Faculty Bibliography

Patients with extremely rare pathogenic variants pose unique challenges to current healthcare systems. Nano-rare mutations have been defined as mutations with a known prevalence of <30 patients worldwide, but because of the small fraction of humans who have undergone genetic testing, neither the precise prevalence of individual mutations nor the total prevalence of patients with nano-rare mutations is known. n-Lorem is a non-profit founded in 2020 with the mission of equitably discovering, developing, and providing bespoke experimental antisense oligonucleotides (ASOs) for free, for life, to patients with nano-rare mutations that are amenable to ASO treatment. In this perspective, we provide an overview of the n-Lorem processes and systems, the characteristics of the first 329 patients who have applied for treatment for whom initial assessment was completed and suitability for ASO treatment determined, and a summary of the results of ASO treatment for patients treated to date. Detailed data on individual patients and the overall clinical safety and tolerability profiles of the ASOs for which there are clinical data are the subjects of other manuscripts.

BACKGROUND:mutations present in more than 90% of cases. Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS. METHODS:G12 and overall populations. Safety was also assessed. RESULTS:G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; the hazard ratios were 0.45 and 0.49, respectively (P<0.001 for both comparisons). Adverse events that occurred after the start of treatment were reported in all the patients in the daraxonrasib group and in 97.7% of those in the chemotherapy group; the incidence of adverse events of grade 3 or higher was 61.8% and 69.6%, respectively. Treatment-related adverse events that led to treatment discontinuation occurred in 1.2% of the patients in the daraxonrasib group and in 11.2% of those in the chemotherapy group. CONCLUSIONS:Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy. (Funded by Revolution Medicines; RASolute 302 ClinicalTrials.gov number, NCT06625320.).

IMPORTANCE/UNASSIGNED:Neighborhood segregation, a mechanism of structural racism, is associated with racial and ethnic disparities in health care access and outcomes. Live donor liver transplant (LDLT) is the ideal treatment for cirrhosis, improving survival and quality of life. Understanding the role of segregation in LDLT access is important to address disparities. OBJECTIVE/UNASSIGNED:To assess the associations between residential and transplant center neighborhood segregation and LDLT access. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study used data from a US national transplant registry on adult candidates (age ≥18 years) for first-time liver transplant between February 1, 2016, and June 30, 2025, at centers that performed 1 or more LDLT annually during that time. EXPOSURE/UNASSIGNED:Residential and transplant center neighborhood segregation, measured using the Thiel H method at the zip code tabulation area level and dichotomized at the respective median values. MAIN OUTCOMES AND MEASURES/UNASSIGNED:A Cox proportional hazards regression model quantified the adjusted hazard ratio (AHR) of LDLT and included interactions with race and ethnicity and insurance. LDLT access within high-segregation residential neighborhoods by racial and ethnic composition (predominantly White or predominantly racial and ethnic minoritized population) was also quantified. RESULTS/UNASSIGNED:Among 22 223 adult liver transplant candidates, mean (SD) age was 55.3 (11.2) years, 13 518 (60.8%) were male, 1476 (6.6%) were Black, 5097 (22.9%) were Hispanic or Latino, and 15 650 (70.4%) were White. Most (11 669 [52.5%]) had private insurance. After adjustment, candidates residing in high-segregation neighborhoods had lower likelihood of LDLT access (AHR, 0.81; 95% CI, 0.74-0.88). Hispanic or Latino candidates in high-segregation neighborhoods had lower likelihood of LDLT access than their counterparts in low-segregation neighborhoods (AHR, 0.59; 95% CI, 0.49-0.72; P < .001 for interaction), but associations between neighborhood segregation and LDLT did not vary significantly by insurance type (P = .52 for interaction). Candidates wait-listed at transplant centers in high-segregation neighborhoods had lower likelihood of LDLT access (AHR, 0.64; 95% CI, 0.59-0.70). Candidates with Medicare or Medicaid wait-listed at centers in high-segregation neighborhoods had lower likelihood of LDLT access than their counterparts in low-segregation neighborhoods (AHR, 0.53; 95% CI, 0.45-0.51; P < .001 for interaction). Within high-segregation residential neighborhoods, candidates in neighborhoods with a larger racial and ethnic population had lower likelihood of LDLT access than those living in neighborhoods with a larger White population (AHR, 0.68; 95% CI, 0.59-0.78). CONCLUSION AND RELEVANCE/UNASSIGNED:In this national cohort study, living in or being wait-listed at centers in high-segregation neighborhoods was associated with lower likelihood of LDLT access and candidates living in high-segregation neighborhoods with a larger racial and ethnic minority population compared with a larger White population had lower likelihood of LDLT. Investing in high-segregation neighborhoods to address these structural disadvantages may help improve equity in LDLT access.

Vertebral metastatic disease results from many types of cancer and can have a devastating impact on patient mobility, psychological health, quality of life, and ultimately overall patient survival. However, the development of radiotherapy and surgical techniques has rapidly surged in conjunction with ongoing advances in basic science and translational studies. In this review, we discuss the paradigm shift in our understanding of the epidemiology and treatment algorithms for spinal oncology, ranging from preoperative optimization strategies, radiation and surgical techniques, the utilization of molecular markers and targeted therapeutics in medical oncology, and prognostication tools that underscore a new multidisciplinary approach to spinal oncology care.

BACKGROUND:Remote patient monitoring (RPM) and telehealth improve hypertension management but remain underutilized in resource-constrained settings. The Advancing Long-term Improvements in Hypertension Outcomes through a Team-based Care Approach (ALTA) intervention integrates RPM and virtual health coaching into routine care across a large urban FQHC network and has improved blood pressure outcomes. OBJECTIVE:Explore contextual and mechanistic factors shaping ALTA's implementation outcomes from the perspective of intervention deliverers. DESIGN/METHODS:Following 1 year of ALTA implementation, we conducted a realist-informed qualitative evaluation to examine factors influencing intervention uptake using semi-structured interviews and focus groups conducted from September to November 2023. PARTICIPANTS/METHODS:Practice leadership, clinicians, and staff. APPROACH/METHODS:Participants were recruited through convenience sampling. Transcripts were analyzed using a stepwise deductive and inductive coding approach. Deductive codes were drawn from Proctor's taxonomy of implementation outcomes. Themes were developed using context-mechanism-outcome (C-M-O) configurations. KEY RESULTS/RESULTS:Analysis of 32 semi-structured interviews and four focus groups with a total of 46 intervention deliverers revealed five primary C-M-O-oriented themes: (1) Appropriateness, determined by perceptions of fit, drives acceptability. (2) Demanding workflows raise concerns around ALTA's additional burden, influencing perceptions of appropriateness. (3) Intervention challenges are mitigated by practice facilitation and team-based problem-solving, enhancing acceptability, feasibility, and fidelity. (4) Repeated exposure promotes workflow optimizations, fostering intervention penetration over time. (5) Staff desire insight into ALTA's impact, and communication about intervention progress increases motivation and buy-in. Five of Proctor's implementation outcomes emerged most prominently: appropriateness, acceptability, feasibility, fidelity, and penetration. Notably, these outcomes were interdependent, with one acting as an important contextual factor or mechanistic element for another. CONCLUSIONS:This evaluation highlights important contextual factors, mechanisms, and interconnected outcomes underlying implementation of ALTA. Shared understanding and peer learning, workflow optimization, and communication of outcomes with frontline staff improve reach, equity, and sustainability of RPM-enabled interventions for hypertension management in FQHCs. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT03713515, date of registration: October 19, 2018, https://classic. CLINICALTRIALS/RESULTS:gov/ct2/show/NCT03713515.

OBJECTIVE:Amnioinfusions in anhydramnios aim to promote fetal lung development, but currently used fluids (Normal Saline [NS], Lactated Ringer's [LR]) fail to mimic the intrauterine environment and increase reactive oxygen species (ROS). We developed a synthetic amniotic fluid (Amnio-well, AW) designed to reduce intrauterine ROS. This study evaluated the pulmonary and gastrointestinal effects of 2 formulations of AW compared with those of NS and LR in a pre-clinical model. METHOD:At gestational age E17.5, pregnant rats underwent amniotic fluid replacement with NS, LR, AW, AW plus epidermal growth factor and transforming growth factor-β (AW++), or sham control. Fetal lungs were harvested at E20.5 for histology, fractional airspace, and blinded pathological evaluation. Surfactant protein (SP-A, SP-B, SP-C) expression and inflammatory gene panels were assessed in lungs and gastrointestinal (GI) tissue. RESULTS:NS and LR lungs demonstrated edema, macrophage infiltration, and reduced airspace (p < 0.001). AW improved SP-B and SP-C relative to control, whereas AW++ suppressed SP-B and SP-C (p < 0.05). Lung gene profiling showed NS/LR induced alterations in histamines, annexins, and immune recruitment, while AW closely resembled control. GI histology was similar across groups, though NS/LR altered TNF, prostaglandin, and adhesion pathways (p < 0.05). CONCLUSION:AW reduced lung inflammation and enhanced surfactant expression compared with NS or LR, with minimal GI effects.

BackgroundThe pathophysiology of CS is complex and is associated with increased inflammation and impaired vascular tone. Corticosteroids are recommended in septic shock and have been proposed as a potential treatment for other types of shock.ObjectivesWe sought to evaluate the clinical outcomes associated with early corticosteroid use in patients with cardiogenic shock (CS).MethodsUsing a nationally representative database including over 1000 hospitals, we identified adults ≥18 years of age admitted from 2015-2023 with a diagnosis of CS. Patients with adrenal insufficiency, chronic rheumatologic conditions, COVID-19 infection and acute COPD exacerbation were excluded. Using inverse probability treatment weighting (IPTW), we assessed for the association of receiving early corticosteroids (within the first 2 days of admission) versus no early corticosteroids and in-hospital mortality.ResultsOf the 167,721 identified patients with CS, the mean (SD) age was 65.5 (±15.2) years and 35.0% were women. A total of 13.2% received any corticosteroid within the first 2 days of admission. The most common corticosteroid was hydrocortisone (73.9%). Mortality for those receiving and not receiving early corticosteroids was 48.8% and 29.6% (p < 0.001), respectively. After IPTW, early corticosteroid use remained associated with a 3.1% (95% confidence interval [CI]: 2.4% to 3.8%, p < 0.001) higher mortality. Among patients with CS and concomitant sepsis, 27.6% received early corticosteroids, which was similarly associated with a higher mortality (weighted mean 5.8% [95% CI: 4.6% to 7.0%, p < 0.001]).ConclusionsApproximately 1 in 7 patients with CS received corticosteroids early during their admission, which was associated with higher in-hospital mortality.

OBJECTIVE:receptor-related epilepsies. Here, we extend these observations with a retrospective observational study evaluating the response to vinpocetine in an additional seven patients. METHODS:Patients initiated treatment with vinpocetine between 2018 and 2025 at the Danish Epilepsy Centre or abroad. Clinical data were collected from medical records, seizure diaries, and neuropsychological assessments. The modulatory efficacy of vinpocetine was investigated using electrophysiological studies. RESULTS:receptor LoF variants were given add-on vinpocetine treatment. Electrophysiological analyses confirmed dose-dependent positive modulation by vinpocetine across tested variants. Six patients with a median age of 15.5 years (range = 6-29) continued treatment for a median of 24 months (range = 12-90), whereas three discontinued due to adverse effects (AEs) or lack of efficacy. The patients' level of function ranged from normal to moderate intellectual disability, psychiatric comorbidities, and behavioral disturbances. Four patients initiated vinpocetine due to uncontrolled seizures. One became seizure-free, and two experienced a 50%-55% reduction. Electroencephalograms demonstrated improved spike-wave indexes in four patients. Six showed improvement in nonseizure factors, and caregivers reported reduced aggressivity and better vocabulary in one. Vinpocetine was well tolerated, with only mild and reversible AEs reported. SIGNIFICANCE/CONCLUSIONS:receptor-related epilepsies, which should be investigated further in future N-of-1 trials.

BACKGROUND AND PURPOSE/UNASSIGNED:Radiotherapy is typically delivered in consecutive equi-dose fractions, but research suggests a non-uniform dose schedule may produce a higher tumor control probability (TCP). We developed an optimization method that automatically constructs the best dose schedule with variable fraction sizes and treatment breaks based on a tumor dose-response model calibrated to head-and-neck squamous cell carcinoma, which captures the impact of cellular resource competition and hypoxia. MATERIALS AND METHODS/UNASSIGNED:We formulated the dose scheduling problem as a finite-horizon optimal control problem. Fraction size was constrained by an upper bound on the biologically effective dose to normal tissue, along with a daily dose limit. This problem is nonconvex, so we employed a heuristic called the convex-concave procedure to solve a sequence of mixed-integer convex approximations that converges to a good estimate of the solution. RESULTS/UNASSIGNED:The optimal schedules adhered to a pattern consisting of an initial "primer shot", followed by a 1 week break, and concluding with six small equi-dose fractions and a final large fraction. The primer shot killed proliferating cells, freeing up resources so hypoxic cells could reoxygenate during the treatment break. These reoxygenated cells are more radiosensitive, therefore the schedule waited until all cells have reoxygenated before delivering its largest dose. In computational experiments, our schedule achieved a 12% higher TCP than the standard equi-dose weekday schedule. CONCLUSIONS/UNASSIGNED:An optimization method was developed to construct non-uniform dose schedules based on a model of tumor dose-response in the presence of hypoxia, yielding significant improvements in TCP.