Noncoding Vault RNA1-1 Impairs Intestinal Epithelial Renewal and Barrier Function by Interacting with CUG-binding Protein 1.

BACKGROUND & AIMS: Small noncoding vault RNAs (vtRNAs) are involved in many cell processes important for health and disease, but their pathobiological functions in the intestinal epithelium are underexplored. Here, we investigated the role of human vtRNA1-1 in regulating intestinal epithelial renewal and barrier function. METHODS: Studies were conducted in vtRNA1-1 transgenic (vtRNA1-1Tg) mice, primary enterocytes, and Caco-2 cells. Extracellular vesicles (EVs) were isolated from the serum of shock patients and septic mice. Intestinal organoids (enteroids) were prepared from vtRNA1-1Tg and littermate mice. Mucosal growth was measured by Ki67 immunostaining or BrdU incorporation, and gut permeability assessed using the FITC-dextran assay. RESULTS: Intestinal tissues recovered from shock patients and septic mice evidenced mucosal injury and gut barrier dysfunction; vtRNA levels were elevated in EVs isolated from their sera. In mice, intestinal epithelial-specific transgenic expression of vtRNA1-1 inhibited mucosal growth, reduced Paneth cell numbers and intercellular junction (IJ) protein expression, and increased gut barrier vulnerability to lipopolysaccharide exposure. Conversely, in vitro silencing of vtRNA1-1 increased IJ protein levels and enhanced epithelial barrier function. Exposing enteroids to vtRNA1-1-rich EVs augmented paracellular permeability. Mechanistically, vtRNA1-1 interacted with CUG-binding protein 1 (CUGBP1) and increased CUGBP1 association with claudin-1 and occludin mRNAs, thereby inhibiting their expression. CONCLUSIONS: These findings indicate that elevated levels of vtRNA1-1 in EVs and mucosal tissues repress intestinal epithelial renewal and barrier function. Notably, this work reveals a novel role for dysregulation of the vtRNA1-1/CUGBP1 axis in the pathogenesis of gut mucosal disruption in critical illness.

[Analysis of factors for anxiety and anxiety tendency in tinnitus patients].

Objective: To explore the related factors of anxiety and anxiety tendency in patients with tinnitus. Methods: A cross-sectional study was carried out. Basic information, tinnitus characteristics, and psychological status of patients who complained of tinnitus in the Outpatient Department of Eye & ENT Hospital, Fudan University between January 2020 and December 2023 were collected. All patients filled out the self-rating anxiety scale (SAS) and underwent pure tone audiometry testing. According to the SAS scores, patients were divided into three groups: non-anxiety group (SAS<40), anxiety tendency group (40≤SAS<50), and anxiety group (SAS≥50). The related factors of anxiety and anxiety tendency were analyzed using multivariate ordered logistic regression analysis. Results: A total of 176 patients (57 males and 119 females) aged (49.4±10.7) years (range: 13-76 years)were included, with the onset time of 3 days-37 years. There were 78 cases (44.3%), 65 cases (36.9%) and 33 cases (18.8%) in the non-anxiety group, the anxiety tendency group and the anxiety group, respectively. The duration of disease in the anxiety group [(43.4±15.1) months] was significantly longer than that in the anxiety tendency group [(27.2±5.3) months] and the non-anxiety group [(19.6±3.5) months], with statistically significant differences (both P<0.05). The proportion of female patients in the anxiety group [81.8% (27/33)] and anxiety tendency group [75.4% (47/65)] was significantly higher than that in the non-anxiety group [57.7% (45/78)], and the differences were statistically significant (both P<0.05). The proportion of patients with emotional disorders [12.1% (4/33) vs 2.6% (2/78)], stress [15.1% (5/33) vs 3.9% (3/78)], and sleep disorders [48.5% (16/33) vs 23.1% (18/78)] in the anxiety group was significantly higher than that in the non-anxiety group (all P<0.05). The proportion of patients only had sleep disorders in the anxiety tendency group [38.5% (25/65) vs 23.1% (18/78)] was higher than that in the non-anxiety group, with a statistically significant difference (P<0.05). The results of multivariate ordered logistic regression analysis showed that sleep disorders werethe most significant factor affecting anxiety and anxiety tendency in tinnitus patients (OR=2.667, 95%CI: 1.451-4.909, P=0.002). Conclusion: A significant proportion of tinnitus patients exhibit anxiety and anxiety tendency, and sleep disorders play a major role in the development of anxiety and anxiety tendencies in tinnitus patients.

The effect of intravenous thrombolysis in stroke patients with unsuccessful thrombectomy.

BACKGROUND: The benefit of intravenous thrombolysis (IVT) is well established. We aim to study the benefits of IVT in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO) who underwent unsuccessful mechanical thrombectomy (MT). METHODS: We included AIS patients who underwent MT for anterior circulation LVO with failed recanalization (modified treatment in cerebral ischemia [mTICI] score ≤ 2A). Patients who received IVT prior to MT were compared to those who received MT alone. Propensity score matching using demographic, clinical, radiographic and procedural variables was used to match patients with and without IVT. The primary outcome was favorable 90-day good functional outcome (defined as modified Rankin scale of 0-2), and secondary outcomes included intracranial hemorrhage (ICH), symptomatic ICH (sICH), and 90-day mortality. RESULTS: Totally, 610 AIS patients with unsuccessful MT were included. After propensity matching, 219 patients were identified in each group. Median age was 70 years and 73 years in the IVT + MT and MT alone groups, respectively. In the IVT + MT group, final mTICI scores of 0, 1, and 2A were achieved in 92 (42.0%), 33 (15.1%), and 94 (42.9%) patients, respectively, versus 76 (34.7%), 29 (13.2%), and 114 (52.1%) in the MT alone group. The IVT + MT group had greater odds of 90-day good functional outcome (adjusted odds ratio 2.54, 95% confidence interval 1.53-4.32). There were no significant differences in secondary outcomes. CONCLUSIONS: IVT is associated with improved functional outcomes in AIS patients with LVO despite unsuccessful MT.

Outcomes of Mechanical Thrombectomy for Patients With Stroke Presenting With Low Alberta Stroke Program Early Computed Tomography Score in Early and Late Time Windows.

BACKGROUND AND OBJECTIVES: This study aimed to compare outcomes of low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) patients with stroke who underwent mechanical thrombectomy (MT) within 6 hours or 6 to 24 hours after stroke onset. METHODS: A retrospective cohort study was conducted using data from a large multicenter international registry from 2013 to 2023. Patients with low ASPECTS (2-5) who underwent MT for anterior circulation intracranial large vessel occlusion were included. A propensity matching analysis was conducted for patients presented in the early (<6 hours) vs late (6-24 hours) time window after symptom onset or last known normal. RESULTS: Among the 10 229 patients who underwent MT, 274 met the inclusion criteria. 122 (44.5%) patients were treated in the late window. Early window patients were older (median age, 74 years [IQR, 63-80] vs 66.5 years [IQR, 54-77]; P < .001), had lower proportion of female patients (40.1% vs 54.1%; P = .029), higher median admission National Institutes of Health Stroke Scale score (20 [IQR, 16-24] vs 19 [IQR, 14-22]; P = .004), and a higher prevalence of atrial fibrillation (46.1% vs 27.3; P = .002). Propensity matching yielded a well-matched cohort of 84 patients in each group. Comparing the matched cohorts showed there was no significant difference in acceptable outcomes at 90 days between the 2 groups (odds ratio = 0.90 [95% CI = 0.47-1.71]; P = .70). However, the rate of symptomatic ICH was significantly higher in the early window group compared with the late window group (odds ratio = 2.44 [95% CI = 1.06-6.02]; P = .04). CONCLUSION: Among patients with anterior circulation large vessel occlusion and low ASPECTS, MT seems to provide a similar benefit to functional outcome for patients presenting <6 hours or 6 to 24 hours after onset.

Improved technical outcomes with converting thrombectomy techniques after failed first pass recanalization.

BACKGROUND: A higher number of recanalization attempts reduces the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke secondary to large vessel occlusion (LVO). We assessed the impact of switching EVT techniques after a failed first pass on procedural and clinical outcomes. METHODS: This multicenter international study, conducted between January 2013 and December 2022, included patients undergoing EVT for anterior circulation LVO (internal carotid artery or M1 segments) with failed first pass recanalization. Propensity score matching identified a 1:1 matched cohort of patients in whom EVT technique was changed after a failed first pass and those with the same technique repeated. The primary outcome was successful recanalization at second attempt defined as Thrombolysis in Cerebral Ischemia (TICI) score of 2B or higher. Secondary outcomes were 90-day modified Rankin Score (mRS) and postprocedural hemorrhage. RESULTS: Among 2167 patients, converting to an alternative technique after a failed first pass was associated with higher odds of successful recanalization (adjusted OR (aOR)=1.5, p=0.041), and higher odds of mRS 0-2 at 90 days (aOR=1.6, p=0.005) without additional risk of symptomatic hemorrhage (p=0.379). Using a propensity score matched cohort of 490 patients, technique conversion at second attempt increased odds of successful recanalization at second attempt (aOR=1.32, p=0.006) and 90-day mRS 0-2 (aOR=1.38, p=0.008). CONCLUSIONS: Early conversion to an alternative EVT technique after a failed first pass recanalization in patients with AIS is associated with better technical success and clinical outcomes.

Identification of the Biotransformation Pathways of a Potential Oral Male Contraceptive, 11ß-Methyl-19-Nortestosterone (11ß-MNT) and Its Prodrugs: An In Vitro Study Highlights the Contribution of Polymorphic Intestinal UGT2B17.

11ß-Methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC) is a prodrug of 11ß-MNT and is being considered as a promising male oral contraceptive candidate in clinical development. However, the oral administration of 11ß-MNTDC exhibits an ~200-fold lower serum concentration of 11ß-MNT compared to 11ß-MNTDC, resulting in the poor bioavailability of 11ß-MNT. To elucidate the role of the first-pass metabolism of 11ß-MNT in its poor bioavailability, we determined the biotransformation products of 11ß-MNT and its prodrugs in human in vitro models. 11ß-MNT and its two prodrugs 11ß-MNTDC and 11ß-MNT undecanoate (11ß-MNTU) were incubated in cryopreserved human hepatocytes (HHs) and subjected to liquid chromatography-high resolution tandem mass spectrometry analysis, which identified ten 11ß-MNT biotransformation products with dehydrogenated and glucuronidation (11ß-MNTG) metabolites being the major metabolites. However, 11ß-MNTG formation is highly variable and prevalent in human intestinal S9 fractions. A reaction phenotyping study of 11ß-MNT using thirteen recombinant UDP-glucuronosyltransferase (UGT) enzymes confirmed the major role of UGT2B17 in 11ß-MNTG formation. This was further supported by a strong correlation (R2 > 0.78) between 11ß-MNTG and UGT2B17 abundance in human intestinal microsomes, human liver microsomes, and HH systems. These results suggest that 11ß-MNT and its prodrugs are rapidly metabolized to 11ß-MNTG by the highly polymorphic intestinal UGT2B17, which may explain the poor and variable bioavailability of the drug.

Interaction between microRNA-195 and HuR regulates Paneth cell function in the intestinal epithelium by altering SOX9 translation.

Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here, we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.NEW & NOTEWORTHY Our results indicate that intestinal epithelial tissue-specific transgenic miR-195 expression decreases the levels of SOX9 expression, along with reduced numbers of Paneth cells. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restores Paneth cell development ex vivo. miR-195 inhibits SOX9 translation by preventing binding of HuR to Sox9 mRNA. These findings suggest that interaction between miR-195 and HuR controls Paneth cell function via SOX9 in the intestinal epithelium.

Clinical and radiographic outcomes after mechanical thrombectomy in medium-vessel posterior cerebral artery occlusions: Subgroup analysis from STAR.

BACKGROUND: Whereas mechanical thrombectomy (MT) has become standard-of-care treatment for patients with salvageable brain tissue after acute stroke caused by large-vessel occlusions, the results of MT in patients with medium-vessel occlusions (MEVOs), particularly in the posterior cerebral artery (PCA), are not well known. METHODS: Using data from the international Stroke Thrombectomy and Aneurysm Registry (STAR), we assessed presenting characteristics and clinical outcomes for patients who underwent MT for primary occlusions in the P2 PCA segment. As a subanalysis, we compared the PCA MeVO outcomes with STAR's anterior circulation MeVO outcomes, namely middle cerebral artery (MCA) M2 and M3 segments. RESULTS: Of the 9812 patients in STAR, 43 underwent MT for isolated PCA MeVOs. The patients' median age was 69 years (interquartile range 61-79), and 48.8% were female. The median NIH Stroke Scale score was 9 (range 6-17). After recanalization, 67.4% of patients achieved successful recanalization (modified treatment in cerebral infarction score [mTICI] ≥ 2b), with a first-pass success rate of 44.2%, and 39.6% achieved a modified Rankin score of 0-2 at 90 days. Nine patients (20.9%) had died by the 90-day follow-up. In comparison with M2 and M3 MeVOs, there were no differences in presenting characteristics among the three groups. Patients with PCA MeVOs were less likely to undergo intra-arterial thrombolysis (4.7% PCA vs. 10.1% M2 vs. 16.2% M3, p = 0.046) or to achieve successful recanalization (mTICI ≥ 2b, 67.4%, 86.7%, 82.3%, respectively, p < 0.001); however, there were no differences in the rates of successful first-pass recanalization (44.2%, 49.8%, 52.3%, respectively, p = 0.65). CONCLUSIONS: We describe the STAR experience performing MT in patients with PCA MeVOs. Our analysis supports that successful first-pass recanalization can be achieved in PCA MEVOs at a rate similar to that in MCA MeVOs, although further study and possible innovation may be necessary to improve successful PCA MeVO recanalization rates.

Comparison of combined intravenous and intra-arterial thrombolysis with intravenous thrombolysis alone in stroke patients undergoing mechanical thrombectomy: a propensity-matched analysis.

BACKGROUND: A combination of intravenous (IVT) or intra-arterial (IAT) thrombolysis with mechanical thrombectomy (MT) for acute ischemic stroke due to large vessel occlusion (AIS-LVO) has been investigated. However, there is limited data on patients who receive both IVT and IAT compared with IVT alone before MT. METHODS: STAR data from 2013 to 2023 was utilized. We performed propensity score matching between the two groups. The primary outcomes were symptomatic intracranial hemorrhage (sICH) and 90-day modified Rankin Scale (mRS) score 0-2. Secondary outcomes included successful recanalization (modified treatment in cerebral infarction (mTICI) ≥2B, ≥2C), early neurological improvement, any intracranial hemorrhage (ICH), and 90-day mortality. RESULTS: A total of 2454 AIS-LVO patients were included. Propensity matching yielded 190 well-matched patients in each group. No significant differences were observed between the groups in either ICH or sICH (odds ratio (OR): 0.80, 95% confidence interval (CI) 0.51-1.24, P=0.37; OR: 0.60, 95% CI 0.29 to 1.24, P=0.21, respectively). Rates of successful recanalization and early neurological improvement (ENI) were significantly lower in MT+IVT + IAT. mRS 0-1 and mortality were not significantly different between the two groups. However, the MT+IVT + IAT group demonstrated superior rates of good functional outcomes (90-day mRS 0-1) compared with patients in the MT+IVT group who had mTICI ≤2B, (OR: 2.18, 95% CI 1.05 to 3.99, P=0.04). CONCLUSION: The combined use of IAT and IVT thrombolysis in AIS-LVO patients undergoing MT is safe. Although the MT+IVT+ IAT group demonstrated lower rates of recanalization and early neurological improvement, long-term functional outcomes were favorable in this group suggesting a potential delayed benefit of IAT.

Clinical Outcomes of Arteriovenous Fistula Treatment Using the Penumbra SMART COIL System: A Subgroup Analysis from the Multicenter SMART Registry.

BACKGROUND: Endovascular embolization procedures are typically the primary treatment modality for arteriovenous fistula (AVF). The objective of this subset analysis was to evaluate the prospective long-term clinical outcomes of AVF patients treated with the SMART COIL System. METHODS: Patients who had AVFs and underwent endovascular coiling using the Penumbra SMART COIL system were part of a subset analysis within the SMART registry. The SMART registry is a postmarket registry that is prospective, multicenter, and single-arm in design. After the treatment, these patients were monitored for a period of 12 ± 6 months. RESULTS: A total of 41 patients were included. No patients (0/41) had a procedural device-related serious adverse event (SAE). Reaccess involving a guidewire due to catheter kickout was unnecessary for 85.4% (35/41) of the patients. Complete occlusion after the procedure was achieved in 87.8% (36/41) of patients. The periprocedural SAE rate was 2.4% (1/41), and no periprocedural deaths occurred (0/41). During the follow-up period, there were instances of retreatment in 3.4% (1/29) of patients. At 1 year, the lesion occlusion was better or stable in 93.3% (28/30) of patients. The rate of SAE from 24 hours to 1 year (±6 months) following the procedure was 26.8% (11/41). The 1-year all-cause mortality rate stood at 2.4% (1/41), and at the 1-year follow-up, 90.9% (20/22) of patients had a modified Rankin Scale score within the range of 0 to 2. CONCLUSIONS: The coiling procedure for AVFs using the SMART COIL System proved to be safe and effective at the 1-year follow-up.

Outcomes and differences by occluded vessel after endovascular thrombectomy for isolated medium vessel occlusions.

BACKGROUND: The outcomes of endovascular thrombectomy (EVT) for medium vessel occlusions (MeVOs) of specific vascular territories remain unknown. We aimed to investigate EVT outcomes by MeVO locations using the data from an ongoing international multicenter registry. METHODS: Patients with isolated MeVO who underwent EVT between January 2013 and December 2022 were retrospectively analyzed. Isolated MeVO was defined as an occlusion of the A2 or A3 (A2/A3), M2 or M3, and P2 or P3 (P2/P3). Outcomes included a 90-day modified Rankin score (mRS) of 0-2, successful recanalization (modified Thrombolysis in Cerebral Infarction score ≥ 2b), early neurological deterioration (END) or improvement (ENI), and 90-day mortality. END was defined as a worsening of ≥4 points from the baseline National Institutes of Health Stroke Scale (NIHSS) score within 24 h of EVT, while ENI was defined as an improvement of ≥4 points from the baseline NIHSS score within 24 h of EVT. RESULTS: 1744 MeVOs included. Compared to M2 occlusions (n = 1542, 88.4%), A2/A3 (n = 36, 2.1%) occlusions had lower odds of 90-day mRS 0-2 (adjusted odds ratio [aOR] 0.30, 95% confidence interval [CI] 0.11-0.80), and P2/P3 occlusions (n = 49, 2.8%) had lower odds of successful recanalization (aOR 0.19, 95% CI 0.07-0.50), and higher odds of END (aOR 3.53, 95% CI 1.35-9.25). Other outcomes showed no significant differences. CONCLUSIONS: A2/A3 occlusions were more likely to have worse outcomes compared to M2 occlusions after EVT for patients with isolated MeVOs.

Earlier Endovascular Thrombectomy and Mortality in Patients with Anterior Circulation Large Vessel Occlusion: A Propensity-Matched Analysis of the Stroke Thrombectomy and Aneurysm Registry.

BACKGROUND: The definitive impact of onset to arterial puncture time (OPT) on 90-day mortality after endovascular thrombectomy (EVT) in patients with acute ischemic stroke (AIS) caused by anterior circulation large vessel occlusion (LVO) remains unknown. The present study aimed to evaluate the influence of OPT on 90-day mortality in anterior circulation AIS-LVO patients who underwent EVT. METHODS: Data from 33 international centers were retrospectively analyzed. The receiver operating characteristic curve analysis was used to identify a cutoff for OPT. A propensity score-matched analysis was performed. The primary outcome was 90-day mortality (modified Rankin Scale [mRS] 6). Secondary outcomes included mortality at discharge, 90-day good outcome (mRS 0-2), 90-day poor outcome (mRS 5-6), successful recanalization (defined as postprocedure modified Thrombolysis in Cerebral Infarction scale ≥2b), and intracranial hemorrhage. RESULTS: A total of 2842 AIS-LVO patients with EVT were included. The cutoff for OPT for 90-day mortality was 180 min. Of these 378 patients had OPT <180 min and 378 patients had OPT ≥180 min in the propensity score-matched cohort (n = 756). Patients with OPT <180 min were less likely to have 90-day mortality (odds ratio [OR] 0.70, 95% confidence interval [CI] 0.51-0.96) and poor outcome (OR 0.71, 95% CI 0.53-0.96), and more likely to have 90-day good outcome (OR 1.55, 95% CI 1.16-2.08). Other outcomes showed no significant differences. CONCLUSIONS: This study showed that OPT <180 min was less related to 90-day mortality and poor outcome, and more to 90-day good outcome in AIS-LVO patients who underwent EVT.

Primary Embolization of Cerebral Arteriovenous Malformations With Intention to Cure: A Systematic Review of Literature and Meta-Analysis.

BACKGROUND AND OBJECTIVES: The treatment of brain arteriovenous malformations (AVMs) involves multiple approaches, including embolization, microsurgical resection, and radiosurgery. With the advent of new embolisates, dual-lumen balloon catheters, detachable tip microcatheters, and transvenous embolization, endovascular AVM obliteration has become more effective. Although adjuvant embolization and embolization are commonly used, the safety and effectiveness of curative embolization remain unclear. METHODS: We conducted a systematic literature review using PubMed, Ovid Medline, and Web of Science to identify studies reporting outcomes in patients with AVMs who underwent primary embolization with the intention to cure. We collected data on patient characteristics, AVM features, complications, and radiographic and clinical outcomes for meta-analysis. RESULTS: We identified 25 studies with a total of 1425 patients with 1427 AVMs who underwent curative embolization. Of these patients, 70% were low grade (pooled = 61% [39-82]), 67% were <3 cm (pooled = 78% [60-92]), and 75% were in superficial locations (pooled = 80% [72-86]). At last radiographic follow-up (mean, 16.7 ± 10.9 months), the full obliteration rate was 52% (pooled = 61% [43-77]) and retreatment rate was 25% (pooled = 17% [8.3-27]). At last clinical follow-up (mean, 24.2 ± 13.3 months), the poor clinical outcome rate was 7.9% (pooled = 4.4% [1.3-8.7]) and symptomatic complication rate was 13% (pooled = 13% [8-19]). There was no significant difference in the rate of radiographic cure, need for retreatment, and poor outcomes between ruptured and unruptured AVMs. Symptomatic complications were more common in the treatment of unruptured AVMs. The primary outcomes showed high heterogeneity (I2 = 72%-94%). CONCLUSION: Curative embolization of AVM is primarily reserved for small and low-grade AVMs, with highly variable outcomes. Our findings suggest poor radiographic outcomes and increased risk of complications. Outcomes are highly dependent on patient selection and technique used. Large multicenter prospective studies are required to further guide patient selection, categorize clinical and radiographic outcomes, and identify subgroup of patients that may benefit from curative embolization.

Outcomes of Mechanical Thrombectomy for Patients With Stroke Presenting With Low Alberta Stroke Program Early Computed Tomography Score in Early and Late Time Windows.

BACKGROUND AND OBJECTIVES: This study aimed to compare outcomes of low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) patients with stroke who underwent mechanical thrombectomy (MT) within 6 hours or 6 to 24 hours after stroke onset. METHODS: A retrospective cohort study was conducted using data from a large multicenter international registry from 2013 to 2023. Patients with low ASPECTS (2-5) who underwent MT for anterior circulation intracranial large vessel occlusion were included. A propensity matching analysis was conducted for patients presented in the early (<6 hours) vs late (6-24 hours) time window after symptom onset or last known normal. RESULTS: Among the 10 229 patients who underwent MT, 274 met the inclusion criteria. 122 (44.5%) patients were treated in the late window. Early window patients were older (median age, 74 years [IQR, 63-80] vs 66.5 years [IQR, 54-77]; P < .001), had lower proportion of female patients (40.1% vs 54.1%; P = .029), higher median admission National Institutes of Health Stroke Scale score (20 [IQR, 16-24] vs 19 [IQR, 14-22]; P = .004), and a higher prevalence of atrial fibrillation (46.1% vs 27.3; P = .002). Propensity matching yielded a well-matched cohort of 84 patients in each group. Comparing the matched cohorts showed there was no significant difference in acceptable outcomes at 90 days between the 2 groups (odds ratio = 0.90 [95% CI = 0.47-1.71]; P = .70). However, the rate of symptomatic ICH was significantly higher in the early window group compared with the late window group (odds ratio = 2.44 [95% CI = 1.06-6.02]; P = .04). CONCLUSION: Among patients with anterior circulation large vessel occlusion and low ASPECTS, MT seems to provide a similar benefit to functional outcome for patients presenting <6 hours or 6 to 24 hours after onset.

Development of new hormonal male contraception for the couple.

BACKGROUND: Current options for male contraception are limited to condoms, the withdrawal method, or a vasectomy. Studies indicate that men have expressed growing interest in bearing responsibility for family planning. OBJECTIVES: To review prior studies investigating the role of an androgen-only or androgen with progestin regimen for hormonal male contraception and to provide an update of a promising new hormonal agent, a transdermal gel. DISCUSSION: Thus far, there have been six studies conducted in couples evaluating the contraceptive efficacy of an androgen-only or androgen co-administered with a progestin regimen for hormonal male contraception. The only ongoing study is by the National Institute of Child Health and Human Development, in collaboration with the Population Council. They have developed a novel transdermal gel containing testosterone and segesterone acetate (Nestorone), a progestin. An ongoing phase II study enrolling more than 460 couples has shown great potential with respect to the product's efficacy, safety, reversibility, and acceptability. As this agent advances in development, a rapid at-home test for sperm concentration will provide couples with immediate feedback regarding their potential for pregnancy. CONCLUSION: There is promise for the first-of-its-kind hormonal male contraceptive, a transdermal gel, to achieve market approval for distribution in the United States and elsewhere. Its safety, efficacy, reversibility, and user-control are all appealing qualities that make it readily adoptable for clinical practice.

Impact of Procedure Time on First Pass Effect in Mechanical Thrombectomy for Anterior Circulation Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: First pass effect (FPE) is a metric increasingly used to determine the success of mechanical thrombectomy (MT) procedures. However, few studies have investigated whether the duration of the procedure can modify the clinical benefit of FPE. We sought to determine whether FPE after MT for anterior circulation large vessel occlusion acute ischemic stroke is modified by procedural time (PT). METHODS: A multicenter, international data set was retrospectively analyzed for anterior circulation large vessel occlusion acute ischemic stroke treated by MT who achieved excellent reperfusion (thrombolysis in cerebral infarction 2c/3). The primary outcome was good functional outcome defined by 90-day modified Rankin scale scores of 0-2. The primary study exposure was first pass success (FPS, 1 pass vs ≥2 passes) and the secondary exposure was PT. We fit-adjusted logistic regression models and used marginal effects to assess the interaction between PT (≤30 vs >30 minutes) and FPS, adjusting for potential confounders including time from stroke presentation. RESULTS: A total of 1310 patients had excellent reperfusion. These patients were divided into 2 cohorts based on PT: ≤30 minutes (777 patients, 59.3%) and >30 minutes (533 patients, 40.7%). Good functional outcome was observed in 658 patients (50.2%). The interaction term between FPS and PT was significant ( P = .018). Individuals with FPS in ≤30 minutes had 11.5% higher adjusted predicted probability of good outcome compared with those who required ≥2 passes (58.2% vs 46.7%, P = .001). However, there was no significant difference in the adjusted predicted probability of good outcome in individuals with PT >30 minutes. This relationship appeared identical in models with PT treated as a continuous variable. CONCLUSION: FPE is modified by PT, with the added clinical benefit lost in longer procedures greater than 30 minutes. A comprehensive metric for MT procedures, namely, FPE 30 , may better represent the ideal of fast, complete reperfusion with a single pass of a thrombectomy device.

Thrombectomy in Stroke Patients With Low Alberta Stroke Program Early Computed Tomography Score: Is Modified Thrombolysis in Cerebral Infarction (mTICI) 2c/3 Superior to mTICI 2b?

BACKGROUND AND PURPOSE: Outcomes following mechanical thrombectomy (MT) are strongly correlated with successful recanalization, traditionally defined as modified Thrombolysis in Cerebral Infarction (mTICI) ≥2b. This retrospective cohort study aimed to compare the outcomes of patients with low Alberta Stroke Program Early Computed Tomography Score (ASPECTS; 2-5) who achieved mTICI 2b versus those who achieved mTICI 2c/3 after MT. METHODS: This study utilized data from the Stroke Thrombectomy and Aneurysm Registry (STAR), which combined databases from 32 thrombectomy-capable stroke centers between 2013 and 2023. The study included only patients with low ASPECTS who achieved mTICI 2b, 2c, or 3 after MT for internal carotid artery or middle cerebral artery (M1) stroke. RESULTS: Of the 10,229 patients who underwent MT, 234 met the inclusion criteria. Of those, 98 (41.9%) achieved mTICI 2b, and 136 (58.1%) achieved mTICI 2c/3. There were no significant differences in baseline characteristics between the two groups. The 90-day favorable outcome (modified Rankin Scale score: 0-3) was significantly better in the mTICI 2c/3 group than in the mTICI 2b group (adjusted odds ratio 2.35; 95% confidence interval [CI] 1.18-4.81; P=0.02). Binomial logistic regression revealed that achieving mTICI 2c/3 was significantly associated with higher odds of a favorable 90-day outcome (odds ratio 2.14; 95% CI 1.07-4.41; P=0.04). CONCLUSION: In patients with low ASPECTS, achieving an mTICI 2c/3 score after MT is associated with a more favorable 90-day outcome. These findings suggest that mTICI 2c/3 is a better target for MT than mTICI 2b in patients with low ASPECTS.

Comparison between transradial and transfemoral mechanical thrombectomy for ICA and M1 occlusions: insights from the Stroke Thrombectomy and Aneurysm Registry (STAR).

BACKGROUND: The role for the transradial approach for mechanical thrombectomy is controversial. We sought to compare transradial and transfemoral mechanical thrombectomy in a large multicenter database of acute ischemic stroke. METHODS: The prospectively maintained Stroke Thrombectomy and Aneurysm Registry (STAR) was reviewed for patients who underwent mechanical thrombectomy for an internal carotid artery (ICA) or middle cerebral artery M1 occlusion. Multivariate regression analyses were performed to assess outcomes including reperfusion time, symptomatic intracerebral hemorrhage (ICH), distal embolization, and functional outcomes. RESULTS: A total of 2258 cases, 1976 via the transfemoral approach and 282 via the transradial approach, were included. Radial access was associated with shorter reperfusion time (34.1 min vs 43.6 min, P=0.001) with similar rates of Thrombolysis in Cerebral Infarction (TICI) 2B or greater reperfusion (87.9% vs 88.1%, P=0.246). Patients treated via a transradial approach were more likely to achieve at least TICI 2C (59.6% vs 54.7%, P=0.001) and TICI 3 reperfusion (50.0% vs 46.2%, P=0.001), and had shorter lengths of stay (mean 9.2 days vs 10.2, P<0.001). Patients treated transradially had a lower rate of symptomatic ICH (8.0% vs 9.4%, P=0.047) but a higher rate of distal embolization (23.0% vs 7.1%, P<0.001). There were no significant differences in functional outcome at 90 days between the two groups. CONCLUSIONS: Radial and femoral thrombectomy resulted in similar clinical outcomes. In multivariate analysis, the radial approach had improved revascularization rates, fewer cases of symptomatic ICH, and faster reperfusion times, but higher rates of distal emboli. Further studies on the optimal approach are necessary based on patient and disease characteristics.

Cortical depth profiles in primary visual cortex for illusory and imaginary experiences.

Visual illusions and mental imagery are non-physical sensory experiences that involve cortical feedback processing in the primary visual cortex. Using laminar functional magnetic resonance imaging (fMRI) in two studies, we investigate if information about these internal experiences is visible in the activation patterns of different layers of primary visual cortex (V1). We find that imagery content is decodable mainly from deep layers of V1, whereas seemingly 'real' illusory content is decodable mainly from superficial layers. Furthermore, illusory content shares information with perceptual content, whilst imagery content does not generalise to illusory or perceptual information. Together, our results suggest that illusions and imagery, which differ immensely in their subjective experiences, also involve partially distinct early visual microcircuits. However, overlapping microcircuit recruitment might emerge based on the nuanced nature of subjective conscious experience.

A Low-Noise Low-Power 0.001Hz-1kHz Neural Recording System-on-Chip With Sample-Level Duty-Cycling.

Advances in brain-machine interfaces and wearable biomedical sensors for healthcare and human-computer interactions call for precision electrophysiology to resolve a variety of biopotential signals across the body that cover a wide range of frequencies, from the mHz-range electrogastrogram (EGG) to the kHz-range electroneurogram (ENG). Existing integrated wearable solutions for minimally invasive biopotential recordings are limited in detection range and accuracy due to trade-offs in bandwidth, noise, input impedance, and power consumption. This article presents a 16-channel wide-band ultra-low-noise neural recording system-on-chip (SoC) fabricated in 65nm CMOS for chronic use in mobile healthcare settings that spans a bandwidth of 0.001 Hz to 1 kHz through a featured sample-level duty-cycling (SLDC) mode. Each recording channel is implemented by a delta-sigma analog-to-digital converter (ADC) achieving 1.0 µ V rms input-referred noise over 1Hz-1kHz bandwidth with a Noise Efficiency Factor (NEF) of 2.93 in continuous operation mode. In SLDC mode, the power supply is duty-cycled while maintaining consistently low input-referred noise levels at ultra-low frequencies (1.1 µV rms over 0.001Hz-1Hz) and 435 M Ω input impedance. The functionalities of the proposed SoC are validated with two human electrophysiology applications: recording low-amplitude electroencephalogram (EEG) through electrodes fixated on the forehead to monitor brain waves, and ultra-slow-wave electrogastrogram (EGG) through electrodes fixated on the abdomen to monitor digestion.