Structural perspectives on adenosine to inosine RNA editing by ADARs.

Adenosine deaminases acting on RNA (ADARs) are enzymes that catalyze the hydrolytic deamination of adenosine to inosine. The editing feature of ADARs has garnered much attention as a therapeutic tool to repurpose ADARs to correct disease-causing mutations at the mRNA level in a technique called site-directed RNA editing (SDRE). Administering a short guide RNA oligonucleotide that hybridizes to a mutant sequence forms the requisite dsRNA substrate, directing ADARs to edit the desired adenosine. However, much is still unknown about ADARs' selectivity and sequence-specific effects on editing. Atomic-resolution structures can help provide additional insight to ADARs' selectivity and lead to novel guide RNA designs. Indeed, recent structures of ADAR domains have expanded our understanding on RNA binding and the base-flipping catalytic mechanism. These efforts have enabled the rational design of improved ADAR guide strands and advanced the therapeutic potential of the SDRE approach. While no full-length structure of any ADAR is known, this review presents an exposition of the structural basis for function of the different ADAR domains, focusing on human ADAR2. Key insights are extrapolated to human ADAR1, which is of substantial interest because of its widespread expression in most human tissues.

An assessment of nationwide trends in emergency department (ED) resuscitative endovascular balloon occlusion of the aorta (REBOA) use - A trauma quality improvement program registry analysis.

BACKGROUND: Use of resuscitative endovascular balloon occlusion of the aorta (REBOA) for temporary hemorrhage control in severe non-compressible torso trauma remains controversial, with limited data on patient selection and outcomes. This study aims to analyze the nationwide trends of its use in the emergency department (EDs). METHODS: A retrospective analysis of the American College of Surgeons Trauma Quality Improvement Program (ACS-TQIP) from 2017 to 2022 was performed, focusing on REBOA placements in EDs. RESULTS: The analysis included 3398 REBOA procedures. Majority patients were male (76 â€‹%) with a median age of 40 years (27-58) and injury severity score of 20 (20-41). The most common mechanism was collision (64 â€‹%), with emergency surgeries most frequently performed for pelvic trauma (14 â€‹%). Level 1 trauma centers performed 82 â€‹% of these procedures, with consistent low annual utilization (<200 facilities). Survival rates were 85 â€‹% at 1-h post-placement, decreasing significantly to 42 â€‹% by discharge. CONCLUSIONS: REBOA usage in remains limited but steady, primarily occurring at level 1 trauma center EDs. While short-term survival rates are favorable, they drop significantly by the time of discharge.

Venous thromboembolic events associated with blood product administration in an era of whole blood use.

BACKGROUND: The risks associated with blood product administration and venous thromboembolic events remains unclear. We sought to determine which blood products were associated with the development of deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: We analyzed data from patients ≥18 years of age in the Trauma Quality Improvement Program (TQIP) database that received ≥1 blood product and survived ≥24 â€‹h. RESULTS: There were 42,399 that met inclusion, of whom, 2086 had at least one VTE event. In our multivariable logistic regression model, we found that WB had a unit odds ratio (uOR) of 1.05 (95 â€‹% CI 1.02-1.08) for DVT and 1.08 (1.05-1.12) for PE. Compared to WB, platelets had a higher uOR for DVT of 1.09 (1.04-1.13) but similar uOR for PE of 1.08 (1.03-1.14). CONCLUSIONS: We found an association of both DVT and PE with early whole blood and platelets.

A safety and feasibility analysis on the use of cold-stored platelets in combat trauma.

BACKGROUND: Damage-control resuscitation has come full circle, with the use of whole blood and balanced components. Lack of platelet availability may limit effective damage-control resuscitation. Platelets are typically stored and transfused at room temperature and have a short shelf-life, while cold-stored platelets (CSPs) have the advantage of a longer shelf-life. The US military introduced CSPs into the battlefield surgical environment in 2016. This study is a safety analysis for the use of CSPs in battlefield trauma. METHODS: The Department of Defense Trauma Registry and Armed Services Blood Program databases were queried to identify casualties who received room-temperature-stored platelets (RSPs) or both RSPs and CSPs between January 1, 2016, and February 29, 2020. Characteristics of recipients of RSPs and RSPs-CSPs were compared and analyzed. RESULTS: A total of 274 patients were identified; 131 (47.8%) received RSPs and 143 (52.2%) received RSPs-CSPs. The casualties were mostly male (97.1%), similar in age (31.7 years), with a median Injury Severity Score of 22. There was no difference in survival for recipients of RSPs (88.5%) versus RSPs-CSPs (86.7%; p = 0.645). Adverse events were similar between the two cohorts. Blood products received were higher in the RSPs-CSPs cohort compared with the RSPs cohort. The RSPs-CSPs cohort had more massive transfusion (53.5% vs. 33.5%, p = 0.001). A logistic regression model demonstrated that use of RSPs-CSPs was not associated with mortality, with an adjusted odds ratio of 0.96 (p > 0.9; 95% confidence interval, 0.41-2.25). CONCLUSION: In this safety analysis of RSPs-CSPs compared with RSPs in a combat setting, survival was similar between the two groups. Given the safety and logistical feasibility, the results support continued use of CSPs in military environments and further research into how to optimize resuscitation strategies. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

A Scoping Review of Military Combat Casualty Data on Submassive, Massive, and Supermassive Transfusions.

INTRODUCTION: Blood transfusions are common during combat casualty care, aiming to address the loss of blood volume that often accompanies severe battlefield injuries. This scoping review delves into the existing military combat casualty data to analyze the efficacy, challenges, and advances in the use of massive and super-massive transfusions in the management of critically injured warfighters. MATERIALS AND METHODS: We performed a scoping review of combat-related literature published between 2006 and 2023 pertaining to massive transfusions used during combat deployments. We utilized PubMed to identify relevant studies and utilized the PRISMA-ScR Checklist to conduct the review. RESULTS: We identified 53 studies that met the inclusion criteria with the majority being retrospective studies from registries used by the United States, British, French, and Dutch Militaries. Most of the studies focused on transfusion ratios, the movement of blood transfusions to more forward locations, implementation of massive transfusions with different fibrinogen-to-red blood cell ratios, the addition of recombinant factor VII, and the use of predictive models for transfusion. Lastly, we identified reports of improved survival for casualties with the rapid implementation of various blood products (warm fresh whole blood, cold-stored low titer group O blood, freeze-dried plasma, and component therapy) and literature relating to pediatric casualties and submassive transfusions. Notable findings include the establishment of hemodynamic and cell blood count parameters as predictors of the requirement for massive transfusions and the association of higher fibrinogen-to-red blood cell ratios with decreased mortality. CONCLUSIONS: We identified 53 studies focused on blood transfusions from the Global War on Terrorism conflicts. The majority were related to transfusion ratios and the movement of blood transfusions to more forward locations. We highlight key lessons learned on the battlefield that have been translated into scientific developments and changes in civilian trauma methods.

Measuring patient-reported experience of solid organ transplantation healthcare: A scoping review of condition- and transplant-specific measures.

BACKGROUND: Measures of patient experience are increasingly valued as key to healthcare quality assessment. We aimed to identify and describe publicly available measures assessing patient-reported experience of solid organ transplantation healthcare, and identify patient groups, healthcare settings, or aspects of patient experience underserved by existing measures. METHODS: We systematically searched MEDLINE, Embase, CINAHL, PsycINFO, Cochrane CENTRAL, Scopus and Web of Science from inception to 6th July 2023; supplemented with grey literature searches. Two reviewers independently screened search hits; outputs reporting patient-reported measures of multiple aspects of established solid organ transplantation healthcare were eligible. We abstracted measure context, characteristics, content (i.e., attributes of patient experience assessed), and development and validation processes. RESULTS: We identified nine outputs reporting eight measures of patient experience; these related only to kidney (n = 5) or liver (n = 3) transplantation, with no available measures relating to heart, lung, pancreas or intestinal transplantation. Of the identified measures, four were specific to solid organ transplant recipients. Measures sought to assess "patient satisfaction" (n = 4) and "patient experience" (n = 4) of healthcare. Measures mapped to between five and 16 of 20 attributes of patient experience, most often Information and education, Communication, and Access to care (all n = 7). Six measures reported a development process, only three reported a validation process. CONCLUSIONS: Publicly available patient-reported measures of organ transplantation healthcare experiences are limited to kidney and liver transplantation. There is heterogeneity in measure context, characteristics, and content, and insufficient clarity concerning how well measures capture the specific experiences of transplant recipients. Formalised measures of patient experience, specific to solid organ transplantation, with transparent reporting of development and validity are needed.

PAAD: Panelization algorithm for architectural designs.

Due to the competitive nature of the construction industry, the efficiency of requirement analysis is important in enhancing client satisfaction and a company's reputation. For example, determining the optimal configuration of panels (generally called panelization) that form the structure of a building is one aspect of cost estimation. However, existing methods typically rely on rule-based approaches that may lead to suboptimal material usage, particularly in complex designs featuring angled walls and openings. Such inefficiency can increase costs and environmental impact due to unnecessary material waste. To address these challenges, this research proposes a Panelization Algorithm for Architectural Designs, referred to as PAAD, which utilizes a genetic evolutionary strategy built on the 2D bin packing problem. This method is designed to balance between strict adherence to manufacturing constraints and the objective of optimizing material usage. PAAD starts with multiple potential solutions within the predefined problem space, facilitating dynamic exploration of panel configurations. It approaches structural rules as flexible constraints, making necessary corrections in post-processing, and through iterative developments, the algorithm refines panel sets to minimize material use. The methodology is validated through an analysis against an industry implementation and expert-derived solutions, highlighting PAAD's ability to surpass existing results and reduce the need for manual corrections. Additionally, to motivate future research, a synthetic data generator, the architectural drawing encodings used, and a preliminary interface are also introduced. This not only highlights the algorithm's practical applicability but also encourages its use in real-world scenarios.

An Analysis of Tube Thoracostomy in Combat Implications for Improved Prehospital Recognition and Treatment.

BACKGROUND: Thoracic trauma occurs frequently in combat and is associated with high mortality. Tube thoracostomy (chest tube) is the treatment for pneumothorax resulting from thoracic trauma, but little data exist to characterize combat casualties undergoing this intervention. We sought to describe the incidence of these injuries and procedures to inform training and materiel development priorities. METHODS: This is a secondary analysis of a Department of Defense Trauma Registry (DoDTR) data set from 2007 to 2020 describing prehospital care within all theaters in the registry. We described all casualties who received a tube thoracostomy within 24 hours of admission to a military treatment facility. Variables described included casualty demographics; abbreviated injury scale (AIS) score by body region, presented as binary serious (=3) or not serious (<3); and prehospital interventions. RESULTS: The database identified 25,897 casualties, 2,178 (8.4%) of whom received a tube thoracostomy within 24 hours of admission. Of those casualties, the body regions with the highest proportions of common serious injury (AIS >3) were thorax 62% (1,351), extremities 29% (629), abdomen 22% (473), and head/neck 22% (473). Of those casualties, 13% (276) had prehospital needle thoracostomies performed, and 19% (416) had limb tourniquets placed. Most of the patients were male (97%), partner forces members or humanitarian casualties (70%), and survived to discharge (87%). CONCLUSIONS: Combat casualties with chest trauma often have multiple injuries complicating prehospital and hospital care. Explosions and gunshot wounds are common mechanisms of injury associated with the need for tube thoracostomy, and these interventions are often performed by enlisted medical personnel. Future efforts should be made to provide a correlation between chest interventions and pneumothorax management in prehospital thoracic trauma.

Considerations in gender-affirming hormone therapy in transgender and gender diverse patients undergoing liver transplantation.

Liver transplantation is lifesaving for patients with end-stage liver disease. Similar to the role of transplantation for patients with end-stage liver disease, gender-affirming hormone therapy (GAHT) can be lifesaving for transgender and gender diverse (TGGD) patients who experience gender dysphoria. However, management of such hormone therapy during the perioperative period is unknown and without clear guidelines. Profound strides can be made in improving care for TGGD patients through gender-affirming care and appropriate management of GAHT in liver transplantation. In this article, we call for the transplant community to acknowledge the integral role of GAHT in the care of TGGD liver transplant candidates and recipients. We review the current literature and describe how the transplant community is ethically obligated to address this health care gap. We suggest tangible steps that clinicians may take to improve health outcomes for this minoritized patient population.

Incidence of Coagulopathy After Resuscitation at a Role 1 Facility: The Prehospital Trauma Registry Experience.

BACKGROUND: The development of acute traumatic coagulopathy is associated with increased mortality and morbidity in patients with battlefield traumatic injuries. Currently, the incidence of acute traumatic coagulopathy in the Role 1 setting is unclear. METHODS: We queried the Prehospital Trauma Registry (PHTR) module of the Department of Defense Trauma Registry (DoDTR) for all encounters from inception through May 2019. The PHTR captures data on Role 1 prehospital care. Data from the PHTR was linked to the DoDTR to analyze laboratory data and patient outcomes using descriptive statistics. We defined coagulopathy as an international normalized ratio (INR) of ≥1.5 or platelet count ≤150×109/L. RESULTS: A total of 595 patients met the inclusion criteria; 36% (212) met our definition for coagulopathy, with 31% (185) carrying low platelet numbers, 11% (68) showing an elevated INR, and 7% (41) with both. The baseline (no coagulopathy) cohort had a mean INR of 1.10 (95% CI 1.09-1.12) versus 1.38 (95% CI 1.33-1.43) in the coagulopathic cohort. The mean platelet count was 218 (95% CI 213-223) ×109/L in the baseline cohort versus 117 (95% CI 110-125) ×109/L in the coagulopathic cohort. CONCLUSIONS: Our findings indicate a high incidence of coagulopathy in trauma patients. Approximately one-third of wounded patients had laboratory evidence of coagulopathy upon presentation to a forward medical care facility. Advanced diagnostic facilities are therefore needed to facilitate early diagnosis of acute traumatic coagulopathy. Blood products with a long shelf life can aid in early correction.

Sexual Health for Transgender and Gender Diverse Individuals: Routine Examination, Sexually-Transmitted Infection Screening, and Prevention.

Gynecologists play a critical role in the office evaluation of transgender and gender diverse individuals. This includes the provision of essential healthcare services including the treatment and prevention of human immunodeficiency virus and sexually-transmitted infections and screening for human papillomavirus infection-related diseases and cancers. Caring for patients who identify as transgender or gender diverse (TGD) and who have undergone gender-affirming surgical treatments is challenging due in part to clinical gaps in knowledge resulting from insufficient training and educational resources. A patient-centered approach to the care of TGD individuals requires knowledge of the general principles of affirming, holistic care with attention to the risk factors, and anatomic considerations unique to this population. This review aims to provide basic knowledge needed for the successful gynecologic evaluation of a gender diverse patient.

Extracorporeal photopheresis (ECP) in the treatment of chronic lung allograft dysfunction (CLAD): a prospective, multicentre, open-label, randomised controlled trial studying the addition of ECP to standard care in the treatment of bilateral lung transplant patients with CLAD (E-CLAD UK).

BACKGROUND: Long-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop via multiple immune pathways, is captured under the umbrella term chronic lung allograft dysfunction (CLAD). Despite the availability of powerful immunosuppressive drugs, there are presently no treatments proven to reverse or reliably halt the loss of lung function caused by CLAD. The aim of the E-CLAD UK trial is to determine whether the addition of immunomodulatory therapy, in the form of extracorporeal photopheresis (ECP), to standard care is more efficacious at stabilising lung function in CLAD compared with standard care alone. METHODS AND ANALYSIS: E-CLAD UK is a Phase II clinical trial of an investigational medicinal product (Methoxsalen) delivered to a buffy coat prepared via an enclosed ECP circuit. Target recruitment is 90 bilateral lung transplant patients identified as having CLAD and being treated at one of the five UK adult lung transplant centres. Participants will be randomised 1:1 to intervention plus standard of care, or standard of care alone. Intervention will comprise nine ECP cycles spread over 20 weeks, each course involving two treatments of ECP on consecutive days. All participants will be followed up for a period of 24 weeks.The primary outcome is lung function stabilisation derived from change in forced expiratory volume in one second and forced vital capacity at 12 and 24 weeks compared with baseline at study entry. Other parameters include change in exercise capacity, health-related quality of life and safety. A mechanistic study will seek to identify molecular or cellular markers linked to treatment response and qualitative interviews will explore patient experiences of CLAD and the ECP treatment.A patient and public advisory group is integral to the trial from design to implementation, developing material to support the consent process and interview materials. ETHICS AND DISSEMINATION: The East Midlands-Derby Research Ethics Committee has provided ethical approval (REC 22/EM/0218). Dissemination will be via publications, patient-friendly summaries and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT number 2022-002659-20; ISRCTN 10615985.

The employment of resuscitative endovascular balloon occlusion of the aorta in deployed settings.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) has been often used in place of open aortic occlusion for management of hemorrhagic shock in trauma. There is a paucity of data evaluating REBOA usage in military settings. STUDY DESIGN AND METHODS: We queried the Department of Defense Trauma Registry (DODTR) for all cases with at least one intervention or assessment available within the first 72 h after injury between 2007 and 2023. We used relevant procedural codes to identify the use of REBOA within the DODTR, and we used descriptive statistics to characterize its use. RESULTS: We identified 17 cases of REBOA placed in combat settings from 2017 to 2019. The majority of these were placed in the operating room (76%) and in civilian patients (70%). A penetrating mechanism caused the injury in 94% of cases with predominantly the abdomen and extremities having serious injuries. All patients subsequently underwent an exploratory laparotomy after REBOA placement, with moderate numbers of patients having spleen, liver, and small bowel injuries. The majority (82%) of included patients survived to hospital discharge. DISCUSSION: We describe 17 cases of REBOA within the DODTR from 2007 to 2023, adding to the limited documentation of patients undergoing REBOA in military settings. We identified patterns of injury in line with previous studies of patients undergoing REBOA in military settings. In this small sample of military casualties, we observed a high survival rate.

Early Vital Sign Thresholds Associated with 24-Hour Mortality among Trauma Patients: A Trauma Quality Improvement Program (TQIP) Study.

BACKGROUND: Identifying patients at imminent risk of death is critical in the management of trauma patients. This study measures the vital sign thresholds associated with death among trauma patients. METHODS: This study included data from patients ≥15 years of age in the American College of Surgeons Trauma Quality Improvement Program (TQIP) database. Patients with vital signs of zero were excluded. Documented prehospital and emergency department (ED) vital signs included systolic pressure, heart rate, respiratory rate, and calculated shock index (SI). The area under the receiver operator curves (AUROC) was used to assess the accuracy of these variables for predicting 24-hour survival. Optimal thresholds to predict mortality were identified using Youden's Index, 90% specificity, and 90% sensitivity. Additional analyses examined patients 70+ years of age. RESULTS: There were 1,439,221 subjects in the 2019-2020 datasets that met inclusion for this analysis with <0.1% (10,270) who died within 24 hours. The optimal threshold for prehospital systolic pressure was 110, pulse rate was 110, SI was 0.9, and respiratory rate was 15. The optimal threshold for the ED systolic was 112, pulse rate was 107, SI was 0.9, and respiratory rate was 21. Among the elderly sub-analysis, the optimal threshold for prehospital systolic was 116, pulse rate was 100, SI was 0.8, and respiratory rate was 21. The optimal threshold for ED systolic was 121, pulse rate was 95, SI was 0.8, and respiratory rate was 0.8. CONCLUSIONS: Systolic blood pressure (SBP) and SI offered the best predictor of mortality among trauma patients. The SBP values predictive of mortality were significantly higher than the traditional 90mmHg threshold. This dataset highlights the need for better methods to guide resuscitation as initial vital signs have limited accuracy in predicting subsequent mortality.

The use of extracorporeal photopheresis in solid organ transplantation-current status and future directions.

Prevention and management of allograft rejection urgently require more effective therapeutic solutions. Current immunosuppressive therapies used in solid organ transplantation, while effective in reducing the risk of acute rejection, are associated with substantial adverse effects. There is, therefore, a need for agents that can provide immunomodulation, supporting graft tolerance, while minimizing the need for immunosuppression. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy currently recommended in international guidelines as an adjunctive treatment for the prevention and management of organ rejection in heart and lung transplantations. This article reviews clinical experience and ongoing research with ECP for organ rejection in heart and lung transplantations, as well as emerging findings in kidney and liver transplantation. ECP, due to its immunomodulatory and immunosuppressive-sparing effects, offers a potential therapeutic option in these settings, particularly in high-risk patients with comorbidities, infectious complications, or malignancies.