Rescue Therapy for Failed Mechanical Thrombectomy in Acute Ischemic Stroke: A Pooled Analysis of the Society of Vascular and Interventional Neurology Registry.

OBJECTIVE: We aimed to evaluate the association between rescue therapy (RT) and functional outcomes compared to medical management (MM) in patients presenting after failed mechanical thrombectomy (MT). METHODS: This cross-sectional study utilized prospectively collected and maintained data from the Society of Vascular and Interventional Neurology Registry, spanning from 2011 to 2021. The cohort comprised patients with large vessel occlusions (LVOs) with failed MT. The primary outcome was the shift in the degree of disability, as gauged by the modified Rankin Scale (mRS) at 90 days. Additional outcomes included functional independence (90-day mRS score of 0-2), symptomatic intracranial hemorrhage (sICH), and 90-day mortality. RESULTS: Of a total of 7,018 patients, 958 presented failed MT and were included in the analysis. The RT group comprised 407 (42.4%) patients, and the MM group consisted of 551 (57.5%) patients. After adjusting for confounders, the RT group showed a favorable shift in the overall 90-day mRS distribution (adjusted common odds ratio = 1.79, 95% confidence interval [CI] = 1.32-2.45, p < 0.001) and higher rates of functional independence (RT: 28.8% vs MM: 15.7%, adjusted odds ratio [aOR] = 1.93, 95% CI = 1.21-3.07, p = 0.005) compared to the MM group. RT also showed lower rates of sICH (RT: 3.8% vs MM: 9.1%, aOR = 0.52, 95% CI = 0.28-0.97, p = 0.039) and 90-day mortality (RT: 33.4% vs MM: 45.5%, aOR = 0.61, 95% CI = 0.42-0.89, p = 0.009). INTERPRETATION: Our findings advocate for the utilization of RT as a potential treatment strategy for cases of LVO resistant to first-line MT techniques. Prospective studies are warranted to validate these observations and optimize the endovascular approach for failed MT patients. ANN NEUROL 2024.

Brain and cognitive changes in patients with long COVID compared with infection-recovered control subjects.

Between 2.5 and 28% of people infected with SARS-CoV-2 suffer Long COVID or persistence of symptoms for months after acute illness. Many symptoms are neurological, but the brain changes underlying the neuropsychological impairments remain unclear. This study aimed to provide a detailed description of the cognitive profile, the pattern of brain alterations in Long COVID and the potential association between them. To address these objectives, 83 patients with persistent neurological symptoms after COVID-19 were recruited, and 22 now healthy controls chosen because they had suffered COVID-19 but did not experience persistent neurological symptoms. Patients and controls were matched for age, sex and educational level. All participants were assessed by clinical interview, comprehensive standardized neuropsychological tests and structural MRI. The mean global cognitive function of patients with Long COVID assessed by ACE III screening test (Overall Cognitive level - OCLz= -0.39± 0.12) was significantly below the infection recovered-controls (OCLz= +0.32± 0.16, p< 0.01). We observed that 48% of patients with Long COVID had episodic memory deficit, with 27% also impaired overall cognitive function, especially attention, working memory, processing speed and verbal fluency. The MRI examination included grey matter morphometry and whole brain structural connectivity analysis. Compared to infection recovered controls, patients had thinner cortex in a specific cluster centred on the left posterior superior temporal gyrus. In addition, lower fractional anisotropy (FA) and higher radial diffusivity (RD) were observed in widespread areas of the patients' cerebral white matter relative to these controls. Correlations between cognitive status and brain abnormalities revealed a relationship between altered connectivity of white matter regions and impairments of episodic memory, overall cognitive function, attention and verbal fluency. This study shows that patients with neurological Long COVID suffer brain changes, especially in several white matter areas, and these are associated with impairments of specific cognitive functions.

Ambulatory Surgery Center in Rural Uganda: A Novel Approach to Providing Surgical Care.

BACKGROUND: Despite evidence that ambulatory surgery is safe with faster recovery compared to in-patient hospitalization, surgeons in low- and middle-income countries like Uganda have been hesitant to embrace this practice. Kyabirwa Surgical Center (KSC) is the first freestanding ambulatory surgery center (ASC) in rural Uganda. We aim to report the impact of a rural ASC since its establishment, in alleviating surgically-treatable morbidity within its catchment area. METHODS: KSC is located in Jinja, Uganda. The center's electronic medical record was used to analyze the utilization of services, and the Uganda Bureau of Statistics was used to calculate KSC's catchment area. Effectiveness was calculated using disability-adjusted life years (DALYs) averted. RESULTS: Between July 2019 and December 2021, 7,391 patients (57.7% female, 42.3% male) visited KSC from a catchment area of 570,790 people. Of 1,355 procedures, 64.6% were general surgery, 21.3% endoscopy, 9.2% gynecological/genitourinary), 2.8% ENT, 1.5% colorectal, and 0.6% orthopedics. There were no postoperative hospital admissions for complications or mortalities. From the seven most common procedures with an associated disability weight, 2,193.16 total DALYs were averted. CONCLUSION: ASCs can be effective in addressing surgical care gaps in Uganda by increasing the yearly surgical capacity of the local catchment area and averting DALYs within the population.

Superagers resist typical age-related white matter structural changes.

Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age 81.9; 59% women) and 55 typical older adults (mean age 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibres and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional ageing pattern is in line with the last-in-first-out hypothesis.Significance Statement Episodic memory is one of the cognitive abilities most vulnerable to ageing. Although memory normally declines with age, some older people may have memory performance similar to that of people 30 years younger, and this phenomenon is often conceptualised as superageing. Understanding the superager phenotype can provide insights into mechanisms of protection against age-related memory loss and dementia. We studied the white matter structure of a large sample of 64 superagers over the age of 80 and 55 age-matched typical older adults during 5 years with yearly follow-ups showing evidence of slower age-related changes in the brains of superagers especially in protracted maturation tracts, indicating resistance to age-related changes and a regional ageing pattern in line with the last-in-first-out hypothesis.

Hydrogen-Stabilized ScYNdGd Medium-Entropy Alloy for Hydrogen Storage.

The research on the functional properties of medium- and high-entropy alloys (MEAs and HEAs) has been in the spotlight recently. Many significant discoveries have been made lately in hydrogen-based economy-related research where these alloys may be utilized in all of its key sectors: water electrolysis, hydrogen storage, and fuel cell applications. Despite the rapid development of MEAs and HEAs with the ability to reversibly absorb hydrogen, the research is limited to transition-metal-based alloys that crystallize in body-centered cubic solid solution or Laves phase structures. To date, no study has been devoted to the hydrogenation of rare-earth-element (REE)-based MEAs or HEAs, as well as to the alloys crystallizing in face-centered-cubic (FCC) or hexagonal-close-packed structures. Here, we elucidate the formation and hydrogen storage properties of REE-based ScYNdGd MEA. More specifically, we present the astounding stabilization of the single-phase FCC structure induced by the hydrogen absorption process. Moreover, the measured unprecedented high storage capacity of 2.5 H/M has been observed after hydrogenation conducted under mild conditions that proceeded without any phase transformation in the material. The studied MEA can be facilely activated, even after a long passivation time. The results of complementary measurements showed that the hydrogen desorption process proceeds in two steps. In the first, hydrogen is released from octahedral interstitial sites at relatively low temperatures. In the second, high-temperature process, it is associated with the desorption of hydrogen atoms stored in tetrahedral sites. The presented results may impact future research of a novel group of REE-based MEAs and HEAs with adaptable hydrogen storage properties and a broad scope of possible applications.

Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.

During aging, blood cell production becomes dominated by a limited number of variant hematopoietic stem cell (HSC) clones. Differentiated progeny of variant HSCs are thought to mediate the detrimental effects of such clonal hematopoiesis on organismal health, but the mechanisms are poorly understood. While somatic mutations in DNA methyltransferase 3A (DNMT3A) frequently drive clonal dominance, the aging milieu also likely contributes. Here, we examined in mice the interaction between high-fat diet (HFD) and reduced DNMT3A in hematopoietic cells; strikingly, this combination led to weight gain. HFD amplified pro-inflammatory pathways and upregulated inflammation-associated genes in mutant cells along a pro-myeloid trajectory. Aberrant DNA methylation during myeloid differentiation and in response to HFD led to pro-inflammatory activation and maintenance of stemness genes. These findings suggest that reduced DNMT3A in hematopoietic cells contributes to weight gain, inflammation, and metabolic dysfunction, highlighting a role for DNMT3A loss in the development of metabolic disorders.

KARR-seq reveals cellular higher-order RNA structures and RNA-RNA interactions.

RNA fate and function are affected by their structures and interactomes. However, how RNA and RNA-binding proteins (RBPs) assemble into higher-order structures and how RNA molecules may interact with each other to facilitate functions remain largely unknown. Here we present KARR-seq, which uses N3-kethoxal labeling and multifunctional chemical crosslinkers to covalently trap and determine RNA-RNA interactions and higher-order RNA structures inside cells, independent of local protein binding to RNA. KARR-seq depicts higher-order RNA structure and detects widespread intermolecular RNA-RNA interactions with high sensitivity and accuracy. Using KARR-seq, we show that translation represses mRNA compaction under native and stress conditions. We determined the higher-order RNA structures of respiratory syncytial virus (RSV) and vesicular stomatitis virus (VSV) and identified RNA-RNA interactions between the viruses and the host RNAs that potentially regulate viral replication.

SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cells.

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase, Mg2+/Mn2+ dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacologic target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate the protective role of SOD1 against oxidative stress in PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

Voxel-based dysconnectomic brain morphometry with computed tomography in Down syndrome.

OBJECTIVE: Alzheimer's disease (AD) is a major health concern for aging adults with Down syndrome (DS), but conventional diagnostic techniques are less reliable in those with severe baseline disability. Likewise, acquisition of magnetic resonance imaging to evaluate cerebral atrophy is not straightforward, as prolonged scanning times are less tolerated in this population. Computed tomography (CT) scans can be obtained faster, but poor contrast resolution limits its function for morphometric analysis. We implemented an automated analysis of CT scans to characterize differences across dementia stages in a cross-sectional study of an adult DS cohort. METHODS: CT scans of 98 individuals were analyzed using an automatic algorithm. Voxel-based correlations with clinical dementia stages and AD plasma biomarkers (phosphorylated tau-181 and neurofilament light chain) were identified, and their dysconnectomic patterns delineated. RESULTS: Dementia severity was negatively correlated with gray (GM) and white matter (WM) volumes in temporal lobe regions, including parahippocampal gyri. Dysconnectome analysis revealed an association between WM loss and temporal lobe GM volume reduction. AD biomarkers were negatively associated with GM volume in hippocampal and cingulate gyri. INTERPRETATION: Our automated algorithm and novel dysconnectomic analysis of CT scans successfully described brain morphometric differences related to AD in adults with DS, providing a new avenue for neuroimaging analysis in populations for whom magnetic resonance imaging is difficult to obtain.

Epitranscriptional regulation of TGF-ß pseudoreceptor BAMBI by m6A/YTHDF2 drives extrinsic radioresistance.

Activation of TGF-ß signaling serves as an extrinsic resistance mechanism that limits the potential for radiotherapy. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) antagonizes TGF-ß signaling and is implicated in cancer progression. However, the molecular mechanisms of BAMBI regulation in immune cells and its impact on antitumor immunity after radiation have not been established. Here, we show that ionizing radiation (IR) specifically reduces BAMBI expression in immunosuppressive myeloid-derived suppressor cells (MDSCs) in both murine models and humans. Mechanistically, YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2) directly binds and degrades Bambi transcripts in an N6-methyladenosine-dependent (m6A-dependent) manner, and this relies on NF-κB signaling. BAMBI suppresses the tumor-infiltrating capacity and suppression function of MDSCs via inhibiting TGF-ß signaling. Adeno-associated viral delivery of Bambi (AAV-Bambi) to the tumor microenvironment boosts the antitumor effects of radiotherapy and radioimmunotherapy combinations. Intriguingly, combination of AAV-Bambi and IR not only improves local tumor control, but also suppresses distant metastasis, further supporting its clinical translation potential. Our findings uncover a surprising role of BAMBI in myeloid cells, unveiling a potential therapeutic strategy for overcoming extrinsic radioresistance.

Endovascular treatment of acute ischemic stroke patients with tandem lesions: antegrade versus retrograde approach.

OBJECTIVE: The optimal technique for treating tandem lesions (TLs) with endovascular therapy is debatable. The authors evaluated the functional, safety, and procedural outcomes of different approaches in a multicenter study. METHODS: Anterior circulation TL patients treated from January 2015 to December 2020 were divided on the basis of antegrade versus retrograde approach and included. The evaluated outcomes were favorable modified Rankin Scale (mRS) score (mRS score 0-2) at 3 months, ordinal shift in mRS score, successful recanalization, excellent recanalization, first-pass effect (FPE), time from groin puncture to successful recanalization, symptomatic intracranial hemorrhage (sICH), and 90-day mortality. RESULTS: Among 691 patients treated at 16 centers, 286 patients (174 antegrade and 112 retrograde approach patients) with acute stenting were included in the final analysis. There were no significant differences in mRS score 0-2 at 90 days (52.2% vs 50.0%, adjusted odds ratio [aOR] 0.83, 95% CI 0.42-1.56, p = 0.54), favorable shift in 90-day mRS score (aOR 1.03, 95% CI 0.66-1.29, p = 0.11), sICH (4.0% vs 4.5%, aOR 0.64, 95% CI 0.24-1.51, p = 0.45), successful recanalization (89.4% vs 93%, aOR 0.49, 95% CI 0.19-1.28, p = 0.19), excellent recanalization (51.4% vs 58.9%, aOR 0.59, 95% CI 0.40-1.07, p = 0.09), FPE (58.3% vs 69.7%, aOR 0.62, 95% CI 0.44-1.15, p = 0.21), and mortality at 90 days (16.6% vs 14.0%, aOR 0.94, 95% CI 0.35-2.44, p = 0.81) between the groups. The median (interquartile range) groin puncture to recanalization time was significantly longer in the antegrade group (59 [43-90] minutes vs 49 [35-73] minutes, p = 0.036). CONCLUSIONS: The retrograde approach was associated with faster recanalization times with a similar functional and safety profile when compared with the antegrade approach in patients with acute ischemic stroke with TL.

Novel use of an image-guided supraorbital craniotomy via an eyebrow approach for the repair of a delayed traumatic orbital encephalocele: illustrative cases.

BACKGROUND: Traumatic orbital encephaloceles are rare but severe complications of orbital fractures. These encephaloceles can present months to years after the initial injury. OBSERVATIONS: The authors present two cases of traumatic orbital encephalocele in young males struck by motor vehicles. LESSONS: The exact traumatic mechanism of these encephaloceles is unknown, and diagnosis can be confounded by concomitant injuries. The use of a minimally invasive supraorbital keyhole craniotomy has the potential to change how this disease process is managed and has not been previously documented in this setting.

Taxifolin inhibits NETosis through activation of Nrf2 and provides protective effects in models of lupus and antiphospholipid syndrome.

OBJECTIVES: Taxifolin (dihydroquercetin) is a bioactive plant flavonoid that exhibits anti-inflammatory and anti-oxidative properties. We hypothesized that taxifolin might be an effective dietary supplement to ameliorate symptoms arising from thrombo-inflammatory diseases such as lupus and antiphospholipid syndrome (APS). METHODS: We used in vitro assays and a mouse model to determine mechanisms by which taxifolin inhibits neutrophil extracellular trap (NET) formation (i.e., NETosis) and venous thrombosis in lupus and APS. RESULTS: At doses ranging from 0.1 to 1 µg/ml, taxifolin inhibited NETosis from control neutrophils stimulated with autoantibodies isolated from lupus and APS patients, and its suppressive effects were mitigated by blocking the antioxidant transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). Furthermore, taxifolin at a dose as low as 20 mg/kg/day reduced in vivo NETosis in thrombo-inflammatory mouse models of lupus and APS while also significantly attenuating autoantibody formation, inflammatory cytokine production, and large-vein thrombosis. CONCLUSION: Our study is the first to demonstrate the protective effects of taxifolin in the context of lupus and APS. Importantly, our study also suggests a therapeutic potential to neutralize neutrophil hyperactivity and NETosis that could have relevance to a variety of thrombo-inflammatory diseases.

SRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation.

Somatic mutations accumulate in all cells with age and can confer a selective advantage, leading to clonal expansion over time. In hematopoietic cells, mutations in a subset of genes regulating DNA repair or epigenetics frequently lead to clonal hematopoiesis (CH). Here, we describe the context and mechanisms that lead to enrichment of hematopoietic stem cells (HSCs) with mutations in SRCAP, which encodes a chromatin remodeler that also influences DNA repair. We show that SRCAP mutations confer a selective advantage in human cells and in mice upon treatment with the anthracycline-class chemotherapeutic doxorubicin and bone marrow transplantation. Furthermore, Srcap mutations lead to a lymphoid-biased expansion, driven by loss of SRCAP-regulated H2A.Z deposition and increased DNA repair. Altogether, we demonstrate that SRCAP operates at the intersection of multiple pathways in stem and progenitor cells, offering a new perspective on the functional impact of genetic variants that promote stem cell competition in the hematopoietic system.

Opportunities for Global Health Diplomacy in Transnational Robotic Telesurgery.

Globally, barriers to the widespread adoption of robotic surgery have worsened existing inequities in surgical care between low- and middle- income countries (LMICs) and high-income countries (HICs). This article advocates for the creation of sustainable robotic surgery programs in LMICs by drawing from ethical and philosophical theories, including preference utilitarianism, procedural justice, structural violence, and human rights. On this basis, robotic telesurgery is proposed as a form of global health diplomacy (GHD) between LMICs and HICs, and particular emphasis is placed on considerations in robotic surgery GHD program negotiations between LMICs and HICs and on political and ethical questions related to the transnational use of artificial intelligence.

Ex vivo gliadin stimulation of intestinal cells.

Celiac disease is an autoimmune response to gluten proteins. While causes for celiac disease have been identified, there is no effective treatment other than diet control. In vitro models for celiac disease are important for quickly gaining understanding of the disease mechanism and testing potential treatments. Here we describe an ex vivo stimulation of intestinal epithelial cells with gliadin peptides as a method to induce celiac disease features in vitro.

Associations Between Cancer Predisposition Mutations and Clonal Hematopoiesis in Patients With Solid Tumors.

PURPOSE: Clonal hematopoiesis (CH), the expansion of clones in the hematopoietic system, has been linked to different internal and external features such as aging, genetic ancestry, smoking, and oncologic treatment. However, the interplay between mutations in known cancer predisposition genes and CH has not been thoroughly examined in patients with solid tumors. METHODS: We used prospective tumor-blood paired sequencing data from 46,906 patients who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing to interrogate the associations between CH and rare pathogenic or likely pathogenic (P/LP) germline variants. RESULTS: We observed an enrichment of CH-positive patients among those carrying P/LP germline mutations and identified a significant association between P/LP germline variants in ATM and CH. Germline and CH comutation patterns in ATM, TP53, and CHEK2 suggested biallelic inactivation as a potential mediator of clonal expansion. Moreover, we observed that CH-PPM1D mutations, similar to somatic tumor-associated PPM1D mutations, were depleted in patients with P/LP germline mutations in the DNA damage response (DDR) genes ATM, CHEK2, and TP53. Patients with solid tumors and harboring P/LP germline mutations, CH mutations, and mosaicism chromosomal alterations might be at an increased risk of developing secondary leukemia while germline variants in TP53 were identified as an independent risk factor (hazard ratio, 36; P < .001) for secondary leukemias. CONCLUSION: Our results suggest a close relationship between inherited variants and CH mutations within the DDR genes in patients with solid tumors. Associations identified in this study might translate into enhanced clinical surveillance for CH and associated comorbidities in patients with cancer harboring these germline mutations.