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Take a look at a selection of our recent media coverage:
19th December 2024
Daily monitoring of the blood biomarker procalcitonin (PCT) can pinpoint when to safely stop antibiotics in adults hospitalised for suspected sepsis, reducing the duration of therapy compared with standard care, a large study finds.
It was known that optimising duration of antibiotic therapy helped to reduce overtreatment, limit unwanted effects and preserve antibiotic effectiveness by minimising resistance, a team of UK-based researchers wrote in JAMA.
However, there was currently no agreed optimal duration for antibiotic therapy for sepsis.
Clinicians tended to use clinical judgment on when to cease antibiotics, with evidence remaining uncertain for the efficacy and safety of therapy guided by inflammatory biomarkers, such as PCT or C-reactive protein (CRP).
To close this evidence gap, the National Institute for Health and Care Research (NIHR) commissioned and funded a three-arm, randomised trial across 41 NHS intensive care units, which enrolled 2,760 adult patients requiring critical care for suspected sepsis.
Eligible patients, who had started intravenous antibiotics before study enrolment, were randomly assigned to either a daily PCT-protocol, a daily CRP-protocol or standard care.
Blood was drawn daily from all participants and sent for testing according to the treatment arm, but the results were concealed from the treating clinicians to minimise bias.
Instead, clinicians received daily written advice from their local clinical research team on either standard care or on PCT or CRP biomarker-guided antibiotic discontinuation.
From randomisation to 28 days, the PCT-guided protocol led to a significant reduction in antibiotic duration compared with standard care (mean duration, 10.7 days for standard care versus 9.8 days for PCT; mean difference, 0.88 days).
For all-cause mortality up to 28 days, the daily PCT-guided protocol was noninferior to standard care, where the noninferiority margin was set at 5.4%.
‘The duration reduction is in the order of 10% in antibiotic use for sepsis, which could provide significant cost and labour savings, and might also reduce the development of antimicrobial resistance,” the study authors wrote.
No difference was found in antibiotic duration for standard care compared with the daily CRP-guided protocol and the all-cause mortality for CRP compared with standard care was inconclusive.
The researchers from the University of Manchester, Northern Care Alliance NHS Foundation Trust and the Clinical Trials Unit of the University of Warwick’s Medical School also noted that the trial could not provide evidence for biomarker use in initiating antibiotic therapy as participants had commenced treatment before enrolling.
Chief investigator Professor Paul Dark, professor of critical care at the University of Manchester, said the simple protocol could significantly change the way sepsis is treated and combat antibiotic overuse and resistance.
‘It is also a powerful illustration of how precision medicine can make a real difference to patient care when treatment is tailored to individual test results of each patient,’ he said.
Professor Dark, who is also an NHS consultant in critical care medicine at Salford Royal, said sepsis had been at the forefront of UK policymaking since a 2013 Health Service Ombudsman report focusing on sepsis patients who were not treated urgently enough.
‘Ever since then, developing better diagnostics and treatment guidance for GPs and hospital clinicians to help them recognise sepsis at an early stage has been a national priority,’ he said.
Figures suggest there are at least 245,000 sepsis cases diagnosed in the UK every year.
In late 2023, research presented at the European Society of Emergency Medicine Congress suggested that two of the four internationally recommended sepsis screening tools are inadequate for recognising the condition.
Earlier this year, NICE released updated guidance on identifying and managing sepsis in over-16s recommending better targeting of antibiotics for suspected sepsis.
The updates specified that secondary care teams should target antibiotic use as more is learned about a patient’s condition to ensure the right people receive treatment as soon as possible but the medicines are not overused.
12th December 2024
A machine learning model can more accurately estimate the age of acute ischemic brain lesions than current methods, with researchers predicting the software could mean up to 50% more stroke patients receive appropriate treatment.
The efficacy and appropriateness of stroke treatment depended on the progression stage or biological age of the lesion and whether it was deemed to be reversible, researchers wrote in the journal NPJ Digital Medicine.
‘Biological age is closely related to chronometric lesion age – i.e. time from symptom onset – although these ages disassociate due to variability in tissue vulnerability and arterial collateral supply,’ they said.
Acute ischemic lesions scanned with non-contrast computerised tomography (NCCT), become progressively hypoattenuated over time, the research team explained, a feature which helped to estimate biological lesion age.
At present, clinicians measured the relative intensity (RI) of a lesion on NCCT using a method termed Net Water Uptake (NWU).
However, the researchers noted this approach could be confounded by alternative sources of hypointensity, was also insensitive to additional ischemic features and dependant on lesion segmentation.
For this trial, researchers from Imperial College London and University of Edinburgh, UK, and the Technical University of Munich, Germany, developed a convolutional neural network – radiomics (CNN-R) model to optimise lesion age estimation from NCCT.
They noted that machine learning models had several advantages over current methods for stroke assessment such as the ability to screen high-dimensional imaging features for associations with ischemia progression, including those imperceptible to experts, as well as account for lesion anatomy variability and signal heterogeneity.
They trained the CNN-R model on chronometric lesion age, while validating against chronometric and biological lesion age in external datasets of almost 2,000 stroke patients.
Analysis showed the deep-learning model was approximately twice as accurate as NWU for estimating chronometric and biological ages of lesions.
‘The practical importance of our results lies in the CNN-R lesion age biomarker providing more accurate estimates, compared to current methods, of stroke onset time (unknown in ~20% of cases), and lesion reversibility, both currently used for decisions regarding revascularisation treatments,’ the researchers wrote.
As well as validating the method in a large, independent cohort, the researchers said they had demonstrated the technique could be embedded within a central pipeline of automated lesion segmentation and clinically-based expert selection.
Future research should assess whether the higher accuracy of a CNN-R approach to lesion age estimation carries over to predicting lesion reversibility and functional outcomes, they added.
Lead author Dr Adam Marcus, of Imperial College London’s Department of Brain Sciences, estimated up to 50% more stroke patients could be treated appropriately because of this machine learning method.
‘We aim to deploy our software in the NHS, possibly by integrating with existing artificial intelligence-analytic software that is already in use in hospital Trusts,’ he said.
Study senior author Dr Paul Bentley, of Imperial College London’s Department of Brain Sciences and consultant neurologist at Imperial College Healthcare NHS Trust, said the information would help clinicians make emergency decisions about stroke treatment.
‘Not only is our software twice as accurate at time-reading as current best practice, but it can be fully automated once a stroke becomes visible on a scan,’ he said.
The study follows research released last month showing artificial intelligence-enabled electrocardiography (ECG) can accurately predict an individual patient’s risk of future cardiovascular events as well as their short and long-term risk of dying.
Lead author of this study Dr Arunashis Sau, an academic clinical lecturer at Imperial College London’s National Heart and Lung Institute and cardiology registrar at Imperial College Healthcare NHS Trust, said compared with cardiologists the AI model could detect more subtle detail in the ECGs.
11th December 2024
Three quarters (75%) of the public support sharing some of their personal health data to aid the development of artificial intelligence (AI) systems in the NHS, a Health Foundation report has found.
The research surveyed 7,201 people across the UK between June and July 2024 and found that 29% were happy for any of their health data to be used to develop AI systems and a further 46% were happy to use ‘some’ of their data for this purpose.
A quarter of people (25%) however were not happy to share any of their data for this purpose.
When surveyed about the type of data being shared, 59% were willing to share data on eye health, 58% on the medicines they are taking and 57% were willing to share long-term conditions, dental health and medical test data, such as blood tests or scans.
However, less than half (47%) were willing to share smartphone-tracked data, such as sleep activity, and only 44% were happy to share sexual health information.
Those from lower socio-economic households were significantly less likely to support the use of their health data for developing AI technologies compared to those from other socio-economic groups.
Those of a higher managerial level, administrative or professional in their work, were more likely to think that using technology makes the quality of healthcare better, with 65% of this group saying this, compared to just 41% of casual or lowest-grade workers and others who depend on the welfare state for their income.
The survey also showed that most people trust the NHS with their health data, with 68% saying they trust GP practices and 66% stating trust in local NHS hospitals and clinics.
However, only 40% said they trusted companies providing the NHS with software to collect, store and use data.
The report called for policymakers and NHS leaders to ‘actively engage with the public to understand and address concerns’, especially with social groups who are less supportive.
Director of innovation and improvement at the Health Foundation, Dr Malte Gerhold, said: ‘It is only with the public’s support that the Government will successfully achieve its ambition of shifting the NHS from analogue to digital.
‘It is encouraging that most people are open to sharing their data to develop AI systems in the NHS. When properly implemented, we know that AI has the potential to free up staff by supporting clinical and administrative tasks. However, these systems are only as good as the data used to design and develop them.’
However, he added: ‘There are significant differences between socioeconomic groups in levels of support for sharing data for AI development and for taking part in activities to shape how technology is used in the NHS.
‘Policymakers, NHS leaders and those involved in designing and implementing healthcare technologies must proactively engage with people across different social groups to ensure that healthcare technologies help tackle inequalities, rather than worsen them.’
In July, a survey from the Health Foundation revealed that NHS staff and patients are both split on the use of AI in healthcare.
And in April a white paper from the Microsoft company Nuance reported that over a third of patients are in favour of clinicians using AI in consultations to improve documentation processes such as clinical letters.
A version of this article was originally published by our sister publication Healthcare Leader.
Patients with syncope typically present with a transient loss of consciousness, which can have a broad spectrum of causes. Here, Professor Martin Möckel, of the EUSEM syncope group, summarises how group’s new European consensus provides detailed, process-driven guidance on managing and caring for patients with suspected syncope in the emergency setting.
Transient loss of consciousness (TLOC) is a brief period of unconsciousness followed by a complete recovery. Loss of consciousness can result from a variety of reasons, including traumatic and non-traumatic causes.
Syncope, which is defined as a decrease in blood pressure with a subsequent global cerebral hypoperfusion and loss of postural tone, is a subset of TLOC. It is a major healthcare issue, as approximately half of the population will likely experience at least one syncope episode during their lifetime.1
Patients with syncope represent approximately 1–5% of patients visiting the emergency department (ED).2
In 2018, the European Society of Cardiology (ESC) published guidelines for the diagnosis and management of syncope, which, for the first time, explicitly addressed management in the ED.2
The ESC guidelines2 proposed three risk categories: low-risk, neither high- nor low-risk and high-risk. These are important for determining how treatment should proceed after an initial assessment in the ED. Whereas low-risk patients can be discharged into outpatient care, high-risk patients require careful monitoring and admission to hospital.
Recently, a European prospective cohort study quantified that 75.3% of syncope patients in European EDs were at high risk and required further work-up.3 The European Society for Emergency Medicine (EUSEM) syncope group, therefore, aimed to establish a consensus to create a universal core process for diagnosing syncope, risk stratification and its initial management in the ED.
The group assessed current clinical practices in different European countries through literature searches. A modified three-step Delphi process was then used and a universal core process map for syncope management in European EDs was subsequently modelled.4
The map allows regional specifications due to different healthcare systems while ensuring that all critical steps from admission to diagnosis are carried out and that no high-risk situation is overlooked.
From an emergency medicine perspective, the care process starts with the patient who has presented with a TLOC. Thus, the first step after triage is to determine non-syncopal causes of the TLOC such as seizures, head trauma or physical shock.
Then, a systematic work-up is suggested to determine vital parameters including blood pressure, heart rate, oxygen saturation, temperature and respiratory rate; history; physical examination; ECG; and lab tests, with haemoglobin and blood glucose being the minimum.
At this stage, syncope as a symptom of an underlying cause (e.g. aortic valve stenosis) or as part of an acute disease-like infection is determined and the patient is referred to a care pathway for the principal disease as appropriate.
The ESC guideline criteria are used to stratify any remaining unexplained syncopes and patients are scheduled for further ambulatory care (low risk only), monitoring or hospital care, mainly to determine cardiac syncope or other rare causes of TLOC. The core process diagram included in the consensus allows European EDs to create regional digital flow charts.
Most TLOC presentations can be clarified by following the pathway. However, certain specific situations need special attention.
These patients may not have typical high-risk criteria but present with injuries due to reflex or orthostatic syncopes with nearly no prodromes. These patients need specialist care and individual therapeutic regimens. They should be admitted or sent to dedicated syncope units.
Older patients with dementia and no observed TLOC may have syncope even though a geriatric fall might be suspected. A thorough cardiovascular evaluation is recommended in these patients, who almost always present with high-risk features and comorbidities. Measurement of cardiovascular markers such as copeptin could help determine or rule out true syncope.
Transient coma is a major challenge in the emergency setting. It is associated with high mortality and is usually a result of severe underlying pathologies. It must not be confused with syncope in the ED.5
The spectrum of syncope patients presenting with TLOC in the ED can be broad.
In the ED, the challenge is to determine cardiac syncope, geriatric falls or other diagnoses as the cause in this heterogeneous group of patients because it has been determined that three-quarters of patients have high-risk features and need urgent further hospital-based monitoring and subsequent work-up.
The 2018 ESC guidelines included recommendations for managing syncope in the ED but lacked detailed instructions on patient management. The EUSEM consensus aids informed decision-making regarding risk stratification, ruling out life-threatening causes and distinguishing syncopal and non-syncopal causes of loss of consciousness to achieve efficient and optimal patient care.
Martin Möckel MD PhD FESC FAHA
Charité – University Medicine Berlin, Germany
9th December 2024
The World Health Organization (WHO) has raised the alarm about soaring cases of tuberculosis (TB) around the world.
Last year, more than eight million people were newly diagnosed with the condition, the highest number since monitoring began in 1995, WHO said.
While TB-related deaths did fall last year from 1.32 million to 1.25 million, the total number of people falling ill with TB rose, a report said.
This means the world is not on track for international targets to reduce the burden of TB by 2027 and elimination by 2035, it added.
There is also ongoing concern about multidrug-resistant TB which the WHO described in the report as a ‘public health crisis’.
Treatment success rates for multidrug-resistant or rifampicin-resistant TB have now reached 68%.
But, of the 400 000 people estimated to have developed it, only 44% were diagnosed and treated in 2023, the report found.
Global funding for TB prevention and care decreased further in 2023 and remains far below target, it added with low- and middle-income countries bearing 98% of the TB burden.
India (26%), Indonesia (10%), China (6.8%), the Philippines (6.8%) and Pakistan (6.3%) together accounted for 56% of the global TB burden, it said.
Earlier this year, the UK Health Security Agency (UKHSA) said it was investigating an 11% rise in TB cases in England.
There were 4,850 tuberculosis cases in 2023 compared to 4,380 in 2022, representing a jump of 10.7%, according to provisional data.
Even before the Covid-19 pandemic, TB incidence was lower than this, with 4,615 cases in 2018 and 4,725 cases in 2019, UKHSA figures showed.
Some of the increase related to people born outside the UK, but in 2023 the rise was also seen in UK-born individuals, they noted.
Speaking on the findings of the latest WHO report, Dr Tereza Kasaeva, director of WHO’s Global Tuberculosis Programme said there was a multitude of formidable challenges including ‘funding shortfalls and catastrophic financial burden on those affected, climate change, conflict, migration and displacement, pandemics and drug-resistant tuberculosis, a significant driver of antimicrobial resistance’.
WHO director-general Tedros Adhanom Ghebreyesus added: ‘The fact that TB still kills and sickens so many people is an outrage, when we have the tools to prevent it, detect it and treat it.’
Dr Esther Robinson, head of the TB Unit at UKHSA, is encouraging people to speak to a healthcare professional if they think they could be at risk of TB.
‘TB is curable and preventable, but the disease remains a serious public health issue in the UK,‘ she said.
‘It is very important that those with relevant symptoms are tested for TB and appropriate treatment is started promptly. Not every persistent cough, along with a fever, is caused by flu or Covid-19.
‘A cough that usually has mucus and lasts longer than three weeks can be caused by a range of other issues, including TB.’
A version of this article was originally published by our sister publication Pulse.
Eating higher amounts of foods such as oily fish, cereals, vegetables and the nutrient vitamin D, as well as moderating alcohol intake, could reduce the risk of developing rheumatoid arthritis, a new study has revealed.
Researchers at the University of Leeds examined 32 different food groups, drinks and nutrients and determined the associated risks of developing rheumatoid arthritis. They found that some food groups could help reduce rheumatoid arthritis onset, while others, such as tea and coffee, were associated with an increased risk of developing the disease.
The findings are published in the journal Nutrients and highlight how controlling certain dietary factors could protect some people from developing the disease.
The researchers conducted a meta-analysis review of 30 studies undertaken between 2000 and 2024 involving almost 10,000 people. A total of 12 studies were conducted in Europe, 15 in America and three in Asia.
A higher intake of fruits and cereals was associated with a lower risk of rheumatoid arthritis and showed potential protective effects against its development. The association was linear, and consuming a greater amount continued to offer an increase in protection.
Vegetables, oily fish and vitamin D, followed a non-linear association. Increased consumption initially led to led to potential protective effects against rheumatoid arthritis development, but the effect plateaued beyond this level.
Drinking small amounts of alcohol (around two units per week) had a protective effect against rheumatoid arthritis, but at higher consumption levels, the risk of developing the disease increased. Excess alcohol intake negated the benefits seen at lower levels, and the protective effect disappeared at around consumption levels of 7.5 units per week.
Tea and coffee were associated with an increased risk of developing the disease. Each additional cup of tea consumed daily was associated with a 4% increase in risk. However, the baseline risk from tea was low, and the researchers stressed the many health benefits of tea. There was no evidence of an association between sugar-sweetened soda and rheumatoid arthritis risk.
Yuanyuan Dong, a PhD student at the School of Food Science and Nutrition at the University of Leeds, said: ‘Rheumatoid arthritis is a typical multifactorial disease, driven by both genetic and environmental factors. These findings offer a deeper understanding of how diet can impact rheumatoid arthritis risk and suggest potential dietary modifications for disease prevention and management.’
The researchers suggested that dietary factors contribute to the risk of rheumatoid arthritis by increasing inflammation and affecting the immune system. However, stressing the ‘one-size-fits-all’ advice to follow a generally healthy diet is not helpful for people with autoimmune diseases, and the research highlights the need for a more personalised approach.
Study co-author and PhD supervisor Janet Cade, professor of nutritional epidemiology at the University of Leeds, said: ‘The results are promising, showing that by eating higher amounts of foods like oily fish, cereals, vegetables and the nutrient vitamin D, people may be able to lower their chances of developing this painful and debilitating condition.’
She added: ‘More research will help us pinpoint exactly why these foods have the effect we have observed and develop tailored nutritional advice for people living with rheumatoid arthritis and other autoimmune diseases.’
A version of this article was originally published by our sister publication Nursing in Practice.
6th December 2024
Around half of adults in the UK struggle to access trusted health information, according to a new report.
The study, published by the Patient Information Forum and Ipsos, called Knowledge is Power, found that 53% of people felt they could trust the health information they found offline, while only 45% said they could trust the information found online.
But, eight in 10 adults with a long-term condition agreed that access to trusted health information would help them to manage their health better.
A further one in 10 adults said they had been affected by misinformation, which rose to one in five for ethnic minorities, according to the study, which surveyed 2,003 adults between May and June 2024.
One in six respondents said they did not feel listened to by their healthcare professional, rising to one in four for ethnic minorities.
The report made several recommendations including patients having the right to health information as a core part of their care, tackling inequality by making health information accessible and appropriate for all, and eliminating misinformation through robust content standards and effective signposting of credible health information from health professionals.
It also highlighted the need for a mandate to effectively deliver health information with a named lead in all NHS organisations, and embedding patient experience as a measure of NHS performance.
Melissa Moodley, UK head of healthcare research at Ipsos, said: ‘This timely research reveals a critical gap in access to trustworthy health information, with half of UK adults struggling to find reliable sources.
‘This challenge is particularly acute for those with long-term conditions and minority groups. The impact is clear: eight in 10 adults believe better access to credible health information would improve their health management.
‘These findings underscore the urgent need to improve the provision of verified, accessible health information. Doing so is not just beneficial, but essential for enhancing overall health outcomes across the UK.’
Sue Farrington, chair of the Patient Information Forum, added: ‘Credible information supports people’s health decisions, from childhood vaccinations to joint replacement surgery. For people with long term conditions, it is a core element of care.
‘Resolving these issues will ensure everyone gets the information they need, supporting the prevention agenda and contributing to the delivery of positive health outcomes for all.’
In a recent interview with Hospital Healthcare Europe, consultant clinical oncologist Dr John Conibear said: ‘What mustn’t be forgotten is the dissemination of information to patients, arming them with the knowledge of what’s available, and what’s potentially suitable for them so they can also be an advocate for their own care.’
For example, new self-management app designed for teenagers, young adults and the parents/carers of pre-teens with asthma is designed to improve knowledge of their condition, making it easier for them to monitor and control it.
A version of this article was originally published by our sister publication Healthcare Leader.
The Covid-19 pandemic boosted advancing technology to create vaccines incorporating messenger RNA. Professor Alain Astier discusses how these vaccines have further potential to be rapidly tailored to target oncogenic profiles and provide significant benefits in personalising cancer treatment.
Edward Jenner’s pioneering work in his 1801 treatise On the Origin of the Vaccine Inoculation and the first successful vaccination against smallpox heralded the development of vaccine therapy from the second part of the 19th century onwards.
One area in which exciting progress has been made is in immunotherapy and the development of cancer vaccines including messenger RNA (mRNA) variants. Unlike traditional immunisation, the situation in cancer is more complex. It requires sophisticated approaches to develop appropriate vaccines as the cancer cells more closely resemble normal, healthy cells than bacterial or fungal allergens do.
The first preventive cancer vaccine, against hepatitis B virus-induced hepatocarcinoma, was launched in 1982. Other preventive vaccines, such as those against human papillomavirus, are currently in use.
There are four main types of therapeutic cancer vaccines:
1. Cell-based vaccines
Cell-based cancer vaccines use all the antigens expressed by tumour cells: tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs).
TAAs, such as HER2/neu, are self-proteins (antigens originating within the body) abnormally overexpressed by cancer cells. TSAs are antigens specific to some tumour cells, such as mutated Kras or β-catenin.
In cellular cancer vaccines, cultured cells from tumour cell banks are injected globally to provoke the immune response, similar to classic vaccination, or incubated with cultured dendritic cells. The dendritic cells present the antigens to T lymphocyte CD4+ helper and CD8+ cytotoxic cells, which induces activation, multiplication and migration into the tumour through the lymphatic system.
Cancer cell cultures can also liberate soluble TAAs or TSAs into the culture media, which can be injected as an alternative to the cells.
‘Antigenic essence’ technologies comprise a target fraction of cellular antigens, the composition of which is precisely controlled by mass spectrometry. Antigenic essence technology makes it possible to update many existing cellular vaccines and to develop new ones, thereby introducing a further direction for anticancer vaccine research.
2. Viral-based vaccines
Viral-based cancer vaccines use engineered viruses as vectors to deliver tumour antigens to the immune system. This requires virus proliferation and requires complex and potentially hazardous handling.
3. Peptide-based vaccines
Peptide-based cancer vaccines stimulate the immune system using antigenic peptides corresponding to cancer epitopes of interest. These antigenic peptides can be produced via fractionating larger antigen proteins or by bioengineering after the DNA sequences coding for them are identified.
4. Nucleic acid-based vaccines
Nucleic acid-based cancer vaccines utilise DNA or RNA to encode tumour antigens that are presented to the immune system using various delivery platforms such as liposomes or nanoparticles. A typical nucleic acid vaccine is the mRNA Covid-19 vaccine. Although designed to fight a non-oncogenic virus, it provoked much interest in the potential of mRNA vaccine technologies in cancer.
At the industrial level, the production of cancer vaccines is a complex process. Indeed, mass culture, which requires trypsinisation to detach the adherent cells, all under strict aseptic conditions, is complicated and expensive.
In the case of personalised vaccines, the cancer cells are derived from individual patients, and the industrial-scale production of cellular-based vaccines can, again, be complex and challenging. However, production at the local level, such as within hospitals, could be encouraged.
The production of peptide-based vaccines is more affordable. Mass production of peptides via automation does not require cell culture; it only involves sequencing of the DNA coding for the protein or peptides of interest.
The principle is to obtain a tumour sample from an individual patient or a cancer cell bank to establish a DNA mutation map compared to healthy cells from the same patient or from normal cells and the organ of origin. The map is used to identify the corresponding DNA sequence of numerous tumour antigens and to synthesise the corresponding peptides. However, this approach requires producing and purifying large quantities of peptides.
Problems with protein or peptide handling, such as aggregation or instabilities, frequently occur and require substantial expertise. Moreover, these foreign peptides can also induce severe allergic responses.
A more innovative approach is theoretically to inject the corresponding mRNAs directly, which ‘orders’ the synthesis of corresponding peptides by the patient’s cells with good efficiency and safety.
Thus, after identifying the DNA sequence coding for the antigenic peptides and combining it with today’s methods for nucleic acid synthesis, it is straightforward to produce sufficient mRNA.
However, a severe limitation previously was significant instability and poor intrinsic cellular penetration due to the very polar nature of the mRNA. Moreover, simple mRNAs are recognised as foreign substances and are rapidly eliminated from the body.
Thanks to the 2023 Nobel Laureates Katalin Karikó and Drew Weissman, whose pivotal discoveries concerning nucleoside base modification enabled the development of effective mRNA vaccines against Covid-19, it is now possible to overcome the underlying instability of engineered mRNAs.
State-of-the-art mRNA constructs confer many improvements regarding purification, the structure and length of untranslated regions, regulatory elements and modifications of coding sequences.2 For example, replacing uridine bases with pseudouridine in an mRNA sequence dramatically improves the yield of the corresponding protein.1
Using nano-delivery systems can overcome the difficulties in transporting and encapsulating these custom-made mRNAs into cells.3,4 These include lipid-based nano vectors, such as liposomes or lipoplex particles, and dendrimer polymer nano vectors, which are often commercially available or easily manufactured.5
Moreover, mRNAs can also be vectorised by viruses or polypeptides rich in arginine, which neutralise very polar polynucleotides and facilitate penetration through the cell membrane.
The main benefits of the mRNA approach to producing vaccines are the ease of manufacture on an individual scale, the lack of need to handle viruses or perform cell culture, the lack of complex protein production, and very rapid processes that are less expensive than those for classical vaccines.
Thus, small-scale units such as academic facilities can easily produce personalised vaccines. Several mRNAs coding for several cancer antigens can be administered simultaneously. The rapidity of obtaining mRNAs could also permit adapting the vaccine to the evolution of the tumour in terms of neoantigen expression. Furthermore, an excellent tolerance has been demonstrated in several clinical trials as an mRNA vaccine is, per se, non-immunogenic.
mRNAs can also help promote the production of a corresponding antibody by the host B cells. In this case, the idea is to replace the repetitive administration of a large quantity of a monoclonal antibody with a single injection of its corresponding mRNA.
As demonstrated by Pardi and colleagues, a single injection of the mRNAs that encode the VRC01 monoclonal antibody against HIV surface protein led to robust production of this antibody protein in the livers of mice within 24 hours.6 A weekly injection was enough to maintain high levels of circulating VRC01 antibodies.
This approach could also benefit by dramatically simplifying the production of anticancer monoclonal antibodies, making it achievable at the hospital level.
From the pioneering work with mRNA anti-Covid vaccines, mRNA therapeutic vaccines are now regarded as an attractive and promising alternative to conventional vaccines for transmissible diseases and cancers.7,8
Although most of these cancer vaccines are still experimental, some have shown promising results in clinical trials, with positive responses in shrinking tumours and improving patient survival.
Alain Astier PharmD PhD
Honorary head of the Department of Pharmacy, Henri Mondor University Hospital, and French Academy of Pharmacy, Paris, France
1 Karikó K et al. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005;23,(2):165–75.
2 Duan L-J et al. Potentialities and Challenges of mRNA Vaccine in Cancer Immunotherapy. Front Immunol 2022;13:923647.
3 Liu T, Liang Y, Huang L. Development and delivery systems of mRNA vaccines. Front Bioeng Biotechnol 2021;9:718753.
4 Hou X et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 2021;6(12):1078–94.
5 Campani V et al. Lipid Nanovectors to Deliver RNA Oligonucleotides in Cancer. Nanomaterials 2016;6(7):131.
6 Pardi N et al. Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat Commun 2017;2:8:14630.
7 Jackson NAC et al. The promise of mRNA vaccines: a biotech and industrial perspective. npj Vaccines 2020;5:11.
8 Li Y et al. mRNA vaccine in cancer therapy: Current advance and future outlook. Transl Med 2023;13:e1384.
5th December 2024
Genetics partly influence the shape of the heart’s left and right ventricles, a study shows for the first time, with the findings potentially helping to refine cardiovascular disease (CVD) risk assessment in clinical settings.
Variations in heart shape were more strongly related to cardiovascular risk factors and more predictive of major adverse cardiovascular events than traditional measures of cardiac structure such as mass and volume, researchers wrote in the journal Nature Communications.
‘Genetic associations with heart shape variation may therefore provide information not found from genetic analyses on standard cardiac structural phenotypes and may assist in understanding the mechanisms underlying the development of CVD,’ they said.
The UK and Spanish research team used cardiac magnetic resonance images from 45,683 individuals from the UK Biobank – a large-scale biomedical database and research resource – to create 3D models of hearts before using principal component analysis (PCA) to examine the characteristics of heart shapes.
The analysis identified principal components including heart size, apex-base length and anterior-posterior width.
Genome-wide associated studies were then performed on the first 11 principal components, that captured 83.6% of shape variance, reported the researchers from King’s College London, Queen Mary University of London, and University College London, UK, and University of Zaragoza and University Hospital of A Coruña, Spain.
Through this statistical analysis, they identified 43 significant genomic loci, 14 of which were previously unreported for cardiac traits.
‘This is the first study to examine the genetic architecture of multi-dimensional biventricular heart shape using PCA,’ they wrote.
Most of the principal components were found to be moderately heritable, consistent with previous traditional measures of cardiac structure.
The principal components also demonstrated significant associations with cardiometabolic diseases, including atrial fibrillation and myocardial infarction.
Study co-author Professor Patricia B. Munroe, professor of molecular medicine and centre lead for clinical pharmacology and precision medicine at Queen Mary University of London, said the study provided new information about how researchers considered CVD risk.
‘We’ve long known that size and volume of the heart matter, but by examining shape, we’re uncovering new insights into genetic risks,’ she said.
‘This discovery could provide valuable additional tools for clinicians to predict disease earlier and with more precision.’
Dr Richard Burns, statistical geneticist at Queen Mary University of London, said: ‘This study sets an important foundation for the exploration of genetics in both ventricles. The study confirms that combined cardiac shape is influenced by genetics, and demonstrates the usefulness of cardiac shape analysis in both ventricles for predicting individual risk of cardiometabolic diseases alongside established clinical measures.’
The researchers are keen for further studies to be undertaken on how these findings could be integrated into clinical practice.
And future research could also further examine the anatomical cardiac shape features informed by the identified principal components, they suggested.
Mechanistic studies are also needed to examine the direction of effect between multidimensional heart shape and cardiometabolic disease, the researchers added, including further exploration of the functionality of the identified candidate genes.
The findings follow another study drawing on UK Biobank data published earlier this month which found adults who have irregular sleep patterns were 26% more likely to have a major cardiovascular event than those with a regular sleep-wake cycle.
Published in the Journal of Epidemiology & Community Health, the researchers designed an observational study involving 72,269 people from the UK Biobank aged between 40 and 79 with no history of cardiovascular disease.
For moderately irregular sleepers, meeting sleep duration recommendations could largely offset the elevated risk of cardiovascular events, the researchers found.
4th December 2024
Our latest Clinical Excellence in Respiratory Care event included a fascinating panel discussion on managing pulmonary hypertension as a multidisciplinary team (MDT). Here, you have exclusive access to the session recording.
Hospital Healthcare Europe and Hospital Pharmacy Europe editor Helena Beer was delighted to be joined by three specialist clinicians for this panel discussion: David Kiely, consultant respiratory physician and professor of pulmonary vascular medicine at Sheffield Teaching Hospitals NHS Foundation Trust, alongside Colm McCabe, respiratory consultant in pulmonary hypertension, and Heba Nashat, consultant cardiologist in pulmonary hypertension – both at the Royal Brompton Hospital in London.
Recorded on 21 November 2024 and shared at the Clinical Excellence event the following week, the panellists discussed diagnostic challenges and the role of imaging technology in pulmonary hypertension, integrating cardiology and pulmonology treatment plans and how to best work together as an MDT for the benefit of the patient. Scroll down to watch now.
You can find brand new interviews and case studies, plus round ups of previous Clinical Excellence event sessions and much more in our Respiratory zone – just look out for the orange Clinical Excellence tag to read a whole host of content that can help to inspire your practice.
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