ABSTRACT
As of 2020, penetrating injuries became the leading cause of death among children and adolescents ages 1-19 in the United States. For the patients who initially survive and receive advanced medical care, vascular injuries are a significant cause of morbidity and additionally trigger notable trauma team angst. Moreover, penetrating injuries can lead to life-threatening hemorrhage and/or limb-threatening ischemia if not addressed promptly. Vascular injury management demands timely and unique expertise, particularly for pediatric patients. As the frequency of vascular injuries requiring operative management increases, it becomes clear that an ad hoc approach is not ideal. An integrated team would provide the best approach for rapid hemorrhage control and revascularization, but the structure of vascular response teams at children's hospitals is highly variable. In part 1 of this review, we will evaluate the scope and extent of the epidemic of traumatic vascular injuries in pediatric patients, review current evidence and outcomes, discuss various challenges and advantages of different team structures, and outline potential outcome targets and pediatric vascular trauma response solutions. LEVEL OF EVIDENCE: n/a.
ABSTRACT
As of 2020, penetrating injuries became the leading cause of death among children and adolescents ages 1-19 in the United States. For those patients who survive and receive advanced medical care, vascular injuries are a significant cause of morbidity and trigger notable trauma team angst. Moreover, penetrating injuries can lead to life-threatening hemorrhage and/or limb-threatening ischemia if not addressed promptly. Vascular injury management demands timely and unique expertise, particularly for pediatric patients. In part 1 of this review, we discussed the scope and extent of the epidemic of traumatic vascular injuries in pediatric patients, reviewed current evidence and outcomes, discussed various challenges and advantages of a myriad of existing team structures, and outlined potential outcome targets and solutions. However, in order to optimize care for pediatric vascular trauma, we must also understand the fundamental best practice principles, surgical options and approaches, medical management, and recommendations for ongoing, outpatient follow-up. In part 2, we will address the best evidence, combined with expert consensus, regarding strategies for diagnosing, managing, and ongoing follow-up of vascular trauma, with particular focus on the nuances that define the unique approaches to pediatric patients. LEVEL OF EVIDENCE: n/a.
ABSTRACT
The microgeometry of the cellular microenvironment profoundly impacts cellular behaviors, yet the link between it and the ubiquitously expressed mechanosensitive ion channel PIEZO1 remains unclear. Herein, we describe a fluorescent micropipette aspiration assay that allows for simultaneous visualization of intracellular calcium dynamics and cytoskeletal architecture in real-time, under varied micropipette geometries. By integrating elastic shell finite element analysis with fluorescent lifetime imaging microscopy and employing PIEZO1-specific transgenic red blood cells and HEK cell lines, we demonstrate a direct correlation between the microscale geometry of aspiration and PIEZO1-mediated calcium signaling. We reveal that increased micropipette tip angles and physical constrictions lead to a significant reorganization of F-actin, accumulation at the aspirated cell neck, and subsequently amplify the tension stress at the dome of the cell to induce more PIEZO1's activity. Disruption of the F-actin network or inhibition of its mobility leads to a notable decline in PIEZO1 mediated calcium influx, underscoring its critical role in cellular mechanosensing amidst geometrical constraints.
Subject(s)
Actins , Calcium , Cytoskeleton , Ion Channels , Mechanotransduction, Cellular , Humans , Ion Channels/metabolism , Actins/metabolism , HEK293 Cells , Cytoskeleton/metabolism , Calcium/metabolism , Calcium Signaling/physiology , Finite Element Analysis , Animals , Microscopy, Fluorescence/methodsABSTRACT
Venous thromboembolism (VTE), comprising pulmonary embolism and deep vein thrombosis, is one of the most common complications after knee arthroscopy. Sequelae of VTE include VTE recurrence, postthrombotic syndrome, and potential for loss of limb or life. Given the increasing volume of knee arthroscopy procedures worldwide and the considerable morbidity and mortality associated with VTE, it is important to prevent, diagnose, and treat VTEs efficiently and effectively. Risk factors such as history of VTE, family history of VTE, genetic coagulopathy, oral contraceptive use, cancer history, and old age increase the risk of postoperative VTE and warrant consideration of prophylaxis. Diagnosis and treatment should be initiated rapidly in the setting of concerning symptoms and positive imaging diagnosis, respectively. The purpose of this review was to provide a framework to individualized VTE risk, weigh prophylaxis options, expedite diagnostic pathways, and implement outpatient treatment algorithms.
Subject(s)
Arthroscopy , Knee Joint , Postoperative Complications , Venous Thromboembolism , Humans , Arthroscopy/adverse effects , Venous Thromboembolism/prevention & control , Venous Thromboembolism/etiology , Risk Factors , Postoperative Complications/prevention & control , Postoperative Complications/etiology , Incidence , Knee Joint/surgery , Anticoagulants/therapeutic useSubject(s)
Breast Neoplasms , Carcinoma, Intraductal, Noninfiltrating , Mastectomy, Segmental , Humans , Breast Neoplasms/surgery , Breast Neoplasms/radiotherapy , Breast Neoplasms/pathology , Female , Mastectomy, Segmental/methods , Carcinoma, Intraductal, Noninfiltrating/surgery , Carcinoma, Intraductal, Noninfiltrating/pathology , Carcinoma, Intraductal, Noninfiltrating/radiotherapy , Prognosis , Decision Making , Biomarkers, Tumor/genetics , Clinical Decision-Making , Radiotherapy, AdjuvantABSTRACT
BACKGROUND: Breast-conserving surgery (BCS) followed by adjuvant radiotherapy (RT) is a standard treatment for ductal carcinoma in situ (DCIS). A low-risk patient subset that does not benefit from RT has not yet been clearly identified. The DCISionRT test provides a clinically validated decision score (DS), which is prognostic of 10-year in-breast recurrence rates (invasive and non-invasive) and is also predictive of RT benefit. This analysis presents final outcomes from the PREDICT prospective registry trial aiming to determine how often the DCISionRT test changes radiation treatment recommendations. METHODS: Overall, 2496 patients were enrolled from February 2018 to January 2022 at 63 academic and community practice sites and received DCISionRT as part of their care plan. Treating physicians reported their treatment recommendations pre- and post-test as well as the patient's preference. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendation. The impact of the test on RT treatment recommendation was physician specialty, treatment settings, individual clinical/pathological features and RTOG 9804 like criteria. Multivariate logisitc regression analysis was used to estimate the odds ratio (ORs) for factors associated with the post-test RT recommendations. RESULTS: RT recommendation changed 38% of women, resulting in a 20% decrease in the overall recommendation of RT (p < 0.001). Of those women initially recommended no RT (n = 583), 31% were recommended RT post-test. The recommendation for RT post-test increased with increasing DS, from 29% to 66% to 91% for DS <2, DS 2-4, and DS >4, respectively. On multivariable analysis, DS had the strongest influence on final RT recommendation (odds ratio 22.2, 95% confidence interval 16.3-30.7), which was eightfold greater than clinicopathologic features. Furthermore, there was an overall change in the recommendation to receive RT in 42% of those patients meeting RTOG 9804-like low-risk criteria. CONCLUSIONS: The test results provided information that changes treatment recommendations both for and against RT use in large population of women with DCIS treated in a variety of clinical settings. Overall, clinicians changed their recommendations to include or omit RT for 38% of women based on the test results. Based on published clinical validations and the results from current study, DCISionRT may aid in preventing the over- and undertreatment of clinicopathological 'low-risk' and 'high-risk' DCIS patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03448926 ( https://clinicaltrials.gov/study/NCT03448926 ).
Subject(s)
Breast Neoplasms , Carcinoma, Intraductal, Noninfiltrating , Mastectomy, Segmental , Humans , Female , Breast Neoplasms/radiotherapy , Breast Neoplasms/surgery , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/radiotherapy , Carcinoma, Intraductal, Noninfiltrating/surgery , Carcinoma, Intraductal, Noninfiltrating/pathology , Middle Aged , Radiotherapy, Adjuvant , Prognosis , Prospective Studies , Aged , Follow-Up Studies , Neoplasm Recurrence, Local/pathology , Clinical Decision-Making , Adult , Decision Making , Biomarkers, TumorABSTRACT
Transient receptor potential (TRP) channels are implicated in a wide array of mechanotransduction processes. However, a question remains whether TRP channels directly sense mechanical force, thus acting as primary mechanotransducers. We use several recent examples to demonstrate the difficulty in definitively ascribing mechanosensitivity to TRP channel subfamilies. Ultimately, despite being implicated in an ever-growing list of mechanosignalling events in most cases limited robust or reproducible evidence supports the contention that TRP channels act as primary transducers of mechanical forces. They either (i) possess unique and as yet unspecified structural or local requirements for mechanosensitivity; or (ii) act as mechanoamplifiers responding downstream of the activation of a primary mechanotransducer that could include Ca2+-permeable mechanosensitive (MS) channels or other potentially unidentified mechanosensors.
Subject(s)
Mechanotransduction, Cellular , Transient Receptor Potential Channels , Transient Receptor Potential Channels/metabolism , Humans , AnimalsABSTRACT
OSCA/TMEM63 channels are the largest known family of mechanosensitive channels1-3, playing critical roles in plant4-7 and mammalian8,9 mechanotransduction. Here we determined 44 cryogenic electron microscopy structures of OSCA/TMEM63 channels in different environments to investigate the molecular basis of OSCA/TMEM63 channel mechanosensitivity. In nanodiscs, we mimicked increased membrane tension and observed a dilated pore with membrane access in one of the OSCA1.2 subunits. In liposomes, we captured the fully open structure of OSCA1.2 in the inside-in orientation, in which the pore shows a large lateral opening to the membrane. Unusually for ion channels, structural, functional and computational evidence supports the existence of a 'proteo-lipidic pore' in which lipids act as a wall of the ion permeation pathway. In the less tension-sensitive homologue OSCA3.1, we identified an 'interlocking' lipid tightly bound in the central cleft, keeping the channel closed. Mutation of the lipid-coordinating residues induced OSCA3.1 activation, revealing a conserved open conformation of OSCA channels. Our structures provide a global picture of the OSCA channel gating cycle, uncover the importance of bound lipids and show that each subunit can open independently. This expands both our understanding of channel-mediated mechanotransduction and channel pore formation, with important mechanistic implications for the TMEM16 and TMC protein families.
Subject(s)
Calcium Channels , Cryoelectron Microscopy , Ion Channel Gating , Mechanotransduction, Cellular , Humans , Anoctamins/chemistry , Anoctamins/metabolism , Calcium Channels/chemistry , Calcium Channels/metabolism , Calcium Channels/ultrastructure , Lipids/chemistry , Liposomes/metabolism , Liposomes/chemistry , Models, Molecular , Nanostructures/chemistryABSTRACT
BACKGROUND AIMS: In this paper, we present a review of several selected talks presented at the CTTACC conference (Cellular Therapies in Trauma and Critical Care) held in Scottsdale, AZ in May 2023. This conference review highlights the potential for cellular therapies to "reset" the dysregulated immune response and restore physiologic functions to normal. Improvements in medical care systems and technology have increasingly saved lives after major traumatic events. However, many of these patients have complicated post-traumatic sequelae, ranging from short-term multi-organ failure to chronic critical illness. METHODS/RESULTS: Patients with chronic critical illness have been found to have dysregulated immune responses. These abnormal and harmful immune responses persist for years after the initial insult and can potentially be mitigated by treatment with cellular therapies. CONCLUSIONS: The sessions emphasized the need for more research and clinical trials with cellular therapies for the treatment of a multitude of chronic illnesses: post-trauma, radiation injury, COVID-19, burns, traumatic brain injury (TBI) and other chronic infections.
Subject(s)
Burns , COVID-19 , Cell- and Tissue-Based Therapy , Humans , Brain Injuries, Traumatic/therapy , Brain Injuries, Traumatic/immunology , Brain Injuries, Traumatic/complications , Burns/therapy , Burns/immunology , Burns/complications , Cell- and Tissue-Based Therapy/methods , Chronic Disease , COVID-19/immunology , COVID-19/therapy , Critical Illness , Immune System , Infections/therapy , Infections/immunology , Infections/etiology , SARS-CoV-2 , Wounds and Injuries/therapy , Wounds and Injuries/immunology , Wounds and Injuries/complications , Congresses as TopicABSTRACT
BACKGROUND: Blunt cerebrovascular injury (BVCI), injury to the carotid or vertebral arteries, may result from forces involving seatbelts. Although previous studies have not found a seat belt sign to be a significant predictor for BCVI, it is still used to screen patients for BCVI. OBJECTIVE: This study aims to determine risk factors for BCVI within a cohort of patients with seat belt signs. METHODS: We conducted a retrospective cohort study using our institutional trauma registry and included patients younger than 18 years with blunt trauma who both had a computed tomography angiography (CTA) of the neck performed and had evidence of a seat belt sign per the medical record. We reported frequencies, proportions, and measures of central tendency and conducted univariate analysis to evaluate factors associated with BCVI. We estimated the magnitude of the effect of each variable associated with the study outcome by conducting logistic regression and reporting odds ratios and 95% confidence intervals. RESULTS: Among all study patients, BCVI injuries were associated with Injury Severity Score higher than 15 ( P = 0.04), cervical spinal fractures ( P = 0.007), or basilar skull fractures ( P = 0.01). We observed higher proportions of children with BCVI when other motorized and other blunt mechanisms were reported as the mechanisms of injury ( P = 0.002) versus motor vehicle collision. CONCLUSIONS: Significant risk factors for BCVI in the presence of seat belt sign are: Injury severity score greater than 15, cervical spinal fracture, basilar skull fracture, and the other motorized mechanism of injury, similar to those in all children at risk of BCVI.
Subject(s)
Accidents, Traffic , Cerebrovascular Trauma , Computed Tomography Angiography , Seat Belts , Wounds, Nonpenetrating , Humans , Seat Belts/adverse effects , Retrospective Studies , Male , Female , Risk Factors , Child , Wounds, Nonpenetrating/diagnostic imaging , Wounds, Nonpenetrating/complications , Wounds, Nonpenetrating/epidemiology , Child, Preschool , Cerebrovascular Trauma/diagnostic imaging , Cerebrovascular Trauma/epidemiology , Adolescent , Accidents, Traffic/statistics & numerical data , Injury Severity Score , Infant , Registries , Spinal Fractures/epidemiology , Spinal Fractures/diagnostic imagingABSTRACT
Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17â years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6â months and 12â months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1â year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.
Subject(s)
Bone Marrow Transplantation , Brain Injuries, Traumatic , Transplantation, Autologous , Humans , Child , Brain Injuries, Traumatic/therapy , Male , Female , Adolescent , Double-Blind Method , Child, Preschool , Bone Marrow Transplantation/methods , Transplantation, Autologous/methods , Magnetic Resonance Imaging , Treatment Outcome , Leukocytes, Mononuclear/transplantation , Bayes TheoremABSTRACT
INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of death and morbidity in the trauma population. Microglia drive the secondary neuroinflammatory response after TBI. We sought to determine if the microglial response to neurologic injury was exacerbated by a second stimulus after exposure to neurologic injury. METHODS: Sprague-Dawley rats (age 2-3 wk) were divided into injured and noninjured groups. Injured rats underwent a controlled cortical impact injury; noninjured rats remained naïve to any injury and served as the control group. Primary rat microglia were isolated and applied to in vitro cultures. After incubation for 24 h, the microglia were stimulated with lipopolysaccharide (LPS) or norepinephrine. Twenty-four hours after stimulation, cell culture supernatant was collected. Tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) production were measured by standard enzyme-linked immunosorbent assays. GraphPad Prism was used for statistical analysis. RESULTS: When compared to noninjured microglia, LPS induced a significantly greater production of TNF-α in microglia isolated from the injured ipsilateral (versus noninjured = 938.8 ± 155.1, P < 0.0001) and injured contralateral hemispheres (versus noninjured = 426.6 ± 155.1, P < 0.0001). When compared to microglia from noninjured cerebral tissue, IL-6 production was significantly greater after LPS stimulation in the injured ipsilateral hemisphere (mean difference versus noninjured = 9540 ± 3016, P = 0.0101) and the contralateral hemisphere (16,700 ± 3016, P < 0.0001). Norepinephrine did not have a significant effect on IL-6 or TNF-α production. CONCLUSIONS: LPS stimulation may amplify the release of proinflammatory cytokines from postinjury microglia. These data suggest that post-TBI complications, like sepsis, may propagate neuroinflammation by augmenting the proinflammatory response of microglia.
Subject(s)
Brain Injuries, Traumatic , Cytokines , Rats , Animals , Microglia/pathology , Lipopolysaccharides/pharmacology , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/pharmacology , Interleukin-6 , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/pathology , NorepinephrineABSTRACT
OBJECTIVE: Randomized controlled trials (RCTs) are a gold standard for estimating the benefits of clinical interventions, but their decision-making utility can be limited by relatively short follow-up time. Longer-term follow-up of RCT participants is essential to support treatment decisions. However, as time from randomization accrues, loss to follow-up and competing events can introduce biases and require covariate adjustment even for intention-to-treat effects. We describe a process for synthesizing expert knowledge and apply this to long-term follow-up of an RCT of treatments for meniscal tears in patients with knee osteoarthritis (OA). METHODS: We identified 2 post-randomization events likely to impact accurate assessment of pain outcomes beyond 5 years in trial participants: loss to follow-up and total knee replacement (TKR). We conducted literature searches for covariates related to pain and TKR in individuals with knee OA and combined these with expert input. We synthesized the evidence into graphical models. RESULTS: We identified 94 potential covariates potentially related to pain and/or TKR among individuals with knee OA. Of these, 46 were identified in the literature review and 48 by expert panelists. We determined that adjustment for 50 covariates may be required to estimate the long-term effects of knee OA treatments on pain. CONCLUSION: We present a process for combining literature reviews with expert input to synthesize existing knowledge and improve covariate selection. We apply this process to the long-term follow-up of a randomized trial and show that expert input provides additional information not obtainable from literature reviews alone.
Subject(s)
Knee Injuries , Osteoarthritis, Knee , Humans , Osteoarthritis, Knee/complications , Osteoarthritis, Knee/therapy , Pain/etiology , Physical Therapy ModalitiesABSTRACT
BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) are multipotent adult cells that can be isolated from tissues including bone marrow [MSC(BM)], adipose [MSC(AT)] and umbilical cord [MSC(CT)]. Previous studies have linked expression of tissue factor (TF) on MSC surfaces to a procoagulant effect. Venous thromboembolism (VTE), immediate blood-mediated inflammatory reaction (IBMIR) and microvascular thrombosis remain a risk with intravascular MSC therapy. We examined the effect of low molecular weight heparin (LMWH) on clinical-grade MSCs using calibrated automated thrombography (CAT). METHODS: Clinical grade MSC(BM)s, MSC(AT)s and MSC(CT)s harvested at passage 4 were added to normal pooled plasma (NPP) to a final concentration of either 400 000 or 50 000 cells/mL. LMWH was added to plasma in increments of 0.1 U/mL. Thrombin generation (TG) was measured using CAT. Flow cytometry was conducted on the cells to measure MSC phenotype and TF load. RESULTS: Presence of MSCs decreased lag time and increased peak TG. All cell lines demonstrated a dose response to LMWH, with MSC(AT) demonstrating the least thrombogenicity and most sensitivity to LMWH. TG was significantly reduced in all cell lines at doses of 0.2 U/mL LMWH and higher. DISCUSSION: All MSC types and concentrations had a decrease in peak thrombin and TG with increasing amounts of LMWH. While this in vitro study cannot determine optimal dosing, it suggests that LMWH can be effectively used to lower the risk of VTE associated with intravascular administration of MSCs. Future in vivo work can be done to determine optimal dosing and effect on IBMIR and VTE.
Subject(s)
Coagulants , Thrombosis , Venous Thromboembolism , Adult , Humans , Heparin, Low-Molecular-Weight/pharmacology , Heparin, Low-Molecular-Weight/therapeutic use , Venous Thromboembolism/drug therapy , Coagulants/therapeutic use , Thrombin/therapeutic use , Heparin/therapeutic useABSTRACT
The transient receptor potential melastatin 4 (TRPM4) channel contributes extensively to cardiac electrical activity, especially cardiomyocyte action potential formation. Mechanical stretch can induce changes in heart rate and rhythm, and the mechanosensitive channel Piezo1 is expressed in many cell types within the myocardium. Our previous study showed that TRPM4 and Piezo1 are closely co-localized in the t-tubules of ventricular cardiomyocytes and contribute to the Ca2+ -dependent signalling cascade that underlies hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ. In the present study, we employed the HL-1 mouse atrial myocyte-like cell line as an in vitro model to investigate whether Piezo1-TRPM4 coupling can affect action potential properties. We used the small molecule Piezo1 agonist, Yoda1, as a surrogate for mechanical stretch to activate Piezo1 and detected the action potential changes in HL-1 cells using FluoVolt, a fluorescent voltage sensitive dye. Our results demonstrate that Yoda1-induced activation of Piezo1 changes the action potential frequency in HL-1 cells. This change in action potential frequency is reduced by Piezo1 knockdown using small intefering RNA. Importantly knockdown or pharmacological inhibition of TRPM4 significantly affected the degree to which Yoda1-evoked Piezo1 activation influenced action potential frequency. Thus, the present study provides in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte-like cell line. The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+ -activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction. KEY POINTS: The transient receptor potential melastatin 4 (TRPM4) and Piezo1 channels have been confirmed to contribute to the Ca2+ -dependent signalling cascade that underlies cardiac hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ. We employed the HL-1 mouse atrial myocyte-like cell line as an in vitro model to investigate the effect of Piezo1-TRPM4 coupling on cardiac electrical properties. The results show that both pharmacological and genetic inhibition of TRPM4 significantly affected the degree to which Piezo1 activation influenced action potential frequency in HL-1 cells. Our findings provide in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte-like cell line. The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+ -activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction in various (patho)physiological processes.
ABSTRACT
Objectives: Recent studies evaluating fibrinogen replacement in trauma, along with newly available fibrinogen-based products, has led to an increase in debate on where products such as cryoprecipitate belong in our resuscitation strategies. We set out to define the phenotype and outcomes of those with hypofibrinogenemia and evaluate whether fibrinogen replacement should have a role in the initial administration of massive transfusion. Methods: All patients <18 years of age presenting to our trauma center 11/17-4/21 were reviewed. We then evaluated all patients who received emergency-release and massive transfusion protocol (MTP) products. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen <150 or rapid thrombelastography (r-TEG) angle <60 degrees. Our analysis sought to define risk factors for presenting with HYPOFIB, the impact on outcomes, and whether early replacement improved mortality. Results: 4169 patients were entered into the trauma registry, with 926 level 1 trauma activations, of which 186 patients received emergency-release blood products during this time; 1%, 3%, and 10% were HYPOFIB, respectively. Of the 186 patients of interest, 18 were HYPOFIB and 168 were non-HYPOFIB. The HYPOFIB patients were significantly younger, had lower field and arrival Glasgow Coma Scale, had higher head Abbreviated Injury Scale, arrived with worse global coagulopathy, and died from brain injury. Non-HYPOFIB patients were more likely to have (+)focused assessment for the sonography of trauma on arrival, sustained severe abdominal injuries, and die from hemorrhage. 12% of patients who received early cryoprecipitate (0-2 hours) had higher mortality by univariate analysis (55% vs 31%, p=0.045), but no difference on multivariate analysis (OR 0.36, 95% CI 0.07 to 1.81, p=0.221). Those receiving early cryoprecipitate who survived after pediatric intensive care unit (PICU) admission had lower PICU fibrinogen and r-TEG alpha-angle values. Conclusion: In pediatric trauma, patients with hypofibrinogenemia on admission are most likely younger and to have sustained severe brain injury, with an associated mortality of over 80%. Given the absence of bleeding-related deaths in HYPOFIB patients, this study does not provide evidence for the empiric use of cryoprecipitate in the initial administration of a massive transfusion protocol. Level of Evidence: Level III - Therapeutic/Care Management.
ABSTRACT
BACKGROUND: Injecting bioactive substances into the knee is common in orthopaedic practice, and recently it has been shown to mitigate risk factors for posttraumatic osteoarthritis. Therefore, understanding the influence of these injections on postoperative infection rate is imperative. HYPOTHESIS: Postinjury aspiration and corticosteroid injection (CSI) of the knee before anterior cruciate ligament (ACL) reconstruction (ACLR) would not increase the risk of postoperative infection. STUDY DESIGN: Cohort Study; Level of evidence, 3. METHODS: All patients between the ages of 10 and 65 years who underwent primary bone-patellar tendon-bone ACLR by 1 fellowship-trained sports medicine orthopaedic surgeon between January 1, 2011, and September 8, 2020, at 1 of 2 major academic centers were evaluated for inclusion. A total of 693 patients were included, with 273 patients receiving postinjury and preoperative aspiration and CSI. A postoperative infection was defined as a patient returning to the operating room for an intra-articular washout. The intervals-measured in days-between the CSI and ACLR and between ACLR and the final follow-up were recorded. To further evaluate the infection risk in each cohort (total cohort; aspiration and injection cohort; no aspiration and injection cohort), the upper 95% confidence bound for the infection risk was calculated for each cohort. RESULTS: There were no postoperative infections in the 693 patients included in this study. The upper 95% confidence bounds were 0.4%, 1.1%, and 0.7% for the total cohort, the cohort that underwent aspiration and injection, and the cohort that did not, respectively. The median number of days between the surgical date and that of the aspiration and injection was 34 days, and the mean follow-up for the entire cohort was 337.4 days (95% CI, 307.6-367.3). CONCLUSION: Postinjury and preoperative aspiration and CSI is a safe intervention that can be used before ACLR. Future studies with larger sample sizes, longer patient follow-ups, and multiple surgeons would be helpful to both better understand infection risk and better identify the influence of CSI on preventing posttraumatic osteoarthritis.
Subject(s)
Anterior Cruciate Ligament Injuries , Anterior Cruciate Ligament Reconstruction , Osteoarthritis , Humans , Child , Adolescent , Young Adult , Adult , Middle Aged , Aged , Anterior Cruciate Ligament Injuries/surgery , Cohort Studies , Knee Joint/surgery , Anterior Cruciate Ligament Reconstruction/adverse effects , Postoperative Complications/surgery , Osteoarthritis/surgeryABSTRACT
Background: Humeral avulsion of the glenohumeral ligament (HAGL) lesions are an uncommon cause of anterior glenohumeral instability and may occur in isolation or combination with other pathologies. As HAGL lesions are difficult to detect via magnetic resonance imaging (MRI) and arthroscopy, they can remain unrecognized and result in continued glenohumeral instability. Purpose: To compare patients with anterior shoulder instability from a large multicenter cohort with and without a diagnosis of a HAGL lesion and identify preoperative physical examination findings, patient-reported outcomes, imaging findings, and surgical management trends associated with HAGL lesions. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients with anterior glenohumeral instability who underwent surgical management between 2012 and 2020 at 11 orthopaedic centers were enrolled. Patients with HAGL lesions identified intraoperatively were compared with patients without HAGL lesions. Preoperative characteristics, physical examinations, imaging findings, intraoperative findings, and surgical procedures were collected. The Student t test, Kruskal-Wallis H test, Fisher exact test, and chi-square test were used to compare groups. Results: A total of 21 HAGL lesions were identified in 915 (2.3%) patients; approximately one-third (28.6%) of all lesions were visualized intraoperatively but not identified on preoperative MRI. Baseline characteristics did not differ between study cohorts. Compared with non-HAGL patients, HAGL patients were less likely to have a Hill-Sachs lesion (54.7% vs 28.6%; P = .03) or an anterior labral tear (87.2% vs 66.7%; P = .01) on preoperative MRI and demonstrated increased external rotation when their affected arm was positioned at 90° of abduction (85° vs 90°; P = .03). Additionally, HAGL lesions were independently associated with an increased risk of undergoing an open stabilization surgery (odds ratio, 74.6 [95% CI, 25.2-221.1]; P < .001). Conclusion: Approximately one-third of HAGL lesions were missed on preoperative MRI. HAGL patients were less likely to exhibit preoperative imaging findings associated with anterior shoulder instability, such as Hill-Sachs lesions or anterior labral pathology. These patients underwent open procedures more frequently than patients without HAGL lesions.