Citations

Background: Whether thrombolysis improves outcomes in non-arteritic central retinal artery occlusion (naCRAO) is uncertain. We aimed to evaluate the rate of visual recovery after intra-venous thrombolysis (IVT) or intra-arterial thrombolysis (IAT) administration of tissue plasminogen activator (tPA) or urokinase among patients with naCRAO and explore the parameters affecting the final visual acuity (VA). Aim: We systematically searched six databases. Logarithm of the minimum angle of resolution (logMAR) and VA of ⩾20/100 were used to quantify visual recovery. To explore the role of other factors on visual recovery, we defined two models for studies with aggregated data (designs 1 and 2) and 16 models for individual participant data (IPD, models 1–16). Summary of Review: We included data from 771 patients out of 72 publications in nine languages. Visual improvement for ⩾0.3 logMAR was reported in 74.3% of patients who received IVT-tPA within 4.5 h (CI: 60.9–86.0%; unadjusted rate: 73.2%) and 60.0% of those who received IAT-tPA within 24 h (CI: 49.1–70.5%; unadjusted rate: 59.6%). VA of ⩾20/100 was observed among 39.0% of patients after IVT-tPA within 4.5 h and 21.9% of those with IAT-tPA within 24 h. IPD models highlighted the association between improved visual outcomes and VA at presentation, at least 2 weeks follow-up before reporting the final VA, antiplatelet therapy, and shorter symptom onset to thrombolysis window. Conclusion: Early thrombolytic therapy with tPA is associated with enhanced visual recovery in naCRAO. Future studies should refine the optimum time window for thrombolysis in naCRAO.

Abstract The geroscience hypothesis proposes that addressing the biology of aging could directly prevent the onset or mitigate the severity of multiple chronic diseases. Understanding the interplay between key aspects of the biological hallmarks of aging is essential in delivering the promises of the geroscience hypothesis. Notably, the nucleotide nicotinamide adenine dinucleotide (NAD) interfaces with several biological hallmarks of aging, including cellular senescence, and changes in NAD metabolism have been shown to be involved in the aging process. The relationship between NAD metabolism and cellular senescence appears to be complex. On the one hand, the accumulation of DNA damage and mitochondrial dysfunction induced by low NAD + can promote the development of senescence. On the other hand, the low NAD + state that occurs during aging may inhibit SASP development as this secretory phenotype and the development of cellular senescence are both highly metabolically demanding. However, to date, the impact of NAD + metabolism on the progression of the cellular senescence phenotype has not been fully characterized. Therefore, to explore the implications of NAD metabolism and NAD replacement therapies, it is essential to consider their interactions with other hallmarks of aging, including cellular senescence. We propose that a comprehensive understanding of the interplay between NAD boosting strategies and senolytic agents is necessary to advance the field.

Unlike other adverse drug reactions, visceral organ involvement is a prominent feature of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and correlates with mortality. The aim of this study was to systematically review cases published in PubMed-indexed, peer-reviewed journals in which patients had renal injury during the episode of DRESS syndrome (DS). We found 71 cases, of which 67 were adults and 56% were males. Female sex was associated with higher mortality. Chronic kidney disease (CKD) was present in 14% of patients who developed acute kidney injury (AKI) during DS. In 21% of cases, the kidneys were the only visceral organ involved, while 54% of patients had both liver and kidney involvement. Eosinophilia was absent in 24% of patients. The most common classes of medication associated with renal injury in DS were antibiotics in 34%, xanthine oxidase inhibitors in 15%, and anticonvulsants in 11%. Among antibiotics, vancomycin was the most common culprit in 68% of patients. AKI was the most common renal manifestation reported in 96% of cases, while isolated proteinuria or hematuria was present in only 4% of cases. In cases with AKI, 88% had isolated increase in creatinine and decrease in glomerular filtration (GFR), 27% had AKI concomitantly with proteinuria, 18% had oliguria, and 13% had concomitant AKI with hematuria. Anuria was the rarest manifestation, occurring in only 4% of patients with DS. Temporary renal replacement therapy was needed in 30% of cases, and all but one patient fully recovered renal function. Mortality of DS in this cohort was 13%, which is higher than previously reported. Medication class, latency period, or pre-existing CKD were not found to be associated with higher mortality. More research, particularly prospective studies, is needed to better recognize the risks associated with renal injury in patients with DS. The development of disease-specific biomarkers would also be useful so DS with renal involvement can be easier distinguished from other eosinophilic diseases that might affect the kidney.

Background: Adequate response to moderate (conscious) sedation varies significantly between individuals. Polymorphisms in genes encoding drug metabolizing enzymes can lead to inter-individual variability in drug efficacy, potentially influencing sedation requirements during endoscopic procedures. Objectives: The aim of this study was to assess the potential role of inter-individual variation in inherited polymorphisms of drug-metabolizing enzymes, cytochrome P450 (CYP450), specifically CYP3A4 and CYP3A5, in sedation requirements for outpatient endoscopic procedures. Methods: A retrospective analysis of sedation requirements and pharmacogenomics data in 106 unique patients who received outpatient esophagogastroduodenoscopy (EGD), colonoscopy, or both between December 2011 and February 2019 was conducted. Patients were divided into two groups based on their sedation requirements during endoscopy (high vs. normal sedation). Results: Patients with reduced a CYP2C19 metabolism (poor + intermediate metabolizers) (odds ratio [OR] = 0.38, 95% confidence interval [CI]: 0.16–0.91, p = 0.03), poor CYP3A5 metabolism (OR = 0.25, 95% CI: 0.095–0.65, p = 0.0046), and poor UGT1A1 (OR = 2.76, 95% CI: 1.07–7.13, p = 0.08) had higher odds of requiring normal sedation compared to those with CYP2C19 increased metabolism, CYP3A5 intermediate metabolism, and UGT1A1 intermediate metabolism. Conclusion: Information about inter-individual variation in (CYP450) genes may be useful for determining the sedation requirements for outpatient endoscopic procedures. We found that patients with reduced CYP2C19 metabolism, poor CYP3A5 metabolism, and poor UGT1A1 metabolism were more likely to require normal sedation requirements during outpatient endoscopic procedures.

Abstract Background Implicit cognitive markers may assist with the prediction of suicidality beyond clinical risk factors. The aim of this study was to investigate neural correlates associated with the Death/Suicide Implicit Association Test (DS-IAT) via event-related potentials (ERP) in suicidal adolescents. Methods Thirty inpatient adolescents with suicidal ideations and behaviors (SIBS) and 30 healthy controls from the community were recruited. All participants underwent 64-channel electroencephalography, DS-IAT, and clinical assessments. Hierarchical generalized linear models with spatiotemporal clustering were used to identify significant ERPs associated with the behavioral outcome of DS-IAT (D scores) and group differences. Results Behavioral results (D scores) showed that the adolescents with SIBS had stronger implicit associations between “death” and “self” than the healthy group (P = .02). Within adolescents with SIBS, participants with stronger implicit associations between “death” and “self” reported more difficulty in controllability of suicidal ideation in the past 2 weeks based on the Columbia-Suicide Severity Rating Scale (P = .03). For the ERP data, the D scores and N100 component over the left parieto-occipital cortex had significant correlations. Significant group differences without behavioral correlation were observed for a second N100 cluster (P = .01), P200 (P = .02), and late positive potential (5 clusters, all P ≤ .02). Exploratory predictive models combining both neurophysiological and clinical measures distinguished adolescents with SIBS from healthy adolescents. Conclusions Our results suggest that N100 may be a marker of attentional resources involved in the distinction of stimuli that are congruent or incongruent to associations between death and self. Combined clinical and ERP measures may have utility in future refinements of assessment and treatment approaches for adolescents with suicidality.

Glioblastomas (GBM) are aggressive tumors that lack effective treatments. Here, we show that the Rho family guanine nucleotide exchange factor Syx promotes GBM cell growth both in vitro and in orthotopic xenografts derived from patients with GBM. Growth defects upon Syx depletion are attributed to prolonged mitosis, increased DNA damage, G2/M cell cycle arrest, and cell apoptosis, mediated by altered mRNA and protein expression of various cell cycle regulators. These effects are phenocopied by depletion of the Rho downstream effector Dia1 and are due, at least in part, to increased phosphorylation, cytoplasmic retention, and reduced activity of the YAP/TAZ transcriptional coactivators. Furthermore, targeting Syx signaling cooperates with radiation treatment and temozolomide (TMZ) to decrease viability in GBM cells, irrespective of their inherent response to TMZ. The data indicate that a Syx-RhoA-Dia1-YAP/TAZ signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in GBM and argue for its targeting for cancer treatment.

Abstract INTRODUCTION We examined the progression of extrapyramidal symptoms and signs in autopsy‐confirmed dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and Alzheimer's disease dementia (AD). METHODS Longitudinal data were obtained from Arizona Study of Aging and Neurodegenerative Disease, with PDD ( n = 98), AD ( n = 47) and DLB ( n = 48) further sub‐grouped as with or without parkinsonism (DLB+ and DLB−). Within‐group Unified Parkinson's Disease Rating Scale (UPDRS) ‐II and UPDRS‐III trajectories were analyzed using non‐linear mixed effects models. RESULTS In DLB, 65.6% had parkinsonism. Baseline UPDRS‐II and III scores (off‐stage) were highest ( P < 0.001) for PDD (mean ± SD 14.3 ± 7.8 and 27.4 ± 16.3), followed by DLB+ (6.0 ± 8.8 and 17.2 ± 17.1), DLB− (1.1 ± 1.3 and 3.3 ± 5.5) and AD (3.2 ± 6.1 and 8.2 ± 13.6). Compared to PDD, the DLB+ group had faster UPDRS‐III progression over 8‐years (Cohen's‐ d range 0.98 to 2.79, P < 0.001), driven by gait ( P < 0.001) and limb bradykinesia ( P = 0.02) subscales. DISCUSSION Motor deficits progress faster in DLB+ than PDD, providing insights about expected changes in motor function. Highlights Dementia with Lewy bodies has faster motor progression than Parkinson's disease dementia Linear and non‐linear mixed modeling analysis of longitudinal data was utilized Findings have implications for clinical prognostication and trial design

Abstract Extramedullary multiple myeloma (EMM) can present either at initial diagnosis (de novo) or at disease relapse (secondary) and confers an aggressive clinical course. Limited data exist for choosing the optimal therapy for EMM and this remains an area of unmet clinical need. After excluding paraskeletal multiple myeloma and primary plasma cell leukemia, we identified 204 (68%) patients with secondary EMM and 95 (32%) with de novo EMM between January 01, 2000 and 31 December, 2021. The median overall survival (OS) was 0.7 (95% CI: 0.6–0.9) years for secondary EMM and 3.6 (95%CI: 2.4–5.6) years for de novo EMM. The median progression‐free survival (PFS) with initial therapy was 2.9 months (95% CI: 2.4–3.2 months) for secondary EMM and 12.9 months (95% CI: 6.7–18 months) for de novo EMM. Patients with secondary EMM treated with CAR‐T therapy ( n = 20) achieved a partial response (PR) or better in 75% with a median PFS of 4.9 months (3.1 months‐not reached; NR). Patients with EMM treated with bispecific antibodies ( n = 12) achieved a ≥ PR in 33%, with a median PFS of 2.9 months (95%CI: 2.2 months‐NR). In a matched cohort, multivariate logistic regression analysis demonstrated younger age at diagnosis, 1q duplication, and t (4;14) at diagnosis of MM to be independent predictors of development of secondary EMM. Presence of EMM was independently associated with inferior OS in the matched cohorts for both de novo (HR 2.9 [95% CI: 1.6–5.4], p = .0007) and secondary EMM (HR 1.5 [95% CI: 1.1–2], p = .001).

Background Nonalcoholic fatty liver disease (NAFLD) and heart failure with preserved ejection fraction (HFpEF) share common risk factors, including obesity and diabetes. They are also thought to be mechanistically linked. The aim of this study was to define serum metabolites associated with HFpEF in a cohort of patients with biopsy‐proven NAFLD to identify common mechanisms. Methods and Results We performed a retrospective, single‐center study of 89 adult patients with biopsy‐proven NAFLD who had transthoracic echocardiography performed for any indication. Metabolomic analysis was performed on serum using ultrahigh performance liquid and gas chromatography/tandem mass spectrometry. HFpEF was defined as ejection fraction >50% plus at least 1 echocardiographic feature of HFpEF (diastolic dysfunction, abnormal left atrial size) and at least 1 heart failure sign or symptom. We performed generalized linear models to evaluate associations between individual metabolites, NAFLD, and HFpEF. Thirty‐seven out of 89 (41.6%) patients met criteria for HFpEF. A total of 1151 metabolites were detected; 656 were analyzed after exclusion of unnamed metabolites and those with >30% missing values. Fifty‐three metabolites were associated with the presence of HFpEF with unadjusted P value <0.05; none met statistical significance after adjustment for multiple comparisons. The majority (39/53, 73.6%) were lipid metabolites, and levels were generally increased. Two cysteine metabolites (cysteine s‐sulfate and s‐methylcysteine) were present at significantly lower levels in patients with HFpEF. Conclusions We identified serum metabolites associated with HFpEF in patients with biopsy‐proven NAFLD, with increased levels of multiple lipid metabolites. Lipid metabolism could be an important pathway linking HFpEF to NAFLD.