Expanded Antigen-Specific Elimination Assay to Measure Human CD8+ T Cell Cytolytic Potential.

Durable cellular immunity against pathogens is dependent upon a coordinated recall response to antigen by memory CD8+ T cells, involving their proliferation and the generation of secondary cytotoxic effector cells. Conventional assays measuring ex vivo cytotoxicity fail to capture this secondary cytolytic potential, especially in settings where cells have not been recently exposed to their cognate antigen in vivo. Here we describe the expanded antigen-specific elimination assay (EASEA), a flow cytometric endpoint assay to measure the capacity of human CD8+ T cells to expand in vitro upon antigen re-exposure and generate secondary effector cells capable of selectively eliminating autologous antigen-pulsed target cells across a range of effector-to-target ratios. Unlike alternative assays, EASEA avoids the hazards of radioactive labeling and viral infection and can be used to study responses to individual or pooled antigens of interest. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Expanded antigen-specific elimination assay.

Proximity Graph Networks: Predicting Ligand Affinity with Message Passing Neural Networks.

Message passing neural networks (MPNNs) on molecular graphs generate continuous and differentiable encodings of small molecules with state-of-the-art performance on protein-ligand complex scoring tasks. Here, we describe the proximity graph network (PGN) package, an open-source toolkit that constructs ligand-receptor graphs based on atom proximity and allows users to rapidly apply and evaluate MPNN architectures for a broad range of tasks. We demonstrate the utility of PGN by introducing benchmarks for affinity and docking score prediction tasks. Graph networks generalize better than fingerprint-based models and perform strongly for the docking score prediction task. Overall, MPNNs with proximity graph data structures augment the prediction of ligand-receptor complex properties when ligand-receptor data are available.

Time to Dementia Diagnosis Among Veterans with Comorbid Insomnia and Depressive Episodes.

Background: Older adults with heart failure are at elevated risk of Alzheimer's disease and related dementias (AD/ADRD). Research suggests that insomnia and depressive episodes contribute somewhat dissociable impacts on risk for AD/ADRD in this patient population, although the temporal ordering of effects is unknown. Objective: This study examined time to dementia diagnosis among patients with comorbid insomnia and/or depressive episodes in an epidemiological sample. Methods: Secondary data analyses were conducted using a cohort study of 203,819 Veterans with a primary admission diagnosis of heart failure in 129 VA Medical Centers. Results: Patients with diagnoses of both insomnia and depressive episodes had the shortest time to a dementia diagnosis at both 1-year (Hazard ratio = 1.43, 95% CI [1.36, 1.51]) and 3-year follow-up time points (Hazard ratio = 1.40, 95% CI [1.34, 1.47]) versus patients with one or neither comorbidity. Conclusions: Individuals with both comorbidities had the shortest time to dementia onset. Screening for these comorbidities may help to identify patients at elevated risk of dementia who could benefit from enhanced monitoring or early intervention strategies for more rapid detection and management of dementia symptoms.

Eliminating Qubit-Type Cross-Talk in the omg Protocol.

The omg protocol is a promising paradigm that uses multiple, application-specific, qubit subspaces within the Hilbert space of each single atom during quantum information processing. A key assumption for omg operation is that a subspace can be accessed independently without deleterious effects on information stored in other subspaces. We find that intensity noise during laser-based quantum gates in one subspace can cause decoherence in other subspaces, potentially complicating omg operation. We show, however, that a magnetic-field-induced vector light shift can be used to eliminate this source of decoherence. As this technique simply requires choosing a specific, magnetic field-dependent polarization for the gate lasers, it is straightforward to implement and potentially helpful for omg-based quantum technology.

Pandemic Paranoia Scale for Adolescents (PPS-A): An Initial Psychometric Evaluation and Prevalence Study of Adolescents in the United States and United Kingdom.

Paranoid thoughts have been reported in 20-30% of adolescents, and preliminary research has shown that paranoia and psychotic-like experiences have increased during the COVID-19 pandemic. However, previous research has typically used general measures to assess paranoia, rather than those specific to COVID-19, which may overlook particular facets of paranoia related to the pandemic and result in an under-reporting of paranoia prevalence rates during this time. Therefore, this study aimed to examine the psychometric properties of the Pandemic Paranoia Scale for Adolescents (PPS-A), which was adapted from the original scale to be appropriate for younger respondents, and to assess the prevalence of pandemic paranoia among adolescents. Adolescents (N = 462) recruited on Qualtrics from the United States (US) and United Kingdom (UK) completed an online survey consisting of the PPS-A and measures of general paranoia and negative affect. A subset of adolescent's parents (N = 146) also completed an online survey providing dyadic data. Findings showed that the PPS-A shared the same three factor structure as the adult PPS (i.e., persecutory threat, paranoid conspiracy, and interpersonal mistrust) and across participant nationality, race, gender, and mental health diagnosis. It also demonstrated strong psychometric properties. The overall prevalence rate of pandemic-related paranoia among adolescents was 21% and prevalence rates were higher among US participants than UK participants. This study provides the most comprehensive psychometric evaluation of a pandemic paranoia scale designed for adolescents and highlights the continued prevalence of pandemic paranoia in this age-group nearly two years after COVID-19 began.

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease.

BACKGROUND: With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-ß (Aß) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). METHODS: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aß-PET/CSF testing as the standard of truth. RESULTS: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aß-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aß positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing. CONCLUSIONS: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aß-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.

Square-planar imido complexes of cobalt: synthesis, reactivity and computational study.

Treatment of [Co(N2)(tBuPNP)] (tBuPNP = anion of 2,5-bis(di-tert-butylphosphinomethyl)pyrrole) with one equivalent of an aryl azide generates the four-coordinate imido complexes [Co(NAr)(tBuPNP)] (Ar = mesityl, phenyl, or 4-tBu-phenyl). X-ray crystallographic analysis of the compounds shows an unusual square-planar geometry about cobalt with nearly linear imido units. In the presence of the hydrogen atom donor, TEMPOH, [Co(NPh)(tBuPNP)] undergoes addition of the H atom to the imido nitrogen to generate the corresponding amido complex, [Co(NHPh)(tBuPNP)], whose structure and composition were verified by independent synthesis. Despite the observation of H atom transfer reactivity with TEMPOH, the imido complexes do not show catalytic activity for C-H amination or aziridination for several substrates examined. In the case of [Co(NPh)(tBuPNP)], addition of excess azide produced the tetrazido complex, [Co(N4Ph2)(tBuPNP)], whose bond metrics were most consistent with an anionic Ph2N4 ligand. Density Functional Theory (DFT) investigations of the imido and tetrazido species suggest that they adopt a ground state best described as possessing a low-spin cobalt(II) ion ferromagnetically coupled to an iminyl radical.

Development of PainFace software to simplify, standardize, and scale up mouse grimace analyses.

ABSTRACT: Facial grimacing is used to quantify spontaneous pain in mice and other mammals, but scoring relies on humans with different levels of proficiency. Here, we developed a cloud-based software platform called PainFace ( http://painface.net ) that uses machine learning to detect 4 facial action units of the mouse grimace scale (orbitals, nose, ears, whiskers) and score facial grimaces of black-coated C57BL/6 male and female mice on a 0 to 8 scale. Platform accuracy was validated in 2 different laboratories, with 3 conditions that evoke grimacing-laparotomy surgery, bilateral hindpaw injection of carrageenan, and intraplantar injection of formalin. PainFace can generate up to 1 grimace score per second from a standard 30 frames/s video, making it possible to quantify facial grimacing over time, and operates at a speed that scales with computing power. By analyzing the frequency distribution of grimace scores, we found that mice spent 7x more time in a "high grimace" state following laparotomy surgery relative to sham surgery controls. Our study shows that PainFace reproducibly quantifies facial grimaces indicative of nonevoked spontaneous pain and enables laboratories to standardize and scale-up facial grimace analyses.

Resolving the chromatin impact of mosaic variants with targeted Fiber-seq.

Accurately quantifying the functional consequences of non-coding mosaic variants requires the pairing of DNA sequence with both accessible and closed chromatin architectures along individual DNA molecules-a pairing that cannot be achieved using traditional fragmentation-based chromatin assays. We demonstrate that targeted single-molecule chromatin fiber sequencing (Fiber-seq) achieves this, permitting single-molecule, long-read genomic and epigenomic profiling across targeted >100 kilobase loci with ~10-fold enrichment over untargeted sequencing. Targeted Fiber-seq reveals that pathogenic expansions of the DMPK CTG repeat that underlie Myotonic Dystrophy 1 are characterized by somatic instability and disruption of multiple nearby regulatory elements, both of which are repeat length-dependent. Furthermore, we reveal that therapeutic adenine base editing of the segmentally duplicated γ-globin ( HBG1/HBG2 ) promoters in primary human hematopoietic cells induced towards an erythroblast lineage increases the accessibility of the HBG1 promoter as well as neighboring regulatory elements. Overall, we find that these non-protein coding mosaic variants can have complex impacts on chromatin architectures, including extending beyond the regulatory element harboring the variant.

Effect of processing speed and memory performance on classification accuracy of the dot counting test in a mixed neuropsychiatric sample.

OBJECTIVE: This study examined the impact of impairment in two specific cognitive abilities, processing speed and memory, on Dot Counting Test (DCT) classification accuracy by evaluating performance validity classification accuracy across cognitively unimpaired, single-domain impairment, and multidomain impairment subgroups within a mixed clinical sample. METHOD: Cross-sectional data were analyzed from 348 adult outpatients classified as valid (n = 284) or invalid (n = 64) based on four independent criterion performance validity tests (PVTs). Unimpaired (n = 164), single-domain processing speed impairment (n = 24), single-domain memory impairment (n = 53), and multidomain processing speed and memory impairment (n = 43) clinical subgroups were established among the valid group. Both the traditional DCT E-score and unrounded E-score were examined. RESULTS: Overall, the DCT demonstrated acceptable to excellent classification accuracy across the unimpaired (area under the curve [AUC] traditional E-score=.855; unrounded E-score=.855) and single-domain impairment groups (traditional E-score AUCs = .690-.754; unrounded E-score AUCs = .692-747). However, it did not reliably discriminate the multidomain processing speed and memory impairment group from the invalid performers (traditional and unrounded E-scores AUC = .557). CONCLUSIONS: Findings support the DCT as a non-memory-based freestanding PVT for use with single-domain cognitive impairment, with traditional E-score ≥17 (unrounded E-score ≥16.95) recommended for those with memory impairment and traditional E-score ≥19 (unrounded ≥18.08) with processing speed impairment. Moreover, results replicated previously established optimal cutoffs for unimpaired groups using both the traditional (≥14) and unrounded (≥13.84) E-scores. However, the DCT did not reliably discriminate between invalid performance and multidomain cognitive impairment, indicating caution is warranted when using the DCT with patients suspected of greater cognitive impairment.

A-Site Doping to Alter Oxygen Vacancy Diffusion in SrTiO3.

Doped SrTiO3 is a promising material for many applications where oxygen vacancy diffusion is either critical to device function or a source of failure. This work provides new insight into long-range oxygen vacancy diffusion in SrTiO3 doped with Mn2+, Cr3+, or Fe2+ on the A-site. Density functional theory and the nudged elastic band method are used to calculate oxygen vacancy diffusion barriers adjacent to the dopant and at remote sites. Relative to the pure SrTiO3 structure, doping was found to raise the diffusion barrier for VO •• vacancies and lower the diffusion barrier for VO x vacancies. Furthermore, a doping trapping radius of 6 Šwas found for both the VO x and VO •• vacancies. Counterintuitively, trapping was observed even in supercells where vacancies and dopants are both positively charged. These results provide new insight into how less common A-site doping can change the electronic structure of this important material.

Multidimensional ADHD Symptom Profiles: Associations with Adverse Childhood Experiences.

OBJECTIVE: Adverse childhood experiences (ACEs) are associated with a range of negative health outcomes, including attention-deficit/hyperactivity disorder (ADHD) and neurocognitive deficits. This study identified symptom profiles in adult patients undergoing neuropsychological evaluations for ADHD and examined the association between these profiles and ACEs. METHODS: Utilizing unsupervised machine learning models, the study analyzed data from 208 adult patients. RESULTS: The Gaussian Mixture Model revealed two distinct symptom profiles: "Severely Impaired" and "Moderately Impaired". The "Severely Impaired" profile, 23.6% of the sample, was characterized by more severe ADHD symptomatology in childhood and worse neurocognitive performance. The "Moderately Impaired" profile, 76.4% of the sample, had scores in the average range for self-reported internalizing and externalizing psychopathology and better neurocognitive performance. There was a greater number of ACEs reported by patients in the Severely Impaired profile than the Moderately Impaired profile (p = .022). Specifically, using an ACEs cutoff of ≥4, 53.1% of patients in the Severely Impaired profile reported four or more ACEs, compared with 34.6% in the Moderately Impaired profile (p = .020). Profiles were not related to clinician-ascribed diagnosis. CONCLUSIONS: Findings underscore the association between ACEs and worse symptom profiles marked by impaired neurocognitive function, increased internalizing and externalizing psychopathology, and heightened perceived stress in adults with ADHD. Future research may explore the effect of ACEs on symptom profiles in diverse populations and potential moderators or mediators of these associations. Findings offers valuable insights for clinicians in their assessment and treatment planning.

Development of novel tools for dissection of central versus peripheral dopamine D2-like receptor signaling in dysglycemia.

Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors including D2 (D2R) and D3 (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2R/D3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.

Controlling Pericellular Oxygen Tension in Cell Culture Reveals Distinct Breast Cancer Responses to Low Oxygen Tensions.

In oxygen (O2)-controlled cell culture, an indispensable tool in biological research, it is presumed that the incubator setpoint equals the O2 tension experienced by cells (i.e., pericellular O2). However, it is discovered that physioxic (5% O2) and hypoxic (1% O2) setpoints regularly induce anoxic (0% O2) pericellular tensions in both adherent and suspension cell cultures. Electron transport chain inhibition ablates this effect, indicating that cellular O2 consumption is the driving factor. RNA-seq analysis revealed that primary human hepatocytes cultured in physioxia experience ischemia-reperfusion injury due to cellular O2 consumption. A reaction-diffusion model is developed to predict pericellular O2 tension a priori, demonstrating that the effect of cellular O2 consumption has the greatest impact in smaller volume culture vessels. By controlling pericellular O2 tension in cell culture, it is found that hypoxia vs. anoxia induce distinct breast cancer transcriptomic and translational responses, including modulation of the hypoxia-inducible factor (HIF) pathway and metabolic reprogramming. Collectively, these findings indicate that breast cancer cells respond non-monotonically to low O2, suggesting that anoxic cell culture is not suitable for modeling hypoxia. Furthermore, it is shown that controlling atmospheric O2 tension in cell culture incubators is insufficient to regulate O2 in cell culture, thus introducing the concept of pericellular O2-controlled cell culture.

Arthroscopic Bankart Repair with Remplissage Yields Similar Outcomes to Open Latarjet for Primary and Revision Stabilization in The Setting of Subcritical Glenoid Bone Loss.

BACKGROUND: Management of patients with recurrent anterior glenohumeral instability in the setting of subcritical glenoid bone loss (GBL), defined in this study as 20% GBL or less, remains controversial. This study aimed to compare arthroscopic Bankart with remplissage (ABR+R) to open Latarjet for subcritical GBL in primary or revision procedures. We hypothesized that ABR+R would yield higher rates of recurrent instability and reoperation compared to Latarjet in both primary and revision settings. METHODS: A retrospective study was conducted on patients undergoing either arthroscopic ABR+R or an open Latarjet procedure. Patients with connective tissue disorders, critical GBL (>20%), < 2 year follow-up, or insufficient data were excluded. Recurrent instability and revision were the primary outcomes of interest. Additional outcomes of interest included subjective shoulder value (SSV), strength and range of motion (ROM) RESULTS: 108 patients (70 ABR+R, 38 Latarjet) were included with an average follow-up of 4.3 ±2.1 years. In the primary and revision settings, similar rates of recurrent instability (Primary: p=0.60; Revision: p=0.28) and reoperation (Primary: p=0.06; Revision: p=1.00) were observed between Latarjet and ABR+R. Primary ABR+R exhibited better SSV, active ROM, and internal rotation strength compared to primary open Latarjet. However, no differences were observed in the revision setting. CONCLUSION: Similar rates of recurrent instability and reoperation in addition to comparable outcomes with no differences in ROM were found for ABR+R and Latarjet in patients with subcritical GBL in both the primary and revision settings. ABR+R can be a safe and effective procedure in appropriately selected patients with less than 20% GBL for both primary and revision stabilization.

Battery electronification: intracell actuation and thermal management.

Electrochemical batteries - essential to vehicle electrification and renewable energy storage - have ever-present reaction interfaces that require compromise among power, energy, lifetime, and safety. Here we report a chip-in-cell battery by integrating an ultrathin foil heater and a microswitch into the layer-by-layer architecture of a battery cell to harness intracell actuation and mutual thermal management between the heat-generating switch and heat-absorbing battery materials. The result is a two-terminal, drop-in ready battery with no bulky heat sinks or heavy wiring needed for an external high-power switch. We demonstrate rapid self-heating (∼ 60 °C min-1), low energy consumption (0.138% °C-1 of battery energy), and excellent durability (> 2000 cycles) of the greatly simplified chip-in-cell structure. The battery electronification platform unveiled here opens doors to include integrated-circuit chips inside energy storage cells for sensing, control, actuating, and wireless communications such that performance, lifetime, and safety of electrochemical energy storage devices can be internally regulated.

Diversity of Research Participant Gender, Race, and Ethnicity in Communication Sciences and Disorders: A Systematic Review and Quantitative Synthesis of American Speech-Language-Hearing Association Publications in 2020.

Purpose: One manifestation of systemic inequities in communication sciences and disorders (CSD) is the chronic underreporting and underrepresentation of sex, gender, race, and ethnicity in research. The present study characterized recent demographic reporting practices and representation of participants across CSD research. Methods: We systematically reviewed and extracted key reporting and participant data from empirical studies conducted in the United States (US) with human participants published in the year 2020 in journals by the American Speech-Language-Hearing Association (ASHA; k = 407 articles comprising a total n = 80,058 research participants, search completed November 2021). Sex, gender, race, and ethnicity were operationalized per National Institutes of Health guidelines (National Institutes of Health, 2015a, 2015b). Results: Sex or gender was reported in 85.5% of included studies; race was reported in 33.7%; and ethnicity was reported in 13.8%. Sex and gender were clearly differentiated in 3.4% of relevant studies. Where reported, median proportions for race and ethnicity were significantly different from the US population, with underrepresentation noted for all non-White racial groups and Hispanic participants. Moreover, 64.7% of studies that reported sex or gender and 67.2% of studies that reported race or ethnicity did not consider these respective variables in analyses or discussion. Conclusion: At present, research published in ASHA journals frequently fails to report key demographic data summarizing the characteristics of participants. Moreover, apparent gaps in representation of minoritized racial and ethnic groups threaten the external validity of CSD research and broader health care equity endeavors in the US. Although our study is limited to a single year and publisher, our results point to several steps for readers that may bring greater accountability, consistency, and diversity to the discipline.

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer's disease.

Background: With the approval of disease-modifying treatments (DMTs) for early Alzheimer's disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-ß (Aß) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). Methods: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific training data and BioFINDER-2, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aß-PET/CSF testing as the standard of truth. Results: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aß-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aß positivity in potential DMT candidates (AUC = 0.97 [0.92-1]), with diagnostic accuracy ranging from 0.88 (0.76-0.95, p = 0.028) to 0.96 (0.86-1, p < .001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required from confirmatory testing. Conclusions: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aß-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations.

New focus on cardiac voltage-gated sodium channel ß1 and ß1B: Novel targets for treating and understanding arrhythmias?

Voltage-gated sodium channels (VGSCs) are transmembrane protein complexes that are vital to the generation and propagation of action potentials in nerve and muscle fibers. The canonical VGSC is generally conceived as a heterotrimeric complex formed by two classes of membrane-spanning subunit-an α-subunit (pore forming) and two ß-subunits (non-pore forming). NaV1.5 is the main sodium channel α-subunit of mammalian ventricle, with lower amounts of other α-subunits, including NaV1.6, being present. There are four ß-subunits, ß1-ß4, encoded by four genes, SCN1B-SCN4B, each of which are expressed in cardiac tissues. Recent studies suggest that in addition to assignments in channel gating and trafficking, products of Scn1b may have novel roles in conduction of action potential in the heart and intracellular signaling. This includes evidence that the ß-subunit extracellular Amino-terminal domain facilitates adhesive interactions in intercalated discs and that its Carboxyl-terminal region is a substrate for a regulated intramembrane proteolysis (RIP) signaling pathway-with a Carboxyl-terminal peptide generated by ß1 RIP trafficked to the nucleus and altering transcription of various genes, including NaV1.5. In addition to ß1, the Scn1b gene encodes for an alternative splice variant, ß1B, which contains an identical extracellular adhesion domain to ß1, but has a unique Carboxyl-terminus. Whilst ß1B is generally understood to be a secreted variant, evidence indicates that when co-expressed with NaV1.5, it is maintained at the cell membrane, suggesting potential unique roles for this understudied protein. In this review, we focus on what is known on the two ß-subunit variants encoded by Scn1b in heart, with particular focus on recent findings and the questions raised by this new information. We also explore data that indicate ß1 and ß1B may be attractive targets for novel anti-arrhythmic therapeutics.