Cachd1 interacts with Wnt receptors and regulates neuronal asymmetry in the zebrafish brain.

Neurons on the left and right sides of the nervous system often show asymmetric properties, but how such differences arise is poorly understood. Genetic screening in zebrafish revealed that loss of function of the transmembrane protein Cachd1 resulted in right-sided habenula neurons adopting left-sided identity. Cachd1 is expressed in neuronal progenitors, functions downstream of asymmetric environmental signals, and influences timing of the normally asymmetric patterns of neurogenesis. Biochemical and structural analyses demonstrated that Cachd1 can bind simultaneously to Lrp6 and Frizzled family Wnt co-receptors. Consistent with this, lrp6 mutant zebrafish lose asymmetry in the habenulae, and epistasis experiments support a role for Cachd1 in modulating Wnt pathway activity in the brain. These studies identify Cachd1 as a conserved Wnt receptor-interacting protein that regulates lateralized neuronal identity in the zebrafish brain.

Single-cell guided prenatal derivation of primary fetal epithelial organoids from human amniotic and tracheal fluids.

Isolation of tissue-specific fetal stem cells and derivation of primary organoids is limited to samples obtained from termination of pregnancies, hampering prenatal investigation of fetal development and congenital diseases. Therefore, new patient-specific in vitro models are needed. To this aim, isolation and expansion of fetal stem cells during pregnancy, without the need for tissue samples or reprogramming, would be advantageous. Amniotic fluid (AF) is a source of cells from multiple developing organs. Using single-cell analysis, we characterized the cellular identities present in human AF. We identified and isolated viable epithelial stem/progenitor cells of fetal gastrointestinal, renal and pulmonary origin. Upon culture, these cells formed clonal epithelial organoids, manifesting small intestine, kidney tubule and lung identity. AF organoids exhibit transcriptomic, protein expression and functional features of their tissue of origin. With relevance for prenatal disease modeling, we derived lung organoids from AF and tracheal fluid cells of congenital diaphragmatic hernia fetuses, recapitulating some features of the disease. AF organoids are derived in a timeline compatible with prenatal intervention, potentially allowing investigation of therapeutic tools and regenerative medicine strategies personalized to the fetus at clinically relevant developmental stages.

A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity.

Combinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. CTX-8371 matched or surpassed the activity of anti-PD-1 and PD-L1 benchmark antibodies in several in vitro T cell activation assays and outperformed clinically approved benchmarks in the subcutaneous MC38 colon and the B16F10 lung metastasis mouse tumor models. Investigation into the mechanism of action revealed that CTX-8371 co-engagement of PD-1 and PD-L1 induced the proteolytic cleavage and loss of cell surface PD-1, which is a novel and non-redundant mechanism that adds to the PD-1/PD-L1 signaling axis blockade. The combination of CTX-8371 and an agonistic anti-CD137 antibody further increased the anti-tumor efficacy with long-lasting curative therapeutic effect. In summary, CTX-8371 is a novel checkpoint inhibitor that might provide greater clinical benefit compared to current anti-PD-1 and PD-L1 antibodies, especially when combined with agents with orthogonal mechanisms of action, such as agonistic anti-CD137 antibodies.

Characterizing Negative Online Reviews of Spine Surgeons.

DESIGN: Retrospective review. OBJECTIVE: Characterize negative reviews of spine surgeons in the United States. SUMMARY: Physician rating websites significantly influence the selection of doctors by other patients. Negative experiences are impacted by various factors, both clinical and nonclinical, geography, and practice structure. The purpose of this study was to evaluate and categorize negative reviews of spine surgeons in the United States, with a focus on surgical versus nonsurgical reviewers. METHODS: Spine surgeons were selected from available online professional society membership directories. A search for reviews was performed on Healthgrades.com, Vitals.com, and RateMDs.com for the past 10 years. Free response reviews were coded by complaint, and qualitative analysis was performed. χ 2 and Fisher exact tests were used to compare categorical variables, and multiple comparisons were adjusted with Benjamini-Hochberg correction. A binary logistic regression model was performed for the top three most mentioned nonclinical and clinical complaint labels. A P -value <0.05 was considered statistically significant. RESULTS: A total of 16,695 online reviews were evaluated, including 1690 one-star reviews (10.1%). Among one-star reviews, 64.7% were written by nonsurgical patients and 35.3% by surgical patients. Nonclinical and clinical comments constituted 54.9% and 45.1% of reviews, respectively. Surgeons in the South had more "bedside manner" comments (43.3%, P <0.0001), while Northeast surgeons had more "poor surgical outcome" remarks compared with all other geographic regions (14.4%, P <0.001). Practicing in the South and Northeast were independent predictors of having complaints about "bedside manner" and "poor surgical outcome," respectively. CONCLUSION: Most one-star reviews of spine surgeons were attributed to nonsurgical patients, who tended to be unsatisfied with nonclinical factors, especially "bedside manner." However, there was substantial geographic variation. These results suggest that spine surgeons could benefit from focusing on nonclinical factors (bedside manner), especially among nonoperative patients, and that regional nuances should be considered in delivering spine care. LEVEL OF EVIDENCE: Level- 5.

Impact of autophagy inhibition on intervertebral disc cells and extracellular matrix.

Background: Intervertebral disc degeneration (IDD) is a leading contributor to low back pain (LBP). Autophagy, strongly activated by hypoxia and nutrient starvation, is a vital intracellular quality control process that removes damaged proteins and organelles to recycle them for cellular biosynthesis and energy production. While well-established as a major driver of many age-related diseases, autophagy dysregulation or deficiency has yet been confirmed to cause IDD. Methods: In vitro, rat nucleus pulposus (NP) cells treated with bafilomycin A1 to inhibit autophagy were assessed for glycosaminoglycan (GAG) content, proteoglycan synthesis, and cell viability. In vivo, a transgenic strain (Col2a1-Cre; Atg7 fl/fl) mice were successfully generated to inhibit autophagy primarily in NP tissues. Col2a1-Cre; Atg7 fl/fl mouse intervertebral discs (IVDs) were evaluated for biomarkers for apoptosis and cellular senescence, aggrecan content, and histological changes up to 12 months of age. Results: Here, we demonstrated inhibition of autophagy by bafilomycin produced IDD features in the rat NP cells, including increased apoptosis and cellular senescence (p21 CIP1) and decreased expression of disc matrix genes Col2a1 and Acan. H&E histologic staining showed significant but modest degenerative changes in NP tissue of Col2a1-Cre; Atg7 fl/fl mice compared to controls at 6 and 12 months of age. Intriguingly, 12-month-old Col2a1-Cre; Atg7 fl/fl mice did not display increased loss of NP proteoglycan. Moreover, markers of apoptosis (cleaved caspase-3, TUNEL), and cellular senescence (p53, p16 INK4a , IL-1ß, TNF-α) were not affected in 12-month-old Col2a1-Cre; Atg7 fl/fl mice compared to controls. However, p21 CIP1and Mmp13 gene expression were upregulated in NP tissue of 12-month-old Col2a1-Cre; Atg7 fl/fl mice compared to controls, suggesting p21 CIP1-mediated cellular senescence resulted from NP-targeted Atg7 knockout might contribute to the observed histological changes. Conclusion: The absence of overt IDD features from disrupting Atg7-mediated macroautophagy in NP tissue implicates other compensatory mechanisms, highlighting additional research needed to elucidate the complex biology of autophagy in regulating age-dependent IDD.

Access to cancer clinical trials for racialised older adults: an equity-focused rapid scoping review protocol.

BACKGROUND: The intersection of race and older age compounds existing health disparities experienced by historically marginalised communities. Therefore, racialised older adults with cancer are more disadvantaged in their access to cancer clinical trials compared with age-matched counterparts. To determine what has already been published in this area, the rapid scoping review question are: what are the barriers, facilitators and potential solutions for enhancing access to cancer clinical trials among racialised older adults? METHODS: We will use a rapid scoping review methodology in which we follow the six-step framework of Arksey and O'Malley, including a systematic search of the literature with abstract and full-text screening to be conducted by two independent reviewers, data abstraction by one reviewer and verification by a second reviewer using an Excel data abstraction sheet. Articles focusing on persons aged 18 and over who identify as a racialised person with cancer, that describe therapies/therapeutic interventions/prevention/outcomes related to barriers, facilitators and solutions to enhancing access to and equity in cancer clinical trials will be eligible for inclusion in this rapid scoping review. ETHICS AND DISSEMINATION: All data will be extracted from published literature. Hence, ethical approval and patient informed consent are not required. The findings of the scoping review will be submitted for publication in a peer-reviewed journal and presentation at international conferences.

The Evolution, Assembly, and Dynamics of Marine Holobionts.

The holobiont concept (i.e., multiple living beings in close symbiosis with one another and functioning as a unit) is revolutionizing our understanding of biology, especially in marine systems. The earliest marine holobiont was likely a syntrophic partnership of at least two prokaryotic members. Since then, symbiosis has enabled marine organisms to conquer all ocean habitats through the formation of holobionts with a wide spectrum of complexities. However, most scientific inquiries have focused on isolated organisms and their adaptations to specific environments. In this review, we attempt to illustrate why a holobiont perspective-specifically, the study of how numerous organisms form a discrete ecological unit through symbiosis-will be a more impactful strategy to advance our understanding of the ecology and evolution of marine life. We argue that this approach is instrumental in addressing the threats to marine biodiversity posed by the current global environmental crisis.

Effortful Control Protects Against Familial Liability for ADHD: Longitudinal Results from the ABCD Study in the United States.

Effortful control, the ability to regulate complex and goal-directed behavior, may protect individuals from developing mental health symptoms. This study tested the potential for child effortful control and executive functioning to buffer the effects of familial liability for attention deficit hyperactivity disorder (ADHD) problems across a one-year timeframe. Data from the prospectively-collected Adolescent Brain Cognitive Development (ABCD)® study were used to examine whether caregiver-rated child effortful control and executive functioning moderated the association between familial ADHD risk and later ADHD symptoms in a sample of children (N = 6,133; ages 9-10 years at baseline). Two independent variables were considered to compare the predictive powers of specific (family ADHD) and broad (family psychopathology) risk factors. Two additional moderating variables (surgency, negative affect) were tested to examine specificity of effortful control and executive functioning as moderators. All variables of interest were measured on a continuum and via caregiver report. At high levels of effortful control and executive functioning, there was no association between familial liability for ADHD or broad psychopathology and later child ADHD problems. The moderator effects were specific to effortful control and executive functioning domains. Etiological models of heritable psychiatric disorders, such as ADHD, should consider the risk and protective contributions of individual traits, such as effortful control and executive functioning. Clinical prevention and intervention efforts may target self-regulation skills in children to buffer against familial liability for ADHD problems.

Hippocampal sparing radiation therapy for brain metastases: treatment techniques and clinical implementation.

High doses of radiation to the hippocampus have been correlated with increased cognitive decline following radiation therapy for brain metastases. To mitigate these effects, a variety of hippocampal sparing techniques have been implemented for both whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). The goal of this review article is to provide a practical resource for the clinical implementation of hippocampal-sparing radiation therapy, starting with a brief background on the function and delineation of the hippocampal structure, as well as radiation effects on the hippocampus and the most widely recommended dose constraints. Considerations for treatment simulation are discussed, including options for cranial immobilization and optional head tilt. Hippocampal sparing has been demonstrated for WBRT using helical TomoTherapy, static intensity-modulated radiation therapy (IMRT), and volumetric-modulated arc therapy (VMAT) with a variety of patient setup positions, beam arrangements, and planning parameters. Tomotherapy has been shown to achieve slightly greater hippocampal sparing in some studies, while VMAT enables the most efficient treatment delivery. Hippocampal sparing has also been evaluated in a wide range of studies for both GammaKnife and linear accelerator (LINAC)-based SRS, with the proximity of metastases to the hippocampus being the most significant predictor of hippocampal dose. The methods and resulting hippocampal doses from these studies on both WBRT and SRS are discussed, as well as the role of automation in hippocampal sparing radiation therapy.

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.

Remote Ischemic Conditioning in Pediatric Cancer Patients Receiving Anthracycline Chemotherapy: A Sham-Controlled Single-Blind Randomized Trial.

Background: Anthracycline cardiotoxicity is a concern in survivors of childhood cancers. Recent evidence suggests that remote ischemic conditioning (RIC) may offer myocardial protection. Objectives: This randomized sham-controlled single-blind study tested the hypothesis that RIC may reduce myocardial injury in pediatric cancer patients receiving anthracycline chemotherapy. Methods: We performed a phase 2 sham-controlled single-blind randomized controlled trial to determine the impact of RIC on myocardial injury in pediatric cancer patients receiving anthracycline-based chemotherapy. Patients were randomized to receive RIC (3 cycles of 5-minute inflation of a blood pressure cuff placed over 1 limb to 15 mm Hg above systolic pressure) or sham intervention. The intervention was applied within 60 minutes before initiation of the first dose and before up to 4 cycles of anthracycline therapy. The primary outcome was the plasma high-sensitivity cardiac troponin T (hs-cTnT) level. The secondary outcome measures included echocardiographic indexes of left ventricular systolic and diastolic function and the occurrence of cardiovascular events. Results: A total of 68 children 10.9 ± 3.9 years of age were randomized to receive RIC (n = 34) or sham (n = 34) intervention. Plasma levels of hs-cTnT showed a progressive increase across time points in the RIC (P < 0.001) and sham (P < 0.001) groups. At each of the time points, there were no significant differences in hs-cTnT levels or LV tissue Doppler and strain parameters between the 2 groups (all P > 0.05). None of the patients developed heart failure or cardiac arrhythmias. Conclusions: RIC did not exhibit cardioprotective effects in childhood cancer patients receiving anthracycline-based chemotherapy. (Remote Ischaemic Preconditioning in Childhood Cancer [RIPC]; NCT03166813).

Allogeneic haematopoietic stem cell transplantation for myelofibrosis: prognostic indicators and the role of JAK2V617F measurable-residual disease monitoring by droplet-digital polymerase chain reaction.

Relapse after allogeneic haematopoietic stem cell transplantation (HSCT) is one of the key determinants of outcome in myelofibrosis (MF) and remains an important unmet need. In this retrospective single-centre study, we evaluated 35 consecutive patients with MF receiving allogeneic HSCT. At 30 days post-HSCT, full donor chimerism was achieved in 31 patients (88.6%). The median time to neutrophil engraftment was 16.8 (10-42) days and the median time to platelet engraftment was 26 (12-245) days. Four patients (11.4%) experienced primary graft failure. With a median duration of follow-up of 33 (1-223) months, with the 5-year overall survival (OS) and progression-free survival (PFS) were 51.6% and 46.3%, respectively. Relapse after HSCT (P < 0.001), leucocyte count ≥ 18 × 109/L at HSCT (P = 0.003) and accelerated/blast phase disease at HSCT (P < 0.001) were significantly associated with worse OS. Age at HSCT ≥ 54 years (P = 0.01), mutated ETV6 (P = 0.03), leucocyte count ≥ 18 × 109/L (P = 0.02), accelerated/blast phase MF (P = 0.001), and grade 2-3 bone marrow reticulin fibrosis at 12 months post-HSCT (P = 0.002) were significantly associated with worse PFS. JAK2V617F MRD ≥ 0.047 [sensitivity 85.7%; positive predictive value (PPV) 100%; AUC 0.984; P = 0.001] at 6 months and JAK2V617F MRD ≥ 0.009 (sensitivity 100%; PPV 100%; AUC 1.0; P = 0.001) at 12 months were highly predictive of post-HSCT relapse. Inferior OS and PFS were significantly associated with detectable JAK2V617F MRD at 12 months (P = 0.003 and P = 0.0001, respectively).

Late-Onset Seizure Disorder in Adult Cerebral Palsy Associated With COVID-19 Infection.

COVID-19 can affect many organ systems, including the CNS, with symptoms of altered mental status and seizures. We present a case of a 30-year-old man with cerebral palsy who developed seizures after a COVID-19 infection. Admission labs were remarkable for hypernatremia, and elevated creatine kinase, and troponin levels as well as creatinine above baseline. MRI was performed demonstrating a small, evolving acute/subacute abnormality in the midline splenium of the corpus callosum. An EEG showed moderate to severe abnormalities with low-voltage delta waves. The patient was treated with medication and advised to follow up with a neurologist. One month later, no residual CT abnormality corresponding to the previously reported lesion in the midline splenium of the corpus callosum was observed. Although epilepsy is a common finding in patients with cerebral palsy, the complete lack of seizure activity throughout this patient's early life, coupled with previously unremarkable brain imaging, further supports our claim that his recent onset of seizures was directly related to COVID-19. This case highlights the possibility of new seizures in patients with pre-existing neurological conditions after COVID-19 infection and emphasizes the need for more research.

Arabidopsis calmodulin-like proteins CML13 and CML14 interact with proteins that have IQ domains.

In response to Ca2+ signals, the evolutionarily-conserved Ca2+ sensor calmodulin (CaM) regulates protein targets via direct interaction. Plants possess many CaM-like (CML) proteins, but their binding partners and functions are mostly unknown. Here, using Arabidopsis CML13 as 'bait' in a yeast two-hybrid screen, we isolated putative targets from three, unrelated protein families, namely, IQD proteins, calmodulin-binding transcriptional activators (CAMTAs) and myosins, all of which possess tandem isoleucine-glutamine (IQ) structural domains. Using the split-luciferase complementation assay in planta and the yeast 2-hybrid system, CML13 and CML14 showed a preference for interaction with tandem over single IQ domains. Relative to CaM, CML13 and CML14 displayed weaker signals when tested with the non-IQ, CaM-binding domain of glutamate decarboxylase or the single IQ domains of CNGC20 (cyclic-nucleotide gated channel-20) or IQM1 (IQ motif protein1). We examined IQD14 as a representative tandem IQ-protein and found that only CaM, CML13 and CML14 interacted with IQD14 among 12 CaM/CMLs tested. CaM, CML13 and CML14 bound in vitro to IQD14 in the presence or absence of Ca2+ . Binding affinities were in the nM range and were higher when two tandem IQ domains from IQD14 were present. Green fluorescent protein-tagged versions of CaM, CML13 and CML14 localized to both the cytosol and nucleus in plant cells but were partially relocalized to the microtubules when co-expressed with IQD14 tagged with mCherry. These and other data are discussed in the context of possible roles for these CMLs in gene regulation via CAMTAs and cytoskeletal activity via myosins and IQD proteins.

Characterization of thylakoid division using chloroplast dividing mutants in Arabidopsis.

Chloroplasts are double membrane bound organelles that are found in plants and algae. Their division requires a number of proteins to assemble into rings along the center of the organelle and to constrict in synchrony. Chloroplasts possess a third membrane system, the thylakoids, which house the majority of proteins responsible for the light-dependent reactions. The mechanism that allows chloroplasts to sort out and separate the intricate thylakoid membrane structures during organelle division remain unknown. By characterizing the sizes of thylakoids found in a number of different chloroplast division mutants in Arabidopsis, we show that thylakoids do not divide independently of the chloroplast division cycle. More specifically, we show that thylakoid division requires the formation of both the inner and the outer contractile rings of the chloroplast.

Assessment of the Short Grit Scale in patients with substance use disorder: Psychometric properties and patient characteristics.

Background: Recovery from substance use disorder requires sustained effort and perseverance. Hence, the resilience factor of grit may be important for people in recovery. Little research has been conducted on grit in patients with substance use disorder (SUD), especially in a large and varied sample.Objectives: To analyze the psychometric properties of the Short Grit Scale (Grit-S) in patients with SUD and to use demographic and clinical characteristics to predict variance in Grit-S scores.Methods: Participants completed the Grit-S and other self-report measures. Psychometric properties of the Grit-S were assessed in outpatients (N = 94, 77.7% male) and a hierarchical regression predicted Grit-S variance in inpatients (N = 1238, 65.0% male).Results: The Grit-S demonstrated good internal consistency (α=.75) and strong test-retest reliability (adjusted r = .79, p < .001). Mean Grit-S score was 3.15, lower than other clinical samples reported in the literature. Regression modeling indicated a moderate, statistically significant association between demographic and clinical characteristics and Grit-S scores (R2 = 15.5%, p < .001). Of particular interest, the positive factor of recovery protection showed the strongest association with Grit-S of all variables assessed (ß=.185 vs. ß = .052-.175 for the remaining significant independent variables).Conclusion: The psychometric properties of the Grit-S in patients with SUD support its use in this population. Moreover, the particularly low grit scores among inpatients with SUDs and the association of grit scores with substance use risk and recovery factors suggest that grit could be useful as a treatment target in this population.

Acute promyelocytic leukaemia: population-based study of epidemiology and outcome with ATRA and oral-ATO from 1991 to 2021.

BACKGROUND: The epidemiology and treatment of acute promyelocytic leukaemia (APL) are changing. We have incorporated oral arsenic trioxide (oral-ATO) into induction/maintenance. METHODS: Newly-diagnosed APL from 1991 to 2021 divided into three 10-year periods were studied to define its epidemiology and how oral-ATO impacted on its outcome. Primary endpoints included APL incidence, early deaths (ED, first 30 days), and overall survival (OS). Secondary endpoints included post-30-day OS, relapse-free survival (RFS), and incidence of second cancers. RESULTS: APL occurred in 374 males and 387 females at a median age of 44 (1-97) years. Annual incidences increased progressively, averaging 0.32 per 100,000 people. All-trans retinoic acid (ATRA)-based and oral-ATO-based regimens were used in 469 and 282 patients. There were 144 EDs, occurring almost exclusively in ATRA-based inductions (N = 139), being more with males, age > 50 years, leucocyte > 10 × 109/L, diagnosis during 1991-2009 and fewer with oral-ATO-based regimens. After a median of 75 (interquartile range: 14-161) months, 5-year and 10-year OS were 68.1% and 63.3%, inferior with males, age > 50 years, leucocyte > 10 × 109/L, high-risk Sanz score and superior with oral-ATO-based regimens. Factoring out EDs, 5-year and 10-year post-30-day OS were 84.0% and 78.1%, inferior with males and superior with oral-ATO-based regimens. In 607 CR1 patients, the 5-year RFS was 83.8%, superior with diagnosis in 2010-2021 and oral-ATO-based regimens. Second cancers developed in 21 patients, unrelated to oral-ATO-based regimens. CONCLUSIONS: There was an increasing incidence of APL, and all survivals were superior with the use of oral-ATO-based regimens. This study formed part of the Acute Promyelocytic Leukaemia Asian Consortium Project (ClinicalTrials.gov identifier: NCT04251754).

The role of single trial variability in event related potentials in children with attention deficit hyperactivity disorder.

OBJECTIVE: Children with attention deficit hyperactivity disorder (ADHD) show attenuated mean P3 component amplitudes compared to typically developing (TD) children. This finding may be the result of individual differences in P3 amplitudes, P3 latencies, and/or greater single trial variability (STV) in amplitude or latency, suggesting neural "noise." METHODS: Event related potentials (ERPs) from 75 children with ADHD and 29 TD children were recorded with electroencephalography (EEG). Caregivers provided ratings on child ADHD symptoms. Single-trial ERP amplitudes and latencies were extracted from the P3 component time window during a visual oddball task. Additionally, we computed individual-centered and trial-centered P3 amplitudes to account for inter-individual and inter-trial variability in the timing of the P3 peak. RESULTS: In line with prior research, greater ADHD symptom severity was associated with reduced mean P3 amplitude. This correlation was no longer significant after correcting for inter-trial differences in P3 latency. In contrast, greater ADHD symptom severity was associated with reduced STV in P3 amplitude. CONCLUSIONS: Our results suggest that attenuated average P3 amplitude in ADHD samples is due to a consistent reduction in strength of the neurophysiological signal at the single trial level, as well as increased inter-trial variability in the timing of P3 peak amplitudes. The traditional method of extracting P3 amplitudes based on a single time window for all trials may not adequately capture variability in P3 latencies associated with ADHD. SIGNIFICANCE: Inter- and intra-individual differences in brain signatures should be considered in models of neurobiological differences in neurodevelopmental samples.