Faculty Bibliography

Persons with disorders of consciousness (DoC) occupy an ethically charged space in modern medicine and biomedical research. Their decisional capacity is characteristically absent or limited or unpredictably fluctuates, requiring clinicians and investigators to rely on surrogates. Although there is general guidance for informed consent (IC) for research studies, there is no specific guidance for research involving persons with DoC. There are inconsistencies in IC forms for these studies related to explanation of a DoC, evaluation of capacity, description of risks/benefits, and sharing investigational results. This is problematic for persons with DoC, their surrogates, researchers, and institutional review boards (IRBs)/research ethics boards (REBs). To address these issues, the Curing Coma Campaign (CCC) Ethics Workgroup developed the Common Consent Elements for Research Involving Persons with Disorders of Consciousness (CCE-DoC). This practical framework aims to clarify and standardize consent processes in this complex and ethically sensitive research area. Through this structured, adaptable approach, CCE-DoC may have the potential to enhance participant protections, strengthen trust, help families and decision-makers understand studies, reduce duplicative efforts across research groups, and guide investigators and IRBs/REBs in navigating the complex ethical terrain of consent in DoC research. In so doing, CCE-DoC seeks to extend respect for autonomy and trust and promote responsible research urgently needed to advance paradigms of diagnosis, prognosis, and treatment for individuals with disorders of consciousness. The framework offers example language to encourage standardization, while allowing teams flexibility to customize to local needs.

While attention-deficit/hyperactivity disorder (ADHD) medications, particularly stimulants, are among the most effective treatments in psychiatry, there remains a need for novel alternatives, as not all individuals with ADHD respond to or tolerate currently available medications. We aimed to provide an up-to-date overview of randomised controlled trials (RCTs) of agents either not approved for ADHD or approved for ADHD but tested for off-label indications. We updated, using the same methodology, two previous reviews (Cortese et al, 2023 exploring agents in the pipeline for children with ADHD, and Veronesi et al, 2024, focusing on RCTs of novel compounds in adults with ADHD). For the update, we searched ClinicalTrials.gov and the European Union-based EU Clinical Trials registers up to December 14, 2025. Including the RCTs retrieved by the two previous reviews and those from the updated search, we identified a total of 53 eligible RCTs. Of these, 11 reported results in children and adolescents, and 11 in adults. Considering agents with at least two positive trials for ADHD core symptoms without negative trials, only dasotraline, in children, and centanafadine, in adults, emerged as promising (however, the dasotraline development programme was halted in 2020). This review also includes a discussion of opportunities for advancing the development of novel, effective agents and maximising the benefits of currently available options.

OBJECTIVE:Leveraging large language models (LLM), we identified an unregistered subpopulation of individuals with World Trade Center-related exposure and lung cancer who were not previously captured in registries, and assessed how this exposure impacted patients' disease course. METHODS:Associations between exposure type and smoking history, cancer stage, mutation status, disease progression, and survival were statistically analyzed. RESULTS:The highest proportion of never-smokers was observed among residents, compared to first responders and commuters (19% and 24%; p = 0.005). Residents had more than twice the risk of disease progression (HR = 2.14, p = 0.008) and an elevated risk of death (HR = 2.43, p = 0.03). Only EGFR mutations were significantly associated with exposure type (p = 0.01). CONCLUSIONS:This work highlights that LLM can capture a greater population of WTC survivors, including genetics.

INTRODUCTION/BACKGROUND:Many children with abdominal pain-associated disorders of gut-brain interaction (AP-DGBI) have meal-related symptoms. The aim of the current study was to determine if meal-related symptoms defined specific mutually exclusive subgroups (classes) and, if so, whether these relate to other pathophysiologic factors. METHODS:Between 2020 and 2022, 289 children with AP-DGBI completed questionnaires evaluating gastrointestinal symptoms, psychosocial variables (e.g., somatization), and health-related quality of life (HRQoL). Latent class analysis (LCA) evaluated symptom patterns using 10 gastrointestinal symptoms, while univariable latent class regression (LCR) analyzed associations with covariates. KEY RESULTS/RESULTS:Three latent classes emerged: Class 1 (characterized by low meal- and stool-related symptom burden, 35.0%), Class 2 (exhibiting meal-related symptoms, 32.2%), and Class 3 (manifesting meal- and stool-related symptoms, 32.8%). Compared to Class 1, odds of belonging to Class 2 were significantly associated with increasing age, female sex, and lower HRQoL in physical and school functioning. Compared to Class 1, odds of belonging to Class 3 were similarly associated with increasing age, female sex, somatization, and with reduced HRQoL in physical, social, and psychosocial domains. There were no group differences with respect to depression, social stress, or anxiety. CONCLUSIONS AND INFERENCES/CONCLUSIONS:In youth with AP-DGBI, three distinct phenotypic groups are identified. Two of these distinct groups experience meal-related symptoms: one with associated bowel symptoms and the other without. These two meal-related symptom groups are associated with increasing age, female sex, somatization, and reduced HRQoL (particularly physical). These findings underscore the distinctness and importance of identifying the drivers of meal-related symptoms in children with AP-DGBI.

OBJECTIVES/OBJECTIVE:To explore whether the addition of very low-dose recombinant activated factor VII (rFVIIa) to 4-factor prothrombin complex concentrate (4F-PCC) increases postoperative thromboembolic events in patients undergoing orthotopic heart transplantation (OHT) complicated by severe coagulopathy. DESIGN/METHODS:Single-center, retrospective cohort study. SETTING/METHODS:Tertiary academic medical center in Boston, Massachusetts. PARTICIPANTS/METHODS:Adults (aged ≥ 18 years) who underwent OHT between January 1 and December 31, 2023, and received 4F-PCC, with or without rFVIIa, for perioperative coagulopathy. INTERVENTIONS/METHODS:Patients received either combination therapy with 4F-PCC and very low-dose rFVIIa (<20 μg/kg) or 4F-PCC monotherapy. MEASUREMENTS AND MAIN RESULTS/RESULTS:The primary outcome was the incidence of thromboembolic events within 30 days postoperatively or until discharge, whichever occurred first. Secondary outcomes included intraoperative transfusion requirements, perioperative hemostatic agent use, delayed chest closure due to coagulopathy, reoperation for bleeding, 12-hour chest tube output, 24-hour transfusion requirements, and in-hospital mortality. Among 56 patients, 15 received combination therapy with 4F-PCC and rFVIIa while 41 received 4F-PCC monotherapy. Thromboembolic events occurred in 53.3% of the combination group and 34.1% of the monotherapy group (p = 0.32). CONCLUSIONS:The addition of very low-dose rFVIIa to 4F-PCC during OHT demonstrated a non-statistically significant increase in thrombotic events. As this was a single-center cohort study with a relatively small number of patients and an inability to control for severity of illness, these findings should be regarded as exploratory for future studies.

Gastroparesis is a chronic gastrointestinal disorder characterized by delayed gastric emptying, often presenting with symptoms including nausea, vomiting, early satiety, and abdominal pain. Moreover, studies demonstrate higher rates of psychological distress among individuals with gastroparesis, compared with the general population; increasing evidence suggests that anxiety and depression contribute to symptom severity, reduced quality of life, and poorer treatment outcomes. Potential mechanisms underlying this seeming association include dysregulation of the gut-brain axis and the psychosocial burden of living with a chronic illness. Thus, this contemporary, mini review aims to integrate some current literature on the prevalence, pathophysiology, and clinical implications of anxiety and depression in patients with gastroparesis.

Pediatric moderate aplastic anemia (MAA) lacks defined diagnostic criteria and a clear standard of care due to limited understanding of its pathophysiology and natural history. To understand current diagnostic and management practices for pediatric patients with MAA, a survey of the North American Pediatric Aplastic Anemia Consortium (NAPAAC) was conducted among 104 providers across 57 institutions. The survey results show that the approach to MAA remains inconsistent. The survey demonstrates broad variability regarding the working definition, diagnostic work-up, and therapeutic management of children with MAA. The diagnostic work-up and treatment options for children with MAA are largely driven by management guidelines for pediatric severe aplastic anemia (SAA). Treatment triggers and preferred therapy types varied widely among respondents. Curated next-generation sequencing panels and whole exome/whole genome sequencing were included by only 55% and 9% of respondents, respectively, suggesting the need to more broadly consider inherited bone marrow failure syndromes in the differential diagnosis of these patients. Based on the most commonly reported practices across NAPAAC institutions, we have included a proposed diagnostic and management algorithm in this manuscript. Effective, risk-adapted treatment for children with MAA requires a better understanding of the biology, natural history, and treatment outcomes in this heterogeneous population.

There is a lack of consensus in the field about the indefinite use of psychostimulants for adult ADHD and the circumstances under which their deprescribing warrants consideration. To address this gap in knowledge, the American Society of Clinical Psychopharmacology (ASCP) convened a Task Force on the deprescribing of psychotropic medications, including stimulant medications for adult ADHD, which entailed a focused literature review and 2-round Delphi survey querying 45 international psychopharmacology experts on factors related to deprescribing. Consensus (≥75% agreement, defined by endorsements of "strongly agree" or "moderately agree") was reached on 10 of 11 (91%) Delphi statements. Survey responses plus literature review suggest that stimulant deprescribing may be appropriate when 1) the diagnosis of ADHD is deemed incorrect upon reevaluation unless another stimulant-responsive condition is evident; 2) cognitive complaints have other more likely etiologies for which stimulant medications are inappropriate; 3) cognitive benefits are absent; 4) stimulant medications exacerbate medical or other psychiatric comorbidities; 5) adverse effects, if present, are non-remediable; 6) stimulant medications are misused; and 7) untreated comorbid non-cannabis substance use disorders are present. Panelists just fell short of consensus in perceiving regular use of cannabis as an insufficient reason to deprescribe stimulant medications in adult ADHD patients. In sum, clinical circumstances and rationales can be identified that support decisions to deprescribe stimulant medications for adult ADHD. Deliberate stimulant misuse or abuse, comorbid medical or psychiatric contraindications, and diagnostic inaccuracy pose strong reasons to consider deprescribing stimulants, potentially in favor of alternative pharmacotherapies and psychotherapies for adult ADHD.

Quasisymmetric icosahedral viral capsids achieve larger sizes than possible with strictly symmetric icosahedra by tessellating pentagons and hexagons using a single subunit that adopts different conformations in symmetrically non-equivalent locations^1,2. Recapitulating such quasisymmetric architectures through computational design is a considerable challenge in nanomaterials engineering. Here we introduce a computational design strategy based on geometric frustration to generate two-component, quasisymmetric protein cages with customizable properties. We designed complementary trimeric and dimeric protein components that co-assemble into positively curved local hexagonal assemblies. Hexagonal lattices cannot tile spherical surfaces; instead, the components form closed sphere-like cage assemblies through incorporation of curvature-inducing pentagonal defects, as evidenced by electron microscopy. By designing dimers that encode different local curvatures, we programmed cage dimensions ranging from 40 to over 200 nm in diameter and with molecular weights from 2 MDa to over 50 MDa, comparable with natural virus capsids. We further functionalized these large cages with additional protein domains to enable ribonucleoprotein cargo loading and cellular uptake. Fluorescently labelled cage assemblies expressed in mammalian cells function as rheological probes and cargo recruiters, enabling a systematic study of size-dependent cytoplasmic diffusion and protein localization. Thus, the quasi-symmetry that has long fascinated structural biologists can now be achieved by computational protein design, with immediate applications to biologics delivery and molecular cell biology.