Now showing items 21-40 of 27122

    • Maternal and Perinatal Factors Associated With Childhood Brain Tumors: A Case-Control Study in Vietnam

      Pham, Huy Ngoc; Goldberg, Robert J.; Pham, Loc Quang; Nguyen, Hoa L; Pham, Dao Anh; Mai, Linh Thi Thuy; Phung, Toi Lam; Hung, Doan Quoc; Dong, He Van; Duong, Ha Dai (2024-05-23)
      Introduction: Brain cancer is the leading cause of cancer-related deaths in children and the majority of childhood brain tumors are diagnosed without determination of their underlying etiology. Little is known about risk factors for childhood brain tumors in Vietnam. The objective of this case-control study was to identify maternal and perinatal factors associated with brain tumors occurring in young Vietnamese children and adolescents. Methods: We conducted a hospital-based case-control study at Viet Duc University Hospital in Hanoi, Vietnam. Cases consisted of children with brain tumors aged 0-14 years old admitted to the hospital from January 2020 to July 2022 while the controls were age and sex-matched hospitalized children diagnosed with head trauma. Perinatal characteristics were abstracted from hospital medical records and maternal medical, behavioral, and sociodemographic factors were collected through in-person interviews. Conditional logistic regression models were used to examine maternal and perinatal factors associated with childhood brain tumors. Results: The study sample included 220 children (110 cases and 110 controls) whose average age was 8.9 years and 41.8% were girls. Children born to mothers aged greater than 30 years at the time of the child's birth had a higher risk of childhood brain tumors compared to those born to mothers aged from 18 to 30 years old (OR = 2.55; 95% CI: 1.13-5.75). Additionally low maternal body mass index prior to the current pregnancy of <18.5 kg/m2 significantly increased the odds of having a child with a brain tumor in relation to normal maternal body mass index from 18.5-22.9 kg/m2 (OR = 3.19; 95% CI: 1.36 - 7.50). Conclusion: Advanced maternal age and being markedly underweight were associated with an increased odds of having a child with a brain tumor. A population-based study with larger sample size is needed to confirm and extend the present findings.
    • SLIGHT shield dataset on effect of chest shielding during phototherapy in premature infants on the incidence of patent ductus arteriosus

      Amin, Sanjiv; Mannan, Javed (2024-05-23)
      The SLIGHT shield dataset reflects the results from a double blind randomized trial on the effect of chest shielding during phototherapy in premature infants on the incidence of patent ductus arteriosus. All preterm infants ≤ 29 weeks GA or weighing ≤1000 grams at birth admitted to our neonatal intensive care unit (NICU) within the first 24 hours of life were eligible for the study and randomized to chest shield placement or sham shield placement during phototherapy treatment. Enrollment occurred from August 1, 2015 to April 13, 2018. The primary outcome was the incidence of sPDA diagnosed via clinical parameters by the investigator team during the period from 24 hours after initiating phototherapy to 3 days after stopping phototherapy. Secondary outcomes consistent of echo based parameters : 1) ductal diameter with a left to right or bidirectional shunt across the PDA 2) left atrium (LA) to aortic root (AO) diameter ratio (LA/AO) and 3) LA volume. Additional secondary outcomes included the following: 1) surgical ligation of PDA, 2) chronic lung disease (CLD), 3) retinopathy of prematurity (ROP), 4) intraventricular hemorrhage (IVH), 5) peak levels of total serum bilirubin and 6) duration of phototherapy. Baseline/demographc data as well as clinical data were also obtained. Study participants self-reported three items assessing religiosity: strength/comfort from religion, petition prayers for health, and awareness of intercessory prayers by others. All cause-mortality within 2-years of hospital discharge was ascertained by review of medical records at participating study hospitals and from death certificates. Cox proportional hazards models were used to estimate the multivariable adjusted risk of 2-year all-cause mortality.
    • Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements

      Pratt, Henry E; Andrews, Gregory; Shedd, Nicole; Phalke, Nishigandha; Li, Tongxin; Pampari, Anusri; Jensen, Matthew; Wen, Cindy; Gandal, Michael J; Geschwind, Daniel H; et al. (2024-05-23)
      Most genetic variants associated with psychiatric disorders are located in noncoding regions of the genome. To investigate their functional implications, we integrate epigenetic data from the PsychENCODE Consortium and other published sources to construct a comprehensive atlas of candidate brain cis-regulatory elements. Using deep learning, we model these elements' sequence syntax and predict how binding sites for lineage-specific transcription factors contribute to cell type-specific gene regulation in various types of glia and neurons. The elements' evolutionary history suggests that new regulatory information in the brain emerges primarily via smaller sequence mutations within conserved mammalian elements rather than entirely new human- or primate-specific sequences. However, primate-specific candidate elements, particularly those active during fetal brain development and in excitatory neurons and astrocytes, are implicated in the heritability of brain-related human traits. Additionally, we introduce PsychSCREEN, a web-based platform offering interactive visualization of PsychENCODE-generated genetic and epigenetic data from diverse brain cell types in individuals with psychiatric disorders and healthy controls.
    • A Case Study Identifying Barriers to Breast Cancer Screening and Strategies for Improved Access and Participation in an Underserved Community

      Vijayaraghavan, Gopal R (2024-05-20)
      A complex interplay of racial, ethnic, and social determinants are the drivers for disparity in access to screening, quality of care and health outcomes in diverse populations.
    • Spatial Transcriptomics Reconstruction of Mouse Olfactory System

      Wang, I-Hao (2024-05-20)
      The olfactory system is crucial for animals in tasks such as foraging, mate selection, and predator avoidance due to its ability to detect and distinguish a vast array of environmental chemicals. Mice detect these chemicals via olfactory receptor (OR) proteins, which are uniquely expressed by olfactory sensory neurons (OSNs); each OSN expresses only one OR type. OSNs with the same OR converge their axons to a specific location in the olfactory bulb (OB), forming a structure known as a glomerulus. This precise organization ensures a consistent, spatially invariant pattern of glomerular activation for each odorant, playing a likely role in the brain's decoding of odor identities. Nevertheless, the exact locations of most glomeruli are unknown, and the mechanisms that create consistent glomerular maps across different animals are not fully understood. In this study, we leveraged spatial transcriptomics and machine learning to map the majority of glomerular positions within the mouse OB. Furthermore, single-cell RNA sequencing revealed distinct transcriptional profiles for each OSN type, characterized not only by their OR gene but also by a unique set of axon guidance genes. These profiles can predict the eventual location of each OSN's glomerulus within the olfactory bulb. We also identified a correlation between the spatial distribution of glomeruli and the characteristics of their corresponding ORs, suggesting a chemotopic arrangement in the mouse olfactory system. Additionally, we probed the complexity of the OB by creating a spatially resolved cell atlas through spatial single-cell transcriptomics, revealing the identity and distribution of neuron subtypes that contribute to odor perception.
    • Working Together to Mint DOIs on Demand for a DSpace Repository

      Grynoch, Tess; Palmer, Lisa A. (2024-05-20)
      Background: Digital Object Identifiers (DOIs) are a key persistent identifier in the publishing landscape to ensure discoverability and citation of research products. Minting DOIs can be a time-consuming task for repository librarians. This process can be automated since the metadata for DOIs is already in the repository record and DataCite, a DOI minting organization, and Open Repository, a DSpace repository platform, both have application programming interfaces (APIs). Previous software has enabled bulk DOI minting. However, the institutional repository contains a mixture of original materials (dissertations, reports, data, etc.) and previously published materials such as journal articles and preprints. Description: An institutional repository librarian and her librarian colleague with Python experience embarked on a pair programming project to create a script to mint DOIs on demand in DataCite for individual items in the institution’s Open Repository instance. The pair met for one hour each week to develop and test the script. The institutional repository librarian lent invaluable insight into both platforms and the metadata variations the code would need to account for. The project was also a great learning opportunity for both librarians to improve their Python coding skills. This project will be evaluated in terms of how the time spent creating the code compares to the time it takes to mint DOIs manually as well as metadata enhancements and accuracy in DataCite. Program Conclusion: This poster will share the final Python script and highlight the takeaways from this approach for both the institutional repository librarian and the coding librarian. Final evaluation is forthcoming.
    • Inferring causal cell types of human diseases and risk variants from candidate regulatory elements [preprint]

      Kim, Artem; Zhang, Zixuan; Legros, Come; Lu, Zeyun; de Smith, Adam; Moore, Jill E; Mancuso, Nicholas; Gazal, Steven (2024-05-18)
      The heritability of human diseases is extremely enriched in candidate regulatory elements (cRE) from disease-relevant cell types. Critical next steps are to infer which and how many cell types are truly causal for a disease (after accounting for co-regulation across cell types), and to understand how individual variants impact disease risk through single or multiple causal cell types. Here, we propose CT-FM and CT-FM-SNP, two methods that leverage cell-type-specific cREs to fine-map causal cell types for a trait and for its candidate causal variants, respectively. We applied CT-FM to 63 GWAS summary statistics (average N = 417K) using nearly one thousand cRE annotations, primarily coming from ENCODE4. CT-FM inferred 81 causal cell types with corresponding SNP-annotations explaining a high fraction of trait SNP-heritability (~2/3 of the SNP-heritability explained by existing cREs), identified 16 traits with multiple causal cell types, highlighted cell-disease relationships consistent with known biology, and uncovered previously unexplored cellular mechanisms in psychiatric and immune-related diseases. Finally, we applied CT-FM-SNP to 39 UK Biobank traits and predicted high confidence causal cell types for 2,798 candidate causal non-coding SNPs. Our results suggest that most SNPs impact a phenotype through a single cell type, and that pleiotropic SNPs target different cell types depending on the phenotype context. Altogether, CT-FM and CT-FM-SNP shed light on how genetic variants act collectively and individually at the cellular level to impact disease risk.
    • Safety and clinical outcomes of endovascular therapy versus medical management in late presentation of large ischemic stroke

      Mujanovic, Adnan; Strbian, Daniel; Demeestere, Jelle; Marto, João Pedro; Puetz, Volker; Nogueira, Raul G; Abdalkader, Mohamad; Nagel, Simon; Raymond, Jean; Ribo, Marc; et al. (2024-05-17)
      Introduction: The benefit of endovascular therapy (EVT) among stroke patients with large ischemic core (ASPECTS 0-5) in the extended time window outside of trial settings remains unclear. We analyzed the effect of EVT among these stroke patients in real-world settings. Patients and methods: The CT for Late Endovascular Reperfusion (CLEAR) study recruited patients from 66 centers in 10 countries between 01/2014 and 05/2022. The extended time-window was defined as 6-24 h from last-seen-well to treatment. The primary outcome was shift of the 3-month modified Rankin scale (mRS) score. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality. Outcomes were analyzed with ordinal and logistic regressions. Results: Among 5098 screened patients, 2451 were included in the analysis (median age 73, 55% women). Of patients with ASPECTS 0-5 (n = 310), receiving EVT (n = 209/310) was associated with lower 3-month mRS when compared to medical management (median 4 IQR 3-6 vs 6 IQR 4-6; aOR 0.4, 95% CI 0.2-0.7). Patients undergoing EVT had higher sICH (11.2% vs 4.0%; aOR 4.1, 95% CI 1.2-18.8) and lower mortality (31.6% vs 58.4%, aOR 0.4; 95% CI 0.2-0.9) compared to medically managed patients. The relative benefit of EVT was comparable between patients with ASPECTS 0 and 5 and 6-10 in the extended time window (interaction aOR 0.9; 95% CI 0.5-1.7). Conclusion: In the extended time window, patients with ASPECTS 0-5 may have preserved relative treatment benefit of EVT compared to patients with ASPECTS 6-10. These findings are in line with recent trials showing benefit of EVT among real-world patients with large ischemic core in the extended time window. Trial registration number: clinicaltrials.gov; Unique identifier: NCT04096248.
    • Developing an Adeno-Associated Viral Gene Therapy for Sialidosis Using Small and Large Animal Models

      Gallagher, Jillian (2024-05-17)
      Sialidosis is a rare, fatal lysosomal storage disease caused by mutations in NEU1, encoding neuraminidase 1 (NEU1) resulting in toxic accumulation of sialylated glycoproteins. Type I patients have adolescent onset with myoclonus, ataxia, seizures, cherry-red spot, and vision loss, with death in midlife. Type II patients are more severe with the addition of hepatosplenomegaly, coarse facial features, dysostosis multiplex, developmental delay, and death in childhood. There are no approved therapies for sialidosis. We developed three adeno-associated viral (AAV) gene therapy vector strategies to treat sialidosis encoding: Neu1 alone (AAV9-Neu1), Neu1 modified to enhance secretion (AAV9-Idua-Neu1) or Neu1 in combination with its chaperone protein cathepsin A (AAV9-Ctsa-Bici-Neu1). Neonatal Neu1-KO mice were injected by intracerebroventricular injection. Increased survival and significant improvement in motor ability was noted for all vectors, however seizures were observed in AAV9-Neu1 treated mice at 10 months of age. Reduced sialic acid and PPCA were found in peripheral organs and brains of treated mice. NEU1 was increased in peripheral organs and the brain, however AAV9-Ctsa-Bici-Neu1 treated mice had NEU1 levels similar to WT mice. Pathology of peripheral organs were markedly ameliorated with AAV gene therapy. We generated a sialidosis type II sheep using CRISPR-SpCas9 (A320del), which is in the same location as the amino acid change in patients (A319V). Importantly, the A320del sheep exhibits a neurological phenotype unlike the Neu1-KO mouse. Overall, the most efficacious vector is AAV9-Ctsa-Bici-Neu1, which will be further tested in the sialidosis sheep model. These studies will inform future clinical trials for this devastating disease.
    • ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection

      Bazzone, Lindsey E; Zhu, Junji; King, Michael; Liu, GuanQun; Guo, Zhiru; MacKay, Christopher R; Kyawe, Pyae P; Qaisar, Natasha; Rojas-Quintero, Joselyn; Owen, Caroline A; et al. (2024-05-16)
      Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)-a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.
    • Exploring the relationship between school-supervised asthma therapy and social determinants of health in pediatric asthma care

      Al-Halbouni, Layana; Ryan, Grace W; Radu, Sonia; Spano, Michelle; Sabnani, Reshma; Phipatanakul, Wanda; Gerald, Lynn B; Garg, Arvin; Pbert, Lori; Trivedi, Michelle (2024-05-16)
      Background: Social determinants of health (SDoH), including access to care, economic stability, neighborhood factors, and social context, strongly influence pediatric asthma outcomes. School-supervised asthma therapy (SST) is an evidence-based strategy that improves asthma outcomes, particularly for historically marginalized children, by providing support for daily medication adherence in school. However, little is known about the relationship between these programs and the adverse SDoH commonly affecting underrepresented minority and marginalized children with asthma. Methods: We examined qualitative data from interviews (n = 52) conducted between 2017 and 2020 with diverse multi-level partners involved in Asthma Link, a SST intervention. Participants included end-users (children and their parents), deliverers (school nurses and pediatric providers), and systems-level partners (e.g., insurers, legislators, and state officials). We used inductive coding to determine themes and subthemes and deductive coding using the Healthy People 2030 SDoH framework. Results: Three themes emerged: (1) SST mitigates adverse SDoH (improves access to preventive healthcare and asthma health literacy), (2) SST benefits children experiencing specific adverse SDoH (provides a consistent medication routine to children with unstable family/housing situations) and (3) specific adverse SDoH impede SST implementation (economic instability, culture and language barriers). Conclusion: This study suggests an important relationship between SDoH and SST that warrants further evaluation in our future work on this community-based asthma intervention. Moreover, our findings underscore the importance of measuring SDoH in the implementation and evaluation of pediatric asthma interventions, particularly given the strong influence of these social factors on child health outcomes.
    • Race-Based Differences in the Response to a Mindfulness Based Integrative Medical Group Visit Intervention for Chronic Pain

      Incollingo Rodriguez, Angela C; Nephew, Benjamin C; Polcari, Justin J; Melican, Veronica; King, Jean A; Gardiner, Paula (2024-05-16)
      Background: Chronic pain is one of the most common drivers of healthcare utilization and a marked domain for health disparities, as African American/Black populations experience high rates of chronic pain. Integrative Medical Group Visits (IMGV) combine mindfulness techniques, evidence-based integrative medicine, and medical group visits. In a parent randomized controlled trial, this approach was tested as an adjunct treatment in a diverse, medically underserved population with chronic pain and depression. Objective: To determine race-based heterogeneity in the effects of a mindfulness based treatment for chronic pain. Methods: This secondary analysis of the parent trial assessed heterogeneity of treatment effects along racialized identity in terms of primary patient-reported pain outcomes in a racially diverse sample suffering from chronic pain and depression. The analytic approach examined comorbidities and sociodemographics between racialized groups. RMANOVAs examined trajectories in pain outcomes (average pain, pain severity, and pain interference) over three timepoints (baseline, 9, and 21 weeks) between participants identifying as African American/Black (n = 90) vs White (n = 29) across both intervention and control conditions. Results: At baseline, African American/Black participants had higher pain severity and had significantly different age, work status, and comorbidity profiles. RMANOVA models also identified significant race-based differences in the response to the parent IMGV intervention. There was reduced pain severity in African American/Black subjects in the IMGV condition from baseline to 9 weeks. This change was not observed in White participants over this time period. However, there was a reduction in pain severity in White participants over the subsequent interval from 9 to 21 week where IMGV had no significant effect in African American/Black subjects during this latter time period. Conclusion: Interactions between pain and racialization require further investigation to understand how race-based heterogeneity in the response to integrative medicine treatments for chronic pain contribute to the broader landscape of health inequity.
    • Outcomes of Bridging Intravenous Thrombolysis Versus Endovascular Therapy Alone in Late-Window Acute Ischemic Stroke

      Demeestere, Jelle; Qureshi, Muhammad M; Vandewalle, Lieselotte; Wouters, Anke; Strbian, Daniel; Nogueira, Raul G; Nagel, Simon; Yamagami, Hiroshi; Puetz, Volker; Abdalkader, Mohamad; et al. (2024-05-15)
      Background: Studies comparing bridging intravenous thrombolysis (IVT) with direct endovascular therapy (EVT) in patients with acute ischemic stroke who present late are limited. We aimed to compare the clinical outcomes and safety of bridging IVT in patients with acute ischemic stroke due to anterior circulation large vessel occlusion who underwent EVT 6 to 24 hours after time last known well. Methods: We enrolled patients with anterior circulation large vessel occlusion stroke and a National Institutes of Health Stroke Scale score of ≥6 from 20 centers across 10 countries in the multicenter retrospective CLEAR study (CT for Late Endovascular Reperfusion) between January 2014 and May 2022. We used inverse probability of treatment weighting modeling adjusted for clinical and imaging confounders to compare functional outcomes, reperfusion success, symptomatic intracranial hemorrhage, and mortality between EVT patients with and without prior IVT. Results: Of 5098 patients screened for eligibility, we included 2749 patients, of whom 549 received bridging IVT before EVT. The timing of IVT was not recorded. Witnessed stroke onset and transfer rates were higher in the bridging IVT group (25% versus 12% and 77% versus 55%, respectively, P value for both <0.0001), and time intervals between stroke onset and treatment were shorter (time last known well-start of EVT median 560 minutes [interquartile range, 432-791] versus 724 minutes [interquartile range, 544-912]; P<0.0001). After adjustment for confounders, there was no difference in functional outcome at 3 months (adjusted common odds ratio for modified Rankin Scale shift, 1.03 [95% CI, 0.89-1.19]; P=0.72) or successful reperfusion (adjusted odds ratio, 1.19 [95% CI, 0.81-1.75]; P=0.39). There were no safety concerns associated with bridging IVT versus direct EVT (symptomatic intracranial hemorrhage: adjusted odds ratio, 0.75 [95% CI, 0.38-1.48]; P=0.40; mortality: adjusted odds ratio, 1.14 [95% CI, 0.89-1.46]; P=0.31). Results were unchanged when the analysis was limited to patients who received IVT >6 hours after last known well. Conclusions: In patients with an anterior circulation large vessel occlusion stroke who underwent EVT 6 to 24 hours from last known well, bridging IVT was not associated with a difference in outcomes compared with direct EVT. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04096248.
    • Volumetric microscopy of cerebral arteries with a miniaturized optical coherence tomography imaging probe

      Pereira, Vitor M; Lylyk, Pedro; Cancelliere, Nicole; Lylyk, Pedro N; Lylyk, Ivan; Anagnostakou, Vania; Bleise, Carlos; Nishi, Hidehisa; Epshtein, Mark; King, Robert M; et al. (2024-05-15)
      Endovascular interventions are increasingly becoming the preferred approach for treating strokes and cerebral artery diseases. These procedures rely on sophisticated angiographical imaging guidance, which encounters challenges because of limited contrast and spatial resolution. Achieving a more precise visualization of the underlying arterial pathology and neurovascular implants is crucial for accurate procedural decision-making. In a human study involving 32 patients, we introduced the clinical application of a miniaturized endovascular neuro optical coherence tomography (nOCT) imaging probe. This technology was designed to navigate the tortuous paths of the cerebrovascular circulation and to offer high-resolution imaging in situ. The nOCT probe is compatible with standard neurovascular microcatheters, integrating with the procedural workflow used in clinical routine. Equipped with a miniaturized optical fiber and a distal lens, the probe illuminates the tissue and collects the backscattered, near-infrared light. While rotating the fiber and the lens at high speed, the probe is rapidly retracted, creating a spiral-shaped light pattern to comprehensively capture the arterial wall and implanted devices. Using nOCT, we demonstrated volumetric microscopy of cerebral arteries in patients undergoing endovascular procedures. We imaged the anterior and posterior circulation of the brain, including distal segments of the internal carotid and middle-cerebral arteries, as well as the vertebral, basilar, and posterior cerebral arteries. We captured a broad spectrum of neurovascular pathologies, such as brain aneurysms, ischemic stroke, arterial stenoses, dissections, and intracranial atherosclerotic disease. nOCT offered artifact-free, high-resolution visualizations of intracranial artery pathology and neurovascular devices.
    • Cognitive impairment and treatment strategy for atrial fibrillation in older adults: The SAGE-AF study

      Athreya, Deepti S; Saczynski, Jane S; Gurwitz, Jerry H; Monahan, Kevin M; Bamgbade, Benita A; Paul, Tenes J; Sogade, Felix; Lessard, Darleen M; McManus, David D; Helm, Robert H (2024-05-14)
      Background: Cognitive impairment is strongly associated with atrial fibrillation (AF). Rate and rhythm control are the two treatment strategies for AF and the effect of treatment strategy on risk of cognitive decline and frailty is not well established. We sought to determine how treatment strategy affects geriatric-centered outcomes. Methods: The Systematic Assessment of Geriatric Elements-AF (SAGE-AF) was a prospective, observational, cohort study. Older adults with AF were prospectively enrolled between 2016 and 2018 and followed longitudinally for 2 years. In a non-randomized fashion, participants were grouped by rate or rhythm control treatment strategy based on clinical treatment at enrollment. Baseline characteristics were compared. Longitudinal binary mixed models were used to compare treatment strategy with respect to change in cognitive function and frailty status. Cognitive function and frailty status were assessed with the Montreal Cognitive Assessment Battery and Fried frailty phenotype tools. Results: 972 participants (mean age = 75, SD = 6.8; 49% female, 87% non-Hispanic white) completed baseline examination and 2-year follow-up. 408 (42%) were treated with rate control and 564 (58%) with rhythm control. The patient characteristics of the two groups were different at baseline. Participants in the rate control group were older, more likely to have persistent AF, prior stroke, be treated with warfarin and have baseline cognitive impairment. After adjusting for baseline differences, participants treated with rate control were 1.5 times more likely to be cognitively impaired over 2 years (adjusted OR: 1.47, 95% CI:1.12, 1.98) and had a greater decline in cognitive function (adjusted estimate: -0.59 (0.23), p < 0.01) in comparison to rhythm control. Frailty did not vary between the treatment strategies. Conclusions: Among those who had 2-year follow-up in non-randomized observational cohort, the decision to rate control AF in older adults was associated with increased odds of decline in cognitive function but not frailty.
    • Mid-term safety and efficacy in small intracranial aneurysm coiling: results from TARGET nano prospective independent core lab adjudicated multicenter registry

      Ashouri, Yazan; Paul, Alexandra R; Puri, Ajit S; Liaw, Nicholas; Majjhoo, Aniel; Taqi, Asif; Rai, Ansaar; Badruddin, Aamir; Alshekhlee, Amer; Naravetla, Bharath; et al. (2024-05-13)
      Background: The primary objective is to evaluate the safety and effectiveness of Stryker second generation Target® Nano Coils in the treatment of ruptured and unruptured small (<7 mm) intracranial aneurysms. Methods: The TARGET Registry is a prospective, two-arm study with independent medical event monitoring and core-lab adjudication. This paper describes the second arm of the TARGET registry. Patients with de novo intracranial aneurysms were embolized with 2nd generation TARGET Nano coils in 12 US centers. The primary efficacy outcome was adequate aneurysm occlusion (RR occlusion grade I-II) on follow-up. Primary safety outcome was treatment-related morbidity and mortality. Secondary outcomes included aneurysm packing density immediately post-procedure, immediate adequate occlusion, aneurysm re-access rate, retreatment rate and clinical outcomes using modified ranking scale. A secondary analysis investigated the influence of using Nano-predominant coils (≥2/3 of total coil-length) vs. non-Nano-predominant coils (<2/3 of total length). Results: 150 patients with 155 aneurysms met the inclusion and exclusion criteria. (31%) patients with ruptured and (69%) with unruptured aneurysms were treated using TARGET coils. Median age was 58.8 (SD 12.7), 74.7% were females, and 80% were Caucasians. Mean follow-up was 5.23 (SD 2.27) months. Peri-procedural mortality was seen in 2.0% of patients. Good outcome at discharge (mRS 0-2) was seen in 81.3% of the cohort. The median packing density (SD) was 29.4% (14.9). Mid-term complete/near complete occlusion rate was seen in 96% of aneurysms and complete obliteration was seen in 75.2% of aneurysms. Patients treated predominantly with Nano coils had higher PD (32.6% vs. 26.1%, p < 0.001). There was no significant difference in clinical and angiographic outcomes. The mid-term mRS0-2 was achieved in 106/109 (97.2%) patients. All-cause mortality was 5/115 (4.3%). Conclusion: In the multicenter TARGET Registry, 75.8% of aneurysms achieved mid-term complete occlusion, and 96% achieved complete/near complete occlusion with excellent independent functional outcome.
    • Progressive CD4 T-Cell Dysfunction During Chronic Tuberculosis is Associated with Bacterial Recrudescence

      Chang, Evelyn (2024-05-13)
      Tuberculosis remains a leading cause of death globally, and approximately 5-10% of those infected develop pulmonary disease, often after initially controlling infection. Why immunity fails is unknown. CD4 T cells are crucial for immunity against Mtb, yet little is known about how Mtb infection might modulate CD4 T cell function, particularly late during infection. We hypothesize that failure of CD4 T cell function permits bacterial recrudescence and the development of active disease. Here, we develop a minimalistic adoptive transfer model to study antigen-specific T cells in the lungs of Mtb-infected mice. Late during infection, a decrease in T cell polyfunctionality and production of IL-2, TNF, and IFNγ is accompanied by the accumulation of PD-1 and TIM-3 expressing T cells. Transcriptional profiling identifies signatures of senescence and exhaustion in these cells. In C57Bl/6 mice, a similar co-inhibitory receptor expression and loss of function is observed on antigen-specific CD4s. Single-cell sequencing reveals that most expanded parenchymal T cells are hypofunctional, even early post-infection. However, no evidence of exhaustion or senescence was found. As TCR affinity and signaling strength affects T cell differentiation, we next examined whether TCR affinity impacts T cell function. Higher affinity CD4 T cells differentiate into polyfunctional Th1 cells while lower affinity clones skew towards a Th17 phenotype. The distinct clusters formed by high and low affinity clones on a UMAP projection show how TCR signaling strength affects T cell differentiation during chronic infection. These data provide insight into mechanisms modulating CD4 T cell dysfunction during chronic infection. Further study into these mechanisms will inform therapeutic options.
    • Translational insights into the genetics and immunobiology of relapsed/refractory follicular lymphoma

      Yaniv, Benyamin; Tanenbaum, Benjamin; Kazakova, Vera; Patel, Shyam A (2024-05-11)
      Although follicular lymphoma (FL) is traditionally classified as an indolent subtype of B cell non-Hodgkin lymphoma, clinical trajectories are often diverse based on unique disease biology, and many patients will eventually experience relapse of their disease. Furthermore, progression of disease within 24 months is associated with increased mortality rates for FL. In the last five years, we have witnessed an upsurge in the commercial availability of targeted therapies for relapsed/refractory (R/R) FL, including chimeric antigen receptor-T (CAR-T) products, bispecific T cell engagers (BiTEs), epigenetic modifier therapies, and next-generation Bruton tyrosine kinase (BTK) inhibitors. Furthermore, clinical trial options have increased tremendously and now include combinatorial strategies that exert synergy against malignant germinal center B cells. Here, we provide a 2024 update of novel therapeutic agents whose development has been informed by recent advances in the genetics and immunobiology of R/R FL. Specifically, we emphasize high-value targeted therapeutics, including anti-CD3 x anti-CD20 BiTEs and adoptive T cell therapies. We discuss prospects on selection and sequencing of BiTEs and CAR-T therapies for patients with R/R FL. We underscore the principles of FL pathobiology that are paving way for future drug discovery and shed insight into therapeutic targeting within nodal basins based on our increasing understanding of the FL microenvironment. Finally, we summarize how a greater knowledge of FL immunobiology can inform risk stratification and therapy selection on a personalized basis for R/R FL in 2025.
    • Outcomes of mechanical thrombectomy in anticoagulated patients with acute distal and medium vessel stroke

      Salim, Hamza; Musmar, Basel; Adeeb, Nimer; Yedavalli, Vivek; Lakhani, Dhairya; Grewal, Sahibjot Singh; El Naamani, Kareem; Henninger, Nils; Sundararajan, Sri Hari; Kühn, Anna Luisa; et al. (2024-05-10)
      Background: Stroke remains a major health concern globally, with oral anticoagulants widely prescribed for stroke prevention. The efficacy and safety of mechanical thrombectomy (MT) in anticoagulated patients with distal medium vessel occlusions (DMVO) are not well understood. Methods: This retrospective analysis involved 1282 acute ischemic stroke (AIS) patients who underwent MT in 37 centers across North America, Asia, and Europe from September 2017 to July 2023. Data on demographics, clinical presentation, treatment specifics, and outcomes were collected. The primary outcomes were functional outcomes at 90 days post-MT, measured by modified Rankin Scale (mRS) scores. Secondary outcomes included reperfusion rates, mortality, and hemorrhagic complications. Results: Of the patients, 223 (34%) were on anticoagulation therapy. Anticoagulated patients were older (median age 78 vs 74 years; p < 0.001) and had a higher prevalence of atrial fibrillation (77% vs 26%; p < 0.001). Their baseline National Institutes of Health Stroke Scale (NIHSS) scores were also higher (median 12 vs 9; p = 0.002). Before propensity score matching (PSM), anticoagulated patients had similar rates of favorable 90-day outcomes (mRS 0-1: 30% vs 37%, p = 0.1; mRS 0-2: 47% vs 50%, p = 0.41) but higher mortality (26% vs 17%, p = 0.008). After PSM, there were no significant differences in outcomes between the two groups. Conclusion: Anticoagulated patients undergoing MT for AIS due to DMVO did not show significant differences in 90-day mRS outcomes, reperfusion, or hemorrhage compared to non-anticoagulated patients after adjustment for covariates.
    • I saw the 'puff of smoke' sign before it vanished into thin air

      Suh, Lyle; Puri, Ajit S; Singh, Jasmeet; Kuhn, Anna Luisa (2024-05-10)
      Moyamoya is characterized as a non-atherosclerotic and non-inflammatory vasculopathy that leads to progressive stenosis of the intracranial internal carotid arteries as well as the Circle of Willis. While it can be idiopathic (Moyamoya disease) or associated with another condition (Moyamoya syndrome), there is a characteristic 'puff of smoke' sign that can be appreciated on cerebral angiography.