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Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The 51app reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.

From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.

The word limit for letters selected from posted responses remains 300 words.

Re: The GMC’s future vision for medical training must be challenged David Oliver, Louella Vaughan. 384:doi 10.1136/bmj.q728

Dear Editor

In “The GMC’s future vision for medical training must be challenged” (published 27 March) [1], David Oliver and Louella Vaughan outlined their concerns about the vision we have recently set out for reforming medical education and training, and more specifically a worry that this compromises patient safety, lowers standards, and represents a done deal.

Vaughan and Oliver focused on the three areas of change set out in the statement, but ignored the important overarching principles that underpin our regulatory approach to medical education and training: patient safety; maintaining standards; outcomes not time; competency; proportionality and support for diversity. The authors’ conclusions do not take these principles into account and therefore result in a considerable misunderstanding of the intentions behind the GMC statement.

Our intention is to ensure the expansion of medical school places and innovations in medical degrees are completed in ways that are safe and that meet our standards; that educators are supported to meet the education and training needs of medical students and doctors; and that doctors are supported, throughout their careers, to build skills and knowledge.

There is no doubt reforms are needed, to better meet the needs of patients now and in the future as well as to support doctors. Our data show us how much strain the system is under and Marmot [2] and Whitty [3] have highlighted the changes that have taken place and the inequalities that exist in healthcare accessibility and delivery. Given this, as the organisation responsible for setting and maintaining standards, we cannot ignore the evidence of the need for change.

We are in the earliest stages of this. Our recent statement is not a detailed proposal but rather a vision for change. While we have already had some discussions with statutory education bodies, royal colleges, and those representing doctors, including doctors in training, this is still the very beginning of the journey. It will not happen overnight.

However, the experience of the pandemic showed that changes – such as derogations for progression in postgraduate education and early graduation for medical students combined with strong support for the foundation interim year one doctors – can be made at pace and be positively received. [4] [5]

I appreciate that, in the current environment, doctors may fear this as something that is going to be done to them rather than with them, but the entire process will be handled in collaboration, and with extensive consultation.

Vaughan and Oliver are concerned we are approaching this with too much urgency. I would stress that, while we want to improve the system as quickly as possible, this will not be at the cost of engagement, nor in compromising patient safety or our standards.

Over the next 12 to 18 months we’ll be asking for initial feedback from doctors, patients and other stakeholders about the principles we have outlined. We will also hold our annual GMC Symposium, which will be an opportunity for detailed discussion and exploration of these topics.

While we disagree with their conclusions, we welcome the engagement shown by the authors, and want to continue to work with the profession on implementing change. They are right to say there are significant risks to education and training in the UK, but these come from failing to change rather than from updating training to reflect the present and future needs of patients.

We believe the next steps require all of us – regulators, employers, statutory education bodies and the profession – to work together to ensure medical education and training in the UK remains outstanding.

1 Oliver, D., Vaughan, L. The GMC’s future vision for medical training must be challenged. 27 Mar 2024.
2 Marmot, M., Allen, J., Boyce, T., Goldblatt, P., Morrison, J. Health equity in England: The Marmot Review 10 years on. 2020. London: Institute of Health Equity.
3 Department of Health and Social Care. Chief Medical Officer’s Annual Report 2021: Health in Coastal Communities. 21 Jul 2021.
4 Vance, G., Brown, M., Burford, B., Finn, G. Evaluating the Wider Impacts of Changes to UK Medical Education in Response to the COVID-19 Pandemic. Sept 2023.
5 Burford, B., Vance, G. 2020 Medical Graduates: The work and wellbeing of interim Foundation Year 1 doctors during COVID-19. Mar 2021.

Competing interests: No competing interests

12 April 2024
Colin Melville
Medical Director and Director of Education and Standards, GMC
London
Re: What comes next after the extraordinary general meeting on physician associates at the RCP? Partha Kar, Louella Vaughan. 384:doi 10.1136/bmj.q769

Dear Editor

At a recent National Conference [1], the invited guest speaker, a Physician Associate, openly admitted “I introduce myself as an ANP because it saves time as the public are already aware about ANPs”. Is this acceptable? Whose duty is to explain to the public who PAs are? The government, the hospitals and GP surgeries and the PAs as well are all equally responsible. In my view, they have failed on all accounts.

The idea stemmed over research from the US that PAs can deliver cost effective and safe healthcare and fill in the gaps at GP surgeries and in hospitals in various departments once they are appropriately trained [2]. Prospective PAs in the US need to go through an accredited master’s degree level programs, which take 3 academic years. They are also required to engage in 2,000 hours of clinical rotations as well as passing a certification exam, among other requirements [3]. UK has yet to match an equivalent standard of education and scope of practice.

BIDA is extremely apprehensive with all the issues raised regarding the scope of practice and supervision of Physician Associates in both primary and secondary care.

BIDA would like to raise the following fundamental issues:

1. We strongly feel that 2 years of teaching is not sufficient to give them the core knowledge of medicine.
2. Their subsequent training requires competing with other trainees. We are hugely concerned that there will be an unfair competition for educational resources amongst deanery trainees, fellowship trainees, locally employed doctors and PAs. The apprehension is that this competition risks the PAs left behind the order of priorities for the trainer.
3. PAs are at risk of being deployed in positions they are not suitable for, due to their limited training. It is of great concern that at several hospitals, they are put on the doctors’ rota and even at GP surgeries to see patients on their own, which can be unsupervised and remain largely unregulated4.
4. There is still a lack of awareness amongst the public about this group of healthcare workers. Their roles have not been explained to the public.
5. We remain opposed to the legislation of the GMC being the regulator for PAs. This is likely to distort the roles and responsibilities of both doctors and PAs and end up creating a misunderstanding in the minds of the public.

The recent EGM of the Royal College of Physicians voted on five motions covering scope of practice, accountability, evaluation, the impact on training opportunities, and the pace and scale of the roll out of physician associates. This highlights the level of unease that our colleagues have expressed.

BIDA urges the government to step back, consider our concerns, audit and evaluate the whole programme set for PAs.

BIDA supports the guidance for scope of practice for MAPs as recommended by the BMA.

BIDA calls upon the government that until the role of Physician Associates and Anaesthetic Associates are better defined, the proposed increase to 10,000 should be delayed.

Amit Sinha FRCS (Tr& Orth)
Consultant Orthopaedic Surgeon
General Secretary, British International Doctors Association

References

1. British International Doctors Association (BIDA) National Conference, 30th October 2023.

2. Lynn E. What you need to know about physician associates. (published 07 December 2023)

3. AAPA. What is a PA?

4. Colivicchi A. BMA calls for enquiry into Pas replacing doctors on rota. London. Pulse 2024.

Competing interests: No competing interests

12 April 2024
Amit Sinha
Consultant Orthopaedic Surgeon
General Secretary, British International Doctors Association
Swallow Mill Business Centre, Swallow Street, Stockport SK1 3HJ
Re: Ultra-processed food exposure and adverse health outcomes: umbrella review of epidemiological meta-analyses Amelia J McGuinness, Sarah Gauci, Phillip Baker, Mark Lawrence, et al. 384:doi 10.1136/bmj-2023-077310

Dear Editor,

Nunan highlights a pervasive issue in health research is overlooking uncertainty in interpreting findings, potentially leading to misleading conclusions about the strength of the evidence (1). He asks: why assess uncertainty if it is not then communicated effectively?

Conclusion word limits, especially in abstracts, often restrict detailed discussion. Given the extensive scope and numerous pooled analyses in our umbrella review, we primarily emphasise meta-evidence meeting our credibility and quality criteria for the strongest evidence available. These criteria were determined using two assessment tools: objective evidence classification criteria and subjective GRADE methodology, respectively. Both tools, pre-specified and consistently reported throughout our study, are commonly used and recommended within the umbrella review literature.

In our conclusion, we prioritise pooled analyses with convincing ("class I") or highly suggestive ("class II") credibility, coupled with either "moderate" or "low" quality, collectively filtering out those with high uncertainty. A more detailed analysis of potential sources of uncertainty and directions for future research can be found in our discussion section.

Nunan further highlights the challenge of introducing the unvalidated evidence classification criteria alongside GRADE to evaluate the evidence.

In nutrition science, no single rigorously validated tool exists to evaluate evidence. While the GRADE system is commonly employed for assessing evidence quality, its uncertain reliability in evaluating complex diet-related evidence, especially within prevalent observational studies, is questioned (2). On the other hand, although recent umbrella review guidelines advocate for the use of the evidence classification criteria, they also acknowledge the limitations of relying on strict cut-off points (3).

Therefore, to ensure a balanced evaluation of evidence and to avoid overreliance on single tools, we employed both the evidence classification criteria and the GRADE methodology.

Nonetheless, aligning with Tobias et al. (2021), we concur that the nutrition science community must collaborate to establish a consensus on developing fit-for-purpose tools. These tools, tailored for effectively synthesising and grading diet-related evidence, are essential given our field's complexities and the strengths and weaknesses of existing evidence grading systems (2).

References
1. Nunan D. Re: Ultra-processed food exposure and adverse health outcomes: umbrella review of epidemiological meta-analyses. [Rapid Response] 51app 2024. Available from: /content/384/bmj-2023-077310/rr-1
2. Tobias DK, Wittenbecher C, Hu FB. Grading nutrition evidence: where to go from here? Am J Clin Nutr 2021;113(6):1385-87. doi: 10.1093/ajcn/nqab124
3. Fusar-Poli P, Radua J. Ten simple rules for conducting umbrella reviews. Evid Based Ment Health 2018;21(3):95-100. doi: 10.1136/ebmental-2018-300014 [published Online First: 2018/07/15]

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: MML, EG, DNA, AJM, SG, FNJ, AO, and WM are affiliated with the Food & Mood Centre, Deakin University, which has received research funding support from Be Fit Food, Bega Dairy and Drinks, and the a2 Milk Company and philanthropic research funding support from the Waterloo Foundation, Wilson Foundation, the JTM Foundation, the Serp Hills Foundation, the Roberts Family Foundation, and the Fernwood Foundation; MML is secretary for the Melbourne Branch Committee of the Nutrition Society of Australia (unpaid) and has received travel funding support from the International Society for Nutritional Psychiatry 51app, the Nutrition Society of Australia, the Australasian Society of Lifestyle Medicine, and the Gut Brain Congress and is an associate investigator for the MicroFit Study, an investigator-led randomised controlled trial exploring the effect of diets with varying levels of industrial processing on gut microbiome composition and partially funded by Be Fit Food (payment received by the Food and Mood Centre, Deakin University); AMJ is secretary for the International Society for Nutritional Psychiatry 51app (unpaid) and an associate investigator for the MicroFit Study; SG is affiliated with Deakin University, which has received grant funding support from a National Health and Medical 51app Council Synergy Grant (#GNT1182301) and Medical 51app Future Fund Cardiovascular Health Mission (#MRF2022907), is affiliated with Monash University, which has received grant funding support from Medical 51app Future Fund Consumer-led research (#MRF2022907), is secretary for the Australian Cardiovascular Health and Rehabilitation Association—Victoria and Tasmania—(unpaid), and has received travel funding support from the Institute for Mental and Physical Health and Clinical Translation and SOLVE-CHD (solving the long-standing evidence-practice gap associated with cardiac rehabilitation and secondary prevention of coronary heart disease); PB has received funding from an Australian 51app Council Future Fellowship award (project number #FT220100690) and from Bloomberg Philanthropies; ML is affiliated with the Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, which has received grant funding support from the Australian 51app Council (#DP190101323), and has received royalties or license funding from Allen and Unwin (Public Health Nutrition: from Principles to Practice) and Routledge, Taylor and Francis Group (Healthy and Sustainable Food Systems) and consultation and remuneration funding support from WHO and Food Standards Australia New Zealand (in his role as a board member); CMR is affiliated with Johns Hopkins Bloomberg School of Public Health and Johns Hopkins University, which have received grant funding support from the National Heart, Lung, and Blood Institute, Bloomberg American Health Initiative, and the National Institute of Diabetes and Digestive and Kidney Diseases, was chair of the Data and Safety Monitoring Boards for the SUPER Trial: Effect of Dietary Sodium Reduction in Kidney Disease Patients with Albuminuria and the ADEPT Trial: A Clinical Trial of Low-Carbohydrate Dietary Pattern on Glycemic Outcomes, was on the Editorial Board of Diabetes Care (unpaid), was the immediate past chair for the Early Career Committee of the Council on Lifestyle and Cardiometabolic Health, American Heart Association (unpaid), and the Nutritional Epidemiology 51app Interest Section of the American Society for Nutrition (unpaid), and has received funding support as an associate editor of Diabetes Care and editorial fellow of the Journal of the American Society of Nephrology; FNJ has received fellowship funding support from the National Health and Medical 51app Council (#1194982) and payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the Malaysian Society of Gastroenterology and Hepatology, JNPN Congress, American Nutrition Association, Personalised Nutrition Summit, and American Academy of Craniofacial Pain, is a Scientific Advisory Board member of Dauten Family Centre for Bipolar Treatment Innovation (unpaid) and Zoe Nutrition (unpaid), has written two books for commercial publication on the topic of nutritional psychiatry and gut health, and is the principal investigator for the MicroFit Study; AO has received fellowship funding support from the National Health and Medical 51app Council (#2009295) and is affiliated with Deakin University, which has received grant funding support from the Medical 51app Future Fund, Dasman Diabetes Institute, MTP Connect—Targeted Translation 51app Accelerator Program, the National Health and Medical 51app Council, Barwon Health, and the Waterloo Foundation, and has received funding support for academic editing and as a grant reviewer from SLACK Incorporated (Psychiatric Annals) and the National Health and Medical 51app Council, respectively, and travel funding support from the International Society for Nutritional Psychiatry 51app; WM is president of the International Society for Nutritional Psychiatry 51app (unpaid), has received fellowship funding support from the National Health and Medical 51app Council (#2008971) and Multiple Sclerosis 51app Australia, consultation and remuneration funding support from Nutrition 51app Australia and ParachuteBH, and travel funding support from the Nutrition Society of Australia, Mind Body Interface Symposium, and VitaFoods, and was the acting principal investigator and is an associate investigator for the MicroFit Study.

11 April 2024
Melissa M Lane
postdoctoral research fellow 1
Elizabeth Gamage, doctor of philosophy candidate 1, Shutong Du, doctor of philosophy candidate 2 3, Deborah N Ashtree, associate research fellow 1, Amelia J McGuinness, associate research fellow 1, Sarah Gauci, associate research fellow, adjunct research fellow 1 4, Phillip Baker, senior research fellow 5, Mark Lawrence, professor 6, Casey M Rebholz, associate professor, core faculty 2 3, Bernard Srour, junior professor 7, Mathilde Touvier, research director 7, Felice N Jacka, professor 1 8 9, Adrienne O’Neil, professor 1, Toby Segasby, doctor of philosophy candidate 10, Wolfgang Marx, senior research fellow 1
1 Institute for Mental and Physical Health and Clinical Translation, Food & Mood Centre, School of Medicine, Deakin University, Barwon Health, Geelong, Victoria, Australia, 3220; 2 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 3 Welch Center for Prevention, Epidemiology, and Clinical 51app, Johns Hopkins University, Baltimore, MD, USA; 4 Chronic Disease and Ageing, School of Public Health and Preventive Medicine, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Victoria, Australia; 5 Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; 6 Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia; 7 Université Sorbonne Paris Nord and Université Paris Cité, INSERM, INRAE, CNAM, Nutritional Epidemiology 51app Team (EREN), Center of 51app in Epidemiology and StatisticS (CRESS), F-93017 Bobigny, France; 8 Centre for Adolescent Health, Murdoch Children’s 51app Institute, Melbourne, Victoria, Australia; 9 James Cook University, College of Public Health, Medical & Veterinary Sciences, Townsville, Queensland, Australia; 10 School of Biotechnology, Dublin City University, Dublin, Ireland
Health Education & 51app (HERB) Building, Deakin University, School of Medicine, PO Box 281, Geelong, Victoria, 3220
Re: New treatments for Alzheimer’s disease Robert Howard, Helen C Kales. 382:doi 10.1136/bmj.p1852

Dear Editor

We read with interest the editorial by Howard and Kales, New Treatments for Alzheimer’s disease: Blazing trails or the road to nowhere?(51app 2023;382:p1852 ) [1]. The authors discuss new anti-amyloid-β therapeutics and appropriately conclude “Healthcare systems for people with dementia, which have fragile and often limited funding structures, will be at risk of damaging distortion if resources are redirected to support access to such expensive and clinically ineffective treatments.” We add to this discussion the issue of toxicity and the emerging problem of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is a common accompaniment of Alzheimer’s disease and aging that predisposes patients to lobar hemorrhage. Its prevalence in Alzheimer’s disease was estimated at 48% according to a recent meta-analysis [2] and is relatively more common in patients with apolipoprotein E ε4 and ε2 alleles [3]. The diagnosis may be suggested during life according to the Boston critieria [4], but such criteria require detectable hemorrhage. The reality is that most patients with cerebral amyloid angiopathy are unaware of their condition.

Emerging autopsy data suggests that experimental anti-amyloid-β antibodies do not discriminate between senile plaque amyloid and vascular amyloid[ 5-7], leading to vascular destruction per se, rather than a perivascular clearance of amyloid that has been hypothesized8. Both senile plaque and vascular amyloid elicit a robust macrophage/microglial response [5-7], resulting in direct, immune-mediated destruction of cortical blood vessels in patients with cerebral amyloid angiopathy. Two autopsy cases do date, which appeared promptly with the open label extension phase of lecanemab clinical trials, showed identical changes – a necrotizing, histiocytic vasculitis of small, cerebral amyloid angiopathy-laden cortical blood vessels. [5-7]

Infusion of such agents thus appears tantamount to an infusion of vasculitis in patients with vascular amyloid, the extent and severity of which cannot be predicted by current diagnostic methodologies. Idiosyncratic outcomes such as edema and hemorrhage (i.e., amyloid-related imaging abnormalities, or ARIA), headache, confusion, vomiting, visual or gait disturbances [8] and sometimes death [6,9] are not surprising, the only questions being the frequency of such complications, and the long-term brain health of patients subjected to drug-induced cerebral amyloid vasculitis.

Critical reassessment of the appropriateness of such drugs for public dissemination might be warranted, along with a better appreciation for the extent to which ARIA represents iatrogenic necrotizing vasculitis.

1. Howard R, Kales HC. New treatments for Alzheimer's disease. 51app 2023;382:1852. DOI: 10.1136/bmj.p1852.
2. Jakel L, De Kort AM, Klijn CJM, Schreuder F, Verbeek MM. Prevalence of cerebral amyloid angiopathy: A systematic review and meta-analysis. Alzheimers Dement 2022;18(1):10-28. DOI: 10.1002/alz.12366.
3. Nelson PT, Pious NM, Jicha GA, et al. APOE-epsilon2 and APOE-epsilon4 correlate with increased amyloid accumulation in cerebral vasculature. J Neuropathol Exp Neurol 2013;72(7):708-15. DOI: 10.1097/NEN.0b013e31829a25b9.
4. Switzer A, Charidimou A, McCarter SJ, et al. Boston criteria v2.0 for cerebral amyloid angiopathy without hemorrhage: An MRI-neuropathological validation study. medRxiv 2023. DOI: 10.1101/2023.11.09.23298325.
5. Castellani RJ, Shanes ED, McCord M, et al. Neuropathology of Anti-Amyloid-beta Immunotherapy: A Case Report. J Alzheimers Dis 2023;93(2):803-813. DOI: 10.3233/JAD-221305.
6. Solopova E, Romero-Fernandez W, Harmsen H, et al. Fatal iatrogenic cerebral beta-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer's disease. Nat Commun 2023;14(1):8220. DOI: 10.1038/s41467-023-43933-5.
7. Reish NJ, Jamshidi P, Stamm B, et al. Multiple Cerebral Hemorrhages in a Patient Receiving Lecanemab and Treated with t-PA for Stroke. N Engl J Med 2023;388(5):478-479. DOI: 10.1056/NEJMc2215148.
8. Hampel H, Elhage A, Cho M, Apostolova LG, Nicoll JAR, Atri A. Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics. Brain 2023;146(11):4414-4424. DOI: 10.1093/brain/awad188.
9. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA 2023;330(6):512-527. DOI: 10.1001/jama.2023.13239.

Competing interests: No competing interests

11 April 2024
Rudy J Castellani
Professor
George Perry, Pouya Jamshidi
Northwestern University Feinberg School of Medicine
710 N. Fairbanks Ct, Olson Pavilion 2-514, Chicago, Illinois, 60611
Re: Women from more deprived backgrounds are less likely to have an epidural, finds study Zosia Kmietowicz. 384:doi 10.1136/bmj.q411

Dear Editor,

I read with interest the article written by Zosia Kmietowicz (News, 24 February).

The authors of the study published in Anaesthesia suggest several reasons for the difference observed in the uptake of epidural for labour between the poorest and richest women. One potential reason was knowledge regarding epidural analgesia, which should be addressed.

During my obstetric anaesthesia rotation, I have participated in the antenatal anaesthetic clinic for women referred by their midwife or obstetrician. During these consultations, options for labour analgesia are discussed with pregnant women and they are signposted to useful resources such as the Obstetric Anaesthetists Association’s website.[1] This has a wealth of accessible information for labour analgesia and anaesthesia, which is available as text and video format, in twenty-five different languages. This advice appears to be standardised for pregnant women attending the antenatal anaesthetic clinic at my hospital.

The majority of pregnant women do not require referral to the antenatal anaesthetic clinic and many will receive midwifery led care. They are encouraged to consider and design a birth plan, however there are circumstances during labour when care is transferred from midwifery led care and an epidural for labour is clinically indicated. Some pregnant women may not have any prior knowledge of epidural analgesia because their midwifery led care birth plan did not include this.

It would be beneficial for every pregnant woman to be provided with the full range of labour analgesia options that are specifically available at their midwifery or obstetric led units and in the community if a home birth is planned. This information should be standardised across the maternity sites within individual health boards. It is necessary to provide both verbal and written accessible information which should be discussed throughout pregnancy.

1 LabourPains. Information for expectant parents and healthcare professionals on pain relief choices during labour. labourpains.org

Competing interests: No competing interests

11 April 2024
Adam G Mounce
Anaesthetic Core Trainee
Department of Anaesthetics, Prince Charles Hospital, Gurnos Rd, Merthyr Tydfil, CF47 9DT
Re: Intersectionality in health equity research Ash Routen, Helen-Maria Lekas, Julian Harrison, Kamlesh Khunti. 383:doi 10.1136/bmj.p2953

Dear Editor

Accolades to Routen and colleagues [1] for addressing the need to move health inequities research beyond single, heterogeneous, demographic categories by including a combination of variables to better understand the complex array of factors contributing to group differences. Intersectional approaches are readily compatible with population level studies and increasingly warranted in clinical studies [2]. We identify three additional areas that we believe will help to advance health disparities research. First, consistent terminology will improve the interpretation and comparability across studies. Second, organizing research efforts within recognized frameworks will enhance the integration of the findings across studies and inform clinical relevance. Third, study sample identification and statistical approaches play a significant role in the interpretability of findings.

Health inequities are evident across the world. Governing and funding bodies have guidelines to assist with the identification of common terminology that can be applied in clinical and research settings. For example, the National Institutes of Health (NIH) requires investigators to follow Federal Regulations (NOT-OD-01-053) on collecting, reporting, and presenting ethnic and race data, identified as sociopolitical constructs for all clinical research participants [3,4]. Somewhat similar, in the United Kingdom, guided by the Census of England and Wales, data are collected on group classifications of ethnic and heritage backgrounds [5 ,6]. Intersectional approaches will be further enhanced with the use of consistent terminology across studies.

Second, numerous frameworks are available to provide a conceptual infrastructure for integrating collective findings and informing evidence-based interpretations. The World Health Organization has a Social Determinants of Health Equity Operational Framework in development [7]. Additionally, several institutes at the NIH have developed frameworks and models relevant to health disparities research. The National Institute on Aging Health Disparities 51app Framework was designed with the primary goal of evaluating areas of health disparities research that have been addressed and in what areas deficits remain [8 ,9]. The National Institute of Minority Health and Health Disparities 51app Framework extends from the NIA Framework and incorporates components of the Bronfenbrenner Socioecological Model, depicting the complex interactions from the individual (micro) level to the societal (macro) level [10]. Further, the National Center for Complementary and Integrative Health Whole-Person Health Model identifies levels of analysis and domains of influence [11]. Similarly, the National Institute of Mental Health’s 51app Domain Criteria Framework includes environmental factors and levels of analysis [12]. Collectively, the frameworks provide overlapping organization and terms applicable across disciplines.

Third, approaches to improve sample characterization and statistical techniques to strengthen the interpretation of evidence obtained are needed [13]. Inferring group differences requires a sample representative of the identified population. When the sample is not generalizable to the intended population, then additional characteristics of the sample are necessary to interpret findings specific to the group represented, consistent with an intersectional approach. Participants in clinical studies are often not representative and generalizable to the population they are intended to represent and frequently used statistical models are not designed to analyze group differences when groups differ on relevant variables [14]. Addressing existing gaps and increasing the rigor and reproducibility of studies will require researchers report findings on 1) generalizable and representative samples, or 2) provide broader characterizations of the groups represented consistent with intersectional approaches, or 3) match groups on relevant sociodemographic variables [15], and/or apply statistical models which can help account for clinical group imbalances [16].

Advancing health disparities research and improving health outcomes for all individuals requires the involvement of everyone: governing bodies, funders, reviewers, researchers, and clinicians. Working together, we can communicate with consistent terminology, improve the integration of findings within and across disciplines by working within overlapping conceptual models, and enhance study sample characterization and representation with more informative approaches. Let us not allow the processes for deriving and reporting evidence to become one of the factors perpetuating health inequities.

References

1. Routen A, Lekas H-M, Harrison J, Khunti K. Intersectionality in health equity research. 51app 2023;383:p2953. doi: 10.1136/bmj.p2953
2. Domenico LH, Tanner JJ, Mickle AM, et al. Environmental and sociocultural factors are associated with pain-related brain structure among diverse individuals with chronic musculoskeletal pain: intersectional considerations. Scientific Reports 2024;14(1):7796. doi: 10.1038/s41598-024-58120-9
3. National Institute of Health. NIH Policy on Reporting Race and Ethnicity Data: Subjects in Clinical 51app. Office of Management and Budget 2001
4. Town M, Eke P, Zhao G, et al. Racial and Ethnic Differences in Social Determinants of Health and Health-Related Social Needs Among Adults — Behavioral Risk Factor Surveillance System. MMWR Morb Mortal Wkly Rep 2024;73:204-08. doi:
5. United Kingdom Government. Ethnicity facts and figures. List of ethnic groups, 2024.
6. Office for National Statistics. Ethnic group (detailed) classifications: Census 2021 2021 [updated 19 March 2024. Available from: accessed April 2024.
7. World Health Organization. Operational Framework 2024 [Available from: accessed 25 March 2024.
8. Hill CV, Perez-Stable EJ, Anderson NA, Bernard MA. The National Institute on Aging Health Disparities 51app Framework. Ethn Dis 2015;25(3):245-54. doi: 10.18865/ed.25.3.245 [published Online First: 2015/12/18]
9. Patel M, Johnson AJ, Booker SQ, et al. Applying the NIA Health Disparities 51app Framework to Identify Needs and Opportunities in Chronic Musculoskeletal Pain 51app. J Pain 2022;23(1):25-44. doi: 10.1016/j.jpain.2021.06.015 [published Online First: 2021/07/20]
10. Alvidrez J, Castille D, Laude-Sharp M, et al. The National Institute on Minority Health and Health Disparities 51app Framework. American journal of public health 2019;109(S1):S16-s20. doi: 10.2105/ajph.2018.304883 [published Online First: 2019/01/31]
11. National Institue of Health. Whole Person Health: What You Need To Know [accessed October 2022.
12. Morris SE, Sanislow CA, Pacheco J, et al. Revisiting the seven pillars of RDoC. BMC Med 2022;20(1):220. doi: 10.1186/s12916-022-02414-0 [published Online First: 20220630]
13. Gatzke-Kopp L, Keil A, Fabiani M. Diversity and representation. Psychophysiology 2023;60(11):e14431. doi: 10.1111/psyp.14431
14. Miller GA, Chapman JP. Misunderstanding analysis of covariance. Journal of Abnormal Psychology 2001;110(1):40-48. doi: 10.1037/0021-843X.110.1.40
15. Thorpe RJ, Jr., McCleary R, Smolen JR, et al. Racial disparities in disability among older adults: finding from the exploring health disparities in integrated communities study. J Aging Health 2014;26(8):1261-79. doi: 10.1177/0898264314534892 [published Online First: 2014/12/17]
16. Satten GA, Kong M, Datta S. Multisample adjusted U-statistics that account for confounding covariates. Stat Med 2018;37(23):3357-72. doi: 10.1002/sim.7825 [published Online First: 20180619]

Authors

Kimberly Sibille, PhD, MA is a licensed clinical psychologist, an Associate Professor in the Department of Physical Medicine & Rehabilitation, College of Medicine at the University of Florida, and the Director of the Pain TRAIL - Translational 51app in Assessment and Intervention Lab.

Angela Mickle, MS, CCRP is a Clinical 51app Coordinator III in the Department of Physical Medicine & Rehabilitation, College of Medicine at the University of Florida, and the Manager and Data Analyst for the Pain TRAIL - Translational 51app in Assessment and Intervention Lab.

Cynthia Garvan, MA, PhD is a biostatistician in the Department of Anesthesiology, College of Medicine at the University of Florida who specializes in medical statistics, large data organization, team organization, and research mentorship to clinical faculty.

Basma Mohamed, MD is an Associate Professor of Anesthesiology in the Divisions of Perioperative Medicine and Neuroanesthesia at the University of Florida with interests in outcome research and a passion for advancing patient care in perioperative medicine.

Carl V. Hill, Ph.D., MPH is the Chief Diversity, Equity and Inclusion Officer for the Alzheimer's Association, overseeing strategic initiatives to strengthen the Association's outreach to all populations, and providing communities with resources and support to address the Alzheimer's crisis.

Andreas Keil, PhD is a Distinguished Professor of Psychology at the University of Florida. His laboratory examines the building blocks of mental health at the levels of brain, body, and behavior.

Competing interests: Authors have previously received or currently receive funding from the NIH.

11 April 2024
Kimberly T Sibille
Associate Professor
Angela Mickle, MS, CCRP; Cynthia Garvan, MA, PhD; Basma Mohamed, MD; Carl V. Hill, Ph.D., MPH;; Andreas Keil, PhD
College of Medicine
University of Florida
Re: Clinical effectiveness of an online supervised group physical and mental health rehabilitation programme for adults with post-covid-19 condition (REGAIN study): multicentre randomised controlled trial David McWilliams, Joyce Yeung, Christina Jones, Beatriz Lara, et al. 384:doi 10.1136/bmj-2023-076506

Dear Editor

Correspondents have raised some queries about the results of REGAIN trial (1).

1. That we make sweeping conclusions by extrapolating findings from our population to all people with long-covid.

This is incorrect. We clearly define our population of interest throughout the article, in the abstract, introduction, methods, discussion and conclusion. We do not extrapolate our findings to all people with post-covid-19 condition. Our conclusion states:

“Among adults with post-covid-19 condition at least three months after hospital discharge for covid-19, an individualised online, group physical and mental health rehabilitation intervention improved overall heath related quality of life more than usual care at three- and 12-months post-randomisation.”

2. That the trial is unblinded.

It is not possible to blind participants to their treatment allocation in trials of complex interventions. However, as reported in the article, we did maintain blinding of any study team members involved in collecting outcome data.

3. That the trial relied solely on subjective outcomes.

Our patient-partners with post-covid-19 condition, who helped us design the trial, unequivocally identified that improvement in overall quality of life was their top priority over and above objective measures of physical function. The core outcome set for post-covid-19 condition, developed by the COSMIN international group, did not include any objective outcomes of physical function (2). Regardless of any potential merit from collecting objective data such as six-minute walk test, this was clearly impossible during the height of the covid-19 epidemic in the UK. We did, however, collect data on employment status for our forthcoming health economic analysis. The number of participants who reported being unable to work at least one day in the previous three months for intervention vs usual care was 19% (41/216) vs 25% (56/20) at 3 months, 20% (43/216) vs 22% (48/ 223), at six months, and 18% (38/211) vs 28% (61/216) at 12 months.

4. That the REGAIN intervention puts people at risk of post exertional symptom exacerbation and that incomplete compliance in the intervention group may be an indication of this.

On enrolment we did not exclude people who described sequalae consistent with post-exertional symptom exacerbation. Throughout the trial we prospectively monitored for post exertional symptom exacerbation during and after every exercise and psychological support session. This included full and partial compliers. We did not identify any instances in over 1,000 hours of exercise and psychological support sessions.

Attention has been drawn to the difference in full compliance rate between the intervention and control group (90% vs 47%). Compliance will, inevitably, be lower in the intervention group, in a trial of this nature. To fully comply with the control intervention participants needed to attend just one ‘best-practice usual care session’. To fully comply with the REGAIN intervention participants needed to attend an initial one-to-one consultation session, ≥4/6 support sessions, and ≥5/8 exercise sessions. Given the nature of the disorder, it is a testament to the value participants gave to the treatment sessions that nearly half were able to attend both the initial one-to-one session and nine or more group sessions. To suggest that post-exertional symptom exacerbation might have contributed to less than full compliance, in the population recruited this trial, is pure speculation with no supportive evidence.

5. That we have wrongly concluded that the REGAIN intervention is effective because the observed effect size is small.

This criticism is largely a reprise of material from our discussion where we sought to put the observed effect size in context. As the correspondent notes, our observed effect size 0.03 (95% confidence interval 0.01 to 0.05) is at the lower end of what might be considered a ‘minimally clinical important difference’ for preference-based measures (0.03 to 0.05). The currently suggested ‘minimally clinical important difference’ of 0.04 for the PROPr score is from 'work-in-progress', and therefore, may be subject to change (3). Further, it falls into the 95% confidence interval of the effect size observed in our trial.

Important limitations in using uniform ‘minimally clinically important differences’ to define if interventions are worthwhile include that they are not context specific, and they do not take the patient’s perspective into account (4). In our protocol, and methods, we clearly state that what might be a worthwhile benefit has not been defined for an intervention of this nature in this population.

The correspondents have ignored the additional information we present to help patients decide, with support from their clinicians, if this is a treatment suitable for them: numbers needed to treat for participants to report feeling ‘much better now’ (11.9) and at least ‘somewhat better now’ (5.4).

6. That we are basing our conclusions on the treatment effect in the fully compliant sub-set.

Our conclusions are based on the intention to treat analysis. We presented a complier average causal effect analysis to aid interpretation. Complier average causal effect analysis does not simply measure the effect in a sub-set of participants, rather it estimates the treatment effect in people randomly assigned to the intervention who actually received it by comparing participants who fully or partially adhered in the intervention group with participants in the usual care group who would have been classed as adherent had they been allocated to the intervention group. The fully compliant analysis does show a larger effect (0.05 [95% CI; 0.01 to 0.09]) when compared to the intention to treat analysis (0.03 [0.01 to 0.05]). We agree that that such analyses should be interpreted with caution and caveated our interpretation accordingly in the article ‘…suggesting the true effect, in those fully complying with the intervention, might exceed this threshold [0.04]’.

Correspondents have ignored another reason why the true effect size, when compared to no treatment, might possibly be larger than that observed. Our usual care group received more intervention than might have been offered in clinical practice which may have masked the true effect of the REGAIN intervention.

Taking our findings overall we have clearly demonstrated statistically significant clinical benefits, for a treatment with few observed harms, of a magnitude that individual patients might find attractive for a disorder for which, to the best of our knowledge, there is no other treatment of proven effectiveness.

1. McGregor G, Sandhu H, Bruce J, Sheehan B, McWilliams D, Yeung J, et al. Clinical effectiveness of an online supervised group physical and mental health rehabilitation programme for adults with post-covid-19 condition (REGAIN study): multicentre randomised controlled trial. 51app. 2024;384:e076506.
2. Gorst SL, Seylanova N, Dodd SR, Harman NL, O'Hara M, Terwee CB, et al. Core outcome measurement instruments for use in clinical and research settings for adults with post-COVID-19 condition: an international Delphi consensus study. The Lancet Respiratory Medicine. 2023;11(12):1101-14.
3. National Institute for Health. What it this minimally important difference for PROPr? Available at: .
4. Goyal M, McDonough R, Fisher M, Ospel J. The Challenge of Designing Stroke Trials That Change Practice: MCID vs. Sample Size and Pragmatism. J Stroke. 2022;24(1):49-56.

Competing interests: GM, MU, JB, HS are chief or co-investigator on multiple previous and current research grants from the UK National Institute for Health 51app. GM receives payment as a director of Atrium Health Ltd, a non-profit cardiopulmonary rehabilitation provider, which provided the treatment hub for the REGAIN trial. HS is a director of Health Psychology Services Ltd, a private health psychology provider. MU is a current or recent co-investigator on Arthritis 51app UK, Australian NHMRC, and Norwegian MRC grants. He is a director and shareholder of Clinvivo Ltd that provides electronic data collection for health services research. He receives some salary support from University Hospitals Coventry and Warwickshire NHS Trust. He is a co-investigator on two current and one recent NIHR funded studies receiving additional support from Stryker Ltd. JB is supported by NIHR 51app Capability Funding via university Hospitals Coventry and Warwickshire NHS Trust.

11 April 2024
Gordon S McGregor
Professor
Julie Bruce, Harbinder Sandhu and Martin Underwood, on behalf of the REGAIN trial investigators
University Hospitals Coventry & Warwickshire NHS Trust, Coventry, UK; Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK; 51app Institute for Health & Wellbeing, Coventry University, Coventry, UK
University of Warwick Clinical Trials Unit
Re: Autism and ADHD place “unprecedented” demand on NHS Katharine Lang. 385:doi 10.1136/bmj.q802

Dear Editor

Derek Summerfield is unlikely to claim originality for his suggestion, in his recent response, that most psychiatric diagnoses are less certain and solidly based than are most physical diseases that have some proven biological basis. Thomas Szasz was not always popular amongst his psychiatric colleagues for making similar statements. (1) Ironically, when Christopher Exley et al demonstrated significant levels of aluminium in brain tissue in Alzheimer’s disease, autism spectrum disorder and multiple sclerosis (2), his laboratory findings suggesting a possible correlation met with equal disfavour.

In the decades after Leo Kanner published his initial description of children with autism in 1943 (autistic symptoms were described in other psychiatric diseases or syndromes, decades before) it was very rare to see similarly afflicted children. Ask anyone old enough to have done Child Guidance Clinics, or general paediatrics, half a century and more ago.

Summefield would surely acknowledge that those suffering from profound autism, about 30% of the total figure, present a very different picture, and a requirement for basic caring needs, to that of the many adults who nowadays are diagnosed with autism. (3)

The chief executive of the Nuffield Trust whose comments you quote on “ ..the extraordinary, unpredicted, and unprecedented rise in demand for autism assessments .. “ seems to be unaware that warnings of such a necessary increase in service provision have been made in 51app rapid responses in the past, (4). Readers wishing for more evidence, from other countries and centuries, might find it worthwhile to study the work of Olmsted and Blaxill. (5)

1 The Myth of Mental Illness. Thomas Szasz. Harper & Brothers, 1961.
2 Exley C, Clarkson E. Aluminium in human brain tissue from donors without neurodegenerative disease: A comparison with Alzheimer's disease, multiple sclerosis and autism. Sci Rep 10, 7770 (2020).
3 Dachel A. We Must Honor and Acknowledge PROFOUND Autism Too. Age of Autism 2024 Apr 9
4 Stone J. Rapid response to: NHS must prioritise health of children and young people. bmj.com 2018. The government must face up to the autism pandemic, and so must the RCPCH. /content/360/bmj.k1116/rr-0
6 Denial. Olmsted & Blaxill, Skyhorse Publishing, 2017.

Competing interests: No competing interests

11 April 2024
Noel Thomas
retired doc
Bronygarn, Maesteg, Wales
Re: Wegovy: FDA approves weight loss drug to cut cardiovascular risk Janice Hopkins Tanne. 384:doi 10.1136/bmj.q642

Semaglutide and association with deep vein thrombosis: A call for clarification?

Semaglutide, a drug primarily indicated for managing Type 2 diabetes and obesity, has gained significant popularity recently due to its effectiveness in controlling blood sugar levels and promoting weight loss. As recently published in the 51app, [1] the US Food and Drug Administration (FDA) approved a new indication for semaglutide to reduce cardiovascular risks such as heart attacks and strokes in patients with preexisting heart disease and overweight/obesity but without diabetes based on the results of the SELECT trial.[2] While semaglutide is generally well-tolerated, its adverse effects are mainly gastrointestinal, including nausea, vomiting, constipation, and diarrhea. Additionally, there is growing concern about rarer and more serious complications, such as a higher risk of pancreatitis, bowel obstruction, and gastroparesis.[3]

We recently encountered a case of pulmonary embolism (PE) which occurred four weeks after initiating semaglutide therapy for obesity. In our search for literature on semaglutide's potential adverse effects, including deep vein thrombosis (DVT) and PE, we came across Yin et al.’s [4] meta-analysis focusing on semaglutide safety in type 2 diabetes patients. This analysis integrated data from the PIONEER and SUSTAIN trials, involving 12,260 semaglutide users and 14,176 controls. The study demonstrated a 166% increase in diarrhea cases in semaglutide users, consistent with previous findings. More notably, it identified a 266% increase in DVT incidents compared to the controls (RR 3.66), a new adverse effect potentially associated with semaglutide. The authors suggested that this increased DVT risk might be due to dehydration-related changes in blood viscosity.

In the SELECT trial with 17,604 patients, Lincoff et al.[2] demonstrated that weekly subcutaneous semaglutide reduces cardiovascular events in individuals with preexisting heart disease and overweight/obesity but without diabetes. Despite its efficacy over placebo, semaglutide had higher discontinuation rates mainly due to gastrointestinal side effects in this study. While Lincoff et al.[2] did not specifically report data on PE or DVT, serious adverse events related to vascular disorders and other conditions were comparable between the semaglutide and placebo groups. However, their classification of serious adverse events under "vascular disorders" requires further clarification, particularly regarding DVT incidence.

The reason for the conflicting results regarding DVT incidence in these two studies [2,4] is unknown. We cannot definitively attribute the PE observed in our case to the use of semaglutide. Considering the widespread use of semaglutide, it is crucial to urgently and clearly understand its potential role in increasing the risk of DVT. This inquiry becomes even more critical given the speculation that semaglutide’s most common side effect, diarrhea, which potentially raises blood viscosity, might contribute to this risk.

References
.
1) Tanne JH. Wegovy: FDA approves weight loss drug to cut cardiovascular risk. 51app. 2024 Mar 13;384:q642. doi: 10.1136/bmj.q642.

2) Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;14;389(24):2221-2232.

3) Ruder K. As Semaglutide’s Popularity Soars, Rare but Serious Adverse Effects Are Emerging JAMA. 2023 Dec 12;330(22):2140-2142.

4) Yin DG, Ding LL, Zhou HR, et al .Comprehensive analysis of the safety of semaglutide in type 2 diabetes: a meta-analysis of the SUSTAIN and PIONEER trials. Endocr J. 2021; 28;68(6):739-742.

Competing interests: No competing interests

11 April 2024
Mustafa Vakur Bor
Consultant physician
1 Unit for Thrombosis 51app, Department of Regional Health Science, University of Southern Denmark, 2 Department of Clinical Biochemistry, University Hospital of Southern Denmark, Esbjerg, 3 Thrombosis and Anticoagulation Clinic, Department of Cardiology, University Hospital of Southern Denmark, Esbjerg,
University Hospital of Southern Denmark, Esbjerg Department of Clinical Biochemistry, Finsensgade 35, 6700 Esbjerg, Denmark.
Re: A special issue of The 51app, led by patients Emma Doble, Sophie Cook, Kamran Abbasi. 385:doi 10.1136/bmj.q825

Dear Editor

Firstly I would like to thank Richard Smith for opening up the51app to a wider readership years ago and encouraging my early efforts at submitting comments. I make the point about comments as I hope it will still be possible for pretty much anyone to submit relevant responses, without editing, which often have a different take on topics. They provide a place for independent voices which can be obscured by the need for specific groups, although crucially important, to aggregate their messages. The Comments section also provides a space for submissions other than through articles.

My never ending request is to make the Journal truly Open Access. It is divisive to enable only those with the means to make payments usually though membership of an organisation to have access to Important information, which also benefits them personally. Some of us are only made aware of issues initially through reading the51app only to be barred from the educational and potential health benefits to us and to our wider circles by sharing with friends family and so on.

Good Luck with the new project.

Competing interests: No competing interests

11 April 2024
Susanne Stevens
retired
Brecon

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