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Resistance to EGFR inhibitors (EGFRi) presents a major obstacle in treating non-small cell lung cancer (NSCLC). One of the most exciting new ways to find potential resistance markers involves running functional genetic screens, such as CRISPR, followed by manual triage of significantly enriched genes. This triage process to identify ‘high value’ hits resulting from the CRISPR screen involves manual curation that requires specialized knowledge and can take even experts several months to comprehensively complete. To find key drivers of resistance faster we build a recommendation system on top of a heterogeneous biomedical knowledge graph integrating pre-clinical, clinical, and literature evidence. The recommender system ranks genes based on trade-offs between diverse types of evidence linking them to potential mechanisms of EGFRi resistance. This unbiased approach identifies 57 resistance markers from >3,000 genes, reducing hit identification time from months to minutes. In addition to reproducing known resistance markers, our method identifies previously unexplored resistance mechanisms that we prospectively validate. Resistance to EGFR inhibitors presents a major obstacle in treating non-small cell lung cancer. Here, the authors develop a recommender system ranking genes based on trade-offs between diverse types of evidence linking them to potential mechanisms of EGFRi resistance.

Laparoscopic common bile duct exploration (LCBDE) has emerged as a viable and effective alternative to the traditional multistage management of choledocholithiasis involving preoperative or postoperative endoscopic retrograde cholangiopancreatography (ERCP). Despite its advantages, LCBDE remains underused, particularly among trauma and acute care surgeons, due to its technical challenges and limited training opportunities. This practical review examines advancements in LCBDE technology, exploring its clinical applications, outlining key steps for its successful implementation, and evaluating selected current literature. Multiple studies have demonstrated that LCBDE achieves comparable success rates to ERCP and reduces hospital length of stay, overall costs, and the need for additional procedures. However, barriers to widespread adoption persist, primarily related to the technical learning curve, limited exposure during surgical training, and institutional workflow constraints favoring ERCP. With recent advancements in surgical technology and enhanced training models, LCBDE is becoming increasingly adoptable. Given their frequent management of biliary abnormality, trauma and acute care surgeons should develop proficiency in this technique to optimize patient outcomes and minimizing procedural burden.

Methamphetamine (METH) is associated with an elevated risk of injury and the outcomes in the elderly remain unclear. We analyzed METH’s impact in elderly trauma patients. Retrospective analysis (2009–2018) of trauma patients at a Level I trauma center. Elderly patients were defined as age ≥55. Substance use was identified by blood alcohol test and urine drug screen. Cox proportional hazard model was used to assess patient and injury characteristics with mortality. Of 15,770 patient encounters with substance use testing, 5278 (34%) were elderly. Elderly METH use quadrupled over time (2%–8%; p < 0.01). Elderly METH + patients were more likely to require surgical intervention (35% vs. 17%), mechanical ventilation (15% vs. 7%), and a longer hospitalization (6.5 vs. 3.6 days) compared with elderly substance negative. Multivariate analysis showed increasing age, ventilator use, and injury severity were associated with mortality (ps < 0.01); METH was not related to mortality. Substance use in elderly trauma patients increased significantly. METH use in elderly trauma patients is a risk factor for significantly greater resource utilization. •Substance abuse rates are increasing in elderly trauma patients, including METH.•METH use by elderly trauma patients is a risk for using more hospital resources.•Elderly trauma patients should be screened for substances to fully inform care.

Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality worldwide, with decompressive craniectomy (DC) serving as a critical surgical intervention. This article reviews the recent studies evaluating the role of DC in the management of elevated intracranial pressures (ICPs) associated with TBI and its impact on functional outcomes. Decompressive Craniectomy in Diffuse Traumatic Brain Injury (DECRA), Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of intracranial pressure (RESCUEicp), and Randomized Evaluation of Surgery with Craniectomy for patients Undergoing Evacuation of Acute Subdural Hematoma (RESCUE-ASDH) are three landmark trials that used varying thresholds for surgical intervention after TBI and examined how functional outcomes improved with time. The DECRA trial evaluated early DC in patients with moderate ICP elevations, demonstrating reduced intensive care unit and hospital stays but poorer functional outcomes at 6 months. Conversely, the RESCUEicp trial emphasized the benefits of delayed DC as a rescue strategy for refractory ICP, showing reduced mortality and improved Glasgow Outcome Scale-Extended scores at 24 months. The RESCUE-ASDH trial compared DC and craniotomy for acute subdural hematoma, finding no significant differences in functional outcomes but distinct profiles of surgical complications. Key recommendations emphasize individualized decision-making based on patient-specific factors, including preinjury functional status and family involvement. This comprehensive review underscores the importance of tailoring DC timing and techniques to optimize functional recovery and align with patient-centered goals, advancing the multidisciplinary management of severe TBI.

We sought to examine the impact of race on the management and outcomes of appendicitis in children aged 20 years or younger. We studied 96,865 inpatient admissions for children undergoing an appendectomy for acute appendicitis in 2009 using the Kids' Inpatient Database. Perforation at presentation was more common among African-Americans and Hispanics than Caucasians (27.5% and 32.5%, respectively, vs 23.9%, P < .001). African-Americans were less likely to have a laparoscopic procedure (odds ratio [OR]: .839, P < .001) and more likely to experience a complication (OR: 1.753, P < .001). Hispanics were also more likely to have a complication (OR: 1.123, P = .001). African-Americans and Hispanics remained in the hospital for .73 more days than Caucasians (3.07 vs 2.34 days, P < .001). African-American and Hispanic children present more often with perforation. Adjusting for perforation, they were more likely to have a complication and longer hospital stays. Access to care and delayed presentations may be potential explanations.

Pericardiocentesis is a critical skill taught by the Advanced Trauma Life Support (ATLS®) course, yet substantial knowledge gaps exist regarding recent practice changes and indications for pericardiocentesis. This study aims to characterize contemporary practice patterns and nationwide trends in the use of emergency pericardiocentesis in trauma. A retrospective study of the National Trauma Data Bank (2011−2022) identified patients undergoing pericardiocentesis within 48 h of arrival prior to any cardiac repair surgery. The primary outcomes were pericardiocentesis timing and the proportion of patients with significant cardiac injuries (Abbreviated Injury Scale 3, 5, or 6). Patient characteristics and clinical course were analyzed. Trend analysis was conducted using the Cochran–Armitage test. A total of 1036 patients were included; 59 % sustained blunt trauma, and 25 % were hypotensive on arrival. Median time to pericardiocentesis was 38 min [IQR: 19–74] for penetrating trauma and 78 min [IQR: 24–314] for blunt trauma. Following pericardiocentesis, 79 % of penetrating and 34 % of blunt trauma patients were taken to the operating room. From 2011 to 2022, there was a significant downward linear trend in the proportion of patients diagnosed with cardiac injuries in penetrating trauma (range: 55 % to 27 %; P for trend < 0.001), while blunt trauma cases showed no significant change (range: 15 % to 9 %; P for trend = 0.623). Emergent pericardiocentesis is used differently in penetrating and blunt trauma. The likelihood of identifying cardiac injuries has declined over time in penetrating trauma. In contrast, blunt trauma patients were more likely to undergo delayed pericardiocentesis, with fewer proceeding to surgery. These observed differences in timing and surgical progression may reflect evolving clinical practices and decision-making patterns in trauma care. This changing trend provides insight into evolving trauma care and highlights the contemporary role of pericardiocentesis in trauma. •Significant downward trend in cardiac injury diagnoses after pericardiocentesis in penetrating trauma.•Persistent diagnostic challenges in identifying blunt cardiac injury.•Distinct clinical decision thresholds between blunt and penetrating trauma cases.•Opportunities to refine trauma protocols and ATLS® training in accordance with contemporary clinical practice.

Background Drugs targeting the spindle assembly checkpoint (SAC), such as inhibitors of Aurora kinase B (AURKB) and dual specific protein kinase TTK, are in different stages of clinical development. However, cell response to SAC abrogation is poorly understood and there are no markers for patient selection. Methods A panel of 53 tumor cell lines of different origins was used. The effects of drugs were analyzed by MTT and flow cytometry. Copy number status was determined by FISH and Q-PCR; mRNA expression by nCounter and RT-Q-PCR and protein expression by Western blotting. CRISPR-Cas9 technology was used for gene knock-out (KO) and a doxycycline-inducible pTRIPZ vector for ectopic expression. Finally, in vivo experiments were performed by implanting cultured cells or fragments of tumors into immunodeficient mice. Results Tumor cells and patient-derived xenografts (PDXs) sensitive to AURKB and TTK inhibitors consistently showed high expression levels of BH3-interacting domain death agonist (BID), while cell lines and PDXs with low BID were uniformly resistant. Gene silencing rendered BID-overexpressing cells insensitive to SAC abrogation while ectopic BID expression in BID-low cells significantly increased sensitivity. SAC abrogation induced activation of CASP-2, leading to cleavage of CASP-3 and extensive cell death only in presence of high levels of BID. Finally, a prevalence study revealed high BID mRNA in 6% of human solid tumors. Conclusions The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.

Trauma and acute care surgeons commonly perform high acuity and emergent interventions on critically ill or injured patients. This often entails making life or death decisions rapidly and with incomplete and imperfect information, and in patients who may have a variety of comorbidities that contribute to the risk of adverse outcomes. In cases where there are real or perceived breaches of care, a medical malpractice claim may result. In the USA, approximately one-third to one-half of all physicians will be named in medical litigation at least once in their career. Among the various specialties, surgery remains among the highest risk for malpractice litigation, at an average of 10.6 defendants per 100 surgeons. These events can be extremely stressful, demoralizing, or even devastating to the career and well-being of the involved physicians. This can be made better or worse by the individual response and actions of the surgeon on notification of a real or potential claim, and the primary goal of this review is to highlight these key areas and optimal strategies in malpractice scenarios. This includes strategies to manage the initial receipt of a malpractice claim, subsequent courses of action, and advice for incorporating preventive measures into everyday practice.

Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. While patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic vulnerabilities. We identified several vulnerabilities in osimertinib DTPs that were common across models, including sensitivity to MEK, AURKB, BRD4, and TEAD inhibition. We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.