CUT&Tag Applied to Zebrafish Adult Tail Fins Reveals a Return of Embryonic H3K4me3 Patterns During Regeneration.

Regenerative potential is governed by a complex process of transcriptional reprogramming, involving chromatin reorganization and dynamics in transcription factor binding patterns throughout the genome. The degree to which chromatin and epigenetic changes contribute to this process remains partially understood. Here we provide a modified CUT&Tag protocol suitable for improved characterization and interrogation of epigenetic changes during adult fin regeneration in zebrafish. Our protocol generates data that recapitulates results from previously published ChIP-Seq methods, requires far fewer cells as input, and significantly improves signal to noise ratios. We deliver high-resolution enrichment maps for H3K4me3 of uninjured and regenerating fin tissues. During regeneration, we find that H3K4me3 levels increase over gene promoters which become transcriptionally active and genes which lose H3K4me3 become silenced. Interestingly, these epigenetic reprogramming events recapitulate the H3K4me3 patterns observed in developing fin folds of 24-hour old zebrafish embryos. Our results indicate that changes in genomic H3K4me3 patterns during fin regeneration occur in a manner consistent with reactivation of developmental programs, demonstrating CUT&Tag to be an effective tool for profiling chromatin landscapes in regenerating tissues.

Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

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.

Generation, Characterization and Reactivity of a High-valent Mononuclear Cobalt(IV)-diazide Complex.

High-valent Fe(IV)=O intermediates of metalloenzymes have inspired numerous efforts to generate synthetic analogs to mimic and understand their substrate oxidation reactivities. However, high-valent M(IV) complexes of late transition metals are rare. We have recently reported a novel Co(IV)-dinitrate complex (1-NO3) that activates sp3 C-H bonds up to 87 kcal/mol. In this work, we have shown that the nitrate ligands in 1-NO3 can be replaced by azide, a more basic coordinating base, resulting in the formation of a more potent Co(IV)-diazide species (1-N3) that reacts with substrates (hydrocarbons and phenols) at faster rate constants and activates stronger C-H bonds than the parent complex 1-NO3. We have characterized 1-N3 employing a combination of spectroscopic and computational approaches. Our results clearly show that the coordination of azide leads to the modulation of the Co(IV) electronic structure and the Co(IV/III) redox potential. Together with the higher basicity of azide, these thermodynamic parameters contribute to the higher driving forces of 1-N3 than 1-NO3 for C-H bond activation. Our discoveries are thus insightful for designing more reactive bio-inspired high-valent late transition metal complexes for activating inert aliphatic hydrocarbons.

Thromboprophylaxis in hospitalized trauma patients: a systematic review and meta-analysis of implementation strategies.

Introduction: Venous thromboembolism (VTE) prophylaxis implementation strategies are well-studied in some hospitalized medical and surgical patients. Although VTE is associated with substantial mortality and morbidity in trauma patients, implementation strategies for the prevention of VTE in trauma appear to be based on limited evidence. Therefore, we conducted a systematic review and meta-analysis of published literature on active implementation strategies for VTE prophylaxis administration in hospitalized trauma patients and the impact on VTE events. Methods: A systematic review and meta-analysis was performed in adult hospitalized trauma patients to assess if active VTE prevention implementation strategies change the proportion of patients who received VTE prophylaxis, VTE events, and adverse effects such as bleeding or heparin-induced thrombocytopenia as well as hospital length of stay and the cost of care. An academic medical librarian searched Medline, Scopus, and Web of Science until December 2022. Results: Four studies with a total of 1723 patients in the active implementation strategy group (strategies included education, reminders, human and computer alerts, audit and feedback, preprinted orders, and/or root cause analysis) and 1324 in the no active implementation strategy group (guideline creation and dissemination) were included in the analysis. A higher proportion of patients received VTE prophylaxis with an active implementation strategy (OR=2.94, 95% CI (1.68 to 5.15), p<0.01). No significant difference was found in VTE events. Quality was deemed to be low due to bias and inconsistency of studies. Conclusions: Active implementation strategies appeared to improve the proportion of major trauma patients who received VTE prophylaxis. Further implementation studies are needed in trauma to determine effective, sustainable strategies for VTE prevention and to assess secondary outcomes such as bleeding and costs. Level of evidence: Systematic review/meta-analysis, level III. PROSPERO registration number: CRD42023390538.

Pack the chest: Damage control strategy for management in thoracic trauma.

BACKGROUND: Damage control surgery aims to control hemorrhage and contamination in the operating room (OR) with definitive management of injuries delayed until normal physiology is restored in the intensive care unit (ICU). There are limited studies evaluating the use of damage control thoracotomy (DCT) in trauma, and the best method of temporary closure is unclear. METHODS: A retrospective review of trauma patients at two level I trauma centers who underwent a thoracotomy operation was performed. Subjects who underwent a thoracotomy after 24 h, age less than 16, expired in the trauma bay, or in the OR prior to ICU admission were excluded. One-way ANOVA and Kruskal-Wallis test were used to compare continuous and categorical variables between DCT and definitive thoracotomy (DT) patients. RESULTS: 207 trauma patients underwent thoracotomy, 76 met our inclusion criteria. DCT was performed in 30 patients (39%), 46 (61 %) underwent DT operation. Techniques for temporizing the chest varied from skin closure with suture (8), adhesive dressing (5), towel clamps (2), or negative pressure devices (12). Compared to definitive closure, DCT had more derangements in HR, pH, (110 vs. 95, p = 0.04; 7.05 vs 7.24, p < 0.001), and injury severity score (41 vs 25, p < 0.001), and required more blood transfusions (40 vs 6, p < 0.001). Eleven (36.7 %) DCT patients survived to discharge compared to 38 patients (95.0 %) in the DT group. DCT showed significantly higher differences in cardiac arrest and unplanned returns to the OR rates. No differences were observed in ventilator days, or ICU length of stay. CONCLUSIONS: DCT is a viable option for management of patients in extremis following thoracic trauma. DCT was associated with higher mortality rates, likely due to differences in injury and physiologic derangement. Despite this, DCT was associated with similar rates of complications, ICU stay, and ventilator days.

A Collaborative Multidisciplinary Trauma Program Improvement Team Improves VTE Chemoprophylaxis Guideline Compliance In Non-Operative Stable TBI.

BACKGROUND: Delays in initiating venous thromboembolism (VTE) prophylaxis in patients suffering from traumatic brain injury (TBI) persist despite guidelines recommending early initiation. We hypothesized that the expansion of a Trauma Program Performance Improvement (PI) team will improve compliance of early (24-48 hour) initiation of VTE prophylaxis and will decrease VTE events in TBI patients. METHODS: We performed a single-center retrospective review of all TBI patients admitted to a Level I trauma center before (2015-2016,) and after (2019-2020,) the expansion of the Trauma Performance Improvement and Patient Safety (PIPS) team and the creation of trauma process and outcome dashboards. Exclusion criteria included discharge or death within 48 hours of admission, expanding intracranial hemorrhage on CT scan, and a neurosurgical intervention (craniotomy, pressure monitor, or drains) prior to chemoprophylaxis initiation. RESULTS: A total of 1,112 patients met the inclusion criteria, of which 54% (n = 604) were admitted after Trauma PIPS expansion. Following the addition of a dedicated PIPS nurse in the trauma program and creation of process dashboards, the time from stable CT to VTE prophylaxis initiation decreased (52 hours to 35 hours; p < 0.001) and more patients received chemoprophylaxis at 24-48 hours (59% from 36%, p < 0.001) after stable head CT. There was no significant difference in time from first head CT to stable CT (9 vs 9 hours; p = 0.15). The Contemporary group had a lower rate of VTE events (1% vs 4%; p < 0.001) with no increase in bleeding events (2% vs 2%; p = 0.97). On multivariable analysis, being in the Early cohort was an independent predictor of VTE events (aOR: 3.74; 95%CI: 1.45-6.16). CONCLUSION: A collaborative multidisciplinary Trauma PIPS team improves guideline compliance. Initiation of VTE chemoprophylaxis within 24-48 hours of stable head CT is safe and effective. LEVEL OF EVIDENCE: Level III, Therapeutic/Care Management.

Thoracic Cavity Irrigation Prevents Retained Hemothorax and Decreases Surgical Intervention in Trauma Patients.

INTRODUCTION: Retained hemothorax (HTX) is a common complication following thoracic trauma. Small studies demonstrate the benefit of thoracic cavity irrigation at the time of tube thoracostomy for the prevention of retained HTX. We sought to assess the effectiveness of chest irrigation in preventing retained HTX leading to a secondary surgical intervention. METHODS: We performed a single-center retrospective study from 2017-2021 at a Level I trauma center comparing bedside thoracic cavity irrigation via tube thoracostomy (TT) versus no irrigation. Using the trauma registry, patients with traumatic HTX were identified. Exclusion criteria were TT placement at an outside hospital, no TT within 24 hours of admission, thoracotomy or video-assisted thoracoscopic surgery (VATS) prior to or within 6 hours after TT placement, VATS as part of rib fixation or diaphragmatic repair, and death within 96 hours of admission. Bivariate and multivariable analyses were conducted. RESULTS: A total of 370 patients met the inclusion criteria, of whom 225 (61%) were irrigated. Patients who were irrigated were more likely to suffer a penetrating injury (41% vs 30%, p = 0.03) and less likely to have a flail chest (10% vs 21%, p = 0.01) (Table 1). On bivariate analysis, irrigation was associated with lower rates of VATS (6% vs 19%, p < 0.001) and retained HTX (10% vs 21%, p < 0.001) (Figure 1). The irrigated cohort had a shorter TT duration (4 vs 6 days, p < 0.001) and hospital length of stay (LOS) (7 vs 9 days, p = 0.04). On multivariable analysis, thoracic cavity irrigation had lower odds of VATS (aOR: 0.37, 95%CI: 0.30-0.54), retained HTX (aOR: 0.42, 95%CI: 0.25-0.74), and a shorter TT duration (ß: -1.58, 95%CI: -2.52, -0.75). CONCLUSION: Our 5-year experience with thoracic irrigation confirms findings from smaller studies that irrigation prevents retained HTX and decreases the need for surgical intervention. LEVEL OF EVIDENCE: Level III, Therapeutic/Care Management.

Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

Aging is associated with a decline in stem cell functionality and number across the organism. In this study, we aimed to further unravel Muscle Stem Cells (MuSCs) aging by assessing how systemic factors influence MuSC fate decisions through long-term epigenetic landscape remodelling. As aging is intricately linked to a pro-inflammatory shift, we studied the epigenetic effects of inflammatory signals in MuSCs and measured decreased H4K20me1 levels. This loss disrupts MuSC quiescence, largely through epigenetic silencing of Notch target genes. In the setting of inflammatory signals or aging, the lack of Kmt5a and the subsequent absence of de novoH4K20me1 culminate in cell death by ferroptosis. Aged MuSCs manifest abnormal iron metabolism and reduced Gpx4 levels, resulting in the accumulation of intracellular iron, increased reactive oxygen species, genomic instability, and lipid peroxidation. We showed that ferroptosis is the predominant mode of cell death in aged MuSCs, with remarkably high levels of lipid peroxidation; a phenomenon we also observed in aged hematopoietic stem cells. Implementing preventative strategies to inhibit systemic inflammation prevented aged MuSC ferroptosis, preserving their numbers and regenerative capabilities. This intervention significantly enhanced aged muscle regeneration and strength recovery and extended both lifespan and healthspan in mice. This study delineates a previously underappreciated fate trajectory for stem cell aging, and offers meaningful insights into the treatment of age-related disorders.

Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.

Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFß/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.

Annihilation dynamics during spiral defect chaos revealed by particle models.

Pair-annihilation events are ubiquitous in a variety of spatially extended systems and are often studied using computationally expensive simulations. Here we develop an approach in which we simulate the pair-annihilation of spiral wave tips in cardiac models using a computationally efficient particle model. Spiral wave tips are represented as particles with dynamics governed by diffusive behavior and short-ranged attraction. The parameters for diffusion and attraction are obtained by comparing particle motion to the trajectories of spiral wave tips in cardiac models during spiral defect chaos. The particle model reproduces the annihilation rates of the cardiac models and can determine the statistics of spiral wave dynamics, including its mean termination time. We show that increasing the attraction coefficient sharply decreases the mean termination time, making it a possible target for pharmaceutical intervention. Many physical systems exhibit annihilation events during which pairs of objects collide and are removed from the system. These events occur in a number of soft-matter and active-matter systems that exhibit spatiotemporal patterning. For example, topological defects in nematic liquid crystals can develop motile topological defects that annihilate when they meet 1,2. Pair-wise annihilation of defects or singularities also plays a role in a number of biological systems. In bacterial biofilms, for instance, imperfect cell alignment results in point-like defects that carry half-integer topological charge and can annihilate in pairs. These topological defects explain the formation of layers and have been proposed as a model for the buckling of biofilms in colonies of nematically ordered cells3,4.

Early venous thromboembolism chemoprophylaxis in traumatic brain injury requiring neurosurgical intervention: Safe and effective.

BACKGROUND: Traumatic brain injury patients who require neurosurgical intervention are at the highest risk of worsening intracranial hemorrhage. This subgroup of patients has frequently been excluded from prior research regarding the timing of venous thromboembolism chemoprophylaxis. This study aims to assess the efficacy and safety of early venous thromboembolism chemoprophylaxis in patients with traumatic brain injuries requiring neurosurgical interventions. METHODS: This is a single-center retrospective review (2016-2020) of traumatic brain injury patients requiring neurosurgical intervention admitted to a level I trauma center. Interventions included intracranial pressure monitoring, subdural drain, external ventricular drain, craniotomy, and craniectomy. Exclusion criteria included neurosurgical intervention after chemoprophylaxis initiation, death within 5 days of admission, and absence of chemoprophylaxis. The total population was stratified into Early (≤72 hours of intervention) versus Late (>72 hours after intervention) chemoprophylaxis initiation. RESULTS: A total of 351 patients met the inclusion criteria, of whom 204 (58%) had early chemoprophylaxis initiation. Overall, there were no significant differences in baseline and admission characteristics between cohorts. The Early chemoprophylaxis cohort had a statistically significant lower venous thromboembolism rate (5% vs 13%, P < .001) with no increased risk of worsening intracranial hemorrhage (10% vs 13%, P = .44) or neurosurgical reintervention (8% vs 10%, P = .7). On subgroup analysis, a total of 169 patients required either a craniotomy or a craniectomy before chemoprophylaxis. The Early chemoprophylaxis cohort had statistically significant lower venous thromboembolism rates (2% vs 11%, P < .001) with no increase in intracranial hemorrhage (8% vs 11%, P = .6) or repeat neurosurgical intervention (8% vs 10%, P = .77). CONCLUSION: Venous thromboembolism prophylaxis initiation within 72 hours of neurosurgical intervention is safe and effective. Further prospective research is warranted to validate the results of this study.

Global mortality and readmission rates following COPD exacerbation-related hospitalisation: a meta-analysis of 65 945 individual patients.

Background: Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods: A systematic review was performed identifying studies that reported in-hospital mortality, post-discharge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results: Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisations <12 months prior to the index event. Conclusions: This IPDMA stresses the poor outcomes and high heterogeneity of ECOPD-related hospitalisation across the world. Whilst global standardisation of the management and follow-up of ECOPD-related hospitalisation should be at the heart of future implementation research, policy makers should focus on reimbursing evidence-based therapies that decrease (recurrent) ECOPD.

A community-based advanced nurse practitioner-led integrated oncology care model for adults receiving oral anticancer medication: a pilot study.

Oral anti-cancer medications (OAMs) are being used increasingly within cancer care. OAMs offer the potential to improve patient convenience and increase hospital capacity. The clinical assessment for each cycle of OAMs requires specialist patient review often performed in hospital-based oncology units. Consequently, any potential improvement in patient expediency or increased hospital capacity that OAMs can offer is not realised. This study aimed to develop and pilot the specialist assessment of patients receiving OAMs by an Advanced Nurse Practitioner (ANP) in a community-based location.The primary aim of this pilot study was to assess the feasibility of a community-based ANP-led integrated oncology care model for adults receiving OAMs in Ireland who met the pre-specified eligibility criteria. The objectives were to determine the feasibility of a definitive trial of this intervention by measuring patient safety, acceptability to patients and staff and cost of the new model of care.This single-centre pilot study provided patient care (n = 37) to those receiving OAM therapies within a community setting for a 4-month period. Consent rate was high with no attrition other than for clinical reasons. There were 151 contacts with the sample during that time.Results demonstrated that the ANP-led intervention and new model for OAM care was safe, highly acceptable to patients and staff and that related healthcare costs could be captured. Based on the success of this pilot study, the authors conclude that a community-based ANP-led integrated oncology care model for adults receiving OAMs is feasible, and a definitive trial is warranted.Trial registration ISRCTN, ISRCTN10401455 . Registered 30 November 2020.

Role of the histone variant H2A.Z.1 in memory, transcription, and alternative splicing is mediated by lysine modification.

Creating long-lasting memories requires learning-induced changes in gene expression, which are impacted by epigenetic modifications of DNA and associated histone proteins. Post-translational modifications (PTMs) of histones are key regulators of transcription, with different PTMs producing unique effects on gene activity and behavior. Although recent studies implicate histone variants as novel regulators of memory, effects of PTMs on the function of histone variants are rarely considered. We previously showed that the histone variant H2A.Z suppresses memory, but it is unclear if this role is impacted by H2A.Z acetylation, a PTM that is typically associated with positive effects on transcription and memory. To answer this question, we used a mutation approach to manipulate acetylation on H2A.Z without impacting acetylation of other histone types. Specifically, we used adeno-associated virus (AAV) constructs to overexpress mutated H2A.Z.1 isoforms that either mimic acetylation (acetyl-mimic) by replacing lysines 4, 7 and 11 with glutamine (KQ), or H2A.Z.1 with impaired acetylation (acetyl-defective) by replacing the same lysines with alanine (KA). Expressing the H2A.Z.1 acetyl-mimic (H2A.Z.1KQ) improved memory under weak learning conditions, whereas expressing the acetyl-defective H2A.Z.1KA generally impaired memory, indicating that the effect of H2A.Z.1 on memory depends on its acetylation status. RNA sequencing showed that H2A.Z.1KQ and H2A.Z.1KA uniquely impact the expression of different classes of genes in both females and males. Specifically, H2A.Z.1KA preferentially impacts genes involved in synaptic function, suggesting that acetyl-defective H2A.Z.1 impairs memory by altering synaptic regulation. Finally, we describe, for the first time, that H2A.Z is also involved in alternative splicing of neuronal genes, whereby H2A.Z depletion, as well as expression of H2A.Z.1 lysine mutants influence transcription and splicing of different gene targets, suggesting that H2A.Z.1 can impact behavior through effects on both splicing and gene expression. This is the first study to demonstrate that direct manipulation of H2A.Z post-translational modifications regulates memory, whereby acetylation adds another regulatory layer by which histone variants can fine tune higher brain functions through effects on gene expression and splicing.

Open versus endovascular repair of penetrating non-aortic arterial injuries: A systematic review and meta analysis.

BACKGROUND: Non-aortic arterial injuries are common and are associated with high morbidity and mortality. Historically, open surgical repair (OSR) was the conventional method of repair. With recent advancements in minimally invasive techniques, endovascular repair (ER) has gained popularity. We sought to compare outcomes in patients undergoing endovascular and open repairs of traumatic non-aortic penetrating arterial injuries. METHODS: A systematic review and meta-analysis was conducted using MEDLINE (OVID), Web of Science, Cochrane Library, and Scopus Database from January 1st, 1990, to March 20th, 2023. Titles and abstracts were screened, followed by full text review. Articles assessing clinically important outcomes between OSR and ER in penetrating arterial injuries were included. Exclusion criteria included blunt injuries, aortic injuries, pediatric populations, review articles, and non-English articles. Odds ratios (OR) and Cohen's d ratios were used to quantify differences in morbidity and mortality. RESULTS: A total of 3770 articles were identified, of which 8 met inclusion criteria and were included in the review. The articles comprised a total of 8369 patients of whom 90 % were male with a median age of 28 years. 85 % of patients were treated with OSR while 15 % underwent ER. With regards to injury characteristics, those who underwent ER were less likely to present with concurrent venous injuries (OR: 0.41; 95 %CI: 0.18, 0.94; p = 0.03). Regarding hospital outcomes, patients who underwent ER had a lower likelihood of in-hospital or 30-day mortality (OR: 0.72; 95 %CI: 0.55, 0.95; p = 0.02) and compartment syndrome (OR: 0.29, 95 %CI: 0.12, 0.71; p = 0.007). The overall risk of bias was moderate. CONCLUSION: Endovascular repair of non-aortic penetrating arterial injuries is increasingly common, however open repair remains the most common approach. Compared to ER, OSR was associated with higher odds of compartment syndrome and mortality. Further prospective research is warranted to determine the patient populations and injury patterns that most significantly benefit from an endovascular approach. LEVEL OF EVIDENCE: Level III, Systematic Reviews & Meta-Analyses.

Home noninvasive ventilation in severe COPD: in whom does it work and how?

Background: Not all hypercapnic COPD patients benefit from home noninvasive ventilation (NIV), and mechanisms through which NIV improves clinical outcomes remain uncertain. We aimed to identify "responders" to home NIV, denoted by a beneficial effect of NIV on arterial partial pressure of carbon dioxide (PaCO2), health-related quality of life (HRQoL) and survival, and investigated whether NIV achieves its beneficial effect through an improved PaCO2. Methods: We used individual patient data from previous published trials collated for a systematic review. Linear mixed-effect models were conducted to compare the effect of NIV on PaCO2, HRQoL and survival, within subgroups defined by patient and treatment characteristics. Secondly, we conducted a causal mediation analysis to investigate whether the effect of NIV is mediated by a change in PaCO2. Findings: Data of 1142 participants from 16 studies were used. Participants treated with lower pressure support (<14 versus ≥14 cmH2O) and with lower adherence (<5 versus ≥5 h·day-1) had less improvement in PaCO2 (mean difference (MD) -0.30 kPa, p<0.001 and -0.29 kPa, p<0.001, respectively) and HRQoL (standardised MD 0.10, p=0.002 and 0.11, p=0.02, respectively), but this effect did not persist to survival. PaCO2 improved more in patients with severe dyspnoea (MD -0.30, p=0.02), and HRQoL improved only in participants with fewer than three exacerbations (standardised MD 0.52, p=0.03). The results of the mediation analysis showed that the effect on HRQoL is mediated partially (23%) by a change in PaCO2. Interpretation: With greater pressure support and better daily NIV usage, a larger improvement in PaCO2 and HRQoL is achieved. Importantly, we demonstrated that the beneficial effect of home NIV on HRQoL is only partially mediated through a reduction in diurnal PaCO2.

ß-hCG secreting uterine PEComa.

A postmenopausal female patient presented with vaginal bleeding. Initial bloodwork revealed an elevated serum beta human chorionic gonadotropin level (ß-hCG). Pelvic MRI identified a complex heterogeneous uterine mass with central necrosis. She underwent total abdominal hysterectomy with bilateral saplingo-oopherectomy. Pathology reported a malignant perivascular epithelioid cell tumour (PEComa). Postoperatively, her ß-hCG level returned to normal. ß-hCG secreting sarcomas are extremely rare, and to our knowledge, there has only been one previously reported case of a ß-hCG secreting PEComa. Based on the limited literature, these tumours may have a worse prognosis. The role of ß-hCG as a marker of treatment response and disease activity is unclear. Additional studies are required to further ascertain its role as a predictive and prognostic biomarker.

When is it safe to start venous thromboembolism prophylaxis after blunt solid organ injury? A prospective American Association for the Surgery of Trauma multi-institutional trial.

BACKGROUND: The optimal time to initiate venous thromboembolism (VTE) chemoprophylaxis (VTEp) after blunt solid organ injury remains controversial, as VTE mitigation must be balanced against bleeding promulgation. Evidence from primarily small, retrospective, single-center work suggests that VTEp ≤48 hours is safe and effective. This study was undertaken to validate this clinical practice. METHODS: Blunt trauma patients presenting to 19 participating trauma centers in North America were screened over a 1-year study period beginning between August 1 and October 1, 2021. Inclusions were age older than 15 years; ≥1 liver, spleen, or kidney injury; and initial nonoperative management. Exclusions were transfers, emergency department death, pregnancy, and concomitant bleeding disorder/anticoagulation/antiplatelet medication. A priori power calculation stipulated the need for 1,158 patients. Time of VTEp initiation defined study groups: Early (≤48 hours of admission) versus Late (>48 hours). Bivariate and multivariable analyses compared outcomes. RESULTS: In total, 1,173 patients satisfied the study criteria with 571 liver (49%), 557 spleen (47%), and 277 kidney injuries (24%). The median patient age was 34 years (interquartile range, 25-49 years), and 67% (n = 780) were male. The median Injury Severity Score was 22 (interquartile range, 14-29) with Abbreviated Injury Scale Abdomen score of 3 (interquartile range, 2-3), and the median American Association for the Surgery of Trauma grade of solid organ injury was 2 (interquartile range, 2-3). Early VTEp patients (n = 838 [74%]) had significantly lower rates of VTE (n = 28 [3%] vs. n = 21 [7%], p = 0.008), comparable rates of nonoperative management failure (n = 21 [3%] vs. n = 12 [4%], p = 0.228), and lower rates of post-VTEp blood transfusion (n = 145 [17%] vs. n = 71 [23%], p = 0.024) when compared with Late VTEp patients (n = 301 [26%]). Late VTEp was independently associated with VTE (odd ratio, 2.251; p = 0.046). CONCLUSION: Early initiation of VTEp was associated with significantly reduced rates of VTE with no increase in bleeding complications. Venous thromboembolism chemoprophylaxis initiation ≤48 hours is therefore safe and effective and should be the standard of care for patients with blunt solid organ injury. LEVEL OF EVIDENCE: Therapeutic and Care Management; Level III.