Response to: Hand acceleration time (HAT) as a diagnostic tool in the assessment of haemodialysis access-induced distal ischaemia (HAIDI): study protocol for a prospective cohort study in the Barcelona south metropolitan area, by Gonzalez et al.
Reshabh Yadav MD PhD 1, Marc R.M. Scheltinga MD PhD
Department of Surgery, Máxima Medical Center, Veldhoven, The Netherlands
To the Editor,
We congratulate Gonzalez et al. with their research protocol on HAT (hand acceleration time) in end stage renal disease (ESRD) patients requiring a haemodialysis access (1). They propose to conduct a study based on the assumption that HAT assessed by duplex ultrasound (DUS) reflects the vascular status of an arm. Aim is to quantify HAT before and after haemodialysis access construction and to determine whether pre- and postoperative HAT values can predict haemodialysis access-induced distal ischemia (HAIDI).
Based on our experience with HAIDI, some aspects of the protocol are worthwhile commenting on:
HAIDI in relation to ‘steal’.
Earlier studies suggested that HAIDI is caused by reversal of blood flow (‘steal’) that is shunted away from the hand (‘stolen from the hand’) due to the presence of an arteriovenous connection as in a vascular access for haemodialysis. On the contrary, steal is a phenomenon that has no pathophysiological significance related to HAIDI (2). The authors justifiably conclude that ESRD patients who often have diabetes melli...
Response to: Hand acceleration time (HAT) as a diagnostic tool in the assessment of haemodialysis access-induced distal ischaemia (HAIDI): study protocol for a prospective cohort study in the Barcelona south metropolitan area, by Gonzalez et al.
Reshabh Yadav MD PhD 1, Marc R.M. Scheltinga MD PhD
Department of Surgery, Máxima Medical Center, Veldhoven, The Netherlands
To the Editor,
We congratulate Gonzalez et al. with their research protocol on HAT (hand acceleration time) in end stage renal disease (ESRD) patients requiring a haemodialysis access (1). They propose to conduct a study based on the assumption that HAT assessed by duplex ultrasound (DUS) reflects the vascular status of an arm. Aim is to quantify HAT before and after haemodialysis access construction and to determine whether pre- and postoperative HAT values can predict haemodialysis access-induced distal ischemia (HAIDI).
Based on our experience with HAIDI, some aspects of the protocol are worthwhile commenting on:
HAIDI in relation to ‘steal’.
Earlier studies suggested that HAIDI is caused by reversal of blood flow (‘steal’) that is shunted away from the hand (‘stolen from the hand’) due to the presence of an arteriovenous connection as in a vascular access for haemodialysis. On the contrary, steal is a phenomenon that has no pathophysiological significance related to HAIDI (2). The authors justifiably conclude that ESRD patients who often have diabetes mellitus and/or severe atherosclerosis may develop HAIDI due to an impaired arterial remodeling capacity leading to a gradual loss of perfusion pressures down the arm towards the hand (2). Interestingly, one study found that all patients who developed HAIDI following vascular access construction were preoperatively found to have a single-artery dominant hand perfusion pattern indicating a compromised collateralization (3).
The role of finger plethysmography.
It has been demonstrated that abnormal digital brachial indices (<0.8 or >1.0) in ESRD patients prior to haemodialysis access construction are associated with lower 2-year access patency rates and increased cardiovascular related mortality (4). A minimal 40-mm Hg drop in finger pressure during a preoperative modified Allen Test yielded a 10 times greater risk of developing HAIDI later on (3). It may be worthwhile for the authors to include finger plethysmography in their research protocol.
A 6 month time frame for diagnosing chronic HAIDI is (too) short.
An earlier study found that time of onset in HAIDI is related to the access type. Acute HAIDI (within 1 day after access construction) is most often due to upper arm graft insertion. Subacute HAIDI (between 1-30 days after surgery) is four times more frequently observed following native HD accesses compared to non-autogenous HD accesses. However, (sub)acute types of HAIDI are rare. In contrast, the majority of HAIDI patients develop hand ischemia much later (5). One study reported severe HAIDI requiring invasive treatment after 16 ± 3 months following access construction (5). It is mandatory to observe patients at risk for HAIDI for a minimal 2-year time period.
Hand ischemic questionnaire as an objective diagnostic tool.
Symptoms of HAIDI are coldness, pain, and cramps. Severity and frequency of these ischemic symptoms can be assessed by a validated questionnaire (6). Ischemic scores reflected severity of ischemia and may be used to monitor efficacy of surgery aimed at reversing hand hypoperfusion (7). The authors may want to consider the use of this questionnaire as a monitoring tool.
Looking forward to the results of this interesting study.
Sincerely,
Reshabh Yadav, MD PhD
Marc R. M. Scheltinga MD PhD
References
1. Gonzalo B, Videla S, Espinar E, Palacios S, Herranz C, Iborra Ortega E. Hand acceleration time (HAT) as a diagnostic tool in the assessment of haemodialysis access-induced distal ischaemia (HAIDI): study protocol for a prospective cohort study in the Barcelona south metropolitan area. BMJ Open. 2025 Jan 2;15(1).
2. Scheltinga MRM, Bruijninckx CMA. Haemodialysis access-induced distal ischaemia (HAIDI) is caused by loco-regional hypotension but not by steal. Eur J Vasc Endovasc Surg. 2012 Feb;43(2):218–23.
3. Yadav R, Gerrickens MWM, Teijink JAW, Scheltinga MRM. Systolic finger pressures during an Allen test before hemodialysis access construction predict severe postoperative hand ischemia. J Vasc Surg. 2021 Dec;74(6):2040–6.
4. Yadav R, Gerrickens MWM, Teijink JAW, Scheltinga MRM. Abnormal preoperative digital brachial index is associated with lower 2-year arteriovenous fistula access patency. J Vasc Surg. 2021 Jul;74(1):237–45.
5. Scheltinga MRM, van Hoek F, Bruijninckx CMA. Time of onset in haemodialysis access-induced distal ischaemia (HAIDI) is related to the access type. Nephrol Dial Transplant. 2009 Oct;24(10):3198–204.
6. van Hoek F, Scheltinga MRM, Kouwenberg I, Moret KEM, Beerenhout CH, Tordoir JHM. Steal in hemodialysis patients depends on type of vascular access. Eur J Vasc Endovasc Surg. 2006 Dec;32(6):710–7.
7. van Hoek F, Scheltinga MRM, Luirink M, Pasmans H, Beerenhout C. Banding of hemodialysis access to treat hand ischemia or cardiac overload. Semin Dial. 2009;22(2):204–8.
Following the publication of the original article, it has come to the authors’ attention that the timing of the analysis was still based on the wording of the original funding application, and had not been updated prior to publication of the trial protocol paper.
The original funding application where both the short- and long-term outcomes were deemed as co-primary outcomes and as such would have been analysed at study end. At point of funding by the NIHR, we were requested to consider only the short-term outcome to be the primary outcome, and as such the timing of the analysis should have been changed so that short term outcomes were analysed first and longer-term outcomes after 2 years post-partum. The analysis plan was adjusted at that time, according to the NIHRs request.
The article currently states (under the Main analysis section) that: “All analyses will be undertaken after database lock following data collection at 2 years.”
However, the wording in this section should read: “Analysis of the short-term outcomes will be carried out after database lock following data collection at birth. The longer-term outcomes will be analysed after database lock following data collection at 2 years post-partum.”
To ensure that knowledge of the short-term outcomes will not impact the scientific integrity of the longer-term outcomes, we will continue to adhere to strict retention protocols to follow up the mothers at 2 years for the longer-term health...
Following the publication of the original article, it has come to the authors’ attention that the timing of the analysis was still based on the wording of the original funding application, and had not been updated prior to publication of the trial protocol paper.
The original funding application where both the short- and long-term outcomes were deemed as co-primary outcomes and as such would have been analysed at study end. At point of funding by the NIHR, we were requested to consider only the short-term outcome to be the primary outcome, and as such the timing of the analysis should have been changed so that short term outcomes were analysed first and longer-term outcomes after 2 years post-partum. The analysis plan was adjusted at that time, according to the NIHRs request.
The article currently states (under the Main analysis section) that: “All analyses will be undertaken after database lock following data collection at 2 years.”
However, the wording in this section should read: “Analysis of the short-term outcomes will be carried out after database lock following data collection at birth. The longer-term outcomes will be analysed after database lock following data collection at 2 years post-partum.”
To ensure that knowledge of the short-term outcomes will not impact the scientific integrity of the longer-term outcomes, we will continue to adhere to strict retention protocols to follow up the mothers at 2 years for the longer-term health and development outcomes of the child. In addition, we believe that there is no risk of the long-term outcomes being affected by the knowledge of the short-term outcomes as data collection is via a survey completed by the mothers on the health and development of the child.
This clarification has been approved by the Trial Steering Committee.
This rapid response correction is submitted whilst recruitment to the trial is still ongoing.
Yours sincerely,
Dr Rebecca Cannings-John, on behalf of the TRUFFLE 2 Trial Management Group
The study protocol by Zaman et al describes PAK-SEHAT as the research initiative for investigating premature atherosclerotic cardiovascular disease (ASCVD) in Pakistan. The research targets an important knowledge gap in cardiovascular healthcare research for South Asia because its CVD prevalence continues to increase in populations with low-to-middle income status.
Several comments arise from our reading of the research. The research identifies “young adults” as very mature males who are younger than 60 and very mature females who are younger than 65 years but this definition goes beyond the typical age range of 18–44 years [1]. The expanded population inclusion might dim the line separating early and conventional ASCVD manifestation.
CCTA along with CIMT serves as an effective method to detect subclinical plaques in patients [2]. These expensive diagnostic tests represent a major barrier that affects the system-wide implementation of public health screening and intervention programs in Pakistan.
Excluding participants with BMI higher than 40 kg/m² or eGFR lower than 60 ml/min/1.73m² may unintentionally exclude persons at high risk from the study. People with South Asian origins who have metabolic syndrome or renal impairment tend to develop ASCVD at an earlier stage according to research [3] and their removal from the study might diminish the application of study findings to wider populations.
The protocol states it will recruit nationally in P...
The study protocol by Zaman et al describes PAK-SEHAT as the research initiative for investigating premature atherosclerotic cardiovascular disease (ASCVD) in Pakistan. The research targets an important knowledge gap in cardiovascular healthcare research for South Asia because its CVD prevalence continues to increase in populations with low-to-middle income status.
Several comments arise from our reading of the research. The research identifies “young adults” as very mature males who are younger than 60 and very mature females who are younger than 65 years but this definition goes beyond the typical age range of 18–44 years [1]. The expanded population inclusion might dim the line separating early and conventional ASCVD manifestation.
CCTA along with CIMT serves as an effective method to detect subclinical plaques in patients [2]. These expensive diagnostic tests represent a major barrier that affects the system-wide implementation of public health screening and intervention programs in Pakistan.
Excluding participants with BMI higher than 40 kg/m² or eGFR lower than 60 ml/min/1.73m² may unintentionally exclude persons at high risk from the study. People with South Asian origins who have metabolic syndrome or renal impairment tend to develop ASCVD at an earlier stage according to research [3] and their removal from the study might diminish the application of study findings to wider populations.
The protocol states it will recruit nationally in Pakistan although it fails to clarify appropriate representation of every province and ethnic groups and socioeconomic backgrounds. The study requires clarification about population sampling across different regions since cardiovascular health risks differ between areas [4]. This information helps prevent vital subgroup differences from being neglected.
The research depends on single-site data collection and industrial sponsorship which creates issues about research diffusion across diverse settings and possible funding-related biases. Research in public health achieves its best outcomes when an independent assessment maintains strong transparency standards and preserves public trust [5].
The PAK-SEHAT initiative holds great importance to us so we look forward to seeing how our proposals can improve both its application and its impact.,
Sincerely,
Zunaira Kiran, Umaimah Mirza, Imteshal Sarfaraz
Comments related to the findings reported by Warrington and Holm regarding the use of Artificial Intelligence (AI) by UK General Medical Council (GMC) registered doctors (Warrington DJ, Holm S. BMJ Open 2024;14:e089090. doi:10.1136/bmjopen-2024-089090).
A key observation regarding the study is its apparent lack of distinction between participants' use of regulated AI products (classified as medical devices) and non-regulated AI tools (such as general-purpose LLMs). The wide range of respondent specialties reported further highlights this potential issue; for instance, clinicians in radiology or pathology are more likely to encounter regulated, task-specific AI, whereas those in public health or psychiatry might be more likely to experiment with non-regulated, general-purpose models.
During the review process, I used Gemini Advanced (specifically, the model designated by the user as 2.5 Pro Experimental) to assist with processing screenshots of table1, table 2 and fig 1 into spreadsheet processable data. The same Large Language Model (LLM) was also prompted to categorize the clinical risks associated with the AI uses listed in Figure 1 of the original paper. The author is of the opinion that the LLM’s risk categorisation (column 2 in table A below) adopted a patient-centric perspective.
However, the author is of the opinion that a "composite" clinical risk assessment, which considers both the nature of the specific usage instance and the pot...
Comments related to the findings reported by Warrington and Holm regarding the use of Artificial Intelligence (AI) by UK General Medical Council (GMC) registered doctors (Warrington DJ, Holm S. BMJ Open 2024;14:e089090. doi:10.1136/bmjopen-2024-089090).
A key observation regarding the study is its apparent lack of distinction between participants' use of regulated AI products (classified as medical devices) and non-regulated AI tools (such as general-purpose LLMs). The wide range of respondent specialties reported further highlights this potential issue; for instance, clinicians in radiology or pathology are more likely to encounter regulated, task-specific AI, whereas those in public health or psychiatry might be more likely to experiment with non-regulated, general-purpose models.
During the review process, I used Gemini Advanced (specifically, the model designated by the user as 2.5 Pro Experimental) to assist with processing screenshots of table1, table 2 and fig 1 into spreadsheet processable data. The same Large Language Model (LLM) was also prompted to categorize the clinical risks associated with the AI uses listed in Figure 1 of the original paper. The author is of the opinion that the LLM’s risk categorisation (column 2 in table A below) adopted a patient-centric perspective.
However, the author is of the opinion that a "composite" clinical risk assessment, which considers both the nature of the specific usage instance and the potential scale of patient impact arising from a flawed AI output (e.g., contrasting the impact of an error in analyzing an individual patient's test results with that of disseminating flawed guidance derived from an AI-assisted literature review), is more appropriate. Author assumed most probable categorisation of software and composite risk assessments (low, medium and high scale) are recorded in columns 3 and 4 of table A
Table A
Use Case (ref Figure 1,Warrington DJ, Rank (gemini Author assumed Author's
Holm S. BMJ Open 2024;14:e089090. clinical risk most probable composite risk
doi:10.1136/bmjopen-2024-089090) prompt - output) categorisation of assessment
software (low, medium
and high
scale)
search the scientific literature 1 Non-regulated Low
stay up to date with my medical knowledge 2 Non-regulated Low
write educational material 3 Non-regulated High
write research papers or essays 4 Non-regulated High
write reflective pieces for my portfolio 5 Non-regulated Low
automate administerial tasks 6 Non-regulated Medium
perform data analytics 7 Non-regulated Medium
write patient letters or notes 8 Non-regulated Medium
interpret pathology slides 9 Regulated Low
interpret scans or results 10 Regulated Low
make diagnoses 11 Non-regulated Medium
make treatment recommendations 12 Non-regulated Medium
plan or perform radiotherapy 13 Regulated Low
plan or perform surgical operations 14 Regulated Low
Other 15 Non-regulated Medium
Furthermore, regarding the survey questions exploring AI's role in decision-making (specifically referencing the implications of question 5d in Table 2, concerning autonomous decisions), this author is of the view that such questions may implicitly understate the clinician's ultimate responsibility. Under the current UK regulatory system, it is my understanding that the clinician, not the AI device, remains accountable for the clinical decision. Consequently, the onus is on the clinician to critically evaluate and, if necessary, seek "a second opinion" on the AI's output before integrating it into their decision-making. The patient retains the right to request a second opinion on the clinician's final clinical judgment.
Finally, as a point of good practice for maintaining professional accountability and audit trails, healthcare registrants using LLMs for clinical decision support might consider exporting AI outputs to secure documents (e.g., Google Docs or similar platforms), particularly when using tools lacking integrated tracking features.
In breast cancer screening, the term "overdiagnosis" is a misnomer. It would be more accurate to state that the natural history of screen-detected cancer has not been adequately verified.
Overdiagnosis is typically defined as the diagnosis of a lesion as cancer that will not cause symptoms or result in death. This definition assumes that cancer detection is appropriate and occurs in individuals for whom the diagnosis would be clinically relevant. For instance, in elderly patients, cancer may not lead to symptoms or death within their life expectancy. However, the issue in breast cancer screening is not related to the duration of observation but rather to the diagnosis itself.
Cancer is generally diagnosed when a mass is detected through imaging or endoscopy and its malignant nature is confirmed histopathologically. However, early-stage breast cancer is an unusual case. These lesions may not form a detectable mass and are diagnosed as cancer based solely on histopathological findings. There is no scientific or clinical verification that cancers identified in this manner are biologically cancerous. Consequently, most clinical studies on breast cancer screening are essentially uncontrolled case series, lacking rigorous controls and, as such, are not scientifically interpretable or statistically reliable.
A systematic review by the U.S. Preventive Services Task Force (USPSTF) did not provide clear evidence that breast cancer screening reduces cancer...
In breast cancer screening, the term "overdiagnosis" is a misnomer. It would be more accurate to state that the natural history of screen-detected cancer has not been adequately verified.
Overdiagnosis is typically defined as the diagnosis of a lesion as cancer that will not cause symptoms or result in death. This definition assumes that cancer detection is appropriate and occurs in individuals for whom the diagnosis would be clinically relevant. For instance, in elderly patients, cancer may not lead to symptoms or death within their life expectancy. However, the issue in breast cancer screening is not related to the duration of observation but rather to the diagnosis itself.
Cancer is generally diagnosed when a mass is detected through imaging or endoscopy and its malignant nature is confirmed histopathologically. However, early-stage breast cancer is an unusual case. These lesions may not form a detectable mass and are diagnosed as cancer based solely on histopathological findings. There is no scientific or clinical verification that cancers identified in this manner are biologically cancerous. Consequently, most clinical studies on breast cancer screening are essentially uncontrolled case series, lacking rigorous controls and, as such, are not scientifically interpretable or statistically reliable.
A systematic review by the U.S. Preventive Services Task Force (USPSTF) did not provide clear evidence that breast cancer screening reduces cancer mortality. These randomized controlled trials (RCTs) include three phases: mammography as a screening tool, histopathology as a diagnostic test, and treatment. None of these phases have a solid scientific foundation. Even if the results of these trials appear positive, we cannot confidently attribute the outcomes to early detection and treatment. Before designing an RCT, it must first be verified that cancers detected by screening have a higher mortality rate than the general healthy population and that treatment can reduce this rate. If such verification is obtained, retrospective studies comparing imaging and pathology findings could suffice for assessing the efficacy of screening mammography, negating the need for large-scale RCTs.
The USPSTF has assigned a Grade B recommendation to breast cancer screening. This decision may be based on the fact that the complications from breast cancer treatment are mostly psychological, with rare physical consequences. However, without clear evidence of benefit, the potential harm cannot be justified, no matter how small. Given the lack of definitive evidence, a Grade I (Insufficient evidence) recommendation would be more appropriate. It seems to me that the USPSTF's Grade B recommendation has contributed to a misconception within the medical community that breast cancer screening is proven to reduce mortality. In reality, there are no clinical trials that provide the necessary evidence to support this claim.
REFERENCE
US Preventive Services Task Force; Recommendation: Breast Cancer:Screening. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/brea... (accessed Mar 25th 2025)
Zahl PH, Gotzsche PC, Mahlen J. Natural history of breast cancers detected in the Swedish mammography screening programme: a cohort study. Lancet Oncol. 2011 Nov;12(12):1118-24. doi: 10.1016/S1470-2045(11)70250-9.
RJ Forestier, FB Erol Forestier, I Santos, A Muela Garcia, A Françon.
Centre de Recherches Rhumatologiques et Thermales d’Aix-les-Bains, Aix Les Bains, France.
This meta-analysis approaches spa therapy as if it were a pharmaceutical intervention, which we believe does not fully reflect the complex and multifaceted nature of such treatments.
We have been conducting clinical trials and systematic reviews in this field for over 30 years. In our experience, spa therapy is a complex intervention traditionally based on the use of thermal mineral water, often combined with massages, baths, showers, mud applications, and supervised pool-based exercises -each of which may have therapeutic effects of its own.
We were surprised by the conclusions of this meta-analysis regarding both the therapeutic effect and the risk of bias, as they differ markedly from our own findings and appear to stem from several questionable methodological choices.
Bibliographic Incompleteness
The limited scope of the literature search is particularly problematic. In 2020, we identified 122 comparative trials on balneotherapy, whereas this meta-analysis included only 42 randomized controlled trials. Our complementary search updated to 2025 identified 42 trials focused solely on knee osteoarthritis, and a total of 141 trials after removing duplicates related to multiple conditions. The highly selective inclusion criteria adopted in this meta-analysis substantially reduced t...
RJ Forestier, FB Erol Forestier, I Santos, A Muela Garcia, A Françon.
Centre de Recherches Rhumatologiques et Thermales d’Aix-les-Bains, Aix Les Bains, France.
This meta-analysis approaches spa therapy as if it were a pharmaceutical intervention, which we believe does not fully reflect the complex and multifaceted nature of such treatments.
We have been conducting clinical trials and systematic reviews in this field for over 30 years. In our experience, spa therapy is a complex intervention traditionally based on the use of thermal mineral water, often combined with massages, baths, showers, mud applications, and supervised pool-based exercises -each of which may have therapeutic effects of its own.
We were surprised by the conclusions of this meta-analysis regarding both the therapeutic effect and the risk of bias, as they differ markedly from our own findings and appear to stem from several questionable methodological choices.
Bibliographic Incompleteness
The limited scope of the literature search is particularly problematic. In 2020, we identified 122 comparative trials on balneotherapy, whereas this meta-analysis included only 42 randomized controlled trials. Our complementary search updated to 2025 identified 42 trials focused solely on knee osteoarthritis, and a total of 141 trials after removing duplicates related to multiple conditions. The highly selective inclusion criteria adopted in this meta-analysis substantially reduced the number of eligible studies, which is especially concerning given the complexity and diversity of spa therapy interventions. This restrictive approach may have contributed to several other questionable methodological decisions, such as:
• Excluding studies from Türkiye and Israel for the sake of homogeneity, although practices in these countries are very similar to those in Europe;
• Favoring 3-month outcomes as the primary endpoint, even when 6-month data were available - a questionable approach in the context of chronic diseases.
Heterogeneity Amplified by Methodological Choices
We acknowledge that heterogeneity is inherently high in this field, due to the complex and multifaceted nature of spa therapy. However, we believe that the methodological choices made in this meta-analysis have significantly exacerbated the problem. As a result, the primary issue became the amplified heterogeneity, which compromises both the feasibility and the validity of the analysis, and makes it difficult to draw reliable conclusions about the presence or absence of a therapeutic effect. These problematic methodological choices include the following:
• An overall pooled analysis was performed across very different conditions, yet this result is presented as the main finding in both the abstract and the main text, despite the limited clinical relevance of such aggregation.
• The authors attempted to group conditions into mechanical disorders, inflammatory disorders, and fibromyalgia, but from a musculoskeletal medicine perspective, grouping clinically distinct conditions—such as rheumatoid arthritis and spondyloarthritis, or low back pain, knee osteoarthritis, hand osteoarthritis, and tendinitis- is both clinically and methodologically inappropriate.
• As previously noted, there is also substantial heterogeneity in the spa interventions themselves—in terms of duration, intensity, and content. While some studies assessed a single intervention, most involved multiple and diverse components. Control interventions also varied considerably, including active comparators, partial controls, waiting lists, usual care, or no treatment. Therefore, pooling these studies without distinction is not methodologically appropriate. If an overall analysis is conducted, subgroup analyses should at minimum be performed to account for these differences.
• Some studies, such as that by Franke et al. [1], were classified as placebo-controlled, but in reality, they compared two complex interventions: a combination of spa therapy, educational programs, exercise, and physiotherapy—with and without radon. The only difference between groups was the type of water used (radon-rich vs. radon-poor), while the other components of treatment were identical. In such cases, the specific effect of spa therapy—particularly that of radon—is diluted by the presence of multiple active co-interventions. It is therefore questionable whether any conclusions can be drawn about the isolated effect of spa therapy or the water type from such designs, as the associated treatments likely had a substantial impact on outcomes.
• The method of calculating effect sizes is also problematic, as the authors combined “mean change change-from-baseline scores” with “end value” results across studies. End values are sensitive to baseline imbalance. If the baseline scores differ between groups, post-intervention scores may be misleading and may increase heterogeneity.
• The quality-of-life (QoL) measures used across studies varied considerably, with some employing generic instruments and others using condition-specific tools. Even the authors noted that they tried to select the least disease-specific QoL measure when multiple were available, pooling different measures that may have different ranges, scaling and sensitivity to change, makes the interpretation of pooled effect sizes more difficult - even with SMD. Besides, generic QoL instruments are generally recognized to be less responsive to clinical change and are not ideally suited for evaluating the therapeutic effects of interventions in rheumatic conditions. Beside the pain the use function-related outcome measures would have been more appropriate and clinically meaningful.
• The quality-of-life (QoL) measures used across studies varied, with some relying on generic instruments and others on condition-specific tools. The authors noted that they selected the least disease-specific measure when multiple options were available. However, pooling outcomes derived from different instruments—each with distinct ranges, scaling characteristics, and sensitivity to change—complicates the interpretation of effect sizes, even when standardized mean differences (SMDs) are applied.
• Moreover, generic QoL measures are widely recognized as being less responsive to clinical change and are not ideally suited for evaluating the therapeutic effects of interventions in rheumatic conditions. In addition to pain outcomes, the inclusion of function-related, condition-specific measures would have been more appropriate and clinically meaningful.
Problems linked to the risk of bias assessment
We fully agree that some spa therapy trials are of low methodological quality. However, it would be incorrect to assume that this applies to all studies in the field.
The Cochrane ROB2 tool is well-suited to evaluating explanatory drug trials with double-blind, placebo-controlled designs. However, it fails to adequately distinguish between more and less rigorous non-pharmacological studies, especially those with a pragmatic design, due to its limited capacity to address the absence of blinding and the variability in the implementation of complex interventions. These limitations include the following concerns:
• ROB2 particularly assumes that blinding of patients and outcome assessment is feasible, whereas in practice, this is very difficult to achieve [2] - except in rare cases such as radon studies. For example, sulphurous thermal waters have a strong odor, and bicarbonate-rich waters are often fizzy and salty, making them easily distinguishable from tap water. Moreover, patients are frequently the assessors of primary outcomes, particularly in rheumatology, where self-reported questionnaires are commonly used.
• Important contextual factors, such as the therapists’ level of experience and the presence of co-interventions, are not considered in the RoB 2 framework, despite their potential influence on outcomes.
• Alternative strategies for minimizing bias, such as Zelen randomization [3,4] or the use of qualitative outcomes [5,6], are not accounted for by RoB 2, despite their relevance in non-pharmacological trials.
Given the complexity of non-pharmacological interventions, tools such as the CLEAR scale [7] or the PEDro scale [8] would have been better suited for assessing internal validity in this context.
Conclusion
In conclusion, this meta-analysis raises important questions, not only about the evidence surrounding spa therapy, but also about how we choose to evaluate complex, non-pharmacological interventions. While efforts to synthesize the literature are commendable, the methodological decisions made here significantly limit the reliability and applicability of the findings. Spa therapy is a multifaceted intervention, deeply embedded in real-world clinical contexts. Evaluating it with the same methodological lens as a pharmaceutical product not only oversimplifies its nature but risks drawing misleading conclusions. Future reviews must better reflect the diversity and complexity of spa interventions, and adopt evaluation tools that are fit for purpose. Only then can we reach valid and clinically meaningful conclusions that inform both practice and policy.
References
[1] Annegret F, Thomas F. Long-term benefits of radon spa therapy in rheumatic diseases: results of the randomised, multi-centre IMuRa trial. Rheumatol Int. 2013 Nov;33(11):2839-50. doi: 10.1007/s00296-013-2819-8. Epub 2013 Jul 18.
[2] Boutron I, Tubach F, Giraudeau B, Ravaud P. Blinding was judged more difficult to achieve and maintain in nonpharmacologic than pharmacologic trials. J Clin Epidemiol. 2004 Jun;57(6):543-50. doi: 10.1016/j.jclinepi.2003.12.010.
[3] Zelen M. A new design for randomized clinical trials. N Engl J Med. 1979 May 31;300(22):1242-5. doi: 10.1056/NEJM197905313002203.
[4] Simon GE, Shortreed SM, DeBar LL. Zelen design clinical trials: why, when, and how. Trials. 2021 Aug 17;22(1):541. doi: 10.1186/s13063-021-05517-w. PMID: 34404466; PMCID: PMC8371763.
[5] Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med. 2001 May 24;344(21):1594-602. doi: 10.1056/NEJM200105243442106. Erratum in: N Engl J Med 2001 Jul 26;345(4):304. PMID: 11372012.
[6] Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Hilden J, Boutron I, Ravaud P, Brorson S. Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors. BMJ. 2012 Feb 27;344:e1119. doi: 10.1136/bmj.e1119. PMID: 22371859.
[7] Boutron I, Moher D, Tugwell P, Giraudeau B, Poiraudeau S, Nizard R, Ravaud P. A checklist to evaluate a report of a nonpharmacological trial (CLEAR NPT) was developed using consensus. J Clin Epidemiol. 2005 Dec;58(12):1233-40. doi: 10.1016/j.jclinepi.2005.05.004. Epub 2005 Oct 13. PMID: 16291467.
[8] Moseley AM, Rahman P, Wells GA, Zadro JR, Sherrington C, Toupin-April K, Brosseau L. Agreement between the Cochrane risk of bias tool and Physiotherapy Evidence Database (PEDro) scale: A meta-epidemiological study of randomized controlled trials of physical therapy interventions. PLoS One. 2019 Sep 19;14(9):e0222770. doi: 10.1371/journal.pone.0222770. PMID: 31536575; PMCID: PMC6752782.
Overdiagnosis occurs when a lesion is identified as cancer despite the absence of symptoms or subsequent cancer-related death. (1) This is particularly common in elderly patients with shorter follow-up periods, assuming the cancer diagnosis is accurate. For prostate and breast cancers, the natural history of screen-detected cases remains unverified, and many of these cancers remain asymptomatic or non-lethal even with extended observation. Therefore, the issue lies with the diagnostic tests, not the duration of observation. While it is accurate to state that "colorectal cancer screening results in overdiagnosis in the elderly," describing prostate cancer as having an overdiagnosis issue is misleading. Instead, it should be clarified that "the natural history of screen-detected prostate cancer has not been verified" or that "there are limitations in the diagnostic tests."
Cancer is typically diagnosed by detecting the formation of a mass through endoscopy or imaging, followed by histopathological confirmation that the cells are malignant. However, screen-detected prostate and breast cancers do not form masses and are diagnosed based solely on histopathology. Whether a lesion diagnosed in this way is biologically cancerous—that is, its natural history—has not been clinically or scientifically verified. (2-4)
In cancer statistics, both prostate and breast cancers rank among the highest in terms of incidence. (5) However, most of these...
Overdiagnosis occurs when a lesion is identified as cancer despite the absence of symptoms or subsequent cancer-related death. (1) This is particularly common in elderly patients with shorter follow-up periods, assuming the cancer diagnosis is accurate. For prostate and breast cancers, the natural history of screen-detected cases remains unverified, and many of these cancers remain asymptomatic or non-lethal even with extended observation. Therefore, the issue lies with the diagnostic tests, not the duration of observation. While it is accurate to state that "colorectal cancer screening results in overdiagnosis in the elderly," describing prostate cancer as having an overdiagnosis issue is misleading. Instead, it should be clarified that "the natural history of screen-detected prostate cancer has not been verified" or that "there are limitations in the diagnostic tests."
Cancer is typically diagnosed by detecting the formation of a mass through endoscopy or imaging, followed by histopathological confirmation that the cells are malignant. However, screen-detected prostate and breast cancers do not form masses and are diagnosed based solely on histopathology. Whether a lesion diagnosed in this way is biologically cancerous—that is, its natural history—has not been clinically or scientifically verified. (2-4)
In cancer statistics, both prostate and breast cancers rank among the highest in terms of incidence. (5) However, most of these cases are screen-detected cancers, making the statistics less reliable.
REFERENCE
1. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst. 2010 May 5;102(9):605-13. doi: 10.1093/jnci/djq099.
2. Albertsen PC. Observational studies and the natural history of screen-detected prostate cancer. Curr Opin Urol. 2015 May;25(3):232-7. doi: 10.1097/MOU.0000000000000157.
3. Takahashi T. Observational study on screen-detected prostate cancer: case series of empirical clinical practice. BJU Int. 2024 Aug 29. doi: 10.1111/bju.16525.
4. Zahl PH, Gøtzsche PC, Mæhlen J. Natural history of breast cancers detected in the Swedish mammography screening programme: a cohort study. Lancet Oncol. 2011 Nov;12(12):1118-24. doi: 10.1016/S1470-2045(11)70250-9.
5. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024 Jan-Feb;74(1):12-49. doi: 10.3322/caac.21820.
February 23, 2025, Eichinger et al. published a plan for pre-hospital bispectral index measurements (BIS) during CPR in out-of-hospital cardiac arrest patients and at hospitalization to
a) determine feasibility of BIS during CPR,
b) assess neurological outcomes -particularly return of consciousness before ROSC and
c) grade cerebral performance category (CPC) at 1 month
Highlighted strenghts were systematic data collection and focus on feasibility of BIS during and after CPR, whereas limitations included recruiting 45 patients, reliance on a particular EMS system and prioritization study feasibility over clinical outcomes (1).
However, there are more weaknesses:
Muscle signals (EMG) and artifacts in BIS due heart massage are expected to blur the EEG assessments – but easily eliminated by sedatives and paralytic agents. The major problem is 'noise' from EEG devices, electrical installations and human activities at the scene of arrest because the 'noise level' dictates whether electrocortical activities can be identified (2).
Quality of Life (QoL) interviews of family members are suggested although one's own
perception of life quality before CPR does not relate to qualities one month later.
The reference list includes 18 articles of which 17 were published in 2017 or later and one neurosurgical from 1975.
The number of patients is 45 whivch weakens the upper 95% confidence interval for th...
February 23, 2025, Eichinger et al. published a plan for pre-hospital bispectral index measurements (BIS) during CPR in out-of-hospital cardiac arrest patients and at hospitalization to
a) determine feasibility of BIS during CPR,
b) assess neurological outcomes -particularly return of consciousness before ROSC and
c) grade cerebral performance category (CPC) at 1 month
Highlighted strenghts were systematic data collection and focus on feasibility of BIS during and after CPR, whereas limitations included recruiting 45 patients, reliance on a particular EMS system and prioritization study feasibility over clinical outcomes (1).
However, there are more weaknesses:
Muscle signals (EMG) and artifacts in BIS due heart massage are expected to blur the EEG assessments – but easily eliminated by sedatives and paralytic agents. The major problem is 'noise' from EEG devices, electrical installations and human activities at the scene of arrest because the 'noise level' dictates whether electrocortical activities can be identified (2).
Quality of Life (QoL) interviews of family members are suggested although one's own
perception of life quality before CPR does not relate to qualities one month later.
The reference list includes 18 articles of which 17 were published in 2017 or later and one neurosurgical from 1975.
The number of patients is 45 whivch weakens the upper 95% confidence interval for the false positive rate (FPR, a paraphrase for specificity) by 10 % or more.
Current Guidelines do not provide pre-ROSC or pre-hospital brain resuscitation markers but focus on BIS measurements after 6-24 hours with FPR below 16 % (3).
The authors didn't consider the dawn time words: There is nothing new under the sun (4). Data on brainstem functions during CPR and on neurological signs and EEG immediately upon ROSC do exist as well as data on the natural history of brain resuscitation during CPR and through the following year which established that brain recovery courses depend on time limits to potend return of consciousness or lasting unconsciousness (5,6a-c). The original study including 54 and 125 patients were confirmed by modelling studies of 111 patients during CPR and 231 patients after ROSC (7-9).
The limited literature base of the plan makes room for statements like
''Pre-ROSC'' and ''prehospital data are lacking'',
''CPR-induced consciousness (CPRIC) to some level of consciousness'' in patients without ROSC or before it occurs
and ”the CPRIC phenomenon” ( a level of consciousness induced during CPR in no ROSC cases)
and ”a recent systematic review and meta-analysis found that processed EEG can predict 'poor' neurological outcomes ...with notable specificity and sensitivity”.
However, Guidelines describe post-arrest BIS test at 2-24 hours for the correctly portended outcome (sensitivity) with FPR values of 0 -16 % (3).
Finally, outcomes assessed by the CPC scale by social skills and work capacity (which don't necessarily result from the survived arrest) and neurologival status at one month(that may measure intermediate or 'surrogate' results because the best results can be 3 or more months down). Last but not least, it was made public in 1997 that 4 of 5 patients recover neurological functions and consciousness although ROSC failed,
every second patient had electrocortical activity in the EEG immediate upon ROSC (7-9) and every third patient with brain function died due to irreversible heart failure within hours to days after CPR start. The cardiac death occurred mainly when CRP continued beyond 20 minutes (10).
In summary, additional data on signs of brain resuscitation during CPR are urgently needed.
References
1. Eichinger M, Zoldl P, Reisinger AC et al. Assessment of frontal EEG measurement in out-of-hospital cardiac arrest: prospective observational feasibility study – study protocol. February 2025 BMJ open 15/2): e094258 doi: bmjopen-2024-094258).
2. Jørgensen EO. Technical contribution. Requirements for recording the EEG at high
sensitivity in suspected brain death. Electroencephalogr Clin Neurophysiol 1974;36:65-69.
3. Nolan JP, Sandroni C, Bottiger BW et al. European Resuscitation Council and European Society of Intensive Care Medicine Guidelines 2021: Chapter 5: Post- resuscitation care. Resuscitation 2021;02.012.2021.
4.The Old Testament. Book of Ecclesiastes., First chapter, verse 9.
5. Jørgensen EO, Malchow-Møller A. Cerebral prognostic signs during cardiopulmonary
resuscitation. Resuscitation 1978; 6:217-225.
6a.Jørgensen EO, Malchow-Møller A. Natural history of global and critical brain
ischaemia Part I: EEG and neurological signs during the first year after cardiopulmonary resuscitation in patientes subsequently regaining consciousness Resuscitation 1981; 9: 133-153.
6b. Jørgensen EO, Malchow-Møller A. Natural history of global and critical brain ischaemia Part II: EEG and neurological signs in patients remaining unconscious after cardiopulmonary resuscitation. Resuscitation 1981; 9: 155-174.
6c. Jørgensen EO, Malchow-Møller A. Natural history of global and critical brain ischaemia. Part III: cerebral prognostic signs after cardiopulmonary resuscitation. Cerebral recovery course and rate during the first year after global and critical ischaemia monitored and predicted by EEG and neurological signs. Resuscitation 1981; 9:175–188.
7. Jørgensen EO. Course of neurological recovery and cerebral prognostic signs during
cardiopulmonary resuscitation. Resuscitation 1997;35:9-16.
8. Jørgensen EO, Holm S. The natural course of neurological recovery following
cardiopulmonary resuscitation. Resuscitation 1998; 36:11-22.
9. Jørgensen EO, Holm S. Prediction of neurological outcome after cardiopulmonary
resuscitation. Resuscitation 1999;41:145-152.
10. Jørgensen EO. Selective neurological recovery or dissociated cardiac death - to be
or not to be - during cardiopulmonary resuscitation, Resuscitation 1998;36:105-109.
This article continues the evidence that the current Participant Information Sheet isn’t fit for its purpose. It no longer supports fair consent, rather, it has become a legal document focused on the needs of the research team, not the potential participant. Having spent much time as Research Ethics Advisor to the National Research Ethics Advisor and subsequently the Health Research Authority trying (unsuccessfully) to address this, I would support the authors' concluding sentence.
But I believe the tide is turning (https://blogs.bmj.com/medical-ethics/posts-page/). The USA Food and Drug Administration draft guidance / requirements support and expect all patient-facing material to start with a comprehensible summary of information of importance to potential participants. Their requirements, if accepted, will carry great weight (https://www.fda.gov/media/176663/download) . On the Oxford A UK Research Ethics Committee, we were similarly concerned about this issue and together drew up and published proposals, which, perhaps unsurprisingly, overlap with the USA material (https://journals.sagepub.com/doi/10.1177/17470161231176932l ).
These were shown to patient groups who responded very positively, but they now need to be tested in real practice, involving all with...
This article continues the evidence that the current Participant Information Sheet isn’t fit for its purpose. It no longer supports fair consent, rather, it has become a legal document focused on the needs of the research team, not the potential participant. Having spent much time as Research Ethics Advisor to the National Research Ethics Advisor and subsequently the Health Research Authority trying (unsuccessfully) to address this, I would support the authors' concluding sentence.
But I believe the tide is turning (https://blogs.bmj.com/medical-ethics/posts-page/). The USA Food and Drug Administration draft guidance / requirements support and expect all patient-facing material to start with a comprehensible summary of information of importance to potential participants. Their requirements, if accepted, will carry great weight (https://www.fda.gov/media/176663/download) . On the Oxford A UK Research Ethics Committee, we were similarly concerned about this issue and together drew up and published proposals, which, perhaps unsurprisingly, overlap with the USA material (https://journals.sagepub.com/doi/10.1177/17470161231176932l ).
These were shown to patient groups who responded very positively, but they now need to be tested in real practice, involving all with fair interest. We have the tools, they now need to be tested
The recently published study investigates transportability of overall survival estimates from US to UK populations receiving first-line treatment for advanced non-small cell lung cancer. Transportability is indeed an important topic when local data is not available or sufficient, which is especially true for rare diseases or, in this context, rare biomarker alterations. However, upon careful examination of the present paper, several points emerge that demand attention and reflection.
First, since only aggregated data from the UK were available, the authors chose to use unanchored matching-adjusted indirect comparison (MAIC). This method, however, requires the very strong assumption that all effect modifiers and prognostic factors are accounted for [1], which is very improbable given that only few patient characteristics were available from the used comparator study. Additionally, MAIC analyses are subject to assumptions about the distribution of covariates in the population for which only summary measures are available. We strongly recommend discussing these issues in connection with the choice of method.
Moreover, the extrapolation of results from one country to another without considering country-specific factors is quite problematic. Especially, fundamental differences between the US and UK health care systems were only addressed in a half-sentence in the Box on “strengths and limitations of this study“ but were not mentioned in the discussion. Health care c...
The recently published study investigates transportability of overall survival estimates from US to UK populations receiving first-line treatment for advanced non-small cell lung cancer. Transportability is indeed an important topic when local data is not available or sufficient, which is especially true for rare diseases or, in this context, rare biomarker alterations. However, upon careful examination of the present paper, several points emerge that demand attention and reflection.
First, since only aggregated data from the UK were available, the authors chose to use unanchored matching-adjusted indirect comparison (MAIC). This method, however, requires the very strong assumption that all effect modifiers and prognostic factors are accounted for [1], which is very improbable given that only few patient characteristics were available from the used comparator study. Additionally, MAIC analyses are subject to assumptions about the distribution of covariates in the population for which only summary measures are available. We strongly recommend discussing these issues in connection with the choice of method.
Moreover, the extrapolation of results from one country to another without considering country-specific factors is quite problematic. Especially, fundamental differences between the US and UK health care systems were only addressed in a half-sentence in the Box on “strengths and limitations of this study“ but were not mentioned in the discussion. Health care coverage or infrastructure and local availability of health services, but also agreements for cost reimbursements may have a large impact on survival rates.
Furthermore, regarding overall survival, the differences in proportions and types of second-line treatments may have a profound influence on the overall survival time of patients. However, in this study, second line treatments in the two cohorts were only mentioned in the results. but not further considered in the discussion part. We recommend paying attention to this central issue in more detail and examining how this could be solved in the MAIC analysis by at least taking the proportion of second line treatments into account.
Lastly, “similarity” of the OS curves was only assessed by visual inspection, without any further quantitative measure or prospectively defined criteria. For overall and chemotherapy, the course of the curves for UK and US deviated and even crossed, hinting at missing prognostic factors in the weighting [2]. Also, the comparison with the data from Pilleron et al. [3] showed barely any overlap of confidence intervals. Yet, the authors claim that the curves look similar, and that weighting worked well.
Thus, clearly the major drawback of this study is that the authors make very strong and potentially misleading claims, while the data merely show some similarity of the curves. At the same time, limitations of the methodology are barely discussed and missing individual patient data from the UK is interpreted as no data being available, although data are only not available to the authors.
In conclusion, while transportability of data from one population to another is an important topic, especially in comparison between real world evidence and evidence from RCTs, transporting knowledge into another country would require some careful consideration of country specific characteristics like health care systems, local patient characteristics, treatment guidelines and proper discussion of potential drawbacks from this analysis. We hope that the authors will pay attention to these concerns and take proactive steps to refine their work, thereby contributing to the progress of research in this vital area.
Sources:
1. Population-adjusted indirect comparisons (MAIC and STC). https://www.sheffield.ac.uk/nice-dsu/tsds/population-adjusted (2022).
2. Austin, P. C. & Stuart, E. A. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat. Med. 34, 3661–3679 (2015).
3. Pilleron, S., Morris, E. J. A., Dodwell, D. & Franks, K. N. Patterns of chemotherapy use and outcomes in advanced non-small cell lung cancer by age in England: A retrospective analysis of the population-based Systemic Anti-Cancer Treatment (SACT) dataset. J. Geriatr. Oncol. 14, (2023).
Response to: Hand acceleration time (HAT) as a diagnostic tool in the assessment of haemodialysis access-induced distal ischaemia (HAIDI): study protocol for a prospective cohort study in the Barcelona south metropolitan area, by Gonzalez et al.
Reshabh Yadav MD PhD 1, Marc R.M. Scheltinga MD PhD
Department of Surgery, Máxima Medical Center, Veldhoven, The Netherlands
To the Editor,
We congratulate Gonzalez et al. with their research protocol on HAT (hand acceleration time) in end stage renal disease (ESRD) patients requiring a haemodialysis access (1). They propose to conduct a study based on the assumption that HAT assessed by duplex ultrasound (DUS) reflects the vascular status of an arm. Aim is to quantify HAT before and after haemodialysis access construction and to determine whether pre- and postoperative HAT values can predict haemodialysis access-induced distal ischemia (HAIDI).
Based on our experience with HAIDI, some aspects of the protocol are worthwhile commenting on:
HAIDI in relation to ‘steal’.
Show MoreEarlier studies suggested that HAIDI is caused by reversal of blood flow (‘steal’) that is shunted away from the hand (‘stolen from the hand’) due to the presence of an arteriovenous connection as in a vascular access for haemodialysis. On the contrary, steal is a phenomenon that has no pathophysiological significance related to HAIDI (2). The authors justifiably conclude that ESRD patients who often have diabetes melli...
Following the publication of the original article, it has come to the authors’ attention that the timing of the analysis was still based on the wording of the original funding application, and had not been updated prior to publication of the trial protocol paper.
The original funding application where both the short- and long-term outcomes were deemed as co-primary outcomes and as such would have been analysed at study end. At point of funding by the NIHR, we were requested to consider only the short-term outcome to be the primary outcome, and as such the timing of the analysis should have been changed so that short term outcomes were analysed first and longer-term outcomes after 2 years post-partum. The analysis plan was adjusted at that time, according to the NIHRs request.
The article currently states (under the Main analysis section) that: “All analyses will be undertaken after database lock following data collection at 2 years.”
However, the wording in this section should read: “Analysis of the short-term outcomes will be carried out after database lock following data collection at birth. The longer-term outcomes will be analysed after database lock following data collection at 2 years post-partum.”
To ensure that knowledge of the short-term outcomes will not impact the scientific integrity of the longer-term outcomes, we will continue to adhere to strict retention protocols to follow up the mothers at 2 years for the longer-term health...
Show MoreThe study protocol by Zaman et al describes PAK-SEHAT as the research initiative for investigating premature atherosclerotic cardiovascular disease (ASCVD) in Pakistan. The research targets an important knowledge gap in cardiovascular healthcare research for South Asia because its CVD prevalence continues to increase in populations with low-to-middle income status.
Several comments arise from our reading of the research. The research identifies “young adults” as very mature males who are younger than 60 and very mature females who are younger than 65 years but this definition goes beyond the typical age range of 18–44 years [1]. The expanded population inclusion might dim the line separating early and conventional ASCVD manifestation.
CCTA along with CIMT serves as an effective method to detect subclinical plaques in patients [2]. These expensive diagnostic tests represent a major barrier that affects the system-wide implementation of public health screening and intervention programs in Pakistan.
Excluding participants with BMI higher than 40 kg/m² or eGFR lower than 60 ml/min/1.73m² may unintentionally exclude persons at high risk from the study. People with South Asian origins who have metabolic syndrome or renal impairment tend to develop ASCVD at an earlier stage according to research [3] and their removal from the study might diminish the application of study findings to wider populations.
The protocol states it will recruit nationally in P...
Show MoreComments related to the findings reported by Warrington and Holm regarding the use of Artificial Intelligence (AI) by UK General Medical Council (GMC) registered doctors (Warrington DJ, Holm S. BMJ Open 2024;14:e089090. doi:10.1136/bmjopen-2024-089090).
Show MoreA key observation regarding the study is its apparent lack of distinction between participants' use of regulated AI products (classified as medical devices) and non-regulated AI tools (such as general-purpose LLMs). The wide range of respondent specialties reported further highlights this potential issue; for instance, clinicians in radiology or pathology are more likely to encounter regulated, task-specific AI, whereas those in public health or psychiatry might be more likely to experiment with non-regulated, general-purpose models.
During the review process, I used Gemini Advanced (specifically, the model designated by the user as 2.5 Pro Experimental) to assist with processing screenshots of table1, table 2 and fig 1 into spreadsheet processable data. The same Large Language Model (LLM) was also prompted to categorize the clinical risks associated with the AI uses listed in Figure 1 of the original paper. The author is of the opinion that the LLM’s risk categorisation (column 2 in table A below) adopted a patient-centric perspective.
However, the author is of the opinion that a "composite" clinical risk assessment, which considers both the nature of the specific usage instance and the pot...
In breast cancer screening, the term "overdiagnosis" is a misnomer. It would be more accurate to state that the natural history of screen-detected cancer has not been adequately verified.
Show MoreOverdiagnosis is typically defined as the diagnosis of a lesion as cancer that will not cause symptoms or result in death. This definition assumes that cancer detection is appropriate and occurs in individuals for whom the diagnosis would be clinically relevant. For instance, in elderly patients, cancer may not lead to symptoms or death within their life expectancy. However, the issue in breast cancer screening is not related to the duration of observation but rather to the diagnosis itself.
Cancer is generally diagnosed when a mass is detected through imaging or endoscopy and its malignant nature is confirmed histopathologically. However, early-stage breast cancer is an unusual case. These lesions may not form a detectable mass and are diagnosed as cancer based solely on histopathological findings. There is no scientific or clinical verification that cancers identified in this manner are biologically cancerous. Consequently, most clinical studies on breast cancer screening are essentially uncontrolled case series, lacking rigorous controls and, as such, are not scientifically interpretable or statistically reliable.
A systematic review by the U.S. Preventive Services Task Force (USPSTF) did not provide clear evidence that breast cancer screening reduces cancer...
RJ Forestier, FB Erol Forestier, I Santos, A Muela Garcia, A Françon.
Centre de Recherches Rhumatologiques et Thermales d’Aix-les-Bains, Aix Les Bains, France.
This meta-analysis approaches spa therapy as if it were a pharmaceutical intervention, which we believe does not fully reflect the complex and multifaceted nature of such treatments.
Show MoreWe have been conducting clinical trials and systematic reviews in this field for over 30 years. In our experience, spa therapy is a complex intervention traditionally based on the use of thermal mineral water, often combined with massages, baths, showers, mud applications, and supervised pool-based exercises -each of which may have therapeutic effects of its own.
We were surprised by the conclusions of this meta-analysis regarding both the therapeutic effect and the risk of bias, as they differ markedly from our own findings and appear to stem from several questionable methodological choices.
Bibliographic Incompleteness
The limited scope of the literature search is particularly problematic. In 2020, we identified 122 comparative trials on balneotherapy, whereas this meta-analysis included only 42 randomized controlled trials. Our complementary search updated to 2025 identified 42 trials focused solely on knee osteoarthritis, and a total of 141 trials after removing duplicates related to multiple conditions. The highly selective inclusion criteria adopted in this meta-analysis substantially reduced t...
Overdiagnosis occurs when a lesion is identified as cancer despite the absence of symptoms or subsequent cancer-related death. (1) This is particularly common in elderly patients with shorter follow-up periods, assuming the cancer diagnosis is accurate. For prostate and breast cancers, the natural history of screen-detected cases remains unverified, and many of these cancers remain asymptomatic or non-lethal even with extended observation. Therefore, the issue lies with the diagnostic tests, not the duration of observation. While it is accurate to state that "colorectal cancer screening results in overdiagnosis in the elderly," describing prostate cancer as having an overdiagnosis issue is misleading. Instead, it should be clarified that "the natural history of screen-detected prostate cancer has not been verified" or that "there are limitations in the diagnostic tests."
Show MoreCancer is typically diagnosed by detecting the formation of a mass through endoscopy or imaging, followed by histopathological confirmation that the cells are malignant. However, screen-detected prostate and breast cancers do not form masses and are diagnosed based solely on histopathology. Whether a lesion diagnosed in this way is biologically cancerous—that is, its natural history—has not been clinically or scientifically verified. (2-4)
In cancer statistics, both prostate and breast cancers rank among the highest in terms of incidence. (5) However, most of these...
February 23, 2025, Eichinger et al. published a plan for pre-hospital bispectral index measurements (BIS) during CPR in out-of-hospital cardiac arrest patients and at hospitalization to
a) determine feasibility of BIS during CPR,
b) assess neurological outcomes -particularly return of consciousness before ROSC and
c) grade cerebral performance category (CPC) at 1 month
Highlighted strenghts were systematic data collection and focus on feasibility of BIS during and after CPR, whereas limitations included recruiting 45 patients, reliance on a particular EMS system and prioritization study feasibility over clinical outcomes (1).
However, there are more weaknesses:
Show MoreMuscle signals (EMG) and artifacts in BIS due heart massage are expected to blur the EEG assessments – but easily eliminated by sedatives and paralytic agents. The major problem is 'noise' from EEG devices, electrical installations and human activities at the scene of arrest because the 'noise level' dictates whether electrocortical activities can be identified (2).
Quality of Life (QoL) interviews of family members are suggested although one's own
perception of life quality before CPR does not relate to qualities one month later.
The reference list includes 18 articles of which 17 were published in 2017 or later and one neurosurgical from 1975.
The number of patients is 45 whivch weakens the upper 95% confidence interval for th...
This article continues the evidence that the current Participant Information Sheet isn’t fit for its purpose. It no longer supports fair consent, rather, it has become a legal document focused on the needs of the research team, not the potential participant. Having spent much time as Research Ethics Advisor to the National Research Ethics Advisor and subsequently the Health Research Authority trying (unsuccessfully) to address this, I would support the authors' concluding sentence.
Show MoreBut I believe the tide is turning (https://blogs.bmj.com/medical-ethics/posts-page/). The USA Food and Drug Administration draft guidance / requirements support and expect all patient-facing material to start with a comprehensible summary of information of importance to potential participants. Their requirements, if accepted, will carry great weight (https://www.fda.gov/media/176663/download) . On the Oxford A UK Research Ethics Committee, we were similarly concerned about this issue and together drew up and published proposals, which, perhaps unsurprisingly, overlap with the USA material (https://journals.sagepub.com/doi/10.1177/17470161231176932l ).
These were shown to patient groups who responded very positively, but they now need to be tested in real practice, involving all with...
The recently published study investigates transportability of overall survival estimates from US to UK populations receiving first-line treatment for advanced non-small cell lung cancer. Transportability is indeed an important topic when local data is not available or sufficient, which is especially true for rare diseases or, in this context, rare biomarker alterations. However, upon careful examination of the present paper, several points emerge that demand attention and reflection.
Show MoreFirst, since only aggregated data from the UK were available, the authors chose to use unanchored matching-adjusted indirect comparison (MAIC). This method, however, requires the very strong assumption that all effect modifiers and prognostic factors are accounted for [1], which is very improbable given that only few patient characteristics were available from the used comparator study. Additionally, MAIC analyses are subject to assumptions about the distribution of covariates in the population for which only summary measures are available. We strongly recommend discussing these issues in connection with the choice of method.
Moreover, the extrapolation of results from one country to another without considering country-specific factors is quite problematic. Especially, fundamental differences between the US and UK health care systems were only addressed in a half-sentence in the Box on “strengths and limitations of this study“ but were not mentioned in the discussion. Health care c...
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