Publications by Year: 2026

Patients with disorders of consciousness (DoC) characteristically lack decision-making capacity, a central challenge for shared decision-making, as surrogate decision-makers must navigate the uncertainties of making proxy care decisions. The element of uncertainty is especially prominent considering growing recognition of cognitive motor dissociation or covert consciousness, attributable to advances in neurotechnologies that enable the detection of signatures of responsiveness and recovery capacity that evade routine bedside detection. Professional society guidelines now recommend use of advanced neurotechnologies for some patients, marking their transition from investigational into guideline-directed clinical tests. Yet, advanced neurotechnologies themselves introduce uncertainties to the calculus of shared decision-making, particularly given a paucity of guidance on clinical translation. Through semistructured interviews, we examined attitudes of clinicians and family members of patients with potential covert consciousness during three stages of conversation regarding translation of advanced neurotechnologies into DoC practice. Although clinicians described weighing clinical, prognostic, and logistical factors when deciding to introduce advanced testing, most family members regarded clinicians as ethically obligated to offer advanced neurotechnologies in DoC assessment. There was near consensus that results of advanced neurotechnologies must be shared, even in research contexts. The majority of clinicians and family members posited that results of advanced neurotechnologies should be communicated in ways that are sensitive to families' understanding, background, receptiveness to information, and anticipated decision-making role, and they valued transparency regarding the limitations and uncertainties inherent to these modalities. Clinicians placed higher weight on positive rather than negative results. Half of family members reported that results of advanced neurotechnologies impacted care decisions for their loved ones with DoC. Our findings reveal key points of convergence and divergence between clinicians and family members throughout stages of decision-making, grounding an ethically informed discussion guide that clinicians may use as a roadmap to support shared decision-making in this emerging context.

BACKGROUND: Enfortumab vedotin (EV) frequently causes cutaneous eruptions that can mimic erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), complicating management decisions.

OBJECTIVE: The aim of this study was to define reproducible clinicopathologic patterns and evaluate immunohistochemical markers that distinguish EV-induced cutaneous toxicity (EVICT) eruptions from histologic mimics.

METHODS: This retrospective case series included nineteen patients receiving EV (twenty-four biopsies), compared with ten controls (erythema multiforme or SJS/TEN). Blinded review assessed histologic patterns and immunohistochemistry for immunoglobulin G (IgG), Nectin-4, and cytotoxic T-cells.

RESULTS: All cases showed interface dermatitis fitting one of four patterns: classic vacuolar, cytotoxic with epidermal dysmaturation, necrolytic SJS/TEN-like, or spongiotic interface. Epidermal "ring" mitoses were frequent in EV-related biopsies and absent in controls. Intercellular IgG staining occurred in 83% of EV cases versus 20% of controls, yielding an area under the curve of 0.86; any intercellular staining provided 82% sensitivity and 80% specificity, while moderate or strong staining achieved 100% specificity. Cytotoxic T-cell density and Nectin-4 expression did not reliably discriminate groups.

LIMITATIONS: Retrospective design, modest sample size, and potential confounding by concomitant therapies.

CONCLUSION: Intercellular IgG on routine immunohistochemistry, together with characteristic "ring" mitoses, provides a practical framework to identify enfortumab vedotin-associated eruptions and differentiate them from erythema multiforme and SJS/TEN.

Treatment-refractory rheumatoid arthritis (RA) is a major unmet need, and the underlying mechanisms are poorly understood. To identify molecular determinants of refractory RA, we performed spatial transcriptomic profiling on synovial tissue biopsy samples taken 6 months before and after treatment. In the baseline biopsy samples of non-remitting patients, we identified increased fibrogenic signaling within vascular tissue niches, marked by high fibroblast COMP expression. We uncovered a role of endothelial-derived Notch signaling as an upstream regulator of fibroblast transforming growth factor beta (TGFβ) signaling via its opposing ability to induce TGFβ isoform expression while suppressing TGFβ receptors, generating a proximal-to-distal gradient of TGFβ sensitivity that can be altered with disruption of steady-state Notch signaling. In posttreatment biopsy samples, we observed significant immune depletion with expansion of fibrogenic niches, a process that can be reversed by inhibition of Notch and TGFβ signaling in RA patient-derived organoids. Collectively, our data implicate targeting of TGFβ signaling to prevent exuberant synovial tissue fibrosis as a potential therapeutic strategy for refractory RA.

Cachexia is a wasting disorder associated with high morbidity and mortality in patients with cancer. Tumour-host interaction and maladaptive metabolic reprogramming are substantial, yet poorly understood, contributors to cachexia. Here we present a comprehensive overview of the spatio-temporal metabolic reprogramming during cachexia, using integrated metabolomics, RNA sequencing and 13C-glucose tracing data from multiple tissues and tumours of C26 tumour-bearing male mice at different disease stages. We identified one-carbon metabolism as a tissue-overarching pathway characteristic for metabolic wasting in mice and patients and linked to inflammation, glucose hypermetabolism and atrophy in muscle. The same metabolic rewiring also occurred in five additional mouse models, namely Panc02, 8025, ApcMin, LLC and KPP, and a humanised cachexia mouse model. Together, our study provides a molecular framework for understanding metabolic reprogramming and the multi-tissue metabolite-coordinated response during cancer cachexia progression, with one-carbon metabolism as a tissue-overarching mechanism linked to wasting.

Neuroplasticity, the brain's adaptive ability to restructure and reorganize itself, represents one of the most fascinating aspects of the developing brain. Neuroplasticity is maximal during the "first 1000 days" (conception through two years of life), presenting both unique opportunities and vulnerabilities. While neonatal neurology often focuses on the "symptomatic minority" presenting early after birth, there remains an "unrecognized majority" of children who will present with disorders later in childhood. For clinicians working with newborns and young infants, a comprehensive understanding of developmental principles provides the foundation for knowledge to optimize early intervention strategies. This review focuses on the biological basis of neuroplasticity and metaplasticity in the neonatal brain, as well as their role in neurodevelopment. We examine how the "dynamic neural exposome" (the full mix of biological and environmental influences the brain is exposed to over time) and "toxic stressor interplay" (the combined effect of multiple stressors such as pain, infection, and inflammation) influence these processes, often leading to "ontogenetic adaptations" (short-term survival-driven changes in brain wiring that may have long-term consequences). We outline mechanisms shaping early brain development, describe how early experiences and interventions influence outcomes, and emphasize prioritizing prevention over later rescue to improve neurodevelopmental outcomes. IMPACT: The article provides a high-level framework that links the brain's response to experience and injury directly to clinical implications in neonatology, expanding the focus to the "first 1000 days". The effectiveness of interventions hinges on their timing relative to developmental critical and sensitive periods, alongside the dynamic interplay between genetic and environmental influences (including the Maternal-Placental-Fetal triad) on brain development. Neuroplasticity presents both a window for recovery and adaptation, and a susceptibility to adverse experiences, emphasizing the need for evidence-based neuroprotective and neurodevelopmental care that prioritizes preventive approaches to improve long-term outcomes.

BACKGROUND: We describe clinical and biologic characteristics of neuroblastoma in older children, adolescents, and young adults (OCAYA); describe survival outcomes in the post-immunotherapy era; and identify if there is an age cut-off that best discriminates outcomes.

METHODS: Patients diagnosed with neuroblastoma at ≥547 days between 2003 and 2022 from the International Neuroblastoma Risk Group Data Commons were compared by age subgroups. Recursive partitioning, dividing younger versus older at all monthly cut-points between 18 months and 15 years, was undertaken using Cox regression models of event-free survival (EFS), overall survival (OS), and OS post-relapse (OSPR). Kaplan-Meier curves of clinical/biologic subgroups were compared with log-rank tests.

RESULTS: 7,835 patients met inclusion criteria: 18 months to <5 years (n = 5841), 5 to <10 years (n = 1488), 10 to <15 years (n = 357), and ≥15 years (n = 149) at diagnosis. Younger patients were more likely to have MYCN amplification (18 months to 5 years: 31%; 5-10 years: 15%) than older (10-15 years: 8%; ≥15 years: 7%) (p < 0.0001), metastatic disease (p < 0.0001), and high mitosis-karyorrhexis index (MKI) (p < 0.0001) and less likely to have diploid tumors (p < 0.001). Repeatedly dichotomizing the cohort, younger patients had superior EFS and OS (p < 0.05) for all cut-offs ≤40 months (hazard ratios: 1.1-1.3). Among high-risk OCAYA (International Neuroblastoma Staging System [INSS] Stage 4; n = 5005 [64% of cohort]), those diagnosed 2010-2022 had superior EFS/OS versus 2003-2009 in each age group (p < 0.0001). OSPR remained poor for all OCAYA (5-year OSPR 14% ± 0.7%).

CONCLUSIONS: For patients ≥547 days old, any age cut-off ≤40 months discriminated younger (superior EFS/OS) versus older patients; no cut-off was optimal. OCAYA diagnosed 2010-2022 (post-immunotherapy era) had superior outcomes versus 2003-2009. Stratification by comprehensive molecular biomarkers will likely best inform novel therapeutic strategies for OCAYA.

Major depressive disorder (MDD) is a severe and debilitating illness. Despite the available treatments, clinical outcomes remain suboptimal, and hence, it is crucial to identify predictive factors for response. This is a secondary analysis investigating the relationship between treatment preference and response to treatment in the antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) trial (NCT02977299) comparing three treatment arms [aripiprazole augmentation, repetitive transcranial magnetic stimulation (rTMS) augmentation, switching to venlafaxine XR or duloxetine] in MDD patients with treatment-resistant depression (TRD) who are currently on ongoing, stable, and adequate antidepressant therapy. Patient treatment preferences were recorded in the study entry. In total, 278 subjects were randomly assigned to one of three treatment groups: aripiprazole ( n  = 92), rTMS ( n  = 70), or venlafaxine/duloxetine ( n  = 98). Of these 278 subjects, 256 (92.1%) had at least one postbaseline Montgomery-Asberg Depression Rating Scale (MADRS) score and a recorded treatment preference and were included in this secondary analysis. In the total population, participants' preferences did not affect their response to treatment, and the change in MADRS score was similar among patients who received their preferred treatment, had no preference, or received treatment against their preference ( P  = 0.49). These results indicate that patient preference is not a significant factor that predisposes to optimal treatment outcomes.

PURPOSE: Entrustable professional activities (EPAs) detail essential activities within a given specialty. Although 17 general pediatrics EPAs have been defined, it is not known how many are needed to make high-reliability overall entrustment decisions about resident readiness for practice at the time of graduation and initial certification. This study sought to determine how many general pediatrics EPAs are needed.

METHOD: During the 2021 to 2022, 2022 to 2023, and 2023 to 2024 academic years, the authors collected entrustment-supervision levels, determined by clinical competency committees biannually, for the 17 general pediatrics EPAs for residents at 48 U.S. pediatric residency training programs. Midyear reports were collected between November and January of each year, and end-of-year reports were collected between May and July. The authors conducted generalizability and decision studies to determine the number of EPAs needed to make a reliable overall entrustment decision.

RESULTS: A total of 166,077 individual entrustment-supervision levels were collected for 4,250 pediatric residents across the 17 general pediatrics EPAs. Across all data reporting cycles, the authors found that assessing 6 EPAs yields a generalizability coefficient of 0.8 and assessing 12 EPAs yields a generalizability coefficient of 0.9. However, results differed for midyear compared with end-of-year data collection timepoints as well as by postgraduate year. At graduation, 9 to 13 EPAs are needed to make a highly reliable (generalizability coefficient of 0.9) overall decision about degree of entrustment for unsupervised practice.

CONCLUSIONS: This study provides rich insight into the number of EPAs needed to make reliable entrustment decisions about resident readiness to provide patient care. Although readiness can be determined with as few as 9 general pediatrics EPAs (an assessment task), more may be needed to inform a comprehensive curriculum that ensures focus in all areas important to developing general pediatricians during residency training (a curricular task).

PURPOSE: Sleep timing and regularity are associated with various health and performance outcomes, but limited research has investigated the relationship of these sleep dimensions with cancer incidence. The objective of this study was to investigate the associations of sleep midpoint and social jetlag with cancer risk among US adults.

METHODS: The Cancer Prevention Study-3 is a large prospective study of US adults aged 30-65 years. At the first triennial follow-up (2015), participants were asked to report the average time they spent sleeping during a 24-h weekday and weekend, respectively. Sleep midpoint was calculated as the wake time minus half of sleep duration on a weekday and weekend to create a 5:2 weekday:weekend weighted average which was categorized as < 2:30AM, 2:30- < 3:30AM (referent), and ≥ 3:30AM. Social jetlag measures were calculated to estimate the difference in sleep midpoint on the weekend and weekday and categorized as < 1 h (referent), 1- < 2 h, and ≥ 2 h. Cancer incidence was determined via linkage to state registries; follow-up time ended at the time of cancer diagnosis or death or end of follow-up (12/31/2020). We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals adjusted for socio-demographics, socioeconomic status, comorbidities, and lifestyle behaviors.

RESULTS: A total of 5,537 incident cancer cases were reported among 145,386 CPS-3 participants. We found no statistically significant associations of sleep midpoint or measures of social jetlag with overall cancer or breast cancer-specific risk.

CONCLUSION: Our findings suggest no significant associations of sleep midpoint and social jetlag with cancer risk.