Tag: 18/9/23

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Free State Bottom of the List when it Comes to Multi-month Dispensing of ARVs, Survey Finds

On By ModernMedia
Photo by Miguel Á. Padriñán

By Refilwe Mochoari for Spotlight

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.”

Republished from Spotlight under a Creative Commons Licence.

Source: Spotlight

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In Public Places, Bystanders are Less Likely to Start CPR on a Woman

On By ModernMedia
Photo by www.testen.no on Unsplash

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.”

Source: EurekAlert!

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An Electrifying Solution to Destroy Glioblastomas

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Photo by Zoltan Tasi on Unsplash

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.”

Source: University of Nottingham

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Ground-breaking Progress in Identifying the Root Cause of Preeclampsia

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Photo by Shvets Production on Pexels

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.

Source: University of Western Ontario

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A Cellular Switch to Shut off Cytokine Storms

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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.”

Source: European Molecular Biology Laboratory