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Introduction: Studies assessing early trauma resuscitation have used long-term endpoints, such as 28- or 30-day mortality or Glasgow Outcomes Scores at 6-months. These endpoints are convenient but may not accurately reflect the effect of early resuscitation. We sought expert opinion and consensus on endpoints and definitions of variables needed to conduct a Department of Defense- (DoD) funded study to epidemiologically assess combat-relevant mortality and morbidity due to timeliness of resuscitation among critically injured civilians internationally. Methods: We conducted an online modified Delphi process with an international panel of civilian and US military experts. In several iterative rounds, experts reviewed background information, appraised relevant scientific evidence, provided comments, and rendered a vote on each variable. A-priori, we set consensus at =80% concordant votes. Results: Twenty panelists participated with a 100% response rate. Eight items were presented, with the following outputs for the epidemiologic study: Assess mortality within 7-days of injury; assess multi-organ failure using SOFA scores measured early (at day 3) and late (at day 7); assess traumatic brain injury mortality early (=7-days) and late (28-days); hybrid (anatomic and physiologic) injury severity scoring is optimal; capture comorbidities per the US National Trauma Data Standard list with specific additions; assign resuscitative interventions to one of five standardized phases of trauma care; and, use a novel trauma death categorization system. Conclusions: A modified Delphi process yielded expert-ratified definitions and endpoints of variables necessary to conduct a combat-relevant epidemiologic study assessing outcomes due to early trauma resuscitation. Outputs may also benefit other groups conducting trauma resuscitation research. [ABSTRACT FROM AUTHOR]

Introduction: Drowning results in more than 360,000 deaths annually, making it the 3rd leading cause of unintentional injury death worldwide. Prior studies have examined airway interventions affecting patient outcomes in cardiac arrest, but less is known about drowning patients in arrest. This study evaluated the outcomes of drowning patients in the Cardiac Arrest Registry to Enhance Survival (CARES) who received advanced airway management.Methods: A retrospective analysis of the CARES database identified cases of drowning etiology between 2013 and 2018. Patients were stratified by airway intervention performed by EMS personnel. Demographics, sustained return of spontaneous circulation [ROSC], survival to hospital admission, survival to hospital discharge, and neurological outcomes were compared between airway groups using chi-squared tests and logistic regression.Results: Among 2388 drowning patients, 70.4% were male, 41.8% white, and 13.1% survived to hospital discharge. Patients that received supraglottic airways [SGA] had statistically significantly lower odds of survival to hospital admission compared to endotracheal tube [ETT] use (adjusted odds ratio [aOR] = 0.56, 95% confidence interval [CI] 0.42-0.76) as well as lower odds of survival to discharge compared to bag valve mask [BVM] use (aOR = 0.40, 95% CI 0.19-0.86) when accounting for relative ROSC timing.Conclusion: In this national cohort of drowning patients in cardiac arrest, SGA use was associated with significantly lower odds of survival to hospital admission and discharge. However, survival to discharge with favorable neurological outcome did not differ significantly between airway management techniques. Further studies will need to examine if airway intervention order or time to intervention affects outcomes. [ABSTRACT FROM AUTHOR]

Background: Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve.Methods: Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient).Results: Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients.Conclusions: Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine.Trial Registration: SAMURAI (NCT02439320); SPARTAN (NCT02605174). [ABSTRACT FROM AUTHOR]

Background: Treprostinil, a prostacyclin analog, remedies pulmonary arterial hypertension through vasodilation of both pulmonary and systemic arterial vascular beds. Headache is a known side effect of treprostinil and prostacyclin analogs in general, but the mechanism by which they cause headache is unknown. Current recommendations for treatment of severe headaches from prostacyclin analogs include only one drug class, opioids. Acetazolamide is a carbonic anhydrase inhibitor that lowers intracranial pressure by reducing the production of cerebrospinal fluid., Case: A 44-year-old female inpatient developed a continuous headache, much worse supine than standing, shortly after starting treprostinil for pulmonary artery hypertension. Imaging studies showed no explanatory anatomical process. Her comorbidities precluded the use of triptans, ergots, and non-steroidal anti-inflammatory drugs, but her headache resolved rapidly with acetazolamide 250 mg twice daily. Acetazolamide and furosemide were stopped due to hypokalemia and vomiting, whereupon her headaches returned. Acetazolamide but not furosemide was then restarted, again with resolution of her headaches despite cessation of oxycodone., Discussion/conclusion: This sequence suggests that treprostinil may cause headache by elevating intracranial pressure (ICP), possibly through cerebral vasodilation. We suspect that acetazolamide may have reduced her ICP enough to resolve her headache. To our knowledge, this report is the first description of both the possible underlying mechanism of action whereby prostacyclin analogs may cause headache, as well as treatment of the underlying cause of the headache rather than the symptom., (© 2025 American Headache Society.)

Background: The TROG 99.03 trial demonstrated improved progression-free survival for patients with early-stage follicular lymphoma (FL) treated with systemic therapy using rituximab-cyclophosphamide, vincristine, prednisolone (R-CVP) after involved-field radiotherapy (RT) versus RT. As systemic therapy was associated with more acute toxicity, the possibility of long-term toxicity, and no survival benefit yet, the cost-effectiveness of RT+R-CVP is important., Aim: We performed a cost-effectiveness analysis of RT (reference), RT+CVP, and RT+R-CVP from the TROG 99.03 trial., Methods: We constructed a Markov model (15-year horizon) to compare treatments: RT (reference), RT+CVP and RT+R-CVP from the 150 patients in the TROG 99.03 trial. Median follow-up was 11.3 years (range: 4.4-17.8). Lifetime direct health care costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. Australian dollars AUD$50,000 was defined as the proposed willingness-to-pay threshold (WTP)., Results: RT+R-CVP was associated with an improvement of 0.711 QALYs compared to RT, 0.532 QALYs compared to RT+CVP, and was the dominant strategy. The costs of adverse events or retreatment for relapses or transformation had a minimal influence on the ICERs. Sensitivity analyses resulted in ICER values below the WTP with RT+R-CVP remaining the dominant strategy., Conclusion: RT+R-CVP is clearly cost-effective and was the dominant strategy in early-stage FL compared to RT or RT+CVP as it delivers superior outcomes at a lower cost from the Australian tax-payer's perspective., Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission., Competing Interests: John F. Seymour: AbbVie: Advisory board, speakers' bureau, research funding. Astra Zeneca: Advisory board. Beigene: Advisory Board. BMS: Advisory board, speakers' bureau, research funding, expert testimony. Genor Bio: Scientific Advisory Board. Gilead: Advisory Board. Janssen: Advisory board, research funding. Roche: Advisory board, speakers' bureau, research funding, expert testimony. TG Therapeutics: Consultant, expert testimony. The other authors declare no conflicts of interest., (© 2025 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Drowning is the third leading cause of death from unintentional injury worldwide, accounting for 7% of all injury-related deaths. The World Health Organization estimates that there are ≈236 000 deaths due to drowning worldwide each year. Significant efforts have focused on creating systems to prevent drowning, but an average of 4000 fatal and 8000 nonfatal drownings still occur annually in the United States-likely an underestimate. Drowning generally progresses from initial respiratory arrest due to submersion-related hypoxia to cardiac arrest; thus, it can be challenging to distinguish respiratory arrest from cardiac arrest because pulses are difficult to accurately palpate within the recommended 10-second window. Therefore, resuscitation from cardiac arrest attributable to this specific circumstance must focus on restoring breathing as much as it does circulation. Resuscitation from drowning may begin with in-water rescue breathing when safely provided by rescuers trained in the technique and should continue with chest compressions, in keeping with basic life support guidelines, once the drowned individual and the rescuer are in a safe environment (eg, dry land, a boat). This focused update incorporates systematic reviews from 2021 to 2023 performed by the International Liaison Committee on Resuscitation related to the resuscitation of drowning. These clinical guidelines are the product of a committee of experts representing the American Heart Association and the American Academy of Pediatrics. The writing group reviewed the recent International Liaison Committee on Resuscitation systematic reviews, including updated literature searches, prior guidelines related to resuscitation from cardiac arrest following drowning, and other drowning-related publications from the American Heart Association and American Academy of Pediatrics. The writing group used these reviews to update its recommendations aimed at resuscitation of cardiac arrest following drowning in adults and children.

Drowning is the third leading cause of death from unintentional injury worldwide, accounting for 7% of all injury-related deaths. In the United States, drowning is the leading cause of death in children 1 to 4 years of age and second leading cause of death due to unintentional injury in those aged 5 to 14 years. Drowning generally progresses from initial respiratory arrest due to submersion-related hypoxia to cardiac arrest; thus, it can be challenging to distinguish respiratory arrest from cardiac arrest because pulses are difficult to accurately palpate within the recommended 10-second window. Therefore, resuscitation from cardiac arrest due to this specific circumstance must focus on restoring breathing as much as it does circulation. Resuscitation from drowning may begin with in-water rescue breathing when safely provided by rescuers trained in the technique and should continue with chest compressions, in keeping with basic life support guidelines, once the drowned individual and the rescuer are in a safe environment (eg, dry land, boat). This focused update incorporates systematic reviews from 2021 to 2023 performed by the International Liaison Committee on Resuscitation related to the resuscitation of drowning. These clinical guidelines are the product of a committee of experts representing the American Academy of Pediatrics and the American Heart Association. The writing group reviewed the recent International Liaison Committee on Resuscitation systematic reviews, including updated literature searches, prior guidelines related to resuscitation from cardiac arrest following drowning, and other drowning-related publications from the American Academy of Pediatrics and the American Heart Association. The writing group used these reviews to update its recommendations aimed at resuscitation from cardiac arrest following drowning in children., (Copyright © 2024 by the American Academy of Pediatrics and American Heart Association, Inc.)

Background: We report extended follow-up of TROG99.03, a randomised phase III trial in early-stage follicular lymphoma (ESFL) including new information on the role of adjuvant rituximab and translational studies., Methods: Patients with ESFL were randomised to involved field radiotherapy (IFRT) or IFRT plus 6-cycles cyclophosphamide/vincristine/prednisolone (IFRT + CVP). From 2006 rituximab was added to IFRT + CVP (IFRT + R-CVP). Clinical and multi-omic parameters were evaluated. Findings were validated in two independent ESFL cohorts (99 and 60 patients respectively)., Findings: Between 2000 and 2012, 150 (75 per arm) patients were recruited. 48% were positron emission tomography (PET)-staged. By protocol, at median follow-up 11.3-years, progression-free survival (PFS) remained superior for IFRT+(R)CVP vs. IFRT (hazard ratio [HR] = 0.60, 95% CI = 0.37-0.98, p = 0.043; 10-year PFS 62% vs. 43%) respectively. Although no significant difference in overall survival was observed (HR = 0.44, 95% CI = 0.16-1.18, p = 0.11, 10-year OS 95% vs. 84%), patients receiving IFRT+(R)CVP experienced fewer composite (histological transformation and death) events (p = 0.045). PFS of IFRT + R-CVP-treated patients compared with all other treatments lacking rituximab (IFRT alone plus IFRT + CVP) was superior (HR = 0.36, 95% CI = 0.13-0.82, p = 0.013). Amongst PET-staged patients, PFS differences between IFRT + R-CVP vs. IFRT were maintained (HR = 0.38, 95% CI = 0.16-0.89, p = 0.027) indicating benefit distinct from stage migration. FL-related mutations and BCL2-translocations were not associated with PFS. However, by multivariate analysis elevated CD8A gene expression in diagnostic biopsy tissue was independently associated with improved PFS (HR = 0.45, 95% CI = 0.26-0.79, p = 0.037), a finding confirmed in both ESFL validation cohorts. CD8A gene expression was raised (p = 0.02) and CD8+ T-cell density higher within follicles in ESFL vs. advanced-stage FL (p = 0.047). Human leucocyte antigen class I specific neoantigens were detected in 43% of patients, suggesting neoantigen-specific CD8+ T-cells have a role in confining the spread of the disease., Interpretation: Adjuvant R-CVP and elevated intratumoural CD8 expression were independently associated with sustained disease control after radiotherapy in ESFL., Funding: Cancer Council Victora; National Health and Medical Research Council; Leukaemia Foundation; Mater Foundation., Competing Interests: Declaration of interests Amgen (GCSF) and Roche (Rituximab) for the provision of study materials. There are no other relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Introduction: Prolonged Casualty Care (PCC) is a military adaptation aimed at providing pre-hospital care in austere settings when evacuation is delayed or even impossible. Current lack of standardized medical equipment and size/weight restrictions of military packs during dismounted operations hinder effective PCC. We sought to design a standardized, practical, and effective prolonged field care kit (PFAK) to enable widespread implementation of PCC., Materials and Methods: We reviewed Joint Trauma System Clinical Practice Guidelines to generate a list of potential contents of the PFAK. We obtained Institutional Review Board (IRB) exemption and then conducted stakeholder surveys of combat casualty care experts across the Joint Trauma System using a modified Delphi survey approach. We established a civil-military working group that provided in-depth qualitative feedback on the PFAK contents and provided an initial design of a long-range medical rucksack (LMR) to house it. Responses were analyzed using mean rank scores to help determine initial components of the PFAK. Tactical subject-matter experts tested and evaluated the PFAK and LMR prototype in austere conditions to refine the design., Results: Review of the PCC Clinical Practice Guidelines generated 49 medications and 301 potential supplies as potential PFAK contents. The first Delphi survey was sent to 100 stakeholders (overall response rate of 60%). After the first survey, contents were narrowed to a list of the most essential 27 medications and 105 other components. Iterative prototypes of the PFAK and LMR were tested to determine ergonomics, portability, flexibility, and equipment compartmentalization to facilitate use in emergencies. The prototype was optimized to address the clinical, logistical, and tactical requirements of PCC across a variety of platforms and environmental conditions., Conclusions: Given the changing battlefield environment, efficient and effective PCC will play an increasingly important role in the management of combat trauma. The PFAK can meet this need by providing a practical and standardized resuscitation kit generated by expert military and trauma personnel consensus, carried conveniently in the LMR., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma subtype, accounting for 15-20% of all lymphoma diagnoses. Although typically slow-growing and responsive to frontline therapies, advanced-stage FL remains incurable with current treatments and typically follows a chronic relapsing/remitting course with increasingly shorter responses to subsequent lines of therapy. Outcomes are highly variable; some patients experience prolonged first remissions that may approximate a 'functional cure'. By contrast, a significant minority of patients experience disease progression shortly after frontline treatment resulting in high rates of lymphoma-related mortality. Reflecting on the heterogeneous natural history of FL, clinical practice varies widely, particularly in controversial areas, including appropriate disease staging, selection of management strategies and duration of clinical follow-up. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice., (© 2024 Royal Australasian College of Physicians.)

With increasing computing power, artificial intelligence (AI) and machine learning (ML) have prospered, which facilitate the analysis of large datasets, especially those found in critical care. It is important to define these terminologies, to inform a standardized approach to critical care research. This manuscript hopes to clarify these terms with examples from medical literature. Three major components that are required for a successful ML implementation: (i) reliable dataset, (ii) ML algorithm, and (iii) unbiased model evaluation, are discussed. A reliable dataset can be structured or unstructured with limited noise, outliers, and missing values. ML, a subset of AI, is typically focused on supervised or unsupervised learning tasks in which the output is based on inputs and derived from iterative pattern recognition algorithms, while AI is the overall ability of a machine to "think" or mimic human behavior; and to analyze data free from human influence. Even with successful implementation, advanced AI and ML algorithms have faced challenges in adoption into practice, mainly due to their lack of interpretability, which hinders trust, buy-in, and engagement from clinicians. Consequently, traditional algorithms, such as linear and logistic regression, that may have reduced predictive power but are highly interpretable, continue to be widely used., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable., (© 2024. The Author(s).)

Epstein-Barr virus (EBV)-associated lymphomas cover a range of histological B- and T-cell non-Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO-HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: The International Liaison Committee on Resuscitation, in collaboration with drowning researchers from around the world, aimed to review the evidence addressing seven key resuscitation interventions: 1) immediate versus delayed resuscitation; (2) compression first versus ventilation first strategy; (3) compression-only CPR versus standard CPR (compressions and ventilations); (4) ventilation with and without equipment; (5) oxygen administration prior to hospital arrival; (6) automated external defibrillation first versus cardiopulmonary resuscitation first strategy; (7) public access defibrillation programmes., Methods: The review included studies relating to adults and children who had sustained a cardiac arrest following drowning with control groups and reported patient outcomes. Searches were run from database inception through to April 2023. The following databases were searched Ovid MEDLINE, Pre-Medline, Embase, Cochrane Central Register of Controlled Trials. Risk of bias was assessed using the ROBINS-I tool and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. The findings are reported as a narrative synthesis., Results: Three studies were included for two of the seven interventions (2,451 patients). No randomised controlled trials were identified. A retrospective observational study reported in-water resuscitation with rescue breaths improved patient outcomes compared to delayed resuscitation on land ( n  = 46 patients, very low certainty of evidence). The two observational studies ( n  = 2,405 patients), comparing compression-only with standard resuscitation, reported no difference for most outcomes. A statistically higher rate of survival to hospital discharge was reported for the standard resuscitation group in one of these studies (29.7% versus 18.1%, adjusted odds ratio 1.54 (95% confidence interval 1.01-2.36) (very low certainty of evidence)., Conclusion: The key finding of this systematic review is the paucity of evidence, with control groups, to inform treatment guidelines for resuscitation in drowning., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This systematic review was part of the ILCOR continuous evidence evaluation process, which is guided by a rigorous conflict of interest policy (see www.ilcor.org). GDP declares roles as co-chair of ILCOR, Director of Science and Research for the European Resuscitation Council, Vice President of the Resuscitation Council UK and Editor roles with Resuscitation and Resuscitation Plus journals. He is supported by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. JB declares her role as an Associate Editor for Resuscitation Plus. The paper was handled by Associate Editor Keith Couper., (© 2023 The Author(s).)

Diffuse large B-cell lymphoma (DLBCL) is the most common form of B-cell non-Hodgkin lymphoma (B-NHL) with significant morbidity and mortality despite advancements in treatment. Lymphoma and autoimmune disease both result from breakdowns in normal cell regulatory pathways, and epidemiological studies have confirmed both that B-NHL is more likely to develop in the setting of autoimmune diseases and vice versa. Red cell immunity, as evidenced by direct antiglobulin test (DAT) positivity, has been linked to DLBCL and more recently the pathogenic causes of this association have begun to be better understood using molecular techniques. This project aimed to explore the relationship between red cell autoimmunity and DLBCL. DAT positivity was more common in DLBCL as compared to healthy controls (20.4% vs 3.7%, p=0.0005). Univariate analysis found a non-significant trend towards poorer overall survival in the DAT positive (DAT+) compared to the DAT negative (DAT-) groups (p=0.087). High throughput sequencing was used to compare mutations in DLBCL from DAT+ and DAT- patients. The most frequently mutated genes in 15 patient samples were KMT2D (n=13), MYOM2 (n=9), EP300 (n=8), SPEN (n=7), and ADAMTSL3 (n=7), which were mutated in both DAT+ and DAT- groups. BIRC3 (n=3), FOXO1 (n=3) and CARD11 (n=2) were found to be mutated only in samples from the DAT+ group. These gene mutations may be involved in disease development and progression, and potentially represent targets for future therapy. The immunoglobulin genotype IGHV4-34 is seen more frequently in DLBCL clones than in normal B cells and has intrinsic autoreactivity to self-antigens on red cells, which is largely mediated by two motifs within the first framework region (FR1); Q 6 W 7 and A 24 V 25 Y. 26 These motifs form a hydrophobic patch which determines red cell antigen binding and are frequently mutated away from self-reactivity in normal B cells. If this does not occur this may provide constant B cell receptor signalling which encourages lymphoma development, a theory known as antigen driven lymphomagenesis. As with previous studies, IGHV4-34 was over-represented (15.6%) in our DLBCL cohort. Furthermore, of 6 IGHV4-34-expressing DLBCL samples five had unmutated hydrophobic patch mutations providing further evidence for antigen-driven lymphomagenesis. Mutation analysis of these five samples demonstrated high frequency of mutations in several genes, including CREBBP and NCOR2. Further research could explore if mutations in CREBBP and NCOR2 work in conjunction with the preserved QW and AVY motifs to promote lymphomagenesis in IGHV4-34-expressing B cells, and if so, could guide future targeted therapy., (Copyright © 2022 Royal College of Pathologists of Australasia. All rights reserved.)

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

Current quantitative descriptions of the cardiovascular system in hemorrhagic shock focus on pressure based metrics. This approach is often incomplete; overlooking the important role of tissue perfusion. Electrical analogs to the cardiovascular system may offer a more complete description of hemorrhage. Application of fundamental concepts in electrical circuit theory (i.e.; Kirchhoff's Voltage Law and Ohm's Law) to analogs of the cardiovascular system offers a more refined description of this complex process. This manuscript hopes to serve as a starting point for a more mathematically robust, and clinically relevant description of hemorrhagic shock., (© 2021. Biomedical Engineering Society.)

Introduction: Studies assessing early trauma resuscitation have used long-term endpoints, such as 28- or 30-day mortality or Glasgow Outcomes Scores at 6-months. These endpoints are convenient but may not accurately reflect the effect of early resuscitation. We sought expert opinion and consensus on endpoints and definitions of variables needed to conduct a Department of Defense- (DoD) funded study to epidemiologically assess combat-relevant mortality and morbidity due to timeliness of resuscitation among critically injured civilians internationally., Methods: We conducted an online modified Delphi process with an international panel of civilian and US military experts. In several iterative rounds, experts reviewed background information, appraised relevant scientific evidence, provided comments, and rendered a vote on each variable. A-priori, we set consensus at ≥80% concordant votes., Results: Twenty panelists participated with a 100% response rate. Eight items were presented, with the following outputs for the epidemiologic study: Assess mortality within 7-days of injury; assess multi-organ failure using SOFA scores measured early (at day 3) and late (at day 7); assess traumatic brain injury mortality early (≤7-days) and late (28-days); hybrid (anatomic and physiologic) injury severity scoring is optimal; capture comorbidities per the US National Trauma Data Standard list with specific additions; assign resuscitative interventions to one of five standardized phases of trauma care; and, use a novel trauma death categorization system., Conclusions: A modified Delphi process yielded expert-ratified definitions and endpoints of variables necessary to conduct a combat-relevant epidemiologic study assessing outcomes due to early trauma resuscitation. Outputs may also benefit other groups conducting trauma resuscitation research.

Data on the prognostic impact of pretherapy 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in follicular lymphoma (FL) is conflicting. The predictive utility of pretherapy total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) on outcome appears to vary between regimens. Chemoimmunotherapies vary in the extent of T-cell depletion they induce. The role of intratumoral T cells on pretherapy FDG-PET parameters is undefined. We assessed pretherapy FDG-PET parameters and quantified intratumoral T cells by multiple methodologies. Low intratumoral T cells associated with approximately sixfold higher TMTV, and FL nodes from patients with high TMTV showed increased malignant B-cell infiltration and fewer clonally expanded intratumoral CD8+ and CD4+ T-follicular helper cells than those with low TMTV. However, fluorescently labeled glucose uptake was higher in CD4+ and CD8+ T cells than intratumoral B cells. In patients with FDG-PET performed prior to excisional biopsy, SUVmax within the subsequently excised node associated with T cells but not B cells. In summary, TMTV best reflects the malignant B-cell burden in FL, whereas intratumoral T cells influence SUVmax. This may contribute to the contradictory results between the prognostic role of different FDG-PET parameters, particularly between short- and long-term T-cell-depleting chemoimmunotherapeutic regimens. The impact of glucose uptake in intratumoral T cells should be considered when interpreting pretherapy FDG-PET in FL., (© 2021 by The American Society of Hematology.)

Background: Galcanezumab is a calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) indicated for the preventive treatment of migraine. While galcanezumab has demonstrated efficacy in patients who did not respond to prior preventive medications in general, its efficacy in patients who did not benefit from individual, commonly prescribed preventive treatments due to inadequate efficacy or safety/tolerability remains unknown., Methods: CONQUER was a 3-month, randomized, double-blind, placebo-controlled, phase 3b study that enrolled patients with episodic or chronic migraine who had 2 to 4 migraine preventive medication category failures in the past 10 years. Patients were randomly assigned 1:1 to receive placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). Post hoc analyses were conducted to determine the efficacy of galcanezumab in patients who had not benefited from six of the most commonly prescribed migraine preventive medications. The mean change from baseline in monthly migraine headache days and ≥ 50 % response rates were assessed over months 1-3. Improvement in Migraine-Specific Questionnaire Role Function-Restrictive (MSQ-RFR) scores were assessed at month 3. The endpoints were estimated via mixed model with repeated measures., Results: The most common treatment failures due to inadequate efficacy or safety/tolerability, which at least 20 % of patients reported trying without benefit, included topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and metoprolol. Patients who had not previously benefited from these treatments had a greater mean reduction in monthly migraine headache days across months 1-3 in the galcanezumab group compared to placebo (all p < 0.01). More patients treated with galcanezumab experienced a ≥ 50 % reduction from baseline in monthly migraine headache days across months 1-3 compared to placebo (all p < 0.05). Galcanezumab-treated patients had a greater improvement in mean MSQ-RFR scores at month 3 compared to placebo (all p < 0.01)., Conclusions: In this population, galcanezumab was effective in reducing monthly migraine headache days, improving response rates, and enhancing quality of life in patients who had not previously benefited from topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and/or metoprolol due to inadequate efficacy or safety/tolerability., Trial Registration: ClinicalTrials.gov NCT03559257 (CONQUER).

Background: Surgical management of trauma in the last 20 years has evolved in parallel with the military's experience in the current conflicts. Therapies such as widespread tourniquet use, empiric administration of fresh frozen plasma, and airborne intensive care units had been viewed skeptically but are now common practice. There is an opportunity to expand the envelope of care even further through similarly innovative approaches and varied avenues of research., Results: As the molecular biology of trauma is elucidated, research methodologies must also be developed to capitalize on innovative approaches to resuscitation. Blood component therapy and control of bleeding remain as the fundamental concepts in trauma care. The inflammo-immune response to injury, however, plays an increasingly recognized role in recovery of organ function. Perhaps the inflammatory cascade of trauma can be manipulated to extend the treatment envelope of at risk trauma patients.In trauma, the additional challenge of delivering effective treatment, often required very early after injury, necessitates the development of treatments to be implemented on the front lines of trauma care that are cost-effective, portable, and environmentally stable. Future conflicts may not offer ready access to high-level surgical care; therefore, resuscitative therapies will be needed for wounded service members because they are evacuated to the surgeon. Manipulation of the inflammatory response to trauma may offer a solution. As our understanding of the immune response continues to develop, the potential for improved outcomes for the wounded expands., Conclusion: A review of basic concepts in immunology is necessary to appreciate any potential impact of immunotherapeutic approaches to trauma and inflammation. An overview of current options will focus on outcome benefits of available therapies and suggest possible areas for future investigation. Quantitative approaches will leverage basic science to identify high-yield strategies to improve care of the injured combatant., Level of Evidence: Review, level III.

Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4 + T cells in vitro. Tumors with hyperactive CTSS showed increased CD4 + T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P < .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators., (© 2020 by The American Society of Hematology.)

Management practices in early-stage (I/II) follicular lymphoma (FL) are variable and include radiation (RT), systemic therapy, or combined modality therapy (CMT). There is a paucity of data regarding maintenance rituximab in this cohort. We conducted an international retrospective study of patients with newly diagnosed early-stage FL staged with positron emission tomography (PET)-computed tomography and bone marrow biopsy. Three hundred sixty-five patients (stage I, n = 221), median age 63 years, treated from 2005-2017 were included, with a median follow-up of 45 months. Management included watchful waiting (WW; n = 85) and active treatment (n = 280). The latter consisted of RT alone (n = 171) or systemic therapy (immunochemotherapy [n = 63] or CMT [n = 46]). Forty-nine systemically treated patients received maintenance rituximab; 72.7% of stage I patients received RT alone, compared to 42.6% with stage II ( P < .001). Active therapies yielded comparable overall response rates ( P = .87). RT alone and systemic therapy without maintenance rituximab yielded similar progression-free survival (PFS) (hazard ratio [HR], 1.32; 95% confidence interval [CI], 0.77-2.34; P = .96). Maintenance rituximab improved PFS (HR, 0.24; 95% CI, 0.095-0.64; P = .017). The incidence of transformation was lower with systemic therapy compared to RT or WW (HR, 0.20; 95% CI, 0.070-0.61; P = .034). Overall survival was similar among all practices, including WW ( P = .40). In the largest comparative assessment of management practices in the modern era, variable practices each resulted in similar excellent outcomes. Randomized studies are required to determine the optimal treatment in early-stage FL., (© 2019 by The American Society of Hematology.)

The point-of-care ultrasound exam has become an essential tool for hemodynamic monitoring and resuscitation in the trauma bay as well as the intensive care unit. Transthoracic ultrasound provides a dynamic assessment of cardiac function, volume status, and fluid responsiveness that offers potential advantage over traditional methods of hemodynamic monitoring. More recently, a focused transthoracic echocardiography exam was described to improve immediate resuscitation of severely injured patients in the trauma bay. Transesophageal echocardiography (TEE) for trauma could expand upon the role of focused echocardiography. TEE offers improved visualization of cardiac anatomy and physiology, improved diagnostic accuracy, and real-time assessment of intraoperative resuscitation progress, particularly in the operating room. This review discusses the fundamental principles of echocardiography as well as different ultrasound modes with their respective strengths and limitations. It reviews the current literature on the use of TEE in trauma, and suggests views for a trauma resuscitation transesophageal echocardiography exam (TREE), including sample images and videos., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Cardiac arrest associated with drowning is a major public health concern with limited research available on outcome. This investigation aims to define the population at risk, and identify factors associated with neurologically favourable survival., Methods: The Cardiac Arrest Registry for Enhanced Survival (CARES) database was queried for patients who had suffered cardiac arrest following drowning between January 1, 2013 and December 31, 2015. The primary outcomes of interest were for favourable or unfavourable neurological outcome at hospital discharge, as defined by Cerebral Performance Category (CPC)., Results: A total of 919 drowning patients were identified. Neurological outcome data was available in 908 patients. Neurologically favourable survival was significantly associated with bystander CPR (Odds Ratio (OR)=2.94; 95% Confidence Interval (CI) 1.86-4.64; p<0.001), witnessed drowning (OR=2.6; 95% CI 1.69-4.01; p<0.001) and younger age (OR=0.97, 95% CI 0.96-0.98; p<0.001). Public location of drowning (OR=1.17; 95% CI 0.77-1.79; p=0.47), male gender (OR=0.9, 95% CI 0.57-1.43; p=0.66), and shockable rhythm (OR=1.54; 95% CI 0.76-3.12; p=0.23), were not associated with favourable neurological survival. AED application prior to EMS was associated with a decreased likelihood of favourable neurological outcome (OR=0.38; 95% CI 0.28-0.66; p<0.001). In multivariate analysis, bystander CPR (adjusted OR 3.02, 95% CI 1.85-4.92, p<0.001), witnessed drowning (adjusted OR 3.27, 95% CI 2.0-5.36, p<0.001) and younger age (adjusted OR 0.97, 95% CI 0.96-0.98, p<0.001) remained associated with neurologically favourable survival., Conclusions: Neurologically favourable survival after drowning remains low but is improved by bystander CPR. Shockable rhythms were uncommon and not associated with improved outcomes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The management of trauma patients has matured significantly since a systematic approach to trauma care was introduced nearly a half century ago. The resuscitation continuum emphasizes the effect that initial therapy has on the outcome of the trauma patient. The initiation of this continuum begins with prompt field medical care and efficient transportation to designated trauma centers, where lifesaving procedures are immediately undertaken. Resuscitation with packed red blood cells and plasma, in parallel with surgical or interventional radiologic source control of bleeding, are the cornerstones of trauma management. Adjunctive pharmacologic therapy can assist with resuscitation. Tranexamic acid is used in Europe with good results, but the drug is slowly being added to the pharmacy formulary of trauma centers in United States. Recombinant factor VIIa can correct abnormal coagulation values, but its outcome benefit is less clear. Vasopressin shows promise in animal studies and case reports, but has not been subjected to a large clinical trial. The concept of "early goal-directed therapy" used in sepsis may be applicable in trauma as well. An early, appropriately aggressive resuscitation with blood products, as well as adjunctive pharmacologic therapy, may attenuate the systemic inflammatory response of trauma. Future investigations will need to determine whether this approach offers a similar survival benefit.