Global prevalence of claudin 18 isoform 2 in tumors of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma.

BACKGROUND: Limited data exist for global prevalence of claudin 18 isoform 2 (CLDN18.2) positivity and association of CLDN18.2 status with clinical and tumor characteristics in patients with locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. We report prevalence of CLDN18.2 positivity (phase 3; SPOTLIGHT, NCT03504397; GLOW, NCT03653507) and concordance of CLDN18.2 status between a subset of pair-matched tumor samples (phase 2, ILUSTRO, NCT03505320; phase 1, NCT03528629) from clinical studies of zolbetuximab. METHODS: Tumor samples from patients with LA unresectable or mG/GEJ adenocarcinoma were tested for CLDN18.2 status by immunohistochemistry. Human epidermal growth factor receptor 2 (HER2) expression was tested per central or local assessment. RESULTS: Across SPOTLIGHT and GLOW, the prevalence of CLDN18.2 positivity (≥ 75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 38.4%. Prevalence was similar in gastric versus GEJ adenocarcinoma samples and regardless of collection method (biopsy versus resection) or collection site (primary versus metastatic). CLDN18.2 positivity was most prevalent in patients with diffuse-type tumors. In ILUSTRO and the phase 1 study, concordance of CLDN18.2 positivity was 61.1% between archival (i.e., any time before treatment) and baseline (i.e., ≤ 3 months before first treatment) samples, and concordance of any CLDN18 staining (≥ 1% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining) was 88.9%. CONCLUSIONS: CLDN18.2 was a highly prevalent biomarker in patients with HER2-negative, LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 positivity remained relatively stable over time in many patients. Biomarker testing for CLDN18.2 should be considered in standard clinical practice in these patients.

Structural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan.

The human cytochrome P450 (CYP) 1, 2 and 3 families of enzymes are responsible for the biotransformation of a majority of the currently available pharmaceutical drugs. The highly polymorphic CYP2C9 predominantly metabolizes many drugs including anticoagulant S-warfarin, anti-hypertensive losartan, anti-diabetic tolbutamide, analgesic ibuprofen, etc. There are >80 single nucleotide changes identified in CYP2C9, many of which significantly alter the clearance of important drugs. Here we report the structural and biophysical analysis of two polymorphic variants, CYP2C9*14 (Arg125His) and CYP2C9*27 (Arg150Leu) complexed with losartan. The X-ray crystal structures of the CYP2C9*14 and *27 illustrate the binding of two losartan molecules, one in the active site near heme and another on the periphery. Both losartan molecules are bound in an identical conformation to that observed in the previously solved CYP2C9 wild-type complex, however, the number of losartan differs from the wild-type structure, which showed binding of three molecules. Additionally, isothermal titration calorimetry experiments reveal a lower binding affinity of losartan with *14 and *27 variants when compared to the wild-type. Overall, the results provide new insights into the effects of these genetic polymorphisms and suggests a possible mechanism contributing to reduced metabolic activity in patients carrying these alleles.

Zolbetuximab plus chemotherapy for locally advanced unresectable or metastatic stomach or gastroesophageal junction cancers: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of two articles. The first article is about a clinical trial called SPOTLIGHT and it was published in the medical journal The Lancet in in April of 2023. The second article is about a clinical trial called GLOW and it was published in the medical journal Nature Medicine in July of 2023. WHAT ARE THE KEY TAKEAWAYS?: Until recently, chemotherapy was the first treatment given to people with stomach cancer or gastroesophageal junction (or GEJ) cancer that is locally advanced unresectable or metastatic. When cancer cells have high amounts of the protein CLDN18.2 but do not have high amounts of the protein HER2, the cancer is known as CLDN18.2-positive (or CLDN18.2+) and HER2-negative (or HER2-). New medicines to treat cancer are being developed. These medicines attach to proteins on cancer cells to help the body recognize and kill cancer cells.The clinical trials SPOTLIGHT and GLOW included participants with CLDN18.2+ and HER2- stomach or GEJ cancer that was locally advanced unresectable or metastatic. These trials looked at whether adding a medicine called zolbetuximab to chemotherapy as the first treatment for cancer helped people live longer before their tumors grew bigger or new tumors grew, after starting the trial. These studies also looked at whether adding zolbetuximab to chemotherapy helped people live longer after starting the trial. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: In SPOTLIGHT and GLOW, on average, participants assigned to zolbetuximab plus chemotherapy lived 1.4 to 1.9 months longer before their tumors grew bigger or new tumors grew, after starting the trial, than participants assigned to a placebo plus chemotherapy. On average, participants assigned to zolbetuximab plus chemotherapy also lived 2.2 to 2.7 months longer, after starting the trial, than participants assigned to a placebo plus chemotherapy. These results suggest that zolbetuximab plus chemotherapy could be a new first treatment for people with CLDN18.2+ and HER2- stomach or GEJ cancer that is locally advanced unresectable or metastatic.Clinical Trial Registration: NCT03504397 (SPOTLIGHT); NCT03653507 (GLOW).

The clinical trials SPOTLIGHT and GLOW showed that, on average, participants with stomach or GEJ cancer assigned to zolbetuximab plus chemotherapy lived 2.2 to 2.7 months longer than participants assigned to a placebo plus chemotherapy.

Call me Dr Ishmael: trends in electronic health record notes available at emergency department visits and admissions.

Objectives: Numerous studies have identified information overload as a key issue for electronic health records (EHRs). This study describes the amount of text data across all notes available to emergency physicians in the EHR, trended over the time since EHR establishment. Materials and Methods: We conducted a retrospective analysis of EHR data from a large healthcare system, examining the number of notes and a corresponding number of total words and total tokens across all notes available to physicians during patient encounters in the emergency department (ED). We assessed the change in these metrics over a 17-year period between 2006 and 2023. Results: The study cohort included 730 968 ED visits made by 293 559 unique patients and a total note count of 132 574 964. The median note count for all encounters in 2006 was 5 (IQR 1-16), accounting for 1735 (IQR 447-5521) words. By the last full year of the study period, 2022, the median number of notes had grown to 359 (IQR 84-943), representing 359 (IQR 84-943) words. Note and word counts were higher for admitted patients. Discussion: The volume of notes available for review by providers has increased by over 30-fold in the 17 years since the implementation of the EHR at a large health system. The task of reviewing these notes has become commensurately more difficult. These data point to the critical need for new strategies and tools for filtering, synthesizing, and summarizing information to achieve the promise of the medical record.

Health-related quality-of-life analysis from KEYNOTE-590: pembrolizumab plus chemotherapy versus chemotherapy for advanced esophageal cancer.

BACKGROUND: In the KEYNOTE-590 study, first-line pembrolizumab plus chemotherapy provided statistically significant improvement in overall survival, progression-free survival, and objective response rate compared with chemotherapy, with a manageable safety profile in patients with advanced esophageal cancer. Prespecified health-related quality-of-life (HRQoL) outcomes are reported. MATERIALS AND METHODS: Change from baseline to week 18 in the EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) global health status/QoL (GHS/QoL) and QLQ-Esophageal cancer module (OES18) dysphagia, pain, and reflux scales were evaluated. RESULTS: The HRQoL analysis included 730 patients who received treatment and completed ≥1 HRQoL assessment. Least squares mean (LSM) change from baseline to week 18 was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 reflux scales. The QLQ-OES18 dysphagia (LSM difference, -5.54; 95% CI, -10.93 to -0.16) and pain (LSM difference, -2.94; 95% CI, -5.86 to -0.02) scales favored pembrolizumab plus chemotherapy over placebo plus chemotherapy. Median time to confirmed deterioration (TTD) was similar between treatment groups for QLQ-C30 GHS/QoL and physical functioning and QLQ-OES18 dysphagia and reflux scales. Compared with chemotherapy, pembrolizumab plus chemotherapy prolonged median TTD, as seen on the QLQ-OES18 pain scale (HR, 0.69; 95% CI, 0.51 to 0.95). CONCLUSION: The use of pembrolizumab plus chemotherapy maintained HRQoL at week 18 relative to baseline and was comparable with placebo plus chemotherapy. These HRQoL results together with published reports of efficacy, support the use of pembrolizumab plus chemotherapy as first-line therapy for advanced/metastatic esophageal cancer. CLINICALTRIALS.GOV ID: NCT03189719.

LEAP-014: first-line lenvatinib + pembrolizumab + chemotherapy in advanced/metastatic esophageal squamous cell carcinoma.

Treatment options for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) are improving. Current guidelines recommend first-line pembrolizumab plus chemotherapy for patients with unresectable or metastatic ESCC, which has led to improvements in survival outcomes. Antiangiogenic therapy combined with immune checkpoint inhibitors can act synergistically to convert the immunosuppressive tumor microenvironment to an immune supportive microenvironment, thus enhancing antitumor immune responses. In preclinical models, the antiangiogenic agent lenvatinib combined with an anti-PD-1 agent showed synergistic antitumor activity. We describe the design and rationale for the randomized, open-label, phase III LEAP-014 study of lenvatinib in combination with pembrolizumab plus chemotherapy in patients with advanced or metastatic ESCC. Overall survival and progression-free survival are the dual primary end points.Clinical Trial Registration: NCT04949256 (ClinicalTrials.gov).

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Academic Detailing as a Health Information Technology Implementation Method: Supporting the Design and Implementation of an Emergency Department-Based Clinical Decision Support Tool to Prevent Future Falls.

BACKGROUND: Clinical decision support (CDS) tools that incorporate machine learning-derived content have the potential to transform clinical care by augmenting clinicians' expertise. To realize this potential, such tools must be designed to fit the dynamic work systems of the clinicians who use them. We propose the use of academic detailing-personal visits to clinicians by an expert in a specific health IT tool-as a method for both ensuring the correct understanding of that tool and its evidence base and identifying factors influencing the tool's implementation. OBJECTIVE: This study aimed to assess academic detailing as a method for simultaneously ensuring the correct understanding of an emergency department-based CDS tool to prevent future falls and identifying factors impacting clinicians' use of the tool through an analysis of the resultant qualitative data. METHODS: Previously, our team designed a CDS tool to identify patients aged 65 years and older who are at the highest risk of future falls and prompt an interruptive alert to clinicians, suggesting the patient be referred to a mobility and falls clinic for an evidence-based preventative intervention. We conducted 10-minute academic detailing interviews (n=16) with resident emergency medicine physicians and advanced practice providers who had encountered our CDS tool in practice. We conducted an inductive, team-based content analysis to identify factors that influenced clinicians' use of the CDS tool. RESULTS: The following categories of factors that impacted clinicians' use of the CDS were identified: (1) aspects of the CDS tool's design (2) clinicians' understanding (or misunderstanding) of the CDS or referral process, (3) the busy nature of the emergency department environment, (4) clinicians' perceptions of the patient and their associated fall risk, and (5) the opacity of the referral process. Additionally, clinician education was done to address any misconceptions about the CDS tool or referral process, for example, demonstrating how simple it is to place a referral via the CDS and clarifying which clinic the referral goes to. CONCLUSIONS: Our study demonstrates the use of academic detailing for supporting the implementation of health information technologies, allowing us to identify factors that impacted clinicians' use of the CDS while concurrently educating clinicians to ensure the correct understanding of the CDS tool and intervention. Thus, academic detailing can inform both real-time adjustments of a tool's implementation, for example, refinement of the language used to introduce the tool, and larger scale redesign of the CDS tool to better fit the dynamic work environment of clinicians.

Public support for and concerns regarding pediatric dose optimization for seizures in emergency medical services: An exception from informed consent (EFIC) trial.

BACKGROUND: Federal regulations allow exception from informed consent (EFIC) to study emergent conditions when obtaining prospective consent is not feasible. Little is known about public views on including children in EFIC studies. The Pediatric Dose Optimization for Seizures in EMS (PediDOSE) trial implements age-based, standardized midazolam dosing for pediatric seizures. The primary objective of this study was to determine public support for and concerns about the PediDOSE EFIC trial. The secondary objective was to assess how support for PediDOSE varied by demographics. METHODS: We conducted a mixed-methods study in 20 U.S. communities. Participants reviewed information about PediDOSE before completing an online survey. Descriptive data were generated. Univariable and multivariable logistic regression analysis identified factors associated with support for PediDOSE. Reviewers identified themes from free-text response data regarding participant concerns. RESULTS: Of 2450 respondents, 79% were parents/guardians, and 20% had a child with previous seizures. A total of 96% of respondents supported PediDOSE being conducted, and 70% approved of children being enrolled without prior consent. Non-Hispanic Black respondents were less likely than non-Hispanic White respondents to support PediDOSE with an adjusted odds ratio (aOR) of 0.57 (95% CI 0.42-0.75). Health care providers were more likely to support PediDOSE, with strongest support among prehospital emergency medicine clinicians (aOR 5.82, 95% CI 3.19-10.62). Age, gender, parental status, and level of education were not associated with support of PediDOSE. Common concerns about PediDOSE included adverse effects, legal and ethical concerns about enrolling without consent, and potential racial bias. CONCLUSIONS: In communities where this study will occur, most respondents supported PediDOSE being conducted with EFIC and most approved of children being enrolled without prior consent. Support was lowest among non-Hispanic Black respondents and highest among health care providers. Further research is needed to determine optimal ways to address the concerns of specific racial and ethnic groups when conducting EFIC trials.

Risk Factors for Blunt Cerebrovascular Injury in a Cohort of Pediatric Patients With Cervical Seat Belt Sign.

BACKGROUND: Blunt cerebrovascular injury (BVCI), injury to the carotid or vertebral arteries, may result from forces involving seatbelts. Although previous studies have not found a seat belt sign to be a significant predictor for BCVI, it is still used to screen patients for BCVI. OBJECTIVE: This study aims to determine risk factors for BCVI within a cohort of patients with seat belt signs. METHODS: We conducted a retrospective cohort study using our institutional trauma registry and included patients younger than 18 years with blunt trauma who both had a computed tomography angiography (CTA) of the neck performed and had evidence of a seat belt sign per the medical record. We reported frequencies, proportions, and measures of central tendency and conducted univariate analysis to evaluate factors associated with BCVI. We estimated the magnitude of the effect of each variable associated with the study outcome by conducting logistic regression and reporting odds ratios and 95% confidence intervals. RESULTS: Among all study patients, BCVI injuries were associated with Injury Severity Score higher than 15 ( P = 0.04), cervical spinal fractures ( P = 0.007), or basilar skull fractures ( P = 0.01). We observed higher proportions of children with BCVI when other motorized and other blunt mechanisms were reported as the mechanisms of injury ( P = 0.002) versus motor vehicle collision. CONCLUSIONS: Significant risk factors for BCVI in the presence of seat belt sign are: Injury severity score greater than 15, cervical spinal fracture, basilar skull fracture, and the other motorized mechanism of injury, similar to those in all children at risk of BCVI.

Bleach suit for atopic dermatitis.

Bleach baths are an important adjunct in the management of atopic dermatitis. However, many homes do not have bath tubs. We tried to overcome this by soaking a cotton pajama suit or Indian kurta pajama in dilute bleach solution and then having the child wear it for ten minutes. This is done two to three times a week, as in standard bleach tub baths. We have tried this technique in eleven patients with satisfactory outcomes and no adverse effects.

Elevation of Depressed Skull Fracture in Neonates Using a Breast Pump and a Custom-Molded Flange.

BACKGROUND AND IMPORTANCE: "Ping-pong fractures" (PPF) can occur in neonates and result in cosmetic deformity and local mass effect. Standard treatment involves surgical elevation of the depressed bone when the indentation is considerable or cosmetically apparent. Surgical correction of PPF subjects patients to the risks of surgery and general anesthesia. This article and corresponding video demonstrate a novel means of correcting PPF at bedside without surgery or anesthesia. We used a hospital-grade breast pump connected to a custom-fabricated flange to successfully elevate PPF in two neonates. CLINICAL PRESENTATION: Two moderately preterm infants were noted at birth to have large parietal PPF. To avoid surgical intervention, elevation using a suction device was attempted. A hospital-grade breast pump was used to provide suction. A custom device was fabricated out of a breast pump flange and molded Coloplast Brava® protective seal rings. This device was carefully applied to the skull to exactly match the diameter of the PPF and contour of the bone. Brief (15-30 seconds) periods of suction were applied several times until the PPF was successfully elevated as documented on subsequent computed tomography scans. Both infants achieved excellent cosmetic results with no adverse effects over 24- and 9-month follow-ups, respectively. DISCUSSION: This technique eliminates the risks of open surgical correction and corrected the PPF without general anesthesia or adverse effects to the infant. While there may be limitations due to patient age and/or location of the PPF, the use of widely available and inexpensive custom-fitted materials with a hospital grade breast pump achieves maximal efficacy without requiring higher negative pressure suction application. CONCLUSION: Elevation of PPF can be safely achieved in some neonates using readily available equipment: a hospital-grade breast pump, flange, and moldable adherent material. This technique is reasonable to attempt in lieu of surgical elevation.

Incidence of Fit Test Failure During N95 Respirator Reuse and Extended Use.

Importance: The COVID-19 pandemic resulted in a widespread acute shortage of N95 respirators, prompting the Centers for Disease Control and Prevention to develop guidelines for extended use and limited reuse of N95s for health care workers (HCWs). While HCWs followed these guidelines to conserve N95s, evidence from clinical settings regarding the safety of reuse and extended use is limited. Objective: To measure the incidence of fit test failure during N95 reuse and compare the incidence between N95 types. Design, Setting, and Participants: This prospective cohort study, conducted from April 2, 2021, to July 15, 2022, at 6 US emergency departments (EDs), included HCWs who practiced N95 reuse for more than half of their clinical shift. Those who were unwilling to wear an N95 for most of their shift, repeatedly failed baseline fit testing, were pregnant, or had facial hair or jewelry that interfered with the N95 face seal were excluded. Exposures: Wearing the same N95 for more than half of each clinical shift and for up to 5 consecutive shifts. Participants chose an N95 model available at their institution; models were categorized into 3 types: dome (3M 1860R, 1860S, and 8210), trifold (3M 1870+ and 9205+), and duckbill (Halyard 46727, 46767, and 46827). Participants underwent 2 rounds of testing using a different mask of the same type for each round. Main Outcomes and Measures: The primary outcome was Occupational Safety and Health Administration-approved qualitative fit test failure. Trained coordinators conducted fit tests after clinical shifts and recorded pass or fail based on participants tasting a bitter solution. Results: A total of 412 HCWs and 824 N95s were fit tested at baseline; 21 N95s (2.5%) were withdrawn. Participants' median age was 34.5 years (IQR, 29.5-41.8 years); 252 (61.2%) were female, and 205 (49.8%) were physicians. The overall cumulative incidence of fit failure after 1 shift was 38.7% (95% CI, 35.4%-42.1%), which differed by N95 type: dome, 25.8% (95% CI, 21.2%-30.6%); duckbill, 28.3% (95% CI, 22.2%-34.7%); and trifold, 61.3% (95% CI, 55.3%-67.3%). The risk of fit failure was significantly higher for trifold than dome N95s (adjusted hazard ratio, 1.75; 95% CI, 1.46-2.10). Conclusions and Relevance: In this cohort study of ED HCWs practicing N95 reuse, fit failure occurred in 38.7% of masks after 1 shift. Trifold N95s had higher incidence of fit failure compared with dome N95s. These results may inform pandemic preparedness, specifically policies related to N95 selection and reuse practices.

Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients.

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Progressive vascular tumor in infant: A case report and literature review of PIK3CA vascular malformation.

PURPOSE: Vascular anomalies are classified as either vascular tumors or vascular malformations. Vascular malformations can be difficult to diagnose and treat in the pediatric population and can masquerade as malignant processes. Understanding the genetics behind vascular malformations can lead to identification of specific mutations which can be treated with targeted immunotherapy. METHODS: Our case presents a pediatric patient with progressively enlarging vascular malformation despite multiple surgical resections and systemic medical treatments who underwent genetic evaluation and was found to have PIK3CA mutation. RESULTS: After identification of PIK3CA mutation, our patient was successfully treated with the p110ɑ-specific inhibitor, alpelisib, with both shrinkage of malformation on follow-up imaging as well as gains in her developmental milestones. CONCLUSION: Progressive vascular malformations in the pediatric population can be hard to diagnose and treat and are thought to arise from somatic mutations. Our case highlights a patient with progressive malformation despite multiple surgical resections who was successfully treated with targeted immunotherapy after proper identification of genetic mutation.

Accuracy of the American College of Surgeons Minimum Criteria for Full Trauma Team Activation for Children.

OBJECTIVE: Pediatric trauma centers use reports from emergency medical service providers to determine if a trauma team should be sent to the emergency department to prepare to care for the patient. Little scientific evidence supports the current American College of Surgeons (ACS) indicators for trauma team activation. The objective of this study was to determine the accuracy of the ACS Minimum Criteria for Full Trauma Team Activation for children as well as the accuracy of the modified criteria used at the local sites for trauma activation. METHODS: Emergency medical service providers who transported an injured child aged 15 years or younger to a pediatric trauma center in 1 of 3 cities were interviewed after emergency department arrival. Emergency medical service providers were asked if each of the activation indicators were present based on their evaluation. The need for full trauma team activation was determined through a medical record review using a published criterion standard definition. Undertriage and overtriage rates and positive likelihood ratios (+LRs) were calculated. RESULTS: Emergency medical service provider interviews were conducted and outcome data were obtained for 9483 children. There were 202 (2.1%) cases that met the criterion standard for need for trauma team activation. Based on the ACS Minimum Criteria, 299 (3.0%) cases should have received a trauma activation. The ACS Minimum Criteria undertriaged 44.1% and overtriaged 20% (+LR, 27.9; 95% confidence interval, 23.1-33.7). Based on the actual activation status using the local criteria, 238 cases received a full trauma activation, 45% were undertriaged, and 1.4% were overtriaged (+LR, 40.1; 95% confidence interval, 32.4-49.7). There was 97% agreement between the ACS Minimum Criteria and the actual local activation status at the receiving institution. CONCLUSIONS: The ACS Minimum Criteria for Full Trauma Team Activation for children have a high rate of undertriage. Changes that individual institutions have made to improve the accuracy of activations at their institutions seem to have had a limited effect on decreasing undertriage.

Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial (EASI-AS-ODT).

BACKGROUND: In the emergency department (ED), prompt administration of systemic corticosteroids for pediatric asthma exacerbations decreases hospital admission rates. However, there is sparse evidence for whether earlier administration of systemic corticosteroids by emergency medical services (EMS) clinicians, prior to ED arrival, further improves pediatric asthma outcomes. METHODS: Early Administration of Steroids in the Ambulance Setting: An Observational Design Trial is a multicenter, observational, nonrandomized stepped-wedge design study with seven participating EMS agencies who adopted an oral systemic corticosteroid (OCS) into their protocols for pediatric asthma treatment. Using univariate analyses and multivariable mixed-effects models, we compared hospital admission rates for pediatric asthma patients ages 2-18 years before and after the introduction of a prehospital OCS and for those who did and did not receive a systemic corticosteroid from EMS. RESULTS: A total of 834 patients were included, 21% of whom received a systemic corticosteroid from EMS. EMS administration of systemic corticosteroids increased after the introduction of an OCS from 14.7% to 28.1% (p < 0.001). However, there was no significant difference between hospital admission rates and ED length of stay before and after the introduction of OCS or between patients who did and did not receive a systemic corticosteroid from EMS. Mixed-effects models revealed that age 14-18 years (coefficient -0.83, p = 0.002), EMS administration of magnesium (coefficient 1.22, p = 0.04), and initial EMS respiratory severity score (coefficient 0.40, p < 0.001) were significantly associated with hospital admission. CONCLUSIONS: In this multicenter study, the addition of an OCS into EMS agency protocols for pediatric asthma exacerbations significantly increased systemic corticosteroid administration but did not significantly decrease hospital admission rates. As overall EMS systemic corticosteroid administration rates were low, further work is required to understand optimal implementation of EMS protocol changes to better assess potential benefits to patients.

Automating risk stratification for geriatric syndromes in the emergency department.

BACKGROUND: Geriatric emergency department (GED) guidelines endorse screening older patients for geriatric syndromes in the ED, but there have been significant barriers to widespread implementation. The majority of screening programs require engagement of a clinician, nurse, or social worker, adding to already significant workloads at a time of record-breaking ED patient volumes, staff shortages, and hospital boarding crises. Automated, electronic health record (EHR)-embedded risk stratification approaches may be an alternate solution for extending the reach of the GED mission by directing human actions to a smaller subset of higher risk patients. METHODS: We define the concept of automated risk stratification and screening using existing EHR data. We discuss progress made in three potential use cases in the ED: falls, cognitive impairment, and end-of-life and palliative care, emphasizing the importance of linking automated screening with systems of healthcare delivery. RESULTS: Research progress and operational deployment vary by use case, ranging from deployed solutions in falls screening to algorithmic validation in cognitive impairment and end-of-life care. CONCLUSIONS: Automated risk stratification offers a potential solution to one of the most pressing problems in geriatric emergency care: identifying high-risk populations of older adults most appropriate for specific GED care. Future work is needed to realize the promise of improved care with less provider burden by creating tools suitable for widespread deployment as well as best practices for their implementation and governance.

Comparison of 2 Robotic Systems for Pediatric Stereoelectroencephalography Implantation.

BACKGROUND: Stereoelectroencephalography (SEEG) remains critical in guiding epilepsy surgery. Robot-assisted techniques have shown promise in improving SEEG implantation outcomes but have not been directly compared. In this single-institution series, we compared ROSA and Stealth AutoGuide robots in pediatric SEEG implantation. METHODS: We retrospectively reviewed 21 sequential pediatric SEEG implantations consisting of 6 ROSA and 15 AutoGuide procedures. We determined mean operative time, time per electrode, root mean square (RMS) registration error, and surgical complications. Three-dimensional radial distances were calculated between each electrode's measured entry and target points with respective errors from the planned trajectory line. RESULTS: Mean overall/per electrode operating time was 73.5/7.5 minutes for ROSA and 126.1/10.9 minutes for AutoGuide (P = 0.030 overall, P = 0.082 per electrode). Mean RMS registration error was 0.77 mm (0.55-0.93 mm) for ROSA and 0.6 mm (0.2-1.0 mm) for AutoGuide (P = 0.26). No procedures experienced complications. The mean radial (entry point error was 1.23 ± 0.11 mm for ROSA and 2.65 ± 0.12 mm for AutoGuide (P < 0.001), while the mean radial target point error was 1.86 ± 0.15 mm for ROSA and 3.25 ± 0.16 mm for AutoGuide (P < 0.001). CONCLUSIONS: Overall operative time was greater for AutoGuide procedures, although there was no statistically significant difference in time per electrode. Both systems are highly accurate with no significant RMS error difference. While the ROSA robot yielded significantly lower entry and target point errors, both robots are safe and reliable for deep electrode insertion in pediatric epilepsy.

Early Ventricular Arrhythmias After Left Ventricular Assist Device Implantation.

BACKGROUND: Although sustained ventricular arrhythmias (VAs) are a common complication after durable left ventricular assist device (LVAD) implantation, the incidence, risk factors, and prognostic implications of postoperative early VAs (EVAs) in contemporary patients with LVAD are poorly understood. METHODS AND RESULTS: A single-center retrospective analysis was performed of patients who underwent LVAD implantation from October 1, 2006, to October 1, 2022. EVA was defined as an episode of sustained VA identified ≤30 days after LVAD implantation. A total of 789 patients underwent LVAD implantation (mean age 62.9 ± 0. years 5, HeartMate 3 41.4%, destination therapy 43.3%). EVAs occurred in 100 patients (12.7%). A history of end-stage renal disease (odds ratio [OR] 5.6, 95% confidence interval [CI] 1.45-21.70), preoperative electrical storm (OR 2.82, 95% CI 1.11-7.16), and appropriate implantable cardiac defibrillator therapy before implantation (OR 2.8, 95% CI 1.26-6.19) are independently associated with EVAs. EVA was associated with decreased 30-day survival (hazard ratio 3.02, 95% CI 1.1-8.3, P = .032). There was no difference in transplant-free survival time between patients with and without EVAs (hazard ratio 0.82, 95% CI 0.5-1.4, P = .454). CONCLUSIONS: EVAs are common after durable LVAD implantation and are associated with an increased risk of 30-day mortality.

Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy.

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development.