokoena. “In the past, we have had challenges of stockouts in the Free State.”
Bystanders are less likely to give cardiopulmonary resuscitation (CPR) to women than men, particularly if the emergency takes place in a public area, according to research presented at the European Emergency Medicine Congress. The study also shows that in private locations older people, especially older men, are less likely to receive CPR.
The researchers say that CPR saves lives and urge people to learn how to perform CPR and to give it without hesitation to anyone who needs it, regardless of gender, age or location.
The research was presented by Dr Sylvie Cossette, a PhD nurse researcher at the Montreal Heart Institute research center, Canada. She conducted the research with Dr Alexis Cournoyer, an emergency medicine physician and researcher at the Hôpital du Sacré-Coeur de Montréal, Canada.
Dr Cournoyer said: “In an emergency when someone is unconscious and not breathing properly, in addition to calling an ambulance, bystanders should give CPR. This will give the patient a much better chance of survival and recovery.”
Dr Cossette added: “We carried out this study to try to uncover factors that might discourage people from delivering CPR, including any factors that might deter people from giving CPR to a woman.”
The researchers used data from records of cardiac arrests that happened outside of hospital in Canada and the US between 2005 and 2015, including a total of 39 391 patients, average age 67. They looked at whether or not a bystander performed CPR, where the emergency took place, and the age and gender of the patient.
They found that only around half of patients received CPR from a bystander (54%). Overall, women were slightly less likely to be given CPR (52% of women compared to 55% of men).
However, when the researchers looked only at cardiac arrests that happened in a public place, such as the street, the difference was greater (61% of women compared to 68% of men). These lower rates of CPR in public were found in women regardless of their age.
When the researchers looked at cardiac arrests that happened in a private setting, such as a home, the data indicated that with every ten-year increase in age, men were around 9% less likely to be given CPR during a cardiac arrest. For women having a cardiac arrest in a private setting the chances of receiving CPR were around 3% lower with every ten-year increase in age.
Dr Cournoyer said: “Our study shows that women experiencing a cardiac arrest are less likely to get the CPR they need compared to men, especially if the emergency happens in public. We don’t know why this is the case. It could be that people are worried about hurting or touching women, or that they think a woman is less likely to be having a cardiac arrest. We wondered if this imbalance would be even worse in younger women, because bystanders may worry even more about physical contact without consent, but this was not the case.”
Dr Cossette said: “We would like to study this issue in greater detail to understand what lies behind the difference. This could help us make sure that anyone who needs CPR gets it, regardless of gender, age or location.”
In Nature Nanotechnology, researchers report a new way to target and kill cancer cells in glioblastomas, hard-to-treat brain tumours, using electrically charged molecules to trigger self-destruction, that could be developed into a spray treatment used during surgery.
Researchers from the University of Nottingham found a new way to harness the extraordinary capabilities of bio-nanoantennae: gold nanoparticles intricately coated with specialised redox active molecules to induce apoptosis, in cancer cells on electrical stimulation.
The research focuses on patient-derived glioblastoma cells, an elusive and formidable form of brain cancer that has long evaded effective treatment. The five-year survival rate for glioblastoma is only 6.8% and the estimated average length of survival is about only 8 months from diagnosis.
The bio-nanoantennae were able to specifically target glioblastoma cells, leaving healthy cells unscathed. This unprecedented level of precision opens up new possibilities for developing treatment for glioblastoma during surgical resection of the tumour, when the bio-nanoantennae would be sprayed or injected.
The researchers, which included experts from the Schools of Engineering, Physics and Medicine have now established what is thought to be the first ‘quantum therapeutic’, which taps into the potential of quantum signalling to combat cancer.
Dr Frankie Rawson led the research and explains: “The team showed that cancer cells succumb to the intricate dance of electrons, orchestrated by the enchanting world of quantum biology. With the advent of bio-nanoantennae, this vision of real-world quantum therapies edge closer to reality. By precisely modulating quantum biological electron tunnelling, these ingenious nanoparticles create a symphony of electrical signals that trigger the cancer cells’ natural self-destruction mechanism.”
The team has now secured MRC impact acceleratory funding, have filed patent, to begin translating the technology to this eventual clinical application. Further rigorous research and validation are essential to ensure the safety and effectiveness of bio-nanoantennae for human use.
Dr Ruman Rahman from the School of Medicine and co-author of the study, adds: “Treating glioblastoma tumours has long presented challenges for clinicians and prognosis for patients is still poor, which is why any research showing the promise of a new effective treatment is hugely exciting. This research has shown the possibilities presented by quantum therapeutics as a new technology to communicate with biology. The fusion of quantum bioelectronics and medicine brings us one step closer to a new treatment paradigm for disease.”
Researchers report in Nature Communications that they have made ground-breaking progress towards identifying the root cause and potential therapy for preeclampsia. They identified a toxic protein, cis P-tau, in the blood and placenta of preeclampsia patients. This protein is also linked to the development of memory loss after brain injury or Alzheimer’s.
The pregnancy complication affects up to 8% of pregnancies globally and is the leading cause of maternal and foetal mortality due to premature delivery, complications with the placenta and lack of oxygen. It also disproportionately affects women of certain races.
According to the study, led by Drs Kun Ping Lu and Xiao Zhen Zhou at the University of Western Ontario, and Drs Surendra Sharma and Sukanta Jash at Brown University, cis P-tau is a central circulating driver of preeclampsia.
“The root cause of preeclampsia has (so far) remained unknown, and without a known cause there has been no cure. Preterm delivery is the only life-saving measure,” said Lu, professor of biochemistry and oncology at Schulich School of Medicine & Dentistry.
“Our study identifies cis P-tau as a crucial culprit and biomarker for preeclampsia. It can be used for early diagnosis of the complication and is a crucial therapeutic target,” said Sharma.
In 2016, Sharma, a leading preeclampsia researcher, and his team had identified that preeclampsia and diseases like Alzheimer’s had similar root causes related to protein issues. This research builds on that finding.
Until now, cis P-tau was mainly associated with neurological disorders like Alzheimer’s disease, traumatic brain injuries (TBI) and stroke. This association was discovered by Lu and Zhou in 2015 as a result of their decades of research on the role of tau protein in cancer and Alzheimer’s.
An antibody developed by Zhou in 2012 to target only the toxic protein while leaving its healthy counterpart unscathed is currently undergoing clinical trials in human patients suffering from TBI and Alzheimer’s Disease. The antibody has shown promising results in animal models and human cell cultures in treating the brain conditions.
The researchers were curious whether the same antibody could work as a potential treatment for preeclampsia. Upon testing the antibody in mouse models they found astonishing results.
“In this study, we found the cis P-tau antibody efficiently depleted the toxic protein in the blood and placenta, and corrected all features associated with preeclampsia in mice. Clinical features of preeclampsia, like elevated blood pressure, excessive protein in urine and foetal growth restriction, among others, were eliminated and pregnancy was normal,” said Sharma.
Sharma and his team at Brown have been working on developing an assay for early detection of preeclampsia and therapies to treat the condition. He believes the findings of this study have brought them closer to their goal.
Preeclampsia, genetics and the brain
Recent research has also thrown light on preeclampsia’s long-term impacts and possible links to brain health.
“Research has shown that women of certain races have genes that could possibly lead to higher than average blood pressure levels, eventually creating conditions for preeclampsia during pregnancy. However, it’s also true that in many low socio-economic countries there’s no registry to record PE cases. So, its link to other environmental factors is still unclear,” said Sharma.
“Preeclampsia presents immediate dangers to both the mother and foetus, but its long-term effects are less understood and still unfolding,” said Sharma. “Research has suggested a heightened risk of dementia later in life for both mothers who have experienced preeclampsia and their children.” However, the causal link between preeclampsia and dementia is not known.
The researchers say this new study has pinpointed a potential underlying cause of the complex relationship between preeclampsia and brain health.
“Our study adds another layer to this complexity. For the first time, we’ve identified significant levels of cis P-tau outside the brain in the placenta and blood of preeclampsia patients. This suggests a deeper connection between preeclampsia and brain-related issues,” said Jash, the lead author of the study.
As researchers delve deeper, how our bodies respond to stress is also emerging as a potential factor in the onset of preeclampsia.
“Although genetics play a role, factors like stress could be an important piece of the puzzle. Understanding how stress and other environmental factors intersect with biological markers like cis P-tau may offer a more complete picture,” said Jash, assistant professor of molecular biology, cell biology and biochemistry (research) and paediatrics (research) at Brown.
A stress-response enzyme called Pin1
In 1996 and 1997, Lu and Zhou made the ground-breaking discovery of Pin1, which turns out to be a stress-response enzyme. This is a specific protein in the cells that becomes active or changes its behaviour in response to stressors, such as environmental challenges, toxins or physiological changes.
“Pin1 plays a pivotal role in keeping proteins, including the tau protein, in the functional shape during stress. When Pin1 becomes inactivated, it leads to the formation of a toxic, misshapen, variant of tau — cis P-tau,” said Zhou, associate professor, pathology and laboratory medicine at Schulich Medicine & Dentistry.
Interestingly, Pin1 is a key player in cancer signalling networks, turning on numerous cancer-causing proteins and turning off many cancer-suppressing ones. Found in high levels in most human cancers, it’s particularly active in cancer stem cells, which are thought to be central to starting and spreading tumours and are hard to target with existing treatments.
“Essentially, when Pin1 is activated, it can lead to cancer. On the other hand, when there’s a decrease or deactivation in Pin1, it results in the formation of the toxic protein cis P-tau, which leads to memory loss in Alzheimer’s and after TBI or stroke. Now, we’ve uncovered its connection to preeclampsia as well,” said Zhou.
“The results have far-reaching implications. This could revolutionise how we understand and treat a range of conditions, from pregnancy-related issues to brain disorders,” said Lu.
Signalling from inflammatory cytokines activates several protein kinases in a chain – at the end of this process MKK6 (yellow) ‘switches on’ p38α (green) by binding it and adding phosphates. The combination of computer simulations, SAXS, and cryo-EM has shown how the two proteins interact and bind to each other to transmit the signal. Credits: Ella Marushchenko, Isabel Romero Calvo/EMBL
Cytokine storms, where inflammatory cascades during an infection that can spiral out of control and lead to severe disease and even death, were recently highlighted during the COVID-19 pandemic. In a new paper published in Science, researchers report their discovery of a cellular ‘switch’ which may lead to new drugs to prevent deadly cytokine storms.
EMBL Grenoble and University of Geneva researchers provide essential insights on a protein called p38α which is an important cellular ‘switch’ triggering the inflammatory response. They have obtained the first structure of p38α being activated by another regulatory protein kinase, MKK6, opening up new directions to develop drugs to stop cytokine storms.
The final switch: a drug target
Matthew Bowler, a researcher at EMBL Grenoble, has been studying kinases for more than a decade. This group of enzymes plays an important role in regulating complex processes in the cell by acting as a ‘switch’ to transmit signals and activate gene expression. They do so by phosphorylation, in which phosphate is added to other molecules to modulate their function.
Bowler’s work particularly focuses on belonging to the Mitogen Activated Protein (MAP) family of kinases, key players involved in the inflammatory response. Inflammation is switched on via a series of kinases, which activate each other in a cascade of reactions, the final kinase in the series being responsible for activating gene transcription required for inflammation. This process releases cytokines, pro-inflammatory signalling molecules, which, in case of overactivation, can lead to cytokine storms.
This kinase chain reaction is well regulated and is similar to a logic circuit: the inflammation response requires specific buttons to be switched on, ultimately activating p38α – the convergence point for all the signals and the last switch of the inflammatory process.
Because the kinase chain reaction can come from different ‘branches’ of the logic circuit, this last switch is a particularly relevant drug target. The inflammatory response is regulated by p38α and is highly activated during a cytokine storm. Inactivating it could prevent inflammation from occurring, instead of trying to treat it while it is already underway.
Protein kinases, including p38α, have therefore been heavily studied. The first protein kinase structure was solved 30 years ago and many more structures have followed, with over 7000 structures now available in the Protein Data Bank.
However, important parts of the puzzles are still missing. “Structural biologists have obtained detailed information on the structure and functions of protein kinases, but mostly in isolation. So we don’t really know how these enzymes are activated along the chain reaction,” explained Bowler.
Without this essential information about how the activation is triggered, drugs have mostly targeted the kinases’ nucleotide-binding site – a common and well-known pocket present in all kinases, where the phosphate transfer occurs. The lack of drug specificity due to a common binding site across kinases means that a drug designed to stop one kinase from signalling could also stop others. This presents a problematic side effect, considering the essential role of kinases as key regulators in cellular processes.
“There are many molecules that have been designed to target p38α, especially its nucleotide-binding site, but none have yet made it past clinical trials due to this lack of specificity,” added Bowler.
Cracking the activation mechanism
Since 2009, Bowler and a former PhD student in his lab, Erika Pellegrini, have therefore been investigating the interactions between p38α and MKK6, the kinase which activates it. But studying the interaction between kinases proves to be extremely complex. “These enzymes are very dynamic molecules; they transmit important signals and need to act quickly. In the case of p38α, it has to go into the nucleus and activate lots of other different proteins,” said Bowler.
They were hampered by the fact that the interactions of the MKK6-p38α complex cannot be determined by macromolecular crystallography, a structural biology technique often employed to investigate proteins but that is particularly challenging to apply in the case of such dynamic proteins.
Recent developments in cryo-electron microscopy (cryo-EM), particularly during the last decade, raised new hopes. In 2016, Bowler and new PhD student and first author of the paper, Pauline Juyoux, decided to switch to this technique – even though the protein complex was at the time considered too small for cryo-EM analysis. They were supported by Pellegrini, who had acquired expertise in this technique.
Using cryo-EM and complementary techniques, such as X-ray crystallography and small-angle X-ray scattering (SAXS), the team managed to obtain the 3D structure of the complex and identify a previously unknown docking site where the two enzymes interact – crucial information for understanding how p38? is activated. “This could be an interesting target for inhibitors that block this specific interaction, and consequently the signal triggering the inflammatory response,” explained Juyoux.
A collaboration with the Gervasio Lab from the University of Geneva, which uses molecular dynamics simulations, provided further insight into how the two kinases interact. “They showed that the model we had generated was compatible with the enzymatic activity and that the phosphorylation site was at the right distance from the active site,” explained Juyoux. “They also classified the different types of conformations of the complex to show how they assemble.”
Crucially, by comparing these simulations with the SAXS data they were able to model how the two proteins interact prior to catalysis. “The beauty of combining the state-of-the-art simulations with SAXS and cryo-EM data through advanced statistical approaches is that we can ‘see’ the dance of the two kinases approaching one another, while knowing that what we see in the computer is fully supported by all the experimental data available,” explained Francesco Gervasio. “The simulations required several months of supercomputing time generously allocated by the Swiss National Supercomputing Centre,” he continued, “But it was well worth it, given the relevance of the final results.”
These results provide an alternative drug target site to explore and also open the door to studying similar processes in two other families of MAP kinases: ERK kinases, which are involved in cancer, and JNK kinases, which are also involved in inflammation, especially in Alzheimer’s disease.
“Kinases are very similar to one another in terms of sequence and structure, but we don’t know how and why they respond or send a specific signal,” said Juyoux, whose current research project as a postdoctoral fellow at Institut de Biologie Structurale in Grenoble focuses on JNK kinases. “Comparing these different families of kinases could help explain the specificity of interactions and lead the way to new therapeutic approaches.”
With four in ten patients injured in primary and outpatient healthcare and 134 million adverse events occurring on the back of unsafe care in hospitals globally every year,1 World Patient Safety Day aims to address the avoidable challenges that will bolster patient safety across the healthcare spectrum.
Even in an era marked by incredible innovation and advancements in medical science, the reality is that within the four walls of the hospital environment, patients continue to face preventable challenges that could potentially threaten their health and well-being.
Recognising the seriousness of this, the World Health Organization (WHO) launched its World Patient Safety Day initiative in 2005 to increase awareness of unsafe healthcare, and to drive high-level support and commitment to address patient safety issues across all parts of the world.2
Bada Pharasi, CEO of the Innovative Pharmaceutical Association of South Africa, adds that under the theme of “engaging patients for patient safety”, World Patient Safety Day 2023 is positioned to recognise the crucial role that patients, families and caregivers play in safety in the healthcare sector.3
“Patients are the core of all healthcare systems, and evidence shows that when patients are treated as partners in their care, significant gains are made in safety, patient satisfaction and overall health outcomes,” explains Pharasi.
Patient safety is fundamental to delivering quality and essential health services and prevents and reduces risks, errors and harm to patients. A cornerstone of this lies in continuous improvement based on learning from errors and previous adverse events that have impacted patient well-being.
More than 10% of patients have experienced harm due to negligence during treatment, and alarmingly, this has resulted in over three million deaths globally every year.5 Even more concerning is that up to 80% of these instances are avoidable, with the most significant factors accounting for these errors being related to misdiagnosis and the prescribing and use of incorrect medications.1
“An integral part of addressing this plight is to elevate patients’ voices,” adds Pharasi. “This can be accomplished by ensuring that patients are involved in policy formulation, represented in governance structures, engaged in co-designing safety strategies, and are active partners in their own care.”3
Here, patients should enquire why the medication has been prescribed, how long the medication will take to resolve symptoms if the medication can be taken with others, and what are the potential side effects of the medication.6
Furthermore, patients should be cognisant of not taking medication prescribed to someone else, discarding medicines that have passed their expiry date, never exceeding dosage recommendations, carefully reading the patient information leaflets included with medications, and being aware that some medications may contain addictive substances.
For patient safety strategies to be successful, patients need to report instances where they have been prescribed the incorrect medication and the adverse effects it may have caused. To report these, patients can record their complaints on the Med Safety app, the SAHPRA e-reporting portal on its website, or via email or telephone.7
“As IPASA, we are committed to a healthier South Africa and a patient-centred healthcare system. We support the WHO mandate to ensure safer patient treatments and outcomes, and strive to continue informing healthcare professionals and patients about the benefits and risks of pharmaceutical products. In doing so, we believe we can make a notable difference in ensuring patient safety across all facets of the South African healthcare sector,” concludes Pharasi.
7. Matlala MF, Lubbe MS, Steyn H. The completeness of adverse drug reaction reports in South Africa: An analysis in VigiBase®. African Journal of Primary Health Care & Family Medicine [Internet]. 2023 [cited 2023 Sep 8];15(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9900287/
In a study published in the journal Nanoscale, researchers encased Narasin, a new antibacterial compound, in tiny, soft nanoparticles 1000 times smaller than a single strand of human hair and applied in a gel form to targeted acne sites. The University of South Australia (UniSA)-led research team found that the drug proved successful against drug-resistant acne bacteria and delivered via nanocarriers achieved a 100-fold increase in absorption than simply taken with water.
Lead author UniSA PhD student Fatima Abid says this is the first time that nano-micelle formulations of Narasin have been developed and trialled.
“Acne severely impacts approximately 9.4% of the world’s population, mainly adolescents, and causes distress, embarrassment, anxiety, low self-confidence and social isolation among sufferers,” Abid says.
“Although there are many oral medications prescribed for acne, they have a range of detrimental side effects, and many are poorly water soluble, which is why most patients and clinicians prefer topical treatments.”
Abid’s supervisor, pharmaceutical scientist Professor Sanjay Garg, says a combination of increasing antibiotic resistance and the ineffectiveness of many topical drugs to penetrate hair follicles in acne sites means there is a pressing need to develop new antibacterial therapies that are effective and safe.
Narasin is commonly used for bacterial infections in livestock but has never been previously investigated as a viable treatment for acne.
Abid, Prof Garg and researchers from UniSA, the University of Adelaide, and Aix-Marseille Université in France also investigated how well Narasin encased in nanoparticles penetrated various layers of skin, using pig’s ear skin as a model.
“The micelle formulation was effective in delivering Narasin to acne targets sites, as opposed to the compound solution which failed to permeate through skin layers,” Prof Garg says.
Up to an hour after cardiac arrest, some patients revived by cardiopulmonary resuscitation (CPR) had clear memories afterward of experiencing death and had brain patterns while unconscious linked to thought and memory, report investigators in the journal Resuscitation.
In a study led by researchers at NYU Grossman School of Medicine, some survivors of cardiac arrest described lucid death experiences that occurred while they were seemingly unconscious. Despite immediate treatment, fewer than 10% of the 567 patients studied, who received CPR in the hospital, recovered sufficiently to be discharged. Of the survivors, four in 10 recalled some degree of consciousness during CPR not captured by standard measures.
The study also found that in a subset of these patients, who received brain monitoring, nearly 40% had brain activity that returned to normal, or nearly normal, from a “flatline” state, at points even an hour into CPR. As captured by EEG, the patients saw spikes in the gamma, delta, theta, alpha, and beta waves associated with higher mental function.
Survivors have long reported having heightened awareness and powerful, lucid experiences, say the study authors. These have included a perception of separation from the body, observing events without pain or distress, and a meaningful evaluation of their actions and relationships. This new work found these experiences of death to be different from hallucinations, delusions, illusions, dreams, or CPR-induced consciousness.
The study authors hypothesise that the “flatlined”, dying brain removes natural inhibitory (braking) systems. These processes, known collectively as disinhibition, may open access to “new dimensions of reality,” they say, including lucid recall of all stored memories from early childhood to death, evaluated from the perspective of morality. While no one knows the evolutionary purpose of this phenomenon, it “opens the door to a systematic exploration of what happens when a person dies.”
Senior study author Sam Parnia, MD, PhD, associate professor in the Department of Medicine at NYU Langone Health and director of critical care and resuscitation research at NYU Langone, says, “Although doctors have long thought that the brain suffers permanent damage about 10 minutes after the heart stops supplying it with oxygen, our work found that the brain can show signs of electrical recovery long into ongoing CPR. This is the first large study to show that these recollections and brain wave changes may be signs of universal, shared elements of so-called near-death experiences.”
Dr Parnia adds, “These experiences provide a glimpse into a real, yet little understood dimension of human consciousness that becomes uncovered with death. The findings may also guide the design of new ways to restart the heart or prevent brain injuries and hold implications for transplantation.”
The AWAreness during REsuscitation (AWARE)-II study followed 567 adults who suffered in-hospital cardiac arrest between May 2017 and March 2020 in the US and UK. Only hospitalised patients were enrolled to standardise the CPR and resuscitation methods used, as well as recording methods for brain activity. A subset of 85 patients received brain monitoring during CPR. Additional testimony from 126 community survivors of cardiac arrest with self-reported memories was also examined to provide greater understanding of the themes related to the recalled experience of death.
The study authors conclude that research to date has neither proved nor disproved the reality or meaning of patients’ experiences and claims of awareness in relation to death. They say the recalled experience surrounding death merits further empirical investigation and plan to conduct studies that more precisely define biomarkers of clinical consciousness and that monitor the long-term psychological effects of resuscitation after cardiac arrest.
