Effects of renin-angiotensin system inhibitor and beta-blocker use on mortality in older patients with heart failure with reduced ejection fraction in Japan.

Introduction: Guideline-directed medical therapy with renin-angiotensin system (RAS) inhibitors and beta-blockers has improved the survival of patients with heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, it is unclear whether RAS inhibitors and beta-blockers can be administered to older patients with HF. Therefore, this study aimed to investigate the effects of beta-blockers and RAS inhibitors on the prognosis of older patients with HFrEF. Methods: Demographic, clinical, and pharmacological data from 1,061 patients with acute decompensated HF, enrolled in the Kochi Registry of Subjects with Acute Decompensated Heart Failure (Kochi YOSACOI study), were analyzed to assess their impact on mortality. Additionally, a machine learning approach was applied to complement the conventional statistical model for analysis. Patients with HFrEF (n = 314) were divided into the all-cause mortality within 2 years group (n = 80) and the survivor group (n = 234). Results: Overall, 41.1% (129/314) of the patients were aged ≥80, and 25.5% (80/314) experienced all-cause mortality within 2 years. Furthermore, 57.6% (181/314) and 79.0% (248/314) were prescribed RAS inhibitors and beta-blockers, respectively. Our analysis showed that RAS inhibitor use was associated with reduced all-cause mortality and cardiac death in patients with HFrEF of all ages (P < 0.001), and beta-blocker use had an interaction with age. Machine learning revealed that the use of beta-blockers altered the risk of mortality, with a threshold of approximately 80 years of age. Beta-blocker use was associated with lower all-cause mortality and cardiac death in patients with HFrEF aged <80 years (P < 0.001) but not in those aged ≥80 years (P = 0.319 and P = 0.246, respectively). These results suggest that beta blockers may differ in their all-cause mortality benefits according to age. Conclusions: RAS inhibitors prevented all-cause mortality and cardiac death at all ages, whereas beta-blockers had different effects depending on the patient's age. This study suggested that the choice of beta-blockers and RAS inhibitors is more important in older patients with HFrEF than in younger patients with the same condition.

Retrograde thrombectomy of acute common carotid artery occlusion with mobile thrombus: illustrative cases.

BACKGROUND: Acute embolic occlusion of the common carotid artery (CCA) alone is rare. However, once it occurs, recanalization is challenging due to the large volume of the clot, larger diameter of the CCA, and risk of procedure-related distal embolism into the intracranial arteries. OBSERVATIONS: The authors report two cases of acute embolic occlusion of CCA alone, caused by a cardiac embolus trapped at the proximal end of a preexisting atherosclerotic plaque at the cervical carotid bifurcation. In both cases, the CCA was successfully recanalized using retrograde thrombectomy in a hybrid operating room. In case 1, a 78-year-old male with acute right CCA occlusion underwent retrograde thrombectomy, where the cervical carotid bifurcation was exposed and incised, and the entire embolus was retrieved with forceps. Despite successful revascularization, massive bleeding from the CCA just after the retrieval remained a concern. In case 2, a 79-year-old female with acute right CCA occlusion underwent retrograde thrombectomy in the same manner. Because manual retrieval failed, a Fogarty balloon catheter inserted from the arteriotomy successfully retrieved the entire thrombus with minimal blood loss. LESSONS: Retrograde thrombectomy through the arteriotomy of the cervical carotid bifurcation safely and effectively recanalizes acute embolic occlusion of the CCA alone.

Cerebrospinal Fluid Refill Test as a Novel Diagnostic Tool for Cerebrospinal Fluid Hypovolemia: Preliminary Result.

OBJECTIVE: Cerebrospinal fluid (CSF) hypovolemia presents with orthostatic headaches due to CSF leakage. However, a direct association between the lack of CSF and clinical symptoms has not been found. CSF hypovolemia can be improved by refilling CSF. Therefore, we assessed the validity of a CSF refill test. METHODS: From November 2019 to August 2021, we included 10 patients (≥18 years old) with potential CSF hypovolemia, clear orthostatic headaches, and a CSF opening pressure <10 cmH2O. In the CSF refill test, 10 mL of artificial CSF was injected intrathecally. The primary outcome was improvement in orthostatic headache assessed using a visual analog scale (VAS), while the secondary outcomes were the 10-m walk time and adverse events. When the symptoms temporarily improved after intrathecal injection, the patients underwent radiologic imaging to identify the CSF leak, and an epidural blood patch was proposed accordingly. RESULTS: All patients showed post-test improvements in the VAS score (median [interquartile range], pretest 63.0 [50.3-74.3] vs. post-test 1.5 [0.0-26.0]). The 10-m walk time also significantly improved (9.5 [8.5-10.2] s vs. 8.2 [7.9-8.7] s). One patient experienced temporary right leg numbness associated with a lumbar puncture. After radiologic investigation, 9 patients underwent epidural blood patches, of which 6 were completely cured, and 3 revealed partial improvement. CONCLUSIONS: The cerebrospinal fluid (CSF) refill test was safe and effective in demonstrating the direct association between the lack of CSF and clinical symptoms and may help predict the outcome of an epidural blood patch.

Superiority of Endovascular Coiling Over Surgical Clipping for Clinical Outcomes at Discharge in Patients With Poor-Grade Subarachnoid Hemorrhage: A Registry Study in Japan.

BACKGROUND AND OBJECTIVES: The differences in clinical outcomes between endovascular coiling (EC) and surgical clipping (SC) in patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) are controversial. Therefore, this study aimed to evaluate whether EC is superior to SC and identify risk factors in patients with poor-grade aSAH. METHODS: We used data from the "Predict for Outcome Study of aneurysmal SubArachnoid Hemorrhage." World Federation of Neurological Societies (WFNS) grade III-V aSAH was defined as poor-grade aSAH, and unfavorable clinical outcomes (modified Rankin Scale scores 3-6) were compared between SC and EC after propensity score matching (PSM). In-hospital mortality was similarly evaluated. Predictors of unfavorable clinical outcomes were identified using multivariable analysis. RESULTS: Ultimately, 1326 (SC: 847, EC: 479) and 632 (SC: 316, EC: 316) patients with poor-grade aSAH were included before and after PSM, respectively. Unfavorable clinical outcomes at discharge were significantly different between SC and EC before (72.0% vs 66.2%, P = .026) and after PSM (70.6% vs 63.3%, P = .025). In-hospital mortality was significantly different between groups before PSM (10.5% vs 16.1%, P = .003) but not after PSM (10.4% vs 12.7%, P = .384). Predictors of unfavorable clinical outcomes in both SC and EC were WFNS grade V, older than 70 years, and Fisher computed tomography (CT) grade 4. Predictors of unfavorable clinical outcomes only in SC were WFNS grade IV (odds ratio: 2.46, 95% CI: 1.22-4.97, P = .012) and Fisher CT grade 3 (4.90, 1.42-16.9, P = .012). Predictors of unfavorable clinical outcome only in EC were ages of 50s (3.35, 1.37-8.20, P = .008) and 60s (3.28, 1.43-7.52, P = .005). CONCLUSION: EC resulted in significantly more favorable clinical outcomes than SC in patients with poor-grade aSAH, without clear differences in in-hospital mortality. The benefit of EC over SC might be particularly remarkable in patients with WFNS grade IV and Fisher CT grade 3.

Impact of areal socioeconomic status on prehospital delay of acute ischaemic stroke: retrospective cohort study from a prefecture-wide survey in Japan.

OBJECTIVES: To examine whether the Areal Deprivation Index (ADI), an indicator of the socioeconomic status of the community the patient resides in, is associated with delayed arrival at the hospital and poor outcomes in patients with acute ischaemic stroke from a prefecture-wide stroke database in Japan. DESIGN: Retrospective study. SETTING: Twenty-nine acute stroke hospitals in Kochi prefecture, Japan. PARTICIPANTS: Nine thousand and six hundred fifty-one patients with acute ischaemic stroke who were urgently hospitalised, identified using the Kochi Acute Stroke Survey of Onset registry. Capital and non-capital areas were analysed separately. PRIMARY AND SECONDARY OUTCOME MEASURES: Prehospital delay defined as hospital arrival ≥4-hour after stroke onset, poor hospital outcomes (in-hospital mortality and discharge to a nursing facility) and the opportunities of intravenous recombinant tissue plasminogen activator (rt-PA) and endovascular reperfusion therapy. RESULTS: In the overall cohort, prehospital delay was observed in 6373 (66%) patients. Among individuals residing in non-capital areas, those living in municipalities with higher ADI (more deprived) carried a significantly higher risk of prehospital delay (per one-point increase, OR (95% CI) 1.45 (1.26 to 1.66)) by multivariable logistic regression analysis. In-hospital mortality (1.45 (1.02 to 2.06)), discharge to a nursing facility (1.31 (1.03 to 1.66)), and delayed candidate arrival ≥2-hour of intravenous rt-PA (2.04 (1.30 to 3.26)) and endovascular reperfusion therapy (2.27 (1.06 to 5.00)), were more likely to be observed in the deprived areas with higher ADI. In the capital areas, postal-code-ADI was not associated with prehospital delay (0.97 (0.66 to 1.41)). CONCLUSIONS: Living in socioeconomically disadvantaged municipalities was associated with prehospital delays of acute ischaemic stroke in non-capital areas in Kochi prefecture, Japan. Poorer outcomes of those patients may be caused by delayed treatment of intravenous rt-PA and endovascular reperfusion therapy. Further studies are necessary to determine social risk factors in the capital areas. TRIAL REGISTRATION NUMBER: This article is linked to a clinical trial to UMIN000050189, No.: R000057166 and relates to its Result stage.

Formation of Amino Acids and Carboxylic Acids in Weakly Reducing Planetary Atmospheres by Solar Energetic Particles from the Young Sun.

Life most likely started during the Hadean Eon; however, the environmental conditions which contributed to the complexity of its chemistry are poorly known. A better understanding of various environmental conditions, including global (heliospheric) and local (atmospheric, surface, and oceanic), along with the internal dynamic conditions of the early Earth, are required to understand the onset of abiogenesis. Herein, we examine the contributions of galactic cosmic rays (GCRs) and solar energetic particles (SEPs) associated with superflares from the young Sun to the formation of amino acids and carboxylic acids in weakly reduced gas mixtures representing the early Earth's atmosphere. We also compare the products with those introduced by lightning events and solar ultraviolet light (UV). In a series of laboratory experiments, we detected and characterized the formation of amino acids and carboxylic acids via proton irradiation of a mixture of carbon dioxide, methane, nitrogen, and water in various mixing ratios. These experiments show the detection of amino acids after acid hydrolysis when 0.5% (v/v) of initial methane was introduced to the gas mixture. In the set of experiments with spark discharges (simulation of lightning flashes) performed for the same gas mixture, we found that at least 15% methane was required to detect the formation of amino acids, and no amino acids were detected in experiments via UV irradiation, even when 50% methane was used. Carboxylic acids were formed in non-reducing gas mixtures (0% methane) by proton irradiation and spark discharges. Hence, we suggest that GCRs and SEP events from the young Sun represent the most effective energy sources for the prebiotic formation of biologically important organic compounds from weakly reducing atmospheres. Since the energy flux of space weather, which generated frequent SEPs from the young Sun in the first 600 million years after the birth of the solar system, was expected to be much greater than that of GCRs, we conclude that SEP-driven energetic protons are the most promising energy sources for the prebiotic production of bioorganic compounds in the atmosphere of the Hadean Earth.

National trends in the outcomes of subarachnoid haemorrhage and the prognostic influence of stroke centre capability in Japan: retrospective cohort study.

OBJECTIVES: To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan. DESIGN: Retrospective study. SETTING: Six hundred and thirty-one primary care institutions in Japan. PARTICIPANTS: Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database. PRIMARY AND SECONDARY OUTCOME MEASURES: Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3-6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1-25 points). RESULTS: In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality. CONCLUSIONS: The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.

Quantitative evaluation for intravascular structures of vertebral artery dissection with a novel zoomed high-resolution black-blood MR imaging.

BACKGROUND: Although non-stroke vertebral artery dissection (VAD) is diagnosed using MRI, detecting the subtle intravascular structure remains challenging. This study aimed to evaluate the validity of quantitative intravascular scanning based on novel zoomed high-resolution black blood (Z-HB) MRI for distinguishing VAD from other vessel pathologies. METHODS: Twenty-one patients with non-stroke VAD and 18 with symptomatic atherosclerotic plaques in their vertebral artery underwent Z-HB MRI and subsequent profile curve processing. Axial Z-HB imaging was obtained from dissected and normal segments in patients with VAD and atherosclerotic plaque in patients with ischemia. We investigated the qualitative categorization of the scanning patterns of the intravascular signals. We also evaluated the quantitative ability of each profile curve to discriminate multiple vessel pathologies by analyzing the receiver operating characteristics curves. RESULTS: Profile curve processing of 140 Z-HB images categorized the intravascular signal patterns into luminal, asymmetrical, and omega types. The asymmetrical type included both dissecting and atherosclerotic vessels, and the omega type included dissecting and normal vessels. In the asymmetrical type, quantitative evaluation successfully distinguished intramural hematomas of VAD from atherosclerotic plaque with an area under the curve of 0.80. The intimal flap of the VAD was distinguished from the blood flow artifact of the normal vessel with an area under the curve of 0.93 in the omega type. CONCLUSIONS: A combination of novel Z-HB MRI and profile curve processing provided an ultra-high-resolution analysis of the intravascular structure of non-stroke VAD and successfully distinguished VAD from normal vessels or atherosclerotic plaques.

Recent Declining Trend of Incidence Rate of Subarachnoid Hemorrhage in Shimane, Japan: The Japan Incidence of Subarachnoid Hemorrhage (JIS) Study.

The "Izumo Study" revealed the incidence rate of subarachnoid hemorrhage (SAH) in Izumo City, Shimane Prefecture, Japan, from 1980 to 1998. However, no study has been published regarding the incidence of SAH in Shimane Prefecture after 1998. Most studies reporting the incidence of SAH in Japan have been conducted before 2000, although a few have been reported after 2000. This study aimed to assess the estimated age-adjusted incidence rate (AAIR) of SAH in Shimane Prefecture after 1998, following the Izumo Study. A retrospective study was conducted to identify the estimated AAIR of SAH in Shimane Prefecture, using the age-adjusted SAH mortality rate for this population from 1999 to 2017 and assuming that the case-fatality rate of SAH decreased by 0.7% annually from 45% in 1999 to 32.4% in 2017. We used linear regression analysis for trend to the estimated AAIR of SAH. Sensitivity analyses were also conducted by various case-fatality rates of SAH using assuming case-fatality rate based on previous reports. The estimated AAIR of SAH in Shimane Prefecture declined from 33.6 (95% confidence interval [CI]: 29.7-37.9) per 100,000 person-years in 1999, by 26.5%, to 24.7 (95% CI: 21.4-28.5) in 2017 (p < 0.01, r = 0.58). Declining trend of incidence rate of SAH in Shimane Prefecture from 1999 to 2017 was confirmed in this study.

Flow alteration therapy for impending rupture of intracranial giant aneurysm after flow diverter placement.

Background: Flow diverter (FD) placement is generally effective for intractable internal carotid artery (ICA) aneurysms. However, salvage treatment for the aneurysm enlarging even after FD placement remains to be elucidated. Additional overlapping FD placement is considered the first-line treatment for residual or recurrent aneurysms. However, it is unclear whether overlapping FD is also effective for enlarging giant aneurysms that are considered impending rupture status. Although parent artery occlusion is a promising option, treatment strategy must be optimized, especially when a critical perforating artery is involved. Case Description: A 74-year-old woman experienced rapid symptomatic growth of her giant supraclinoid ICA aneurysm 10 months after FD placement. We assumed that reinforcement of flow diverting effect alone would be less effective for this extremely intractable aneurysm with more aggressive clinical feature so that surgical bailout by parent artery occlusion was planned. Complete ICA obliteration underneath the aneurysm was unavailable due to the presence of anterior choroidal artery. Thus, we took a flow alteration strategy, where we created minimal retrograde flow through the parent artery by a combination of an extracranial-intracranial bypass and targeted endovascular proximal parent artery obliteration, resulting in prevention of aneurysmal rupture and further growth. Conclusion: Impending rupture of the intracranial giant aneurysm after FD placement may be controllable with a tailor-made parent artery occlusion strategy even when a critical perforating artery is involved.

Association of Aggression and Antiepileptic Drugs: Analysis Using the Japanese Adverse Drug Event Report (JADER) Database.

Aggression is the most common adverse effect of antiepileptic drugs (AEDs). This study aimed to investigate the association of aggression with AED use. The reporting odds ratio (ROR) from adverse event reports, submitted to the Japanese Adverse Drug Event Report database between 2004 and 2020, was used to calculate and investigate the association between AEDs and aggression. We also analyzed the association of aggression with the combined use of AEDs and the relationship between AED-associated aggression and patient characteristics. A total of 433 patients developed aggression. Significant aggression signals were detected for perampanel (crude ROR: 325.04, 95% confidence interval (CI): 118.48-752.58, p < 0.01), levetiracetam (crude ROR: 17.14, 95% CI: 10.33-26.90, p < 0.01), lacosamide (crude ROR: 16.90, 95% CI: 2.02-62.51, p < 0.01), lamotrigine (crude ROR: 15.98, 95% CI: 9.99-24.39, p < 0.01), valproate (crude ROR: 6.68, 95% CI: 4.27-10.02, p < 0.01), and carbamazepine (crude ROR: 2.47, 95% CI: 1.17-4.59, p < 0.01). The combined therapy with perampanel and levetiracetam had a significant aggression signal (adjusted ROR: 25.90, 95% CI: 1.14-59.10, p < 0.01). In addition, we found that aggression frequently occurred in patients <60 year (adjusted ROR: 2.88, 95% CI: 1.49-5.56, p < 0.01) treated with levetiracetam. These results may be useful for minimizing the risk of aggression during the treatment of AEDs.

Assisted Living and Medication Adherence in Super-aged Patients With Heart Failure in the Japanese Population.

ABSTRACT: Poor adherence to medication in patients with heart failure (HF) is associated with poor clinical outcomes. Although social support has been reported to improve medication adherence in patients with HF, the detailed underlying mechanism of this association is unclear. This study investigated appropriate social support types to ensure medication adherence, as well as patient characteristics that benefit from such social support in patients with HF. This was a retrospective observational study investigating the association of social support with medication adherence in 824 patients with HF who were registered in a prospective multicenter database. First, we analyzed the association between social support types and poor medication adherence leading to hospitalization. An interaction analysis was performed to detect patients' characteristics that benefited most from social support in terms of medical adherence. Fifty patients (6.1%) were hospitalized for poor adherence to medications. Multivariable analysis revealed that not receiving assisted living, which was defined as having supporting individuals at least once a week, was independently associated with poor medication adherence-related hospitalization. An interaction analysis revealed that patients with dementia benefited from assisted living significantly, whereas male patients or current smokers did not. Summarily, assisted living at least once a week was appropriate for improving medication adherence in patients with HF and was particularly effective in patients with dementia. Performed in a super-aging region in Japan, this study may also suggest the relevance of social support in preventing HF exacerbation in other developed countries that will experience an aging society in the near future.

Association of 5-aminolevulinic acid with intraoperative hypotension in malignant glioma surgery.

BACKGROUND: Use of 5-aminolevulinic acid for photodynamic malignant tumor diagnosis reportedly causes intraoperative hypotension (systolic blood pressure < 70 mmHg) during urologic surgery. However, its association with intraoperative hypotension in malignant glioma surgery and underlying mechanisms has not yet been elucidated.. This study aimed to investigate whether 5-aminolevulinic acid administration is associated with intraoperative hypotension in malignant glioma surgery and explore the mechanisms of 5-aminolevulinic acid-induced hypotension in vitro. METHODS: In this retrospective multicenter cohort study, we investigated intracellular nitric oxide as a candidate mediator of hypotension in response to 5-aminolevulinic acid in vitro in human umbilical vein endothelial cell cultures. RESULTS: Of 142 patients, 94 underwent 5-aminolevulinic acid-guided surgery. Systolic blood pressure was significantly lower throughout surgery with 5-aminolevulinic acid administration. 5-Aminolevulinic acid administration was an independent risk factor for intraoperative hypotension according to multivariable logistic regression analysis (89% vs. 56%; odds ratio = 6.72, 95% confidence interval [2.05-22.1], P = 002). In subgroup analysis of the 5-aminolevulinic acid group, increasing age and use of renin-angiotensin system inhibitors had a synergistic effect with 5-aminolevulinic acid on decreased blood pressure. In the vascular endothelial cell culture study, 5-aminolevulinic acid induced a significant increase in intracellular nitric oxide generation. CONCLUSIONS: 5-Aminolevulinic acid administration was associated with intraoperative hypotension in malignant glioma surgery, with increasing age and use of renin-angiotensin system inhibitors boosting the blood pressure-lowering effect of 5-aminolevulinic acid. According to in vitro results, the low blood pressure induced by 5-aminolevulinic acid may be mediated by a nitric oxide increase in vascular endothelial cells.

Rescue therapy for vasospasm following aneurysmal subarachnoid hemorrhage: a propensity score-matched analysis with machine learning.

OBJECTIVE: Rescue therapies have been recommended for patients with angiographic vasospasm (aVSP) and delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH). However, there is little evidence from randomized clinical trials that these therapies are safe and effective. The primary aim of this study was to apply game theory-based methods in explainable machine learning (ML) and propensity score matching to determine if rescue therapy was associated with better 3-month outcomes following post-SAH aVSP and DCI. The authors also sought to use these explainable ML methods to identify patient populations that were more likely to receive rescue therapy and factors associated with better outcomes after rescue therapy. METHODS: Data for patients with aVSP or DCI after SAH were obtained from 8 clinical trials and 1 observational study in the Subarachnoid Hemorrhage International Trialists repository. Gradient boosting ML models were constructed for each patient to predict the probability of receiving rescue therapy and the 3-month Glasgow Outcome Scale (GOS) score. Favorable outcome was defined as a 3-month GOS score of 4 or 5. Shapley Additive Explanation (SHAP) values were calculated for each patient-derived model to quantify feature importance and interaction effects. Variables with high SHAP importance in predicting rescue therapy administration were used in a propensity score-matched analysis of rescue therapy and 3-month GOS scores. RESULTS: The authors identified 1532 patients with aVSP or DCI. Predictive, explainable ML models revealed that aneurysm characteristics and neurological complications, but not admission neurological scores, carried the highest relative importance rankings in predicting whether rescue therapy was administered. Younger age and absence of cerebral ischemia/infarction were invariably linked to better rescue outcomes, whereas the other important predictors of outcome varied by rescue type (interventional or noninterventional). In a propensity score-matched analysis guided by SHAP-based variable selection, rescue therapy was associated with higher odds of 3-month GOS scores of 4-5 (OR 1.63, 95% CI 1.22-2.17). CONCLUSIONS: Rescue therapy may increase the odds of good outcome in patients with aVSP or DCI after SAH. Given the strong association between cerebral ischemia/infarction and poor outcome, trials focusing on preventative or therapeutic interventions in these patients may be most able to demonstrate improvements in clinical outcomes. Insights developed from these models may be helpful for improving patient selection and trial design.

Space Exposure of Amino Acids and Their Precursors during the Tanpopo Mission.

Amino acids have been detected in extraterrestrial bodies such as carbonaceous chondrites (CCs), which suggests that extraterrestrial organics could be the source of the first life on Earth, and interplanetary dust particles (IDPs) or micrometeorites (MMs) are promising carriers of extraterrestrial organic carbon. Some amino acids found in CCs are amino acid precursors, but these have not been well characterized. The Tanpopo mission was conducted in Earth orbit from 2015 to 2019, and the stability of glycine (Gly), hydantoin (Hyd), isovaline (Ival), 5-ethyl-5-methylhydantoin (EMHyd), and complex organics formed by proton irradiation from CO, NH3, and H2O (CAW) in space were analyzed by high-performance liquid chromatography and/or gas chromatography/mass spectrometry. The target substances showed a logarithmic decomposition over 1-3 years upon space exposure. Recoveries of Gly and CAW were higher than those of Hyd, Ival, and EMHyd. Ground simulation experiments showed different results: Hyd was more stable than Gly. Solar ultraviolet light was fatal to all organics, and they required protection when carried by IDPs/MMs. Thus, complex amino acid precursors (such as CAW) were possibly more robust than simple precursors during transportation to primitive Earth. The Tanpopo 2 mission is currently being conducted to expose organics to more probable space conditions.

Impact of subcallosal artery origin and A1 asymmetry on surgical outcomes of anterior communicating artery aneurysms.

BACKGROUND: Surgical clipping of anterior communicating artery (ACoA) aneurysms remains challenging due to their complex anatomy. Anatomical risk factors for ACoA aneurysm surgery require further elucidation. The aim of this study is to investigate whether proximity of the midline perforating artery, subcallosal artery (SubCA), and associated anomaly of the ACoA complex affect functional outcomes of ACoA aneurysm surgery. METHODS: A total of 92 patients with both unruptured and ruptured ACoA aneurysms, who underwent surgical clipping, were retrospectively analyzed from a multicenter, observational cohort database. Association of ACoA anatomy with SubCA origin at the aneurysmal neck under microsurgical observation was analyzed in the interhemispheric approach subgroup (n = 56). Then, we evaluated whether anatomical factors associated with SubCA neck origin affected surgical outcomes in the entire cohort (both interhemispheric and pterional approaches, n = 92). RESULTS: In the interhemispheric approach cohort, combination of A1 asymmetry and aneurysmal size ≥ 5.0 mm was stratified to have the highest probability of the SubCA neck origin by a decision tree analysis. Then, among the entire cohort using either interhemispheric or pterional approach, combination of A1 asymmetry and aneurysmal size ≥ 5.0 mm was significantly associated with poor functional outcomes by multivariable logistic regression analysis (OR 6.76; 95% CI 1.19-38.5; p = 0.03) as compared with A1 symmetry group in the acute subarachnoid hemorrhage settings. CONCLUSION: Combination of A1 asymmetry and larger aneurysmal size was significantly associated with SubCA aneurysmal neck origin and poor functional outcomes in ACoA aneurysm surgery. Interhemispheric approach may be proposed to provide a wider and unobstructed view of SubCA for ACoA aneurysms with this high-risk anatomical variant.

Commentary on Post, et al. Ultra-early tranexamic acid after subarachnoid hemorrhage: A randomized controlled trial. Lancet 2021.

BACKGROUND: Tranexamic acid (TA) administration in aneurysmal subarachnoid hemorrhage (SAH) within the first 24 hours may reduce the incidence of early aneurysmal rebleeding. However, this is also the potential for an increased risk of delayed cerebral ischemia if TA is administered for more than 72 hours following the initial aneurysmal rupture. METHODS: In the ultra-early tranexamic acid after subarachnoid hemorrhage randomized controlled trial by Post et al., patients were randomized to receive TA within the first 24 hours, or until start of aneurysm treatment. These results were compared to a matched control group. RESULTS: Ultra-early administration (≤24 h) of TA reduced the incidence of rebleeding, and did not alter the incidence of delayed cerebral ischemia and/or extracranial thrombosis. Further, no significant differences were noted between the TA group and control arm in the incidence of good (modified Rankin scores 0-3) clinical outcomes at 6 months. CONCLUSION: Ultra-early administration of TA (≤24 h) resulted in a lower rate of recurrent hemorrhage, without increasing the incidence of delayed cerebral ischemia in SAH patients.

Added value of anxiolytic benzodiazepines in predictive models on severe delirium in patients with acute decompensated heart failure: A retrospective analysis.

BACKGROUND: Delirium in patients with acute decompensated heart failure (ADHF) is associated with poor clinical outcomes. Although some medications have been reported as risk factors for delirium, their impact on patients with ADHF is still unclear. This study aimed to determine the association of specific medication use with delirium and their additive predictive value in models based on conventional risk factors. METHODS AND RESULTS: In this single-center, retrospective study, 650 patients treated for ADHF were included. Fifty-nine patients (9.1%) had delirium. In multivariate analysis, anxiolytic benzodiazepines [odds ratio (OR): 6.4, 95% confidence interval (CI): 2.8-15], mechanical ventilation or noninvasive positive pressure ventilation (OR: 6.0, 95% CI: 2.9-12), depression (OR: 3.2, 95% CI: 1.5-6.5), intensive care or high care unit admission (OR: 2.9, 95% CI: 1.5-5.6), male sex (OR: 2.0, 95% CI: 1-3.7), and age (OR: 1.1, 95% CI: 1-1.1) were independently associated with severe delirium. The predictive model that included anxiolytic benzodiazepines had a significantly better discriminatory ability for the incidence of severe delirium than the conventional model. CONCLUSIONS: The use of anxiolytic benzodiazepines was independently correlated with severe delirium, and their use in models based on conventional risk factors had an additive value for predicting delirium in patients with ADHF.