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30th June 2025
Patients who have been hospitalised for acute pancreatitis after using glucagon-like peptide-1 (GLP-1) receptor agonists are being urged to report this through the Yellow Card scheme as part of an investigation into whether this side effect may be influenced by genetics.
The Medicines and Healthcare products Regulatory Agency (MHRA) has partnered with Genomics England to look into the issue in detail, with the aim of reducing the occurrence of these side effects through personalised treatment approaches in future.
Healthcare professionals are also being encouraged to submit a Yellow Card report on behalf of impacted patients to support recruitment to the project.
Patients aged 18 or over who have had acute pancreatitis flagged as a side effect of GLP-1 medicines through the Yellow Card scheme will be contacted by the MHRA to take part in a Yellow Card Biobank study to investigate risk factors, the medicines regulator said.
This will involve providing further information and submitting an at-home saliva or spit sample, which will be used to explore whether some people are at a higher risk of acute pancreatitis when taking these medicines due to their genetic make-up.
Commenting on the project, Professor Matt Brown, chief scientific officer of Genomics England, said: ‘GLP-1 medicines like Ozempic and Wegovy have been making headlines, but like all medicines there can be a risk of serious side effects. We believe there is real potential to minimise these with many adverse reactions having a genetic cause.
‘This next step in our partnership with the MHRA will generate data and evidence for safer and more effective treatment through more personalised approaches to prescription, supporting a shift towards an increasingly prevention-focused healthcare system.’
According to Dr Alison Cave, MHRA chief safety officer, ‘evidence shows that almost a third of side effects to medicines could be prevented with the introduction of genetic testing. It is predicted that adverse drug reactions cost the NHS more than £2.2bn a year in hospital stays alone.’
This is the second investigation currently underway by the Yellow Card Biobank after it began recruiting patients in February 2024 who experienced severe bleeding after taking direct oral anticoagulants.
This latest Yellow Card Biobank project comes as researchers urged healthcare professionals to be vigilant to signs of acute pancreatitis in patients who are taking GLP-1 receptor agonists alongside issuing evidence-based guidance for those working in primary care on how to manage these patients.
Among the recommendations from the team at King’s College London and the University of East Anglia is routinely asking patients about the use of GLP-1 medicines – whether purchased privately or prescribed on the NHS – and watching out for red flag symptoms such as severe abdominal pain, which may signal acute pancreatitis or biliary disease.
Prescribers should also consider the need to alter doses of other medications such as insulin, sulphonylureas and antihypertensives to avoid hypoglycaemia and postural hypotension as weight reduces, the paper in the journal Obesity Facts advised.
Lead author Dr Laurence Dobbie, academic clinical fellow in general practice at Kings College London, said: ‘More than a million people are taking these medicines privately and seeing GPs with lots of different problems.
‘We want GPs to have the basic knowledge to prioritise patient safety and demystify side effects. I’ve seen patients in primary care who are clearly taking the medications, but they haven’t been given wrap-around care.’
The guidance is the first output of the Obesity Management Collaborative UK (OMC-UK) – a network set up in 2024 to provide education and professional development for clinicians in supporting the management of patients with obesity.
OMC-UK chair Professor Barbara McGowan, consultant and honorary senior lecturer in diabetes and endocrinology at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, said: ‘These 10 top tips aim to upskill GPs in the management and monitoring of patients on these medications. By embedding these recommendations into routine clinical practice, we can ensure patient safety and optimise the care of individuals living with obesity.’
Tuberculosis (TB) is once again the world’s deadliest infectious disease, causing an estimated 1.25 million deaths in 2023. Despite longstanding knowledge that TB is both preventable and curable, progress has stalled. Here, Gerry Hughes discusses the latest research, consensus and progress in fighting TB with insights from sessions at ESCMID Global 2025.
With an estimated 10.8 million people falling ill with tuberculosis (TB) globally in 2023, the burden of disease remains staggeringly high – and, alarmingly, it is rising, with the World Health Organization (WHO) warning of this ‘unnecessary’ public health crisis.
In his keynote address at the recent ESCMID Global congress, Professor Guy Thwaites, professor of infectious diseases at the University of Oxford, offered a sober appraisal of the current landscape. ‘Tuberculosis is a disease of poverty,’ he said, calling out the structural and political forces that continue to drive global disparities in TB control.
Quoting data from the WHO Global TB Report 2024, he underlined how TB incidence rates, after a brief dip, have plateaued and begun to climb once more.
The targets set by the WHO in its 2015 End TB Strategy – particularly the goal of a 50% reduction in incidence – remain far from reach. Just an 8.3% reduction has been achieved over those nine years. ‘We still remain in the wrong place with TB,’ Professor Thwaites said.
An important contributor to this inertia is because the medical community is ‘still using old tools’ in the fight against TB, according to Professor Thwaites. He took aim at the diagnostic and preventive tools that have defined TB control for decades: the Bacillus Calmette-Guérin vaccine, Ziehl-Neelsen staining, microscopy and the tuberculin skin test.
While new technologies have emerged, they remain largely inaccessible to those who need them most. The GeneXpert platform, for example, offers improved diagnostics but is expensive and underutilised in many high-burden settings.
Professor Thwaites went on to challenge the conventional latent versus active TB paradigm. He described a recent pre-print study, where clinical imaging of 250 asymptomatic household contacts of rifampicin-resistant TB identified subclinical lesions in nearly 12% of individuals. These lesions strongly predicted progression to culture-positive disease, but this progression occurred slowly, taking up to four years for microbiological detection.
‘We are learning that subclinical TB can persist undetected for years,’ he said, which blurs the line between infection and disease. A recent paper aptly titled ‘Latent Tuberculosis: Two Centuries of Confusion’ discusses this conundrum for healthcare professionals.
Indeed, an international consensus now proposes four states of early TB – two subclinical and two clinical – based on symptomology. The International Consensus for Early TB framework, known as ICE-TB, distinguishes disease from infection by the presence of macroscopic pathology and confirms that the presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Understanding these disease dynamics, Professor Thwaites argued, will be critical to reimagining both diagnosis and prevention.
Encouragingly, TB vaccine development has somewhat accelerated. For example, a new candidate M72/AS01E, now in phase 3 trials across South Africa, Kenya, Zambia, Malawi and Indonesia, has recruited 90% of its 20,000 participants. Designed to prevent progression in those with latent TB, the vaccine could save an estimated 8.5 million lives, prevent 76 million new cases over 25 years and save $41.5bn in revenue if proven effective.
While drug-susceptible TB can be treated with a six-month course of antibiotics, multidrug-resistant TB (MDR-TB) presents far greater challenges. For many, therapy remains lengthy, toxic and poorly tolerated.
Professor Thwaites discussed progress with research on newer, shorter regimens in his ESCMID Global session. Trials have demonstrated non-inferiority of a four-month regimen using rifapentine and moxifloxacin in adults when compared to standard treatment and non-inferiority of a four-month versus six-month standard regimen in children. ‘But even four months is too long,’ he argues, pointing to recent studies evaluating ‘ultra-short’ regimens.
One such phase 2/3 multicentre clinical trial assessed an eight-week bedaquiline-linezolid combination, demonstrating non-inferiority to the standard six-month regimen, with no apparent safety concerns.
Another promising avenue is the use of bedaquiline as short-course preventive therapy. With a half-life of around 160 days, bedaquiline is being explored as a single-month preventive regimen in the ongoing BREACH-TB trial. This trial focuses on people who are at high risk of having TB, such as those living with HIV and those who have had close contact with someone with drug resistant TB. It will also include populations who are conventionally excluded from such trials such as lactating adults.
While Professor Thwaites noted that further research is required for these ultra-short regimens, he said that such research may also lead to discovery of biomarkers which could predict relapse arising from these shorter regimens.
However, emerging resistance to bedaquiline threatens to undermine these advances. A study from India, published earlier this year, found 36% of 117 previously treated TB patients had bedaquiline-resistant strains, with unfavourable outcomes exceeding 80%. ‘We are developing new drugs,’ says Professor Thwaites, ‘but access remains unequal, and resistance is rapidly gaining ground.’
TB meningitis (TBM) presents a particularly devastating form of the disease, with high mortality and complex treatment needs being highlighted by several ESCMID Global speakers.
Professor Thwaites discussed the role of adjunctive anti-inflammatory therapies, including dexamethasone, noting that while a recent trial in HIV-positive adults with TBM showed no survival benefit, further investigation is warranted.
He advocated for larger studies and exploration of alternative anti-inflammatory agents such as infliximab and anakinra.
The clinical imperative to improve outcomes in TBM was the focus of a major late-breaker presentation at ESCMID Global, where Professor Reinout van Crevel unveiled findings from the HARVEST-TB trial.
Professor van Crevel, professor of infectious diseases at Radboud University Medical Centre, presented the first results of the HARVEST-TB trial – a phase 3, double-blind, randomised controlled trial evaluating high-dose oral rifampicin (35 mg/kg) for TBM.
This study was driven by the fact that rifampicin does not achieve satisfactory central nervous system concentrations. High dose rifampicin is currently being investigated in several TBM trials.
Furthermore, a previous phase 2 study demonstrated that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. Conducted in Uganda, Indonesia, and South Africa, the trial enrolled 529 patients with confirmed TBM. Participants received either high-dose or standard-dose rifampicin alongside standard TB therapy and corticosteroids.
Disappointingly, results showed no measurable benefit. The hazard ratio was 1.17 (95% CI 0.89–1.54; p = 0.25), and subgroup analysis revealed no survival advantage in those with HIV, bacteriological confirmation or severe disease. Adverse event rates were similar between groups.
Professor van Crevel addressed ESCMID Global audience questions about the discrepancy between this result and earlier phase 2 findings using intravenous rifampicin. He attributed the difference not to formulation, but to study power: ‘This underlines the importance of doing adequately powered studies to detect clinical endpoints,’ he said.
On whether intravenous formulations should be revisited, his reply was ‘I don’t think so’, although he acknowledged the need to measure blood levels of both rifampicin and dexamethasone to explore possible drug interactions.
The ESCMID Global presentations by Professors Thwaites and van Crevel delivered a compelling message: TB control in 2025 demands radical rethinking. From vaccine deployment and subclinical disease classification to high-dose regimens and drug resistance, innovation is crucial. But so too is equitable access, rigorous research and the political will to act.
Professor Thwaites reiterated that exploiting and researching host-defence mechanisms is crucial: ‘We cannot just obsess over killing bacteria, we need to control the inflammatory response as well,’ he said.
Ending TB is not just a scientific challenge; it is a global moral imperative. The tools are within reach. The time to use them is now.
27th June 2025
Patients will be able to access more information about their healthcare via the NHS App under changes coming in the 10-year plan, health secretary Wes Streeting has said.
Two new features of the NHS App are to be enabled, including a feature called My Companion, which will give patients access to trusted health information.
This feature will also support patients to ask questions about their health conditions and, including any they have felt too embarrassed to raise in a face-to-face appointment, the Department of Health and Social Care (DHSC) said.
Last year, a report by the Patient Information Forum found that half of adults in the UK struggle to access trusted health information 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.
The second feature, called My Choices, will help patients find their nearest pharmacy or the best rated providers for heart, hip or knee surgery.
Mr Streeting, said: ‘The NHS feels increasingly slow and outdated to the generation that organises their lives at the touch of a button. If you get annoyed at Deliveroo not getting your dinner to you in less than an hour, how will you feel being told to wait a year for a knee operation? A failure to modernise risks this generation walking away from the NHS, first for their healthcare, and then with their taxes.
‘People won’t accept paying higher and higher taxes to fund a health service that no longer meets their needs. And the lack of control people feel over their own lives is made worse by an analogue, ‘computer says no’, NHS. We can only close this inequality and shut down this risk to the NHS’s future, through a revolution in patient power.’
He added that the ambition of the 10-year plan was ‘nothing less than to provide NHS patients with the same ease and convenience that’s afforded to private patients’.
‘The good news is that technology gives us the opportunity to democratise healthcare in a way never before possible. It can empower patients with choice and control and make managing our healthcare as convenient as doing our shopping or banking online,’ he said.
‘Technology can be the great leveller. Look at what Martin Lewis, the Money Saving Expert, has done for personal finances. For ordinary people – who could never afford their own financial adviser – it is simple and easy to make your hard-earned money go further. Our 10-year plan for health will do the same for NHS patients – giving them easy access to information, to help them improve their health.’
Earlier this month it was announced that all ‘appropriate’ messages were to be sent via the NHS App within three years and that the 10-year plan is also going to enable patients to access clinical trials through the NHS App.
In April, the DHSC announced that the NHS App had been adopted by 87% of hospitals in the UK, saving 1.26 million clinical hours since July 2024.
A version of this article was originally published by our sister publication Healthcare Leader.
26th June 2025
A groundbreaking opt-out testing programme for blood-borne viruses at the emergency department at Nottingham University Hospitals NHS Trust has uncovered dozens of previously undiagnosed cases since its launch. HIV specialist Dr Ashini Fox and colleagues explain how the initiative is improving early detection, breaking down stigma and linking patients to vital treatment – all crucial steps in the drive to end new HIV transmissions by 2030.
Early diagnosis of HIV, hepatitis B (HBV) and hepatitis C (HCV) is vital in improving health outcomes for people living with these conditions. As the infections can be asymptomatic during the early stages, testing is often the only way of detecting them before someone becomes seriously unwell or transmits the virus to others.
On World AIDS Day 2021, the UK Government agreed a £20 million investment to expand opt-out HIV testing in emergency departments (EDs) as part of their commitment to achieve zero new HIV infections by 2030. In April 2022, the programme began in areas of ‘very high’ HIV prevalence, including 34 EDs in London, Manchester, Blackpool and Brighton.
It then expanded to include HCV and HBV testing as part of the HCV Elimination programme. ED testing proved highly successful in finding those living with an undiagnosed blood-borne virus (BBV) and linking those previously diagnosed but lost to follow-up back into care.
The HIV and hepatitis clinical teams at Nottingham University Hospitals NHS Trust (NUH) were keen to implement this initiative locally and actively sought funding. In 2024, the ED testing programme was extended to an additional 47 sites across England in areas of ‘high’ HIV prevalence. NUH was the first of these ‘second wave’ sites to go live on 30 July 2024.
Standardising testing removes the implication that someone is being singled out due to a specific identity or risky behaviour. It helps to reduce fear and fosters a more informed and supportive culture around testing. It helps to reduce stigma by making testing normal, non-judgmental and health-focused rather than targeted or judgment-based.
Every adult patient attending the ED who requires a blood test as part of their care is automatically screened for HIV, HBV and HCV unless they choose to opt out. No additional sampling is required as the screening uses the same blood being taken for other clinical purposes. Information about the testing is clearly displayed throughout the ED in multiple formats and languages, and verbal explanations are provided for partially sighted patients.
A clinical nurse specialist oversees the process, managing all results and directly contacting anyone with a positive or indeterminate result to arrange appropriate follow-up care. Patients who return to the ED within 12 months of a previous BBV screen are not retested unless there is a clinical reason to do so.
In addition to clinical nursing support, this project requires a multispecialist, multidisciplinary effort. It involves members from sexual health (HIV), hepatology, emergency medicine, research, microbiology, digital services, pathology IT and external partners. A steering group originally met weekly and now meets monthly, and education sessions were delivered to ED nurses, advanced clinical practitioners and doctors to introduce the project and increase knowledge around BBVs. Regular communication between these teams keeps the programme running smoothly and addresses any challenges that arise.
Some 151 BBV screens were carried out on the first day of the testing programme at NUH. Now, more than 43,445 BBV tests have been completed, with an average uptake of 82% among eligible patients.
As of 14 May 2025, the initiative has identified 70 new BBV diagnoses: 16 cases of HIV, 33 of HBV and 21 of HCV. Of these, 62 individuals – including all the individuals who are HIV positive – have been successfully linked to specialist care and, where appropriate, have started treatment. With earlier diagnosis comes the opportunity for earlier intervention, significantly improving long-term health outcomes. Efforts to engage the remaining eight individuals is ongoing.
Through partner notification following the 16 HIV diagnoses, a further three individuals who were previously unaware of their status have also been diagnosed and supported into specialist care. Additionally, 21 people with a prior BBV diagnosis who had been lost to follow-up have been re-identified and reconnected with care services.
Beyond individual diagnoses, the programme has helped foster a culture of prevention and awareness around BBVs across the Trust and within the wider community. Promotional efforts have opened doors to present at the board level and across various clinical specialties. This has offered the chance to challenge misconceptions and stigma commonly associated with these viruses and highlight the benefits of integrating BBV testing into routine care for all patients and their community.
Implementing the programme has not been without challenges. The ED operates under significant pressure, with staff working exceptionally hard to deliver patient care. Introducing a change to service in this demanding environment requires patience and a clear understanding of staff priorities. High staff turnover and reliance on agency and locum personnel could make sustained engagement and enthusiasm challenging. However, regular education sessions and support from senior ED nurses helped to address this.
Implementing a large-scale programme like this also presents the challenge of coordinating multiple teams with different priorities. The screening coordinator nurse sits centrally to ensure all teams are working towards the same objective and assists in supporting patient pathways for follow-up care. Any logistical difficulties, such as changes to IT systems, could have led to stalls in the project, but with collaborative teamwork, these have been prevented.
Implementing opt-out BBV testing in the ED requires close collaboration between specialties and secure, sustainable funding. For organisations looking to introduce similar programmes, a key first step would be fostering joint working between HIV and hepatitis teams to pool expertise and resources. At NUH, creating a dedicated coordinator role, spanning both specialties, has been particularly effective. This role not only ensures timely follow-up of results but also acts as a visible project champion within the fast-paced ED environment, helping embed the programme into routine care and drive its ongoing success.
The programme is well received by patients, and many have expressed gratitude for being tested. Most attended the ED for a problem unrelated to their undiagnosed BBV, and so although a new diagnosis may have come as a shock, it proved to be an opportunity to prevent ill health and for their partners to get tested, too. Any concerns or queries are directed to the screening coordinator nurse specialist, who addresses them sensitively.
Each person with a positive BBV result is followed up by a clinical nurse specialist who supports them with their diagnoses, provides essential information and rapidly links them to the appropriate specialty for full assessment, further support and treatment initiation. Ongoing support is also offered through peer support services, such as tHrIVe Support Group or the Hepatitis C Trust.
While it is a little too early to fully assess the programme’s impact on the wider community, we do know that the East Midlands has some of the highest rates of late-stage HIV diagnosis in the country. By identifying infections earlier, the programme aims to reduce the number of late diagnoses, ultimately leading to better health outcomes, lower morbidity and mortality and less pressure on primary and secondary care services.
Without early detection, many of these individuals may have progressed to becoming immunocompromised and seriously unwell, requiring more intensive treatment and support. The National Institute for Health and Care Excellence has previously estimated that the health economic costs of each subsequent year for a person with a late diagnosis of HIV are approximately 50% greater than those of someone with an early diagnosis.
The surprising number of HBV infections that we have uncovered highlights the need for improvements in national policy on how testing and treatment for these patients are coordinated and funded.
NUH’s ED opt-out BBV testing programme has made a measurable impact, identifying 70 people, at the time of writing, living with undiagnosed HIV, HBV and HCV, many of whom would likely not have been tested through conventional routes.
The initiative has enabled rapid access to treatment and support and helped normalise BBV testing within emergency care.
By embedding routine screening into everyday practice and reducing stigma around diagnosis, the programme is not only saving lives but also changing the culture of care. With continued support, this model holds the potential to contribute to national goals of ending new HIV transmissions and improving health outcomes for all affected by BBV.
Ashini Fox FRCP
Consultant in sexual health
Molly Hansell RN BSc
ED BBV opt-out screening coordinator and clinical nurse specialist
Sarah Montague MSc
Hepatitis C operational delivery network manager
All of Nottingham University Hospitals Trust, UK
Tommy Morton
East Midlands hepatitis C data manager
With thanks to:
The Nottingham University Hospitals ED Opt-out Steering group
Patients and staff at the Nottingham University Hospitals Trust Emergency Department
Children with juvenile idiopathic arthritis (JIA) are more likely to respond to methotrexate therapy if they have higher baseline expression of interferon (IFN)-stimulated genes, UK research finds.
Methotrexate has been the first-line treatment for most forms of non-systemic JIA, however only half of patients adequately respond to the therapy, which also has unpleasant side effects, the study authors wrote in the journal Annals of the Rheumatic Diseases.
Non-responders to methotrexate would likely benefit from earlier intervention with biologic agents if they could be reliably identified, however, there were no validated biomarker tests to predict which children needed early escalation.
In this latest study from the UK’s CLUSTER Consortium, researchers identified and validated gene expression biomarkers in the peripheral blood of 97 children with JIA before they started methotrexate treatment and examined their response after six months of therapy.
They found genes in the IFN alpha (type-I) and gamma (type-II) response pathways were associated with response to methotrexate at six months.
The findings were replicated in two validation cohorts of JIA, the researchers said, and the association was confirmed using an independent score of five IFN-driven genes (IGS5).
Importantly, they found the association between IFN-driven pathways and response differed between children with JIA and a cohort of adults with rheumatoid arthritis (RA), emphasising the need for age-specific research in inflammatory arthritis.
‘Given that parents and patients report uncertainty about treatment response as a major burden, and that methotrexate intolerance is very prevalent in JIA, the clinical value of a biomarker measured in a small blood sample that could predict response to methotrexate and aid clinical choices of medication would be high,’ they wrote.
‘Our study provides proof of principle that carefully designed analyses can yield hope for a more precision-based approach to treatment in the future for children and families living with arthritis.’
The CLUSTER Consortium, which includes researchers from Great Ormond Street Hospital (GOSH) and University College London (UCL), is a large multidisciplinary group of researchers working in JIA who have come together to find ways to improve treatment.
CLUSTER lead investigator Professor Lucy Wedderburn, consultant in paediatric rheumatology at GOSH and UCL Great Ormond Street Institute of Child Health, explained it was difficult to choose the right treatment for a particular child with JIA.
‘Therefore, it is important to find indicators or ‘biomarkers’ that can tell the doctors and healthcare team which drug treatment is most likely to work for each child depending on their disease status,’ she said.
‘Our findings mean that in the future, a simple blood test could help doctors know early if methotrexate will work. This means that children could get the right treatment faster, avoid side effects and stay healthier.’
In an interview with Hospital Healthcare Europe last year, Professor Wedderburn said CLUSTER, which represented about 5,000 families, was about moving to a point where there is true precision medicine.
‘Many of my patients are in these studies, if they’re willing, and most people want to be involved because we explain it’s the way to get real-world data,’ she said.
‘This consortium brought together childhood data from huge cohorts – absolutely fabulous for such a rare disease.’
Last year the team reported results from a study of four cohorts of children who began their methotrexate treatment before January 2018, which used machine learning to find patterns in treatment outcomes and determine how effective methotrexate was on different elements of JIA.
The researchers noted that machine learning would play an essential role in improving understanding of treatment outcomes, minimising children’s exposure to unnecessary treatments, optimising treatment selection and ultimately improving the quality of care for children with JIA.
A series of recommendations to address burnout and understaffing in paediatrics and support child health outcomes has been shared by the Royal College of Paediatrics and Child Health (RCPCH).
Focusing on training and recruitment, retention and wellbeing, collaborative care, and workforce planning, the recommendations build on the RCPCH’s blueprint for child health services published in September 2024.
This ‘landmark’ policy report highlighted how the lack of investment in children’s health was having severe consequences and now, a year on, the RCPCH says it is ‘reiterating what is now an urgent call for Government action to address the pressure that paediatricians are facing, so that they can effectively tackle worsening health outcomes and growing inequalities.’
The recommendations are part of a policy briefing report, which highlights the ‘uphill battle’ paediatricians are facing against a backdrop of ‘growing complexity in paediatric care’ and without adequate support from the Government.
A snapshot survey in May of 400 UK paediatricians found that 82% felt there was insufficient staffing to meet the needs of children and young people.
This understaffing has led to ‘significant strain’ and ‘heightened levels of stress’, with three quarters (75%) of respondents saying they felt pressure to work overtime in the last year – and 11% stating this was always the case.
Some 71% had gone to work despite not feeling mentally or physically well enough, with over half (55%) saying this had happened on more than one occasion in the last 12 months.
A third of respondents (63%) said they had experienced burnout, with 44% experiencing it in the last year.
Commenting on the survey results and their context, RCPCH president, Professor Steve Turner, said: ‘For too long, child health has not been a priority across the UK healthcare systems. The lack of focus in policy at local and national level has led to our children and young people now having some of the worst health outcomes in Europe. This unacceptable reality demands an urgent change.
‘As a paediatrician, I understand the importance of timely, high-quality care for children and young people. Insufficient numbers of healthcare staff, many of whom are overworked, unappreciated and burnt-out, is a huge concern to me. The pressures paediatricians are working under poses serious risks to patient care, delays treatments and creates stress for children, their families and the whole NHS staff.’
In 2023, the RCPCH warned that the number of children waiting for consultant-led care had reached an all-time high and data from 2024 showed that while paediatric waiting lists had increased by 67% since 2020, there had only been a 15% increase in consultant numbers during the same time period.
In the last two years the number of children waiting over 52 weeks for treatment rose by 60% for elective services and 94% for community health services, the RCPCH added.
Its latest recommendations therefore include committing to expanding paediatric training and consultant posts in line with changes in working, service provision and demand.
Implementing structures that allow clinicians to treat patients in a safe and sustainable way is also advised, particularly when it comes to improving working conditions, maintaining sustainable rota practices and investing in staff mental health and wellbeing.
Among other recommendations is the urgent need to support the transition of care across the primary-secondary care interface and ensuring competence, coordination and investment at all stages, with Connecting Care for Children shared as an example of best practice.
Professor Turner added: ‘Without real change, the child health workforce will continue to struggle to meet mounting demands. The UK Government must act now. With NHS reform and the new 10-Year Health Plan, we have a chance to strengthen the child health workforce and ensure better care for children. Investment in children today will benefit the UKs health and economy tomorrow.’
23rd June 2025
Despite the increasing use of PARP inhibitors in treating several solid tumours including ovarian, prostate and breast cancers, pre-existing innate or intrinsic resistance remains a challenge. Drs Olga Brieieva and Martin Higgs discuss new advances using in vitro genomic models that offer promising insights into predicting clinical resistance to PARP inhibitors and developing strategies to overcome it.
Poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitors were first identified as potential targeted treatments for tumours deficient in homologous recombination (HR), a sub-pathway of DNA double-strand break repair. Indeed, four different PARP inhibitors are now approved for the treatment of both early- and late-stage breast1 and ovarian cancers2 that harbour mutations in the HR factors BRCA1 or BRCA2. These are olaparib, rucaparib, talazoparib and niraparib.
PARP inhibitors are also approved for use in prostate3,4 and pancreatic cancers5 encoding mutations in BRCA1/2, and their use is expanding into other genetic deficiencies of DNA repair. This ranges from widespread use as maintenance therapy to a more limited use in metastatic settings after failure of other treatment options.
Unfortunately, the clinical utility of PARP inhibitors is hampered by both pre-existing and de novo resistance, which limits their use as long-term maintenance therapies. Although estimates vary between tumour subgroups, approximately 40% of patients with metastatic breast cancer or ovarian cancer fail to benefit from olaparib.1,6,7 This likely reflects high proportions of both intrinsic and innate resistance and is relevant for thousands of patients across Europe receiving PARP inhibitors.
Extensive studies using in vitro cellular models and/or patient-derived xenografts have revealed multiple mechanisms that drive resistance to PARP inhibitors.8–10 These can be classified into four categories:
In many of these cases, mechanisms that restore HR in BRCA1-deficient cells, including loss of proteins that promote non-homologous end-joining (NHEJ), or secondary mutation of BRCA1/2 that restore HR, drive PARP inhibitor resistance in vitro. Of relevance, loss of pro-NHEJ factors, such as 53BP1, partially restores HR in BRCA1-deficient cells and thus allows repair of PARP inhibitor-induced lesions, thereby driving resistance.11–16
However, despite these mechanistic advances, predicting resistance in the clinic is less straightforward. Several of these alterations – including secondary alterations in BRCA1/2, increased expression of drug efflux effectors and deregulation of pro-NHEJ factors – are observed in a small subset of patients receiving PARP inhibitors or derived xenografts.17–23 However, in approximately 50% of patients, the mechanism of resistance remains unclear, likely due to unidentified factors such as epigenetic alterations.22
Moreover, few, if any, biomarkers for PARP inhibitors have been systematically analysed or tested in the clinic, and the field sorely lacks robust predictors for the onset of PARP inhibitor resistance in patient populations.
The lysine methyltransferase SETD1A has multiple roles in DNA repair, including the response to replication damage and in promoting NHEJ. Our two recent studies have identified an epigenetic mechanism of PARP inhibitor resistance that involves loss of SETD1A.
Mechanistically, PARP inhibitor resistance upon the loss of SETD1A involves two pathways that hinge around the ability of SETD1A to catalyse methylation of lysine 4 of histone H3 (H3K4). We originally demonstrated that PARP inhibitor resistance in BRCA1-deficient cells lacking SETD1A was due to defective H3K4 methylation and subsequent destabilisation of replication-independent factor-1 (RIF1) on damaged chromatin.24 This led to a concomitant loss of NHEJ and restoration of HR, driving PARP inhibitor resistance.
More recent studies from our group suggest that this is not the only mechanism.25 Analyses of BRCA1-deficient cells depleted of SETD1A revealed that SETD1A is required for efficient expression of the structure-specific nuclease EME1 specifically in HR-deficient cells. Moreover, loss of EME1 alone can drive resistance of BRCA1-deficient cells to PARP inhibitors, and at least partially restore HR.25 This is somewhat surprising, as EME1 is not a pro-NHEJ factor; rather, it maintains genome integrity by resolving recombination intermediates.26
Therefore, it seems that loss of either of these pathways can partially restore HR and render BRCA1-deficient cells resistant to olaparib, although it remains to be seen whether these pathways are linked. However, in keeping with multiple previous studies, neither of these pathways has any impact on the sensitivity of BRCA2-deficient cells to PARP inhibitors.
Our data from two-dimensional cell models implies that low SETD1A activity would correlate with PARP inhibitor resistance in HR-deficient breast and ovarian tumours. One question arising from these studies is whether SETD1A, H3K4me3 and/or EME1 expression can be used in the clinic as predictive biomarkers for PARP inhibitor resistance.
There is some correlation between levels of SETD1A/EME1 mRNA and overall survival of BRCA1-deficient patients from the Cancer Genomic Atlas,25 which is seen neither in BRCA2-deficient nor BRCA wild-type tumours. However, these data predate the use of PARP inhibitors in the clinic. Moreover, they are unlikely to provide information on SETD1A enzymatic activity as mRNA levels only partly correlates with protein expression in these samples.27,28
Therefore, further work needs to be done to profile the protein expression and levels of these targets and to investigate how they might be used as a combinatorial biomarker to predict pre-existing or acquired resistance.
Increasing knowledge of in vitro mechanisms of PARP inhibitor resistance has led to the discovery and characterisation of important potential biomarkers. However, there is a lack of a systematic approach to including these in the clinical study of PARP inhibitors, for current approvals and novel indications.
We recommend that future studies involving PARP inhibitors assess the expression and mutation status of biomarkers such as SETD1A, RIF1 and 53BP1 and their downstream targets alongside clinical response and resistance. This will also likely shed light on novel combinations of PARP inhibitors with epigenetic drugs, such as those targeting lysine methyltransferases and/or lysine demethylases, to overcome such resistance.
Olga Brieieva BSc MSc PhD
Visiting research fellow and Cara fellow, Department of Cancer and Genomic Sciences, School of Medical Sciences, University of Birmingham, UK
Martin Higgs BSc PhD
Associate professor and head of research, School of Medical Sciences and deputy director of the Centre for Rare Disease Studies, University of Birmingham, UK
Speaking at Hospital Healthcare Europe’s Spring 2025 Clinical Excellence in Respiratory Care event, Dr Ernie Wong provided an in-depth overview of biological infections in asthma. Here, you have exclusive access to the session recording.
According to Dr Ernie Wong, consultant respiratory physician and clinical lead for asthma at Imperial College Healthcare NHS Trust, when people refer to pathogens in asthma, they often mean bacteria. ‘But actually,’ he says, ‘we need to think about all sorts of potential pathogens: viruses, bacteria and fungi.’
In this Clinical Excellence session, Dr Wong, who is also an honorary clinical senior lecturer at Imperial College London’s National Heart and Lung Institute, provides an overview of the common and varied biological infections and hypersensitivities seen in asthma patients.
Kicking off with an in-depth look at the well-documented ‘September epidemic’ in secondary care and the impact of viruses on asthma exacerbations and T2 airway inflammation, Dr Wong also covers the need to improve patient adherence to inhaled corticosteroids and the use of antiviral treatment.
He then turns his attention to the role of bacteria in asthma, including insights into the airway microbiome, the concept of dysbiosis and the best-practice use of antibiotics for both chronic and acute disease to support antimicrobial stewardship and optimal patient care.
The discussion concludes with a look into the role of fungi in asthma – specifically allergic bronchopulmonary aspergillosis – the hypersensitivities fungi cause, and the antifungal management required.
Watch more Clinical Excellence event sessions via our Clinical Excellence Catch-up zone and watch this space as the autumn schedule for Clinical Excellence will be announced soon.
You can find brand new interviews and case studies on respiratory care – plus round ups of previous Clinical Excellence event sessions by looking out for the orange Clinical Excellence tag – and much more content that can help to inspire your practice in our Respiratory zone.
Speaking at Hospital Healthcare Europe’s Spring 2025 Clinical Excellence in Respiratory Care event, Dr Sophie West focused on the use of wearables and artificial intelligence in the future of sleep medicine. Here, you have exclusive access to the session recording.
The challenge of obstructive sleep apnoea (OSA) for clinicians is the sheer volume of work it presents, according to Dr Sophie West, consultant respiratory and sleep physician at Newcastle upon Tyne NHS Foundation Trust.
She puts this down to the increasing prevalence of OSA due to the rise in both obesity and recognition of its association with other comorbidities, citing a 2019 paper estimating 936 million adults aged 30-69 have mild-to-severe OSA. ‘It’s probably more now [post-Covid],’ she says, ‘although that study’s not been repeated’.
With so many other sleep disorders to also contend with, driving efficiencies in clinical practice is crucial, and the potential for wearables and artificial intelligence (AI) to do just this is mounting.
In this Clinical Excellence session, Dr West focuses on the future of sleep medicine, specifically wearable devices and how they work in sleep monitoring, emerging technologies in sleep medicine and the use of AI in sleep diagnosis.
Watch more Clinical Excellence event sessions via our Clinical Excellence Catch-up zone and watch this space as the autumn schedule for Clinical Excellence will be announced soon.
You can find brand new interviews and case studies on respiratory care – plus round ups of previous Clinical Excellence event sessions by looking out for the orange Clinical Excellence tag – and much more content that can help to inspire your practice in our Respiratory zone, plus more content on wearables and AI in our Health Technology zone.
Read about the deep learning-enabled garment that accurately captures and classifies sleep disorders and new research suggesting that sleep disorders may be predictive marker of future neurodegeneration.
Speaking at Hospital Healthcare Europe’s Spring 2025 Clinical Excellence in Respiratory Care event, Professor Paul Corris shared insights into the when, why and how of lung transplantation. Here, you have exclusive access to the session recording.
Organ transplantation is one of the most significant advancements in the history of medicine, but disparities have been well documented in terms of access to these procedures and the often lengthy waiting lists are notable.
For lung transplantation, of which there are now around 4,500 transplantations undertaken every year, progress since the 1980s has been commendable and a slow but steady increase in overall survival has been noted. This has been driven by a strengthening of clinical criteria for appropriate recipients; a focus on appropriate donor lungs – including the development of novel approaches such as ex vivo lung perfusion (EVLP) – optimising the surgery itself; and careful post-operative care, which now includes extracorporeal membrane oxygenation (ECMO).
Professor Paul Corris is emeritus professor of thoracic medicine at Newcastle University and the University of Oxford. In this Clinical Excellence session, he discusses the clinical indicators for lung transplantation and the patients that need them, pre-transplant investigations and post-transplant complications and management, as well as the latest advancements in lung transplantation making a difference for clinicians and patients.
Watch more Clinical Excellence event sessions via our Clinical Excellence Catch-up zone and watch this space as the autumn schedule for Clinical Excellence will be announced soon.
You can also find brand new interviews and case studies on respiratory care – plus round ups of previous Clinical Excellence event sessions by looking out for the orange Clinical Excellence tag – and much more content that can help to inspire your practice in our Respiratory zone.
This includes a write up of Professor Corris’ previous Clinical Excellence session on lung transplantation.
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