Author contributions First, despite a registry-based

The gap

Evidence profile

Stated in the limitations section of the source papers, classified as general, spanning 5 journals.

Supporting evidence — 5 representative gaps

• Machine learning-based prediction of ischemic cardio-cerebrovascular events after endovascular or microsurgical treatment of unruptured intracranial aneurysms and risk stratification by the early post-treatment triglyceride-glucose index (2026) · Frontiers in Neurology · doi

  Author contributions First, despite a registry-based design, data were collected mainly from two centers, which may limit generalizability and introduce selection bias. Second, the model was only validated internally; external validation is needed to confirm clinical appli- cability. Third, TyG was measured only at postoperative day 3 and may be affected by perioperative stress, so it should be inter- preted as a prognostic marker rather than a causal factor. Fourth, detailed information regarding antiplatelet therapy timing and adherence was incomplete, representing a potential confounder. Fifth, as an observational study, residual confounding and treat- ment-selection bias could not be fully eliminated. Although ACS and cerebral infarction represent distinct clinical entities, the consistent directionality and robust predictive performance observed in component-specific analyses support the clinical validity of the composite ICCE endpoint for capturing overall post-treatment vascular vulnerability. YH: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing, Software. SC: Data curation, Investigation, Writing  – review & editing. DL: Data curation, Investigation, Writing – review & editing. ZZ: Methodology, Validation, Writing – review & editing. YL: Methodology, Validation, Writing – review & editing. YW: Conceptualization, Funding acquisition, Project admin- istration, Supervision, Writing – review & editing.

  generalstated in limitationsevidence 5/5
  Keywords: writing review editing validation clinical curation investigation methodology selection bias conceptualization author contributions first despite
• Associations of Blood Soluble Fas and IGF-I with Risk of Hemorrhagic Stroke: The Circulatory Risk Communities Study (CIRCS) (2026) · Translational Stroke Research · doi

  The strength of this study was that it was conducted within a large cohort of the general population in Japan, where the incidence of hemorrhagic stroke is relatively high. Our study was based on systematic surveillance for incident stroke and employed standardized epidemiological methods for measuring biomarkers. This study has several potential limitations. First, only single-point measurements of biomarkers and risk factors at baseline were available, which could lead to regression dilution bias. Second, statistical power was limited, particu- larly in subtype analyses (SAH and ICH), location-specific analyses (deep and lobar ICH), and tertile-based analyses; therefore, these findings should be interpreted with caution. Nevertheless, these analyses may still provide meaning- ful insights into the association between IGF-I and hem- orrhagic stroke, and possibly its underlying mechanisms. Third, although we adjusted for potential confounders, we cannot rule out residual confounding from unmeasured fac- tors, such as antithrombotic medication use, which was not available in this study. Fourth, the study population was limited to Japanese residents, so generalizability should be considered with caution. Nevertheless, because biomarkers and risk factors for hemorrhagic stroke may be common across racial and ethnic groups, the evidence may pro- vide a basis for extrapolation to other populations. Lastly, we used frozen serum samples to estimate sFas and IGF-I and did not examine long-term changes in the samples. A previous report showed that these biomarkers remained stable in serum samples stored for up to nine years at -70 °C in another Japanese cohort, where sample management methods were nearly identical to those in our study [32]. 1 3Translational Stroke Research (2026) 17:57  57 Page 6 of 7 As additional analyses stratified by storage duration yielded similar results, it is unlikely that long-term storage affected the findings.

  generalstated in limitationsevidence 5/5
  Keywords: stroke analyses biomarkers samples cohort population hemorrhagic based potential risk factors available limited caution nevertheless
• Endovascular thrombectomy with or without intravenous thrombolysis in large-vessel ischemic stroke: an updated meta-analysis (2026) · Scientific Reports · doi

  This meta-analysis has limitations. Our analyses were based on aggregated trial-level data, which is considered less informative than patient-level data. However, individual patient data were unavailable, precluding harmonized subgroup analyses and covariate-adjusted analyses. Nevertheless, we assume that patient-level data would not have revealed any significant differences in the findings of the primary endpoint due to the homogeneity and randomized design of included studies [36]. Although we pooled all the available randomized evidence (7 trials; n=2884), several results remained imprecise, which was reflected by wide CIs and limit the precision of our estimates. Moreover, subgroup cut-off values varied between studies. Thrombolytic regimens were not uniform across trials and differences in dosing and administration (infusion versus bolus) may dilute agent-specific effects and limit applicability to any single thrombolysis protocol. Additionally, data were predominantly derived from anterior circulation large-vessel occlusion. Occlusions in the basilar artery ARTICLE IN PRESSARTICLE IN PRESS ACCEPTED MANUSCRIPT were included in two trials and only in small numbers. Therefore, external validity to posterior circulation is limited. Moreover, hemorrhage outcomes were defined using different criteria (Heidelberg, SITS-MOST and NINDS), which reduced the comparability and precision of the pooled safety estimates. Nonetheless, sensitivity analyses were comparable (Figure 4B). The overall risk of bias was primarily driven by the open-label treatment allocation, whereas randomization procedures, outcome assessment, and follow-up were largely at low risk. However, certainty was limited mainly by imprecision and inconsistency.

  generalstated in limitationsevidence 5/5
  Keywords: analyses level patient trials subgroup differences randomized included pooled limit precision estimates circulation article press
• Differential impact of cumulative cerebral small-vessel disease burden on ischemic versus hemorrhagic stroke recurrence in hemorrhage-prone patients (2026) · Neurological Sciences · doi

  There are some methodological limitations to be considered. First, this study is an exploratory post hoc analysis. While our results demonstrate strong associations between m-cSVD burden and recurrent stroke risk in hemorrhageprone patients, they should be interpreted as suggesting potential relationships rather than establishing causality. Furthermore, as most prospective clinical trials including PICASSO largely excluded patients who are in poor medical condition or in a functionally dependent state, our study population might not reflect a real-world setting. Second, significant baseline imbalances existed across m-cSVD groups; patients with higher scores were older and had greater clinical and vascular frailty. This disparity, potentially reflecting clinical caution regarding intensive therapy in patients with high hemorrhagic burden, is noteworthy given the established role of statins in secondary prevention. Although we performed multivariable adjustments to mitigate these imbalances, the possibility of residual confounding remains, necessitating a cautious interpretation of the independent prognostic value attributed to the m-cSVD score. Third, the relatively low incidence of hemorrhagic stroke compared to ischemic events might have resulted in insufficient statistical power to provide precise estimates of the association with m-cSVD scores. Consequently, the findings regarding hemorrhagic risk should be interpreted with caution, and larger-scale studies are warranted to further validate these associations. Forth, given that the phenotypes of cSVD markers are heterogeneous and vary according to their numbers, simple scoring of total cSVD by adding a point may jeopardizes the precision of estimates for assessing recurrent stroke risk. A detailed cSVD scoring approach that quantitatively incorporated the severity of each phenotype may be more informative. Fifth, our study did not distinguish between the anatomical locations (deep vs. lobar) of ICH or CMBs, which could reflect different underlying etiologies such as hypertensive arteriopathy and CAA. However, since approximately nine out of ten participants had hypertension, our results may reflect the outcomes of a population with hypertensive arteriopathy. Lastly, the use of a m-cSVD score that excludes EPVS was necessitated by data availability within the PICASSO database, and this modified score has not undergone full external validation. However, WMH, CMBs/ICH, and lacune are considered the core imaging markers in predicting vascular outcomes, which may mitigate the potential impact of excluding EPVS on our primary findings regarding stroke recurrence risk.

  generalstated in limitationsevidence 5/5
  Keywords: csvd stroke risk patients clinical reflect regarding hemorrhagic score associations burden recurrent interpreted potential picasso
• Acute ischemic stroke after scuba diving in a patient with patent foramen ovale: a case of paradoxical embolism (2026) · Romanian Journal of Neurology · doi

  This case report is limited by its single-patient design and therefore does not allow definitive causal inference. The presumed embolic mechanism remains indirect, as no thrombus or gas embolus was directly visualized. Although venous Doppler ultrasonography was negative, occult thrombosis cannot be fully excluded. Reperfusion after intravenous thrombolysis was not angiographically confirmed and is inferred from rapid clinical recovery and diffusion-negative MRI findings. cONcLUsION Ischemic stroke is a medical emergency associated with high disability and mortality rates. A multirEFErENcEs 1. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021 Oct;20(10):795-820. doi: 10.1016/S1474-4422(21)00252-0. 2. Dimitrova M. Diagnostic and therapeutical approaches in cryptogenic stroke. Sofia: J.A.M.G. BOOKS, 2021. p. 68. 3. Buttinelli C, Beccia M, Argentino C. Stroke in a scuba diver with patent foramen ovale. Eur J Neurol. 2002 Jan;9(1):89-91. doi: 10.1046/j.1468- 1331.2002.00347.x. 4. Ries S, Knauth M, Kern R, Klingmann C, Daffertshofer M, Sartor K, Hennerici M. Arterial gas embolism after decompression: correlation with right-to-left shunting. Neurology. 1999 Jan 15;52(2):401-4. doi: 10.1212/wnl.52.2.401. 5. Schwerzmann M, Seiler C, Lipp E, Guzman R, Lövblad KO, Kraus M, Kucher N. Relation between directly detected patent foramen ovale and ischemic brain lesions in sport divers. Ann Intern Med. 2001 Jan 2;134(1):21-4. doi: 10.7326/0003-4819-134-1-200101020-00009. 6. Gerriets T, Tetzlaff K, Liceni T, Schäfer C, Rosengarten B, Kopiske G, et al. Arteriovenous bubbles following cold water sport dives: relation to right-todisciplinary approach is mandatory in order to identify the etiological causes of its occurrence in young individuals. In patients with neurological symptoms after diving, paradoxical embolism through a PFO should be strongly considered. Assessing the individual risk profile is essential for implementing an optimal, personalized secondary stroke prevention plan. Authors' contributions: Conceptualization, M.A., M.T.-M., and A.K.; clinical management of the patient, M.A., V.D.-K., M.T.-M., and A.K.; diagnostic evaluation and interpretation, M.A., V.D.-K., and A.K.; data collection and curation, M.A. and V.D.-K.; writing—original draft preparation, M.A. and M.T.-M.; writing—review and editing, M.A., V.D.-K., M.T.-M., and A.K.; supervision, M.T.-M. and A.K. All authors have read and agreed to the published version of the manuscript.

  generalstated in limitationsevidence 5/5
  Keywords: stroke authors patient directly negative clinical ischemic global burden risk neurol diagnostic patent foramen ovale

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