Citations

Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs. A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories—“thyroid”, “pituitary and adrenal”, and “diabetes mellitus”. A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements. Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.

Background: Cardiac fibrosis is a central pathological process that leads to worse outcomes in various cardiomyopathies. Recent evidence shows that CDCP1 (CUB domain-containing protein 1) modulates myocardial recovery by attenuating human cardiac fibroblast (HCF) proliferation. This study investigates the hypothesis that selective targeting of the CDCP1 cleavage domain can mitigate fibroblast proliferation, thereby offering a novel therapeutic approach to reducing cardiac fibrosis. Methods: A high-throughput in silico screening was performed using the Enamine compound library, focusing on structural regions that include the cleavage and adjacent sites of CDCP1 . A total of 147 candidate compounds were prioritized based on docking scores and binding stability profiles. Selected compounds were subsequently evaluated in vitro using HCF cultures seeded at 3,000 cells/well in 96-well plates. Each compound was administered at 10 μM concentration, and cell proliferation and viability were assessed by time-lapse imaging in the Incucyte® system at 24 and 96 hours. All experiments were done in triplicate with appropriate DMSO vehicle controls. Results: Compound C3 significantly reduced HCF proliferation (Fig B) to 27.3±2.4% relative to DMSO controls (99.9±0.5%, P <0.001) at 96 hours. Detailed structural modeling indicated that C3 binds to the CDCP1 cleavage site (Fig C) with a favorable Glide XP docking score of -7.66 kcal/mol. The interaction is stabilized by hydrogen bonds with Lys365 and Cys374 (Fig D), and supplementary hydrophobic interactions between aromatic rings and aliphatic groups, which contribute to a strong inhibitory effect. Conclusion: Targeting the CDCP1 cleavage domain with compound C3 effectively diminishes HCF proliferation in vitro. Therefore, these results substantiate the therapeutic potential of CDCP1 inhibition in cardiac fibrosis. Ongoing in vivo studies will explore the translational relevance of these findings.

Abstract Background: Medical education commonly utilizes the “see one, do one” two-step approach for teaching psychomotor skills; however, recent evidence suggests that Peyton’s four-step method leads to superior learning. The effect of Peyton’s four-step method on long term skill retention is less apparent and has never been assessed for Point-of-Care Ultrasound (POCUS). The purpose of this research project was to evaluate the effectiveness of Peyton’s four-step method on teaching the POCUS psychomotor skills of image acquisition to novice learners. Additionally, this research project assessed the influence of Peyton’s four-step method at three different points in time during the skill acquisition phase, in the setting of ongoing deliberate skill practice. Methods: A single-blinded, repeated measures interventional study based on experimental design was completed. PA students from one large academic medical center were randomized into a control group (using the two-step method) and intervention group (using Peyton’s four-step method). Students were taught POCUS of the aorta, bladder, heart, lungs, and kidneys. Students' POCUS skills were assessed during the immediate, intermediate, and delayed learning phases. At each assessment, an organ-specific score and a total score were obtained. Scores were compared using a Wilcoxon rank sum test. An ordinal logistic regression analysis was performed using a generalized linear mixed model with a multinomial distribution and cumulative logit link function to assess overall effect of Peyton's four-step method. Results: Students who were taught using Peyton’s method were found to have an increased likelihood of higher total scores compared to those taught using usual instruction (OR = 4.2, p = 0.003). Peyton’s method was found to have increased likelihood of higher scores for cardiac (OR = 2.3, p = 0.032), lung (OR = 2.5, p = 0.034), and kidney (OR = 3.0, p = 0.015). Student performance statistically improved with Peyton’s four-step method during the immediate (p = 0.031) and delayed (p = 0.011) skill acquisition phases, but not in the intermediate phase. Conclusion: Peyton’s four-step method improves overall psychomotor skill acquisition for POCUS. Peyton’s four-step method specifically improved psychomotor skills in the immediate skill acquisition phase and the delayed skill acquisition phase. The benefit of Peyton’s four-step method was more prominent in higher complexity POCUS applications.

Background: Housing instability and HIV are both associated with early onset of aging-related health conditions, including frailty. However, little is known about the relationship between housing and frailty among people with HIV. Methods: We analyzed data on adults in HIV care collected during routine clinical visits at 6 sites within the US Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) between 2019 and 2024. We measured frailty using a previously validated approach, defined as having at least three of four components (fatigue, weight loss, immobility, inactivity) vs. less than three components. Housing status was based on self-perceived living situation in the past month (“Stable,” “Unstable,” “Homeless,” or “Don’t know”). We estimated the association between most recent housing status and frailty with prevalence ratios from relative risk regression adjusted for sociobehavioral and clinical characteristics. Results: Among 6961 people with HIV (84% men, 16% women) with a median age of 52 years (IQR: 40–60), 11% ( n = 760) were frail and 9% ( n = 625) were unstably housed (5% unstable, 3% homeless, 1% do not know). Compared to individuals with stable housing, the prevalence of frailty more than doubled among those experiencing unstable housing [prevalence ratio = 2.41, 95% confidence interval (95% CI): 1.95–2.97] or homelessness (prevalence ratio = 2.05, 95% CI: 1.56–2.69). Stratified analyses indicated stronger associations among younger vs. older individuals and among those virally suppressed vs. unsuppressed. Conclusion: Housing instability and frailty were both prevalent and strongly associated among adults in HIV care, including within younger and virally suppressed subgroups. These findings highlight the importance of social determinants of health for clinical outcomes among all people with HIV.

Abstract Background The COVID-19 pandemic magnified longstanding racial and ethnic disparities in pediatric health, but it is unclear which populations experienced the largest disparities. Our objective was to determine whether disparities in COVID-19 severity differed with respect to patient factors analyzed as effect modifiers. Methods Using data from the Premier Healthcare Database, this retrospective cohort study included encounters among inpatients &lt; 19 years old from April 2020 through September 2022 in the USA with a COVID-19 diagnosis. Outcomes of COVID-19 severity were intensive care unit (ICU) admission and ventilator use. Comparisons between Black and White patients and Hispanic and White patients were adjusted for confounders using propensity score weights, reported as risk differences (RDs) in percentage points, and tested for heterogeneity (interaction P) across subgroups of effect modifiers such as complex chronic conditions (CCCs) and insurance status. Results Of 8947 pediatric inpatients with primary COVID-19 diagnosis, 3858 were White, 2153 were Black, and 2936 were Hispanic. Among children with a CCC, 14.3% of Black inpatients required a ventilator compared to 9.8% of White inpatients; among children without a CCC, 3.2% of both Black and White inpatients required a ventilator (RDs 4.5 vs 0.0; interaction P = .013). Comparisons of Hispanic and White inpatients showed a similar trend in ventilator use, with larger disparities among inpatients with CCCs and no difference among those without CCCs (RDs 2.7 vs −0.7; interaction P=.031). Among children with government insurance, 25.9% of Black inpatients were admitted to the ICU compared to 20.8% of White inpatients; among children with private insurance, Black and White inpatients had comparable ICU admission rates of 20.0% and 21.4%, respectively (RDs 5.1 vs −1.4; interaction P = .025). Conclusions Among hospitalized children, racial and ethnic disparities in COVID-19 severity were largest for those with CCCs or government insurance. These results can help identify target populations for interventions to reduce inequity.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Abstract Objective To share findings of a quality improvement initiative to capture employment status in the electronic medical record (EMR) to mitigate the potential impact of work loss on the health of patients by utilizing the results to identify eligible individuals for resources to assist return-to-work efforts. Materials and Methods Patients self-identified employment status through a structured new social determinants of health (SDOH) question within the EMR. An electronic outreach campaign was developed to provide information via the patient portal detailing services within healthcare and the community that could benefit the patients. Results Over the course of 12 months, 2059 patients were identified from the employment SDOH question. Resources to support stay at work and return to work efforts were provided to patients through an automated electronic portal campaign with 87% of patients reading the message and 7% engaging with a healthcare return to work case manager. Discussion Loss of employment has detrimental impacts on individual and population health. Most EMRs do not capture information on employment status. Adding this simple question identified individuals with potential gaps in SDOH, and in this case allowed specific resources to be shared with patients with an illness or injury that was acutely impacting work. Conclusion Medical center decision makers and EMR programmers should consider adding employment status as a social determinant of health.

Background: Variable terminology is used in the literature to describe facial synkinesis and hypertonicity following incomplete recovery from facial paralysis and its associated medical and surgical treatments. Study Objectives: Establish a nomenclature consensus for this condition among a group of facial nerve experts. Design Type: Consensus study. Methods: Using modified Delphi methodology, an international, multidisciplinary group of facial nerve experts reviewed the terminology for the name of the clinical condition and treatments of interest. Online surveys and a virtual discussion were performed to establish consensus, defined a priori as agreement by 80% of the group. Results: Twenty-five facial nerve experts established consensus after three Delphi rounds. Consensus terminology for the condition is “facial synkinesis” with 84% agreement. Medical treatment is termed “chemodenervation” with 100% agreement. Surgical treatments including “selective facial neurectomy,” “selective facial neurotomy,” “selective facial myectomy,” and “selective facial myotomy,” were defined and reached agreement of 100%. Conclusions: This international group of facial nerve experts has recommended standardized nomenclature for the condition of facial synkinesis and its various treatments. While “facial synkinesis” reached consensus as the preferred term, some experts noted it may insufficiently describe the full clinical spectrum, which includes muscle hypertonicity, weakness, and spontaneous twitching.

Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS -mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.