Early Ischemic Stroke Research Articles

Analysis of the Association between Telomere Length and Neurological Disability in Stroke Types.

Background and Objectives: The association between neurological disability, prognosis, and telomere length (TL) in patients with stroke has been investigated in various ways. However, analysis of the type of stroke and ischemic stroke subgroups is limited. In this study, we aimed to determine the association between TL and neurological disability according to stroke type. Materials and Methods: This prospective study included patients with stroke who visited a single-center emergency department (ED) between January 2022 and December 2023. The association between TL and neurological disabilities, using the Modified Rankin Scale (mRS) and National Institutes of Health Stroke Scale (NIHSS), was evaluated according to the patient's stroke type and subgroup of ischemic stroke. Multivariate analysis was performed to determine the association between neurological disabilities in patients with ischemic stroke and the subgroups. Results: A total of 271 patients with stroke were enrolled. The NIHSS score was found to be higher at the time of ED visit (adjusted odds ratio [OR], 5.23; 95% confidence interval [CI], 1.59-17.2, p < 0.01) and 1 day later (adjusted OR, 7.78; 95% CI, 1.97-30.70, p < 0.01) in the ischemic stroke group with a short TL. In the other determined etiology (OD) or undetermined etiology (UD) group, the NIHSS was higher in the short TL group at the ED visit (adjusted OR, 7.89; 95% CI, 1.32-47.25, p = 0.02) and 1 day after (adjusted OR, 7.02; 95% CI, 1.14-43.47, p = 0.04). Conclusions: TL is associated with neurological disability in early ischemic stroke and is prominent in the UD and OD subgroups.

Efficacy of a new video observational training method (intensive visual simulation) for motor recovery in the upper limb in subacute stroke: a feasibility and proof-of-concept study.

To demonstrate the feasibility and efficacy of a new video-observation training method (intensive visual simulation) to improve upper limb function. Small sample, randomized, evaluator-blind, monocentric study. Seventeen early subacute ischaemic stroke patients with complete hemiplegia were randomly assigned to the therapeutic group (n = 8) or control group (CG, n = 9). Thirty sessions of intensive visual simulation combined with corrected visual feedback (therapeutic group) or uncorrected visual feedback (control group) were performed over 6 weeks on top of a standard rehabilitation programme. 400-point hand assessment test (400p-HA). Box and Blocks (B&B), Purdue Pegboard test, Minnesota. The 400p-HA test improved significantly from T0 to 6 months for both groups, with a significant difference between groups at 3 months (MW-UT p = 0.046) and 4 months (MW-UT p = 0.046) in favour of the therapeutic group. One-phase exponential modelling of 400p-HA showed a greater plateau for the therapeutic group (F test p = 0.0021). There was also faster recovery of the ability to perform the B&B tests for the therapeutic group (log-rank test p = 0.03). This study demonstrated the feasibility and potential efficacy of an intensive visual simulation training programme to improve upper limb function in subacute stroke patients. A larger study is needed to confirm these results.

A Clinical-Radiomics Nomogram for Predicting Early Ischemic Stroke Risk in Patients with Transient Ischemic Attack

To develop and validate a clinical-radiomics nomogram for predicting early ischemic stroke risk in patients who sustain a transient ischemic attack (TIA). A retrospective training dataset (n= 76) and a prospective validation dataset (n= 34) of patients with TIA were studied. Image processing was performed using ITK-snap and Artificial Intelligent Kit. Radiomics features were selected in R. A nomogram predicting recurrent TIA/stroke in 90 days as a recurrent ischemic event was established. Model performance was assessed by computing the receiver operating characteristic curve and decision curve analysis (DCA). We found a higher proportion of diabetes and hypertension in the patients with recurrent TIA compared with the stable patients in both the training and validation datasets (P < 0.05). Recurrent patients had significantly higher ABCD2 scores and plaque scores compared to stable patients. ABCD2 score and necrotic/lipid core area were independent risk factors for recurrent ischemic events (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.47-6.40; and OR, 1.20; 95% CI, 1.07-1.41, respectively). The radiomics model had area under the curve values of 0.737 (95% CI, 0.715-0.878) in the training dataset and 0.899 (95% CI, 0.706-0.936) in the validation dataset, which was superior to the ABCD2 score and plaque model for predicting stroke recurrence (P < 0.05). The nomogram predicting recurrent ischemic events was 0.923 (95% CI, 0.895-0.978) in the training dataset and 0.935 (95% CI, 0.830-0.959) in the validation dataset. DCA confirmed the clinical value of this nomogram. The nomogram, based on clinical ABCD2 score, carotid plaque components and radiomics score, shows good performance in predicting the risk of recurrent ischemic events in patients with TIA.

Prognosis of ischemic stroke patients with both aortic atheroma and cardioembolic sources

This study aimed to investigate the relationship between complex aortic plaque (CAP) and short-term as well as long-term outcomes following cardioembolic stroke. CAP is a known risk factor for occurrence and recurrence of ischemic stroke. However, the association of CAP on cardioembolic stroke remains unclear. This was retrospective study using prospective cohort of consecutive patients with cardioembolic stroke who underwent transesophageal echocardiography. The functional outcome was evaluated using the modified Rankin Scale score at 3 months, and long-term outcomes were assessed by recurrence of ischemic stroke and occurrence of major adverse cardiovascular events (MACE). Among 759 patients with cardioembolic stroke, 91 (12.0%) had CAP. Early ischemic stroke recurrence within 3 months was associated with CAP (p = 0.025), whereas CAP was not associated with functional outcome at 3 months (odd ratio 1.01, 95% confidence interval [CI] 0.57–1.84, p = 0.973). During a median follow-up of 3.02 years, CAP was significantly associated with ischemic stroke recurrence (hazard ratio = 2.68, 95% CI 1.48–4.88, p = 0.001) and MACE occurrence (hazard ratio = 1.61, 95% CI 1.03–2.51, p = 0.039). In conclusion, CAP was associated with early ischemic stroke recurrence and poor long-term outcomes in patients with cardioembolic stroke. It might be helpful to consider transesophageal echocardiography for patients with cardioembolic stroke to identify CAP.

ABCD2-I Score Predicts Unplanned Emergency Department Revisits within 72 Hours Due to Recurrent Acute Ischemic Stroke.

the ABCD2 score is valuable for predicting early stroke recurrence after a transient ischemic attack (TIA), and Doppler ultrasound can aid in expediting stroke triage. The study aimed to investigate whether combining the ABCD2 score with carotid duplex results can enhance the identification of early acute ischemic stroke after TIA. we employed a retrospective cohort design for this study, enrolling patients diagnosed with TIA who were discharged from the emergency department (ED). The modified ABCD2-I (c50) score, which incorporates a Doppler ultrasound assessment of internal carotid artery stenosis > 50%, was used to evaluate the risk of acute ischemic stroke within 72 h. Patients were categorized into three risk groups: low risk (with ABCD2 and ABCD2-I scores = 0-4), moderate risk (ABCD2 score = 4-5 and ABCD2-I score = 5-7), and high risk (ABCD2 score = 6-7 and ABCD2-I score = 8-9). between 1 January 2014, and 31 December 2019, 1124 patients with new neurological deficits were screened, with 151 TIA patients discharged from the ED and included in the analysis. Cox proportional hazards analysis showed that patients in the high-risk group, as per the ABCD2-I (c50) score, were significantly associated with revisiting the ED within 72 h due to acute ischemic stroke (HR: 3.12, 95% CI: 1.31-7.41, p = 0.0102), while the ABCD2 alone did not show significant association (HR: 1.12, 95% CI: 0.57-2.22, p = 0.7427). ABCD2-I (c50) scores effectively predict early acute ischemic stroke presentations to the ED within 72 h after TIA.

Stroke outcomes following durable left ventricular assist device implant in patients bridged with micro-axial flow pump: Insights from a large registry.

Stroke after durable left ventricular assist device (d-LVAD) implantation portends high mortality. The incidence of ischemic and hemorrhagic stroke and the impact on stroke outcomes of temporary mechanical circulatory support (tMCS) management among patients requiring bridge to d-LVAD with micro-axial flow-pump (mAFP, Abiomed) is unsettled. Consecutive patients, who underwent d-LVAD implantation after being bridged with mAFP at 19 institutions, were retrospectively included. The incidence of early ischemic and hemorrhagic stroke after d-LVAD implantation (<60 days) and association of pre-d-LVAD characteristics and peri-procedural management with a specific focus on tMCS strategies were studied. Among 341 patients, who underwent d-LVAD implantation after mAFP implantation (male gender 83.6%, age 58 [48-65] years, mAFP 5.0/5.5 72.4%), the early ischemic stroke incidence was 10.8% and early hemorrhagic stroke 2.9%. The tMCS characteristics (type of mAFP device and access, support duration, upgrade from intra-aortic balloon pump, ECMELLA, ECMELLA at d-LVAD implantation, hemolysis, and bleeding) were not associated with ischemic stroke after d-LVAD implant. Conversely, the device model (mAFP 2.5/CP vs. mAFP 5.0/5.5: HR 5.6, 95%CI 1.4-22.7, p = 0.015), hemolysis on mAFP support (HR 10.5, 95% CI 1.3-85.3, p = 0.028) and ECMELLA at d-LVAD implantation (HR 5.0, 95% CI 1.4-18.7, p = 0.016) were associated with increased risk of hemorrhagic stroke after d-LVAD implantation. Both early ischemic (HR 2.7, 95% CI 1.9-4.5, p < 0.001) and hemorrhagic (HR 3.43, 95% CI 1.49-7.88, p = 0.004) stroke were associated with increased 1-year mortality. Among patients undergoing d-LVAD implantation following mAFP support, tMCS characteristics do not impact ischemic stroke occurrence, while several factors are associated with hemorrhagic stroke suggesting a proactive treatment target to reduce this complication.

Bioinformatics Approach to Identify the Pathogenetic Link of Gut Microbiota-Derived Short-Chain Fatty Acids and Ischemic Stroke.

Stroke is a life-threatening condition that impairs the arteries and causes neurological impairment. The incidence of stroke is increasing year by year with the arrival of the aging population. Thus, there is an urgent need for early stroke diagnosis. Short-chain fatty acids (SCFAs) can modulate the central nervous system and directly and indirectly impact behavioral and cognitive functions. This study aimed to investigate the connection between SCFA metabolism and stroke development via bioinformatic analysis. Initially, the Gene Set Enrichment Analysis (GSEA) and immune cell infiltration analysis were performed based on RNA data from stroke patients to comprehend the mechanisms governing stroke pathogenesis. The functional analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI), was performed based on the Differentially Expressed Gene (DEG) selected by the limma package. 1220 SCFA metabolism-related genes screened from Genecards databases were intersected with 242 genes in main modules determined by Weighted Gene Co-Expression Network Analysis (WGCNA), and the final 10 SCFA key genes were obtained. GO analysis revealed that these genes were involved in immune response processes. Through lasso regression analyses, we established a stroke early diagnosis model and selected 6 genes with diagnostic value. The genes were validated by the area under curve (AUC) values and had a relatively good diagnostic performance. Finally, 4 potential therapeutic drugs targeting these genes were predicted using the Drug Signatures Database (DSigDB) via Enrichr. In conclusion, this paper analyzes the involvement of SCFAs in the complex gut-brain axis mechanism, which contributes to developing new targets for treating central nervous system diseases and provides new ideas for early ischemic stroke diagnosis.

A systematic review and meta-analysis of clinical efficacy of early and late rehabilitation interventions for ischemic stroke

IntroductionAt present, stroke has become the first cause of death and disability among Chinese adults. With the coming of the aging population in China, the disease burden brought by stroke will be increasingly aggravated. And stroke is a leading cause of disability. There is a golden plastic period after stroke, during which timely and safe intervention and rehabilitation therapy can effectively improve the disability status. However, there is still controversy about the duration of interventional rehabilitation after stroke. This study conducted a meta-analysis on the influence of intervention in early and late ischemic stroke rehabilitation.MethodChinese language databases such as CNKI, Wanfang, and VIP, and English language databases such as Embase, PubMed, Web of Science, and The Cochrane Library were searched, and RCT related to early and late rehabilitation of ischemic stroke from the establishment of the database to October 2023 was collected. Review Manager 5.4.1 was used for relevant analysis. The main outcomes were Barthel Index or Modified Barthel Index, Fugl-Meyer Assessment scale, NIHSS, China Stroke Scale. Standardized Mean Difference (SMD) was used as an effective indicator of continuity variables, and the estimated interval was expressed by 95% confidence interval (CI).ResultsA total of 1908 patients were included in 16 studies. The results showed that, compared with late rehabilitation, early rehabilitation improved clinical efficacy. Barthel Index or Modified Barthel Index score was [SMD = 1.40, 95%CI(1.16,1.63), p < 0.001]; the score of Fugl-Meyer Assessment Scale was [SMD = 1.18, 95%Cl (0.85, 1.52), P < 0.001]; the score of NIHSS was [SMD= -0.44, 95% CI(-0.65, -0.24), P < 0.001]; the result of China Stroke Scale score was [SMD= -0.37, 95%CI(-0.56, -0.18), P < 0.001].ConclusionIn comparison with late rehabilitation, early rehabilitation can significantly improve self-care abilities, daily activities, and neurological functions of ischemic stroke patients.Trial registrationThis meta-analysis has been registered with Prospero, and the registration number is CRD42022309911. The registration period is March 22, 2022.

Abstract TMP70: Association of Distal Hyperintense Vessel Sign and Outcomes in Patients With Symptomatic Posterior Circulation Intracranial Atherosclerotic Disease

Objectives: The Distal Hyperintense Vessel (DHV) sign on FLAIR imaging is a radiographic marker of inadequate blood flow due to poor collateral flow distal to the stenotic artery. Previous studies suggest that the DHV sign was associated with early recurrent ischemic stroke in the anterior circulation secondary to intracranial atherosclerotic disease (ICAD). However, its significance in ischemic stroke in the posterior circulation is unknown. Here, we investigate the association of DHV sign in the basilar artery and outcomes at discharge in patients with posterior circulation stroke or TIA secondary to ICAD. Methods: We retrospectively reviewed patients with ischemic strokes or TIA attributed to ICAD of the basilar or vertebral arteries admitted to two comprehensive stroke centers affiliated with UTSW Medical Center from 2010 to 2022. Patients were included if they met VERiTAS criteria (≥50% vertebrobasilar stenosis). The DHV sign was defined as positive when the increased intensity in the basilar artery distal to stenosis was higher than the surrounding CSF signal. The DHV sign was evaluated by blinded vascular neurologists and neuro-radiologists. The primary outcome was mRS at discharge. The secondary outcome was the incidence of clinical deterioration during admission, defined as any worsened neurological exam with associated new infarct or infarct expansion in the posterior circulation. Results: A total of 135 patients were included in the study. A total of 33 (24%) patients had the presence of the DHV sign on admission MRI. Compared to patients without DHV sign, patients with DHV sign had higher NIHSS scores on admission (median 7 vs 2, p&lt;0.001), higher risk of clinical deterioration during hospitalization (27% vs 2%, p&lt;0.001), higher mRS scores at discharge (median 3.45 vs 1.8, p&lt;0.001) and higher mortality rate (24% vs 0%, p&lt;0.001). In multivariate analysis, the DHV sign was an independent predictor of higher mRS scores at discharge. Conclusions: In patients with ischemic stroke or TIA secondary to basilar or vertebral artery atherosclerotic stenosis, the presence of the DHV sign in the basilar artery is associated with more severe disease and poorer outcomes at discharge compared to patients without DHV sign.

Abstract 95: Associations of Ischemic Stroke With Known Stroke Susceptibility Loci Vary by Age

Objective: The goal of this study was to test whether the strength of association of stroke-associated genetic variants differs by age of stroke onset. Background: In the MEGASTROKE GWAS study, 55 variants were robustly associated with ischemic stroke in predominantly older populations. Yet limited research has been carried out to date to understand how these genetic associations are modified by age, which could provide clues to the underlying biological mechanisms of these associations. Methods: Analyses were based on 16,000 stroke cases of European ancestry identified from the Stroke Genetics Network (SiGN) and Early Onset Ischemic Stroke Consortium and 24,838 stroke-free controls. We tested if the associations of each variant with stroke differed by age using two complementary approaches. First, we used a case-control logistic regression model testing for the associations of stroke with variant, age, and a variant*age interaction term and second, we used a case-only approach, testing for an association of variant with age of stroke onset. All analyses were adjusted for sex and population structure. Results: We identified six variants whose associations were significantly modified by age (p ≤ 0.001) by either analysis; 5 variants by the case-control analysis and 4 variants by the case-only analysis. Among these were 2 variants at the ABO locus that have been previously shown to be more strongly associated with early compared to late onset stroke, tagging blood groups A and O, respectively, and a variant in WNT2B that has previously been associated with early, but not late, onset ischemic stroke in a small case-control study. Conclusions: Six out of 55 variants previously associated with ischemic stroke in large GWAS studies show differential effects by age, with the stroke risk allele more strongly associated with early onset stroke for 5 variants or more strongly associated with older onset stroke (1 variant). Future work is needed to understand the reasons for this age dependency. Disclosures: None. Study Supported By: R01NS100178, R01NS105150, R01NS114045

Identification and validation of platelet-related diagnostic markers and potential drug screening in ischemic stroke by integrating comprehensive bioinformatics analysis and machine learning.

Ischemic stroke (IS), caused by blood and oxygen deprivation due to cerebral thrombosis, has links to activated and aggregated platelets. Discovering platelet-related biomarkers, developing diagnostic models, and screening antiplatelet drugs are crucial for IS diagnosis and treatment. Combining and normalizing GSE16561 and GSE22255 datasets identified 1,753 upregulated and 1,187 downregulated genes. Fifty-one genes in the platelet-related module were isolated using weighted gene co-expression network analysis (WGCNA) and other analyses, including 50 upregulated and one downregulated gene. Subsequent enrichment and network analyses resulted in 25 platelet-associated genes and six diagnostic markers for a risk assessment model. This model's area under the ROC curve outperformed single genes, and in the peripheral blood of the high-risk group, immune infiltration indicated a higher proportion of CD4, resting CD4 memory, and activated CD4 memory T cells, along with a lower proportion of CD8 T cells in comparison to the low-risk group. Utilizing the gene expression matrix and the CMap database, we identified two potential drugs for IS. Finally, a rat MACO/R model was used to validate the diagnostic markers' expression and the drugs' predicted anticoagulant effects. We identified six IS platelet-related biomarkers (APP, THBS1, F13A1, SRC, PPBP, and VCL) for a robust diagnostic model. The drugs alpha-linolenic acid and ciprofibrate have potential antiplatelet effects in IS. This study advances early IS diagnosis and treatment.

Repeated intravenous thrombolysis in recurrent ischemic stroke within 3 months: a systematic review

BackgroundRepeated intravenous thrombolysis (RIVT) within 3 months is an off-guideline therapy, however, may be an effective and safe way to treat early recurrent ischemic stroke. This study was conducted to assess the potential influencing factors on the efficacy and safety of RIVT in recurrent ischemic stroke within 3 months and to explore the strategy of RIVT within 3 months.MethodsPubMed, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wanfang Database were searched for cases of RIVT in recurrent ischemic stroke within 3 months up to February 1, 2023. Clinical characteristics were compared and analyzed between the good-outcome and poor-outcome groups and between the symptomatic intracranial hemorrhage (sICH) and non-sICH groups respectively.ResultsA total of 16 studies including 24 cases of RIVT within 3 months were retrospectively analyzed in the present study. The patients’ ages ranged from 42 to 87 years (median 73.5 years) and the intervals between thrombolysis were from 0.25 to 90 days (median 9.5 days). Comparing the clinical characteristics between the good-outcome group and the poor-outcome group, no statistically significant differences were found (P > 0.05), but the differences in baseline National Institutes of Health stroke scale (NIHSS) score of the recurrent stroke (P = 0.056) and good outcome after the previous IVT (P = 0.054) nearly reached statistical significance. Comparing the data between the non-sICH group and the sICH group, statistically significant differences were found in terms of the proportion of cardiogenic embolism (P = 0.036), baseline NIHSS score in the recurrent stroke (P = 0.007) and the interval between thrombolysis (P = 0.041), but no significant difference was found by regression analysis.ConclusionIn patients with recurrent ischemic stroke within 3 months, those with a good outcome after the previous IVT and a low baseline NIHSS score in the recurrent stroke may be considered for RIVT, whereas those with a high baseline NIHSS score, a short interval between thrombolysis, and cardiogenic embolism may suffer a higher risk of sICH. Due to sample size and publication bias, more studies with larger sample sizes and more rigorous designs are needed to confirm this conclusion.

Near-Infrared Afterglow ONOO--Triggered Nanoparticles for Real-Time Monitoring and Treatment of Early Ischemic Stroke.

Early detection and drug intervention with the appropriate timing and dosage are the main clinical challenges for ischemic stroke (IS) treatment. The conventional therapeutic agents relay fluorescent signals, which require real-time external light excitation, thereby leading to inevitable autofluorescence and poor tissue penetration. Herein, we report endogenous peroxynitrite (ONOO-)-activated BDP-4/Cur-CL NPs that release NIR afterglow signals (λmax 697 nm) for real-time monitoring of the progression of ischemia reperfusion (I/R) brain injury while releasing curcumin for the safe treatment of IS. The BDP-4/Cur-CL NPs exhibited bright NIR afterglow luminescence (maximum 732-fold increase), superb sensitivity (LOD = 82.67 nM), high energy-transfer efficiency (94.6%), deep tissue penetration (20 mm), outstanding antiapoptosis, and anti-inflammatory effects. The activated NIR afterglow signal obtained in mice with middle cerebral artery occlusion (MCAO) showed three functions: (i) the BDP-4/Cur-CL NPs are rapidly activated by endogenous ONOO-, instantly illuminating the lesion area, distinguishing I/R damage from normal areas, which can be successfully used for endogenous ONOO- detection in the early stage of IS; (ii) real-time reporting of in situ generation and dynamic fluctuations of endogenous ONOO- levels in the lesion area, which is of great value in monitoring the evolutionary mechanisms of IS; and (iii) dynamic monitoring of the release of curcumin drug for safe treatment. Indeed, the released curcumin effectively decreased apoptosis, enhanced survival, alleviated neuroinflammation, reduced brain tissue loss, and improved the cognition of MCAO stroke mice. This work is the first example of afterglow luminescence for early diagnosis, real-time reporting, drug tracing, and treatment for IS.

A Teleradiology System for Early Ischemic and Hemorrhagic Stroke Evaluation and Management

Abstract Purpose Stroke is a cardinal cause of death and disability globally. It is an emergency condition where the rapidity of diagnosis is directly linked to the outcome. “Imaging is Brain” is, therefore, an important concept. The early diagnosis of stroke is crucial not only in guiding its effective treatment but also in estimating prognosis. This study aims to provide perspective on the implementation of international teleradiology in stroke evaluation, management, and care. Methods A dedicated international teleradiology stroke network has been evaluated in our study between March 2019 and July 2022 where the interpretation and analysis of the computed tomography (CT) scans of the patients from distant hospitals in United States were performed by teleradiologists via high-quality Digital Imaging and Communications in Medicine (DICOM)-image transfer through a cloud-based radiology information system/picture archival and communication system platform RADspa. Results Over a period of three and a half years, starting from March 2019, a total of 30,406 CT scans of 19,342 patients from 96 hospitals of 15 states in the United States were interpreted and reported by board-certified radiologists empaneled by Teleradiology Solutions. The mean report turnaround time for all noncontrast CT studies was 9.97 minutes at 95% confidence interval (CI: 9.89–10.05); for CT angiogram studies, it was 20.57 minutes 95% CI (20.38–20.77); and for CT perfusion studies, it was 13.72 minutes 95% CI (13.42–14.03). Conclusion A dedicated international teleradiology stroke network designed in our study allowed for transmission, prioritization, evaluation, and management of CT cases performed in the setting of acute stroke in the study population. The results of our investigation indicate that teleradiology provides an effective solution for early diagnosis/interpretation of CT examinations performed internationally in the setting of acute stroke. This may further be used as a model or template for the development of a nationwide stroke network within our own country.

Factors associated with stroke after COVID-19 vaccination: a statewide analysis.

The objective of our study was to evaluate vaccine type, COVID-19 infection, and their association with stroke soon after COVID-19 vaccination. In a retrospective cohort study, we estimated the 21-day post-vaccination incidence of stroke among the recipients of the first dose of a COVID-19 vaccine. We linked the Georgia Immunization Registry with the Georgia Coverdell Acute Stroke Registry and the Georgia State Electronic Notifiable Disease Surveillance System data to assess the relative risk of stroke by the vaccine type. Approximately 5 million adult Georgians received at least one COVID-19 vaccine between 1 December 2020 and 28 February 2022: 54% received BNT162b2, 41% received mRNA-1273, and 5% received Ad26.COV2.S. Those with concurrent COVID-19 infection within 21 days post-vaccination had an increased risk of ischemic (OR = 8.00, 95% CI: 4.18, 15.31) and hemorrhagic stroke (OR = 5.23, 95% CI: 1.11, 24.64) with no evidence for interaction between the vaccine type and concurrent COVID-19 infection. The 21-day post-vaccination incidence of ischemic stroke was 8.14, 11.14, and 10.48 per 100,000 for BNT162b2, mRNA-1273, and Ad26.COV2.S recipients, respectively. After adjusting for age, race, gender, and COVID-19 infection status, there was a 57% higher risk (OR = 1.57, 95% CI: 1.02, 2.42) for ischemic stroke within 21 days of vaccination associated with the Ad26.COV2.S vaccine compared to BNT162b2; there was no difference in stroke risk between mRNA-1273 and BNT162b2. Concurrent COVID-19 infection had the strongest association with early ischemic and hemorrhagic stroke after the first dose of COVID-19 vaccination. Although not all determinants of stroke, particularly comorbidities, were considered in this analysis, the Ad26.COV2.S vaccine was associated with a higher risk of early post-vaccination ischemic stroke than BNT162b2.

#3589 OXALATE METABOLISM IN PRIMARY HYPEROXALURIA TYPE 1 TREATED WITH LUMASIRAN IMMEDIATELY AFTER BIRTH: STILL NOT EARLY ENOUGH

Abstract Background and Aims Severe primary hyperoxaluria type 1 (PH1) with rapid onset nephrocalcinosis and renal function loss in early infancy required so far combined liver and kidney transplant. RNA interfering drugs are the new challenge for these children. Here we present the first case of a newborn affected by PH1 treated with RNA-interfering Lumasiran 6 hours after birth. Method Diagnosis of PH1 (homozygous mutation AGXT c.731T&amp;gt;C9 [p.Ile244Thr]) was done at 11 weeks of pregnancy on chorionic villus due to family history. Parents are first cousins, both heterozygous carriers of the mutation. Their first child is homozygous, affected by PH1, in dialysis for massive nephrocalcinosis since two months of life, kidney-liver transplanted at 14 months, with multiple comorbidities, severe retinal oxalate deposition, early ischemic stroke and post-transplant lympho-proliferative disease. Mother blood Oxalate, Glycolate and Urinary Oxalate during pregnancy proved normal (3 umol/L and 4 umol/L; 35 umol/mmol). Fetal morphology at ultrasound was normal, showing a male fetus large for gestational age, due to gestational diabetes, and polyhydramnios. At 37w cesarean section was performed. Birth weight 4120 g; Length 49.9 cm (99° centile for gestational age). Apgar score 9/9. Cord blood and amniotic fluid were obtained for Oxalate dosage and Sanger sequencing for diagnosis confirmation. Umbilical central venous line and bladder catheter were placed for immediate start of infusions and serial sampling. Results PH1 was confirmed due to Homozygous mutation AGXT c.731T&amp;gt;C9 [p.(Ile244Thr)]. Oxalate on cord blood was 15 umol/L (nv &amp;lt;10), on amniotic fluid 55 umol/L (nv 19-71), on first urine 401 umol/mmolCr (nv &amp;lt; 300 umol/mmolCr). Blood Oxalate at 6h of life rose to 32 umol/L, Glycolate to 107 umol/L and urinary Oxalate to 573 umol/mmolCr. Serum Creatinin was normal (0.3 mg/dl). At 6 hours of life the child was treated with Glycolate Oxidase RNAi Lumasiran at the dose 6 mg/kg subcutaneously, in combination with Pyridoxin 10 mg/kg/day. Hyperhydration (240 ml/kg/day) was maintained iv for 16 days in combination with oral water and potassium citrate (500 mg in 500 ml/day) above breast feeding. Blood Oxalate was serially assessed every 48 hrs showing a peak level of 108 umol/l (nv &amp;lt;10) at day 6, higher than the supersaturation level of 60 umol/L, then a gradual decline (65-56-62 umol/L at 10-20-30 days respectively). Lumasiran 6 mg/kd was repeated at 30 and 60 days according to schedule, then at 3 mg/kg every month. After the second dose of Lumasiran a steeper decline of blood Oxalate was observed (31-17 umol/L at 45-60 days respectively) reaching the upper normal limit of 12 umol/L after three doses, at 80 days. Urinary Oxalate in spite of Lumasiran early start rose until a maximum of 4173 umol/mmolCr (nv for age &amp;lt;300 umol/mmolCr) at 13 days and gradually declined to 765 umol/mmolCr at 80 days, after three doses. Blood and urine Glycolate initially paralleled Oxalate then increased after each Lumasiran dose. Renal ultrasound normal at birth, showed only minimal hyperechogenic spots during the first 2 months, then mild bilateral hyperechogenic papillary deposits without signs of nephrocalcinosis/stones. Renal function at 3 months of life is normal (serum Creatinine 0.2 mg/dl); child growth on the higher centiles (7 kg), with no adverse events. Conclusion Blood and urine Oxalate serial analysis in a severe case of PH1 treated immediately after birth show that Glycolate Oxidase inhibition has a latency of at least 15 days, even when no previous deposits are present. In these days extremely high level of urine and blood Oxalate, far higher than supersaturation level, are reached, in spite of normal renal function, hyperhydration, B6 and citrate supplementation. This case confirms that familiar severe forms of PH1 should be treated immediately after birth with Lumasiran in combination with aggressive supportive therapy to avoid irreversible nephrocalcinosis and renal failure. Prenatal treatment of these cases might be considered in future.

A case series of ten plus one deficiency of adenosine deaminase 2 (DADA2) patients in Iran

BackgroundDeficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disease caused by mutations in the ADA2 gene. DADA2 has a broad spectrum of clinical presentations. Apart from systemic manifestations, we can categorize most of the signs and symptoms of DADA2 into the three groups of vasculitis, hematologic abnormalities, and immunologic dysregulations. The most dominant vasculitis features are skin manifestations, mostly in the form of livedo racemosa/reticularis, and early onset ischemic or hemorrhagic strokes. Hypogammaglobulinemia that is found in many cases of DADA2 brings immunodeficiencies into the differential diagnosis. Cytopenia, pure red cell aplasia (PRCA), and bone marrow failure (BMF) are the hematologic abnormalities commonly found in DADA.Case presentationWe introduce eleven patients with DADA2 diagnosis, including two brothers and sisters, one set of twin sisters, and one father and his daughter and son. Ten patients (91%) had consanguineous parents. All the patients manifested livedo racemose/reticularis. Ten patients (91%) reported febrile episodes, and seven (64%) had experienced strokes. Only one patient had hypertension. Two of the patients (11%) presented decreased immunoglobulin levels. One of the patients presented with PRCA. Except for the PRCA patient with G321E mutation, all of our patients delivered G47R mutation, the most common mutation in DADA2 patients. Except for one patient who unfortunately passed away before the diagnosis was made and proper treatment was initiated, the other patients’ symptoms are currently controlled; two of the patients presented with mild symptoms and are now being treated with colchicine, and the eight others responded well to anti-TNFs. The PRCA patient still suffers from hematologic abnormalities and is a candidate for a bone marrow transplant.ConclusionsConsidering the manifestations and the differential diagnoses, DADA2 is not merely a rheumatologic disease, and introducing this disease to hematologists, neurologists, and immunologists is mandatory to initiate prompt and proper treatment. The efficacy of anti-TNFs in resolving the symptoms of DADA2 patients have been proven, but not for those with hematologic manifestations. Similarly, they were effective in controlling the symptoms of our cohort of patients, except for the one patient with cytopenia.

Brain‐oscillation-synchronized stimulation to enhance motor recovery in early subacute stroke: a randomized controlled double‐blind three‐ arm parallel‐group exploratory trial comparing personalized, non‐ personalized and sham repetitive transcranial magnetic stimulation (Acronym: BOSS-STROKE)

BackgroundStroke is a major cause of death and the most frequent cause of permanent disability in western countries. Repetitive transcranial brain stimulation (rTMS) has been used to enhance neuronal plasticity after stroke, yet with only moderate effect sizes. Here we will apply a highly innovative technology that synchronizes rTMS to specific brain states identified by real-time analysis of electroencephalography.MethodsOne hundred forty-four patients with early subacute ischemic motor stroke will be included in a multicenter 3-arm parallel, randomized, double-blind, standard rTMS and sham rTMS-controlled exploratory trial in Germany. In the experimental condition, rTMS will be synchronized to the trough of the sensorimotor µ-oscillation, a high-excitability state, over ipsilesional motor cortex. In the standard rTMS control condition the identical protocol will be applied, but non-synchronized to the ongoing µ-oscillation. In the sham condition, the same µ-oscillation-synchronized protocol as in experimental condition will be applied, but with ineffective rTMS, using the sham side of an active/placebo TMS coil. The treatment will be performed over five consecutive work days (1,200 pulses per day, 6,000 pulses total). The primary endpoint will be motor performance after the last treatment session as measured by the Fugl-Meyer Assessment Upper Extremity.DiscussionThis study investigates, for the first time, the therapeutic efficacy of personalized, brain-state-dependent rTMS. We hypothesize that synchronization of rTMS with a high-excitability state will lead to significantly stronger improvement of paretic upper extremity motor function than standard or sham rTMS. Positive results may catalyze a paradigm-shift towards personalized brain-state-dependent stimulation therapies.Trial registrationThis study was registered at ClinicalTrials.gov (NCT05600374) on 10–21-2022.

Crosstalk between oxidative stress and neutrophil response in early ischemic stroke: a comprehensive transcriptome analysis.

Ischemic stroke (IS) is the second leading cause of mortality worldwide, continuing to be a serious health concern. It is well known that oxidative stress and neutrophil response play vital roles in the pathophysiology of early IS. However, the complex interactions and critical genes associated with them have not been fully understood. Two datasets (GSE37587 and GSE16561) from the Gene Expression Omnibus database were extracted and integrated as the discovery dataset. Subsequent GSVA and WGCNA approaches were used to investigate IS-specific oxidative stress-related genes (ISOSGS). Then, we explored IS-specific neutrophil-associated genes (ISNGS) using CIBERSORT analysis. Next, the protein-protein interaction network was established to ascertain candidate critical genes related with oxidative stress and neutrophil response. Furthermore, these candidate genes were validated using GSE58294 dataset and our clinical samples by RT-qPCR method. Finally, functional annotation, diagnostic capability evaluation and drug-gene interactions were performed by using GSEA analysis, ROC curves and DGIDB database. In our analysis of discovery dataset, 155 genes were determined as ISOSGS and 559 genes were defined as ISNGS. Afterward, 9 candidate genes were identified through the intersection of ISOSGS and ISNGS, PPI network construction, and filtration by degree algorithm. Then, six real critical genes, including STAT3, MMP9, AQP9, SELL, FPR1, and IRAK3, passed the validation using the GSE58294 dataset and our clinical samples. Further functional annotation analysis indicated these critical genes were associated with neutrophil response, especially neutrophil extracellular trap. Meanwhile, they had a good diagnostic performance. Lastly, 53 potential drugs targeting these genes were predicted by DGIDB database. We identified 6 critical genes, STAT3, FPR1, AQP9, SELL, MMP9 and IRAK3, related to oxidative stress and neutrophil response in early IS, which may provide new insights into understanding the pathophysiological mechanism of IS. We hope our analysis could help develop novel diagnostic biomarkers and therapeutic strategies for IS.

ADDED UTILITY OF COMPUTED TOMOGRAPHY PERFUSION STUDY IN THE ASSESSMENT OF EARLY ISCHEMIC STROKE IN COMPARISON WITH NONCONTRAST COMPUTED TOMOGRAPHY - A PROSPECTIVE OBSERVATIONAL STUDY

Objective: 1. T o study the added utility of computed tomography perfusion study in the assessment of early ischemic stroke in comparison with non-contrast computed tomography. 2. To study the role of computed tomography perfusion study in deciding thrombolytic treatment/ therapeutic protocols aimed at reversing the cerebral ischemic insult. Conclusions and Results: It was observed that 15 (46.68%) patients were in the 61-70 years of age group followed by 8 (25%) in the age group of 51-60 years. The mean age of the patients was 58.87 ±12.14 years. Ÿ Females were affected more i.e. 18 (56.25%) compared to the male patients 14 (43.75%). Ÿ Most observed co-morbid condition was hypertension in 9 (28.13%) patients followed by hypertension and diabetes in 7 (21.87%) patients and diabetes in 6 (18.75%) patients. Ÿ Among the study participants 4 (12.50%) were smokers followed by 6 (18.75%) were alcoholic and smokers &amp; alcoholic (15.62%) respectively. Ÿ It was observed that the symptoms of palsy were present among 23 (71.88%) patients Ÿ The most commonly observed time of onset of symptoms was 3-5 hours in 23 (71.88%) patients followed by 1-3 hours (21.87%) and &gt;5 hours in 2 (6.25%) patients. Ÿ NCCT ndings observed was denite signs of stroke in 12 (37.5%) patients followed by suspected signs of stroke on NCCT (25%) Ÿ It was observed that no sign of stroke was observed in 12 (37.5%) patients. Ÿ CT perfusion ndings observed was increased mean transient time (MTT) in all (100%) patients followed by decreased blood ow in all (100%) patients. It was observed that cerebral blood volume decreased in 12 (37.5%) patients, increased in 8 (25%) and normal in 12 (37.5%) patients. Ÿ The correlation of NCCT and CT perfusion ndings observed that out of total 32 patients NCCT study identies 20 patients while all 32 patients were identied by CT perfusion study with sensitivity of 100%. Ÿ CT perfusion provides early diagnosis of ischemic stroke thus helps in management of stroke patients. Inference : The present study concludes that CT-perfusion had more sensitivity compared to NCCT in identifying early ischemic stroke. CT perfusion has additional utility in management of early ischemic stroke. CT Perfusion study provides important information to the neurologist and neuro-interventionalist when evaluating patients for endovascular reperfusion therapy by identifying the size of core infarction and penumbra