Citations

Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.

Abstract Increased innate immune activity promotes neurodegeneration and contributes to progression in multiple sclerosis. This prospective case-control study aims to investigate thalamic microglia density on 18kDa translocator protein PET in patients with multiple sclerosis using a third-generation radioligand, 11C-ER176, and investigate the associations of 11C-ER176 PET uptake with imaging and clinical measures of progression in multiple sclerosis. Patients with multiple sclerosis (n = 50) and controls (n = 55) were prospectively enrolled and they underwent 11C-ER176 PET and MRI including diffusion MRI with neurite orientation dispersion and density imaging. Disease characteristics, expanded disability status scale and multiple sclerosis functional composite scores were obtained in patients with multiple sclerosis. Age at imaging (mean ± standard deviation: patients = 49.6 ± 12.9 years, controls = 48.2 ± 15.4 years, P = 0.63) and sex (female ratio; patients = 72%, controls = 65%, P = 0.47) were not different between the groups. Thalamus 11C-ER176 PET uptake was highest in patients with progressive multiple sclerosis (1.272 ± 0.072 standardized uptake value ratio), followed by patients with relapsing multiple sclerosis (1.209 ± 0.074 standardized uptake value ratio) and lowest in controls (1.162 ± 0.067 standardized uptake value ratio, P < 0.001). Patients with thalamic lesions had higher thalamus 11C-ER176 PET uptake than those without thalamic lesions in both relapsing multiple sclerosis and progressive multiple sclerosis (P < 0.001). In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with lower thalamic volume (r = −0.45, P = 0.001), higher mean diffusivity (r = 0.56, P < 0.001), lower neurite density index (r = −0.43, P = 0.002), lower orientation dispersion index (r = −0.40, P = 0.005) and higher free water fraction (r = 0.42, P = 0.003) in the thalamus. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake also correlated with higher mean diffusivity (r = 0.47, P < 0.001) and lower neurite density index (r = −0.36, P = 0.012) in the corpus callosum. In patients with multiple sclerosis, higher thalamus 11C-ER176 PET uptake correlated with worse expanded disability status scale scores (r = 0.33, P = 0.02), paced auditory serial addition test scores (r = −0.43, P = 0.003) and multiple sclerosis functional composite z-scores (r = −0.46, P = 0.001). Microglia density in the thalamus is highest in patients with progressive multiple sclerosis and is associated with imaging biomarkers of neurodegeneration and clinical disease severity. As a signature imaging biomarker of progression in multiple sclerosis, effectively reflecting the global disease burden, 11C-ER176 PET may aid development and efficacy evaluation of therapeutics targeting microglia.

ABSTRACT Ventricular arrhythmias (VA), including ventricular tachycardia and fibrillation, are critical cardiac conditions that are often managed by catheter ablation among those unresponsive to pharmacologic therapy. The choice of anesthesia and sedation regimens for VA ablations may impact arrhythmia inducibility and hemodynamic stability, which can affect procedural success and complication rates. This systematic review and meta-analysis aimed to compare the efficacy and safety of sedation versus general anesthesia (GA) among patients undergoing VA ablation. The review was prospectively registered on PROSPERO (CRD42023441553). Database searches were conducted across five major databases from inception to March 9, 2024 to identify randomized trials or observational studies including adult patients undergoing ablations for VA. Screening and data extraction were completed in duplicate. Risk-of-bias assessments were conducted using ROBINS-I as all included studies were observational, and the quality of evidence was evaluated using the GRADE framework. Six observational studies (N = 16,435) were included. No significant differences were found between sedation and GA for total procedure time (MD: −14.16 minutes; 95%CI: −38.61 to 10.29 minutes), arrhythmia non-inducibility (RR: 0.73; 95% CI: 0.33–1.58), acute ablation success (RR: 1.06; 95% CI: 0.65–1.71), or procedural complications (RR: 0.72; 95% CI: 0.28–1.85). However, sedation was associated with significantly lower intraprocedural hemodynamic instability (RR: 0.28; 95% CI: 0.12–0.70). These findings indicate that while sedation and GA have comparable outcomes, sedation may be associated with less hemodynamic instability during VA ablation. However, more high-quality studies are needed to confirm these results.

AbstractBackgroundTandem mass spectrometry (MS/MS) has become a common clinical laboratory testing modality has demonstrated success in distinguishing between small protein variations in transthyretin amyloidosis. Since many common clinically significant RBC antigens are also small protein variations, this study aimed to determine if MS/MS could correctly detect common RBC antigens within the Rh, Kell, Duffy, MNS, Kidd, Diego, and Lutheran blood group systems.Study Design and MethodsResidual samples from serotyped/genotyped blood donors at a hospital‐based blood donation center from February to August 2021 were analyzed. RBC membrane protein preparations underwent protease digestion prior to MS/MS analysis for RhD, RhCE, Kell, atypical chemokine receptor 1 (Duffy), glycophorin A (MNS), glycophorin B (MNS), urea transporter 1 (Kidd), band 3 anion transport protein (Diego), and basal cell adhesion molecule (Lutheran). Untargeted liquid chromatography (LC)‐MS/MS detected protein‐specific peptides, while targeted LC‐selected reaction monitoring (LC‐SRM) detected RBC antigen‐containing peptides.ResultsThrough the use of multiple proteases, untargeted LC–MS/MS detected protein‐specific peptides in all but glycophorin B, with band 3 anion transport protein, basal cell adhesion molecule, Kell, and glycophorin A having the greatest protein sequence coverage. Targeted LC‐SRM detected antigen‐specific peptides for Cw, Dia/Dib, Kpb, and Wra/Wrb, which agreed with the donors' previous typing results.DiscussionMS/MS can successfully detect peptides from several blood group systems but only detected a subset of their common RBC antigens. Further sample enrichment and MS/MS detection improvements will need to occur before MS/MS could be considered a clinical RBC phenotyping modality.

ABSTRACT The rare human neuroendocrine tumors pheochromocytoma and paraganglioma (PPGL) can result from loss of mitochondrial succinate dehydrogenase. The resulting succinate accumulation is tumorigenic in certain neuroendocrine cells. Here, we explore two theoretical approaches to mitigate tumorigenic succinate accumulation in a cell culture model of PPGL. We first study a gene replacement strategy using transposition technology, and conclude that many of the changes in mitochondrial morphology, oxidative cell metabolism and succinate accumulation can be reversed by this process. We then investigate whether riboflavin supplementation has the potential to rescue succinate dehydrogenase activity in the intact SDHA catalytic subunit to suppress succinate accumulation even in the absence of SDHB. We show that this latter strategy is not successful.

ABSTRACT Iron deficiency (ID) is a top five leading cause of disability‐adjusted life‐years in women of reproductive age around the world. Despite its enormous health burden, no screening guidelines exist for the detection and treatment of ID in women of reproductive age. We sought to determine the cost‐effectiveness of screening versus no screening for ID in women of reproductive age in the United States. A lifetime simulation of women of reproductive age was conducted using a Markov cohort model under three strategies: (1) no screening, (2) screening at a ferritin threshold of 15 μg/L, and (3) screening at a ferritin threshold of 25 μg/L, from the US health system perspective, and at a willingness‐to‐pay threshold of $100 000/quality‐adjusted life year (QALY). Epidemiologically informed ID prevalence estimates sourced from the National Health and Nutrition Examination Survey were employed for model parameterization. The primary outcome was the incremental cost‐effectiveness ratio (ICER, in $/QALY). Base‐case results for the three strategies accrued $209 700, $210 200, and $210 200 discounted lifetime costs and 23.6, 24.0, and 24.4 discounted lifetime QALYs, respectively. Screening at a ferritin threshold of 25 μg/L was the cost‐effective intervention with an ICER of $680/QALY (95% credible interval $350–$750/QALY). In dual base‐case analyses examining intravenous rather than oral iron repletion for treatment, screening at a ferritin threshold of 25 μg/L remained the cost‐effective intervention with an ICER of $2300/QALY (95% CI $1800–$3800/QALY). In probabilistic sensitivity analyses, screening at a ferritin threshold of 25 μg/L was the cost‐effective intervention in 100% of 10 000 second order Monte Carlo iterations.

ABSTRACTIntraluminal infection of central venous catheters, used for long‐term treatment, can result in central line‐associated bloodstream infection (CLABSI). These infections can be challenging to prevent and treat due to formation of biofilms within catheter lumens, which shield bacteria from the human immune response and conventional antimicrobial therapies. Preventing bacterial colonization of catheter hubs is a strategy to prevent CLABSI. To address this, we developed a nonantibiotic, animal‐ready electrochemical catheter hub (e‐catheter hub), operated by a wearable, battery‐powered micropotentiostat (MP), that internally generates tunable hypochlorous acid (HOCl) for preventing intraluminal infection. The design evaluated three different electrode materials—titanium, platinum, and gold—for HOCl generation and biocidal activity, using working and counter electrodes of the same materials and a silver/silver chloride‐plated wire as a quasi‐reference electrode. e‐catheter hubs operated by MPs at 1.5 VAg/AgCl for 3 h generated HOCl, reducing Acinetobacter baumannii ATCC‐17978 below the detection limit (average reduction of 4.40 ± 0.05 log10 CFU/mL). The efficacy of e‐catheter hubs operated by MPs in generating HOCl and achieving biocidal activity is comparable to that of a commercial potentiostat. This study represents the first step in developing a localized, nonantibiotic strategy to mitigate CLABSI risk.

Objectives Few studies have investigated health outcomes associated with arthritis in low-middle-income countries. Our objective was to examine the association between arthritis and all-cause hospitalization and mortality among middle-aged and older adults in Mexico. Methods Our sample included 12,106 participants aged >50 years from the 2012, 2015, and 2018 waves of the Mexican Health and Aging Study. Logistic regression was used for the associations between arthritis and hospitalization. Kaplan–Meier and Cox proportional hazard models were used for the association between arthritis and mortality. Results Arthritis was associated with higher odds of hospitalization (OR = 1.23; 95% CI = 1.09–1.38), but not mortality. Arthritis with physical limitations had the highest odds of hospitalization (OR = 1.48; 95% CI = 1.27–1.73). Arthritis with joint pain (OR = 1.24; 95% CI = 1.10–1.41) and medication use (OR = 1.28; 95% CI = 1.11–1.48) had higher odds of hospitalization. Conclusion Among middle-aged and older adults in Mexico, arthritis was associated with a high risk of hospitalization.