A Decade of Damage Control Resuscitation: New Transfusion Practice, New Survivors, New Directions.

OBJECTIVE: The aim of this study was to identify the effects of recent innovations in trauma major hemorrhage management on outcome and transfusion practice, and to determine the contemporary timings and patterns of death. BACKGROUND: The last 10 years have seen a research-led change in hemorrhage management to damage control resuscitation (DCR), focused on the prevention and treatment of trauma-induced coagulopathy. METHODS: A 10-year retrospective analysis of prospectively collected data of trauma patients who activated the Major Trauma Centre's major hemorrhage protocol (MHP) and received at least 1 unit of red blood cell transfusions (RBC). RESULTS: A total of 1169 trauma patients activated the MHP and received at least 1 unit of RBC, with similar injury and admission physiology characteristics over the decade. Overall mortality declined from 45% in 2008 to 27% in 2017, whereas median RBC transfusion rates dropped from 12 to 4 units (massive transfusion rates from 68% to 24%). The proportion of deaths within 24 hours halved (33%-16%), principally with a fall in mortality between 3 and 24 hours (30%-6%). Survivors are now more likely to be discharged to their own home (57%-73%). Exsanguination is still the principal cause of early deaths, and the mortality associated with massive transfusion remains high (48%). Late deaths are now split between those due to traumatic brain injury (52%) and multiple organ dysfunction (45%). CONCLUSIONS: There have been remarkable reductions in mortality after major trauma hemorrhage in recent years. Mortality rates continue to be high and there remain important opportunities for further improvements in these patients.

Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening.

4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and ß with low nanomolar affinity and <20-fold selectivity for α over ß and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERß (compound 42; 170-fold selectivity).

Helicobacter pylori gastritis in HIV-infected patients: a review.

BACKGROUND: The risk factors for acquiring Helicobacter pylori and Human Immunodeficiency Virus (HIV) infections are different: H. pylori is transmitted by gastro- or fecal-oral routes and is associated with low socioeconomic conditions, while HIV is transmitted through sexual intercourse, infected body fluids, and transplacentally. If the host responses to these infections were independent, the prevalence of H. pylori should be similar in HIV-infected and non-infected patients. Yet, several studies have detected a lower prevalence of H. pylori in patients with HIV infection, whereas other studies found either no differences or greater rates of H. pylori infection in HIV-positive subjects. OBJECTIVE: To review studies that addressed the issue of these two simultaneous infections and attempt to determine whether reliable conclusions can be drawn from this corpus of often contrasting evidence. METHODS: Electronic literature search for relevant publications, followed by manual search of additional citations from extracted articles. RESULTS: The initial search yielded 44 publications; after excluding case reports, reviews, narrowly focused articles, and duplicate reports, there remained 29 articles, which are the corpus of this review. With one exception, all studies reported higher rates of H. pylori infection in HIV-negative subjects. Five studies also examined the CD4 lymphocyte counts and found an inverse correlation between the degree of immunosuppression and the prevalence of active H. pylori infection. CONCLUSIONS: Current evidence suggests that it is likely that H. pylori needs a functional immune system to successfully and persistently colonize the human gastric mucosa.

Prehospital Partial Resuscitative Endovascular Balloon Occlusion of the Aorta for Exsanguinating Subdiaphragmatic Hemorrhage.

Importance: Hemorrhage is the most common cause of preventable death after injury. Most deaths occur early, in the prehospital phase of care. Objective: To establish whether prehospital zone 1 (supraceliac) partial resuscitative endovascular balloon occlusion of the aorta (Z1 P-REBOA) can be achieved in the resuscitation of adult trauma patients at risk of cardiac arrest and death due to exsanguination. Design, Setting, and Participants: This was a prospective observational cohort study (Idea, Development, Exploration, Assessment and Long-term follow-up [IDEAL] 2A design) with recruitment from June 2020 to March 2022 and follow-up until discharge from hospital, death, or 90 days evaluating a physician-led and physician-delivered, urban prehospital trauma service in the Greater London area. Trauma patients aged 16 years and older with suspected exsanguinating subdiaphragmatic hemorrhage, recent or imminent hypovolemic traumatic cardiac arrest (TCA) were included. Those with unsurvivable injuries or who were pregnant were excluded. Of 2960 individuals attended by the service during the study period, 16 were included in the study. Exposures: ZI REBOA or P-REBOA. Main Outcomes and Measures: The main outcome was the proportion of patients in whom Z1 REBOA and Z1 P-REBOA were achieved. Clinical end points included systolic blood pressure (SBP) response to Z1 REBOA, mortality rate (1 hour, 3 hours, 24 hours, or 30 days postinjury), and survival to hospital discharge. Results: Femoral arterial access for Z1 REBOA was attempted in 16 patients (median [range] age, 30 [17-76] years; 14 [81%] male; median [IQR] Injury Severity Score, 50 [39-57]). In 2 patients with successful arterial access, REBOA was not attempted due to improvement in clinical condition. In the other 14 patients (8 [57%] of whom were in traumatic cardiac arrest [TCA]), 11 successfully underwent cannulation and had aortic balloons inflated in Z1. The 3 individuals in whom cannulation was unsuccessful were in TCA (failure rate = 3/14 [21%]). Median (IQR) pre-REBOA SBP in the 11 individuals for whom cannulation was successful (5 [46%] in TCA) was 47 (33-52) mm Hg. Z1 REBOA plus P-REBOA was associated with a significant improvement in BP (median [IQR] SBP at emergency department arrival, 101 [77-107] mm Hg; 0 of 10 patients were in TCA at arrival). The median group-level improvement in SBP from the pre-REBOA value was 52 (95% CI, 42-77) mm Hg (P < .004). P-REBOA was feasible in 8 individuals (8/11 [73%]) and occurred spontaneously in 4 of these. The 1- and 3-hour postinjury mortality rate was 9% (1/11), 24-hour mortality was 27% (3/11), and 30-day mortality was 82% (9/11). Survival to hospital discharge was 18% (2/11). Both survivors underwent early Z1 P-REBOA. Conclusions and Relevance: In this study, prehospital Z1 P-REBOA is feasible and may enable early survival, but with a significant incidence of late death. Trial Registration: ClinicalTrials.gov Identifier: NCT04145271.

Feasibility and impact of a bespoke pre-hospital point of care ultrasound teaching and training programme at London's air ambulance service.

Introduction: Point-of-care ultrasound has seen an increase in its use in pre-hospital emergency care. There is lack of literature around the training requirement for point-of-care ultrasound of pre-hospital clinicians. This service evaluation assesses the effectiveness of a bespoke hybrid teaching programme. Methods: This is a service evaluation of the point-of-care ultrasound teaching programme at London's Air Ambulance from 1 April to 28 May 2021. Subjects' knowledge, image interpretation and confidence were assessed at two different points. Data were gathered using REDCap and exported to Excel for analysis. Mean values and delta were calculated, and t-test was applied for statistical significance. Results: In total, 57 participants were included; out of which 11 were excluded, as they did not complete a post-course survey. Of these, 41.3% participants were point-of-care ultrasound naïve. Mean pre- and post-course scores were 76.5% and 81.7%, respectively, with an average delta improvement of 5.2% (95% confidence interval = 4.70%-5.68%) which was statistically significant (p < 0.002). There was a statistically significant mean improvement of pre- and post-course scores between point-of-care ultrasound naïve and point-of-care ultrasound experienced groups (p = 0.014). Confidence in using point-of-care ultrasound showed mean overall improvement from 2.36/4 to 3.34/4, a mean difference of 0.98 (95% confidence interval = 0.61-1.34), which was statistically significant (p = 0.0039). Conclusion: Our service evaluation highlighted that a hybrid teaching model used by London's Air Ambulance was feasible and had shown significant improvement in the knowledge, image interpretation and confidence of both the point-of-care ultrasound naïve and the PoCUS experienced cohort of clinicians.

An audit of endoscopic complications in adult eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) in adults, characterized by the triad of dysphagia, a ringed esophagus, and mucosal eosinophilic infiltration, has associated complications that include vertical mucosal lacerations, instrumental perforation, and emesis-induced rupture. The aim of this study was to determine whether clinical, endoscopic, and histologic features can be used to predict the risk for development of these complications. METHODS: A review was conducted of 36 patients with EoE. Complications were defined as mucosal lacerations or radiographic evidence of perforation. RESULTS: The mean age at presentation was 33.9 years. Twenty-eight (78%) patients were men. Complications occurred in 11 patients (31%). There were 7 mucosal lacerations, 3 perforations, and 1 emesis-induced rupture. Strictures were reported in 7 of 11 complicated cases compared with 2 of 25 of uncomplicated cases. Dilatation procedures had been performed in 6 of 7 complicated cases associated with stricture. Biopsy specimens obtained from 7 of 9 patients with complications showed 40 or more eosinophils/high-power field. There were no statistical differences between complicated and uncomplicated patients regarding demographics, clinical features, endoscopic characteristics, or histopathologic findings. CONCLUSIONS: EoE is a high-risk disorder with a range of complications. Although demographics, clinical presentation, and endoscopic features cannot distinguish risk, the presence of stricture, a longer duration of symptoms, and a greater density of eosinophilic infiltration suggest increased risk. The density of eosinophilic infiltration cannot be determined prospectively; therefore, the performance of endoscopy and subsequent dilatation should be deferred until biopsy specimens are reviewed or treatment is completed.

Helicobacter infections with rare bacteria or minimal gastritis: Expecting the unexpected.

BACKGROUND: The routine use of special stains for detection of Helicobacter remains controversial. AIMS: To determine the frequency of histologically atypical Helicobacter infection. METHODS: All gastric biopsies received at a large pathology reference laboratory over a 6-month period were stained for Helicobacter, and the histologic and clinicopathologic parameters evaluated. RESULTS: Amongst 7663 Helicobacter-positive biopsies, 823 (10.7%) did not show typical chronic active gastritis with numerous Helicobacter organisms, and were therefore considered histologically atypical. Rare Helicobacter pylori organisms accounted for 58.0% of all atypical infections; the next most common atypical Helicobacter infection was that with minimal or no gastric inflammation (23.3% of atypical infections). Patients in these groups did not differ demographically from those with other forms of atypical or typical Helicobacter infection, although a small subgroup (6%) was more likely to have had a previously treated infection. CONCLUSIONS: In many of these atypical infections, Helicobacter would not have been suspected based on the histologic findings alone, and would have been missed without routine special stains. Performing a sensitive stain could prevent additional testing and allow prompt treatment of the affected patients, thus substantially reducing the risk for peptic ulcer and gastric cancer and preventing the transmission of the infection to family members.

Guanidinium-based derivatives: searching for new kinase inhibitors.

Considering the structural similarities between the kinase inhibitor sorafenib and 4,4'-bis-guanidinium derivatives previously prepared by Rozas and co., which display interesting cytotoxicity in cancer cells, we have studied whether this activity could result from kinase inhibition. Five new families have been prepared consisting of unsubstituted and aryl-substituted 3,4'-bis-guanidiniums, 3,4'-bis-2-aminoimidazolinium and 3-acetamide-4'-(4-chloro-3-trifluoromethylphenyl)guanidinium derivatives. Cytotoxicity (measuring the IC50 values) and apoptosis studies in human HL-60 promyelocytic leukemia cells were carried out for these compounds. Additionally, their potential inhibitory effect was explored on a panel of kinases known to be involved in apoptotic pathways. The previously prepared cytotoxic 4,4'-bis-guanidiniums did not inhibit any of these kinases; however, some of the novel 3,4'-substituted derivatives showed a high percentage inhibition of RAF-1/MEK-1, for which the potential mode of binding was evaluated by docking studies. The interesting antitumour properties showed by these compounds open up new exciting lines of investigation for kinase inhibitors as anticancer agents and also highlights the relevance of the guanidinium moiety for protein kinase inhibitors chemical design.

Retinazone inhibits certain blood-borne human viruses including Ebola virus Zaire.

BACKGROUND: Human HBV and HIV integrate their retro-transcribed DNA proviruses into the human host genome. Existing antiretroviral drug regimens fail to directly target these intrachromosomal xenogenomes, leading to persistence of viral genetic information. Retinazone (RTZ) constitutes a novel vitamin A-derived (retinoid) thiosemicarbazone derivative with broad-spectrum antiviral activity versus HIV, HCV, varicella-zoster virus and cytomegalovirus. METHODS: The in vitro inhibitory action of RTZ on HIV-1 strain LAI, human HBV strain ayw, HCV-1b strain Con1, enhanced green fluorescent protein-expressing Ebola virus Zaire 1976 strain Mayinga, wild-type Ebola virus Zaire 1976 strain Mayinga, human herpesvirus 6B and Kaposi's sarcoma-associated herpesvirus replication was investigated. The binding of RTZ to human glucocorticoid receptor was determined. RESULTS: RTZ inhibits blood-borne human HBV multiplication in vitro by covalent inactivation of intragenic and intraexonic viral glucocorticoid response elements, and, in close analogy, RTZ suppresses HIV-1 multiplication in vitro. RTZ disrupts the multiplication of blood-borne human HCV and Ebola Zaire virus at nanomolar concentrations in vitro. RTZ has the capacity to bind to human glucocorticoid receptor, to selectively and covalently bind to intraexonic viral glucocorticoid response elements, and thereby to inactivate human genome-integrated proviral DNA of human HBV and HIV. CONCLUSIONS: RTZ represents the first reported antiviral agent capable of eradicating HIV and HBV proviruses from their human host. Furthermore, RTZ represents a potent and efficacious small-molecule in vitro inhibitor of Ebola virus Zaire 1976 strain Mayinga replication.

The relationship between head injury severity and hemodynamic response to tracheal intubation.

INTRODUCTION: The acutely injured brain is sensitive to fluctuations in blood pressure. During tracheal intubation, airway stimulation provokes acute surges in blood pressure that have the potential to cause further harm in patients with intracranial pathology. Although reduced consciousness is thought to suppress airway reflexes, its influence on these hemodynamic reflexes is unknown.We aimed to investigate the relationship between head injury severity and hemodynamic response to laryngoscopy and intubation. METHODS: This retrospective observational study included 97 consecutive patients with head injuries who underwent prehospital tracheal intubation by a physician-led helicopter emergency medical service. The primary outcome was the acute hemodynamic response to the procedure. Secondary outcomes included the incidence of serious intracranial pathology and mortality. RESULTS: A hypertensive response to laryngoscopy and tracheal intubation occurred in 80% of patients. In 11% of patients, blood pressure increased by ≥100%. The hemodynamic response was attenuated with increasing head injury severity but unpredictably and not to clinically acceptable levels. The incidence of serious intracranial bleeding (61%) and raised intracranial pressure (22%) was high in patients with head injuries, requiring tracheal intubation. CONCLUSION: A clinically significant hemodynamic response to laryngoscopy and intubation is common in patients with head injuries and is not effectively attenuated by increasing head injury severity. The need to attenuate the hemodynamic response should be assessed independently of head injury severity. LEVEL OF EVIDENCE: Therapeutic study, level III.

Integrated virtual screening for the identification of novel and selective peroxisome proliferator-activated receptor (PPAR) scaffolds.

We describe a fully customizable and integrated target-specific "tiered" virtual screening approach tailored to identifying and characterizing novel peroxisome proliferator activated receptor γ (PPARγ) scaffolds. Built on structure- and ligand-based computational techniques, a consensus protocol was developed for use in the virtual screening of chemical databases, focused toward retrieval of novel bioactive chemical scaffolds for PPARγ. Consequent from application, three novel PPAR scaffolds displaying distinct chemotypes have been identified, namely, 5-(4-(benzyloxy)-3-chlorobenzylidene)dihydro-2-thioxopyrimidine-4,6(1H,5H)-dione (MDG 548), 3-((4-bromophenoxy)methyl)-N-(4-nitro-1H-pyrazol-1-yl)benzamide (MDG 559), and ethyl 2-[3-hydroxy-5-(5-methyl-2-furyl)-2-oxo-4-(2-thienylcarbonyl)-2,5-dihydro-1H-pyrrol-1-yl]-4-methyl-1,3-thiazole-5-carboxylate (MDG 582). Fluorescence polarization(FP) and time resolved fluorescence resonance energy transfer (TR-FRET) show that these compounds display high affinity competitive binding to the PPARγ-LBD (EC(50) of 215 nM to 5.45 µM). Consequent characterization by a TR-FRET activation reporter assay demonstrated agonism of PPARγ by all three compounds (EC(50) of 467-594 nM). Additionally, differential PPAR isotype specificity was demonstrated through assay against PPARα and PPARδ subtypes. This work showcases the ability of target specific "tiered screen" protocols to successfully identify novel scaffolds of individual receptor subtypes with greater efficacy than isolated screening methods.

Consensus Computational Ligand-Based Design for the Identification of Novel Modulators of Human Estrogen Receptor Alpha.

We describe the first targeted validation of fFLASH, a molecular similarity program from IBM that has been previously proposed as suitable for the virtual screening (VS) of compound libraries based on explicit 3D flexible superimpositions, as part of its deployment within a novel consensus ligand-based virtual screening cascade. A virtual screening protocol using fFLASH for the human estrogen receptor alpha (ERα) was advanced and benchmarked against screens completed using established commercial screening softwares - Catalyst and ROCS. The optimised protocol was applied to a ∼6000 member physical screening collection and virtual 'hits' sourced and biologically assayed. The approach identified a novel, potent and highly selective partial antagonist of the ERα. This study firstly validates the clique detection algorithm utilised by fFLASH and secondly, emphasises the benefits of the consensus approach of employing more than one program in a VS protocol.

Assessment of immunohistochemistry for p16INK4 and high-risk HPV DNA by in situ hybridization in esophageal squamous cell carcinoma.

The role of high-risk human papillomavirus (HPV) in the pathogenesis of esophageal squamous cell carcinoma (ESCC) remains unclear. p16(INK4) is used as a surrogate marker to detect HPV-related tumors but has had discrepant results in ESCC. In this study, 32 cases of ESCC were examined to determine the relationship between p16(INK4) expression and high-risk HPV. All the tumors were stained by immunohistochemistry for p16(INK4). Tumors having p16(INK4) nuclear and/or nuclear and cytoplasmic expression were considered positive. Tumors positive for p16(INK4) expression were tested for high-risk HPV by in situ hybridization (ISH). In all, 20 cases of ESCC (63%) showed only cytoplasmic staining for p16(INK4), and 11 cases (34%) showed both cytoplasmic and nuclear staining for p16(INK4); 4 cases (13%) showed no staining for p16(INK4). None of the p16(INK4) -positive cases were positive for high-risk HPV by ISH. These results indicate that p16(INK4) expression in ESCC does not correlate with the presence of high-risk HPV DNA by ISH. High-risk HPV does not seem to play a major role in the carcinogenesis of ESCC in low-risk areas.