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Case study research for better evaluations of complex interventions: rationale and challenges

• Sara Paparini   ORCID: orcid.org/0000-0002-1909-2481 1 ,
• Judith Green 2 ,
• Chrysanthi Papoutsi 1 ,
• Jamie Murdoch 3 ,
• Mark Petticrew 4 ,
• Trish Greenhalgh 1 ,
• Benjamin Hanckel 5 &
• Sara Shaw 1  

BMC Medicine volume  18 , Article number:  301 ( 2020 ) Cite this article

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The need for better methods for evaluation in health research has been widely recognised. The ‘complexity turn’ has drawn attention to the limitations of relying on causal inference from randomised controlled trials alone for understanding whether, and under which conditions, interventions in complex systems improve health services or the public health, and what mechanisms might link interventions and outcomes. We argue that case study research—currently denigrated as poor evidence—is an under-utilised resource for not only providing evidence about context and transferability, but also for helping strengthen causal inferences when pathways between intervention and effects are likely to be non-linear.

Case study research, as an overall approach, is based on in-depth explorations of complex phenomena in their natural, or real-life, settings. Empirical case studies typically enable dynamic understanding of complex challenges and provide evidence about causal mechanisms and the necessary and sufficient conditions (contexts) for intervention implementation and effects. This is essential evidence not just for researchers concerned about internal and external validity, but also research users in policy and practice who need to know what the likely effects of complex programmes or interventions will be in their settings. The health sciences have much to learn from scholarship on case study methodology in the social sciences. However, there are multiple challenges in fully exploiting the potential learning from case study research. First are misconceptions that case study research can only provide exploratory or descriptive evidence. Second, there is little consensus about what a case study is, and considerable diversity in how empirical case studies are conducted and reported. Finally, as case study researchers typically (and appropriately) focus on thick description (that captures contextual detail), it can be challenging to identify the key messages related to intervention evaluation from case study reports.

Whilst the diversity of published case studies in health services and public health research is rich and productive, we recommend further clarity and specific methodological guidance for those reporting case study research for evaluation audiences.

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The need for methodological development to address the most urgent challenges in health research has been well-documented. Many of the most pressing questions for public health research, where the focus is on system-level determinants [ 1 , 2 ], and for health services research, where provisions typically vary across sites and are provided through interlocking networks of services [ 3 ], require methodological approaches that can attend to complexity. The need for methodological advance has arisen, in part, as a result of the diminishing returns from randomised controlled trials (RCTs) where they have been used to answer questions about the effects of interventions in complex systems [ 4 , 5 , 6 ]. In conditions of complexity, there is limited value in maintaining the current orientation to experimental trial designs in the health sciences as providing ‘gold standard’ evidence of effect.

There are increasing calls for methodological pluralism [ 7 , 8 ], with the recognition that complex intervention and context are not easily or usefully separated (as is often the situation when using trial design), and that system interruptions may have effects that are not reducible to linear causal pathways between intervention and outcome. These calls are reflected in a shifting and contested discourse of trial design, seen with the emergence of realist [ 9 ], adaptive and hybrid (types 1, 2 and 3) [ 10 , 11 ] trials that blend studies of effectiveness with a close consideration of the contexts of implementation. Similarly, process evaluation has now become a core component of complex healthcare intervention trials, reflected in MRC guidance on how to explore implementation, causal mechanisms and context [ 12 ].

Evidence about the context of an intervention is crucial for questions of external validity. As Woolcock [ 4 ] notes, even if RCT designs are accepted as robust for maximising internal validity, questions of transferability (how well the intervention works in different contexts) and generalisability (how well the intervention can be scaled up) remain unanswered [ 5 , 13 ]. For research evidence to have impact on policy and systems organisation, and thus to improve population and patient health, there is an urgent need for better methods for strengthening external validity, including a better understanding of the relationship between intervention and context [ 14 ].

Policymakers, healthcare commissioners and other research users require credible evidence of relevance to their settings and populations [ 15 ], to perform what Rosengarten and Savransky [ 16 ] call ‘careful abstraction’ to the locales that matter for them. They also require robust evidence for understanding complex causal pathways. Case study research, currently under-utilised in public health and health services evaluation, can offer considerable potential for strengthening faith in both external and internal validity. For example, in an empirical case study of how the policy of free bus travel had specific health effects in London, UK, a quasi-experimental evaluation (led by JG) identified how important aspects of context (a good public transport system) and intervention (that it was universal) were necessary conditions for the observed effects, thus providing useful, actionable evidence for decision-makers in other contexts [ 17 ].

The overall approach of case study research is based on the in-depth exploration of complex phenomena in their natural, or ‘real-life’, settings. Empirical case studies typically enable dynamic understanding of complex challenges rather than restricting the focus on narrow problem delineations and simple fixes. Case study research is a diverse and somewhat contested field, with multiple definitions and perspectives grounded in different ways of viewing the world, and involving different combinations of methods. In this paper, we raise awareness of such plurality and highlight the contribution that case study research can make to the evaluation of complex system-level interventions. We review some of the challenges in exploiting the current evidence base from empirical case studies and conclude by recommending that further guidance and minimum reporting criteria for evaluation using case studies, appropriate for audiences in the health sciences, can enhance the take-up of evidence from case study research.

Case study research offers evidence about context, causal inference in complex systems and implementation

Well-conducted and described empirical case studies provide evidence on context, complexity and mechanisms for understanding how, where and why interventions have their observed effects. Recognition of the importance of context for understanding the relationships between interventions and outcomes is hardly new. In 1943, Canguilhem berated an over-reliance on experimental designs for determining universal physiological laws: ‘As if one could determine a phenomenon’s essence apart from its conditions! As if conditions were a mask or frame which changed neither the face nor the picture!’ ([ 18 ] p126). More recently, a concern with context has been expressed in health systems and public health research as part of what has been called the ‘complexity turn’ [ 1 ]: a recognition that many of the most enduring challenges for developing an evidence base require a consideration of system-level effects [ 1 ] and the conceptualisation of interventions as interruptions in systems [ 19 ].

The case study approach is widely recognised as offering an invaluable resource for understanding the dynamic and evolving influence of context on complex, system-level interventions [ 20 , 21 , 22 , 23 ]. Empirically, case studies can directly inform assessments of where, when, how and for whom interventions might be successfully implemented, by helping to specify the necessary and sufficient conditions under which interventions might have effects and to consolidate learning on how interdependencies, emergence and unpredictability can be managed to achieve and sustain desired effects. Case study research has the potential to address four objectives for improving research and reporting of context recently set out by guidance on taking account of context in population health research [ 24 ], that is to (1) improve the appropriateness of intervention development for specific contexts, (2) improve understanding of ‘how’ interventions work, (3) better understand how and why impacts vary across contexts and (4) ensure reports of intervention studies are most useful for decision-makers and researchers.

However, evaluations of complex healthcare interventions have arguably not exploited the full potential of case study research and can learn much from other disciplines. For evaluative research, exploratory case studies have had a traditional role of providing data on ‘process’, or initial ‘hypothesis-generating’ scoping, but might also have an increasing salience for explanatory aims. Across the social and political sciences, different kinds of case studies are undertaken to meet diverse aims (description, exploration or explanation) and across different scales (from small N qualitative studies that aim to elucidate processes, or provide thick description, to more systematic techniques designed for medium-to-large N cases).

Case studies with explanatory aims vary in terms of their positioning within mixed-methods projects, with designs including (but not restricted to) (1) single N of 1 studies of interventions in specific contexts, where the overall design is a case study that may incorporate one or more (randomised or not) comparisons over time and between variables within the case; (2) a series of cases conducted or synthesised to provide explanation from variations between cases; and (3) case studies of particular settings within RCT or quasi-experimental designs to explore variation in effects or implementation.

Detailed qualitative research (typically done as ‘case studies’ within process evaluations) provides evidence for the plausibility of mechanisms [ 25 ], offering theoretical generalisations for how interventions may function under different conditions. Although RCT designs reduce many threats to internal validity, the mechanisms of effect remain opaque, particularly when the causal pathways between ‘intervention’ and ‘effect’ are long and potentially non-linear: case study research has a more fundamental role here, in providing detailed observational evidence for causal claims [ 26 ] as well as producing a rich, nuanced picture of tensions and multiple perspectives [ 8 ].

Longitudinal or cross-case analysis may be best suited for evidence generation in system-level evaluative research. Turner [ 27 ], for instance, reflecting on the complex processes in major system change, has argued for the need for methods that integrate learning across cases, to develop theoretical knowledge that would enable inferences beyond the single case, and to develop generalisable theory about organisational and structural change in health systems. Qualitative Comparative Analysis (QCA) [ 28 ] is one such formal method for deriving causal claims, using set theory mathematics to integrate data from empirical case studies to answer questions about the configurations of causal pathways linking conditions to outcomes [ 29 , 30 ].

Nonetheless, the single N case study, too, provides opportunities for theoretical development [ 31 ], and theoretical generalisation or analytical refinement [ 32 ]. How ‘the case’ and ‘context’ are conceptualised is crucial here. Findings from the single case may seem to be confined to its intrinsic particularities in a specific and distinct context [ 33 ]. However, if such context is viewed as exemplifying wider social and political forces, the single case can be ‘telling’, rather than ‘typical’, and offer insight into a wider issue [ 34 ]. Internal comparisons within the case can offer rich possibilities for logical inferences about causation [ 17 ]. Further, case studies of any size can be used for theory testing through refutation [ 22 ]. The potential lies, then, in utilising the strengths and plurality of case study to support theory-driven research within different methodological paradigms.

Evaluation research in health has much to learn from a range of social sciences where case study methodology has been used to develop various kinds of causal inference. For instance, Gerring [ 35 ] expands on the within-case variations utilised to make causal claims. For Gerring [ 35 ], case studies come into their own with regard to invariant or strong causal claims (such as X is a necessary and/or sufficient condition for Y) rather than for probabilistic causal claims. For the latter (where experimental methods might have an advantage in estimating effect sizes), case studies offer evidence on mechanisms: from observations of X affecting Y, from process tracing or from pattern matching. Case studies also support the study of emergent causation, that is, the multiple interacting properties that account for particular and unexpected outcomes in complex systems, such as in healthcare [ 8 ].

Finally, efficacy (or beliefs about efficacy) is not the only contributor to intervention uptake, with a range of organisational and policy contingencies affecting whether an intervention is likely to be rolled out in practice. Case study research is, therefore, invaluable for learning about contextual contingencies and identifying the conditions necessary for interventions to become normalised (i.e. implemented routinely) in practice [ 36 ].

The challenges in exploiting evidence from case study research

At present, there are significant challenges in exploiting the benefits of case study research in evaluative health research, which relate to status, definition and reporting. Case study research has been marginalised at the bottom of an evidence hierarchy, seen to offer little by way of explanatory power, if nonetheless useful for adding descriptive data on process or providing useful illustrations for policymakers [ 37 ]. This is an opportune moment to revisit this low status. As health researchers are increasingly charged with evaluating ‘natural experiments’—the use of face masks in the response to the COVID-19 pandemic being a recent example [ 38 ]—rather than interventions that take place in settings that can be controlled, research approaches using methods to strengthen causal inference that does not require randomisation become more relevant.

A second challenge for improving the use of case study evidence in evaluative health research is that, as we have seen, what is meant by ‘case study’ varies widely, not only across but also within disciplines. There is indeed little consensus amongst methodologists as to how to define ‘a case study’. Definitions focus, variously, on small sample size or lack of control over the intervention (e.g. [ 39 ] p194), on in-depth study and context [ 40 , 41 ], on the logic of inference used [ 35 ] or on distinct research strategies which incorporate a number of methods to address questions of ‘how’ and ‘why’ [ 42 ]. Moreover, definitions developed for specific disciplines do not capture the range of ways in which case study research is carried out across disciplines. Multiple definitions of case study reflect the richness and diversity of the approach. However, evidence suggests that a lack of consensus across methodologists results in some of the limitations of published reports of empirical case studies [ 43 , 44 ]. Hyett and colleagues [ 43 ], for instance, reviewing reports in qualitative journals, found little match between methodological definitions of case study research and how authors used the term.

This raises the third challenge we identify that case study reports are typically not written in ways that are accessible or useful for the evaluation research community and policymakers. Case studies may not appear in journals widely read by those in the health sciences, either because space constraints preclude the reporting of rich, thick descriptions, or because of the reported lack of willingness of some biomedical journals to publish research that uses qualitative methods [ 45 ], signalling the persistence of the aforementioned evidence hierarchy. Where they do, however, the term ‘case study’ is used to indicate, interchangeably, a qualitative study, an N of 1 sample, or a multi-method, in-depth analysis of one example from a population of phenomena. Definitions of what constitutes the ‘case’ are frequently lacking and appear to be used as a synonym for the settings in which the research is conducted. Despite offering insights for evaluation, the primary aims may not have been evaluative, so the implications may not be explicitly drawn out. Indeed, some case study reports might properly be aiming for thick description without necessarily seeking to inform about context or causality.

Acknowledging plurality and developing guidance

We recognise that definitional and methodological plurality is not only inevitable, but also a necessary and creative reflection of the very different epistemological and disciplinary origins of health researchers, and the aims they have in doing and reporting case study research. Indeed, to provide some clarity, Thomas [ 46 ] has suggested a typology of subject/purpose/approach/process for classifying aims (e.g. evaluative or exploratory), sample rationale and selection and methods for data generation of case studies. We also recognise that the diversity of methods used in case study research, and the necessary focus on narrative reporting, does not lend itself to straightforward development of formal quality or reporting criteria.

Existing checklists for reporting case study research from the social sciences—for example Lincoln and Guba’s [ 47 ] and Stake’s [ 33 ]—are primarily orientated to the quality of narrative produced, and the extent to which they encapsulate thick description, rather than the more pragmatic issues of implications for intervention effects. Those designed for clinical settings, such as the CARE (CAse REports) guidelines, provide specific reporting guidelines for medical case reports about single, or small groups of patients [ 48 ], not for case study research.

The Design of Case Study Research in Health Care (DESCARTE) model [ 44 ] suggests a series of questions to be asked of a case study researcher (including clarity about the philosophy underpinning their research), study design (with a focus on case definition) and analysis (to improve process). The model resembles toolkits for enhancing the quality and robustness of qualitative and mixed-methods research reporting, and it is usefully open-ended and non-prescriptive. However, even if it does include some reflections on context, the model does not fully address aspects of context, logic and causal inference that are perhaps most relevant for evaluative research in health.

Hence, for evaluative research where the aim is to report empirical findings in ways that are intended to be pragmatically useful for health policy and practice, this may be an opportune time to consider how to best navigate plurality around what is (minimally) important to report when publishing empirical case studies, especially with regards to the complex relationships between context and interventions, information that case study research is well placed to provide.

The conventional scientific quest for certainty, predictability and linear causality (maximised in RCT designs) has to be augmented by the study of uncertainty, unpredictability and emergent causality [ 8 ] in complex systems. This will require methodological pluralism, and openness to broadening the evidence base to better understand both causality in and the transferability of system change intervention [ 14 , 20 , 23 , 25 ]. Case study research evidence is essential, yet is currently under exploited in the health sciences. If evaluative health research is to move beyond the current impasse on methods for understanding interventions as interruptions in complex systems, we need to consider in more detail how researchers can conduct and report empirical case studies which do aim to elucidate the contextual factors which interact with interventions to produce particular effects. To this end, supported by the UK’s Medical Research Council, we are embracing the challenge to develop guidance for case study researchers studying complex interventions. Following a meta-narrative review of the literature, we are planning a Delphi study to inform guidance that will, at minimum, cover the value of case study research for evaluating the interrelationship between context and complex system-level interventions; for situating and defining ‘the case’, and generalising from case studies; as well as provide specific guidance on conducting, analysing and reporting case study research. Our hope is that such guidance can support researchers evaluating interventions in complex systems to better exploit the diversity and richness of case study research.

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Abbreviations

Qualitative comparative analysis

Quasi-experimental design

Randomised controlled trial

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This work was funded by the Medical Research Council - MRC Award MR/S014632/1 HCS: Case study, Context and Complex interventions (TRIPLE C). SP was additionally funded by the University of Oxford's Higher Education Innovation Fund (HEIF).

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Paparini, S., Green, J., Papoutsi, C. et al. Case study research for better evaluations of complex interventions: rationale and challenges. BMC Med 18 , 301 (2020). https://doi.org/10.1186/s12916-020-01777-6

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Giving Feedback

Giving feedback is hard. Giving effective feedback can be even more challenging. Remember that your ultimate goal is to discuss what the authors would need to do in order to qualify for publication. The point is not to nitpick every piece of the manuscript. Your focus should be on providing constructive and critical feedback that the authors can use to improve their study.

If you’ve ever had your own work reviewed, you already know that it’s not always easy to receive feedback. Follow the golden rule: Write the type of review you’d want to receive if you were the author. Even if you decide not to identify yourself in the review, you should write comments that you would be comfortable signing your name to.

In your comments, use phrases like “ the authors’ discussion of X” instead of “ your discussion of X .” This will depersonalize the feedback and keep the focus on the manuscript instead of the authors.

General guidelines for effective feedback

• Justify your recommendation with concrete evidence and specific examples.
• Be specific so the authors know what they need to do to improve.
• Be thorough. This might be the only time you read the manuscript.
• Be professional and respectful. The authors will be reading these comments too.
• Remember to say what you liked about the manuscript!

Don’t

• Recommend additional experiments or  unnecessary elements that are out of scope for the study or for the journal criteria.
• Tell the authors exactly how to revise their manuscript—you don’t need to do their work for them.
• Use the review to promote your own research or hypotheses.
• Focus on typos and grammar. If the manuscript needs significant editing for language and writing quality, just mention this in your comments.
• Submit your review without proofreading it and checking everything one more time.

Before and After: Sample Reviewer Comments

Keeping in mind the guidelines above, how do you put your thoughts into words? Here are some sample “before” and “after” reviewer comments

✗ Before

“The authors appear to have no idea what they are talking about. I don’t think they have read any of the literature on this topic.”

✓ After

“The study fails to address how the findings relate to previous research in this area. The authors should rewrite their Introduction and Discussion to reference the related literature, especially recently published work such as Darwin et al.”

“The writing is so bad, it is practically unreadable. I could barely bring myself to finish it.”

“While the study appears to be sound, the language is unclear, making it difficult to follow. I advise the authors work with a writing coach or copyeditor to improve the flow and readability of the text.”

“It’s obvious that this type of experiment should have been included. I have no idea why the authors didn’t use it. This is a big mistake.”

“The authors are off to a good start, however, this study requires additional experiments, particularly [type of experiment]. Alternatively, the authors should include more information that clarifies and justifies their choice of methods.”

Suggested Language for Tricky Situations

You might find yourself in a situation where you’re not sure how to explain the problem or provide feedback in a constructive and respectful way. Here is some suggested language for common issues you might experience.

What you think : The manuscript is fatally flawed. What you could say: “The study does not appear to be sound” or “the authors have missed something crucial”.

What you think : You don’t completely understand the manuscript. What you could say : “The authors should clarify the following sections to avoid confusion…”

What you think : The technical details don’t make sense. What you could say : “The technical details should be expanded and clarified to ensure that readers understand exactly what the researchers studied.”

What you think: The writing is terrible. What you could say : “The authors should revise the language to improve readability.”

What you think : The authors have over-interpreted the findings. What you could say : “The authors aim to demonstrate [XYZ], however, the data does not fully support this conclusion. Specifically…”

What does a good review look like?

Check out the peer review examples at F1000 Research to see how other reviewers write up their reports and give constructive feedback to authors.

Time to Submit the Review!

Be sure you turn in your report on time. Need an extension? Tell the journal so that they know what to expect. If you need a lot of extra time, the journal might need to contact other reviewers or notify the author about the delay.

Tip: Building a relationship with an editor

You’ll be more likely to be asked to review again if you provide high-quality feedback and if you turn in the review on time. Especially if it’s your first review for a journal, it’s important to show that you are reliable. Prove yourself once and you’ll get asked to review again!

• Getting started as a reviewer
• Responding to an invitation
• Reading a manuscript
• Writing a peer review

The contents of the Peer Review Center are also available as a live, interactive training session, complete with slides, talking points, and activities. …

The contents of the Writing Center are also available as a live, interactive training session, complete with slides, talking points, and activities. …

There’s a lot to consider when deciding where to submit your work. Learn how to choose a journal that will help your study reach its audience, while reflecting your values as a researcher…

A framework for assessing the peer review duration of journals: case study in computer science

• Published: 05 November 2020
• Volume 126 , pages 545–563, ( 2021 )

Cite this article

• Besim Bilalli   ORCID: orcid.org/0000-0002-0575-2389 1 ,
• Rana Faisal Munir 2 &
• Alberto Abelló 1  

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In various fields, scientific article publication is a measure of productivity and in many occasions it is used as a critical factor for evaluating researchers. Therefore, a lot of time is dedicated to writing articles that are then submitted for publication in journals. Nevertheless, the publication process in general and the review process in particular tend to be rather slow. This is the case for instance of computer science (CS) journals. Moreover, the process typically lacks in transparency, where information about the duration of the review process is at best provided in an aggregated manner, if made available at all. In this paper, we develop a framework as a step towards bringing more reliable data with respect to review duration. Based on this framework, we implement a tool—journal response time (JRT), that allows for automatically extracting the review process data and helps researchers to find the average response times of journals, which can be used to study the duration of CS journals’ peer review process. The information is extracted as metadata from the published articles, when available. This study reveals that the response times publicly provided by publishers differ from the actual values obtained by JRT (e.g., for ten selected journals the average duration reported by publishers deviates by more than 500% from the actual average value calculated from the data inside the articles), which we suspect could be from the fact that, when calculating the aggregated values, publishers consider the review time of rejected articles too (including quick desk-rejections that do not require reviewers).

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Bilalli, B., Munir, R.F. & Abelló, A. A framework for assessing the peer review duration of journals: case study in computer science. Scientometrics 126 , 545–563 (2021). https://doi.org/10.1007/s11192-020-03742-9

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• Published: 02 May 2024

Use of the International IFOMPT Cervical Framework to inform clinical reasoning in postgraduate level physiotherapy students: a qualitative study using think aloud methodology

• Katie L. Kowalski 1 ,
• Heather Gillis 1 ,
• Katherine Henning 1 ,
• Paul Parikh 1 ,
• Jackie Sadi 1 &
• Alison Rushton 1  

BMC Medical Education volume  24 , Article number:  486 ( 2024 ) Cite this article

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Vascular pathologies of the head and neck are rare but can present as musculoskeletal problems. The International Federation of Orthopedic Manipulative Physical Therapists (IFOMPT) Cervical Framework (Framework) aims to assist evidence-based clinical reasoning for safe assessment and management of the cervical spine considering potential for vascular pathology. Clinical reasoning is critical to physiotherapy, and developing high-level clinical reasoning is a priority for postgraduate (post-licensure) educational programs.

To explore the influence of the Framework on clinical reasoning processes in postgraduate physiotherapy students.

Qualitative case study design using think aloud methodology and interpretive description, informed by COnsolidated criteria for REporting Qualitative research. Participants were postgraduate musculoskeletal physiotherapy students who learned about the Framework through standardized delivery. Two cervical spine cases explored clinical reasoning processes. Coding and analysis of transcripts were guided by Elstein’s diagnostic reasoning components and the Postgraduate Musculoskeletal Physiotherapy Practice model. Data were analyzed using thematic analysis (inductive and deductive) for individuals and then across participants, enabling analysis of key steps in clinical reasoning processes and use of the Framework. Trustworthiness was enhanced with multiple strategies (e.g., second researcher challenged codes).

For all participants ( n  = 8), the Framework supported clinical reasoning using primarily hypothetico-deductive processes. It informed vascular hypothesis generation in the patient history and testing the vascular hypothesis through patient history questions and selection of physical examination tests, to inform clarity and support for diagnosis and management. Most participant’s clinical reasoning processes were characterized by high-level features (e.g., prioritization), however there was a continuum of proficiency. Clinical reasoning processes were informed by deep knowledge of the Framework integrated with a breadth of wider knowledge and supported by a range of personal characteristics (e.g., reflection).

Conclusions

Findings support use of the Framework as an educational resource in postgraduate physiotherapy programs to inform clinical reasoning processes for safe and effective assessment and management of cervical spine presentations considering potential for vascular pathology. Individualized approaches may be required to support students, owing to a continuum of clinical reasoning proficiency. Future research is required to explore use of the Framework to inform clinical reasoning processes in learners at different levels.

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Introduction

Musculoskeletal neck pain and headache are highly prevalent and among the most disabling conditions globally that require effective rehabilitation [ 1 , 2 , 3 , 4 ]. A range of rehabilitation professionals, including physiotherapists, assess and manage musculoskeletal neck pain and headache. Assessment of the cervical spine can be a complex process. Patients can present to physiotherapy with vascular pathology masquerading as musculoskeletal pain and dysfunction, as neck pain and/or headache as a common first symptom [ 5 ]. While vascular pathologies of the head and neck are rare [ 6 ], they are important considerations within a cervical spine assessment to facilitate the best possible patient outcomes [ 7 ]. The International IFOMPT (International Federation of Orthopedic Manipulative Physical Therapists) Cervical Framework (Framework) provides guidance in the assessment and management of the cervical spine region, considering the potential for vascular pathologies of the neck and head [ 8 ]. Two separate, but related, risks are considered: risk of misdiagnosis of an existing vascular pathology and risk of serious adverse event following musculoskeletal interventions [ 8 ].

The Framework is a consensus document iteratively developed through rigorous methods and the best contemporary evidence [ 8 ], and is also published as a Position Statement [ 7 ]. Central to the Framework are clinical reasoning and evidence-based practice, providing guidance in the assessment of the cervical spine region, considering the potential for vascular pathologies in advance of planned interventions [ 7 , 8 ]. The Framework was developed and published to be a resource for practicing musculoskeletal clinicians and educators. It has been implemented widely within IFOMPT postgraduate (post-licensure) educational programs, influencing curricula by enabling a comprehensive and systemic approach when considering the potential for vascular pathology [ 9 ]. Frequently reported curricula changes include an emphasis on the patient history and incorporating Framework recommended physical examination tests to evaluate a vascular hypothesis [ 9 ]. The Framework aims to assist musculoskeletal clinicians in their clinical reasoning processes, however no study has investigated students’ use of the Framework to inform their clinical reasoning.

Clinical reasoning is a critical component to physiotherapy practice as it is fundamental to assessment and diagnosis, enabling physiotherapists to provide safe and effective patient-centered care [ 10 ]. This is particularly important for postgraduate physiotherapy educational programs, where developing a high level of clinical reasoning is a priority for educational curricula [ 11 ] and critical for achieving advanced practice physiotherapy competency [ 12 , 13 , 14 , 15 ]. At this level of physiotherapy, diagnostic reasoning is emphasized as an important component of a high level of clinical reasoning, informed by advanced use of domain-specific knowledge (e.g., propositional, experiential) and supported by a range of personal characteristics (e.g., adaptability, reflective) [ 12 ]. Facilitating the development of clinical reasoning improves physiotherapist’s performance and patient outcomes [ 16 ], underscoring the importance of clinical reasoning to physiotherapy practice. Understanding students’ use of the Framework to inform their clinical reasoning can support optimal implementation of the Framework within educational programs to facilitate safe and effective assessment and management of the cervical spine for patients.

To explore the influence of the Framework on the clinical reasoning processes in postgraduate level physiotherapy students.

Using a qualitative case study design, think aloud case analyses enabled exploration of clinical reasoning processes in postgraduate physiotherapy students. Case study design allows evaluation of experiences in practice, providing knowledge and accounts of practical actions in a specific context [ 17 ]. Case studies offer opportunity to generate situationally dependent understandings of accounts of clinical practice, highlighting the action and interaction that underscore the complexity of clinical decision-making in practice [ 17 ]. This study was informed by an interpretive description methodological approach with thematic analysis [ 18 , 19 ]. Interpretive description is coherent with mixed methods research and pragmatic orientations [ 20 , 21 ], and enables generation of evidence-based disciplinary knowledge and clinical understanding to inform practice [ 18 , 19 , 22 ]. Interpretive description has evolved for use in educational research to generate knowledge of educational experiences and the complexities of health care education to support achievement of educational objectives and professional practice standards [ 23 ]. The COnsolidated criteria for REporting Qualitative research (COREQ) informed the design and reporting of this study [ 24 ].

Research team

All research team members hold physiotherapy qualifications, and most hold advanced qualifications specializing in musculoskeletal physiotherapy. The research team is based in Canada and has varying levels of academic credentials (ranging from Clinical Masters to PhD or equivalent) and occupations (ranging from PhD student to Director of Physical Therapy). The final author (AR) is also an author of the Framework, which represents international and multiprofessional consensus. Authors HG and JS are lecturers on one of the postgraduate programs which students were recruited from. The primary researcher and first author (KK) is a US-trained Physical Therapist and Postdoctoral Research Associate investigating spinal pain and clinical reasoning in the School of Physical Therapy at Western University. Authors KK, KH and PP had no prior relationship with the postgraduate educational programs, students, or the Framework.

Study setting

Western University in London, Ontario, Canada offers a one-year Advanced Health Care Practice (AHCP) postgraduate IFOMPT-approved Comprehensive Musculoskeletal Physiotherapy program (CMP) and a postgraduate Sport and Exercise Medicine (SEM) program. Think aloud case analyses interviews were conducted using Zoom, a viable option for qualitative data collection and audio-video recording of interviews that enables participation for students who live in geographically dispersed areas across Canada [ 25 ]. Interviews with individual participants were conducted by one researcher (KK or KH) in a calm and quiet environment to minimize disruption to the process of thinking aloud [ 26 ].

Participants

AHCP postgraduate musculoskeletal physiotherapy students ≥ 18 years of age in the CMP and SEM programs were recruited via email and an introduction to the research study during class by KK, using purposive sampling to ensure theoretical representation. The purposive sample ensured key characteristics of participants were included, specifically gender, ethnicity, and physiotherapy experience (years, type). AHCP students must have attended standardized teaching about the Framework to be eligible to participate. Exclusion criteria included inability to communicate fluently in English. As think-aloud methodology seeks rich, in-depth data from a small sample [ 27 ], this study sought to recruit 8–10 AHCP students. This range was informed by prior think aloud literature and anticipated to balance diversity of participant characteristics, similarities in musculoskeletal physiotherapy domain knowledge and rich data supporting individual clinical reasoning processes [ 27 , 28 ].

Learning about the IFOMPT Cervical Framework

CMP and SEM programs included standardized teaching of the Framework to inform AHCP students’ clinical reasoning in practice. Delivery included a presentation explaining the Framework, access to the full Framework document [ 8 ], and discussion of its role to inform practice, including a case analysis of a cervical spine clinical presentation, by research team members AR and JS. The full Framework document that is publicly available through IFOMPT [ 8 ] was provided to AHCP students as the Framework Position Statement [ 7 ] was not yet published. Discussion and case analysis was led by AHCP program leads in November 2021 (CMP, including research team member JS) and January 2022 (SEM).

Think aloud case analyses data collection

Using think aloud methodology, the analytical processes of how participants use the Framework to inform clinical reasoning were explored in an interview with one research team member not involved in AHCP educational programs (KK or KH). The think aloud method enables description and explanation of complex information paralleling the clinical reasoning process and has been used previously in musculoskeletal physiotherapy [ 29 , 30 ]. It facilitates the generation of rich verbal [ 27 ]as participants verbalize their clinical reasoning protocols [ 27 , 31 ]. Participants were aware of the aim of the research study and the research team’s clinical and research backgrounds, supporting an open environment for depth of data collection [ 32 ]. There was no prior relationship between participants and research team members conducting interviews.

Participants were instructed to think aloud their analysis of two clinical cases, presented in random order (Supplementary  1 ). Case information was provided in stages to reflect the chronology of assessment of patients in practice (patient history, planning the physical examination, physical examination, treatment). Use of the Framework to inform clinical reasoning was discussed at each stage. The cases enabled participants to identify and discuss features of possible vascular pathology, treatment indications and contraindications/precautions, etc. Two research study team members (HG, PP) developed cases designed to facilitate and elicit clinical reasoning processes in neck and head pain presentations. Cases were tested against the research team to ensure face validity. Cases and think aloud prompts were piloted prior to use with three physiotherapists at varying levels of practice to ensure they were fit for purpose.

Data collection took place from March 30-August 15, 2022, during the final terms of the AHCP programs and an average of 5 months after standardized teaching about the Framework. During case analysis interviews, participants were instructed to constantly think aloud, and if a pause in verbalizations was sustained, they were reminded to “keep thinking aloud” [ 27 ]. As needed, prompts were given to elicit verbalization of participants’ reasoning processes, including use of the Framework to inform their clinical reasoning at each stage of case analysis (Supplementary  2 ). Aside from this, all interactions between participants and researchers minimized to not interfere with the participant’s thought processes [ 27 , 31 ]. When analysis of the first case was complete, the researcher provided the second case, each lasting 35–45 min. A break between cases was offered. During and after interviews, field notes were recorded about initial impressions of the data collection session and potential patterns appearing to emerge [ 33 ].

Data analysis

Data from think aloud interviews were analyzed using thematic analysis [ 30 , 34 ], facilitating identification and analysis of patterns in data and key steps in the clinical reasoning process, including use of the Framework to enable its characterization (Fig.  1 ). As established models of clinical reasoning exist, a hybrid approach to thematic analysis was employed, incorporating inductive and deductive processes [ 35 ], which proceeded according to 5 iterative steps: [ 34 ]

Data analysis steps

Familiarize with data: Audio-visual recordings were transcribed verbatim by a physiotherapist external to the research team. All transcripts were read and re-read several times by one researcher (KK), checking for accuracy by reviewing recordings as required. Field notes supported depth of familiarization with data.

Generate initial codes: Line-by-line coding of transcripts by one researcher (KK) supported generation of initial codes that represented components, patterns and meaning in clinical reasoning processes and use of the Framework. Established preliminary coding models were used as a guide. Elstein’s diagnostic reasoning model [ 36 ] guided generating initial codes of key steps in clinical reasoning processes (Table  1 a) [ 29 , 36 ]. Leveraging richness of data, further codes were generated guided by the Postgraduate Musculoskeletal Physiotherapy Practice model, which describes masters level clinical practice (Table  1 b) [ 12 ]. Codes were refined as data analysis proceeded. All codes were collated within participants along with supporting data.

Generate initial themes within participants: Coded data was inductively grouped into initial themes within each participant, reflecting individual clinical reasoning processes and use of the Framework. This inductive stage enabled a systematic, flexible approach to describe each participant’s unique thinking path, offering insight into the complexities of their clinical reasoning processes. It also provided a comprehensive understanding of the Framework informing clinical reasoning and a rich characterization of its components, aiding the development of robust, nuanced insights [ 35 , 37 , 38 ]. Initial themes were repeatedly revised to ensure they were grounded in and reflected raw data.

Develop, review and refine themes across participants: Initial themes were synthesized across participants to develop themes that represented all participants. Themes were reviewed and refined, returning to initial themes and codes at the individual participant level as needed.

Organize themes into established models: Themes were deductively organized into established clinical reasoning models; first into Elstein’s diagnostic reasoning model, second into the Postgraduate Musculoskeletal Physiotherapy Practice model to characterize themes within each diagnostic reasoning component [ 12 , 36 ].

Trustworthiness of findings

The research study was conducted according to an a priori protocol and additional steps were taken to establish trustworthiness of findings [ 39 ]. Field notes supported deep familiarization with data and served as a means of data source triangulation during analysis [ 40 ]. One researcher coded transcripts and a second researcher challenged codes, with codes and themes rigorously and iteratively reviewed and refined. Frequent debriefing sessions with the research team, reflexive discussions with other researchers and peer scrutiny of initial findings enabled wider perspectives and experiences to shape analysis and interpretation of findings. Several strategies were implemented to minimize the influence of prior relationships between participants and researchers, including author KK recruiting participants, KK and KH collecting/analyzing data, and AR, JS, HG and PP providing input on de-identified data at the stage of synthesis and interpretation.

Nine AHCP postgraduate level students were recruited and participated in data collection. One participant was withdrawn because of unfamiliarity with the standardized teaching session about use of the Framework (no recall of session), despite confirmation of attendance. Data from eight participants were used for analysis (CMP: n  = 6; SEM: n  = 2; Table  2 ), which achieved sample size requirements for think aloud methodology of rich and in-depth data [ 27 , 28 ].

Diagnostic reasoning components

Informed by the Framework, all components of Elstein’s diagnostic reasoning processes [ 36 ] were used by participants, including use of treatment with physiotherapy interventions to aid diagnostic reasoning. An illustrative example is presented in Supplement  3 . Clinical reasoning used primarily hypothetico-deductive processes reflecting a continuum of proficiency, was informed by deep Framework knowledge and breadth of prior knowledge (e.g., experiential), and supported by a range of personal characteristics (e.g., justification for decisions).

Cue acquisition

All participants sought to acquire additional cues early in the patient history, and for some this persisted into the medical history and physical examination. Cue acquisition enabled depth and breadth of understanding patient history information to generate hypotheses and factors contributing to the patient’s pain experience (Table  3 ). All participants asked further questions to understand details of the patients’ pain and their presentation, while some also explored the impact of pain on patient functioning and treatments received to date. There was a high degree of specificity to questions for most participants. Ongoing clinical reasoning processes through a thorough and complete assessment, even if the patient had previously received treatment for similar symptoms, was important for some participants. Cue acquisition was supported by personal characteristics including a patient-centered approach (e.g., understanding the patient’s beliefs about pain) and one participant reflected on their approach to acquiring patient history cues.

Hypothesis generation

Participants generated an average of 4.5 hypotheses per case (range: 2–8) and most hypotheses (77%) were generated rapidly early in the patient history. Knowledge from the Framework about patient history features of vascular pathology informed vascular hypothesis generation in the patient history for all participants in both cases (Table  4 ). Vascular hypotheses were also generated during the past medical history, where risk factors for vascular pathology were identified and interpreted by some participants who had high levels of suspicion for cervical articular involvement. Non-vascular hypotheses were generated during the physical examination by some participants to explain individual physical examination or patient history cues. Deep knowledge of the patient history section in the Framework supported high level of cue identification and interpretation for generating vascular hypotheses. Initial hypotheses were prioritized by some participants, however the level of specificity of hypotheses varied.

Cue evaluation

All participants evaluated cues throughout the patient history and physical examination in relationship to hypotheses generated, indicating use of hypothetico-deductive reasoning processes (Table  5 ). Framework knowledge of patient history features of vascular pathology was used to test vascular hypotheses and aid differential diagnosis. The patient history section supported high level of cue identification and interpretation of patient history features for all but one participant, and generation of further patient history questions for all participants. The level of specificity of these questions was high for all but one participant. Framework knowledge of recommended physical examination tests, including removal of positional testing, supported planning a focused and prioritized physical examination to further test vascular hypotheses for all participants. No participant indicated intention to use positional testing as part of their physical examination. Treatment with physiotherapy interventions served as a form of cue evaluation, and cues were evaluated to inform prognosis for some participants. At times during the physical examination, some participants demonstrated occasional errors or difficulty with cue evaluation by omitting key physical exam tests (e.g., no cranial nerve assessment despite concerns for trigeminal nerve involvement), selecting physical exam tests in advance of hypothesis generation (e.g., cervical spine instability testing), difficulty interpreting cues, or late selection of a physical examination test. Cue acquisition was supported by a range of personal characteristics. Most participants justified selection of physical examination tests, and some self-reflected on their ability to collect useful physical examination information to inform selection of tests. Precaution to the physical examination was identified by all participants but one, which contributed to an adaptable approach, prioritizing patient safety and comfort. Critical analysis of physical examination information aided interpretation within the context of the patient for most participants.

Hypothesis evaluation

All participants used the Framework to evaluate their hypotheses throughout the patient history and physical examination, continuously shifting their level of support for hypotheses (Table  6 , Supplement  4 ). This informed clarity in the overall level of suspicion for vascular pathology or musculoskeletal diagnoses, which were specific for most participants. Response to treatment with physiotherapy interventions served as a form of hypothesis evaluation for most participants who had low level suspicion for vascular pathology, highlighting ongoing reasoning processes. Hypotheses evaluated were prioritized by ranking according to level of suspicion by some participants. Difficulties weighing patient history and physical examination cues to inform judgement on overall level of suspicion for vascular pathology was demonstrated by some participants who reported that incomplete physical examination data and not being able to see the patient contributed to difficulties. Hypothesis evaluation was supported by the personal characteristic of reflection, where some students reflected on the Framework’s emphasis on the patient history to evaluate a vascular hypothesis.

The Framework supported all participants in clinical reasoning related to treatment (Table  7 ). Treatment decisions were always linked to the participant’s overall level of suspicion for vascular pathology or musculoskeletal diagnosis. Framework knowledge supported participants with high level of suspicion for vascular pathology to refer for further investigations. Participants with a musculoskeletal diagnosis kept the patient for physiotherapy interventions. The Framework patient history section supported patient education about symptoms of vascular pathology and safety netting for some participants. Framework knowledge influenced informed consent processes and risk-benefit analysis to support the selection of musculoskeletal physiotherapy interventions, which were specific and prioritized for some participants. Less Framework knowledge related to treatment was demonstrated by some students, generating unclear recommendations regarding the urgency of referral and use of the Framework to inform musculoskeletal physiotherapy interventions. Treatment was supported by a range of personal characteristics. An adaptable approach that prioritized patient safety and was supported by justification was demonstrated in all participants except one. Shared decision-making enabled the selection of physiotherapy interventions, which were patient-centered (individualized, considered whole person, identified future risk for vascular pathology). Communication with the patient’s family doctor facilitated collaborative patient-centered care for most participants.

This is the first study to explore the influence of the Framework on clinical reasoning processes in postgraduate physiotherapy students. The Framework supported clinical reasoning that used primarily hypothetico-deductive processes. The Framework informed vascular hypothesis generation in the patient history and testing the vascular hypothesis through patient history questions and selection of physical examination tests to inform clarity and support for diagnosis and management. Most postgraduate students’ clinical reasoning processes were characterized by high-level features (e.g. specificity, prioritization). However, some demonstrated occasional difficulties or errors, reflecting a continuum of clinical reasoning proficiency. Clinical reasoning processes were informed by deep knowledge of the Framework integrated with a breadth of wider knowledge and supported by a range of personal characteristics (e.g., justification for decisions, reflection).

Use of the Framework to inform clinical reasoning processes

The Framework provided a structured and comprehensive approach to support postgraduate students’ clinical reasoning processes in assessment and management of the cervical spine region, considering the potential for vascular pathology. Patient history and physical examination information was evaluated to inform clarity and support the decision to refer for further vascular investigations or proceed with musculoskeletal physiotherapy diagnosis/interventions. The Framework is not intended to lead to a vascular pathology diagnosis [ 7 , 8 ], and following the Framework does not guarantee vascular pathologies will be identified [ 41 ]. Rather, it aims to support a process of clinical reasoning to elicit and interpret appropriate patient history and physical examination information to estimate the probability of vascular pathology and inform judgement about the need to refer for further investigations [ 7 , 8 , 42 ]. Results of this study suggest the Framework has achieved this aim for postgraduate physiotherapy students.

The Framework supported postgraduate students in using primarily hypothetico-deductive diagnostic reasoning processes. This is expected given the diversity of vascular pathology clinical presentations precluding a definite clinical pattern and inherent complexity as a potential masquerader of a musculoskeletal problem [ 7 ]. It is also consistent with prior research investigating clinical reasoning processes in musculoskeletal physiotherapy postgraduate students [ 12 ] and clinical experts [ 29 ] where hypothetico-deductive and pattern recognition diagnostic reasoning are employed according to the demands of the clinical situation [ 10 ]. Diagnostic reasoning of most postgraduate students in this study demonstrated features suggestive of high-level clinical reasoning in musculoskeletal physiotherapy [ 12 ], including ongoing reasoning with high-level cue identification and interpretation, specificity and prioritization during assessment and treatment, use of physiotherapy interventions to aid diagnostic reasoning, and prognosis determination [ 12 , 29 , 43 ]. Expert physiotherapy practice has been further described as using a dialectical model of clinical reasoning with seamless transitions between clinical reasoning strategies [ 44 ]. While diagnostic reasoning was a focus in this study, postgraduate students considered a breadth of information as important to their reasoning (e.g., patient’s perspectives of the reason for their pain). This suggests wider reasoning strategies (e.g., narrative, collaborative) were employed to enable shared decision-making within the context of patient-centered care.

Study findings also highlighted a continuum of proficiency in use of the Framework to inform clinical reasoning processes. Not all students demonstrated all characteristics of high-level clinical reasoning and there are suggestions of incomplete reasoning processes, for example occasional errors in evaluating cues. Some students offered explanations such as incomplete case information as factors contributing to difficulties with clinical reasoning processes. However, the ability to critically evaluate incomplete and potentially conflicting clinical information is consistently identified as an advanced clinical practice competency [ 14 , 43 ]. A continuum of proficiency in clinical reasoning in musculoskeletal physiotherapy is supported by wider healthcare professions describing acquisition and application of clinical knowledge and skills as a developmental continuum of clinical competence progressing from novice to expert [ 45 , 46 ]. The range of years of clinical practice experience in this cohort of students (3–14 years) or prior completed postgraduate education may have contributed to the continuum of proficiency, as high-quality and diverse experiential learning is essential for the development of high-level clinical reasoning [ 14 , 47 ].

Deep knowledge of the Framework informs clinical reasoning processes

Postgraduate students demonstrated deep Framework knowledge to inform clinical reasoning processes. All students demonstrated knowledge of patient history features of vascular pathology, recommended physical examination tests to test a vascular hypothesis, and the need to refer if there is a high level of suspicion for vascular pathology. A key development in the recent Framework update is the removal of the recommendation to perform positional testing [ 8 ]. All students demonstrated knowledge of this development, and none wanted to test a vascular hypothesis with positional testing. Most also demonstrated Framework knowledge about considerations for planning treatment with physiotherapy interventions (e.g., risk-benefit analysis, informed consent), though not all, which underscores the continuum of proficiency in postgraduate students. Rich organization of multidimensional knowledge is a required component for high level clinical reasoning and is characteristic of expert physiotherapy practice [ 10 , 48 , 49 ]. Most postgraduate physiotherapy students displayed this expert practice characteristic through integration of deep Framework knowledge with a breadth of prior knowledge (e.g., experiential, propositional) to inform clinical reasoning processes. This highlights the utility of the Framework in postgraduate physiotherapy education to develop advanced level evidence-based knowledge informing clinical reasoning processes for safe assessment and management of the cervical spine, considering the potential for vascular pathology [ 9 , 8 , 50 , 51 , 52 ].

Framework supports personal characteristics to facilitate integration of knowledge and clinical reasoning

The Framework supported personal characteristics of postgraduate students, which are key drivers for the complex integration of advanced knowledge and high-level clinical reasoning [ 10 , 12 , 48 ]. For all students, the Framework supported justification for decisions and patient-centered care, emphasizing a whole-person approach and shared decision-making. Further demonstrating a continuum of proficiency, the Framework supported a wider breadth of personal characteristics for some students, including critical analysis, reflection, self-analysis, and adaptability. These personal characteristics illustrate the interwoven cognitive and metacognitive skills that influence and support a high level of clinical reasoning [ 10 , 12 ] and the development of clinical expertise [ 48 , 53 ]. For example [ 54 ], reflection is critical to developing high-level clinical reasoning and advanced level practice [ 12 , 55 ]. Postgraduate students reflected on prior knowledge, experiences, and action within the context of current Framework knowledge, emphasizing active engagement in cognitive processes to inform clinical reasoning processes. Reflection-in-action is highlighted by self-analysis and adaptability. These characteristics require continuous cognitive processing to consider personal strengths and limitations in the context of the patient and evidence-based practice, adapting the clinical encounter as required [ 53 , 55 ]. These findings highlight use of the Framework in postgraduate education to support development of personal characteristics that are indicative of an advanced level of clinical practice [ 12 ].

Synthesis of findings

Derived from synthesis of research study findings and informed by the Postgraduate Musculoskeletal Physiotherapy Practice model [ 12 ], use of the Framework to inform clinical reasoning processes in postgraduate students is illustrated in Fig.  2 . Overlapping clinical reasoning, knowledge and personal characteristic components emphasize the complex interaction of factors contributing to clinical reasoning processes. Personal characteristics of postgraduate students underpin clinical reasoning and knowledge, highlighting their role in facilitating the integration of these two components. Bolded subcomponents indicate convergence of results reflecting all postgraduate students and underscores the variability among postgraduate students contributing to a continuum of clinical reasoning proficiency. The relative weighting of the components is approximately equal to balance the breadth and convergence of subcomponents. Synthesis of findings align with the Postgraduate Musculoskeletal Physiotherapy Practice model [ 12 ], though some differences exist. Limited personal characteristics were identified in this study with little convergence across students, which may be due to the objective of this study and the case analysis approach.

Use of the Framework to inform clinical reasoning in postgraduate level musculoskeletal physiotherapy students. Adapted from the Postgraduate Musculoskeletal Physiotherapy Practice model [ 12 ].

Strengths and limitations

Think aloud case analyses enabled situationally dependent understanding of the Framework to inform clinical reasoning processes in postgraduate level students [ 17 ], considering the rare potential for vascular pathology. A limitation of this approach was the standardized nature of case information provided to students, which may have influenced clinical reasoning processes. Future research studies may consider patient case simulation to address this limitation [ 30 ]. Interviews were conducted during the second half of the postgraduate educational program, and this timing could have influenced clinical reasoning processes compared to if interviews were conducted at the end of the program. Future research can explore use of the Framework to inform clinical reasoning processes in established advanced practice physiotherapists. The sample size of this study aligns with recommendations for think aloud methodology [ 27 , 28 ], achieved rich data, and purposive sampling enabled wide representation of key characteristics (e.g., gender, ethnicity, country of training, physiotherapy experiences), which enhances transferability of findings. Students were aware of the study objective in advance of interviews which may have contributed to a heightened level of awareness of vascular pathology. The prior relationship between students and researchers may have also influenced results, however several strategies were implemented to minimize this influence.

Implications

The Framework is widely implemented within IFOMPT postgraduate educational programs and has led to important shifts in educational curricula [ 9 ]. Findings of this study support use of the Framework as an educational resource in postgraduate physiotherapy programs to inform clinical reasoning processes for safe and effective assessment and management of cervical spine presentations considering the potential for vascular pathology. Individualized approaches may be required to support each student, owing to a continuum of clinical reasoning proficiency. As the Framework was written for practicing musculoskeletal clinicians, future research is required to explore use of the Framework to inform clinical reasoning in learners at different levels, for example entry-level physiotherapy students.

The Framework supported clinical reasoning that used primarily hypothetico-deductive processes in postgraduate physiotherapy students. It informed vascular hypothesis generation in the patient history and testing the vascular hypothesis through patient history questions and selection of physical examination tests, to inform clarity and support for diagnosis and management. Most postgraduate students clinical reasoning processes were characterized as high-level, informed by deep Framework knowledge integrated with a breadth of wider knowledge, and supported by a range of personal characteristics to facilitate the integration of advanced knowledge and high-level clinical reasoning. Future research is required to explore use of the Framework to inform clinical reasoning in learners at different levels.

Data availability

The dataset used and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to acknowledge study participants and the transcriptionist for their time in completing and transcribing think aloud interviews.

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Katie L. Kowalski, Heather Gillis, Katherine Henning, Paul Parikh, Jackie Sadi & Alison Rushton

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Katie Kowalski: Conceptualization, methodology, validation, formal analysis, investigation, data curation, writing– original draft, visualization, project administration. Heather Gillis: Validation, resources, writing– review & editing. Katherine Henning: Investigation, formal analysis, writing– review & editing. Paul Parikh: Validation, resources, writing– review & editing. Jackie Sadi: Validation, resources, writing– review & editing. Alison Rushton: Conceptualization, methodology, validation, writing– review & editing, supervision.

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Author AR is an author of the IFOMPT Cervical Framework. Authors JS and HG are lecturers on the AHCP CMP program. AR and JS led standardized teaching of the Framework. Measures to reduce the influence of potential competing interests on the conduct and results of this study included: the Framework representing international and multiprofessional consensus, recruitment of participants by author KK, data collection and analysis completed by KK with input from AR, JS and HG at the stage of data synthesis and interpretation, and wider peer scrutiny of initial findings. KK, KH and PP have no potential competing interests.

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Kowalski, K.L., Gillis, H., Henning, K. et al. Use of the International IFOMPT Cervical Framework to inform clinical reasoning in postgraduate level physiotherapy students: a qualitative study using think aloud methodology. BMC Med Educ 24 , 486 (2024). https://doi.org/10.1186/s12909-024-05399-x

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Summary of Peer review study: “Library involvement in an autism support program: A case study” – Pionke et al 2019

Pionke et al (2019) did a case study in which they interviewed students with autism at Easter Illinois University and were part of the Students with Autism Transitional Education Program (STEP). Seven students were interviewed about their experiences with academic libraries and the services they used or wanted. While the students expressed similar needs to neurotypical students, the main differences were an emphasis on the need for secluded study spaces, access to food/drink, access to use online systems, and the need for library staff training to be aware of the communication styles of people with Autism. The limitations of this study were: small sample sizes, and funding being cut after interviews were conducted so there was a lack of resources to address the needs/changes the STEP students addressed in their interviews.

The interview questions were an expanded script for interviewing students with disabilities that Pionke had developed in 2017 in regard to library use (Pionke et al, 2019). According to OrcId ( https://orcid.org/0000-0002-3261-7684 ), Pionke is currently (at the time of this writing) employed as a Librarian at the University of Illinois at Urbana-Champaign and whose main research focus is on disability in libraries.

This article confirmed my current findings of there being a lack of research on students with autism beyond K-12, and what research has been done has either had low sample sizes or that people with autism were never asked about their experiences (Pionke et al (2019). The article provided resources that I will be looking into for the future in researching the information needs of the Autism community (and possibly for future literature review) including the Job Accommodation Network (JAN), Project ENABLE, the website, WrongPlanet, and further articles pertaining to how libraries can provide technology to assist patrons with autism.

As far as current course readings go (in addition to previous posts on LIS models and theories I’ve discussed in previous assignments and blog posts), the readings involving cultural competence and addressing equity of access seem to be the most applicable as far as supporting research that can be applied to the Autism community.

Pionke, J. J., Knight-Davis, S., & Brantley, J. (2019). Library involvement in an autism support program: A case study. College & Undergraduate Libraries, 26(3), 221-233, https://doi.org/10.1080/10691316.2019.1668896

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Plagiarism in peer-review reports could be the ‘tip of the iceberg’

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Jackson Ryan is a freelance science journalist in Sydney, Australia.

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Time pressures and a lack of confidence could be prompting reviewers to plagiarize text in their reports. Credit: Thomas Reimer/Zoonar via Alamy

Mikołaj Piniewski is a researcher to whom PhD students and collaborators turn when they need to revise or refine a manuscript. The hydrologist, at the Warsaw University of Life Sciences, has a keen eye for problems in text — a skill that came in handy last year when he encountered some suspicious writing in peer-review reports of his own paper.

Last May, when Piniewski was reading the peer-review feedback that he and his co-authors had received for a manuscript they’d submitted to an environmental-science journal, alarm bells started ringing in his head. Comments by two of the three reviewers were vague and lacked substance, so Piniewski decided to run a Google search, looking at specific phrases and quotes the reviewers had used.

To his surprise, he found the comments were identical to those that were already available on the Internet, in multiple open-access review reports from publishers such as MDPI and PLOS. “I was speechless,” says Piniewski. The revelation caused him to go back to another manuscript that he had submitted a few months earlier, and dig out the peer-review reports he received for that. He found more plagiarized text. After e-mailing several collaborators, he assembled a team to dig deeper.

Meet this super-spotter of duplicated images in science papers

The team published the results of its investigation in Scientometrics in February 1 , examining dozens of cases of apparent plagiarism in peer-review reports, identifying the use of identical phrases across reports prepared for 19 journals. The team discovered exact quotes duplicated across 50 publications, saying that the findings are just “the tip of the iceberg” when it comes to misconduct in the peer-review system.

Dorothy Bishop, a former neuroscientist at the University of Oxford, UK, who has turned her attention to investigating research misconduct, was “favourably impressed” by the team’s analysis. “I felt the way they approached it was quite useful and might be a guide for other people trying to pin this stuff down,” she says.

Peer review under review

Piniewski and his colleagues conducted three analyses. First, they uploaded five peer-review reports from the two manuscripts that his laboratory had submitted to a rudimentary online plagiarism-detection tool . The reports had 44–100% similarity to previously published online content. Links were provided to the sources in which duplications were found.

The researchers drilled down further. They broke one of the suspicious peer-review reports down to fragments of one to three sentences each and searched for them on Google. In seconds, the search engine returned a number of hits: the exact phrases appeared in 22 open peer-review reports, published between 2021 and 2023.

The final analysis provided the most worrying results. They took a single quote — 43 words long and featuring multiple language errors, including incorrect capitalization — and pasted it into Google. The search revealed that the quote, or variants of it, had been used in 50 peer-review reports.

Predominantly, these reports were from journals published by MDPI, PLOS and Elsevier, and the team found that the amount of duplication increased year-on-year between 2021 and 2023. Whether this is because of an increase in the number of open-access peer-review reports during this time or an indication of a growing problem is unclear — but Piniewski thinks that it could be a little bit of both.

Why would a peer reviewer use plagiarized text in their report? The team says that some might be attempting to save time , whereas others could be motivated by a lack of confidence in their writing ability, for example, if they aren’t fluent in English.

The team notes that there are instances that might not represent misconduct. “A tolerable rephrasing of your own words from a different review? I think that’s fine,” says Piniewski. “But I imagine that most of these cases we found are actually something else.”

The source of the problem

Duplication and manipulation of peer-review reports is not a new phenomenon. “I think it’s now increasingly recognized that the manipulation of the peer-review process, which was recognized around 2010, was probably an indication of paper mills operating at that point,” says Jennifer Byrne, director of biobanking at New South Wales Health in Sydney, Australia, who also studies research integrity in scientific literature.

Paper mills — organizations that churn out fake research papers and sell authorships to turn a profit — have been known to tamper with reviews to push manuscripts through to publication, says Byrne.

The fight against fake-paper factories that churn out sham science

However, when Bishop looked at Piniewski’s case, she could not find any overt evidence of paper-mill activity. Rather, she suspects that journal editors might be involved in cases of peer-review-report duplication and suggests studying the track records of those who’ve allowed inadequate or plagiarized reports to proliferate.

Piniewski’s team is also concerned about the rise of duplications as generative artificial intelligence (AI) becomes easier to access . Although his team didn’t look for signs of AI use, its ability to quickly ingest and rephrase large swathes of text is seen as an emerging issue.

A preprint posted in March 2 showed evidence of researchers using AI chatbots to assist with peer review, identifying specific adjectives that could be hallmarks of AI-written text in peer-review reports .

Bishop isn’t as concerned as Piniewski about AI-generated reports, saying that it’s easy to distinguish between AI-generated text and legitimate reviewer commentary. “The beautiful thing about peer review,” she says, is that it is “one thing you couldn’t do a credible job with AI”.

Preventing plagiarism

Publishers seem to be taking action. Bethany Baker, a media-relations manager at PLOS, who is based in Cambridge, UK, told Nature Index that the PLOS Publication Ethics team “is investigating the concerns raised in the Scientometrics article about potential plagiarism in peer reviews”.

How big is science’s fake-paper problem?

An Elsevier representative told Nature Index that the publisher “can confirm that this matter has been brought to our attention and we are conducting an investigation”.

In a statement, the MDPI Research Integrity and Publication Ethics Team said that it has been made aware of potential misconduct by reviewers in its journals and is “actively addressing and investigating this issue”. It did not confirm whether this was related to the Scientometrics article.

One proposed solution to the problem is ensuring that all submitted reviews are checked using plagiarism-detection software. In 2022, exploratory work by Adam Day, a data scientist at Sage Publications, based in Thousand Oaks, California, identified duplicated text in peer-review reports that might be suggestive of paper-mill activity. Day offered a similar solution of using anti-plagiarism software , such as Turnitin.

Piniewski expects the problem to get worse in the coming years, but he hasn’t received any unusual peer-review reports since those that originally sparked his research. Still, he says that he’s now even more vigilant. “If something unusual occurs, I will spot it.”

doi: https://doi.org/10.1038/d41586-024-01312-0

Piniewski, M., Jarić, I., Koutsoyiannis, D. & Kundzewicz, Z. W. Scientometrics https://doi.org/10.1007/s11192-024-04960-1 (2024).

Article   Google Scholar  

Liang, W. et al. Preprint at arXiv https://doi.org/10.48550/arXiv.2403.07183 (2024).

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• Published: 04 May 2024

Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study

• Emily L. Graul 1 ,
• Clementine Nordon 2 ,
• Kirsty Rhodes 2 ,
• Shruti Menon 3 ,
• Mahmoud Al Ammouri 1 ,
• Constantinos Kallis 1 ,
• Anne E. Ioannides 1 ,
• Hannah R. Whittaker 1 ,
• Nicholas S. Peters 4 &
• Jennifer K. Quint 1  

BMC Pulmonary Medicine volume  24 , Article number:  221 ( 2024 ) Cite this article

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An immediate, temporal risk of heart failure and arrhythmias after a Chronic Obstructive Pulmonary Disease (COPD) exacerbation has been demonstrated, particularly in the first month post-exacerbation. However, the clinical profile of patients who develop heart failure (HF) or atrial fibrillation/flutter (AF) following exacerbation is unclear. Therefore we examined factors associated with people being hospitalized for HF or AF, respectively, following a COPD exacerbation.

We conducted two nested case-control studies, using primary care electronic healthcare records from the Clinical Practice Research Datalink Aurum linked to Hospital Episode Statistics, Office for National Statistics for mortality, and socioeconomic data (2014-2020). Cases had hospitalization for HF or AF within 30 days of a COPD exacerbation, with controls matched by GP practice (HF 2:1;AF 3:1). We used conditional logistic regression to explore demographic and clinical factors associated with HF and AF hospitalization.

Odds of HF hospitalization (1,569 cases, 3,138 controls) increased with age, type II diabetes, obesity, HF and arrhythmia history, exacerbation severity (hospitalization), most cardiovascular medications, GOLD airflow obstruction, MRC dyspnea score, and chronic kidney disease. Strongest associations were for severe exacerbations (adjusted odds ratio (aOR)=6.25, 95%CI 5.10-7.66), prior HF (aOR=2.57, 95%CI 1.73-3.83), age≥80 years (aOR=2.41, 95%CI 1.88-3.09), and prior diuretics prescription (aOR=2.81, 95%CI 2.29-3.45).

Odds of AF hospitalization (841 cases, 2,523 controls) increased with age, male sex, severe exacerbation, arrhythmia and pulmonary hypertension history and most cardiovascular medications. Strongest associations were for severe exacerbations (aOR=5.78, 95%CI 4.45-7.50), age≥80 years (aOR=3.15, 95%CI 2.26-4.40), arrhythmia (aOR=3.55, 95%CI 2.53-4.98), pulmonary hypertension (aOR=3.05, 95%CI 1.21-7.68), and prescription of anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15).

Conclusions

Cardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding factors will help target people for prevention.

Peer Review reports

Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are associated with an increased risk of cardiovascular disease (CVD) [ 1 ] likely due to linked pathophysiology, hypoxic state, and an amplified systemic inflammatory response [ 2 , 3 ]. Previous studies have demonstrated an increased, immediate period of risk for hospitalized cardiovascular events following a COPD exacerbation compared with non-exacerbating patients, [ 1 , 4 ] with the risk highest within the first month and following a severe (hospitalized) exacerbation [ 1 , 5 , 6 ]. The 30 day risk of arrhythmias and heart failure (HF) following an exacerbation, [ 6 , 7 , 8 ] approach [ 4 , 6 ] or even surpass [ 7 , 9 ] 3-fold, compared to those who did not have an exacerbation.

Globally, the prevalence of HF in COPD is high, [ 10 ] and, of patients hospitalized for exacerbation, 20% have existing, undertreated HF [ 11 ]. Incident HF attributed to exacerbations is thought to come from the increase in pulmonary arterial pressures, low blood oxygen levels [ 12 ] and activation of adrenoceptors of the autonomic nervous system [ 12 , 13 ]. However, shared symptomology of HF and COPD exacerbations makes new HF diagnosis difficult, with HF often missed [ 3 , 12 , 14 ] or occurring in tandem; approximately 8% of people primarily diagnosed with HF also have a secondary diagnosis of exacerbation [ 15 ]. Studies have investigated COPD progression in HF [ 12 ] and conversely, HF progression across COPD phenotypes, [ 12 , 16 ] but few have focused on exacerbating COPD alone [ 15 ] and no studies have examined factors associated with hospitalization with a HF diagnosis following a COPD exacerbation.

Arrhythmias are also common among people with COPD, with prevalence ranging from 5 to 15% globally, [ 10 ] and atrial fibrillation (AF) is the most common arrhythmia [ 17 ]. AF diagnoses at the time of an exacerbation are also common, with estimates around 17% [ 18 ], but due to shared, nonspecific symptoms between AF and COPD, differential diagnosis can be difficult [ 19 ]. During a COPD exacerbation, changes in blood gases from hypoxia and rising pulmonary pressure can lead to electrophysiological and structural changes of the atrium, and together are thought to contribute to exacerbation-related disturbances in rhythm and progression of AF [ 6 , 10 , 19 , 20 , 21 ] The understanding of COPD progression alongside AF progression is unclear [ 19 ]. Few studies have examined factors associated with hospitalization for incident AF after an exacerbation, with the focus on the short-term [ 21 , 22 ]. Several have however investigated factors associated with concurrent AF at time of an exacerbation [ 18 , 23 ].

Therefore, using a primary-care defined COPD cohort from the Clinical Practice Research Datalink (CPRD) Aurum database linked with hospital, mortality, and socioeconomic deprivation data, we explored factors associated with incident hospitalization for non-fatal HF, or AF or atrial flutter, within the 30 days following a COPD exacerbation.

Study design and methods

Data source.

We obtained pseudonymized, routinely-collected electronic healthcare record data from CPRD Aurum, [ 24 ] a primary care database broadly representative by age, sex, deprivation, and regional distribution, [ 25 ] and covering approximately 20% of GP-registered patients in England [ 24 ]. Primary care data from the May 2022 build [ 24 ] were linked to the Office for National Statistics (ONS) for mortality, socioeconomic data from the 2015 Index of Multiple Deprivation (IMD), and secondary care data from NHS England’s Hospital Episode Statistics (HES) Admitted Patient Care (APC) database.

Source population

The source population were people with a COPD diagnosis who had been included in the Exacerbations of COPD and their OutcomeS on CardioVascular diseases (EXACOS-CV) observational open cohort study [ 4 ]. People were eligible for inclusion in that original cohort study if they met the following criteria: 1) aged 40 years or older, 2) had a COPD diagnosis using a validated algorithm (86.5% PPV) [ 26 ] 3) were eligible for linkage with HES, ONS, and IMD data, 4) had a smoking history (i.e., current or ex-smoker), 5) had continuous GP practice registration with acceptable quality data in the year before start of follow up, and 6) had data recorded after 1 st of January 2014.

Study design and population

We conducted two nested-case control studies, in parallel. The study population for each study consisted of COPD patients in the EXACOS-CV source population, who 1) experienced an exacerbation within cohort follow-up, 2) among the pool of eligible controls had at least 30 days of contributing data post-exacerbation, and 3) had no evidence of HF or arrhythmias in the year before exacerbation. People were excluded from the AF/flutter study population if, within the 30 days post-exacerbation, they had evidence of other non-AF arrhythmias (e.g., cardiac arrest) (Fig. 1 for study designs; Supplementary Figures 1 and 2 for HF and AF/flutter eligibility diagram respectively).

Study design for the parallel, nested case control studies. Abbreviations: HF=heart failure, AF/f = atrial fibrillation/flutter, GP=general practice, CV=cardiovascular. Two nested case control studies, for HF and AF/f respectively, were conducted among all patients who experienced an exacerbation at start of cohort follow up. Full definitions of demographic and clinical factors of interest are in the Supplementary materials

Cases were individuals with a hospitalized, cardiovascular event (HF or AF/flutter, respectively) within 1-30 days post COPD exacerbation. Cases were determined in the HES database using ICD-10 codes in the primary diagnostic position across all episodes in a single hospitalization. The date of admission was the date of the case (index date, HF or AF/flutter, respectively). Extended case definitions are in Supplementary Table 3 .

The set of controls per case was drawn among individuals in the study population who had no in-hospital diagnosis of the cardiovascular event-of-interest (HF or AF/flutter, respectively) and who had 30 days of contributing data post-exacerbation. Controls were assigned a pseudo-end date (i.e., 30 days post-exacerbation) on which to match. Controls were individually matched to cases on GP practice to account for unmeasurable potential clinical differences in disease management by clinicians, within a 30-day window of the index date, and could be used as a control for more than one case. For the HF analysis, controls were matched 2:1 and for the AF/flutter analysis, 3:1.

The choice of matching factors and ratios were chosen based on considerations of 1) maximizing the ratio itself for reasons of power and precision while 2) minimizing cases lost without a full set of controls. Only case sets with the full ratio of controls per case were included for analysis.

We examined factors potentially associated with hospitalization for HF or AF/flutter in the 30 days following an exacerbation of COPD. Factors included demographic characteristics: age (categorized into four age bands; 40-69, 70-74, 75-79, ≥80), sex, IMD quintiles, and ethnicity; and smoking status. Comorbidities included (hypertension, anxiety, depression and depressive symptoms, type II diabetes, chronic kidney disease (CKD), BMI [body mass index; using World Health Organization classification]). COPD factors included GOLD grade of airflow limitation (defined as 1 mild, 2 moderate, 3-4 severe/very severe), Medical Research Council (MRC) dyspnea score (1-2; 3; 4-5), exacerbation severity at cohort entry (moderate/severe) prior exacerbation frequency (infrequent (≤1) versus frequent (≥2) history in a year window preceding one year to cohort entry). Prior CVD history was evidence of the following anytime preceding the year before exacerbation date [acute coronary syndrome (ACS), arrhythmias, HF, ischemic stroke, pulmonary hypertension PH], COPD inhaled therapies, and major classes of cardiovascular medications (prescriptions defined two years before cohort entry). Covariate definitions are in Supplementary Table 4 .

We used validated definitions for COPD exacerbations. A moderate exacerbation was defined as a COPD-related primary care (GP) visit with either a code for exacerbation (including Lower Respiratory Tract Infection (LRTI) SNOMED-CT codes) and/or prescription for respiratory antibiotics and oral systemic corticosteroids not on the same day as an annual review, as validated in CPRD [ 27 ]. A severe exacerbation was defined as a hospitalization with an acute respiratory event code including COPD or bronchitis as a primary diagnosis, or a secondary diagnosis of COPD, as validated in HES [ 28 ]. We considered exacerbations to be the same event if recorded within 14 days in which case the highest level of severity was chosen.

We checked covariate missingness to assess use in adjusted models. Imputation was not considered for covariates with missing data, given the missingness mechanism was Missing-Not-At-Random (MNAR), violating the Missing-Completely-At-Random (MCAR) assumption premising imputation [ 29 ].

Codelists for primary care factors were generated using SNOMED-CT and British National Formulary ontologies; we used our standardizable, reproducible methodology, available on GitHub: for drug [ 30 ] and medical/phenotype codelists , respectively. Codelists for hospitalizations used ICD-10 codes. Codelists are available on our EXACOS-CV GitHub repository .

Statistical analysis

We compared separately the odds of hospitalization for HF or AF/flutter between the comparator groups for each factor, using conditional logistic regression. Our final model was adjusted for all covariates without substantial amount of missing data, including demographic factors, comorbidities, and COPD inhaled therapies and cardiovascular medications. In three sensitivity analyses, we repeated main analyses additionally adjusting for variables-of-interest with substantial missing data, respectively: GOLD, MRC, and CKD.

Analyses were performed using STATA v17.

These data were collected and provided by CPRD. Ethical approval was obtained through CPRD’s Research Data Governance Process (protocol number: 22_002377). The RECORD checklist for observational studies is in Supplementary Table 5 .

Characteristics of study participants

The HF dataset consisted of 1,569 cases experiencing an HF event within the first 30 days post-exacerbation, matched to 3,138 controls. The AF/flutter dataset consisted of 841 cases experiencing an AF/flutter event within the first 30 days post-exacerbation, matched to 2,523 controls. Tables 1 and 2 show the characteristics of the participants for HF and AF/flutter, respectively.

Across both study populations, cases tended to have had a severe exacerbation, were more likely to be older, male, an ex-smoker, have comorbidities including prior prevalent cardiovascular disease, and be prescribed cardiovascular medications. Cases and controls both tended to have infrequent exacerbation history, have prescriptions for long-acting therapies, but tended to not have prescriptions for short-acting inhaled therapies.

Factors associated with HF hospitalization 1-30 days post exacerbation

Age, type II diabetes, obesity, prior HF diagnosis, prior arrhythmia diagnosis, having a severe exacerbation, and most cardiovascular medications were associated with increased odds of being hospitalized for HF within 30 days of a COPD exacerbation (Table 1 ). The factors most strongly associated with HF were exacerbation severity (aOR=6.25, 95%CI 5.10-7.66), a prior HF diagnosis (aOR=2.57, 95%CI 1.73-3.83), age at least 80 years (≥80 vs. 40-69; aOR=2.41, 95%CI 1.88-3.09), and, of the cardiovascular medications, diuretics (aOR=2.81, 95%CI 2.29-3.45).

In sensitivity analyses, GOLD grade, MRC score, and history of CKD were all associated with an increased odds of being hospitalized for HF within the month post exacerbation.(Supplementary Table 1 ) The strongest associations were for CKD (aOR=1.85, 95%CI 1.46-2.35) and higher levels of airflow limitation and breathlessness (GOLD grade 3-4 Severe/Very Severe aOR=1.83, 95%CI 1.32-2.54, versus GOLD grade 1 Mild) (Score 4-5 MRC aOR=1.87, 95%CI 1.42-2.46, versus MRC 1-2).

Factors associated with AF/flutter hospitalization 1-30 days post exacerbation

Age, male sex, prior arrhythmia, prior PH, and having a severe exacerbation were associated with AF/flutter in the 30 days following an exacerbation. Most cardiovascular medications were also associated with AF/flutter (Table 2 ). The factors most strongly associated with AF were exacerbation severity (aOR=5.78 95%CI 4.45-7.50), age ≥80 years (aOR=3.15 95%CI 2.26-4.40), prior arrhythmia and PH (aOR=3.55, 95%CI 2.53-4.98; aOR=3.05, 95%CI 1.21-7.68), and of the cardiovascular medications, anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15).

In sensitivity analyses, GOLD grade, MRC score, and CKD had no association with AF/flutter (Supplementary Table 2 ).

In a primary care defined COPD population, this study examined the clinical profiles of people hospitalized for HF and for AF within a month post exacerbation. We observed that the odds of HF and of AF hospitalization were higher for people with severe, hospitalized exacerbations and with cardiovascular-related history. For HF analyses only, the odds of HF were also higher for people with microvascular factors (i.e., type II diabetes; obesity; CKD) and for people with pulmonary factors, namely those with worse GOLD grade of airflow limitation and higher levels of MRC breathlessness scores.

Heart failure

The pathophysiological links between COPD exacerbations and HF are recognized [ 31 , 32 , 33 ]. Upon exacerbation, dynamic lung hyperinflation from airflow limitation alongside heightened inflammation and hypoxia, can lead to increased strain on both the lungs and heart. The increased cardiopulmonary pressure can then lead to impaired contraction or filling of the left ventricle, namely HF with preserved or with reduced ejection fraction, respectively [ 31 , 32 , 33 ].

Few studies have investigated factors associated with HF in COPD alone, [ 15 , 34 , 35 , 36 ] of which only one [ 15 ] investigated hospitalized exacerbation with concurrent HF, but did not quantify this relationship with ORs, and was conducted in the US National Inpatient Sample (NIS) database. The remaining were post-hoc analyses of trials focused on stable COPD [ 34 , 35 , 36 ].

The strong magnitude of the association for exacerbation severity (hospitalization) but not for exacerbation frequency, suggests two points. First, from a healthcare service-level standpoint, patients hospitalized for exacerbations are more likely to be hospitalized for a future HF (i.e., re-admission) compared with patients whose exacerbation was managed in primary care. Second, clinically, exacerbation severity (e.g., greater intensity of inflammation) has a greater indication of a patients’ future cardiac state, rather than past exacerbation occurrence and management. Findings for older age were anticipated and align with previous studies [ 15 , 34 , 35 , 36 ].

The associations for history of HF, arrhythmia, type II diabetes, and CKD with post-exacerbation HF are unsurprising given their known independent relationships each with HF and exacerbations alone. Chronic, unmanaged HF can lead to future health service utilization for HF [ 16 , 37 ]. Arrhythmia-attributed cardiac remodeling can contribute to development of cardiomyopathy [ 38 ]. Diabetes is a risk factor for substantial HF progression [ 16 , 39 ], and separately a population-based study in COPD patients demonstrated an increased risk of cardiovascular mortality with type II diabetes [ 40 ]. Impaired renal hemodynamics and activation of the renin-angiotensin-aldosterone system (RAAS) can lead to HF, [ 41 ] and separately reduced kidney function is associated with future HF [ 42 ].

Our findings for cardiovascular medications indicate a certain treatment profile in primary care, leading up to the post-exacerbation HF hospitalization. The strongest association for diuretics suggests that leading up to future HF, patients perhaps are receiving treatment indicated for uncontrolled edema from existing HF, diabetic cardiomyopathy, or CKD for example.

GOLD and MRC as factors for post-exacerbation HF likewise were expected. Increased breathlessness and reduced lung function are not only symptoms of an imminent exacerbation or HF; equally, these factors can also indicate delayed diagnosis of unstable COPD or HF, [ 16 , 43 ] given their shared symptomology [ 3 , 12 , 14 ]. Reduced lung function can contribute to worsening prognosis and precipitate a future exacerbation or HF [ 16 , 43 ].

Atrial fibrillation

The pathophysiological mechanisms implicating AF post COPD exacerbation are also established [ 19 , 44 ]. At time of exacerbation, drastic increases in lung hyperinflation and impaired intrathoracic pressures can cause increased pulmonary vascular resistance and damage, leading to alterations to atrial electrophysiology [ 19 , 44 ]. Compromised gas exchange in the lungs can induce systemic inflammation and oxidative stress too, and also put strain on pulmonary vasculature, leading to abnormal atrial structure and ion-channel remodeling, [ 19 , 44 ] while certain treatments prescribed upon exacerbation are arrhythmogenic [ 19 , 44 ].

Only four studies have investigated patient profiles for AF development in unstable COPD, all hospital-based [ 18 , 21 , 22 , 23 ], of which two conducted in the US National Inpatient Sample (NIS) database [ 18 , 22 ]. Two examined factors associated with AF diagnosis after exacerbation [ 21 , 22 ] one of which patients had existing AF [ 21 ]. Two failed to quantify with ORs, only comparing baseline characteristics of exacerbating patients by status of concurrent AF [ 18 , 23 ].

Our findings for older age and male gender are not unexpected; studies similarly found these associations in exacerbating [ 18 , 22 ] and in stable COPD [ 45 ]. Unsurprisingly, exacerbation severity associated with future AF, again adding to the existing evidence of stronger associations for hospitalized exacerbation [ 1 , 6 ] and again, likewise to HF, suggests a distinction between healthcare service-level patient pathways, and intensity versus frequency.

The associations we found for history of PH and arrhythmias aligns with what was anticipated clinically. Electrophysiological and structural changes to the atrium over time, from either AF itself [ 20 ] or from chronic atrial stretching and fibrosis attributed to PH, [ 46 ] can lead to future AF. While a study using Euro Heart Survey data showed COPD as a factor for progression of paroxysmal to persistent AF (aOR=1.51, 95%CI 0.95-2.39) [ 20 ], neither of the two studies looking at patient profiles for post-exacerbation AF, looked at chronic, prevalent arrhythmias itself as a factor [ 21 , 22 ]. No studies have looked at PH, although the study among end-stage COPD patients in the NIS database found a weak association for pulmonary circulatory disorders (aOR=1.44, 95%CI 1.37-1.52) [ 22 ], compared the OR of about 3 for PH. A study found raised pulmonary artery pressure to be associated with AF (p<0.05), but failed to quantify, and it was small, underpowered, and not generalizable as it restricted to hospitalized COPD patients with existing AF [ 21 ].

The lack of associations for prior ACS, ischemic stroke, HF, and hypertension somewhat contradict the study among hospitalized, end-stage COPD patients, [ 22 ] where an association was found for HF (aOR=2.42; 95%CI: 2.36-2.48) and coagulopathy (aOR=1.23; 95%CI:1.16-1.31), but again this may reflect the more severe prognosis of these patients versus those in our study.

Likewise to HF, findings for cardiovascular medications indicate a certain treatment profile in primary care, leading up to the post-exacerbation AF hospitalization. Although we were unable to adjudicate by specific subtype of AF,(e.g., paroxysmal, persistent) the strongest associations for positive inotropes, anti-arrhythmic drugs, and anticoagulants may suggest that leading up to future AF, patients perhaps are receiving treatment to manage abnormal heart rate and/or rhythm, and/or to prevent clotting. Future research could investigate the respective treatment profile relative to paroxysmal AF and to persistent AF [ 47 ] to confirm and extend our findings.

Our null results for other comorbidities (i.e., depression and depressive symptoms, anxiety, BMI, CKD, and type-II diabetes) goes against studies finding an association for diabetes, [ 18 , 22 ] mixed findings for depression, [ 18 , 22 ] among other comorbidities. Yet these observed associations could be due to differing context; using the NIS database in a study population of only hospitalized, exacerbating, insured payors. GOLD airflow obstruction and MRC dyspnea score were not associated with post-exacerbation AF hospitalization, possibly as AF is often associated with vague symptoms of onset and not necessarily immediately thought about as a cause of increasing breathlessness in someone with COPD [ 44 , 48 , 49 ].

Methodological considerations

A key strength is our generalizable COPD cohort, defined within the electronic healthcare record with detailed data to examine and adjust for a range of factors. Unlike other studies, this allowed us to look at two patient pathways: cardiovascular-related hospitalizations post primary-care exacerbation, and re-admissions post hospitalized exacerbation. Our exclusion criteria allowed us to quantify the odds of new onset HF and AF hospitalizations following exacerbation, by ensuring no evidence of AF or HF in the year prior to exacerbation. We chose to study two common cardiovascular conditions in COPD, AF and HF. We could not subdivide HF and AF more granularly, because of insufficient statistical power and the inability to obtain electrocardiogram or echocardiogram results to adjudicate.

We used validated codes to define COPD [ 26 ] and COPD exacerbations [ 27 , 28 ] so misclassification is unlikely. Where possible, we used previously tested methods [ 30 ] and codes to define our factors-of-interest and codes were checked by a pulmonologist and/or cardiologist. The nested case control matched design allowed us to control for unmeasurable potential clinical differences in disease management by clinicians, by matching patients on GP practice.

To minimize selection bias among patients with measured factors only, we adjusted only for covariates without substantial missing data. We reserved GOLD, MRC, and CKD for sensitivity analyses; the associations of these factors with HF are generalizable only to patients with measurements (e.g., patients with greater healthcare monitoring, provision, or access). For this reason, the relationship for ethnicity could not be quantified, and given the data sparsity. For the HF analysis, we were unable to quantify B-type natriuretic peptide testing as a factor (BNP or NT-proBNP) because of 90% missing data for BNP (data not shown).

Confounding by indication is possible, particularly for the associations observed for cardiovascular medications (cases could have been more likely prescribed cardiovascular medications to manage a prevalent co-morbidity (perhaps with delayed diagnosis) that posed future cardiovascular risk, compared with controls) [ 50 ]. For example, although 12.8% of HF cases had prevalent HF diagnoses at baseline (201/1569), over 70% of HF cases were prescribed diuretics (1122/1569). Diuretics, particularly extended use of loop diuretics, can indicate possible, pre-HF diagnoses [ 51 ], given HF diagnoses tend to be delayed in COPD patients [ 14 , 37 , 51 ]. Taking this information together, this suggests a substantial proportion of cases could have been prescribed diuretics to manage possible-yet-undiagnosed HF, in which case, the later case-defining hospitalization was the delayed, first-time diagnosis of HF.

Our results for cardiovascular medications do not imply these medications are increasing the cardiovascular risk, rather they add to an understanding of the exacerbating patient profile. Furthermore, although these medications could indicate delayed CVD diagnosis, alternatively they could be medically indicated for management of a co-morbidity we did not adjust for, e.g., beta-blockers can be prescribed for thyroid conditions [ 52 ].

Implications for clinical practice

Within the month-window following an exacerbation, largely exacerbation intensity and cardiovascular-related management and disease history were associated with odds of incident HF and AF. For HF specifically, existing type II diabetes, CKD, lung function (GOLD grade), and levels of breathlessness (MRC) had an association too—but not for AF. These factors can help better identify patients most at-risk for HF and AF, to streamline efforts to allocate screening, vigilant monitoring, and prevention.

At the time of a COPD exacerbation, particularly hospitalized exacerbation, we recommend preemptively monitoring markers of possible HF, through taking medication history of loop diuretics, [ 51 ] and through BNP testing [ 53 ]. At present however, HF prevention is narrow in scope, with guidelines for early identification of HF not explicitly considering unstable COPD [ 53 , 54 ]. Our results suggest that HF monitoring should widen to include patients with COPD exacerbations.

Upon exacerbation, particularly hospitalized exacerbation, we recommend proactively screening for AF (e.g., electrocardiogram) [ 19 ] as AF commonly presents subclinically [ 17 ]. Still, at present, AF screening is narrow in scope; it is primarily conducted in patients with existing or suspected AF with the goal of preventing stroke, with AF guidelines not explicitly considering unstable COPD [ 17 , 55 ]. Our results suggest that AF screening should widen to include patients with COPD exacerbations, to help prevent future AF—even before stroke.

Cardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding risk factors will help to target people for prevention. Future studies with the intent of improving risk prediction for HF and AF should consider exacerbations of COPD.

Availability of data and materials

Data are available on request from the CPRD. Their provision requires the purchase of a license, and this license does not permit the authors to make them publicly available to all. This work used data from the CPRD Aurum version collected in May 2022 and have clearly specified the data selected within the Methods section, and linked data in the Supplementary Materials . To allow identical data to be obtained by others, via the purchase of a license, the code lists will be provided upon request. Licenses are available from the CPRD ( http://www.cprd.com ): The Clinical Practice Research Datalink Group, The Medicines and Healthcare products Regulatory Agency, 10 South Colonnade, Canary Wharf, London E14 4PU.

Abbreviations

Chronic Obstructive Pulmonary Disease

Clinical Practice Research Datalink

• Cardiovascular Disease

General practice

Hospital Episode Statistics

Index of Multiple Deprivation

Medical Research Council

• Heart Failure
• Atrial Fibrillation

Chronic Kidney Disease

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This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data is provided by patients and collected by the National Health Service (NHS) as part of their care and support. The interpretation and conclusions contained in this study are those of the author/s alone.

This study was funded by AstraZeneca UK. CN, KR, and SM of the funding source took part in initial conceptualization and protocol design and the interpretation of results.

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JQ takes responsibility for the content of the manuscript, including the data and analysis. EG, JQ, CN, KR, and SM conceptualized the study and designed the protocol. JQ, NP and EG contributed to the development of the codelists that defined the study variables. EG, CK contributed to the methodology. EG, HW, CK and AI accessed and verified the data. EG, CK and AI were responsible for data curation and management. EG, CK were responsible for formal analysis. EG wrote the original draft of the manuscript. EG, MA, JQ contributed to the literature review and clinical implications. All authors contributed and approved the final manuscript. All authors had final responsibility for the decision to submit for publication.

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CPRD has NHS Health Research Authority (HRA) Research Ethics Committee (REC) approval to allow the collection and release of anonymized primary care data for observational research [NHS HRA REC reference number: 05/MRE04/87]. Each year CPRD obtains Section 251 regulatory support through the HRA Confidentiality Advisory Group (CAG), to enable patient identifiers, without accompanying clinical data, to flow from CPRD contributing GP practices in England to NHS Digital, for the purposes of data linkage [CAG reference number: 21/CAG/0008]. The protocol for this research was approved by CPRD’s Research Data Governance (RDG) Process (protocol number: 22_002377 ) and the approved protocol is available upon request. Linked pseudonymized data was provided for this study by CPRD. Data is linked by NHS Digital, the statutory trusted third party for linking data, using identifiable data held only by NHS Digital. Select general practices consent to this process at a practice level with individual patients having the right to opt-out.

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JQ reports grants from GlaxoSmithKline, Health Data Research UK, MRC, Asthma+Lung UK, Bayer, BI, AZ and Chiesi, outside this work and AZ for the conduct of this study. JQ has received personal fees for advisory board participation, consultancy or speaking fees from GlaxoSmithKline, Evidera, AstraZeneca, and Insmed. CN, KR, and SM are employees of AZ and hold stock and/or options in the company. HW reports grants from Health Data Research UK outside the submitted work. EG, CK, AI, and MA have nothing to disclose.

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Graul, E.L., Nordon, C., Rhodes, K. et al. Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study. BMC Pulm Med 24 , 221 (2024). https://doi.org/10.1186/s12890-024-03035-4

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Melanotic neuroectodermal tumor of infancy: a case report

• Mesfin Asefa 1 &
• Tedros Hailu 2  

Journal of Medical Case Reports volume  18 , Article number:  230 ( 2024 ) Cite this article

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Melanotic neuroectodermal tumor of infancy (MNTI) is a rare clinically benign, pigmented, tumor of neural crest origin which commonly occurs in the maxilla. It is a rare tumor that may pose difficulty in differentiating from other malignant round cell tumors.

Case presentation

A 5-month-old Ethiopian infant presented with a mass on his forehead. A wide excision of the lesion was done and subjected to histopathologic evaluation. The histologic and immunohistochemistry for synaptophysin studies confirmed that the infant was having MNTI. The patient was followed and there was no sign of recurrence at the 6th and 9th months of follow-up.

MNTI should be considered as a differential diagnosis for tumors occurring in the head region in infants and prolonged follow-up may be needed to check for possible recurrence of the tumor.

Peer Review reports

Introduction

MNTI is a rare clinically benign tumor in infants that needs to be differentiated from other malignant childhood tumors like neuroblastoma and alveolar rhabdomyosarcoma [ 1 , 2 ]. It commonly occurs in the alveolar ridges of the maxilla and less commonly in the skull and extremities [ 3 ]. Computed tomography (CT) and FNA are the choices of initial diagnosis. A histopathologic examination can confirm the diagnosis based on the findings of the two cell populations; small round cells and larger melanocyte-like cells containing dark brown pigment in a fibrillary and collagenized vascular stromal background. The treatment is wide-margin excision and follow-up for a possibility of recurrence and malignant transformation. A classic, rare, case of melanotic neuroectodermal tumor of infancy is presented and its clinical, radiological, pathological, therapeutic, and prognostic aspects are discussed.

Patient information

A 5-month-old Ethiopian male infant presented with a firm, non-tender mass on the forehead at the midline. The swelling was initially noticed at the age of one month by his mother which progressively increased in size. The child was brought to Tikur Anbesa Specialized Teaching Hospital, Addis Ababa, to the Department of Pediatrics. The pregnancy and delivery had been normal and there was no history of medication during pregnancy. The growth and development of the neonate were adequate for his age. There was not any other mass identified on physical examination and by abdominal ultrasound.

Clinical findings and diagnostic assessment

The smooth swelling measures 6 × 6 cm. The overlying skin was intact but stretched. No pulse/thrill was elicited. On palpation it was firm to hard, non-tender and non-fluctuant. The results of routine laboratory studies were within normal limits (urinary vanillylmandelic acid was not possible to determine). Plain radiographs of the skull (posteroanterior and lateral projection) and plain and contrast computed tomography (CT) of the skull were taken. The skull radiographs revealed a soft tissue swelling with sclerosis of the underlying frontal bone along the midline. Plain and contrast computed tomography (CT) of the skull showed a midline frontal (16 × 16 mm) cystic mass with peripheral reactive bone cuffing (hyperostosis) but no underlying bone defect. Dermoid cyst was entertained radiologically (Fig.  1 ). FNAC from the mass revealed small round (Neuroblast-like) cells and reported as small round cell tumor with a suggestion for biopsy confirmation.

Computed tomography showing forehead mass with peripheral bone cuffing (hyperostostic) (arrow)

Therapeutic intervention

At the age of 5 months, wide-based excision and curettage of the area down to the normal bone were done under general anesthesia. The infant tolerated the anesthetic and surgical procedures well and was discharged in good condition on the 6th postoperative day. The removed mass was subjected to histopathologic examination.

Follow-up and outcomes

Histopathologic examination of the excised tissue revealed the characteristic biphasic pattern of cell distribution: (1) smaller round cells with scanty cytoplasm and hyperchromatic nuclei in a fibrillary & vascularized fibrocollagenous background (Fig.  2 A–C) and (2) cell population consisting of larger cells with vesicular nuclei and eosinophilic cytoplasm containing brownish pigment which cluster in alveolar and pseudoglandular patterns (Fig.  2 D, E). Immunohistochemical confirmation of the tumor for neural origin in our case was also done by synaptophysin and chromogranin with control. The small round cells stained strongly for synaptophysin, except few focal areas (Fig.  3 ), and weakly stained for chromogranin. The pigmented larger cells remained pigmented in both cases. No anaplasia or mitosis was noted. This histopathologic examination of the tissue confirmed the diagnosis of MNTI. The postoperative course was uneventful. Three weeks after surgery, the patient was reevaluated and no re-growth was noted. The patient had a follow-up subsequently with no recurrence at the 6th and 9th months of visits.

Predominant small neuroblast-like cells in a collagenized stroma ( A ) (Haematoxylin & Eosin stain(H&E), × 20); High power (H&E, × 40) view of the small round neuroblast-like cells ( B ); The small round cells in a neurofibrillary background, ( window) ( C ); Small round cells & larger pigmented cells in alveolar patterns in a collagenized stromal background ( D ) (H&E, × 10); Larger pigmented cells in a pseudoglandular pattern (arrow) ( E ) (H&E, × 40)

Synaptophysin positivity in the small round cells (dark brown)

Melanotic Neuroectodermal Tumor of Infancy, also named Pigmented Neuroectodermal Tumor of Infancy, is a rare, fast-growing, locally aggressive, clinically benign neoplasm of neuroectodermal origin [ 3 , 4 , 5 ]. It was first described by Krompecher in 1918 as ‘congenital Melanocarcinoma’ thereafter different names were used till the term MNTI was coined by Borello and Gorlin after confirmation of the nature & neuroectodermal origin of the tumor by immunocytochemistry & electromicroscopic study [ 2 , 4 , 6 ]. To date, a few hundred cases have been reported in worldwide literature.

The tumor commonly occurs in ages less than one year characteristically in infants of an average age of five months, with no variation in sex, predominantly in the maxillary alveolar process(~ 70%) as a cystic mass imposing difficulty in making a distinction from dermoid cyst radiographically [ 2 , 7 , 8 ]. In tumors occurring on the skull, plain radiographs may show adjacent bone sclerosis and hyperostosis [ 8 ]. Other less commonly reported sites of occurrence include the skull (~ 10.6%), especially the temporal area, and very few cases on the anterior fontanelle area, mandible, genital organs, and lower extremities [ 7 , 8 , 9 ]. MNTI is very rarely described in adolescents [ 10 ].

The neoplasm is histologically characterized by the presence of two groups of cells in a vascularized fibrocollagenous stroma. Small round cells (neuroblast-like) in sheets and small nests and larger cells with moderate to abundant cytoplasm containing coarse dark-brown pigment which represents a CNS-type melanin according to molecular studies on similar neoplasms. These cells frequently form pseudoglandular and alveolar spaces which are characteristic of this tumor and very useful to rule out other tumors like neuroblastoma and alveolar rhabdomyosarcoma [ 8 , 11 ].

MNTI is known to recur with a reported risk of recurrence reaching 10 to 15%, especially in those where the tumor most probably was not excised completely [ 1 ]. Most recurrences occurred within the first or second month after primary surgical intervention because of incomplete (retrospectively) first resection [ 12 ]. Recurrence is reported after 3 months of the initial surgery in orbital MNTI in one case and after 4 months of the initial resection in mandibular tumor in another case [ 12 , 13 ]. There is a similar description of MNTI on the anterior fontanelle with no recurrence after 10 months of excision [ 14 ]. However, a follow-up of at least two years is recommended by some authors based on the cumulative findings in tumors occurring on the skull [ 15 ]. A primary malignant MNTI is very rare and is usually reported as a component of immature teratoma and in tumors occurring in the thigh [ 7 ]. Rare cases of skull tumors pursuing a malignant course with secondary brain invasion are described [ 8 ].

MNTI being a rare lesion poses a challenge to clinicians not only in its diagnosis but also in management. Total excision including up to 1 cm free margin is recommended without adjuvant chemotherapy or radiotherapy by most authors to achieve a cure [ 2 ].

To the best of our knowledge, this kind of tumor is the first to be reported from Ethiopia. While the most common site of the tumor is the maxillary area, the tumor in this case was on the midline of the frontal skull. The classic histologic findings and the supportive positive immunohistochemistry tests for synaptophysin and chromogranin confirm the diagnosis. The clinical and radiographic findings are also compatible with findings in other reported cases in the skull and other locations. The absence of re-growth on follow-up foretells indeed the benign nature of the tumor in this case.

Melanotic neuroectodermal tumor of infancy should be suspected by clinicians in infants presenting with head and neck tumors. A high index of suspicion is required to diagnose this tumor and should be differentiated from other round-cell tumors. Wide-margin excision is associated with a cure, but patients should be followed for possible recurrence and rare malignant transformation.

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Acknowledgements

We acknowledge the staff of the Department of Neurosurgery who participated in the care of the patient and Professor Jacob Scheinider who prepared the histologic pictures of the case.

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Department of Pathology, St. Paul’s Hospital Millennium Medical College (SPHMMC), Addis Ababa, Ethiopia

Mesfin Asefa

Department of Pediatrics, Medical Faculty, Tikur Anbesa Specialized Hospital, Addis Ababa University, Addis Ababa, Ethiopia

Tedros Hailu

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Dr.Tedros Hailu is the primary care physician of the patient before and after the surgery including follow-up of the patient. He has prepared the drafting of the clinical presentation part of the case report. Dr. Mesfin Asefa has contributed to the histopathologic diagnosis of the patient and the writing up of the final case.

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Asefa, M., Hailu, T. Melanotic neuroectodermal tumor of infancy: a case report. J Med Case Reports 18 , 230 (2024). https://doi.org/10.1186/s13256-024-04550-y

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DOI : https://doi.org/10.1186/s13256-024-04550-y

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Intracranial residual lesions following early intensification in a patient with T-cell acute lymphoblastic leukemia: a case report

• Yuichi Nagamatsu 1 ,
• Takeshi Isoda 1 , 8 ,
• Motoki Inaji 2 ,
• Jun Oyama 3 ,
• Daiki Niizato 1 ,
• Dan Tomomasa 1 ,
• Noriko Mitsuiki 1 ,
• Motoi Yamashita 1 ,
• Takahiro Kamiya 4 ,
• Kohsuke Imai 5 , 6 ,
• Hirokazu Kanegane 7 ,
• Tomohiro Morio 1 &
• Masatoshi Takagi 5  

BMC Pediatrics volume  24 , Article number:  304 ( 2024 ) Cite this article

29 Accesses

Metrics details

T-cell acute lymphoblastic leukemia (T-ALL) tends to involve central nervous system (CNS) infiltration at diagnosis. However, cases of residual CNS lesions detected at the end of induction and post early intensification have not been recorded in patients with T-ALL. Also, the ratio and prognosis of patients with residual intracranial lesions have not been defined.

Case presentation

A 9-year-old boy with T-ALL had multiple intracranial tumors, which were still detected post early intensification. To investigate residual CNS lesions, we used 11 C-methionine (MET)-positron emission tomography. Negative MET uptake in CNS lesions and excellent MRD status in bone marrow allowed continuing therapies without hematopoietic cell transplantation.

Conclusions

In cases with residual lesions on imaging studies, treatment strategies should be considered by the systemic response, direct assessment of spinal fluid, along with further development of noninvasive imaging methods in CNS. Further retrospective or prospective studies are required to determine the prognosis and frequency of cases with residual intracranial lesions after induction therapy.

Peer Review reports

Leukemia is the most common cancer in children and the involvement of the central nervous system (CNS) increases the risk of CNS relapse [ 1 ]. Risk factors of CNS leukemia include infant onset, T-cell acute lymphoblastic leukemia (T-ALL), hyperleukocytosis, and chromosomal abnormalities including KMT2A rearrangements, BCR-ABL1 , and TCF3-PBX1 [ 1 , 2 ]. These features as well as a traumatic tap at initial diagnosis also increase the risk of CNS relapse in ALL [ 1 , 2 , 3 ].

CNS status at initial diagnosis is classified as follows: CNS1, no leukemic cells in cerebrospinal fluid; CNS2, white blood cell (WBC) counts < 5/µL with leukemic cells; CNS3, WBC counts ≥ 5/µL with leukemic cells or neurological symptoms with imaging findings by computed tomography (CT) or magnetic resonance imaging (MRI) [ 4 ]. MRI is helpful to diagnose CNS leukemia in patients with neurological symptoms [ 5 , 6 ]. The percentage of CNS3 leukemia with neurological symptoms and imaging findings in newly diagnosed ALL was estimated to be less than a few percent [ 1 , 5 ].

Residual masses present in the CNS after induction or consolidation therapy are considered treatment failure (TF) [ 7 ]. TF affects later therapies, such as the decision to withdraw from protocol therapy and whether patients proceed to allogeneic hematopoietic cell transplantation (HCT) [ 7 , 8 ]. The percentage of pediatric patients with induction failure (IF), defined by leukemic cells in bone marrow (BM) or extramedullary site after induction, was 2.4% (1041/44,017 cases) [ 8 ]. Among the 1041 cases, CNS status was available for 684 cases. Of these, CNS leukemia accounted for 6% (44/684) [ 8 ]. However, the ratio and prognosis of patients with isolated CNS residual masses by imaging have not been defined.

Here, we report a patient with T-ALL who developed multiple intracranial masses at diagnosis and had remaining residual lesions detected by follow-up MRI at the end of early intensification. We decided treatment strategy based on minimal residual disease (MRD) status in BM, assessment of spinal fluid, and whether 11 C-methionine (MET) uptake in these CNS residual lesions.

A 9-year-old boy was introduced to our hospital with somnolence, slurred speech, and petechiae. A complete blood count showed marked hyperleukocytosis (WBC 760 000/μL). Flow cytometric analysis showed positivity for CD1a, CD2, CD4, CD5, CD7, CD8, cytoplasmic CD3, and terminal deoxynucleotidyl transferase. G-banding revealed a normal karyotype and multiplex polymerase chain reaction (PCR) analysis did not detect fusion genes. Taken together, we diagnosed him with T-ALL. MRI revealed multiple intracranial masses with strong signal heterogeneity consisting of hemorrhage and leukemic infiltrations, which were consistent with definition of CNS3 (Fig.  1 A and B).

Multiple central nervous system infiltrations with hemorrhages on magnetic resonance images (MRI). A and B T2-weighted and T2*-weighted image (T2*WI) MRI shows heterogeneous signals with leukemic masses and hemorrhages. Edema is observed around multiple lesions

We started pre-phase therapy consisting of prednisolone (PSL) in accordance with the Japan Leukemia/Lymphoma Study Group T11 protocol (Fig. 2 A) [ 9 ]. The number of lymphoblasts steadily decreased to 26 (< 1000)/μL in peripheral blood on day 8, and he was considered a PSL good responder (PGR) (Fig. 2 A) [ 9 ]. There was no tumor lysis syndrome under the supportive therapy including hydration and rasburicase administration. His initial symptoms including somnolence and slurred speech gradually improved a week after starting corticosteroid. On day 8, we conducted initial intrathecal therapy (IT). Lumbar puncture (LP) showed a WBC count of 2/µL with mild cellular atypia by conventional cytospin. We completed the induction phase without intracranial hemorrhage. However, the patient had grade 3 hyponatremia due to cerebral salt wasting syndrome, and required additional sodium chloride supplementation by infusion for two weeks. On day 29, he also had grade 3 muscle weakness lower limb due to vincristine or corticosteroid myopathy and skipped vincristine once.

Treatment course, serial MRI, and 11C-methionine (MET) positron emission tomography (PET). A The Japan Leukemia/Lymphoma Study Group (JPLSG) T11 high-risk protocol with treatment response and CNS evaluation by imaging studies. B T2-weighted MRI showed residual multiple lesions at the end of induction. C At the end of early intensification, T2-weighted MRI shows two representative residual lesions at the same position as in ( B ). No significant MET uptake was detected. Scale bar indicates the standardized uptake value (SUV). D MRI images were captured two months after maintenance therapy. BL, blast; BMA, bone marrow analysis; CNS, central nervous system; CRT, cranial radiation therapy; HR, high risk; MET-PET, 11 C-methionine positron emission tomography; MRD, minimal residual disease; NEL, nelarabine; IT, intrathecal; PSL, prednisolone

After day 18 of induction therapy, LP showed no evidence of malignant cells by cytospin. We did not perform flow cytometry analysis for spinal fluid in this case. The minimal residual disease (MRD) determined by PCR to monitor BM responses showed a reduction in lymphoblasts below 0.001% after induction therapy (Fig.  2 A). However, MRI revealed multiple CNS masses (Fig.  2 B). PCR-MRD for BM samples was maintained below 0.001%; however, MRI still showed multiple CNS lesions post early intensification (Fig.  2 C).

To avoid invasive approaches, including needle biopsy or surgical resection, which might cause delaying further intensification therapies, we used 11 C-methionine positron emission tomography (MET-PET) to investigate the activity of the residual lesions. MET-PET revealed no significant uptake, suggesting the low possibility of viable leukemic cells in residual regions (Fig. 2 C). Thus, we classified him as belonging to a high-risk group, but not a very high-risk group requiring HCT, and he received continued chemotherapy including intensive IT, nelarabine, and cranial radiation therapy (CRT) in accordance with the T11 protocol [ 9 ]. The follow-up MRI revealed remission immediately after the maintenance therapy (Fig. 2 D). At 18 months from the cessation of maintenance therapy and 46 months from onset, he has maintained a first remission and can attend regular school without neurological sequelae.

Discussion and conclusions

We experienced a patient with T-ALL who showed multiple residual lesions in the CNS at the end of early intensification. PGR, good PCR-MRD status in BM, and no specific uptake of MET in the CNS allowed a continuation of chemotherapy with CRT, and the avoidance of HCT.

A meta-analysis of hematologic tumors, including pediatric to adult cases with intracranial sarcomas, reported 82 cases from 1999 to 2019 [ 10 ]. The report included 66 cases of AML, 10 cases of CML, 5 cases of APL, and 4 cases of ALL. Among them, three patients with ALL were relapsed cases [ 10 ]. Only two reports showed residual intracranial lesions after the start of treatment in primary ALL, both of which were Philadelphia chromosome positive ALL [ 11 , 12 ]. The prognosis and appropriate treatment for cases of isolated residual CNS masses with excellent treatment responses in the non-CNS region have not been established because of the rarity of these cases.

The prognosis of IF in T-ALL was worse than that of B-ALL, with 10-year survival rates of 28 ± 3% and 41 ± 3%, respectively [ 8 ]. Historically, radiation therapy is beneficial for high-risk groups with T-ALL. The omission of prophylactic CRT in the T-ALL and CNS3 groups has not been established. Patients with CNS3 in the T-ALL group were ineligible in the recent AALL0434 study [ 13 ]. Taken together, chemotherapy with CRT was appropriate for our patient, even with negative MET uptake and good responses in the BM.

18 F-fluorodeoxyglucose (FDG) is involved in glucose transport in tumors and noncancerous lesions including infections, inflammation, and the brain, especially the grey matter. Instead, MET has greater specificity for brain tumors using large amino acid transporter 2 [ 14 ]. MET-PET was developed to detect brain tumors including gliomas [ 14 , 15 , 16 ]. Compared with FDG, MET has an equivalent uptake in children with Hodgkin lymphoma and non-Hodgkin lymphoma at diagnosis and follow-up [ 17 ]. Interim PET has been feasible for evaluating T-lymphoblastic lymphoma [ 18 ]. Furthermore, MET-PET has been used to determine treatment responses in CNS lymphoma [ 19 , 20 ]. Seo-Yeon et al. showed three response patterns correlated with prognosis, including low-, intermediate-, and high-risk, based on the interim tumor-to-normal tissue (T/N) ratio by MET uptake [ 19 ]. The interim T/N ratio in our patient was equivalent to the low-risk category, suggesting the low possibility of viable tumors in residual lesions.

However, there were limitations to this study. We could not perform MET-PET at onset due to his poor initial condition. If the lesion is small-scale or has low uptake of MET, it is difficult to distinguish the viability of residual tumor, which should be judged comprehensively in conjunction with other modalities. Thus, other clinical responses should be taken into account when decision-making. Finally, careful follow-up is required for our patient.

In conclusion, we experienced a patient with T-ALL and multiple residual lesions in the CNS at the end of early intensification. Further retrospective or prospective studies are required to determine the frequency of cases with intracranial residual lesions after induction therapy.

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Abbreviations

Acute lymphoblastic leukemia

Acute myeloid leukemia

Acute promyelocytic leukemia

Bone marrow

Chronic myelogenous leukemia

• Central nervous system

Cranial radiation therapy

Fluorodeoxyglucose

Hematopoietic cell transplantation

• Induction failure

Intrathecal

Lumbar puncture

• Minimal residual disease

Magnetic resonance imaging

Positron emission tomography

Polymerase chain reaction

Prednisolone good responder

Prednisolone

Treatment failure

White blood cells

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Acknowledgements

We thank the patient and his parents for participating in this study. We also thank the staff at the Department of Pediatrics, Tokyo Medical and Dental University. We thank J. Ludovic Croxford, PhD, from Edanz ( https://jp.edanz.com/ac ) for editing a draft of this manuscript.

This work was supported in part by JSPS KAKENHI Grant Number (21H02878) and Takeda Science Foundation to TI.

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Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan

Yuichi Nagamatsu, Takeshi Isoda, Daiki Niizato, Dan Tomomasa, Noriko Mitsuiki, Motoi Yamashita & Tomohiro Morio

Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan

Motoki Inaji

Department of Diagnostic Radiology, Tokyo Medical and Dental University, Tokyo, Japan

Department of Clinical Research Center, Tokyo Medical and Dental University, Tokyo, Japan

Takahiro Kamiya

Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Kohsuke Imai & Masatoshi Takagi

Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan

Kohsuke Imai

Department of Child Health and Development, Tokyo Medical and Dental University, Tokyo, Japan

Hirokazu Kanegane

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

Takeshi Isoda

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Contributions

Conception and design of study: all authors. Acquisition of data: YN, TI, MI, JO, DN, DT, NM, MY, TK. Performing MET-PET: MI. Radiographic reading: JO. Analysis and/or interpretation of data: all authors. Drafting the manuscript: YN, TI, MI, JO, HK. Revising the manuscript critically for important intellectual content: all authors. Approval of the version of the manuscript to be published: all authors.

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Correspondence to Takeshi Isoda .

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Nagamatsu, Y., Isoda, T., Inaji, M. et al. Intracranial residual lesions following early intensification in a patient with T-cell acute lymphoblastic leukemia: a case report. BMC Pediatr 24 , 304 (2024). https://doi.org/10.1186/s12887-024-04790-3

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Triglyceride-glucose index as a potential predictor for in-hospital mortality in critically ill patients with intracerebral hemorrhage: a multicenter, case–control study

• Yang Yang 1   na1 ,
• Shengru Liang 2   na1 ,
• Jiangdong Liu 1   na1 ,
• Minghao Man 3 ,
• Dengfeng Jia 1 ,
• Jianwei Li 1 ,
• Xiaoxi Tian 1   na2 &
• Lihong Li 1   na2  

BMC Geriatrics volume  24 , Article number:  385 ( 2024 ) Cite this article

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Metrics details

The correlation between the triglyceride-glucose index (TyG) and the prognosis of ischemic stroke has been well established. This study aims to assess the influence of the TyG index on the clinical outcomes of critically ill individuals suffering from intracerebral hemorrhage (ICH).

Patients diagnosed with ICH were retrospectively retrieved from the Medical Information Mart for Intensive Care (MIMIC-IV) and the eICU Collaborative Research Database (eICU-CRD). Various statistical methods, including restricted cubic spline (RCS) regression, multivariable logistic regression, subgroup analysis, and sensitivity analysis, were employed to examine the relationship between the TyG index and the primary outcomes of ICH.

A total of 791 patients from MIMIC-IV and 1,113 ones from eICU-CRD were analyzed. In MIMIC-IV, the in-hospital and ICU mortality rates were 14% and 10%, respectively, while in eICU-CRD, they were 16% and 8%. Results of the RCS regression revealed a consistent linear relationship between the TyG index and the risk of in-hospital and ICU mortality across the entire study population of both databases. Logistic regression analysis revealed a significant positive association between the TyG index and the likelihood of in-hospital and ICU death among ICH patients in both databases. Subgroup and sensitivity analysis further revealed an interaction between patients' age and the TyG index in relation to in-hospital and ICU mortality among ICH patients. Notably, for patients over 60 years old, the association between the TyG index and the risk of in-hospital and ICU mortality was more pronounced compared to the overall study population in both MIMIC-IV and eICU-CRD databases, suggesting a synergistic effect between old age (over 60 years) and the TyG index on the in-hospital and ICU mortality of patients with ICH.

Conclusions

This study established a positive correlation between the TyG index and the risk of in-hospital and ICU mortality in patients over 60 years who diagnosed with ICH, suggesting that the TyG index holds promise as an indicator for risk stratification in this patient population.

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Introduction

Spontaneous, nontraumatic, intracerebral hemorrhage (ICH) is a catastrophic disease making up approximately 10–20% of all types of stroke [ 1 ]. Epidemiological data indicate that 30% of ICH patients requiring intensive care unit (ICU) management and 40% of them die within 30 days [ 2 ]. Despite ongoing research and advancements in this medical field, effective therapeutic options for improving the prognosis of patients with ICH are still lacking [ 3 ]. Consequently, there is an urgent need to identify remediable factors that may impact the outcomes of ICH, as this information could potentially lead to the development of new therapeutic targets.

Insulin resistance (IR), a pathological condition where tissue does not respond normally to insulin stimulation, plays a crucial role in the development of metabolic disorders [ 4 ]. More importantly, studies have revealed that compared with peripheral tissue, IR appears earlier in the central nervous system, indicating that brain is more vulnerable to IR, especially under various pathological states such as ICH and ischemic stroke (IS) [ 5 ]. Therefore, the indicators associated with IR may be closely related to the initiation of ICH and its prognosis.

The triglyceride-glucose (TyG) index, consisting of fasting triglyceride (FTG) and fasting blood glucose (FBG), is a valuable tool for analyzing lipid and glucose metabolism [ 6 , 7 ]. It is also recognized as an accurate indicator of IR [ 8 , 9 ]. Some researchers have observed a positive correlation between the TyG index and the incidence and mortality rates of progressed coronary artery disease [ 10 , 11 ]. Additional studies have indicated that the TyG index may have the potential to forecast negative cardiovascular events in individuals with coronary artery disease [ 12 ]. Moreover, multiple studies have demonstrated the predictive ability of the TyG index for the onset and mortality of IS [ 13 , 14 ]. These findings collectively highlight the association of the TyG index with cardiovascular and cerebrovascular diseases. However, the relationship between ICH and the TyG index, as well as the prognostic role of the TyG index in this condition, remains unexplored.

Therefore, the objective of this study is to evaluate the impact of the TyG index on the prognosis of critically ill patients with ICH, which may establish its potential utility as a risk stratification tool in ICH cases.

Data sources

Data used in this study were extracted from the Medical Information Mart for Intensive Care (MIMIC-IV version 2.2) and the eICU Collaborative Research Database (eICU-CRD) [ 15 , 16 ]. MIMIC-IV consists of medical records between 2008 and 2019 from over 190,000 patients who were treated in various types of ICU of the Beth Israel Deaconess Medical Center. The eICU-CRD included medical records of over 200,000 patients receiving clinical management in ICUs from over 200 medical centers between 2014 and 2015. Since data in these two databases are de-identified to hide patients’ information, the informed consent and ethics approval are not essential.

Data extraction

Structure query language (SQL), executed on the PostgresSQL (version 13.7.2), was utilized for data extraction from MIMIC-IV and eICU-CRD. One researcher (Yang Yang) with authorization to access both databases (Record ID: 48,776,647) conducted the data extraction. Inclusive criteria encompassed patients who were (1) aged 18 years and above; (2) diagnosed with ICH in accordance with International Classification of Diseases, 9th and 10th Revision (ICD9 and ICD10). Exclusion criteria included: (1) patients with multiple hospitalization entries, only data from the initial hospitalization due to ICH were considered; (2) patients lacking data of FTG and FBG on the first day of ICU admittance were omitted; (3) individuals who expired or were released within 24 h of ICU admission were excluded due to their significant missing data for key variables used in the regression analysis. Therefore, excluding this group of patients was necessary to ensure the reliability of the results of the regression analysis.

The following information was extracted for the final study cohort: (1) patients’ age and gender; (2) comorbidities identified by ICD-9 and ICD-10 codes; (3) initial FBG and FTG results within 24 h post-ICU admission; (4) average values of laboratory parameters within 24 h of ICU admittance; (5) minimum Glasgow Coma Scale (GCS) score on the first day of ICU admittance; (6) maximum Acute Physiology Score III (APSIII) and Sequential Organ Failure Assessment (SOFA) scores on the first day of ICU management; (7) treatment-related data that may impact the prognosis of ICH patients were extracted, which includes invasive mechanical ventilation, the use of anticoagulants, and the use of antiplatelet agents during hospitalization.

Assessment of the TyG index

The TyG index is calculated using the formula: TyG index = ln [FTG (mg/dl) × FBG (mg/dl)/2], where FTG and FBG represent the first recorded values of FBG and FTG since ICU admission [ 17 , 18 ]. In the subsequent statistical analysis, the TyG index was considered both as a continuous and categorical variable. When treated as a categorical variable, it was divided into four groups based on quartiles. The data extraction process is illustrated in Fig.  1 .

The flow chart for extracting data from the MIMIC-IV and eICU databases

Primary outcomes

The primary outcomes of interest were all-cause in-hospital mortality and ICU mortality, which were defined as deaths occurring during hospitalization and ICU staying, respectively.

Statistical analysis

Continuous variables were expressed as median (interquartile ranges) and categorical variables were described as number (percentages). Comparisons between groups were performed by Mann–Whitney U or Kruskal–Wallis test for continuous variables, and chi-squared or Fisher’s exact test for categorical ones.

In order to investigate the relationship between the TyG index and the primary outcomes, an initial analysis utilizing restricted cubic splines (RCS) with four knots was carried out to assess any potential non-linear associations between the TyG index and the risk of in-hospital and ICU mortality. If a non-linear relationship was not detected, logistic regression analysis were performed using three different models: model 1 included only the TyG index, model 2 adjusted for age and gender, and model 3 further adjusted for various potential confounders relevant to the clinical outcomes of ICH, including GCS, hypertension, congestive heart failure, white blood cell count (WBC), serum urea nitrogen (BUN), serum creatinine, red cell distribution width (RDW), serum bilirubin, serum aspartate aminotransferase (AST), prothrombin time (PT), use of anticoagulants, and use of antiplatelet agents. Additionally, to check for multicollinearity in the logistic regression analysis, a Spearman rank correlation test was carried out and the square root of the variance inflation factor (VIF) was calculated.

To explore potential variations within specific populations, subgroup analysis was conducted by stratifying patients according to gender, age (> 60 vs. ≤ 60 years), diabetes, hypertension, use of anticoagulants, and use of antiplatelet agents. The interaction between the TyG index and the other variables utilized for stratification in subgroup analysis was evaluated through likelihood ratio test. Finally, a sensitivity analysis was performed by using Cox proportional hazard regression to verify the relationship between the TyG index and in-hospital and ICU mortality. The follow-up period was measured from the date of hospital or ICU admission to the date of death during the hospitalization or ICU stay. The Cox regression model was adjusted for possible confounders as outlined in the fully adjusted model (model 3) of logistic regression mentioned above.

All statistical analysis were performed using R software (version 4.3.1). The“VIM”package was used to visualize the distribution of missing values, from which we can see that all variables had missing ratio less than 20% (Additional file 1 : Figure S1). The “mice” package was adopted to address missing values by multiple imputation to obtain 5 imputation datasets in the process of logistic regression. Besides, the “corrplot” package was used to visualize the associations between continuous variables. The“plotRCS” package was used to perform RCS. The“forestploter” package was adopted to visualized the results of subgroup analysis. The “survminer” package was used to conduct Cox regression analysis. Statistically significant was set as a two tailed P  <  0.05 .

Baseline characteristics

A total of 791 patients from MIMIC-IV and 1,113 from eICU-CRD were included in the final analysis. Among them, 418 (53%) individuals in MIMIC-IV and 627 (56%) in eICU-CRD were male. The in-hospital mortality rates were 14% in MIMIC-IV and 16% in eICU-CRD, with ICU mortality rates of 10% and 8% respectively. The median age was 72.25 (60.63, 82.59) years in MIMIC-IV and 66 (55, 77) years in eICU-CRD. Besides, the average value of TyG index was 8.72 (8.38, 9.17) in MIMIC-IV and 8.76 (8.33, 9.21) in eICU-CRD.

When dividing participants into groups based on the quartiles of the TyG index, patients in the upper quartiles had significantly higher APSIII scores, and higher proportion of invasive ventilation than those in the lower quartiles ( P  <  0.001 for all ). Furthermore, hospital stay time, ICU stay time, in-hospital mortality, and ICU mortality all exhibited a gradual increase from the first to the fourth quartile of the TyG index. However, there was no significant difference in the mean hospital and ICU survival time of patients who died in the hospital or ICU across the quartiles of the TyG index. (Table  1 and Additional file 2 : Table S1).

Baseline data of participants divided by the hospital and ICU outcomes are presented in Table  2 and Additional file 3 : Table S2, respectively. Compared to in-hospital and ICU survivors, non-survivors in both the MIMIC-IV and eICU-CRD databases showed significantly higher APSIII and SOFA scores, shorter hospital stays, and a higher proportion of invasive ventilation. However, compared to in-hospital and ICU survivors, ICU stay time was shorter in non-survivors from eICU-CRD and longer in non-survivors from MIMIC-IV. Furthermore, GCS scores were lower in in-hospital and ICU non-survivors compared to survivors in eICU-CRD, but there was no significant difference in GCS scores between in-hospital and ICU survivors and non-survivors in MIMIC-IV. Interestingly, despite the potential risk of secondary hemorrhage associated with antiplatelet agents, their usage was more common among in-hospital and ICU non-survivors than survivors in MIMIC-IV. Moreover, the TyG index was notably higher in the in-hospital non-survivors compared to survivors (MIMIC-IV: 8.94 (8.51–9.48) vs. 8.70 (8.36–9.09); P  <  0.001 . eICU-CRD: 8.98 (8.51–9.49) vs. 8.70 (8.31–9.16); P  <  0.001 ). Similarly, the TyG index was significantly elevated in ICU non-survivors in contrast to ICU survivors (MIMIC-IV: 9.00 (8.51–9.48) vs. 8.70 (8.36–9.10); P  < 0.001. eICU-CRD: 9.09 (8.76–9.65) vs. 8.71 (8.31–9.17); P  < 0.001) (Additional file 4 : Figure S2).

Association between the TyG index and the primary outcomes

We initially conducted a nonlinear correlation analysis between the TyG index and the primary outcomes using RCS. Findings suggested no significant nonlinear correlation between the TyG indicator and the likelihood of either in-hospital or ICU mortality (In-hospital mortality: P for nonlinear  =  0.751 in MIMIC-IV , P for nonlinear  =  0.562 in eICU-CRD. ICU mortality: P for nonlinear  =  0.986 in MIMIC-IV , P for nonlinear  =  0.431 in eICU-CRD) (Fig.  2 ). Subsequently, logistic regression analysis was conducted to assess the linear relationship between the TyG index and the primary outcomes. In the fully adjusted model (model 3) that adjusted for various potential confounders related to the clinical outcomes of ICH, a positive correlation was found between the TyG index and the risk of in-hospital mortality (MIMIC-IV: OR 1.75 [95%CI 1.20–2.52], P  =  0.003 . eICU-CRD: OR 1.37 [95%CI 1.05–1.80], P  <  0.001 ) and ICU mortality (MIMIC-IV: OR 2.15 [95%CI 1.45–3.17], P  <  0.001. eICU-CRD: OR 1.61 [95%CI 1.13–2.27], P  <  0.001 ). Moreover, compared to the first quartile (Q1) of the TyG index, the results of model 3 indicated that the fourth quartile (Q4) was linked to a higher risk of in-hospital mortality (MIMIC-IV: OR 2.31 [95%CI 1.18–4.67], P  =  0.017 . eICU-CRD: 1.73 [95%CI 1.02–3.06], P  =  0.036 ) and ICU mortality (MIMIC-IV: OR 3.24 [95%CI 1.54–7.11], P  =  0.002 . eICU-CRD: 2.30 [95%CI 1.09–5.16], P  =  0.034 ) (Table 3 , Additional file 5 : Table S3).

Restricted cubic spline analysis for the nonlinear association between the TyG index and the risk of, A  in-hospital mortality of ICH patients from MIMIC-IV; B  ICU mortality of ICH patients from MIMIC-IV; C  in-hospital mortality of ICH patients from eICU-CRD; D  ICU mortality of ICH patients from eICU-CRD

To assess multicollinearity in the logistic regression model, the Spearman rank correlation coefficient and VIF were calculated, respectively. Findings revealed that there was no linear correlation between the TyG index and the other continuous variables incorporated in model 3 (Additional file 6 : Figure S3). Additionally, none of the variables in model 3 exhibited a square root of VIF ≥ 2 (data not shown). Taken together, these results suggest that there is no multicollinearity present in the logistic regression model, indicating the reliability of the results.

Subgroup analysis

To investigate potential variations within specific populations, logistic regression analysis was conducted across various subgroups, including gender, age, diabetes, hypertension, use of anticoagulant agents, and use of antiplatelet agents. The forest plot revealed a significant positive correlation between the TyG index and in-hospital mortality among participants over 60 years (MIMIC-IV: OR 2.58 [95%CI 1.92–4.27], P  =  0.005 . eICU-CRD: OR 1.56 [95%CI 1.10–2.22], P  =  0.019 ), those without diabetes (MIMIC-IV: OR 2.20 [95%CI 1.34–3.57], P  =  0.002 . eICU-CRD: OR 1.69 [95%CI 1.18–2.41], P  =  0.004 ), and those with hypertension (MIMIC-IV: OR 1.97 [95%CI 1.28–3.01], P  =  0.002 . eICU-CRD: OR 1.84 [95%CI 1.28–2.99], P  =  0.014 ). Similarly, there was a positive association for ICU mortality in patients over 60 years (MIMIC-IV: OR 3.86 [95%CI 1.31–6.99], P  <  0.001 . eICU-CRD: OR 1.70 [95%CI 1.23–2.90], P  =  0.036 ), those without diabetes (MIMIC-IV: OR 2.62 [95%CI 1.56–4.40], P  <  0.001 . eICU-CRD: OR 2.10 [95%CI 1.34–3.32], P  =  0.001 ), and those with hypertension (MIMIC-IV: OR 2.44 [95%CI 1.54–3.84], P  <  0.001 . eICU-CRD: OR 1.83 [95%CI 1.13–2.97], P  =  0.013 ). Furthermore, in both MIMIC-IV and eICU-CRD, significant interactions were found between the TyG index and patients' age, diabetic status, and history of hypertension concerning in-hospital and ICU outcomes of individuals with ICH ( P for interaction  <  0.05 for all) (Figs. 3 and 4 ).

Subgroup analysis for the correlation between the TyG index and the risk of in-hospital mortality in patients with ICH from MIMIC-IV and eICU-CRD databases

Subgroup analysis for the correlation between the TyG index and the risk of ICU mortality in patients with ICH from MIMIC-IV and eICU-CRD databases

Sensitivity analysis

To further verify the association between the TyG index and in-hospital and ICU mortality, as well as the significant interactions between the TyG index and patients' age regarding in-hospital and ICU outcomes, a sensitivity analysis was performed using Cox proportional hazard regression. Following fully adjusted, a positive correlation was observed between the TyG index and the risk of in-hospital mortality in ICH patients from both MIMI-IV and eICU-CRD datasets. The positive association between the TyG index and in-hospital and ICU mortality was also present in patients over 60 years old, those without diabetes, and those with hypertension in both databases. Importantly, significant interactions were only found between patients' age and the TyG index concerning in-hospital and ICU outcomes of ICH patients in both MIMIC-IV and eICU-CRD datasets (Table  4 and Additional file 7 : Table S4). These findings collectively suggest that the TyG index has the potential to serve as a prognostic indicator for ICH in patients over 60 years of age.

In this retrospective multicenter study, the impact of the TyG index on the prognosis of critically ill patients with ICH was evaluated, uncovering two important findings. Firstly, a positive correlation was found between the TyG index and the risk of in-hospital and ICU all-cause mortality in ICH patients. Secondly, this correlation was notably stronger in patients over 60 years old, especially in those with hypertension or lacking diabetes.

The association between the TyG index and the course of IS has been extensively studied. Wang et al. reported that individuals in the highest quartile of the TyG index face a 1.45 times greater risk of developing IS compared to those in the lowest quartile [ 19 ]. Results from a 9-year prospective study showed that keeping TyG index elevated was strongly related to an increased morbidity of IS, suggesting that monitoring and regulating the TyG index at an appropriate level could be beneficial in preventing IS [ 20 ]. Additionally, various studies have explored the capability of the TyG index in predicting the outcome of IS. Lee and colleagues found that the TyG index could forecast an adverse functional outcome three months post-reperfusion in IS patients [ 21 ]. Yang et al. noted a correlation between higher TyG index and elevated rates of both recurrence and mortality within one year following an IS event [ 22 ]. In critically ill patients, Cai W et al. found that the TyG index may assist in identifying IS patients at high risk of all-cause mortality [ 14 ]. Despite these findings highlight the significant relationship between the TyG index and IS as well as its prognosis, research on the association between the TyG index and ICH remains scarce.

To address this gap in knowledge, we conducted this study and found a positive correlation between the TyG index and the likelihood of either in-hospital or ICU mortality in individuals with ICH. The positive correlation persisted even after adjusting for potential confounders, suggesting that the TyG index could serve as an independent predictor of hospitalization outcomes in patients with ICH, potentially aiding clinicians in their decision-making process. More importantly, subgroup analysis revealed that there is a synergistic effect of old age (over 60 years), hypertension, and non-diabetic status on the TyG index’s impact on hospitalization outcomes in patients with ICH. Sensitivity analysis using Cox regression model further confirmed the synergistic effect between old age (over 60 years) and the TyG index on the in-hospital and ICU mortality of ICH patients in both MIMIC-IV and eICU-CRD databases. These results underscored the population-specific influence of the TyG index on ICH prognosis, highlighting the importance of focusing on elderly patients with ICH.

The exact mechanisms connecting the TyG index with the poor prognosis of ICH are still unclear, but evidence supports a key role of IR in this process. Patients with IR are more susceptible to hyperglycemia. A study has found that hyperglycemia could inhibit the expression of Aquaporin-4, resulting in the aggravation of vasogenic brain edema and blood–brain barrier (BBB) destruction [ 23 ]. Autophagy is a vital cellular process for maintaining homeostasis, but hyperglycemia can decrease autophagic activity in the brain during ICH, leading to the accumulation of macromolecular debris and damaged cells, ultimately causing neuronal injury [ 24 ]. In stoke rat treated with type plasminogen activator, hyperglycemia could enhance superoxide production in brain tissue and blood vessels, increasing BBB permeability in the peri-ischemic area and leading to a 3- to fivefold rise in the volume of secondary hemorrhage after thrombolysis [ 25 ]. This finding establishes a link between hyperglycemia-induced superoxide production and the increased risk of hematoma expansion in IS. The generation of reactive oxygen species has been demonstrated during ICH [ 26 , 27 ]. Moreover, studies have shown that an increase in blood glucose can exacerbate hematoma expansion in a rat model of ICH [ 28 ]. Therefore, it is plausible to infer that IR related hyperglycemia may result in poor outcomes of ICH by promoting superoxide production, thereby increasing the risk of hematoma expansion.

Adequate cerebral perfusion is crucial for determining the prognosis of patients with ICH. The automatic regulation ability of cerebral blood vessels plays a significant role in maintaining appropriate cerebral perfusion during cerebral hemorrhage. Studies have indicated that elevated intracranial pressure in patients with acute ICH can impair cerebrovascular autoregulation within a two-week period [ 29 ]. The myogenic response, which refers to the ability of smooth muscle cells to react to changes in blood pressure, is essential for preserving cerebrovascular autoregulation [ 30 ]. Animal studies have proved that IR can heighten the tension of cerebrovascular myogenic response, leading to a reduction in the diameter of the cerebrovascular lumen, subsequently causing brain tissue ischemia and nerve cell injury [ 31 ]. In addition, the smooth muscle activity of distal cerebral arteries is notably higher than that of proximal ones, making them more vulnerable to IR and resulting in impaired cerebral circulation function [ 30 ].

Chronic inflammatory response is one pathogenesis of IR, and IR in turn can reflect the level of systemic inflammation in the body [ 32 ]. Interestingly, our study revealed a gradual increase in WBC across quartile intervals of the TyG index, with values exceeding the upper limit of the reference range in the fourth quartile, suggesting an escalation of systemic inflammation during the course of ICH in patients with IR. Furthermore, the integrity of BBB was compromised during ICH, allowing the infiltration of peripheral immune cells and pro-inflammatory cytokines into the central nervous system. This heightened inflammatory response in the brain can further compromise the BBB, creating a detrimental cycle [ 33 ]. In addition, study has shown that dysregulation of the insulin signaling pathway can activate NF-κB, leading to the transcription and expression of inflammatory factors in the brain, thereby exacerbating neuroinflammation [ 34 ].

Intriguingly, although the evidence presented supports the significant role of IR in linking the TyG index to the unfavorable prognosis of intracerebral hemorrhage (ICH), our study found no correlation between the TyG index and either in-hospital or ICU mortality in ICH patients with a history of diabetes, a group known to have a higher risk of IR compared to non-diabetic individuals. Explaining the cause of this paradox is challenging. One potential reason could be reverse causality [ 14 , 35 ], where patients diagnosed with diabetes may be more likely to accept appropriate treatment or adopt healthy lifestyle habits. This could lead to their analytical parameters being similar to or even lower than those of non-diabetic counterparts. Consistent to this theory, in our study, no significant differences were observed in FBG, FTC, and TyG indexes between diabetic and non-diabetic individuals in both the MIMC-IV and eICU-CRD study cohorts (TyG index: 8.71 (8.38, 9.17) vs 8.77 (8.39, 9.14), P  = 0.673 for MIMIC-IV. 8.75 (8.34, 9.22) vs 8.78 (8.3, 9.17), P  = 0.925 for eICU-CRD). Additionally, as diabetic patients may have adopted a healthier lifestyle than their non-diabetic counterparts, their prognosis might be improved in subgroup analyses stratified by diabetes status.

The hyper-insulinemic-euglycemic clamp is considered the most accurate method for detecting IR, but its practicality is limited due to high costs, time-consuming procedures, and invasiveness. The homeostasis model assessment index for IR (HOMA-IR) is commonly used in clinical settings to assess beta-cell function and detect IR [ 36 ]. Nevertheless, its applicability is restricted in patients undergoing insulin therapy or those with ineffective beta cells [ 37 ]. Besides, HOMA-IR relies on measuring insulin levels, which are not routinely checked in clinical practice. Therefore, researchers have introduced the TyG index as a potentially reliable and cost-effective alternative marker for IR. Using hyper-insulin-normoglycemia clamp technique as the gold standard, a study showed excellent predictive efficiency of the TyG index for IR, with sensitive and specificity of 96.5% and 85.0%, respectively [ 8 ]. David and colleagues also demonstrated that the TyG index outperforms FBG and FTG in diagnosing type 2 diabetes and monitoring its progression [ 38 ]. Given that FBG and FTG measurements are available in most healthcare facilities, the TyG index has the potential to be widely utilized in blood glucose management and could serve as a valuable tool for risk assessment in patients with ICH.

The study has several limitations. First, the location and volume of hemorrhage, which are crucial factors influencing the prognosis of ICH, could not be extracted from the databases. Therefore, future research should incorporate these indicators to further validate the current findings. Secondly, specific population such as the Chinese or African are scarce in the study cohort. Consequently, the conclusions derived from this study should be cautiously interpreted in these population. Thirdly, the impact of dynamic changes in the TyG index on the prognosis of ICH patients was not assessed in this study. Given that variability in the TyG index has been linked to the incidence of IS [ 20 ], further studies are needed to investigate the cumulative effect of the TyG index on the incidence and outcome of ICH. Fourthly, exclusion of patients without FTG and FBG data on the first day of ICU admission may introduce bias if the missing data pattern is not completely random. Last but not the least, the utilization of propofol, fibrate, and glucose, along with insulin infusion prior to hospitalization, could have a notable effect on FTG and FBG levels. Nevertheless, neither MIMIC-IV nor eICU-CRD databases contains information on pre-hospitalization medications. Therefore, further investigation is required to confirm the current findings by incorporating these treatment-related information before ICU admission.

This study identified a positive correlation between the TyG index and in-hospital as well as ICU all-cause mortality in patients with ICH, particularly among individuals aged over 60 years with a history of hypertension. The findings indicate that the TyG index may be a useful tool for risk stratification in elderly patients with ICH, assisting clinicians in identifying high-risk individuals and providing timely intervention.

Availability of data and materials

The available data for MIMIC-IV can be accessed from the website https://mimic.physionet.org/ . The available data for eICU-CRD can be accessed from the website https://eicu-crd.mit.edu/ . The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Acute Physiology Score III

Serum aspartate aminotransferase

Blood–brain barrier

Serum urea nitrogen

The eICU Collaborative Research Database

Fasting blood glucose

Fasting triglyceride

Glasgow coma scale

The homeostasis model assessment index for IR

International Classification of Diseases

• Intensive care unit
• Intracerebral hemorrhage

Insulin resistance

Ischemic stroke

The Medical Information Mart for Intensive Care

Odds ratios

Prothrombin time

Restricted cubic spline

Red cell distribution width

Sequential Organ Failure Assessment

Structure Query Language

Triglyceride glucose index

Variance inflation factor

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Acknowledgements

The present study utilized data from the MIMIC-IV and eICU database. We express our gratitude to all the staff and patients who contributed to the development of the MIMIC-IV and eICU database.

This research was supported by Innovation Science Fund of Tangdu hospital, China (No. 2023BTDQN001), Shaanxi Province Key Research and Development Plan Project (2024SF-YBXM-210), and Air Force Medical University Clinical Research Program (2023LC2319).

Author information

Yang Yang, Shengru Liang and Jiangdong Liu contribute equally to this work and are co-first authors.

Lihong Li and Xiaoxi Tian contributed equally to this work and are co-corresponding authors.

Authors and Affiliations

Department of Emergency, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China

Yang Yang, Jiangdong Liu, Yue Si, Dengfeng Jia, Jianwei Li, Xiaoxi Tian & Lihong Li

Department of Endocrinology, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China

Shengru Liang

Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China

Minghao Man

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Contributions

YY extracted data from MIMIC-IV and eICU-database, analyzed the data, and wrote the original draft. SL conducted literature review, analyzed the data, and wrote the original draft. JDL conducted literature review, and operated software. MM and DJ organized the data and checked the integrity of the data. YS and JWL assisted in statistical analysis. XT designed the study, and checked the final results. LL designed the study, conceptualized the research aims, and revised the paper. All authors have made an intellectual contribution to the manuscript and approved the final submission.

Corresponding author

Correspondence to Lihong Li .

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Ethics approval and consent to participate.

The study was conducted in accordance with the guidelines of the Helsinki Declaration. As the MIMIC-IV and the eICU-CRD database are publicly available and all data are de-identified to remove patients’ information, the requirement for informed consent of patients is not essential.

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Not applicable.

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The authors declare no competing interests.

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Supplementary Information

Additional file 1: figure s1..

The proportion and distribution of missing data for variables in (A) MIMIC-IV database and (B) eICU-CRD database.

Additional file 2.

Additional file 3., additional file 4: figure s2..

The boxplot of the TyG index stratified by the in-hospital and ICU outcomes. (A) The level of the TyG index in hospital survivors and non-survivors from the MIMIC-IV database. (B) The level of the TyG index in hospital survivors and non-survivors from the eICU-CRD database. (C) The level of the TyG index in ICU survivors and non-survivors from the MIMIC-IV database. (D) The level of the TyG index in ICU survivors and non-survivors from the eICU-CRD database.

Additional file 5.

Additional file 6: figure s3..

The correlation between continuous variables in the cohort derived from (A) MIMIC-IV and (B) eICU-CRD.

Additional file 7.

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Yang, Y., Liang, S., Liu, J. et al. Triglyceride-glucose index as a potential predictor for in-hospital mortality in critically ill patients with intracerebral hemorrhage: a multicenter, case–control study. BMC Geriatr 24 , 385 (2024). https://doi.org/10.1186/s12877-024-05002-4

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Received : 07 March 2024

Accepted : 22 April 2024

Published : 01 May 2024

DOI : https://doi.org/10.1186/s12877-024-05002-4

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