Citations

Abstract Background White matter hyperintensity topography, particularly posterior confluent and subcortical multispot (WMH‐MS), has been implicated as surrogate imaging biomarker of cerebral amyloid angiopathy (CAA). Usefulness of WMH‐MS for prediction of future cerebral microbleeds (CMB's) has significant clinical implications for anti‐amyloid therapy risk assessment. Our primary goal was to identify the prevalence of positive WMH‐MS status and their utility for predicting the incident CMBs in a population‐based sample. Our secondary goal was to evaluate its usefulness after accounting for amyloid (surrogate for CAA) and WMH burden (surrogate of small vessel disease) which are both risk factors for CMBs. Method We identified 651 participants (mean age (SD) 69.8 (10.0) years, 55% male) from the Mayo Clinic Study of Aging, who had 3T baseline whole brain fluid‐attenuated inversion recovery (FLAIR) MRI and at least two T2*‐weighted gradient recalled echo (GRE) sequences (concomitant with or after FLAIR) which were used to ascertain CMBs. Amyloid positron emission tomography (PiB‐PET) scans were available in 87% of the sample. Visual reads on FLAIR scans were performed using a 4‐point Fazekas rating scale of periventricular and deep WMH (positivity: Fazekas ≥ 2) and a 3‐point MS severity visual scale (positivity: nWMH‐MS > 10 circular or ovoid WMH spots, Figure 1) according to established criteria. Using univariate and multivariable logistic regression, we assessed the independent association of WMH‐MS > 10 and Fazekas ≥ 2 for prediction of incident CMB's. Result The frequency of WMH‐MS pattern was greater in those who developed an incident CMB compared to those who did not develop a CMB (20.8% vs. 2.8%, p < 0.001). Older age and male sex were predictive of incident CMBs (Figure 2A). In univariate models, presence of WMH‐MS pattern but not Fazekas was associated with incident CMBs after adjusting for age and sex. The associations remained significant after additional adjustment for APOE4 , hypertension, number of baseline CMBs (Prior CMB), and amyloid effects (Figure 2B). Conclusion Visually identified WMH‐MS patterns on FLAIR‐MRI were predictive of incident CMBs in this population and may be useful markers of CAA. Future studies evaluating its utility as an additional biomarker of amyloid related imaging abnormalities in clinical trials are necessary.

Abstract Background The quantification of Neurofilament Light chain (NfL) in blood and cerebrospinal fluid (CSF) has proven valuable for diagnosing and prognosing various neurological disorders, including Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, parkinsonism, multiple sclerosis, and ischemic damage. However, there is considerable variability in clinical and laboratory practices between centers, primarily due to different contexts of use (COU), analytical methods, and the application of cutoffs or scales. Additionally, for the same biochemical profile, the interpretation and reporting of results may vary from one center to another, raising concerns about the commutability of the tests. To date, no consensus has been reached among laboratories to define the most appropriate use of cutoffs or conclusions/comments based on NfL profiles. Method This international project involves 38 laboratories across 18 countries, all specialized in the biochemical diagnosis of neurological disorders. Using a questionnaire, we obtained descriptions from each center regarding their COU, pre‐analytical and analytical protocols (including the biological fluid and methods used to quantify NfL). Through a consensus approach, we developed a harmonized strategy for the use and reporting of NfL results across different centres according to their respective COU. Results Among the centers, 63% quantified NfL in the CSF, 87% in blood and 53% in both fluids. COU were as follow: frontotemporal dementia (71%), Alzheimer disease (71%), multiple sclerosis (61%), amyotrophic lateral sclerosis (61%), psychiatric syndrome (45%), Creutzfeldt‐Jakob disease (32%), Parkinson disease (39%), peripheral neuropathy (29%), traumatic brain injury (21%), Huntington's disease (13%), amyloid transthyretin related (11%) and cardiac arrest (8%). Most of the centers define pathological cutoffs based on publications (50%) and take age into account for this purpose (42%). Reporting is mostly transmitted through numeric results (95%). Conclusion Harmonizing cutoffs, reporting, and interpretation across various clinical contexts will facilitate the incorporation of this biomarker into routine clinical practice.

Abstract Background The amygdala is closely connected to the olfactory bulb and involved in olfactory processing as well. It is a particularly susceptible region that accumulates a‐synuclein pathology in Parkinson's disease (PD). Our previous work revealed olfactory bulb gene alterations related to neuroinflammation, and neurotransmitter dysfunction to be associated with olfactory function. We aimed to extend this work and assess gene expression changes, affected pathways and co‐expression networks by transcriptomic profiling of the amygdala in subjects with and without clinicopathologically defined PD. Method Bulk RNA sequencing was performed on frozen human amygdala of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative Disorders. Result Differential expression analysis, corrected for age, sex and post‐mortem interval revealed 40 significantly differentially expressed genes (DEGs) in PD. Downregulated genes were mainly related to altered hemoglobin expression while upregulated genes included inflammatory markers and glutamine transporter. Significantly enriched pathways were involved in oxygen and carbon dioxide transport, cellular oxidant detoxification and regulation of glutamine secretion. Cell enrichment revealed these genes to be mainly expressed in neurons. Co‐expression network analysis using Weighted correlation network analysis (WGCNA ) subsequently identified four significant modules correlated with both PD and premortem olfactory dysfunction which were involved in pathways related to neuroinflammatory processes, mitochondrial, endoplasmic reticulum and lysosomal dysfunction. Conclusion These preliminary results suggest cellular alterations in the amygdala related to mitochondrial dysfunction, altered oxygen homeostasis, oxidative stress, inflammation as well as glutamatergic neurotransmitter dysfunction that may contribute to neurodegeneration in PD.

Study Design. Modified Delphi consensus process Objective. To establish a standardized, consensus-driven definition for postoperative spine infection (PSI) for research, diagnosis, and management. Summary of Background Data. Postoperative infection is a devastating and common complication following spine surgery. Rates of PSI in the literature range from 0% to over 20% depending on surgical indication and invasiveness. Despite the implications of PSI, there is no universally accepted diagnostic standard or consensus definition for infection following spine surgery, hindering research and treatment of this challenging clinical condition. Methods. A multispecialty workgroup convened by the Musculoskeletal Infection Society (MSIS) conducted a systematic literature review. Using data from the systematic review, an expert panel completed a modified Delphi process to achieve consensus. The panel included nine fellowship-trained, board-certified physicians with expertise in infectious diseases, orthopaedic and neurologic spine surgery, and musculoskeletal radiology. Iterative rounds focused on criterion selection, importance ranking, categorical grouping, and final constellation development for PSI diagnosis. Consensus was defined as a 2/3 majority, with a target of 100%. Results. The workgroup achieved 100% consensus on a new PSI definition, which incorporates six clinical domains: wound features, microbiology, imaging, inflammatory biomarkers, intraoperative findings, and histology. A single microbiological stand-alone criterion—identification of a phenotypically indistinguishable organism from two or more deep operative site specimens—was established as pathognomonic for postoperative spine infection. Additional primary and secondary supporting criteria were defined, with specific combinations required to classify cases as definite or probable PSI. Final definitions were ratified by the boards of MSIS and the European Bone & Joint Infection Society (EBJIS) Conclusion. This consensus-based definition provides a standardized framework for diagnosing postoperative spine infection, facilitating research and clinical management. The criteria balance sensitivity and specificity across diverse clinical scenarios and represent the first multispecialty, society-endorsed definition for PSI.

Aging is unavoidable and driven, at least in part, by the biologic process termed senescence. Senescence is characterized by cell cycle arrest incurred by one or more stressors wherein there is cellular upregulation of cyclin-dependent kinase inhibitors, p16 Ink4a and/or p21 Cip1 . Senescent cells are metabolically active and resistant to apoptosis, have increased β -galactosidase activity, and express a senescence-associated secretory phenotype (SASP). The SASP produces an array of inflammatory, cytotoxic, fibrotic, and vasoactive factors. Senescence is a diffusible process as, largely through the SASP, a focus of senescent cells can recruit adjacent cells and cells in distant organs, thereby expanding its scope way beyond its original focus. Senescence predisposes not only to chronic diseases (including CKD) but also acute processes (including AKI). This review provides evidence that age increases the risk of human AKI and summarizes clinical factors that predispose older individuals to AKI. It provides an overview of the biology of senescence, and it discusses the role of intrarenal senescent cells in the pathogenesis of AKI, the significance of the extrarenal milieu and distant organs in predisposing to AKI with age, heme as a prosenescent species, and the role of senescence in the AKI to CKD transition. The risk for AKI with aging, in large part, reflects the fact that virtually all processes implicated in AKI, irrespective of age, occur as the kidney ages. Processes discussed include senescent cells, vascular responses, diabetes, impaired NAD + content, sirtuin expression, mitochondrial dysfunction, impaired autophagy, epigenetic changes, telomere shortening, impaired nephroprotectant expression, inflammaging, and immunosenescence. The review concludes by discussing the basis for senolytics (agents that kill senescent cells), senomorphics (agents that block SASP factors), and other aspects of senotherapies.

Abstract The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P&lt; .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P&lt; .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P&lt; .001]; median OS, 136.1 vs 75.3 months [P&lt; .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

Abstract Background These recommendations provide guidance on the optimal timing for transitioning from intravenous to oral antibiotics in patients with complicated urinary tract infection (cUTI), especially in presence of associated Gram-negative bacteremia. Methods The panel's recommendations are based upon evidence derived from systematic literature reviews which focused on comparative benefits and harms of transitioning to oral therapy versus continuing parenteral therapy of the total duration of treatment, including publications since 2000. These recommendations adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Results The guidelines panel suggests transitioning to oral antibiotics in patients with cUTI who are clinically improving, able to take medication, and for whom an effective oral option is available, rather than continuing parenteral therapy for the remaining treatment duration, regardless of the presence of associated Gram-negative bacteremia. An effective oral option needs to be active against the causative pathogen and achieve therapeutic levels in the urine and relevant tissue. Conclusions Parenteral and oral antibiotics used to complete treatment courses for cUTI provide similar efficacy and adverse events, especially in the context of shorter duration of therapy. This recommendation places a high value on reducing avoidable intravenous catheter-related adverse events, costs, and resources, as well as taking into account practical aspects of antibiotic administration.

Abstract Background These recommendations provide guidance on the optimal duration of antibiotics in patients with complicated urinary tract infection (cUTI), especially in presence of associated Gram-negative bacteremia. Methods The panel's recommendations are based upon evidence derived from systematic literature reviews which focused on comparative benefits and harms of shorter (5–7 days) vs prolonged (10–14 days) duration of antibiotics, including publications since 2000. These recommendations adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Results The guidelines panel suggests that patients with cUTI who are improving on effective therapy can be treated with shorter duration of antimicrobials (either 5–7 days of a fluoroquinolone or 7 days of a non-fluoroquinolone) rather than longer courses of antibiotics, regardless of the presence of associated Gram-negative bacteremia. An effective antimicrobial agent achieves therapeutic levels in the urine and relevant tissue and is active against the causative pathogen. However, men with febrile UTI in whom acute bacterial prostatitis is suspected may benefit from a longer treatment duration (10–14 days), and a short courses of oral beta lactams may require higher doses for efficacy. Conclusions Shorter durations of antibiotics for cUTI provide similar efficacy as longer courses, except in men with febrile UTI in whom acute bacterial prostatitis is suspected. This recommendation places a high value on antibiotic stewardship considerations as well as reducing the burden of antimicrobial administration from a healthcare perspective and reducing the burden of taking antibiotics from a patient perspective.