Citations

Abstract Background: Endocrine therapies remain central to estrogen receptor alpha-positive (ERα+) breast cancer treatment, yet their predominantly cytostatic effects highlight the need for combinatorial approaches that promote tumor cell death. We therefore tested BH3 mimetics as single agents and in combination with (Z)-endoxifen (ENDX) across endocrine sensitive and endocrine resistant ERα+ breast cancer models. Methods: Six BH3 mimetics were tested in MCF7 and T47D cells and matched ENDX-resistant and fulvestrant-resistant derivatives. ENDX combinations were assessed using 2D proliferation and synergy assays, 3D RASTRUM® bioprinted cultures, migration assays, and in vivo MCF7 xenograft studies. Results: BH3 mimetics showed broad anti-proliferative activity as single agents in endocrine sensitive and resistant models. ENDX combinations were predominantly additive in 2D assays, with limited synergy confined to specific dose windows. In 3D culture, selected combinations of an MCL1 inhibitor (MCL1i) or navitoclax with ENDX produced greater suppression than single agents and, in several conditions, reduced growth below baseline, consistent with loss of viability. Combination treatment also enhanced suppression of migration under select concentrations. In MCF7 xenograft studies, ENDX robustly suppressed tumor growth; however, adding MCL1i or navitoclax did not provide additional antitumor benefit at the doses, schedules, and timeframes tested. Conclusion: BH3 mimetics show activity in ERα+ breast cancer models in vitro , including endocrine resistant models. Although ENDX combination benefit did not translate in vivo under the conditions tested, these data support further study of optimized BH3 mimetic combinations, including evaluation of dose, ratio, schedule, tumor target engagement, and other clinically advanced agents.

Background The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. Methods We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC‐PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation‐free survival across the new PH clusters. We quantify metabolites of the arginine‐nitric oxide pathway and D‐dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. Results Clustering analysis identify 3 clear clusters in CC ‐ PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation‐free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D‐dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. Conclusions We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Background: We had a large-scale measles exposure event affecting 626 patients. Management of exposed patients was urgent, involving quarantine, post-exposure prophylaxis (PEP), and symptom monitoring on a case-by-case basis. Cases were initially tracked and managed using a combination of multiple spreadsheets amongst stakeholders as well as lists within the electronic health record (EHR). Using shared spreadsheets and lists created significant challenges with maintaining and editing multiple copies and updating workbooks simultaneously. Methods: Infection Prevention and Control (IPAC) worked with primary care personnel and EHR developers to create a shared registry that would prioritize communication and follow-up for exposed patients based on age and immunity. Patients are initially added to the shared registry within the EHR by reviewing non-registry reports and tagging patients, identified using exposure timeframes that overlapped with the index measles cases, in a manner that transferred them to the shared registry. From this registry, measles, mumps, and rubella vaccine status can be confirmed, immune status can be identified, and criteria for PEP assigned. High-risk patients are then contacted with recommendations from IPAC and primary care. Communication and follow-up are tracked directly within the shared registry to ensure appropriate patient management. The exposure management registry is further leveraged throughout the measles outbreak timeframe by allowing real-time monitoring of patients that require additional precautions or guidance related to their exposure. Result: The shared registry enhanced documentation accuracy and transparency between stakeholders. It led to availability of real-time status of exposed patients for the duration of the measles outbreak timeframe. Overall, the registry enabled time-sensitive patient communication to all exposed patients and rapid identification of those who needed PEP. Communication could happen rapidly and seamlessly between care teams within the organization, and the necessary information could be shared quickly with public health authorities as required. Conclusion: Large scale exposures are a challenge to manage and ensure appropriate action and communication occurs. Errors can be prevented by having a single shared exposure management registry. A registry enables care teams to quickly identify and prioritize patients for measles follow-up, communication, PEP, and ongoing management across outbreak timeframes. This process reduces both time and operational burdens of exposure follow-up tracking outside of the EHR.

Background: Measles is a highly transmissible virus. A single case can result in significant exposures within a healthcare facility and prompt action is needed to prevent secondary cases. In October 2025, Infection Prevention and Control (IPAC) was notified of a patient being admitted to our facility with recent international travel and symptoms consistent with measles. The patient was unvaccinated and had five healthcare facility visits prior to measles being suspected and subsequently confirmed. Objective: To describe our facility’s effective identification, prioritization, and prophylaxis of individuals exposed to measles. Methods: IPAC leveraged the electronic medical record to identify potentially exposed patients. Patients were quickly assessed for age and immune status, then prioritized and assigned to primary care teams. These teams promptly contacted patients and coordinated PEP administration. Results: Across five encounters, the index patient exposed 539 other patients. Due to delayed notification, our teams had less than four days to administer PEP for those exposed and still within PEP window. PEP administration began within hours of the index case’s positive test and patients received PEP within three days (Table 1). No secondary measles cases occurred within our facility. Conclusion: Timely and coordinated multidisciplinary effort enabled us to rapidly respond to our first measles case and control secondary transmission. Although the index case resulted in a large exposure, patients that were exposed and eligible for PEP were quickly prioritized to prevent secondary transmission.

Background: Advanced planning and adaptable response strategies are essential for preventing measles transmission in healthcare facilities. Objective: To describe a measles management plan and subsequent modifications in response to a cluster of measles cases. Methods: Drawing on previously published work (doi:10.1017/ice.2025.49), the Infection Prevention and Control (IPAC) team initiated a multi-disciplinary team and developed a measles preparedness plan with the following domains: Guidance and education; early detection and testing; isolation and patient movement; contact tracing and exposure management (Table 1). In October 2025, a patient was admitted during their fifth healthcare encounter and was diagnosed with measles. Two family members were later hospitalized with measles. Delayed recognition of the first case prompted enhancements to our preparedness framework (Table 1). Results: The first case resulted in 539 exposed patients. The second resulted in 87 exposures, and the third resulted in no exposure. Despite the extensive exposure, zero secondary measles were reported. Conclusion: Proactive planning enabled rapid response to our first case and controlled secondary transmission. Despite extensive planning, delayed identification of the first case caused significant exposures. As the cluster unfolded, we refined our plan, resulting in zero exposures from the last patient and zero secondary cases, despite over 850 exposures. These efforts may guide other healthcare facilities in improving their measles preparedness and response.

Background: In 2025, 50 measles outbreaks drove 87% of confirmed cases reported in the United States. As a highly infectious virus with an estimated R ranging from 12-18, we sought rapidly scalable and implementable measles preparedness measures for our facilities. Methods: The electronic health record (EHR) has flags that can be placed on patient records to denote the presence of, or concern for, active, transmissible infections. These flags are highly visible in the EHR and represent a good usability heuristic as front line providers are already trained to look for this information. Infection Prevention and Control (IPAC) worked with nursing informatics to develop measles-specific flags for suspected, confirmed and exposed patients in the EHR, expanding flagging functionality in preparation for potential measles cases and exposures. The flagging was tied to registry functionality to allow for tracking of exposed and confirmed cases longitudinally for supporting IPAC investigations in addition to clinical operations. Results: Three different flags were developed in the EHR to address measles. Specific criteria were created for each flag, as shown in Table 1. Table 1: Attached as Image Conclusion: As a highly contagious virus, measles presents unique challenges to healthcare facilities managing both cases and exposures. Measles flags within the EHR can be leveraged to assist facilities with case tracking, exposure management, and infection prevention and control.

ABSTRACT This study aims to develop MRI‐based 3D statistical shape models for patellar dislocation patients and investigate bone shape features that distinguish between single and recurrent dislocation populations, as well as control and patellar dislocation populations. MRIs from 16 single dislocation patients, 17 recurrent dislocation patients, and 20 control subjects were used to build statistical shape models for femur and patella bones. Bone shape features were extracted and tested for statistical significance ( p < 0.05) for distinguishing the single dislocation group from the recurrent dislocation groups, and the control group from the dislocation group. Statistically significant shape features distinguishing the three groups were identified for both bones. A shallower trochlear groove and smaller patellar ridge told the dislocation groups apart from the control group. A prolonged lateral condyle in femur and a laterally shifted ridge and hood shaped lateral facet in patella distinguished the recurrent dislocation group from the single dislocation group. The study's findings from 3D statistical shape modeling of the femur and patella reveal distinct anatomical differences across control, single dislocation, and recurrent patellar dislocation groups. This advanced understanding aids in identifying individuals at higher risk for initial or recurring patellar dislocations, enabling clinicians to tailor treatment and management strategies more effectively to prevent further dislocations and mitigate potential patellofemoral joint damage.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Abstract Context Biochemical test results are central to clinical decision-making for the diagnosis and management of Cushing syndrome (CS). With emerging research and increasing availability of different tests, updated consensus on the utility of these biomarkers is warranted. Objective To establish an updated consensus on the role of biomarkers in the diagnosis and monitoring of adrenocorticotropic hormone-dependent CS, address novel therapeutic approaches, and identify areas for future research. Design A modified 2-round Delphi panel was conducted. Consensus was defined as ≥70% agreement/disagreement for Likert-scale statements or ≥70% selection of the same option for single-choice questions. Setting Participants represented a range of international expertise. Participants Forty-one participants took part in the Delphi panel, with no attrition between rounds (one nonclinician was not required to complete the second round). An 8-member Steering Committee guided statement development. Results Of statements designed to reach consensus, 45% (14/31) and 44% (11/25) statements reached consensus in Rounds 1 and 2, respectively. Notably, most panelists reported the use of late-night salivary cortisol for diagnosis of mild CS and for monitoring following pituitary surgery or medical or radiation therapy. Most panelists responded that block-and-replace therapies can be considered in patients with cyclical or severe CS, and consensus was reached that restoration of circadian rhythm is a treatment goal for patients with CS. Conclusion Areas of alignment among experts on the diagnosis and monitoring of CS are presented. The findings from this study are intended to support clinicians in their clinical decision-making and highlight priority areas for future research.