Abdominal aortic junctional tourniquet (AAJT-S): a systematic review of utility in military practice.

INTRODUCTION: Haemorrhage is the leading cause of potentially survivable death on the battlefield. Despite overall improvement in battlefield mortality, there has been no improvement in survival following non-compressible torso haemorrhage (NCTH). The abdominal aortic junctional tourniquet-stabilised (AAJT-S) is a potential solution that may address this gap in improving combat mortality. This systematic review examines the evidence base for the safety and utility of the AAJT-S for prehospital haemorrhage control in the combat setting. METHODS: A systematic search of MEDLINE, Cumulated Index to Nursing and Allied Health Literature and Embase (inception to February 2022) was performed using exhaustive terms, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. The search was limited to English-language publications in peer-reviewed journals; grey literature was not included. Human, animal and experimental studies were included. Papers were reviewed by all authors to determine inclusion. Each study was assessed for level of evidence and bias. RESULTS: 14 studies met the inclusion criteria: 7 controlled swine studies (total n=166), 5 healthy human volunteer cases series (total n=251), 1 human case report and 1 mannikin study. The AAJT-S was demonstrated to be effective at cessation of blood flow when tolerated in healthy human and animal studies. It was easy to apply by minimally trained individuals. Complications were observed in animal studies, most frequently ischaemia-reperfusion injury, which was dependent on application duration. There were no randomised controlled trials, and the overall evidence base supporting the AAJT-S was low. CONCLUSIONS: There are limited data of safety and effectiveness of the AAJT-S. However, there is a requirement for a far-forward solution to improve NCTH outcomes, the AAJT-S is an attractive option and high-quality evidence is unlikely to be reported in the near future. Therefore, if this is implemented into clinical practice without a solid evidence base it will need a robust governance and surveillance process, similar to resuscitative endovascular balloon occlusion of the aorta, with regular audit of use.

Red cell haemolysis secondary to intraosseous (IO) blood transfusion in adult patients with major trauma: a systematic review.

INTRODUCTION: Intraosseous (IO) administration of medications and blood products is accepted practice in major trauma when intravenous access is not immediately available. However, there is a concern that the high infusion pressures required for IO transfusion may increase the risk of red cell haemolysis and its associated complications. The aim of this systematic review is to synthesise the existing evidence describing the risks of red cell haemolysis in IO blood transfusion. METHODS: We undertook a systematic search of MEDLINE, CINAHL and EMBASE using the search terms: "intraosseous transfusion" and "haemolysis". Two authors independently screened abstracts, and reviewed full-text articles against the inclusion criteria. Reference lists of included studies were reviewed and a grey literature search undertaken. Studies were assessed for risk of bias. Inclusion criteria were: all human and animal study types that reported novel data on IO-associated red cell haemolysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was used. RESULTS: Twenty-three abstracts were identified; n=9 full papers met the inclusion criteria. No further studies were identified from reference lists or grey literature. These papers included: seven large animal translational studies, a prospective and a retrospective human study. The overall risk of bias was high. One animal study with good translatability to adult patients with trauma demonstrated haemolysis. Other animal studies had methodological constraints that limit their human applicability. No haemolysis was observed in low-density flat bones (sternum), whereas haemolysis was reported in long bones (humerus, tibia). IO infusion using a three-way tap was associated with haemolysis. Conversely, pressure bag transfusion was not associated with haemolysis, but this method may result in insufficient flow rates for effective resuscitation. CONCLUSIONS: There is a paucity of high-quality evidence surrounding the risks of red cell haemolysis in IO blood transfusion. However, evidence from one study suggests that the likelihood is increased by use of a three-way tap to administer blood transfusion to young adult male patients with trauma. Further research is needed to address this important clinical question. PROSPERO REGISTRATION NUMBER: CRD42022318902.

Prehospital emergency care in a humanitarian environment: an overview of the ethical considerations.

Recent history has demonstrated that UK Defence personnel can be used, potentially with little notice, in humanitarian disaster zones. The provision of prehospital emergency care (PHEC) in a humanitarian environment requires an innovative approach to overcome the technical challenges of a resource-limited setting. In addition to technical challenges, prehospital practitioners working in a humanitarian environment can expect to be faced with ethically testing situations that they are not familiar with in their usual practice. The organisational and individual ethical decision-making burden can result in significant harms. Therefore, the aim of this paper is to discuss the ethical considerations relevant to providing PHEC during a humanitarian disaster in order that personnel can be more prepared to optimally deliver care. This is a paper commissioned as a part of the Humanitarian and Disaster Relief Operations special issue of BMJ Military Health.

Killed in action (KIA): an analysis of military personnel who died of their injuries before reaching a definitive medical treatment facility in Afghanistan (2004-2014).

INTRODUCTION: The majority of combat deaths occur before arrival at a medical treatment facility but no previous studies have comprehensively examined this phase of care. METHODS: The UK Joint Theatre Trauma Registry was used to identify all UK military personnel who died in Afghanistan (2004-2014). These data were linked to non-medical tactical and operational records to provide an accurate timeline of events. Cause of death was determined from records taken at postmortem review. The primary objective was to report time between injury and death in those killed in action (KIA); secondary objectives included: reporting mortality at key North Atlantic Treaty Organisation timelines (0, 10, 60, 120 min), comparison of temporal lethality for different anatomical injuries and analysing trends in the case fatality rate (CFR). RESULTS: 2413 UK personnel were injured in Afghanistan from 2004 to 2014; 448 died, with a CFR of 18.6%. 390 (87.1%) of these died prehospital (n=348 KIA, n=42 killed non-enemy action). Complete data were available for n=303 (87.1%) KIA: median Injury Severity Score 75.0 (IQR 55.5-75.0). The predominant mechanisms were improvised explosive device (n=166, 54.8%) and gunshot wound (n=96, 31.7%).In the KIA cohort, the median time to death was 0.0 (IQR 0.0-21.8) min; 173 (57.1%) died immediately (0 min). At 10, 60 and 120 min post injury, 205 (67.7%), 277 (91.4%) and 300 (99.0%) casualties were dead, respectively. Whole body primary injury had the fastest mortality. Overall prehospital CFR improved throughout the period while in-hospital CFR remained constant. CONCLUSION: Over two-thirds of KIA deaths occurred within 10 min of injury. Improvement in the CFR in Afghanistan was predominantly in the prehospital phase.

The role of the skin microbiota in acne pathophysiology.

BACKGROUND: The role of skin microbiota in acne remains to be fully elucidated. Initial culture-based investigations were hampered by growth rate and selective media bias. Even with less biased genomic methods, sampling, lysis and methodology, the task of describing acne pathophysiology remains challenging. Acne occurs in sites dominated by Cutibacterium acnes (formerly Propionibacterium acnes) and Malassezia species, both of which can function either as commensal or pathogen. OBJECTIVES: This article aims to review the current state of the art of the microbiome and acne. METHODS: The literature regarding the microbiome and acne was reviewed. RESULTS: It remains unclear whether there is a quantitative difference in microbial community distribution, making it challenging to understand any community shift from commensal to pathogenic nature. It is plausible that acne involves (i) change in the distribution of species/strains, (ii) stable distribution with pathogenic alteration in response to internal (intermicrobe) or external stimuli (host physiology or environmental) or (iii) a combination of these factors. CONCLUSIONS: Understanding physiological changes in bacterial species and strains will be required to define their specific roles, and identify any potential intervention points, in acne pathogenesis and treatment. It will also be necessary to determine whether any fungal species are involved, and establish whether they play a significant role. Further investigation using robust, modern analytic tools in longitudinal studies with a large number of participants, may make it possible to determine whether the microbiota plays a causal role, is primarily involved in exacerbation, or is merely a bystander. It is likely that the final outcome will show that acne is the result of complex microbe-microbe and community-host interplay.

Rapid sequence induction of anaesthesia via the intraosseous route: a prospective observational study.

BACKGROUND: Intraosseous (IO) drug infusion has been reported to have similar pharmacokinetics to intravenous (IV) infusion. In military and civilian trauma, the IO route is often used to obtain rapid and reliable parenteral access for drug administration. Only a few case reports have described the use of IO infusion to administer drugs for rapid sequence induction of anaesthesia (RSI). OBJECTIVE: We aimed to assess the feasibility of the administration of RSI drugs via an IO catheter in a prospective observational study. METHODS: A prospective observational study was undertaken at a combat hospital in Afghanistan. A validated data form was used to record the use of IO drugs for RSI by the prehospital, physician-led Medical Emergency Response Team (MERT), and by inhospital physicians. Data were captured between January and May 2012 by interview with MERT physicians and inhospital physicians directly after RSI. The primary outcome measure was the success rate of first-pass intubation with direct laryngoscopy. RESULTS: 34 trauma patients (29 MERT and 5 inhospital) underwent RSI with IO drug administration. The median age was 24 years and median injury severity score 25; all were male. The predominant mechanism of injury was blast (n=24), followed by penetrating (n=6), blunt (n=3) and burn (n=1). First-pass intubation success rate was 97% (95% CI 91% to 100%). A Cormack-Lehane grade 1 view, by direct laryngoscopy, was obtained at first look in 91% (95% CI 81% to 100%) of patients. CONCLUSIONS: In this prospective, observational study, IO drug administration was successfully used for trauma RSI, with a comparable first pass intubation success than published studies describing the IV route. TRIAL REGISTRATION NUMBER: RCDM/Res/Audit/1036/12/0162.

Anterior chamber gas bubbles in open globe injury.

We present a case of a 40-year-old soldier who was in close proximity to the detonation of an improvised explosive device (IED). Bubbles of gas were visible within the anterior chamber of his left eye. The authors propose that intraocular gas, present acutely after trauma, is diagnostic of open globe injury and is of particular importance in remote military environments.

Spatial relationships between nitrogen status and pitch canker disease in slash pine planted adjacent to a poultry operation.

Pitch canker disease (Fusarium circinatum Nirenberg & O'Donnell) causes serious shoot dieback, reduced growth and mortality in pines found in the southern and western USA, and has been linked to nutrient imbalances. Poultry houses with forced-air ventilation systems produce nitrogen (N) emissions. This study analyzed spatial correlations between pitch canker disease and foliar, forest floor, soil, and throughfall N in a slash pine (Pinus elliottii var. elliottii Engelm.) plantation adjacent to a poultry operation in north Florida, USA. Tissue and throughfall N concentrations were highest near the poultry houses and remained elevated for 400 m. Disease incidence ranged from 57-71% near the poultry houses and was spatially correlated with N levels. Similarly, stem mortality ranged from 41-53% in the most heavily impacted area, and declined to 0-9% at distances greater than 400 m. These results suggest that nutritional processes exacerbate changes in disease susceptibility and expression in slash pine.

The P2Y nucleotide receptors in the human genome.

Since the first identification of P2Y receptor sequences in 1993, it has quickly become apparent that this family of the G-protein coupled receptors is very diverse. Members of this receptor family are activated extra-cellularly by a wide variety of adenosine and uridine nucleotides including sugar-nucleotides. The recent decipherment of the Human Genome has enabled us to search for new, yet undiscovered P2Y receptor subtypes. In this article we examine the relationships of six orphan G-protein coupled receptor (GPCR) sequences which show considerable sequence homology to various P2Y receptors. The clustering at a few chromosomal loci of P2Y receptor genes and their related orphan genes further suggests that particular P2Y subsets were derived from the same ancestral gene during evolution.

Expression of the P2Y1 nucleotide receptor in chick muscle: its functional role in the regulation of acetylcholinesterase and acetylcholine receptor.

In vertebrate neuromuscular junctions, ATP is stored at the motor nerve terminals and is co-released with acetylcholine during neural stimulation. Here, we provide several lines of evidence that the synaptic ATP can act as a synapse-organizing factor to induce the expression of acetylcholinesterase (AChE) and acetylcholine receptor (AChR) in muscles, mediated by a metabotropic ATP receptor subtype, the P2Y(1) receptor. The activation of the P2Y(1) receptor by adenine nucleotides stimulated the accumulation of inositol phosphates and intracellular Ca(2+) mobilization in cultured chick myotubes. P2Y(1) receptor mRNA in chicken muscle is very abundant before hatching and again increases in the adult. The P2Y(1) receptor protein is shown to be restricted to the neuromuscular junctions and colocalized with AChRs in adult muscle (chicken, Xenopus, and rat) but not in the chick embryo. In chicks after hatching, this P2Y(1) localization develops over approximately 3 weeks. Denervation or crush of the motor nerve (in chicken or rat) caused up to 90% decrease in the muscle P2Y(1) transcript, which was restored on regeneration, whereas the AChR mRNA greatly increased. Last, mRNAs encoding the AChE catalytic subunit and the AChR alpha-subunit were induced when the P2Y(1) receptors were activated by specific agonists or by overexpression of P2Y(1) receptors in cultured myotubes; those agonists likewise induced the activity in the myotubes of promoter-reporter gene constructs for those subunits, actions that were blocked by a P2Y(1)-specific antagonist. These results provide evidence for a novel function of ATP in regulating the gene expression of those two postsynaptic effectors.

An elusive receptor is finally caught: P2Y(12'), an important drug target in platelets.

Despite intensive research, the nucleotide P2 receptor that is involved in the aggregation and activation of platelets by ADP has remained elusive. However, now two research groups have independently identified a new platelet receptor of unexpected structure, P2Y(12), that acts with the P2Y(1) receptor to form the site of ADP activation and explains the multiple transduction mechanisms observed in response to ADP in platelets. Recent evidence also suggests that a third component, ATP action on the P2X(1) receptor ion channel, contributes to platelet activation.

Adenosine nucleotides acting at the human P2Y1 receptor stimulate mitogen-activated protein kinases and induce apoptosis.

For the widely distributed P2Y receptors for nucleotides, the transductional and functional responses downstream of their coupling to G proteins are poorly characterized. Here we describe apoptotic induction and the associated differential stimulation of mitogen-activated protein (MAP) kinase family members by the human P2Y(1) receptor. The potent P2Y(1) receptor agonist, 2-methylthio-ADP (2-MeSADP), stimulated the extracellular-signal regulated kinases (ERK1/2) (EC(50) approximately 5 nm) as well as several, but not all isoforms detected, of the stress-activated protein kinase (SAPK) family. Phospho-isoforms of p38 were unaffected. The induced kinase activity was blocked by the P2Y(1) receptor-selective antagonist, adenosine-2'-phosphate-5'-phosphate, but unaffected by pertussis toxin. In addition, the endogenous ligand ADP, and significantly also 2-MeSATP, induced concentration-dependent phosphorylation changes in the same MAP kinase family members. The sustained activation of ERK1/2 was associated with Elk-1 phosphorylation that was abolished by the MEK1 inhibitor, PD 98059. However, the concomitant transient activation of the SAPKs was not sufficient to induce c-Jun or ATF-2 phosphorylation. The transient phase of the ERK activity was partially inhibited either by the phosphatidylinositol 3-kinase inhibitor, LY 294002, or the PKC inhibitor, Gö 6976. In addition, the Src inhibitor, PP1, or expression of dominant negative Ras also attenuated the transient phase of ERK phosphorylation. In contrast, inhibition of Ras or Src had no effect on the sustained ERK activity, which was critically dependent on phosphatidylinositol 3-kinase. The transient SAPK activity was suppressed by expression of a dominant negative form of MKK4. Furthermore, this kinase-deficient mutant inhibited 2-MeSADP-induced caspase-3 stimulation and the associated decrease in cell number. In conclusion, adenosine di- and triphosphate stimulation of the human P2Y(1) receptor can transiently activate the Ras-ERK cascade via the cooperative effects of phosphatidylinositol 3-kinase, Src and PKC. The sustained ERK stimulation, via a Ras-insensitive pathway, culminates in Elk-1 activation without inducing a proliferation effect. The transient SAPK activity did not evoke transcription factor phosphorylation but was required for the P2Y(1) receptor-mediated apoptotic function.

Structural diversity despite strong evolutionary conservation in the 5'-untranslated region of the P-type dystrophin transcript.

Analysis of the 5'-flanking regions of the Purkinje (P-) dystrophin genes and mRNAs in different species revealed strong sequence conservation but functional diversity. Multiple transcription initiation sites were identified in cerebella and muscles, tissues expressing P-dystrophin. The predominant initiation site was conserved, with another muscle-specific site located upstream. Despite sequence homology, significant tissue- and species-specific structural diversity in the P-type 5'-ends exists, including alternative splicing within the 5'-untranslated region combined with alternative splicing of intron 1. One amino terminus is conserved in mammals and, to a lesser extent, in chicken. However, alternative usage of ATG codons may result in a choice of N-termini or translation of short upstream ORFs in different species. Promoter activity of a fragment upstream of the cap site was shown by transient expression in myoblasts and in vivo following intramuscular injection. It is tissue- and developmentally regulated. Analysis of promoter deletions suggests the existence of negative regulatory elements in the proximal region.

Activity of adenosine diphosphates and triphosphates on a P2Y(T) -type receptor in brain capillary endothelial cells.

1. A P2Y (nucleotide) receptor activity in a clonal population (B10) of rat brain capillary endothelial cells is coupled to inhibition of adenylyl cyclase and has functional similarities to the P2Y(T) (previously designated 'P2T') receptor for ADP of blood platelets. However, the only P2Y receptor which was detectable in a previous study of B10 cells by mRNA analysis was the P2Y(1) receptor, which elsewhere shows no transduction via cyclic nucleotides. We have sought here to clarify these issues. 2. The inhibition of forskolin-stimulated adenylyl cyclase induced by purified nucleotides was measured on B10 cells. The EC(50) value for 2-methylthioADP (2-MeSADP) was 2.2 nM and, surprisingly, 2-MeSATP was an almost equally strong agonist (EC(50)=3.5 nM). ATP and 2-ClATP were weak partial agonists (EC(50)=26 microM and 10 microM respectively) and under appropriate conditions could antagonise the activity on 2-MeSADP. 3. A known selective antagonist of the platelet P2Y(T) receptor, 2-propylthioadenosine-5'-(beta,gamma)-difluoromethylene) triphosphonate (AR-C 66096), was a competitive antagonist of this B10 cell receptor, with pK(B)=7.6. That ligand is inactive at the P2Y(1) receptor in the same cells. Conversely, the competitive P2Y(1) receptor antagonists, the 3', 5'- and 2', 5'-adenosine bis-monophosphates, are, instead, weak agonists at the adenylyl cyclase-inhibitory receptor. 4. The inhibition of adenylyl cyclase by 2-MeSADP was completely abolished by pertussis toxin. 5. In summary, these brain endothelial cells possess a P2Y(T)-type receptor in addition to the P2Y(1) receptor. The two have similarities in agonist profiles but are clearly distinguishable by antagonists and by their second messenger activations. The possible relationships between the B10 and platelet P2Y(T) receptors are discussed.

alpha(1B) adrenergic receptors in gonadotrophin-releasing hormone neurones: relation to Transport-P.

1. Peptidergic neurones accumulate amines via an unusual uptake process, designated Transport-P. [(3)H]-prazosin binds to alpha(1) adrenoceptors on these cells and is displaceable by unlabelled prazosin in concentrations up to 10(-7) M. However, at greater concentrations of prazosin, there is a paradoxical accumulation of [(3)H]-prazosin which we have attributed to Transport-P. Uptake of prazosin via Transport-P is detectable at 10(-10) M prazosin concentration, is linear up to 10(-7) M and at greater concentrations becomes non-linear. In contrast, in noradrenergic neurones, noradrenaline uptake is linear and saturates above 10(-7) M. In noradrenergic neurones and in non-neuronal cells, there is no uptake of prazosin in concentrations up to 10(-6) M, suggesting that Transport-P is a specialised function of peptidergic neurones. 2. Using a mouse peptidergic (gonadotrophin-releasing hormone, GnRH) neuronal cell line which possesses Transport-P, we have studied the interaction of alpha(1) adrenoceptors with Transport-P. Polymerase chain reactions and DNA sequencing of the products demonstrated that only the alpha(1B) sub-type of adrenoceptors is present in GnRH cells. 3. In COS cells transfected with alpha(1b) adrenoceptor cDNA and in DDT(1) MF-2 cells which express native alpha(1B) adrenoceptors, [(3)H]-prazosin was displaced by unlabelled prazosin in a normal equilibrium process, with no prazosin paradox in concentrations up to 10(-6) M. In DDT(1) MF-2 cells, [(3)H]-prazosin was displaced likewise by a series of alpha(1) adrenergic agonists, none of which increased the binding of [(3)H]-prazosin. Hence, the prazosin paradox is not due to some function of alpha(1) adrenoceptors, such as internalization of ligand-receptor complexes. 4. In neurones which possess Transport-P, transfection with alpha(1b) adrenoceptor cDNA resulted in over-expression of alpha(1B) adrenoceptors, but the prazosin paradox was unaltered. Thus, alpha(1) adrenoceptors and Transport-P mediate distinct functions in peptidergic neurones.

Imagination and reality in the search for the P2Y receptors.

A great body of evidence based on tissue and organ physiology and pharmacology led to the recognition, widespread by about 1990, that there must be cell membrane receptors for extracellular nucleotides to transduce their effects. This evidence was provided by the pioneering work of Geoffrey Burnstock and those who worked with him, or was developed by others starting from that information. This article will review how we could start from that foundation to clone the first known gene for such a receptor, P2Y(1). Some unusual properties of that receptor were revealed. I will consider further the P2Y receptors as a class - its definition, now that many such genes have become known. Imagination and reality have been intertwined in this saga.

Inhibition of potassium and calcium currents in neurones by molecularly-defined P2Y receptors.

Messenger RNAs and cDNAs for individual cloned P2Y(1), P2Y2 and P2Y(6) nucleotide receptors have been expressed by micro-injection into dissociated rat superior cervical sympathetic neurones and the effects of stimulating the expressed receptors on voltage-activated N-type Ca(2+) currents and M-type K(+) currents recorded. Both currents were reduced by stimulating all three receptors, with the following mean IC(50) values: P2Y(1) (agonist: ADP) - I(K(M)) 6.9 nM, I(Ca) 8.2 nM; P2Y(2) (agonist: UTP) - I(K(M)) 1.5 microM, I(Ca) 0.5 microM; P2Y(6) (agonist: UDP) - I(K(M)) 30 nM, I(Ca) 5.9 nM. Inhibition of I(K(M)) was voltage-independent and insensitive to Pertussis toxin; inhibition of I(Ca) showed both voltage-sensitive and insensitive, and Pertussis toxin-sensitive and insensitive components. It is concluded that these P2Y receptors can couple to more than one G protein and thereby modulate more than one ion channel. It is suggested that these effects on K(M) and Ca(N) channels may induce both postsynaptic excitory and presynaptic inhibitory responses.

The P2Y(1) receptor closes the N-type Ca(2+) channel in neurones, with both adenosine triphosphates and diphosphates as potent agonists.

The rat P2Y(1) nucleotide receptor, the P2Y subtype abundant in the brain, was heterologously expressed in rat superior cervical ganglion neurones by micro-injection of the receptor cRNA or cDNA. ADP inhibited the N-type Ca(2+) current by 64%, with EC(50) 8.2 nM, an action blocked competitively by the P2Y(1) receptor antagonist adenosine 3', 5'-bis-phosphate (K(i) 0.7 microM). 2-Methylthio-ADP inhibited the Ca(2+) current likewise, but with EC(50) 0.57 nM, giving the highest potency reported therewith for P2Y(1). Significantly, ATP and 2-methylthio-ATP were also agonists, the latter again at a very high potency (EC(50) 2.5 nM). We propose that this neuronal receptor, when present in brain at a high density as at synapses, can respond to very low concentrations of ATP and ADP as agonists, and that this would result in inhibition of N-type Ca(2+) currents and hence can reduce transmitter release or increase neuronal excitability.