Process Evaluation of an Ambulance-delivered Early Intensive Blood Pressure Lowering Stroke Trial: Design, Rationale, and Reflection.

INTRODUCTION: The fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4) is a large-scale, multicenter, prospective, randomized, open-label, blinded endpoint assessment trial, initiated in an ambulance in China, aiming at evaluating the effectiveness and safety of pre-hospital blood pressure (BP) lowering in patients with suspected acute stroke and elevated BP. A prespecified process evaluation is intended to explore the implementation of the trial intervention, provide support to interpret the trial outcomes and put forward suggestions to scale up the intervention in broader settings in the future. METHODS: This process evaluation is a mixed-methods design, and follows the Normalization Process Theory (NPT) and the UK Medical Research Council (UK MRC) guidance. Fidelity, reach, acceptability, appropriateness, adoption, sustainability, and relevant contextual factors and mechanisms affecting the implementation of pre-hospital early intensive BP lowering treatment will be analyzed. Semi-structured interviews with ambulance staff, ward and emergency department clinicians, and nurses are undertaken to explore perceptions of the intervention, contextual factors, and potential suggestions for future implementation in practice. Data from observational records, surveys, conventional monitoring data, on-site records, and case report forms will be analyzed to understand background care and context. CONCLUSION: The process evaluation of INTERACT4 will provide insights for the implementation of pre-hospital early intensive BP lowering intervention in different health systems, and help better explain the trial results for further scale up.

Efficacy and Safety of Chinese Herbal Medicine in Patients with Acute Intracerebral Hemorrhage: Protocol for a Randomized Placebo-Controlled Double-Blinded Multicenter Trial.

INTRODUCTION: The popular traditional Chinese medicine (TCM) compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage (ICH) through effects on brain edema, hematoma absorption, and the immune system. This study is to assess whether FYTF-919 is safe and effective as compared to matching placebo treatment in patients with acute ICH. METHODS: The ongoing Chinese Herbal medicine in patients with Acute INtracerebral hemorrhage (CHAIN) is a multicenter, prospective, randomized, double-blind placebo-controlled trial of FYTF-919 in patients with acute ICH at 20-30 hospital sites in China. Eligible ICH patients presenting within 48 h after symptom onset are randomly allocated to receive either FYTF-919 (100 mL per day × 28 d, oral) or matching placebo. A sample size of 1,504 patients is estimated to provide 90% power (α 0.05) to detect a ≥20% improvement in average utility-weight scores on the modified Rankin scale (UW-mRS) assessed at 90 days, with 6% non-adherence and 10% lost to follow-up. The primary efficacy outcome is UW-mRS at 90 days. Secondary outcomes include binary measures of the mRS, neurological impairment on the National Institute of Health Stroke Scale, and health-related quality of life on the EuroQol EQ-5D-5L scale at different time points over 6 months of follow-up. The key safety measure is serious adverse events. CONCLUSION: CHAIN is on schedule to provide reliable evidence over the benefits of a popular herbal TCM for the treatment of acute ICH.

Twenty-Four-Hour Post-Thrombolysis NIHSS Score As the Strongest Prognostic Predictor After Acute Ischemic Stroke: ENCHANTED Study.

BACKGROUND: This study was conducted to determine optimal predictive ability of National Institutes of Health Stroke Scale (NIHSS) measurements at baseline, 24 hours, and change from baseline to 24 hours after thrombolysis on functional recovery in patients with acute ischemic stroke who participated in the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS AND RESULTS: ENCHANTED was an international, multicenter, 2×2 quasifactorial, prospective, randomized open trial of low-dose versus standard-dose intravenous alteplase and intensive versus guideline-recommended blood pressure lowering in thrombolysis-eligible patients with acute ischemic stroke. Absolute (baseline minus 24 hours) and percentage (absolute change/baseline × 100) changes in NIHSS scores were calculated. Receiver operating characteristic curve analyses assessed performance of different NIHSS measurements on 90-day favorable functional recovery (modified Rankin Scale [mRS] score 0-2) and excellent functional recovery (mRS score 0-1). Youden index was used to identify optimal predictor cutoff points. A total of 4410 patients in the ENCHANTED trial were enrolled. The 24-hour NIHSS score had the highest discriminative ability for predicting favorable 90-day functional recovery (mRS score 0-2; area under the curve 0.866 versus 0.755, 0.689, 0.764; P<0.001) than baseline, absolute, and percentage change of NIHSS score, respectively. The optimal cutoff point of 24-hour NIHSS score for predicting favorable functional recovery was ≤4 (sensitivity 66.5%, specificity 87.1%, adjusted odds ratio, 9.44 [95% CI, 7.77-11.48]). The 24-hour NIHSS score (≤3) was the best predictor of 90-day excellent functional recovery (mRS score 0-1). Findings were consistent across subgroups, including sex, race, baseline NIHSS score, stroke subtype, and age. CONCLUSIONS: In thrombolysis-eligible patients with acute ischemic stroke, 24-hour NIHSS score (optimal cutpoint of 4) is the strongest predictor of 90-day functional recovery over baseline and early change of NIHSS score. REGISTRATION: URL: https://clinicaltrials.gov. Unique Identifier: NCT01422616.

Randomised controlled decentralised feasibility trial of a fixed low-dose combination antihypertensive drug strategy to attenuate cognitive decline in high-risk adults.

OBJECTIVES: The Action To promote brain HEalth iN Adults study aimed to determine the feasibility and applicability of recruitment using home blood pressure (BP) monitoring, routine blood biochemistry and videoconference measures of cognition, in adults at high risk of dementia. DESIGN: A decentralised double-blind, placebo-controlled, randomised feasibility trial with a four-stage screening process. SETTING: Conducted with participants online in the state of New South Wales, Australia. PARTICIPANTS: Participants were aged 50-70 years with moderately elevated BP (systolic >120 and <160 mm Hg or diastolic >80 and <95 mm Hg) and ≥1 additional enrichment risk factor of monotherapy treatment of hypertension, diabetes mellitus, elevated low-density lipoprotein cholesterol, obesity, current smoking or a first degree relative with dementia, which indicated an elevated risk for future cognitive decline. INTERVENTION: Triple Pill (active antihypertensive treatment of telmisartan 20 mg, amlodipine 2.5 mg and indapamide 1.25 mg) or placebo Triple Pill (blinded study capsules). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was feasibility of the study expressed as the percentage of participants randomised from those who were screened. Secondary outcomes were the applicability of videoconference measures of cognition and the overall trial, tolerability of the Triple Pill, safety outcomes and medication adherence. RESULTS: The proportion (95% CI) of patients randomised to those screened was 5% (2%-10%). The applicability of the trial expressed as percentage of those who completed all remote assessments over the number of randomised participants was 67% (95% CI 05 to 22%). There were no serious adverse events or withdrawals from treatment. All participants adhered to study medication, except for one person who had two capsules left at the end of the study period. CONCLUSIONS: The feasibility of this decentralised trial on BP lowering in patients at high risk for dementia is low. However, the applicability of remote assessments of cognitive function is acceptable. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000121864.

Protocol for a randomized controlled trial of intensive blood pressure control on cardiovascular risk reduction in patients with atrial fibrillation: Rationale and design of the CRAFT trial.

BACKGROUND: Co-morbid hypertension is strong predictor of adverse cardiovascular (CV) outcomes in patients with atrial fibrillation (AF) but the optimal target for blood pressure (BP) control in this patient population has not been clearly defined. METHODS: The Cardiovascular Risk reduction in patients with Atrial Fibrillation Trial (CRAFT) is an investigator-initiated and conducted, international, multicenter, open-label, parallel-group, blinded outcome assessed, randomized controlled trial of intensive BP control in patients with AF. The aim is to determine whether intensive BP control (target home systolic blood pressure [SBP] <120 mmHg) is superior to standard BP control (home SBP <135 mmHg) on the hierarchical composite outcome of time to CV death, number of stroke events, time to the first stroke, number of myocardial infarction (MI) events, time to the first MI, number of heart failure hospitalization (HFH) events, and time to the first HFH. A sample size of 1,675 patients is estimated to provide 80% power to detect a win-ratio of 1.50 for intensive versus standard BP control on the primary composite outcome. Study visits are conducted at 1, 2, 3, and 6 months postrandomization, and every 6 months thereafter during the study. CONCLUSIONS: This clinical trial aims to provide reliable evidence of the effects of intensive BP control in patients with AF. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT04347330).

Culture and Awe: Understanding Awe as a Mixed Emotion.

Recent work is establishing awe as an important positive emotion that offers physical and psychological benefits. However, early theorizing suggests that awe's experience is often tinged with fear. How then, do we reconcile emergent positive conceptualizations of awe with its more fearful elements? We suggest that positive conceptualizations of awe may partially reflect modern Western experiences of this emotion, which make up the majority of participant samples when studying awe. To test whether awe contains more fearful qualities outside of Western cultures, we compared participants' experiences of this emotion in China to those in the United States. In a two-week daily diary study (Study 1), Chinese participants reported greater fear than American participants during experiences of awe, but not a comparison positive emotion. In response to a standardized awe induction (Study 2), Chinese participants reported more fear, whereas American participants reported more positive emotions. Physiological changes in autonomic activity differed by culture only for heart rate, but not skin conductance or respiratory sinus arrhythmia. These findings reveal that awe may be experienced as a more fearful, mixed emotion in China than in the United States and suggest that current positive conceptualizations of awe may reflect a disproportionate reliance on modern Western samples. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-024-00243-3.

Statistical analysis plan for the Chinese Herbal medicine in Acute INtracerebral haemorrhage (CHAIN) trial.

INTRODUCTION: The traditional Chinese medicine (TCM) herbal compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage (ICH) by reducing brain edema, hematoma absorption, and enhancement of the immune system. We outline the statistical analysis plan (SAP) for the Chinese Herbal medicine in Acute INtracerebral haemorrhage (CHAIN) study. DESIGN: CHAIN is a multicenter, prospective, randomized, double-blind, placebo-controlled trial being undertaken at 20-30 hospitals in China. After the completion of eligibility checks, patients are randomly allocated to FYTF-919 (100 mL per day, oral) or matching placebo over 28 days. A sample size of 1504 patients is estimated to provide 90% power (α 0.05) for a 0.06 absolute improvement in the primary outcome of utility-weighted modified Rankin scale scores at 90 days, analyzed by general linear regression. METHODS: The statistical analysis plan was developed by the study statistician, principal investigators, international experts, and the study project manager. The plan provides details for analyzing baseline characteristics, patient management, and outcomes. It includes provisions for covariate adjustments, subgroup analysis, the handling missing data, and in the conduct of sensitivity analyzes. RESULTS: A predefined statistical analysis plan was established for CHAIN, facilitating transparent and verifiable analysis. CONCLUSIONS: The CHAIN statistical analysis plan was prospectively developed with a focus on maintaining high-quality standards of internal validity to minimise potential analysis biases. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05066620).

Recommendations for Implementing the INTERACT3 Care Bundle for Intracerebral Hemorrhage in Latin America: Results of a Delphi Method.

INTRODUCTION: The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT3) showed that the implementation of a care bundle improves outcomes after acute intracerebral hemorrhage (ICH). We aimed to establish consensus-based recommendations for the broader integration of the care bundle across Latin American countries (LAC). METHODS: A 3-phase Delphi study allowed a panel of 32 healthcare workers from 14 LAC to sequentially rank statements relevant to 7 domains (training, resources/infrastructure, patient education, blood pressure, temperature, glycemic control, and anticoagulation reversal). The pre-defined consensus threshold was 75%. RESULTS: A total of 43 statements reached consensus by the third round, with 12 new statements emerging through rounds. The highest-ranked statements in each domain emphasized critical aspects, but successful implementation requires appropriate resourcing. Key priorities were continuous training of all healthcare workers in ICH management, establishing protocols aligned with available resources, and collaborative interdisciplinary care supported by institutional networks. Statements related to anticoagulation reversal had the highest priority. CONCLUSIONS: Consensus statements are provided to facilitate integration of the INTERACT3 care bundle to reduce disparities in ICH outcomes in LAC.

Spatiotemporal alterations in the brain oscillations of Arctic explorers.

BACKGROUND: The limited understanding of the physiology and psychology of polar expedition explorers has prompted concern over the potential cognitive impairments caused by exposure to extreme environmental conditions. Prior research has demonstrated that such stressors can negatively impact cognitive function, sleep quality, and behavioral outcomes. Nevertheless, the impact of the polar environment on neuronal activity remains largely unknown. METHODS: In this study, we aimed to investigate spatiotemporal alterations in brain oscillations of 13 individuals (age range: 22-48 years) who participated in an Arctic expedition. We utilized electroencephalography (EEG) to record cortical activity before and during the Arctic journey, and employed standardized low resolution brain electromagnetic tomography to localize changes in alpha, beta, theta, and gamma activity. RESULTS: Our results reveal a significant increase in the power of theta oscillations in specific regions of the Arctic, which differed significantly from pre-expedition measurements. Furthermore, microstate analysis demonstrated a significant reduction in the duration of microstates (MS) D and alterations in the local synchrony of the frontoparietal network. CONCLUSION: Overall, these findings provide novel insights into the neural mechanisms underlying adaptation to extreme environments. These findings have implications for understanding the cognitive consequences of polar exploration and may inform strategies to mitigate potential neurological risks associated with such endeavors. Further research is warranted to elucidate the long-term effects of Arctic exposure on brain function.

Sex Differences in Profile and In-Hospital Death for Acute Stroke in Chile: Data From a Nationwide Hospital Registry.

BACKGROUND: Knowledge of local contextual sex differences in the profile and outcome for stroke can improve service delivery. We aimed to determine sex differences in the profile of patients with acute stroke and their associations with in-hospital death in the national hospital database of Chile. METHODS AND RESULTS: We present a retrospective cohort based on the analysis of the 2019 Chilean database of Diagnosis-Related Groups, which represents 70% of the operational expenditure of the public health system. Random-effects multiple logistic regression models were used to determine independent associations of acute stroke (defined by main diagnosis International Classification of Diseases, Tenth Revision [ICD-10] codes) and in-hospital death, and reported with odds ratios (ORs) and 95% CIs. Of 1 048 575 hospital discharges, 15 535 were for patients with acute stroke (7074 [45.5%] in women), and 2438 (15.6%) of them died during hospitalization. Differences by sex in sociodemographic and clinical characteristics were identified for stroke and main subtypes. After fully adjusted model, women with ischemic stroke had lower in-hospital death (OR, 0.79 [95% CI, 0.69-0.91]) compared with men; other independent predictors included age per year increase (OR, 1.03 [95% CI, 1.03-1.04]), chronic kidney disease (OR, 1.47 [95% CI, 1.20-1.80]), atrial fibrillation (OR, 1.50 [95% CI, 1.26-1.80]), and other risk factors. Conversely, for intracerebral hemorrhage, women had a higher in-hospital mortality rate than men (OR, 1.19 [95% CI, 1.02-1.40]); other independent predictors included age per year increase (OR, 1.009 [95% CI, 1.003-1.01]), chronic kidney disease (OR, 1.55 [95% CI, 1.23-1.97]), oral anticoagulant use (OR, 1.88 [95% CI, 1.37-2.58]), and other risk factors. CONCLUSIONS: Sex differences in characteristics and in-hospital death of hospitalized patients exist for acute stroke in Chile. In-hospital death is higher for acute ischemic stroke in men and higher for intracerebral hemorrhage in women. Future research is needed to better identify contributing factors.

Strand-resolved mutagenicity of DNA damage and repair.

DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution.

Contrast Sensitivity, Visual Field, Color Vision, Motion Perception, and Cognitive Impairment: A Systematic Review.

OBJECTIVES: To examine relationships between visual function (ie, contrast sensitivity, visual field, color vision, and motion perception) and cognitive impairment, including any definition of "cognitive impairment," mild cognitive impairment, or dementia. DESIGN: Systematic review and meta-analyses. SETTING AND PARTICIPANTS: Any settings; participants with (cases) or without (controls) cognitive impairment. METHODS: We searched 4 databases (to January 2024) and included published studies that compared visual function between cases and controls. Standardized mean differences (SMD) with 95% CIs were calculated where data were available. Data were sufficient for meta-analyses when cases were people with dementia. The Joanna Briggs Institute checklists were used for quality assessment. RESULTS: Fifty-one studies/69 reports were included. Cross-sectional evidence shows that people with dementia had worse contrast sensitivity function and color vision than controls: measured by contrast sensitivity (log units) on letter charts, SMD -1.22 (95% CI -1.98, -0.47), or at varied spatial frequencies, -0.92 (-1.28, -0.57); and by pseudoisochromatic plates, -1.04 (-1.59, -0.49); color arrangement, -1.30 (-2.31, -0.29); or matching tests, -0.51 (-0.78, -0.24). They also performed more poorly on tests of motion perception, -1.20 (-1.73, -0.67), and visual field: mean deviation, -0.87 (-1.29, -0.46), and pattern standard deviation, -0.69 (-1.24, -0.15). Results were similar when cases were limited to participants with clinically diagnosed Alzheimer disease. Sources of bias included lack of clarity on study populations or settings and definitions of cognitive impairment. The 2 included longitudinal studies with follow-ups of approximately 10 years were of good quality but reported inconsistent results. CONCLUSIONS AND IMPLICATIONS: In the lack of longitudinal data, cross-sectional studies indicate that individuals with cognitive impairment have poorer visual function than those with normal cognition. Additional longitudinal data are needed to understand whether poor visual function precedes cognitive impairment and the most relevant aspects of visual function, dementia pathologies, and domains of cognition.

Harnessing cold adaptation for postglacial colonisation: Galactinol synthase expression and raffinose accumulation in a polyploid and its progenitors.

Allotetraploid white clover (Trifolium repens) formed during the last glaciation through hybridisation of two European diploid progenitors from restricted niches: one coastal, the other alpine. Here, we examine which hybridisation-derived molecular events may have underpinned white clover's postglacial niche expansion. We compared the transcriptomic frost responses of white clovers (an inbred line and an alpine-adapted ecotype), extant descendants of its progenitor species and a resynthesised white clover neopolyploid to identify genes that were exclusively frost-induced in the alpine progenitor and its derived subgenomes. From these analyses we identified galactinol synthase, the rate-limiting enzyme in biosynthesis of the cryoprotectant raffinose, and found that the extant descendants of the alpine progenitor as well as the neopolyploid white clover rapidly accumulated significantly more galactinol and raffinose than the coastal progenitor under cold stress. The frost-induced galactinol synthase expression and rapid raffinose accumulation derived from the alpine progenitor likely provided an advantage during early postglacial colonisation for white clover compared to its coastal progenitor.

DNA lesion bypass and the stochastic dynamics of transcription-coupled repair.

DNA base damage is a major source of oncogenic mutations and disruption to gene expression. The stalling of RNA polymerase II (RNAP) at sites of DNA damage and the subsequent triggering of repair processes have major roles in shaping the genome-wide distribution of mutations, clearing barriers to transcription, and minimizing the production of miscoded gene products. Despite its importance for genetic integrity, key mechanistic features of this transcription-coupled repair (TCR) process are controversial or unknown. Here, we exploited a well-powered in vivo mammalian model system to explore the mechanistic properties and parameters of TCR for alkylation damage at fine spatial resolution and with discrimination of the damaged DNA strand. For rigorous interpretation, a generalizable mathematical model of DNA damage and TCR was developed. Fitting experimental data to the model and simulation revealed that RNA polymerases frequently bypass lesions without triggering repair, indicating that small alkylation adducts are unlikely to be an efficient barrier to gene expression. Following a burst of damage, the efficiency of transcription-coupled repair gradually decays through gene bodies with implications for the occurrence and accurate inference of driver mutations in cancer. The reinitation of transcription from the repair site is not a general feature of transcription-coupled repair, and the observed data is consistent with reinitiation never taking place. Collectively, these results reveal how the directional but stochastic activity of TCR shapes the distribution of mutations following DNA damage.

Risk of recurrent stroke and dementia following acute stroke by changes in kidney function: results from the Perindopril Protection Against Recurrent Stroke Study.

BACKGROUND: Limited data exist on the relationship between declining kidney function and cardiovascular events, dementia, and mortality in patients with a history of stroke.Thus the aims of the study were to investigate functional relationships between dynamic kidney function change and cardiovascular outcomes, and clarify whether adding kidney parameters to conventional cardiovascular risk factors improves model discrimination. METHODS: Post hoc analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) clinical trial of blood pressure lowering for the secondary prevention of stroke. We examined the association between dynamic kidney function defined as percentage change (declines of >30%, and >0 to ≤30%, and increases of ≥0 to <30%, and ≥30%) in estimated glomerular filtration rate (eGFR) over 2 years and recurrent stroke, major cardiovascular events, dementia and all-cause death over the next 2 years using Cox proportional hazard models controlling for eGFR at registration and potential confounders. Restricted cubic splines were used to assess the functional relationships. C-statistics and Net Reclassification Improvement (NRI) at 2 years were used to assess model discrimination. RESULTS: In 4591 patients followed for a mean of approximately 2 years, 254 (5.5%) developed recurrent stroke, 391 (8.5%) had a major cardiovascular event, 221 (4.8%) developed dementia, and 271 (5.9%) died. Reverse J-like or U-like relationships were observed for percent declines in eGFR and outcomes. Using declines in eGFR of >0 to ≤30% as a reference, increased risks were evident for a greater decline (>30%) in relation to recurrent stroke [adjusted hazard ratio 1.85, 95% confidence interval (CI) 1.20-2.85], major cardiovascular event (2.24, 1.62-3.10) and all-cause death (2.09, 1.39-3.15). A larger increase (≥30%) in eGFR was also associated with a greater risk of all-cause death (1.96, 1.14-3.37). Improvements in the C-statistic were found by adding baseline eGFR and percent change compared with a model with conventional cardiovascular risk factors alone, for major cardiovascular events, dementia, and all-cause mortality. CONCLUSION: Declining kidney function following an incident cerebrovascular event is associated with additional risk of a major cardiovascular events, dementia, and 2-year mortality. However, a large increase in kidney function was also found to be associated with a higher risk of mortality.

Statistical Analysis Plan for the INTEnsive Ambulance-Delivered Blood Pressure Reduction in Hyper-ACute Stroke Trial.

INTRODUCTION: Recruitment is complete in the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4), a multicenter, prospective, randomized, open-label, blinded endpoint assessed trial of prehospital blood pressure (BP) lowering initiated in the ambulance for patients with a suspected acute stroke and elevated BP in China. According to the registered and published trial protocol and developed by the blinded trial Steering Committee and Operations team, this manuscript outlines a detailed statistical analysis plan for the trial prior to database lock. METHODS: Patients were randomized (1:1) to intensive (target systolic BP 130-140 mm Hg within 30 min) or guideline-recommended BP management (BP lowering only considered if systolic BP >220 mm Hg) group. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale at 90 days. A modified sample size of 2,320 was estimated to provide 90% power to detect a 22% reduction in the odds (common odds ratio of 0.78) of a worse functional outcome using ordinal logistic regression, on the assumption of 5% patients with missing outcome and 6% patients with a stroke mimic. CONCLUSION: The statistical analysis plan for the trial has been developed to ensure transparent, verifiable, and prespecified analysis and to avoid potential bias in the evaluation of the trial intervention.

Predictors of Early versus Delayed Neurological Deterioration after Thrombolysis for Ischemic Stroke.

INTRODUCTION: We aimed to determine predictors of early (END) and delayed neurological deterioration (DND) and their association with the functional outcome in patients with acute ischemic stroke (AIS) who participated in the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: END and DND (without END) were defined as scores of a ≥2-point increase on the National Institutes of Health Stroke Scale (NIHSS) or a ≥1-point decrease on the Glasgow coma scale or death, from baseline to 24 h and 24-72 h, respectively. Multivariable logistic regression models were used to determine independent predictors of END and DND and their association with 90-day outcomes (dichotomous scores on the modified Rankin scale [mRS] of 2-6 vs. 0-1 and 3-6 vs. 0-2 and death). RESULTS: Of 4,496 patients, 871 (19.4%) and 302 (8.4%) patients experienced END and DND, respectively. Higher baseline NIHSS score, older age, large-artery occlusion due to significant atheroma, cardioembolic stroke subtype, hemorrhagic infarction and parenchymatous hematoma within 24 h were all independent predictors for both END (all p ≤ 0.01) and DND (all p ≤ 0.024). Moreover, higher baseline systolic blood pressure (BP) (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.02-1.12), higher diastolic BP variability within 24 h (OR 1.07, 95% CI 1.04-1.09), patients from Asia (OR 1.25, 95% CI 1.03-1.52) were the only independent predictors for END. However, Asian ethnicity was negatively associated with DND (OR 0.64, 95% CI 0.47-0.86). Hemorrhagic infarction and parenchymatous hematoma within 24 h were the key predictors of END across all stroke subtypes. END and DND were all associated with a poor functional outcome at 90 days (all p < 0.001). CONCLUSION: We identified overlapping and unique demographic and clinical predictors of END and DND after thrombolysis for AIS. Both END and DND predict unfavorable outcomes at 90 days.

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke.

BACKGROUND: Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain. METHODS: We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group). The primary efficacy outcome was functional status as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days after randomization. The primary safety outcome was any serious adverse event. RESULTS: A total of 2404 patients (mean age, 70 years) in China underwent randomization and provided consent for the trial: 1205 in the intervention group and 1199 in the usual-care group. The median time between symptom onset and randomization was 61 minutes (interquartile range, 41 to 93), and the mean blood pressure at randomization was 178/98 mm Hg. Stroke was subsequently confirmed by imaging in 2240 patients, of whom 1041 (46.5%) had a hemorrhagic stroke. At the time of patients' arrival at the hospital, the mean systolic blood pressure in the intervention group was 159 mm Hg, as compared with 170 mm Hg in the usual-care group. Overall, there was no difference in functional outcome between the two groups (common odds ratio, 1.00; 95% confidence interval [CI], 0.87 to 1.15), and the incidence of serious adverse events was similar in the two groups. Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common odds ratio, 0.75; 95% CI, 0.60 to 0.92) but an increase among patients with cerebral ischemia (common odds ratio, 1.30; 95% CI, 1.06 to 1.60). CONCLUSIONS: In this trial, prehospital blood-pressure reduction did not improve functional outcomes in a cohort of patients with undifferentiated acute stroke, of whom 46.5% subsequently received a diagnosis of hemorrhagic stroke. (Funded by the National Health and Medical Research Council of Australia and others; INTERACT4 ClinicalTrials.gov number, NCT03790800; Chinese Trial Registry number, ChiCTR1900020534.).

Treatment for intracerebral hemorrhage: Dawn of a new era.

Intracerebral hemorrhage (ICH) is a devastating disease, causing high rates of death, disability, and suffering across the world. For decades, its treatment has been shrouded by the lack of reliable evidence, and consequently, the presumption that an effective treatment is unlikely to be found. Neutral results arising from several major randomized controlled trials had established a negative spirit within and outside the stroke community. Frustration among researchers and a sense of nihilism in clinicians has created the general perception that patients presenting with ICH have a poor prognosis irrespective of them receiving any form of active management. All this changed in 2023 with the positive results on the primary outcome in randomized controlled trials showing treatment benefits for a hyperacute care bundle approach (INTERACT3), early minimal invasive hematoma evacuation (ENRICH), and use of factor Xa-inhibitor anticoagulation reversal with andexanet alfa (ANNEXa-I). These advances have now been extended in 2024 by confirmation that intensive blood pressure lowering initiated within the first few hours of the onset of symptoms can substantially improve outcome in ICH (INTERACT4) and that decompressive hemicraniectomy is a viable treatment strategy in patients with large deep ICH (SWITCH). This evidence will spearhead a change in the perception of ICH, to revolutionize the care of these patients to ultimately improve their outcomes. We review these and other recent developments in the hyperacute management of ICH. We summarize the results of randomized controlled trials and discuss related original research papers published in this issue of the International Journal of Stroke. These exciting advances demonstrate how we are now at the dawn of a new, exciting, and brighter era of ICH management.

Impact of guideline-directed medical therapy on systolic blood pressure and cardiovascular outcomes in patients with heart failure and low blood pressure: A systematic review and meta-analysis.

AIMS: Existing research indicates that patients with heart failure (HF) may have restricted access to guideline-directed medical therapy (GDMT) when their blood pressure (BP) is comparatively low. However, recent clinical trials suggest that HF patients with low BP could still benefit from certain HF medications, which have a minimal impact on BP. This systematic review and meta-analysis was conducted to determine whether this applies to all GDMT. METHODS AND RESULTS: A systematic search of MEDLINE and EMBASE was conducted for studies published from inception to 10 January 2024. Randomized controlled trials were selected if they reported on the longitudinal change of systolic BP (SBP) due to GDMT, or the risks of cardiovascular events in HF patients based on SBP categories. Weighted mean difference (WMD), hazard ratio or relative risk, and corresponding 95% confidence intervals (CI) were pooled for meta-analysis where possible. Data from 20 studies, encompassing information on 84 782 individuals, were analysed. Overall, GDMT is associated with lower SBP (WMD, -2.16; 95% CI -2.86 to -1.46), with no significant difference between baseline low and non-low BP subgroups (interaction p = 0.810). However, SBP of the treatment group increased by 5.8 mmHg from baseline in the low SBP subgroup during follow-up, while it decreased by 4.0 mmHg in the baseline non-low SBP subgroup. GDMT demonstrated similar cardiovascular benefits and risk of hypotension between low and non-low SBP subgroups (interaction p = 0.318 and 0.903, respectively). CONCLUSIONS: Guideline-directed medical therapy is associated with a negligible decrease in SBP, but can provide similar cardiovascular benefits in both low and non-low SBP HF patients, with no significant interaction with SBP as to hypotension. Therefore, GDMT should be initiated and maintained in HF patients with low BP.