Citations

OBJECTIVE: A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN: Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING: Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS: A panel of multinational, multiprofessional and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS: A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid-responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds), were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS: A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 micrograms per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.

Abstract Cancer remains one of the most complex and devastating diseases, in part because tumors are not static entities but dynamic ecosystems that evolve in real time. Over the decades, researchers have proposed two major frameworks toexplain tumor development: 1) the clonal evolution model, which emphasizes the stepwise accumulation of mutations insingle cells, and 2) the cancer stem cell model, which posits a hierarchical tumor structure driven by a small population of stem-like cells capable of self-renewal and tumor initiation. In brain tumors, as in other cancer types, the presence of cancer stem cells has been demonstrated; however, their evolutionary role in glioblastoma, the most aggressive primary brain tumor, remains poorly understood. A key unanswered question is how cancer stem cells in the brain evolve intomalignant populations and how evolutionary processes shape this transition. Since Darwin, evolutionary biologists have sought to understand how traits evolve across lineages and have developed several tools to address questions regarding how lineages, species and populations have evolved through time. In recent years there has been an increase in the use of evolutionary statistical methods to study cancer evolution. These approaches remain niche in a few tumor types (e.g., blood and lung cancer), but the rapid growth of sequencing technologies and large-scale datasets has created new opportunities to address evolutionary questions across cancer types that have been understudied (e.g., brain tumor). Researchers are now using whole-genome, exome, single-cell, spatial, and multi-omic data to reconstruct tumor histories, test adaptive hypotheses, and in few cases, quantify rates and modes of evolution within tumors and between tumor types. However, there is not yet a consolidated framework for which evolutionary analyses are most appropriate to test cancer evolution, nor accessible guidance on how to implement these approaches in oncological datasets. We synthesize evolutionary statistical methods currently used in brain cancer research and propose additional approaches for future studies. We identify more than 30 evolutionary tools developed to study trait evolution, diversification, and lineage dynamics in biological systems, of which only one has been applied to brain cancer. We argue that adapting these methods offers a powerful opportunity to investigate cancer stem cell dynamics and tumor progression in glioblastoma and other understudied cancers. By bridging evolutionary biology and cancer genomics, this work provides a roadmap for expanding the evolutionary toolkit used to study tumor evolution and for generating testable hypotheses about malignant transformation. Citation Format: Jhan C. Salazar Salazar, Sean W. McHugh, Maria F. Gonzalez-Aponte, Hugo Guerrero-Cazares. From healthy brain to cancer cells: Understanding the origins of glioblastoma through the lens of Darwinian evolution [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B017.

Purpose To use publicly available injured list (IL) data to 1) describe Major League Baseball injury trends from 2010 to 2024; 2) analyze injury types and body regions affected to report the highest impact injuries; and 3) report the financial implications of time lost due to injury over this 15‐year period. Methods IL data for every Major League Baseball player (pitchers and position players) from the 2010 to 2024 regular seasons were collected using publicly available sources, including player demographics, IL placements, body part injured, and length of each IL stay. Player salaries were compiled to determine the “financial loss” per injury. Results Across 15 seasons, 8078 players were placed on the IL, totaling 478,085 days. The mean IL placements/year was 634, and the annual number increased by an additional 27 injuries/year ( P < .001). Mean total IL days/season was 31,872, and this increased year‐over‐year ( P = .008). Shoulder injuries represented the most IL placements (n = 1555), followed by elbow (n = 1344) and upper leg (n = 769). Elbow injuries averaged the most days missed/IL placement (mean: 93, median: 74) and the greatest total days missed (129,610), followed by shoulder (95,189). Pitchers comprised 55% of IL placements and most commonly injured their shoulder or elbow. Infielders and outfielders accounted for 21% and 16% of IL placements, respectively. A total financial loss of $9,636,753,291 was accumulated over 15 seasons. Financial loss increased season‐to‐season (+$32,309,178/year, P = .002). Elbow injuries accounted for the highest financial loss at $1,932,048,168 ($1,379,049 lost/injury). In 2024, $2,220,432 was lost/elbow injury, $1,110,573/shoulder injury, $1,397,322/any injury, and $952,973,760 total for the season. Conclusions This study observed that the number of players, IL placements, days spent on the IL, and financial loss due to injury increased steadily each year. Pitchers were the most frequently injured players with shoulder and elbow injuries being most common. Over the 15‐season study period, there was a total financial loss of nearly $9.7 billion due to salary paid to injured players, with elbow injuries contributing the highest loss at just under $2 billion. Clinical Relevance Injury trends and financial data from Major League Baseball highlight the growing burden of shoulder and elbow injuries, particularly in pitchers. These findings underscore the need for orthopaedic surgeons to focus on prevention, early intervention, and optimized surgical management of high‐impact injuries to reduce long‐term morbidity and associated financial costs at the elite level.

Abstract INTRODUCTION The infectious hypothesis suggests that microbes like herpesviruses may play a role in the pathogenesis of Alzheimer's disease (AD) and other related dementias through methods that may include viral genome integration. The occurrence of herpesvirus genome integration in dementia patients has not been thoroughly characterized. METHODS Over 7500 total whole‐genome sequences from control, frontotemporal dementia/amyotrophic lateral sclerosis spectrum, Lewy body dementia (LBD), multiple system atrophy (MSA), and AD cohorts were screened for the integration of pathogen genomes using the PathSeq computational tool. RESULTS Low PathSeq scores for human herpesvirus 6 (HHV‐6) were consistent with the suspected integration of viral genome segments. The LBD and MSA cohorts had a significantly higher prevalence of this partial HHV‐6 genome integration. DISCUSSION This higher prevalence in both synucleinopathies was not noted in other herpesviruses, suggesting that the integration of HHV‐6 may play a role in a subset of these patients. Highlights Over 7500 whole‐genome sequences from controls and dementia patients were analyzed. Sequences consistent with integrated herpesviruses were identified using PathSeq. Prevalence of partial HHV‐6 integration was higher in synucleinopathies. Herpesviruses genome integration may play a role in subsets of dementia patients.

Abstract Neuromodulatory subcortical systems (NSSs) are uniquely susceptible to dementia‐related pathology, leading to frequent molecular and behavioral impairments associated with altered function of these nuclei. Some of these systems display clear sex‐specific cytoarchitecture and signaling leading to distinct physiology and behavioral outputs in males and females, while other regions display nominal sex differences. However, the relevance of sex differences in modulating dysfunction of NSSs in Alzheimer's disease (AD) and related dementias is not well understood. This review is a joint effort by the Neuromodulatory Subcortical Systems and Sex and Gender Differences in Alzheimer's Disease Professional Interest Areas of the Alzheimer's Association. We review sex differences in NSSs, both in non‐disease states and in AD models and patients. We highlight the possible role of NSSs in driving sex‐specific AD susceptibility and potential footholds for sex‐based interventions targeting these systems. We conclude by outlining immediate and long‐term actions to address the intersection of NSSs, sex, and AD.

Abstract Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy affecting 1 in 5000 individuals, is the second most common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the US Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median age of 53 (range, 0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13 years, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of postmenarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring IV iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). These data from CHORUS, the first national US registry of its kind, provide reliable, real-world estimates of the incidence, prevalence, and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of &gt;2 decades, during which substantial, serious, and preventable HHT morbidity, including early intracranial hemorrhage, may occur. This trial was registered at clinicaltrials.gov as NCT06259292.

Background: Femoroacetabular impingement (FAI) is a common injury experienced by basketball players. Surgical management with arthroscopic labral repair and femoral osteochondroplasty can lead to successful outcomes for athletes whose nonoperative management fails. Recent studies have demonstrated that athletes undergoing hip arthroscopy in the setting of FAI had favorable return-to-sport (RTS) and sport continuation outcomes. Purpose: To evaluate patient-reported outcome measures (PROMs) and RTS rates at minimum 5-year follow-up in basketball players after hip arthroscopy for FAI. Study Design: Case series; Level of evidence, 4. Methods: All active basketball players at the recreational, high school, and collegiate levels who underwent primary hip arthroscopy with labral repair for FAI between August 2009 and December 2019 were identified. Postoperative RTS, revision rates, and surgery satisfaction at final follow-up were evaluated. PROMs were also analyzed as follows: visual analog scale, Tegner Activity Scale, modified Harris Hip Score, Hip Outcome Score–Activities of Daily Living, and Hip Outcome Score–Sport. Results: Fifty-three patients (64 hips) were included with a mean ± SD age of 21.2 ± 6.0 years. Most athletes played recreational or high school basketball (85%), while 15% played college basketball. Forty-three patients attempted to return to basketball. Of these patients, 35 (81%) returned to basketball after surgery, with 32 (91%) returning to the same level of play. Patients who returned to basketball had significantly improved outcomes on the modified Harris Hip Score ( P = .006), Hip Outcome Score–Activities of Daily Living ( P = .007), Hip Outcome Score–Sport ( P = .004), Tegner Activity Scale ( P = .010), and visual analog scale with use ( P = .041) as compared with those who did not return. High school athletes had decreased odds of RTS when compared with recreational athletes ( P = .01). There was significant improvement in all PROMs from baseline to minimum 5-year follow-up ( P < .05). Conclusion: At minimum 5-year follow-up, basketball players demonstrated durable improvements in PROMs and an RTS rate of 81% after hip arthroscopy for FAI. The majority of athletes returned to the same level of competition. There were significantly improved PROMs in patients who returned to sport versus those who did not. High school athletes had decreased odds of RTS when compared with recreational athletes. However, body mass index, sex, age, alpha angle, and basketball position did not significantly correlate with RTS outcomes.

The 2025 Voice AI Symposium represented a transition from conceptual research to clinical implementation in vocal biomarker science. Hosted by the NIH-funded Bridge2AI-Voice consortium, the meeting convened global experts to address the methodological, ethical, and translational challenges of integrating voice-based artificial intelligence (AI) into healthcare. This mini-review synthesizes symposium insights across six domains: multimodal integration, FAIR (Findable, Accessible, Interoperable, Reusable) and CARE (Collective Benefit, Authority to Control, Responsibility, Ethics) data governance, clinical translation, interdisciplinary training, and cross-sector innovation. Research presented demonstrated voice as a latent, multimodal biomarker reflecting neurological, cardiopulmonary, and psychological states, while discussions emphasized ethical data practices and human-centered design. The implementation-focused panels underscored the importance of workflow alignment and usability for adoption in real-world care. Collectively, the symposium reflects a field advancing toward translational readiness and ethical accountability, positioning voice AI as a scalable, inclusive tool for next-generation healthcare.