Initial Insult Research Articles

Lgr5+ intestinal stem cells are required for organoid survival after genotoxic injury.

Progenitors and mature cells can maintain the intestinal epithelium by dedifferentiation and facultative intestinal stem cell (fISC) function when active ISCs (aISCs) are lost to damage. Here, we modeled fISC activation in intestinal organoids with doxorubicin (DXR), a chemotherapeutic known to ablate Lgr5+ aISCs in vivo. Similar fISC gene activation was observed between organoids treated with low vs high DXR, despite significantly decreased survival at the higher dose. aISCs exhibit dose-dependent loss after DXR but survive at doses compatible with organoid survival. We ablated residual aISCs after DXR using a Lgr52A-DTR allele and observed that aISC survival of the initial genotoxic insult is required for organoid survival following DXR. These results suggest that while typical fISC genes are activated by DXR injury in organoids, functional stemness remains dependent on the aISC pool. Finally, we show that human intestinal organoids require higher doses of DXR to induce loss of survival and downregulation of LGR5. Our data establish a reproducible model of DXR injury in intestinal organoids and reveal differences in in vitro responses to an established in vivo damage modality.

Cardiac function at follow-up in infants treated with therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy.

Compromised myocardial function and persistent elevated pulmonary vascular resistance are common among neonates treated with therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy (HIE). There is a lack of data regarding persistence of cardiac alterations after discharge from the neonatal intensive care unit (NICU). We assessed cardiovascular profiles after NICU discharge. Echocardiogram data, including speckle-tracking echocardiography (STE), were extracted from the latest outpatient scan. Data were compared by initial amplitude-integrated encephalography (aEEG) profiles on admission [normal vs. abnormal]. In total, 70 (19%) neonates had a follow-up echocardiogram (22 with initial normal aEEG, 48 with abnormal aEEG). Age at follow-up was similar between the two groups (6.2 vs. 7.7 months, [p = 0.08]). Neonates with an initially abnormal aEEG showed more negative Right Ventricle (RV)-peak global longitudinal strain (-28.2 vs. -26.0%, [p = 0.02]), RV-peak free wall longitudinal strain rate (-1.24 vs. -1.10 [1/second], [p = 0.01]), and RV-peak free wall longitudinal strain rate (-1.50 vs. -1.27 [1/second], [p = 0.001]). These associations remained after multilinear regression analysis, indicating persistent enhanced RV contraction in the abnormal aEEG group. Neonates with initial abnormal aEEG profiles exhibited increased RV contraction after NICU discharge. Future studies should explore long-term cardiovascular follow-up of neonates with HIE, beyond the perinatal period. What is the key message of your article? Cardiac performance in hypoxic ischemic encephalopathy is linked to adverse outcomes. Survivors with an abnormal aEEG at admission showed increased right ventricular contractility at follow-up, possibly related to an adverse adaptation to the initial insult. What does it add to the existing literature? This study offers insights into long-term cardiovascular outcomes in neonates with HIE, focusing on the link between initial aEEG abnormalities and later RV function. What is the impact? The findings underscore the importance of early cardiovascular assessments and monitoring in neonates undergoing TH for HIE, potentially guiding future follow-up protocols.

Circulating microRNAs and isomiRs as biomarkers for the initial insult and epileptogenesis in four experimental epilepsy models: The EPITARGET study.

Structural epilepsies can manifest months or years after the occurrence of an initial epileptogenic insult, making them amenable for secondary prevention. However, development of preventive treatments has been challenged by a lack of biomarkers for identifying the subset of individuals with the highest risk of epilepsy after the epileptogenic insult. Four different rat models of epileptogenesis were investigated to identify differentially expressed circulating microRNA (miRNA) and isomiR profiles as biomarkers for epileptogenesis. Plasma samples were collected on day 2 and day 9 during the latency period from animals that did or did not develop epilepsy during long-term video-electroencephalographic monitoring. miRNAs and isomiRs were identified and measured in an unsupervised manner, using a genome-wide small RNA sequencing platform. Receiver operating characteristic analysis was performed to determine the performance of putative biomarkers. Two days after an epileptogenic insult, alterations in the levels of several plasma miRNAs and isomiRs predicted epileptogenesis in a model-specific manner. One miRNA, miR-3085, showed good sensitivity (but low specificity) as a prognostic biomarker for epileptogenesis in all four models (area under the curve = .729, sensitivity = 83%, specificity = 64%, p < .05). Identified plasma miRNAs and isomiRs are mostly etiology-specific rather than common prognostic biomarkers of epileptogenesis. These data imply that in preclinical and clinical studies, it may be necessary to identify specific biomarkers for different epilepsy etiologies. Importantly, circulating miRNAs like miR-3085 with high negative predictive value for epileptogenesis in different etiologies could be useful candidates for initial screening purposes of epileptogenesis risk.

Role of genetics and epigenetics in Graves' orbitopathy.

Objectives The pathogenesis of Graves' orbitopathy (GO) remains to be fully elucidated. Here we reviewed the role of genetics and epigenetics. Design We conducted a PubMed search with the following key words: Graves' orbitopathy, thyroid eye disease; or Graves' ophthalmopathy; or thyroid-associated ophthalmopathy; and: genetic, or epigenetic, or gene expression, or gene mutation, or gene variant, or gene polymorphism, or DNA methylation, or DNA acetylation. Articles in which whole DNA and/or RNA sequencing, proteome and methylome analysis were performed were chosen. Results The different prevalence of GO in the two sexes as well as racial differences suggest that genetics play a role in GO pathogenesis. In addition, the long-lasting phenotype of GO and of patient-derived orbital fibroblasts suggest a genetic or epigenetic mechanism. Although no genes have been found to confer a specific risk for GO, differential gene expression has been reported in orbital fibroblasts from GO patients vs control fibroblasts, suggesting that an epigenetic mechanism may be involved. In this regard, a different degree of DNA methylation, which affects gene expression, has been found between GO and control fibroblasts, which was confirmed by whole methylome analysis. Histone acetylation and deacetylation, which also affect gene expression, remain to be investigated. Conclusions Although pathogenetic gene variants have not been reported, epigenetic mechanisms elicited by an initial autoimmune insult seem to be needed for differential gene expression to occur and, thus, for GO to develop and persist over time.

Endothelial pyroptosis-driven microglial activation in choroid plexus mediates neuronal apoptosis in hemorrhagic stroke rats

BackgroundSpontaneous intracerebral hemorrhage (ICH) is associated with alarmingly high rates of disability and mortality, and current therapeutic options are suboptimal. A critical component of ICH pathology is the initiation of a robust inflammatory response, often termed “cytokine storm,” which amplifies the secondary brain injury following the initial hemorrhagic insult. The precise sources and consequences of this cytokine-driven inflammation are not fully elucidated, necessitating further investigation. MethodsTo address this knowledge gap, our study conducted a comprehensive cytokine profiling using Luminex® assays, assessing 23 key cytokines. We then employed single-cell RNA sequencing and spatial transcriptomics at three critical time points post-ICH: the hyperacute, acute, and subacute phases. Integrating these multimodal analyses allowed us to identify the cellular origins of cytokines and elucidate their mechanisms of action. ResultsLuminex® cytokine assays revealed a significant upregulation of IL-6 and IL-1β levels at the 24-h post-ICH time point. Through the integration of scRNA-seq and spatial transcriptomics in the hemorrhagic hemisphere of rats, we observed a pronounced activation of cytokine-related signaling pathways within the choroid plexus. Initially, immune cell presence was sparse, but it surged 24 h post-ICH, particularly in the choroid plexus, indicating a substantial shift in the immune microenvironment. We traced the source of IL-1β and IL-6 to endothelial cells, establishing a link to pyroptosis. Endothelial pyroptosis post-ICH induced the production of IL-1β and IL-6, which activated microglial polarization characterized by elevated expression of Msr1, Lcn2, and Spp1 via the NF-κB pathway in the choroid plexus. Furthermore, we identified neuronal populations undergoing apoptosis, mediated by the Lcn2-SLC22A17 pathway in response to IL-1β and IL-6 signaling. Notably, the inhibition of pyroptosis using VX-765 significantly mitigated neurological impairments. ConclusionsOur study provides evidence that endothelial pyroptosis, characterized by the release of IL-1β and IL-6, triggers microglial polarization through NF-κB pathway activation, ultimately leading to microglia-mediated neuronal apoptosis in the choroid plexus post-ICH. These findings suggest that targeted therapeutic strategies aimed at mitigating endothelial cell pyroptosis and neutralizing inflammatory cytokines may offer neuroprotection for both microglia and neurons, presenting a promising avenue for ICH treatment.

Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction.

The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.

Long-Term Disability After Traumatic Spinal Injuries: A Military Retrospective Study.

Traumatic spinal injuries (TSI) pose a significant life-long burden, impacting both military and civilian populations. Assessing long-term outcomes is crucial for comprehending the enduring consequences of the initial insult and informing effective prevention and management strategies. Most existing studies have narrowly focused on subsets of traumatic cord injuries, leaving a gap in understanding the broader impact of severe spinal trauma. This study aims to examine severe TSIs in military personnel, who may face unique risk factors and injury patterns, and its association with long-term disability. A retrospective cohort study was conducted on all military personnel who suffered traumatic injuries (Injury Severity Score ≥ 9) from 1997 to 2020. Severe spinal injuries were defined using the spinal Abbreviated Injury Scale ≥ 3 (n = 95), and compared to all other injuries as a reference group (n = 1,394). Data were extracted and cross-referenced from three distinct nationwide registries-pre-hospital, admission, and rehabilitation. Logistic regression analysis was used to evaluate the impact of spinal injuries on long-term disabilities (defined as the highest possible disability tier). The study received approval from the institutional review board of the Israel Defense Forces Medical Corps. Motor vehicle accidents and falls were the primary causes of spinal injuries (50.5% and 15.8%, respectively). The median age at injury was 20 years (interquartile range 19-22). Personnel with spinal trauma had a significantly higher prevalence of Injury Severity Score ≥ 25 (46.3% vs. 19.9%, P < .001), longer median hospital stays (11 vs. 8 days, P = .036), and increased intensive care unit admissions (55% vs. 40%, P = .05). The median follow-up duration was 10.9 years (interquartile range 6.7-14.3). Spinal injuries were associated with a more than 10-fold increase in the adjusted odds ratio for severe permanent disability (11.92, 95% CI, 5.95-23.72). Upon long-term follow-up, military personnel with severe TSI exhibit a significantly higher prevalence of debilitating disability compared to those with significant non-spinal traumatic injuries. These findings highlight the critical need for targeted prevention strategies and improved management of spinal injuries to reduce long-term disability. Strengths of this study include its extensive follow-up period and the use of multiple nationwide registries. However, the study may be limited by potential discrepancies in identity matching across databases and the reliance on disability claims, which may underrepresent the true prevalence of long-term disability. Future research should explore the efficacy of early interventions and rehabilitation strategies in mitigating long-term disability following spinal injuries. This study underscores the importance of developing evidence-based policies to enhance care for individuals with TSIs.

515. LAPAROSCOPIC PHARYNGO-COLOPLASTY WITH RIGHT COLON FOR A CASE OF COROSSIVE INJURY

Abstract Introduction Corrosive stricture of esophagus and stomach is more common in Acid poisoning. Management these cases requires good surgical planning, technical expertise in doing these complex procedures Case report A34 year gentleman consumed small quantity of sulphuric acid. Feeding jejunostomy was done for improving the nutrition. After 9 months of initial insult Upper GI scopy and CT NECK, CHEST, ABDOMEN was done which confirmed complete esophageal stricture from cricopharyx, thickened entire stomach. We Did LAPAROSCOPIC PHARYNGO-COLOPLASTY WITH RIGHT COLON. Intraoperatively thickened stomach, total gastrectomy done, Right colon used for Coloplasty.Post procedure patient recovered well, Drins removed on 4th post op day, patient was discharged on 6 th day. https://drive.google.com/file/d/15OkPYKjsoQ-NVceBUzUArFAqMzcnA02S/view?usp=drive_web

Local delivery of platelet-derived factors mitigates ischemia and preserves ovarian function through angiogenic modulation: A personalized regenerative strategy for fertility preservation

As the most prominent and ideal modality in female fertility preservation, ovarian tissue cryopreservation, and transplantation often confront the challenge of ischemic damage and follicular loss from avascular transplantation. To surmount this impediment, we engineered a novel platelet-derived factors-encapsulated fibrin hydrogel (PFH), a paradigmatic biomaterial. PFH encapsulates autologous platelet-derived factors, utilizing the physiological blood coagulation cascade for precise local delivery of bioactive molecules. In our study, PFH markedly bolstered the success of avascular ovarian tissue transplantation. Notably, the quantity and quality of follicles were preserved with improved neovascularization, accompanied by decreased DNA damage, increased ovulation, and superior embryonic development rates under a Low-concentration Platelet-rich plasma-derived factors encapsulated fibrin hydrogel (L-PFH) regimen. At a stabilized point of tissue engraftment, gene expression analysis mirrored normal ovarian tissue profiles, underscoring the effectiveness of L-PFH in mitigating the initial ischemic insult. This autologous blood-derived biomaterial, inspired by nature, capitalizes on the blood coagulation cascade, and combines biodegradability, biocompatibility, safety, and cost-effectiveness. The adjustable properties of this biomaterial, even in injectable form, extend its potential applications into the broader realm of personalized regenerative medicine. PFH emerges as a promising strategy to counter ischemic damage in tissue transplantation, signifying a broader therapeutic prospect. (197 words)

Dextromethorphan Associated Neurotoxicity with Cerebellar Edema (DANCE) Syndrome in Young Children: Neuroimaging Features.

Dextromethorphan toxicity in young children (especially those with age 4 years or younger) can have an extremely poor prognosis if untreated. However, if timely recognized and optimally managed, it can have a good clinical outcome despite significant initial insult. We present 3 pediatric cases (< 5 years old) with sudden unresponsiveness following ingestion of cough medications containing dextromethorphan. All these children showed cytotoxic edema in cerebellar hemispheres on MR brain, with diffusion restricting foci in supratentorial white matter in 2 patients. These features resemble the recently described acute opioid toxidrome in children, the POUNCE syndrome (Pediatric Opioid Use-associated Neurotoxicity with Cerebellar Edema). Hence, we name this entity "DANCE" (Dextromethorphan Associated Neurotoxicity with Cerebellar Edema) to increase the awareness of dextromethorphan toxicity in young children and the need to promptly recognize it to initiate optimal management.ABBREVIATIONS: POUNCE= Pediatric Opioid Use-associated Neurotoxicity with Cerebellar Edema; DANCE= Dextromethorphan Associated Neurotoxicity with Cerebellar Edema.

Beyond the Initial Insult: Clinical Characteristics and Prognosis of Heart Failure with Improved Ejection Fraction

Introduction: Heart failure with improved ejection fraction (HFimpEF) is a recently defined subtype of HF, characterized by an increase in ejection fraction (EF) after a prior diagnosis of reduced EF. There are limited data on the characteristics and outcome of this patient subset. The study aimed to investigate the clinical profile and prognosis of this patient group. Methods: HFimpEF patients from a large echocardiography database with comprehensive clinical and outcome data were evaluated for clinical characteristics and outcomes including mortality and cardiovascular hospitalizations. HFimpEF was defined as prior HF diagnosis with EF ≤40% followed by an EF increase of ≥10% to >40%. Results: The study included 2,883 patients with an EF ≤40%. 27% (777) fulfilled criteria of HFimpEF. Non-ischemic cardiomyopathy, female sex, and smaller left ventricular dimensions were associated with EF improvement. Median follow-up duration was 1,346 days. Patients with HFimpEF had a significantly improved prognosis compared to those without EF improvement. Patients with a significant improvement in the EF (≥50%) experienced a 30% lower mortality rate (HR: 0.70, 95% CI: 0.57–0.86, p < 0.001) and a decreased risk of cardiovascular hospitalizations. Conclusions: HFimpEF is a distinct clinical entity observed in 27% of patients with initially reduced EF and conveys a better prognosis. However, even with improvement, EF in most patients does not fully recover, and clinical events can still occur.

Calcium and Non-Penetrating Traumatic Brain Injury: A Proposal for the Implementation of an Early Therapeutic Treatment for Initial Head Insults.

Finding an effective treatment for traumatic brain injury is challenging for multiple reasons. There are innumerable different causes and resulting levels of damage for both penetrating and non-penetrating traumatic brain injury each of which shows diverse pathophysiological progressions. More concerning is that disease progression can take decades before neurological symptoms become obvious. Currently, the primary treatment for non-penetrating mild traumatic brain injury, also called concussion, is bed rest despite the fact the majority of emergency room visits for traumatic brain injury are due to this mild form. Furthermore, one-third of mild traumatic brain injury cases progress to long-term serious symptoms. This argues for the earliest therapeutic intervention for all mild traumatic brain injury cases which is the focus of this review. Calcium levels are greatly increased in damaged brain regions as a result of the initial impact due to tissue damage as well as disrupted ion channels. The dysregulated calcium level feedback is a diversity of ways to further augment calcium neurotoxicity. This suggests that targeting calcium levels and function would be a strong therapeutic approach. An effective calcium-based traumatic brain injury therapy could best be developed through therapeutic programs organized in professional team sports where mild traumatic brain injury events are common, large numbers of subjects are involved and professional personnel are available to oversee treatment and documentation. This review concludes with a proposal with that focus.

Biliary atresia.

Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.

Targeting the Epigenome Reduces Keloid Fibroblast Cell Proliferation, Migration, and Invasion

Keloids are pathological fibroproliferative scars resulting from abnormal collagen deposition within and beyond the margins of the initial cutaneous insult. Keloids negatively impact quality of life functionally and cosmetically, with current treatment modalities unsatisfactory. Recent studies indicate that epigenetic dysregulation is central to the development and progression of keloids. Here we evaluate the functional significance of epigenetic targeting strategies in vitro using patient-derived keloid fibroblasts treated with small molecule inhibitors of HDACs, LSD1, CoREST and p300, as potential therapies for keloids. We find that both the dual-acting CoREST inhibitor, corin, and the HDAC inhibitor, entinostat, reduce fibroblast proliferation more than the LSD1 inhibitor, GSK-LSD1; additionally, corin was the most effective inhibitor of migration and invasion across keloid fibroblasts. RNA-seq analysis of keloid fibroblasts treated with corin demonstrates coordinate upregulation of many genes including key mediators of cell adhesion such as claudins. Corin also downregulates gene sets involved in cell cycle progression, including reduced expression of cyclins A1 and B2 compared to DMSO. These results highlight a significant role for epigenetic regulation of pathologic mediators of keloidal scarring and suggest that inhibitors of the epigenetic CoREST repressor complex may prove beneficial in the prevention and/or treatment of keloidal scarring in patients.

Insights from serial magnetic resonance imaging in neonatal encephalopathy in term infants.

Limited serial neuroimaging studies use magnetic resonance imaging (MRI) to define the evolution of hypoxic-ischemic insults to the brain of term infants and encompass both the primary injury and its secondary impact on cerebral development. The optimal timing of MRI to fully evaluate the impact of hypoxic-ischemic encephalopathy on brain development and associated neurodevelopmental sequelae remains unknown. Goals: (a) review literature related to serial neuroimaging in term infants with HIE; (b) describe pilot data in two infants with HIE treated with therapeutic hypothermia who had a brain injury at day 3-5 and underwent four additional MRIs over the next 12 weeks of life and developmental evaluation at 24 months of age. Early MRI defines primary injury on diffusion-weighted imaging, yet the full impact may not be fully apparent until after 1 month of life. The full impact of an ischemic injury on the neonatal brain may not be fully visible until several weeks after the initial insult. This suggests the benefit of obtaining later time points for MRI to fully define the extent of injury and its neurodevelopmental impact. Few studies inform the nature of the evolution of brain injury with hypothermia in HIE, limiting understanding of potential neuroprotection. MRI is the standard of care for prognosis in infants with HIE, however timing for optimal prognostic prediction remains unclear. Insights from MRI after the first week of life may assist in defining the full extent of brain injury and prognostic significance. A pilot study using five MRI timepoints up to 3 months of age, is presented. More data is required with a systematic evaluation of the impact of early brain injury on brain development in term infants with HIE following TH.

Understanding epileptogenesis from molecules to network alteration.

Epilepsy is characterized by recurrent seizures. Following an initial insult, a latent period precedes the onset of spontaneous seizures, a process referred to as epileptogenesis. This period plays a critical role in halting the progression toward epilepsy before the onset of abnormal molecular and network alterations. In this study, the fundamental concepts of epileptogenesis as well as the associated molecular and cellular targets are reviewed.

Radiation-induced Renal Artery Stenosis

We present a case of a 33 year old male presenting with uncontrolled hypertension, requiring four drugs and renal dysfunction. Investigations revealed calcific atherosclerosis of abdominal aorta and bilateral renal artery stenosis. He had received radiotherapy for abdominal Non-Hodgkin’s lymphoma 14 years ago. Transluminal angioplasty was done on the right side resulting in improved renal function and normalization of blood pressure. Radiotherapy for intra-abdominal malignancy induces atherosclerosis process in arteries within field of irradiation and they manifest after many years of the initial insult.

Pro- and Anti-Inflammatory Responses Following Active and Passive Ascent to 3600 m

Lowlanders who develop acute mountain sickness (AMS) following rapid ascent to high altitude (HA) demonstrate increased levels of both pro-inflammatory (tumor necrosis factor α (TNFα), Interleukin (IL)- 1β, IL-6, IL-8, and IL-17α) and anti-inflammatory biomarkers (IL-10 and IL-1 receptor agonist; IL-1ra). Whether ascending by self-locomotion (i.e., active ascent) modulates these pro- and anti-inflammatory cytokine responses at HA is unknown. We hypothesized a greater pro-inflammatory response in the AMS-susceptible group following active ascent. To test this hypothesis, 78 healthy Soldiers (mean±SD; age, 26±5yr) were tested at baseline residence (BLR), transported to Taos, NM (2845m), then hiked (n=39) or were driven (n=39) to HA (3600m), and stayed for 4 days. AMS-Cerebral factor score (AMS-C) was assessed using the Environmental Symptoms Questionnaire (ESQ) at HA twice on day 1 (HA1). If AMS-C was ≥0.7 at either assessment, individuals were categorized as AMS-susceptible (AMS+; n=24); others were AMS-resistant (AMS−; n=54). Fasting blood samples were taken at 06:00 at BLR, HA2, HA3 and HA4 and analyzed to determine cytokine (TNFα, IL-1β, IL-6, IL-8, IL-10, IL-17α, and IL-1ra) responses following the initial hypoxic insult. Blood values (pg/mL) were log-transformed and adjusted for plasma volume changes from BLR to HA. The active group expended a greater ( p&lt;0.05) amount of energy (745±435 kcal) than the passive group (55±10 kcal) during ascent. There were no differences in biomarkers between ascent groups, so data were combined. In the AMS-susceptible group, IL-17α increased ( p&lt;0.05) from BLR to HA2 (63.3±8.8 to 73.1±8.8, p=0.002) and remained increased at HA3 (70.1±8.8) and HA4 (73.1±8.8). In the AMS-resistant group, IL-17α did not change from BLR to any of the days at HA. Independent of AMS susceptibility, the anti-inflammatory marker IL-1ra increased from BLR to HA2 (63.5±11.4 to 89.9±11.4, p=0.013) and then fell back down to BLR values on HA3 (70.4±11.4, p=0.560) and HA4 (71.8±11.4, p=0.537). When all days were combined, TNFα (+15%, p=0.036), IL-6 (+50%, p=0.042), and IL-10 (+36%, p=0.040) were increased in the AMS-susceptible compared to the AMS-resistant group. IL-1β and IL-8 did not change ( p&gt;0.05) from BLR to any time point at HA in either group. In conclusion, both a robust pro- (TNFα, IL-6, IL-17α) and anti-inflammatory (IL-10) response occurred at HA in those susceptible to AMS most likely due to inflammation following the initial hypoxic insult followed quickly by an anti-inflammatory response. However, ascent strategy on HA1 had no impact on pro- or anti-inflammatory cytokines on days 2-4 at HA. Authors’ views not offcial U.S. Army or DoD policy. Funding: USAMRDC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A scale-free model of acute and ventilator-induced lung injury: a network theory approach inspired by seismology.

Acute respiratory distress syndrome (ARDS) presents a significant clinical challenge, with ventilator-induced lung injury (VILI) being a critical complication arising from life-saving mechanical ventilation. Understanding the spatial and temporal dynamics of VILI can inform therapeutic strategies to mitigate lung damage and improve outcomes. Histological sections from initially healthy mice and pulmonary lavage-injured mice subjected to a second hit of VILI were segmented with Ilastik to define regions of lung injury. A scale-free network approach was applied to assess the correlation between injury regions, with regions of injury represented as 'nodes' in the network and 'edges' quantifying the degree of correlation between nodes. A simulated time series analysis was conducted to emulate the temporal sequence of injury events. Automated segmentation identified different lung regions in good agreement with manual scoring, achieving a sensitivity of 78% and a specificity of 85% across 'injury' pixels. Overall accuracy across 'injury', 'air', and 'other' pixels was 81%. The size of injured regions followed a power-law distribution, suggesting a 'rich-get-richer' phenomenon in the distribution of lung injury. Network analysis revealed a scale-free distribution of injury correlations, highlighting hubs of injury that could serve as focal points for therapeutic intervention. Simulated time series analysis further supported the concept of secondary injury events following an initial insult, with patterns resembling those observed in seismological studies of aftershocks. The size distribution of injured regions underscores the spatially heterogeneous nature of acute and ventilator-induced lung injury. The application of network theory demonstrates the emergence of injury 'hubs' that are consistent with a 'rich-get-richer' dynamic. Simulated time series analysis demonstrates that the progression of injury events in the lung could follow spatiotemporal patterns similar to the progression of aftershocks in seismology, providing new insights into the mechanisms of injury distribution and propagation. Both phenomena suggest a potential for interventions targeting these injury 'hubs' to reduce the impact of VILI in ARDS management.

The Use of Oxandrolone in the Management of Severe Burns: A Multi-service Survey of Burns Centres and Units Across the United Kingdom.

Introduction Severe thermal burns are a catastrophic injury. Those surviving the initial insult are subject to life-long disability, prolonged hospital admission, nutritional issues and poor wound healing. Oxandrolone has been shown to reduce hospital duration and promote lean body mass. Despite not being licenced for use in burns trauma within the United Kingdom (UK), services across the country utilise Oxandrolone in the management of severe burns. We aim to analyse the use of Oxandrolone in major burns across burns services within the UK. Methods We conducted a survey across all burn centres and units across the UK. Any burns service provider with experience in patient management of patients sustaining burns with a total body surface area >15% was included. All services were identified using the British Burns Association website. We conducted a survey of all centres and units and contacted them via telephone through the trust's switchboard. Responses were accepted from any healthcare staff familiar with the day-to-day in-patient care of patients on the ward. Services with no in-patient services were excluded. Results A total of 24 burns centres and services responded to our survey. Twelve of the respondents were in a burns unit and 12 were in a burns centre. Eight respondents were paediatric facilities, and the remaining 16 dealt with adult burns. In total, 16/24 (66.6%) services reported using Oxandrolone. Conversely, 8/24 (33.3%) burns services denied using Oxandrolone. 7/12 (58.3%) burns units use Oxandrolone in the management of burns. 5/12 (42.7%) burns units do not use Oxandrolone in severe burns. 9/12 (75%) of burns centres described using Oxandrolone, whilst the remaining 3/12 (25%) did not. Discussion Oxandrolone is used varyingly across burns services across the UK. Burns centres were more likely to use Oxandrolone compared to units. We also find that more paediatric services used Oxandrolone in comparison to adult services. Studies have shown that the benefit of Oxandrolone is not age-dependent. Further work is required to assess the impact of this medication on patients with severe burns and national guidance would help further improve burns management across the UK.