Citations

Abstract Associations of Alzheimer’s disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier versus later an individual’s progression on plasma and PET Alzheimer’s disease biomarkers is associated with earlier versus later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed-effects models to estimate how much earlier versus later each individual progresses on plasma phosphorylated tau (p-tau)217, amyloid PET, tau PET and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cut-off points, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R = 0.38–0.47) in the MCSA and stronger (R = 0.74–0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET Alzheimer’s disease biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer’s disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer’s disease co-pathologies.

Abstract Background Immunotherapy has yet to make significant gains in glioblastoma (GBM) treatment, due in part to GBM-mediated immune suppression. Increasing evidence points to critical roles for tumor-derived extracellular vesicles (EVs) and immunosuppressive myeloid cells as key factors in this process. Methods Immunophenotyping of the tumor-immune microenvironment was performed using ultrasonic aspirate collected during GBM resection by high-dimensional flow cytometry. EVs collected from patient-derived GBM cell lines were used to condition myeloid cells collected from healthy donors to generate immunosuppressive myeloid cells. siRNA was used to knockdown TIGIT and/or NLRP3 expression prior to EV conditioning. T cell co-culture studies were performed with donor-matched T cells. Results Immune phenotyping of the tumor microenvironment and EV-conditioned myeloid cells revealed similar immunomodulatory protein expression across myeloid cell populations, with particularly elevated TIGIT expression. Knockdown of TIGIT reduced the immunosuppressive polarization of myeloid cells, resulting in improved T cell function. This finding proceeded in an NLRP3-dependent manner, with substantial co-expression of TIGIT and NLRP3 expression prior to knockdown, and concomitant knockdown of NLRP3 abrogating the effect of TIGIT knockdown. TIGIT expression correlated with increased IL-13 expression, and IL-13 blockade unmasked a pro-inflammatory myeloid cell phenotype. Conclusion TIGIT expression in myeloid cells in the GBM microenvironment is a functional marker of immunosuppressive activity, with TIGIT knockdown reducing IL-13 expression and unmasking the pro-inflammatory activity of NLRP3. This study bolsters our understanding of the immunosuppressive complexities of the GBM microenvironment and supports attenuation of immunosuppressive myeloid cell activity as a strategy to restore immune function in GBM.

Background Multimorbidity is common in patients with atrial fibrillation (AF); however, the impact of the number and type of comorbid conditions on outcomes remains uncertain. Methods This cohort study included patients with new‐onset AF from a Midwest region between 2013 and 2017. Eighteen chronic conditions at the time of AF were classified into groups: cardiometabolic, other somatic, and mental health. Cox regression determined associations between the number of each condition type with death, ischemic stroke/transient ischemic attack, and congestive heart failure, stratified by age. Results Among 16 509 patients with AF (mean age, 74 years; 43% women), the mean number of cardiometabolic, other somatic, and mental health conditions was 2.7, 1.4, and 0.5, respectively. The number and type of conditions had a varying impact on outcomes and differed by age. A higher number of cardiometabolic conditions were associated with increased risk of death within 90 days only in people aged ≥85 years (≥4 conditions versus 0: hazard ratio [HR], 1.74 [95% CI, 1.05–2.87]), whereas for death after 90 days, associations were strongest in the youngest age group (<65 years: HR, 1.83 [95% CI, 1.35–2.46]; 65–74 years: HR, 1.34 [95% CI, 1.04–1.73]; 75–84 years: HR, 1.32 [95% CI, 1.09–1.60]; ≥85 years: HR, 1.14 [95% CI, 0.96–1.35]). Associations with outcomes were generally strongest in the youngest age group and attenuated with older age for higher number of other somatic conditions, whereas the pattern was less consistent for mental health conditions. Conclusions Along with cardiometabolic‐related conditions, other somatic and mental health conditions are important predictors of outcomes in AF, with effects differing by age, and should be considered when caring for these patients.

The systemic impairment that accompanies liver cirrhosis is known to carry a significant burden on death and postoperative complications in cardiovascular interventions. This review analyzes the impact of liver cirrhosis on short‐ and long‐term outcomes after cardiac surgery and percutaneous procedures, providing an evidence‐based guidance in the decision‐making process and perioperative management of these patients. Several parameters should be considered by the heart teams when assessing eligibility, indications for intervention, and perioperative management of these patients. Life expectancy, long‐term procedural outcomes, Child–Pugh or the Model for End‐Stage Liver Disease score, presence of gastroesophageal varices and hepatic venous pressure gradient were extrapolated as the main determinants in decision making in patients with cirrhosis. Assessment and treatment of gastroesophageal varices is mandatory. Hepatic venous pressure gradient values >20 mm Hg preclude patients from a surgical approach. Considering the poor prognosis of advanced liver cirrhosis, futile treatments should be avoided. A multidimensional heart team approach involving surgical, cardiologic, anesthesiologic, hepatological, and medical considerations is recommended.

BACKGROUND: Arteriovenous malformation (AVM) recurrence after complete surgical resection is a rare but significant clinical event. The underlying mechanisms and factors that predict recurrence remain incompletely defined. METHODS: We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. We included case series reporting on AVM recurrence following an angiographically documented complete resection. Data on initial clinical presentation, patients' demographics, AVM features, and patterns of recurrence were extracted and analyzed. RESULTS: We included 15 studies with a total of 1287 patients in our meta-analysis. The overall estimated recurrence rate was 5.4%. Hemorrhagic presentation appeared as a major predictor: in fact, 94% of recurrences occurred in patients with a prior rupture, corresponding to a 7.3% (95% CI, 0.049–0.098) recurrence rate within this high-risk subgroup. Ruptured AVMs were associated with 4-fold higher odds of recurrence compared with unruptured AVMs (odds ratio, 4.072 [95% CI, 1.492–11.113]). Younger age was also found to be a key factor, with pediatric patients accounting for 89% of all recurrences. Deep venous drainage was associated with a nearly 5-fold increased risk of recurrence (odds ratio, 4.96 [95% CI, 1.801–13.662]), while eloquent brain location was not found as a statistically significant predictor. The mean time to recurrence was 39.6 (95% CI, 27.80–51.41) months, while follow-ups varied among patients. CONCLUSIONS: Hemorrhagic presentation, younger age, and deep venous drainage demonstrated to be significant predictors of AVM recurrence after complete resection, whereas vascular aging appears protective. In older individuals, proangiogenic mediators (VEGF [vascular endothelial growth factor], HIF-1 [hypoxia-inducible factor-1] α, eNOS [endothelial nitric oxide synthase], and MMPs [matrix metalloproteinases]) are downregulated via aging-related pathways, limiting neovascularization and making recurrence biologically less likely. These findings underscore the need for prolonged, risk-adapted surveillance protocols, particularly for high-risk pediatric patients who present with hemorrhage.

Functional analyses of mitochondria have been hampered by few effective approaches to manipulate mitochondrial DNA (mtDNA) and a lack of existing animal models. Recently a TALE-derived base editor was shown to induce C-to-T (or G-to-A) sequence changes in mtDNA. We report here the FusX TALE Base Editor (FusXTBE) to facilitate broad-based access to TALE mitochondrial base editing technology. TALE Writer is a de novo in silico design tool to map potential mtDNA base editing sites. FusXTBE was demonstrated to function with comparable activity to the initial base editor in human cells in vitro . Zebrafish embryos were used as a pioneering in vivo test system, with FusXTBE inducing 90+% editing efficiency in mtDNA loci as an example of near-complete induction of mtDNA heteroplasmy in vivo . Gene editing specificity as precise as a single nucleotide was observed for a protein-coding gene. Nondestructive genotyping enables single-animal mtDNA analyses for downstream biological functional genomic applications. FusXTBE is a new gene editing toolkit for exploring important questions in mitochondrial biology and genetics.