Citations

Introductory paragraph The extracellular Calcium-sensing receptor (CaSR) regulates cellular responsiveness to physiological changes in ionized calcium (Ca 2+ ) concentrations. The CaSR is expressed in the brain, including in hypothalamic growth hormone stimulating GHRH and anorectic POMC neurons that control growth and energy homeostasis. We embryonically deleted the Casr gene in neurons to create Neuron CaSR -/- mice to delineate the role of this receptor in regulating growth, skeletal development, and energy metabolism. Neuron CaSR -/- mice had reduced size, weight and bone mass compared to littermate controls, with a dysregulated growth hormone axis. They also showed increased adiposity and circulating leptin levels, leptin resistance, and decreased glucose tolerance, along with reduced expression of the anorectic precursor peptide POMC and secondary increases in the expression of the anorectic peptide AgRP in the hypothalamus of Neuron CaSR -/- mice. Knockdown of CaSR in adult mice specifically in the hypothalamic arcuate nucleus, where GHRH, POMC and AgRP neurons reside, also resulted in increased body weight, adiposity, leptin resistance, and glucose intolerance, and reduced bone mass. Together these data suggest that neuronal CaSR critically regulates energy and skeletal metabolism and body growth by modulating hypothalamic function, representing a new paradigm for central integration of calcaemic activities with body function.

Background/Objectives: Recent advances in artificial intelligence (AI) and machine learning (ML) enable targeted optimization of emergency department (ED) operations. We examine how reworking an ED’s vertical processing pathway (VPP) using AI- and ML-driven recommendations affected patient throughput. Methods: We trained a non-linear ML model using triage data from 49,350 ED encounters to generate a personalized risk score that predicted whether an incoming patient is suitable for vertical processing. This model was integrated into a stochastic patient flow framework using queueing theory to derive an optimized VPP design. The resulting protocol prioritized a vertical assessment for patients with Emergency Severity Index (ESI) scores of 4 and 5, as well as 3 when the chief complaints involved skin, urinary, or eye issues. In periods of ED saturation, our data-driven protocol suggested that any waiting room patient should become VPP eligible. We implemented this protocol during a 13-week prospective trial and evaluated its effect on ED performance using before-and-after data. Results: Implementation of the optimized VPP protocol reduced the average ED length of stay (LOS) by 10.75 min (4.15%). Adjusted analyses controlling for potential confounders during the study period estimated a LOS reduction between 7.5 and 11.9 min (2.89% and 4.60%, respectively). No adverse effects were observed in the quality metrics, including 72 h ED revisit or hospitalization rates. Conclusions: A personalized, data-driven VPP protocol, enabled by ML predictions, significantly improved the ED throughput while preserving care quality. Unlike standard fast-track systems, this approach adapts to ED saturation and patient acuity. The methodology is customizable to patient populations and ED operational characteristics, supporting personalized patient flow optimization across diverse emergency care settings.

Background: Autosomal recessive juvenile Parkinson disease (ARJP) is an early-onset neurodegenerative disorder characterized by Parkinsonian motor symptoms with slow progression and preserved cognition. Biallelic pathogenic variants within the PRKN gene are associated with ARJP. Among PRKN pathogenic variants, deletions are a frequent occurrence and may be identified through chromosomal microarray testing. Methods: Here we present a case with two intragenic PRKN deletions initially identified as a secondary finding using chromosomal microarray. One deletion was paternally inherited and the second initially appeared to be de novo. In addition to microarray which initially identified the two deletions, long-range GAP-PCR and Sanger sequencing were used to further characterize the de novo deletion and phase of the deletions. Results: Molecular characterization of the apparently de novo deletion demonstrated low-level maternal mosaicism of this deletion, thus proving that these deletions are in trans in the proband, yielding a diagnosis of autosomal recessive juvenile Parkinson disease. Conclusions: This case highlights the utility of a diagnostic approach combining microarray, long-range PCR, and Sanger sequencing to establish the phase and confirm biallelic PRKN deletions in a patient with ARJP. Furthermore, these findings highlight the importance of investigating the possibility of parental mosaicism to determine the phase of autosomal recessive variants and establish accurate recurrence risks.

Background Endovascular therapy (EVT) for stroke due to distal or medium vessel occlusion (DMVO) is safe. Due to the distinct anatomical characteristics of DMVOs, further evaluation of EVT is crucial to determine which devices may yield better outcomes. Methods A retrospective analysis of adults with DMVO treated in 37 centers (11 countries) was queried. The primary outcome of favorable shift in 90-day modified Rankin Scale (mRS) was compared between patients treated with Trevo versus other devices on first pass using 1:1 propensity score matching (PSM) with multivariable adjustment. Secondary outcomes included the number of pass attempts, final thrombolysis in cerebral infarction (TICI) score 2b-3, symptomatic intracranial hemorrhage (sICH), improvement in National Institutes of Health Stroke Scale (NIHSS) at 24h, and 90-day mortality. Results Of the 1115 included patients, 264 (24%) were treated with Trevo (PSM cohort of 261 per group). Trevo use was not associated with a favorable 90-day mRS shift (proportional odds ratio [OR] 1.10, 95% confidence interval [CI] 0.80–1.51). Trevo was associated with fewer passes (adjusted β=-0.25, 95% CI −0.48 - −0.03), higher odds of TICI 2b-3 (adjusted OR 1.97, 95% CI 1.11–3.49), and a greater 24h NIHSS improvement (adjusted β= −1.74, 95% CI −3.11 - −0.36), with no difference in sICH or mortality (p>0.05). Results were similar in sensitivity analyses. Conclusions We observed no safety concerns with Trevo as compared to other EVT devices for DMVO recanalization. There was a signal of better technical efficacy and early clinical improvement.

Abstract Abdominally based free flaps are commonly utilized in the context of breast reconstruction. Historically, postoperative care of these patients involved liberal amounts of intravenous fluid administration; however, overadministration of fluids puts patients at risk of developing flap edema via fluid shifts, electrolyte imbalances, wound dehiscence, and other sequelae. The purpose of this study is to assess fluid administration trends in this cohort at the authors' institution and assess its impact on patient outcomes. A retrospective review was performed on patients who underwent free-flap breast reconstruction. Patient demographics and hospitalization data were collected, and type of abdominal flap and reconstruction timing was noted. Perioperative fluid administration volumes were tracked, and primary outcomes included complication rate and type (e.g., acute blood loss anemia [ABLA], partial/total flap loss, etc.). Multivariable logistic regression was performed to assess the impact of fluid volume on patient outcomes. A total of 115 patients (mean age of 51.3 ± 10.5 years) underwent 188 abdominally based free flaps. Deep inferior epigastric artery perforator flaps were performed most often (n = 91), followed by muscle-sparing transverse rectus abdominis flaps (n = 88). Multivariable logistic regression demonstrated that high perioperative fluid administration (≥9,000 mL) was associated with increased odds of medical complications (odds ratio [OR] = 21.7; confidence interval [CI]: 5.54–84.5; p < 0.001). Patients with high fluid administration volumes experienced an increased (but nonstatistically significant) flap complication rate (OR = 2.96; CI: 0.89–9.88; p = 0.08) and developed ABLA at a higher rate (OR = 15.86; CI: 5.30–46.4; p < 0.001). High-volume resuscitation (≥9,000 mL) was associated with increased odds of ABLA as well as a greater likelihood of medical and flap complications in patients undergoing abdominally based free flaps for breast reconstruction. These data should be used to guide the development of protocols within institutions, which perform free flaps for breast reconstruction.

ABSTRACTBackgroundPrior studies have documented that patients with colorectal cancer (CRC) are at an increased risk of cardiovascular disease (CVD).ObjectivesTo examine coronary artery calcium (CAC) as a marker of subclinical atherosclerosis and its association with major adverse cardiovascular events (MACE) in patients with CRC across the cancer treatment trajectory.MethodsAdults with newly diagnosed CRC were enrolled in the prospective ColoCare study from 2017 to 2024. CAC was measured from routine diagnostic computed tomography (CT) and positron emission tomography‐CT scans at CRC diagnosis until 5 years post‐diagnosis. Atherosclerosis was defined as the presence of CAC. We used multivariable‐adjusted Fine and Gray models to assess the association between CAC and MACE risk, accounting for competing risks.ResultsAmong 300 CRC patients, the most common CVD risk factors at cancer diagnosis were hypertension (37%), hyperlipidemia (24%), and diabetes (14%). During follow‐up (median = 5.3 years), 75 (25%) individuals experienced MACE: stroke (3%), new/worsening HF (9%), HF exacerbation requiring hospitalization (2%), coronary revascularization (3%), and death (19%). Among individuals with imaging at baseline (n = 101), 37 (36.6%) had CAC, and statins were not prescribed in 11 (55.0%) patients with moderate/high CAC. For those with serial imaging (n = 61), 31.1% showed worsening CAC and 3% developed new CAC. Baseline CAC conferred a higher risk of MACE (HR = 4.79; 95% CI: 1.05–21.75, p = 0.04) after accounting for cancer‐related deaths as a competing risk.ConclusionsSubclinical atherosclerosis and MACE are common among patients with CRC. Integrating CAC from routine cancer imaging can identify patients who may benefit from cardio‐preventive treatment.

Abstract Background. Sarcopenia (i.e. skeletal muscle loss) and physical frailty are significant contributors to adverse clinical outcomes in lung cancer patients. Nutritional intake and physical activity influence skeletal muscle mass and strength. We determined the impact of lung cancer on clinical outcomes in hospitalized patients with sarcopenia, frailty, or sarcopenia+frailty. Design. The Nationwide Inpatient Sample (NIS) (years 2018-2020) from the United States was analyzed to study adult hospitalized patients with a diagnosis of lung cancer. Sarcopenia and frailty were defined by ICD10 codes that have been previously validated. Multivariate regression models were generated to determine the clinical impact of sarcopenia, frailty, or sarcopenia+frailty in patients with a diagnosis of lung cancer as compared to a general medical population (GMP) without lung cancer. Age was restricted to &gt;40 years old for both cohorts because lung cancer is rare in those less than 40 years old. Models were adjusted for age, race, sex, and comorbidities (cardiovascular disease, anemia, coagulopathy, HIV, depression, diabetes mellitus, and COPD). Results. Compared to the GMP (n=126,099), patients with lung cancer (n=241,913) were older (mean+SD age: 69.6+10.0 vs. 67.6+13.3 years, p&lt;0.001), and had a higher prevalence of sarcopenia (22.5% vs 9.0%, p&lt;0.001), frailty (53.4% versus 49.8%, p&lt;0.001), and sarcopenia+frailty (15.3% versus 6.8%, p&lt;0.001). COPD was common and found in 52.3% of lung cancer patients and 20.2% of the GMP. In lung cancer patients, the most common medical reasons for admission were sepsis, pneumonia, and COPD exacerbation. In GMP patients, the most common medical reasons for admission were sepsis, congestive heart failure, and acute kidney injury. In lung cancer patients, frailty had the greatest association with mortality (unadj OR 3.12, 95% CI: 3.02-3.23; adj OR 3.04, 95% CI: 2.91-3.17). Sarcopenia+frailty was most associated with greater healthcare utilization including greater healthcare cost (unadj OR 1.31, 95% CI: 1.29-1.32; adj OR 1.28, 95% CI: 1.26-1.30) and length of stay (unadj OR 1.57, 95% CI: 1.55-1.58; adj OR 1.50, 95% CI: 1.48-1.52). Sarcopenia+frailty were more likely to require additional healthcare facilities upon discharge and were the least likely to be discharged to home (unadj OR 0.32, 95% CI: 0.32-0.33; adj OR 0.35, 95% CI: 0.33-0.36). (see Table 1). Conclusion. While frailty was most associated with in-hospital mortality in lung cancer patients, sarcopenia+frailty was most associated with greater healthcare utilization. Our findings highlight the need to develop targeted interventions to improve clinical outcomes in lung cancer patients with sarcopenia and/or frailty.

Abstract Background. Sarcopenia (i.e. skeletal muscle loss) is a significant contributor to adverse clinical outcomes in patients with COPD. Nutritional intake and physical activity influence sarcopenia and frailty. There is increasing recognition that social determinants of health (SDOH) play critical roles in nutritional status. We evaluated the impact of SDOH on clinical outcomes in hospitalized patients with COPD and sarcopenia and/or frailty. Design. The Nationwide Inpatient Sample (NIS) (years 2018-2020) was analyzed to study adult hospitalized patients with a primary diagnosis of COPD (J43, J44). SDOH was defined by ICD-10 Z-codes as a composite sum of problems related to housing and economic status, unemployment, occupation, psychosocial, family, and healthcare access. Sarcopenia and frailty were defined by a composite of ICD10 codes that have been previously validated in the literature. Multivariate regression models were generated to determine the impact of sarcopenia, frailty, and sarcopenia+frailty on clinical outcomes in COPD patients, which were adjusted for age, race, sex, SDOH, and comorbidities (cardiovascular disease, anemia, coagulopathy, HIV, depression, diabetes mellitus). Results. Of the 282,164 COPD patients that were analyzed, 7254 (2.6%) had codes related to SDOH, 21,035 (7.5%) had sarcopenia, 106,995 (37.9%) had frailty, and 11,293 (4%) had both sarcopenia and frailty. The predominant SDOH code was related to housing (70.9%) followed by social environment (11.5%). SDOH codes were more prevalent in patients with sarcopenia alone (3.6%), compared with frailty (2.5%) or sarcopenia+frailty (2.6%) (p&lt;0.001). When adjusted for demographics including age, race, and sex, SDOH was associated with greater odds of sarcopenia (adj OR 1.64, 95% CI: 1.51-1.79), frailty (adj OR 1.17, 95% CI: 1.11-1.24), and sarcopenia+frailty (adj OR 1.72; 95% CI: 1.54-1.90). COPD patients with sarcopenia+frailty had the greatest association with adverse clinical outcomes (i.e. in-hospital mortality, higher healthcare cost, and higher length of stay), followed by frailty alone, and sarcopenia alone (Table 1). Conclusion. In COPD patients, SDOH increased the odds for a diagnosis of sarcopenia, frailty, and sarcopenia+frailty. Sarcopenia+frailty had the greatest association with adverse outcomes in COPD patients, followed by frailty alone, and sarcopenia alone.

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improve survival, and enhance the quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing has had a significant impact on clinical practice and patient care. Targeted therapies have demonstrated encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. This selection from the NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer highlights recommendations for biomarker testing and discusses updates for the treatment of advanced disease, including peritoneal carcinoma as only disease and unresectable locally advanced, recurrent, or metastatic disease.

Craniofacial surgery requires a multidisciplinary care approach in the perioperative period. In an effort to guide clinical decision making and standardize care, many institutions have implemented craniofacial surgical pathways, describing numerous variables to monitor and specific actions that must be completed by each involved discipline in the perioperative period. Adherence to these pathways can be challenging given the complexity of the protocol and the multiple disciplines involved. In an effort to improve adherence to our institution’s perioperative pathway, the authors implemented a quarterly, multidisciplinary craniofacial operative team meeting to review the pathway and improve the quality of care. The authors report results from a retrospective review of craniosynostosis suturectomy operations at a single site in the 2 years before and 2 years after the start of our team meeting to review perioperative care. A total of 141 operations were included (70 before the meeting and 71 after). Perioperative outcomes and adherence to our surgical pathway were compared. Following the start of our team meetings, there was a significant decrease in the time under anesthesia, patients requiring blood transfusion, and total hospital length of stay ( P <0.05). There was also improved adherence to the craniofacial pathway, with significantly more operations applying peripheral nerve blocks to all locations specified in our pathway with the proper drug contents ( P <0.05). Our findings suggest that craniofacial operative team meetings with a goal of reviewing the surgical pathway and discussing improvements in care plans with all involved providers can significantly improve adherence to operative pathways and surgical outcomes.