Using accelerometers to identify a high risk of catastrophic musculoskeletal injury in three racing Thoroughbreds.

OBJECTIVE: To describe the process whereby the screening of racing Thoroughbreds with accelerometer-based inertial measurement unit (IMU) sensors followed by clinical evaluation and advanced imaging identified potentially catastrophic musculoskeletal injuries in 3 horses. ANIMALS: 3 Thoroughbred racehorses. CLINICAL PRESENTATION: All cases demonstrated an abnormal stride pattern either during racing (cases 1 and 2) or while breezing (case 3) and were identified as being at very high risk of catastrophic musculoskeletal injury by an algorithm derived from IMU sensor files from > 20,000 horses' race starts. Veterinary examination and 18F-sodium fluoride (18F-NaF) positron emission tomography were performed within 10 days of the respective race or breeze in each of the cases. RESULTS: The intensity and location of the 18F-NaF uptake in the condyles of the third metacarpal bone in cases 1 and 2 identified them as at potential increased risk of condylar fracture. The pattern and intensity of the 18F-NaF uptake in case 3 indicated that the third carpal bone was likely responsible for the horse's lameness, with an impending slab fracture subsequently identified on radiographs. Following periods of convalescence, cases 1 and 2 returned to racing and were identified by the sensor system as no longer being at high risk of catastrophic musculoskeletal injury. Case 3 returned to training but has yet to return to racing. CLINICAL RELEVANCE: When worn by Thoroughbreds while racing or breezing, these IMU sensors can identify horses at high risk of catastrophic musculoskeletal injury, allowing for veterinary intervention and the potential avoidance of such injuries.

Underwater and Scuba Diving Accidents.

The evaluation and care of an injured scuba diver requires an understanding of the different types of underwater activities that may be deemed scuba diving. Such activities may range from the complex (eg, commercial or technical diving) all the way up to basic recreational scuba or snorkeling. A thorough physical examination should be completed as early as possible with a focus on specific areas at risk for injury and etiology, such as a detailed cardiopulmonary, skin, and neurologic examination. Serial reassessments and supportive care are as equally important as consultation with a dive medicine expert, especially one with hyperbaric capabilities.

On an Aggregated Estimate for Human Mobility Regularities through Movement Trends and Population Density.

This article introduces an analytical framework that interprets individual measures of entropy-based mobility derived from mobile phone data. We explore and analyze two widely recognized entropy metrics: random entropy and uncorrelated Shannon entropy. These metrics are estimated through collective variables of human mobility, including movement trends and population density. By employing a collisional model, we establish statistical relationships between entropy measures and mobility variables. Furthermore, our research addresses three primary objectives: firstly, validating the model; secondly, exploring correlations between aggregated mobility and entropy measures in comparison to five economic indicators; and finally, demonstrating the utility of entropy measures. Specifically, we provide an effective population density estimate that offers a more realistic understanding of social interactions. This estimation takes into account both movement regularities and intensity, utilizing real-time data analysis conducted during the peak period of the COVID-19 pandemic.

Danavorexton (TAK-925): an orexin receptor 2 agonist as a new 'arousal' agent.

A preclinical study in animals has further characterised a new 'arousal' agent. Danavorexton (TAK-925) is an agonist for orexin receptor 2 where it promotes recovery from inhalational and i.v. anaesthesia and opioid sedation. Although danavorexton reverses opioid sedation, it does not compromise analgesia. This could be a useful addition to the postoperative drug cupboard.

Ancient and Modern Genomes Reveal Microsatellites Maintain a Dynamic Equilibrium Through Deep Time.

Microsatellites are widely used in population genetics, but their evolutionary dynamics remain poorly understood. It is unclear whether microsatellite loci drift in length over time. This is important because the mutation processes that underlie these important genetic markers are central to the evolutionary models that employ microsatellites. We identify more than 27 million microsatellites using a novel and unique dataset of modern and ancient Adélie penguin genomes along with data from 63 published chordate genomes. We investigate microsatellite evolutionary dynamics over 2 timescales: one based on Adélie penguin samples dating to ∼46.5 ka and the other dating to the diversification of chordates aged more than 500 Ma. We show that the process of microsatellite allele length evolution is at dynamic equilibrium; while there is length polymorphism among individuals, the length distribution for a given locus remains stable. Many microsatellites persist over very long timescales, particularly in exons and regulatory sequences. These often retain length variability, suggesting that they may play a role in maintaining phenotypic variation within populations.

Opioids and opioid receptors; understanding pharmacological mechanisms as a key to therapeutic advances and mitigation of the misuse crisis.

Opioids are a mainstay in acute pain management and produce their effects and side effects (e.g., tolerance, opioid-use disorder and immune suppression) by interaction with opioid receptors. I will discuss opioid pharmacology in some controversial areas of enquiry of anaesthetic relevance. The main opioid target is the µ (mu,MOP) receptor but other members of the opioid receptor family, δ (delta; DOP) and κ (kappa; KOP) opioid receptors also produce analgesic actions. These are naloxone-sensitive. There is important clinical development relating to the Nociceptin/Orphanin FQ (NOP) receptor, an opioid receptor that is not naloxone-sensitive. Better understanding of the drivers for opioid effects and side effects may facilitate separation of side effects and production of safer drugs. Opioids bind to the receptor orthosteric site to produce their effects and can engage monomer or homo-, heterodimer receptors. Some ligands can drive one intracellular pathway over another. This is the basis of biased agonism (or functional selectivity). Opioid actions at the orthosteric site can be modulated allosterically and positive allosteric modulators that enhance opioid action are in development. As well as targeting ligand-receptor interaction and transduction, modulating receptor expression and hence function is also tractable. There is evidence for epigenetic associations with different types of pain and also substance misuse. As long as the opioid narrative is defined by the 'opioid crisis' the drive to remove them could gather pace. This will deny use where they are effective, and access to morphine for pain relief in low income countries.

Soluble Vascular Adhesion Protein 1 (sVAP-1) as a biomarker for pregnancy complications: A pilot study.

BACKGROUND: Vascular adhesion protein 1 (VAP-1) has been implicated in a wide range of clinical conditions. Moreover, serum levels are associated with disease prediction and progression in several clinical studies. There is a paucity of data on VAP-1 and pregnancy. Given the emerging role of VAP-1 in pregnancy, the aim of this study was to examine sVAP-1 as an early biomarker of pregnancy complications, especially hypertension during pregnancy. The objectives of the study are to associate sVAP-1 levels with other pregnancy complications, patient demographics and blood tests performed throughout pregnancy. METHODS: We conducted a pilot study in a cohort of pregnant women (gestational week lower than 20 at the time of recruitment) attending their first antenatal ultrasound scan at the Leicester Royal Infirmary (LRI, UK). Data were both prospectively generated (from blood sample analysis) and retrospectively collected (from hospital records). RESULTS: From July and October 2021, a total of 91 participants were enrolled. Using ELISA (enzyme-linked immunosorbent assay), we found reduced serum levels of sVAP-1 in pregnant women with either pregnancy induced hypertension (PIH) (310 ng/mL) or GDM (366.73 ng/mL) as compared to controls (427.44 ng/mL and 428.34 ng/mL, respectively). No significant difference was found between women with FGR compared to controls (424.32 ng/mL vs 424.52 ng/mL), and patients with any pregnancy complications compared to healthy pregnancies (421.28 ng/mL vs 428.34 ng/mL). CONCLUSION: Further studies are needed to establish whether or not sVAP-1 might be considered as an early, non-invasive, and affordable biomarker to screen women who will develop PIH or GDM. Our data will aid sample size calculations for such larger studies.

In vitro sepsis up-regulates Nociceptin/Orphanin FQ receptor expression and function on human T- but not B-cells.

BACKGROUND AND PURPOSE: In animal models of sepsis, increased activation of the Nociceptin/Orphanin FQ (N/OFQ) receptor NOP is associated with mortality and NOP antagonists improved survival. We have explored the role of the N/OFQ-NOP system in freshly isolated volunteer human B- and T-cells incubated with lipopolysaccharide (LPS) and peptidoglycan G (PepG) as a model of in vitro sepsis. EXPERIMENTAL APPROACH: B- and T-cell NOP expression was measured using the NOP fluorescent probe N/OFQATTO594 , N/OFQ content was measured using immunofluorescence, N/OFQ release was tracked using a CHOhNOPGαiq5 biosensor assay and NOP function was measured using transwell migration and cytokine/chemokine release using a 25-plex assay format. Cells were challenged with LPS/PepG. KEY RESULTS: CD19-positive B-cells bound N/OFQATTO594 ; they also contain N/OFQ. Stimulation with CXCL13/IL-4 increased N/OFQ release. N/OFQ trended to reduced migration to CXCL13/IL-4. Surface NOP expression was unaffected by LPS/PepG, but this treatment increased GM-CSF release in an N/OFQ sensitive manner. CD3-positive T-cells did not bind N/OFQATTO594 ; they did contain N/OFQ. Stimulation with CXCL12/IL-6 increased N/OFQ release. When incubated with LPS/PepG, NOP surface expression was induced leading to N/OFQATTO594 binding. In LPS/PepG-treated cells, N/OFQ reduced migration to CXCL12/IL-6. LPS/PepG increased GM-CSF release in an N/OFQ sensitive manner. CONCLUSIONS AND IMPLICATIONS: We suggest both a constitutive and sepsis-inducible N/OFQ-NOP receptor autocrine regulation of B- and T-cell function, respectively. These NOP receptors variably inhibit migration and reduce GM-CSF release. These data provide mechanistic insights to the detrimental role for increased N/OFQ signalling in sepsis and suggest a potential role for NOP antagonists as treatments.

British Journal of Anaesthesia: a leading publication and a registered charity.

The British Journal of Anaesthesia organisation is a registered charity comprised of two interlinked missions: provision of impactful publications and funding the generation and dissemination of research to the wider anaesthetic community. This centenary editorial highlights our charitable activity that covers funding of research infrastructure, meeting support and funding of a diverse portfolio of international research grants.

Celebrating the first centenary of the British Journal of Anaesthesia: a century of discovery and dissemination.

In 2023, the British Journal of Anaesthesia commemorates its first century of publishing innovations in anaesthesia, pain, critical care and perioperative medicine. In honour of this special anniversary we outline a number of exciting initiatives to occur over the course of the year to commemorate this important milestone, and to highlight the many contributions that the British Journal of Anaesthesia has made to patient care, medical research, and medical education in our first 100 years.

A Medication Hiccup: Chlorpromazine-Induced Agranulocytosis in a 72-Year-Old Male.

INTRODUCTION: Agranulocytosis, a severe decrease or absence of neutrophils, is a side effect of several medications, including chlorpromazine. If not promptly recognized, it can lead to overwhelming infection, sepsis, and death. CASE PRESENTATION: A 72-year-old man with adenocarcinoma of the lung status-post recent lobectomy was admitted for postsurgical pain and electrolyte derangement. During his admission, he had intractable hiccups and was started on chlorpromazine 25 mg by mouth 3 times a day. Within a week, he developed pneumonia, type 1 respiratory failure, and a progressive neutropenia. Chlorpromazine-induced agranulocytosis was suspected and chlorpromazine was discontinued; however, the patient expired, with postmortem findings of aspergillus bronchopneumonia as cause of death. DISCUSSION: Chlorpromazine is a well-studied cause of agranulocytosis. This case is novel in its rapid time course of less than 1 week; most cases report the resultant agranulocytosis on the order of weeks rather than days. CONCLUSION: This case highlights an important need to recognize this medication side effect early so the offending agent may be stopped and the patient properly supported, so as to avoid the severe risk of neutropenic infection, sepsis, and death.

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors.

Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 (KW-495) and RP-170-Gly3-RYYRIK-NH2 (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer.

COVID-19 in orthotopic heart transplant recipients and association with donor specific antibodies.

De novo donor-specific antibodies (DSAs) are associated with increased risk of antibody-mediated rejection and worse clinical outcomes after orthotopic heart transplant (OHT). No study has reported the production of DSAs after infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in an OHT population. In this retrospective study, we described coronavirus disease 2019 (COVID-19) incidence and clinical course in a large, contemporary OHT cohort. We showed that the case-fatality rate has significantly decreased since the early days of the pandemic, although remains higher than that of the general population. In addition, we found that 10% of OHT recipients developed de novo DSAs or experienced an increase in pre-existing DSAs after COVID-19, with the majority occurring in unvaccinated patients (15% vs 2%). Further studies are necessary to substantiate our findings in an external cohort.

In vitro sepsis induces Nociceptin/Orphanin FQ receptor (NOP) expression in primary human vascular endothelial but not smooth muscle cells.

Sepsis is a dysregulated host response to infection that can cause widespread effects on other organs including cardiovascular depression, hypotension and organ failure. The receptor for Nociceptin/Orphanin FQ (N/OFQ), NOP is expressed on immune cells and these cells can release the peptide. Exogenous N/OFQ can dilate blood vessels and this peptide is increased in animal and human sepsis. We hypothesise that NOP receptors are present on vascular endothelial cells and therefore provide the target for released N/OFQ to cause vasodilation and hence hypotension. Using human umbilical vein endothelial cells (HUVEC) and human vascular smooth muscle cells (HVSMC) freshly prepared from umbilical cords and up to passage 4, we assessed NOP mRNA expression by Polymerase Chain Reaction (PCR), NOP surface receptor expression using a fluorescent NOP selective probe (N/OFQATTO594) and NOP receptor function with N/OFQ stimulated ERK1/2 phosphorylation. As an in vitro sepsis mimic we variably incubated cells with 100ng/ml Lipopolysaccharide and Peptidoglycan G (LPS/PepG). HUVECs express NOP mRNA and this was reduced by ~80% (n = 49) after 24-48 hours treatment with LPS/PepG. Untreated cells do not express surface NOP receptors but when treated with LPS/PepG the reduced mRNA was translated into protein visualised by N/OFQATTO594 binding (n = 49). These NOP receptors in treated cells produced an N/OFQ (1µM) driven increase in ERK1/2 phosphorylation (n = 20). One (of 50) HUVEC lines expressed NOP mRNA and receptor protein in the absence of LPS/PepG treatment. In contrast, HVSMC expressed NOP mRNA and surface receptor protein (n = 10) independently of LPS/PepG treatment. These receptors were also coupled to ERK1/2 where N/OFQ (1µM) increased phosphorylation. Collectively these data show that an in vitro sepsis mimic (LPS/PepG) upregulates functional NOP expression in the vascular endothelium. Activation of these endothelial receptors as suggested from in vivo whole animal work may contribute to the hypotensive response seen in sepsis. Moreover, blockade of these receptors might be a useful adjunct in the treatment of sepsis.

Time and charge/pH-dependent activation of K+ channel-mediated K+ influx and K+/H+ exchange in guinea pig heart isolated mitochondria; role in bioenergetic stability.

Mitochondria play an important role not only in producing energy for the cell but also for regulating mitochondrial and cell function depending on the cell's needs and environment. Uptake of cations, anions, and substrates requires a stable, polarized transmembrane charge potential (ΔΨm). Chemiosmosis requires ion exchangers to remove Na+, K+, Ca2+, PO43-, and other charged species that enter mitochondria. Knowledge of the kinetics of mitochondrial (m) cation channels and exchangers is important in understanding their roles in regulating mitochondrial chemiosmosis and bioenergetics. The influx/efflux of K+, the most abundant mitochondrial cation, alters mitochondrial volume and shape by bringing in anions and H2O by osmosis. The effects of K+ uptake through ligand-specific mK+ channels stimulated/inhibited by agonists/antagonists on mitochondrial volume (swelling/contraction) are well known. However, a more important role for K+ influx is likely its effects on H+ cycling and bioenergetics facilitated by mitochondrial (m) K+/H+ exchange (mKHE), though the kinetics and consequences of K+ efflux by KHE are not well described. We hypothesized that a major role of K+ influx/efflux is stimulation of respiration via the influx of H+ by KHE. We proposed to modulate KHE activity by energizing guinea pig heart isolated mitochondria and by altering the mK+ cycle to capture changes in mitochondrial volume, pHm, ΔΨm, and respiration that would reflect a role for H+ influx via KHE to regulate bioenergetics. To test this, mitochondria were suspended in a 150 mM K+ buffer at pH 6.9, or in a 140 mM Cs+ buffer at pH 7.6 or 6.9 with added 10 mM K+, minimal Ca2+ and free of Na+. O2 content was measured by a Clark electrode, and pHm, ΔΨm, and volume, were measured by fluorescence spectrophotometry and light-scattering. Adding pyruvic acid (PA) alone caused increases in volume and respiration and a rapid decrease in the transmembrane pH gradient (ΔpHm = pHin-pHext) at pHext 6.9> > 7.6, so that ΔΨm was charged and maintained. BKCa agonist NS1619 and antagonist paxilline modified these effects, and KHE inhibitor quinine and K+ ionophore valinomycin depolarized ΔΨm. We postulate that K+ efflux-induced H+ influx via KHE causes an inward H+ leak that stimulates respiration, but at buffer pH 6.9 also utilizes the energy of ΔpHm, the smaller component of the overall proton motive force, ΔµH+. Thus ΔpHm establishes and maintains the ΔΨm required for utilization of substrates, entry of all cations, and for oxidative phosphorylation. Thus, K+ influx/efflux appears to play a pivotal role in regulating energetics while maintaining mitochondrial ionic balance and volume homeostasis.

Ketamine; history and role in anesthetic pharmacology.

Ketamine (Ket) was developed in 1962 as a less hallucinogenic and shorter acting agent than phencyclidine. It was given to humans for the first time in 1964. However, Ket produces several adverse reactions such as raised intracranial and blood pressures along with seizures, and patients still show low acceptance due to hallucinations. As new volatile and intravenous anesthetic agents with good emergence and favorable side effect profiles were developed, Ket use markedly decreased. In the 1990s, as the ultrashort-acting opioid remifentanil was developed, high dose opioid could be used to reduce surgical stress in highly invasive procedures. However, high dose opioids can produce hyperalgesia and acute tolerance. As Ket can exert anti-hyperalgesic actions, the clinical use of low dose Ket has been reconsidered. Other beneficial effects of Ket such as; analgesia, anti-shock in hemorrhagic and septic insults, anti-inflammatory effects, anti-tumor effects, brain and spinal cord neuroprotection, and bronchodilation, have all been reported. Moreover, this anesthetic agent at low dose has been recently recognized to possess anti-depressive actions. This diverse profile extends Ket far beyond anesthesia practice and the operating room.