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JAMA Nov 2023Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute...
IMPORTANCE
Critical bleeding is associated with a high mortality rate in patients with trauma. Hemorrhage is exacerbated by a complex derangement of coagulation, including an acute fibrinogen deficiency. Management is fibrinogen replacement with cryoprecipitate transfusions or fibrinogen concentrate, usually administered relatively late during hemorrhage.
OBJECTIVE
To assess whether survival could be improved by administering an early and empirical high dose of cryoprecipitate to all patients with trauma and bleeding that required activation of a major hemorrhage protocol.
DESIGN, SETTING, AND PARTICIPANTS
CRYOSTAT-2 was an interventional, randomized, open-label, parallel-group controlled, international, multicenter study. Patients were enrolled at 26 UK and US major trauma centers from August 2017 to November 2021. Eligible patients were injured adults requiring activation of the hospital's major hemorrhage protocol with evidence of active hemorrhage, systolic blood pressure less than 90 mm Hg at any time, and receiving at least 1 U of a blood component transfusion.
INTERVENTION
Patients were randomly assigned (in a 1:1 ratio) to receive standard care, which was the local major hemorrhage protocol (reviewed for guideline adherence), or cryoprecipitate, in which 3 pools of cryoprecipitate (6-g fibrinogen equivalent) were to be administered in addition to standard care within 90 minutes of randomization and 3 hours of injury.
MAIN OUTCOMES AND MEASURES
The primary outcome was all-cause mortality at 28 days in the intention-to-treat population.
RESULTS
Among 1604 eligible patients, 799 were randomized to the cryoprecipitate group and 805 to the standard care group. Missing primary outcome data occurred in 73 patients (principally due to withdrawal of consent) and 1531 (95%) were included in the primary analysis population. The median (IQR) age of participants was 39 (26-55) years, 1251 (79%) were men, median (IQR) Injury Severity Score was 29 (18-43), 36% had penetrating injury, and 33% had systolic blood pressure less than 90 mm Hg at hospital arrival. All-cause 28-day mortality in the intention-to-treat population was 26.1% in the standard care group vs 25.3% in the cryoprecipitate group (odds ratio, 0.96 [95% CI, 0.75-1.23]; P = .74). There was no difference in safety outcomes or incidence of thrombotic events in the standard care vs cryoprecipitate group (12.9% vs 12.7%).
CONCLUSIONS AND RELEVANCE
Among patients with trauma and bleeding who required activation of a major hemorrhage protocol, the addition of early and empirical high-dose cryoprecipitate to standard care did not improve all cause 28-day mortality.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04704869; ISRCTN Identifier: ISRCTN14998314.
Topics: Adult; Male; Humans; Middle Aged; Female; Hemorrhage; Fibrinogen; Blood Transfusion; Blood Component Transfusion; Wounds, Penetrating
PubMed: 37824155
DOI: 10.1001/jama.2023.21019 -
Indian Dermatology Online Journal 2023Leeches are hermaphroditic parasites of phylum Annelida and class Hirudinea. A minority of these are sanguinivorous and the cause of human morbidity. Historically,...
Leeches are hermaphroditic parasites of phylum Annelida and class Hirudinea. A minority of these are sanguinivorous and the cause of human morbidity. Historically, leeches have been used for medicinal purposes with the earliest recorded being 1500 BC. Medicinal leeches use their suction discs for locomotion, adhesion to the host, and, in the case of the anterior disc, also for blood ingestion. Dermoscopy is a new non-invasive tool that can help in the diagnosis of miscellaneous skin conditions. The new dermoscopic sign of leech bite i.e., the Mercedes Benz Logo sign which corresponds to the retractable tripartite jaw apparatus of the leech, can easily help in the quick diagnosis of the condition and referral of the patient for proper management without any delay.
PubMed: 37727570
DOI: 10.4103/idoj.idoj_414_22 -
JAMA Pediatrics Jul 2023The risk of serious long-term outcomes for infants born to individuals with opioid use disorder (OUD) is not fully characterized, nor is it well understood whether risks...
IMPORTANCE
The risk of serious long-term outcomes for infants born to individuals with opioid use disorder (OUD) is not fully characterized, nor is it well understood whether risks are modified by infant diagnosis of neonatal opioid withdrawal syndrome (NOWS).
OBJECTIVE
To characterize the risk of postneonatal infant mortality among infants with a NOWS diagnosis or born to individuals with OUD.
DESIGN, SETTING, AND PARTICIPANTS
The study team conducted a retrospective cohort study of 390 075 infants born from 2007 through 2018 to mothers who were enrolled in Tennessee Medicaid from 183 days prior to delivery through 28 days post partum (baseline). Maternal and infant baseline characteristics were measured using administrative claims and birth certificates, and infants were followed up from day 29 post partum through day 365 or death. Deaths were identified using linked death certificates through 2019. These data were analyzed from February 10, 2022, through March 3, 2023.
EXPOSURE
Infant exposures included birth to an individual with OUD or postnatal diagnosis of NOWS. The study team defined a pregnant individual's OUD status (maternal OUD) as having OUD diagnosis or a maintenance medication prescription fill during baseline; this study defined NOWS as having NOWS diagnosis up to day 28. Groups were categorized by exposures as maternal OUD with NOWS (OUD positive/NOWS positive), maternal OUD without NOWS (OUD positive/NOWS negative), no documented maternal OUD with NOWS (OUD negative/NOWS positive), and no documented maternal OUD or NOWS (OUD negative/NOWS negative, unexposed).
MAIN OUTCOME AND MEASURES
The outcome was postneonatal infant death, confirmed by death certificates. Cox proportional hazards models were used, adjusting for baseline maternal and infant characteristics, to estimate adjusted hazard ratios (aHRs) and 95% CIs for the association between maternal OUD or NOWS diagnosis with postneonatal death.
RESULTS
Pregnant individuals in the cohort had a mean (SD) age of 24.5 (5.2) years; 51% of infants were male. The study team observed 1317 postneonatal infant deaths and incidence rates of 3.47 (OUD negative/NOWS negative, 375 718), 8.41 (OUD positive/NOWS positive, 4922); 8.95 (OUD positive/NOWS negative, 7196), and 9.25 (OUD negative/NOWS positive, 2239) per 1000 person-years. After adjustment, the risk of postneonatal death was elevated for all groups, relative to the unexposed: OUD positive/NOWS positive (aHR, 1.54; 95% CI, 1.07-2.21), OUD positive/NOWS negative (aHR, 1.62; 95% CI, 1.21-2.17), and OUD negative/NOWS positive (aHR, 1.64; 95% CI, 1.02-2.65).
CONCLUSIONS AND RELEVANCE
Infants born to individuals with OUD or with a NOWS diagnosis had an increased risk of postneonatal infant mortality. Future work is necessary to create and evaluate supportive interventions for individuals with OUD during and after pregnancy to reduce adverse outcomes.
Topics: Infant; Infant, Newborn; Pregnancy; Female; Male; Humans; Young Adult; Adult; Retrospective Studies; Infant Mortality; Opioid-Related Disorders; Mothers; Neonatal Abstinence Syndrome; Analgesics, Opioid
PubMed: 37155175
DOI: 10.1001/jamapediatrics.2023.1047 -
Matrix Biology : Journal of the... Nov 2023Fibrosis is associated with dramatic changes in extracellular matrix (ECM) architecture of unknown etiology. Here we exploit keloid scars as a paradigm to understand...
Fibrosis is associated with dramatic changes in extracellular matrix (ECM) architecture of unknown etiology. Here we exploit keloid scars as a paradigm to understand fibrotic ECM organization. We reveal that keloid patient fibroblasts uniquely produce a globally aligned ECM network in 2-D culture as observed in scar tissue. ECM anisotropy develops after rapid initiation of a fibroblast supracellular actin network, suggesting that cell alignment initiates ECM patterning. Keloid fibroblasts produce elevated levels of IL-6, and autocrine IL-6 production is both necessary and sufficient to induce cell and ECM alignment, as evidenced by ligand stimulation of normal dermal fibroblasts and treatment of keloid fibroblasts with the function blocking IL-6 receptor monoclonal antibody, tocilizumab. Downstream of IL-6, supracellular organization of keloid fibroblasts is controlled by activation of cell-cell adhesion. Adhesion formation inhibits contact-induced cellular overlap leading to nematic organization of cells and an alignment of focal adhesions. Keloid fibroblasts placed on isotropic ECM align the pre-existing matrix, suggesting that focal adhesion alignment leads to active anisotropic remodeling. These results show that IL-6-induced fibroblast cooperativity can control the development of a nematic ECM, highlighting both IL-6 signaling and cell-cell adhesions as potential therapeutic targets to inhibit this common feature of fibrosis.
Topics: Humans; Keloid; Interleukin-6; Anisotropy; Cells, Cultured; Extracellular Matrix; Fibroblasts
PubMed: 37660739
DOI: 10.1016/j.matbio.2023.08.004 -
International Journal of Molecular... Jul 2023When attacks its prey, the prey bleeds profusely but feels little pain. We and other research teams have identified several anticoagulant molecules in the saliva of ,...
When attacks its prey, the prey bleeds profusely but feels little pain. We and other research teams have identified several anticoagulant molecules in the saliva of , but the substance that produces the paralyzing effect in is not known. In this study, we successfully isolated, purified, and identified a serine protease inhibitor containing an antistasin-like domain from the salivary secretions of . This peptide (named poeciguamerin) significantly inhibited elastase activity and slightly inhibited FXIIa and kallikrein activity, but had no effect on FXa, trypsin, or thrombin activity. Furthermore, poeciguamerin exhibited analgesic activity in the foot-licking and tail-withdrawal mouse models and anticoagulant activity in the FeCl-induced carotid artery thrombosis mouse model. In this study, poeciguamerin was found to be a promising elastase inhibitor with potent analgesic and antithrombotic activity for the inhibition of pain and thrombosis after surgery or in inflammatory conditions.
Topics: Animals; Mice; Leeches; Serine Proteinase Inhibitors; Serpins; Anticoagulants; Thrombosis; Pancreatic Elastase; Analgesics; Pain
PubMed: 37446275
DOI: 10.3390/ijms241311097 -
Protein Science : a Publication of the... Dec 2023Hirudin from Hirudo medicinalis is a bivalent α-Thrombin (αT) inhibitor, targeting the enzyme active site and exosite-I, and is currently used in anticoagulant therapy...
From haemadin to haemanorm: Synthesis and characterization of full-length haemadin from the leech Haemadipsa sylvestris and of a novel bivalent, highly potent thrombin inhibitor (haemanorm).
Hirudin from Hirudo medicinalis is a bivalent α-Thrombin (αT) inhibitor, targeting the enzyme active site and exosite-I, and is currently used in anticoagulant therapy along with its simplified analogue hirulog. Haemadin, a small protein (57 amino acids) isolated from the land-living leech Haemadipsa sylvestris, selectively inhibits αT with a potency identical to that of recombinant hirudin (K = 0.2 pM), with which it shares a common disulfide topology and overall fold. At variance with hirudin, haemadin targets exosite-II and therefore (besides the free protease) it also blocks thrombomodulin-bound αT without inhibiting the active intermediate meizothrombin, thus offering potential advantages over hirudin. Here, we produced in reasonably high yields and pharmaceutical purity (>98%) wild-type haemadin and the oxidation resistant Met5 → nor-Leucine analogue, both inhibiting αT with a K of 0.2 pM. Thereafter, we used site-directed mutagenesis, spectroscopic, ligand-displacement, and Hydrogen/Deuterium Exchange-Mass Spectrometry techniques to map the αT regions relevant for the interaction with full-length haemadin and with the synthetic N- and C-terminal peptides Haem(1-10) and Haem(45-57). Haem(1-10) competitively binds to/inhibits αT active site (K = 1.9 μM) and its potency was enhanced by 10-fold after Phe3 → β-Naphthylalanine exchange. Conversely to full-length haemadin, haem(45-57) displays intrinsic affinity for exosite-I (K = 1.6 μM). Hence, we synthesized a peptide in which the sequences 1-9 and 45-57 were joined together through a 3-Glycine spacer to yield haemanorm, a highly potent (K = 0.8 nM) inhibitor targeting αT active site and exosite-I. Haemanorm can be regarded as a novel class of hirulog-like αT inhibitors with potential pharmacological applications.
Topics: Hirudins; Thrombin; Amino Acid Sequence; Peptides; Heme
PubMed: 37924304
DOI: 10.1002/pro.4825 -
Therapeutic Advances in Cardiovascular... 2024Vasospastic angina (VSA) refers to chest pain experienced as a consequence of myocardial ischaemia caused by epicardial coronary spasm, a sudden narrowing of the vessels... (Review)
Review
Vasospastic angina (VSA) refers to chest pain experienced as a consequence of myocardial ischaemia caused by epicardial coronary spasm, a sudden narrowing of the vessels responsible for an inadequate supply of blood and oxygen. Coronary artery spasm is a heterogeneous phenomenon that can occur in patients with non-obstructive coronary arteries and obstructive coronary artery disease, with transient spasm causing chest pain and persistent spasm potentially leading to acute myocardial infarction (MI). VSA was originally described as Prinzmetal angina or variant angina, classically presenting at rest, unlike most cases of angina (though in some patients, vasospasm may be triggered by exertion, emotional, mental or physical stress), and associated with transient electrocardiographic changes (transient ST-segment elevation, depression and/or T-wave changes). Ischaemia with non-obstructive coronary arteries (INOCA) is not a benign condition, as patients are at elevated risk of cardiovascular events including acute coronary syndrome, hospitalization due to heart failure, stroke and repeat cardiovascular procedures. INOCA patients also experience impaired quality of life and associated increased healthcare costs. VSA, an endotype of INOCA, is associated with major adverse events, including sudden cardiac death, acute MI and syncope, necessitating the study of the most effective treatment options currently available. The present literature review aims to summarize current data relating to the diagnosis and management of VSA and provide details on the sequence that treatment should follow.
Topics: Humans; Angina Pectoris, Variant; Coronary Vasospasm; Quality of Life; Coronary Angiography; Coronary Artery Disease; Myocardial Infarction; Chest Pain; Spasm
PubMed: 38343041
DOI: 10.1177/17539447241230400 -
Frontiers in Endocrinology 2024Diabetic nephropathy (DN) is a major microvascular complication of diabetes and a common cause of chronic kidney disease. There is currently a lack of effective... (Review)
Review
Diabetic nephropathy (DN) is a major microvascular complication of diabetes and a common cause of chronic kidney disease. There is currently a lack of effective treatments for DN, and the prognosis for patients remains poor. Hirudin, one of the primary active components derived from leeches, demonstrates anti-coagulant, anti-fibrotic, anti-thrombotic, and anti-inflammatory properties, exhibiting significant protective effects on the kidneys. In recent years, there has been a surge of interest in studying the potential benefits of hirudin, especially in its role in the management of DN. This article delves into the mechanisms by which hirudin contributes to the treatment of DN and its clinical efficacy.
Topics: Animals; Humans; Diabetic Nephropathies; Hirudins; Kidney; Medicine, Chinese Traditional; Leeches; Diabetes Mellitus
PubMed: 38344666
DOI: 10.3389/fendo.2024.1296843 -
Cureus Aug 2023Patients presenting with a post-invasive procedure hematoma can be treated with medicinal leeches to evacuate the hematoma. Our patient, a postmenopausal woman in her...
Patients presenting with a post-invasive procedure hematoma can be treated with medicinal leeches to evacuate the hematoma. Our patient, a postmenopausal woman in her 60s, with a past medical history of hypothyroidism, presented to the outpatient clinic with pain, redness, warmth, and swelling on her right thigh. Ten days prior, the patient had undergone a subcutaneous pellet implant procedure in the right thigh for hormonal replacement therapy. The patient developed post-procedure cellulitis and soft tissue infection and was treated with antibiotics. The patient developed a progressively enlarged hematoma at the implant site. The hematoma was treated with medicinal leeches. Two weeks after treatment, the implant area healed. The patient had a family history of von Willebrand disease and a history of prolonged bleeding during childbirth, menstruation, and dental procedures. A von Willebrand panel was obtained, and the results were consistent with a new diagnosis of von Willebrand disease.
PubMed: 37700963
DOI: 10.7759/cureus.43338 -
BioRxiv : the Preprint Server For... Sep 2023Movement flexibility and automaticity are necessary to successfully navigate different environments. When encountering difficult terrains such as a muddy trail, we can...
Movement flexibility and automaticity are necessary to successfully navigate different environments. When encountering difficult terrains such as a muddy trail, we can change how we step almost immediately so that we can continue walking. This flexibility comes at a cost since we initially must pay deliberate attention to how we are moving. Gradually, after a few minutes on the trail, stepping becomes automatic so that we do not need to think about our movements. Canonical theory indicates that different adaptive motor learning mechanisms confer these essential properties to movement: explicit control confers flexibility, while forward model recalibration confers automaticity. Here we uncover a distinct mechanism of treadmill walking adaptation - an automatic stimulus-response mapping - that confers both properties to movement. The mechanism is flexible as it learns stepping patterns that can be rapidly changed to suit a range of treadmill configurations. It is also automatic as it can operate without deliberate control or explicit awareness by the participants. Our findings reveal a tandem architecture of forward model recalibration and automatic stimulus-response mapping mechanisms for walking, reconciling different findings of motor adaptation and perceptual realignment.
PubMed: 37808648
DOI: 10.1101/2023.09.25.559267