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BACKGROUND: The insertion of peripheral intravenous (PIV) catheters is one of the most performed invasive procedures in acute healthcare settings. However, peripheral difficult vascular access (PDVA) is not uncommon and can lead to delays in administering essential medications. Ultrasound (US) has emerged as a valuable tool for facilitating PIV cannulation. Advancements in technology have introduced a technique known as bi-plane imaging, allowing the simultaneous display of both longitudinal and transverse views of vessels. We aimed to investigate whether the utilization of bi-plane imaging, as opposed to the single-plane approach, would yield superior results for PDVA in the emergency department (ED). METHODS: This study was a single-center randomized controlled trial. We included adult patients admitted to the ED who required PIV cannulation. Patients were randomly assigned to undergo cannulation using either the mono-plane or bi-plane approach, both performed by skilled providers. The primary outcome of the study was to compare the first attempt success rates between the two techniques. RESULTS: A total of 442 patients were enrolled, with 221 undergoing cannulation attempts using the mono-plane approach. Successful placement of a functioning PIV catheter was achieved in a single attempt for 313 out of 442 patients (70.8%). There was no significant difference in the success rates between the two study groups: 68.3% in the mono-plane group and 73.3% in the bi-plane group (p = 0.395). The median time required for a successful attempt differed between the groups, with 45 s (range 18-600) in the mono-plane group and 35 s (range 20-600) in the bi-plane group (p = 0.03). CONCLUSIONS: Our study confirms that US is a highly effective tool for facilitating PIV cannulation in patients with PDVA presenting to the ED. However, our investigation into the use of bi-plane imaging did not reveal a significant improvement when compared to mono-plane imaging.
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Cateterismo Periférico , Adulto , Humanos , Estudios Prospectivos , Ultrasonografía , Cateterismo Periférico/métodos , Servicio de Urgencia en Hospital , Ultrasonografía Intervencional/métodosRESUMEN
Background and Objectives. Acute aortic syndromes (AASs) are emergencies burdened by high morbidity and mortality. Guideline-recommended diagnostic workup is based on pre-test probability assessment (PPA) and d-dimer testing. However, the performance of PPA and d-dimer has never been studied in individuals with previous AAS (pAAS), which represent a challenging population. Materials and Methods. We analyzed a registry of patients with pAAS evaluated in two Emergency Departments (EDs) for suspected novel AAS (nAAS). Enrolment criteria were history of pAAS and the presence of truncal pain, syncope or perfusion deficit. All patients underwent advanced imaging. Clinical data were registered prospectively and PPA was performed by applying the aortic dissection detection (ADD) and an aorta simplified (AORTAs) score. Results. A total of 128 patients were enrolled, including 77 patients with previous Stanford type A aortic dissection and 45 patients with previous Stanford type B aortic dissection. The final diagnosis was nAAS in 40 (31%) patients. Clinical variables associated with nAAS were: aortic valve disease, thoracic aortic aneurysm, severe pain, sudden pain, ripping/tearing pain and hypotension/shock. ADD score ≥ 2 had a sensitivity of 65% and a specificity of 83% for nAAS; AORTAs score ≥ 2 had a sensitivity of 48% and a specificity of 88%. d-dimer (cutoff ≥ 500 ng/mL or age-adjusted cutoff) had a sensitivity of 97% and a specificity of 13%/14.7%, for diagnosis of nAAS. Patients that were candidates for guideline-compliant PPA/d-dimer integrated rule-out were: 5 (4.9%) with ADD ≤ 1/d-dimer and 8 (7.8%) with AORTAs ≤ 1/d-dimer < age-adjusted cutoff. None of them had a nAAS. Conclusions. Patients with pAAS evaluated in the ED for red-flag symptoms showed intermediate-to-high pre-test probability of nAAS. The ADD score had lower sensitivity and specificity than in unselected patients. d-dimer, alone and integrated with PPA, was highly sensitive for nAAS, but very unspecific. PPA/d-dimer integrated strategies are unlikely to significantly reduce the number of patients with pAAS undergoing advanced imaging.
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Sindrome Aortico Agudo , Disección Aórtica , Humanos , Disección Aórtica/diagnóstico , Probabilidad , Dolor , BiomarcadoresRESUMEN
STUDY OBJECTIVE: Accurate diagnostic testing to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical. Although highly specific, SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) has been shown in clinical practice to be affected by a noninsignificant proportion of false-negative results. This study seeks to explore whether the integration of lung ultrasonography with clinical evaluation is associated with increased sensitivity for the diagnosis of coronavirus disease 2019 pneumonia, and therefore may facilitate the identification of false-negative SARS-CoV-2 RT-PCR results. METHODS: This prospective cohort study enrolled consecutive adult patients with symptoms potentially related to SARS-CoV-2 infection who were admitted to the emergency department (ED) of an Italian academic hospital. Immediately after the initial assessment, a lung ultrasonographic evaluation was performed and the likelihood of SARS-CoV-2 infection, based on both clinical and lung ultrasonographic findings ("integrated" assessment), was recorded. RT-PCR SARS-CoV-2 detection was subsequently performed. RESULTS: We enrolled 228 patients; 107 (46.9%) had SARS-CoV-2 infection. Sensitivity and negative predictive value of the clinical-lung ultrasonographic integrated assessment were higher than first RT-PCR result (94.4% [95% confidence interval {CI} 88.2% to 97.9%] versus 80.4% [95% CI 71.6% to 87.4%] and 95% [95% CI 89.5% to 98.2%] versus 85.2% [95% CI 78.3% to 90.6%], respectively). Among the 142 patients who initially had negative RT-PCR results, 21 tested positive at a subsequent molecular test performed within 72 hours. All these false-negative cases were correctly identified by the integrated assessment. CONCLUSION: This study suggests that, in patients presenting to the ED with symptoms commonly associated with SARS-CoV-2 infection, the integration of lung ultrasonography with clinical evaluation has high sensitivity and specificity for coronavirus disease 2019 pneumonia and it may help to identify false-negative results occurring with RT-PCR.
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COVID-19/diagnóstico por imagen , Servicio de Urgencia en Hospital , Pulmón/diagnóstico por imagen , Adulto , Anciano , COVID-19/diagnóstico , Prueba de Ácido Nucleico para COVID-19 , Reacciones Falso Negativas , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , SARS-CoV-2 , Sensibilidad y Especificidad , UltrasonografíaRESUMEN
AIMS: The diagnosis of acute aortic syndromes (AASs) is challenging and requires integrated strategies. Transthoracic focused cardiac ultrasound (FoCUS) is endorsed by guidelines as a first-line/triage tool allowing rapid bedside assessment of the aorta. However, the performance of FoCUS in the European Society of Cardiology-recommended workup of AASs awaits validation. METHODS AND RESULTS: This was a prespecified subanalysis of the ADvISED multicentre prospective study. Patients with suspected AAS underwent FoCUS for detection of direct/indirect signs of AAS. Clinical probability assessment was performed with the aortic dissection detection risk score (ADD-RS). Case adjudication was based on advanced imaging, surgery, autopsy, or 14-day follow-up. An AAS was diagnosed in 146 (17.4%) of 839 patients. Presence of direct FoCUS signs had a sensitivity and specificity of 45.2% [95% confidence interval (CI) 37-53.6%] and 97.4% (95% CI 95.9-98.4%), while presence of any FoCUS sign had a sensitivity and specificity of 89% (95% CI 82.8-93.6%) and 74.5% (95% CI 71-77.7%) for AAS. The additive value of FoCUS was most evident within low clinical probability (ADD-RS ≤1). Herein, direct FoCUS signs were identified in 40 (4.8%) patients (P < 0.001), including 29 with AAS. ADD-RS ≤1 plus negative FoCUS for AAS rule-out had a sensitivity of 93.8% (95% CI 88.6-97.1%) and a failure rate of 1.9% (95% CI 0.9-3.6%). Addition of negative D-dimer led to a failure rate of 0% (95% CI 0-1.2%). CONCLUSION: FoCUS has additive value in the workup of AASs. Direct FoCUS signs can rapidly identify patients requiring advanced imaging despite low clinical probability. In integrated bundles, negative FoCUS is useful for rule-out of AASs.
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Aorta/diagnóstico por imagen , Disección Aórtica/diagnóstico , Ecocardiografía/métodos , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Algoritmos , Aorta/patología , Diagnóstico Diferencial , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Medición de Riesgo , Sensibilidad y Especificidad , Síndrome , TriajeRESUMEN
BACKGROUND: Acute aortic syndromes (AASs) are rare and severe cardiovascular emergencies with unspecific symptoms. For AASs, both misdiagnosis and overtesting are key concerns, and standardized diagnostic strategies may help physicians to balance these risks. D-dimer (DD) is highly sensitive for AAS but is inadequate as a stand-alone test. Integration of pretest probability assessment with DD testing is feasible, but the safety and efficiency of such a diagnostic strategy are currently unknown. METHODS: In a multicenter prospective observational study involving 6 hospitals in 4 countries from 2014 to 2016, consecutive outpatients were eligible if they had ≥1 of the following: chest/abdominal/back pain, syncope, perfusion deficit, and if AAS was in the differential diagnosis. The tool for pretest probability assessment was the aortic dissection detection risk score (ADD-RS, 0-3) per current guidelines. DD was considered negative (DD-) if <500 ng/mL. Final case adjudication was based on conclusive diagnostic imaging, autopsy, surgery, or 14-day follow-up. Outcomes were the failure rate and efficiency of a diagnostic strategy for ruling out AAS in patients with ADD-RS=0/DD- or ADD-RS ≤1/DD-. RESULTS: A total of 1850 patients were analyzed. Of these, 438 patients (24%) had ADD-RS=0, 1071 patients (58%) had ADD-RS=1, and 341 patients (18%) had ADD-RS >1. Two hundred forty-one patients (13%) had AAS: 125 had type A aortic dissection, 53 had type B aortic dissection, 35 had intramural aortic hematoma, 18 had aortic rupture, and 10 had penetrating aortic ulcer. A positive DD test result had an overall sensitivity of 96.7% (95% confidence interval [CI], 93.6-98.6) and a specificity of 64% (95% CI, 61.6-66.4) for the diagnosis of AAS; 8 patients with AAS had DD-. In 294 patients with ADD-RS=0/DD-, 1 case of AAS was observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1.9) and an efficiency of 15.9% (95% CI, 14.3-17.6) for the ADD-RS=0/DD- strategy. In 924 patients with ADD-RS ≤1/DD-, 3 cases of AAS were observed. This yielded a failure rate of 0.3% (95% CI, 0.1-1) and an efficiency of 49.9% (95% CI, 47.7-52.2) for the ADD-RS ≤1/DD- strategy. CONCLUSIONS: Integration of ADD-RS (either ADD-RS=0 or ADD-RS ≤1) with DD may be considered to standardize diagnostic rule out of AAS. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02086136.
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Aneurisma de la Aorta/diagnóstico , Disección Aórtica/diagnóstico , Técnicas de Apoyo para la Decisión , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Enfermedad Aguda , Anciano , Disección Aórtica/sangre , Disección Aórtica/cirugía , Aneurisma de la Aorta/sangre , Aneurisma de la Aorta/cirugía , Aortografía/métodos , Biomarcadores/sangre , Toma de Decisiones Clínicas , Angiografía por Tomografía Computarizada , Diagnóstico Diferencial , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Reproducibilidad de los Resultados , SíndromeRESUMEN
BACKGROUND: Anthracyclines, such as doxorubicin (DOX), are potent anticancer agents for the treatment of solid tumors and hematologic malignancies. However, their clinical use is hampered by cardiotoxicity. This study sought to investigate the role of phosphoinositide 3-kinase γ (PI3Kγ) in DOX-induced cardiotoxicity and the potential cardioprotective and anticancer effects of PI3Kγ inhibition. METHODS: Mice expressing a kinase-inactive PI3Kγ or receiving PI3Kγ-selective inhibitors were subjected to chronic DOX treatment. Cardiac function was analyzed by echocardiography, and DOX-mediated signaling was assessed in whole hearts or isolated cardiomyocytes. The dual cardioprotective and antitumor action of PI3Kγ inhibition was assessed in mouse mammary tumor models. RESULTS: PI3Kγ kinase-dead mice showed preserved cardiac function after chronic low-dose DOX treatment and were protected against DOX-induced cardiotoxicity. The beneficial effects of PI3Kγ inhibition were causally linked to enhanced autophagic disposal of DOX-damaged mitochondria. Consistently, either pharmacological or genetic blockade of autophagy in vivo abrogated the resistance of PI3Kγ kinase-dead mice to DOX cardiotoxicity. Mechanistically, PI3Kγ was triggered in DOX-treated hearts, downstream of Toll-like receptor 9, by the mitochondrial DNA released by injured organelles and contained in autolysosomes. This autolysosomal PI3Kγ/Akt/mTOR/Ulk1 signaling provided maladaptive feedback inhibition of autophagy. PI3Kγ blockade in models of mammary gland tumors prevented DOX-induced cardiac dysfunction and concomitantly synergized with the antitumor action of DOX by unleashing anticancer immunity. CONCLUSIONS: Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.
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Antibióticos Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/farmacología , Cardiopatías/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Quinoxalinas/farmacología , Tiazolidinedionas/farmacología , Carga Tumoral/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/toxicidad , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Cardiotoxicidad , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Citoprotección , Modelos Animales de Enfermedad , Doxorrubicina/toxicidad , Femenino , Genes erbB-2 , Cardiopatías/inducido químicamente , Cardiopatías/enzimología , Cardiopatías/patología , Ratones Endogámicos BALB C , Ratones Transgénicos , Mutación , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismoRESUMEN
Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110γ participates in these processes by sustaining ß-adrenergic receptor internalization through its catalytic function and by controlling phosphodiesterase 3B (PDE3B) activity via an unknown kinase-independent mechanism. We have discovered that p110γ anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP(3) production. This provides local feedback control of PIP(3) and cAMP signaling events. In congestive heart failure, p110γ is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in ß-adrenergic receptor density. Pharmacological inhibition of p110γ normalizes ß-adrenergic receptor density and improves contractility in failing hearts.
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Proteínas de Anclaje a la Quinasa A/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Miocitos Cardíacos/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular , Fosfatidilinositol 3-Quinasa Clase Ib/química , Fosfatidilinositol 3-Quinasa Clase Ib/deficiencia , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Subunidad RIIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , ADN/genética , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Mapeo de Interacción de Proteínas , Quinoxalinas/farmacología , Receptores Adrenérgicos beta/metabolismo , Sistemas de Mensajero Secundario , Homología de Secuencia de Aminoácido , Tiazolidinedionas/farmacologíaRESUMEN
PURPOSE OF REVIEW: Heart Failure with preserved Ejection Fraction (HFpEF) is a prevalent disease with considerable individual and societal burden. HFpEF patients often suffer from multiple pathological conditions thatcomplicate management and adversely affect outcome, including pulmonary hypertension and chronic obstructive pulmonary disease (COPD). To date, no treatment proved to be fully effective in reducing morbidity and mortality in HFpEF, possibly due to an incomplete understanding of the underlying molecular mechanisms. RECENT FINDINGS: The emerging view proposes chronic systemic inflammation, leading to endothelial dysfunction and interstitial fibrosis, as a prominent cause of HFpEF, rather than a mere co-existent disease. In the last decade, efforts from pharmaceutical companies attempted to target pharmacologically enzymes which play key roles in systemic and lung inflammation, such as the cyclic nucleotide-degrading enzymes phosphodiesterases (PDEs) and phosphoinositide-3 phosphate kinases (PI3Ks), especially to limit COPD. In this review, we will summarize major successes and drawbacks of hitting these enzymes to tackle inflammation in HFpEF-associated co-morbidities, with a major focus on the results of completed and ongoing clinical trials. Finally, we will discuss the potential of repurposing and/or developing new PDE and PI3K inhibitors for HFpEF therapy.
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Insuficiencia Cardíaca/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Volumen Sistólico/fisiología , Endotelio Vascular/fisiopatología , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertensión Pulmonar/complicaciones , Inflamación/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/complicacionesRESUMEN
Nuclear hormone receptor liver X receptor-alpha (LXRα) has a vital role in cholesterol homeostasis and is reported to have a role in adipose function and obesity although this is controversial. Conversely, mesenchymal stem cells (MSCs) are suggested to be a major source of adipocyte generation. Accordingly, we examined the role of LXRα in adipogenesis of MSCs. Adult murine MSCs (mMSCs) were isolated from wild-type (WT) and LXR-null mice. Using WT mMSCs, we further generated cell lines stably overexpressing GFP-LXRα (mMSC/LXRα/GFP) or GFP alone (mMSC/GFP) by retroviral infection. Confluent mMSCs were differentiated into adipocytes by the established protocol. Compared with MSCs isolated from WT mice, MSCs from LXR-null mice showed significantly increased adipogenesis, as determined by lipid droplet accumulation and adipogenesis-related gene expression. Moreover, mMSCs stably overexpressing GFP-LXRα (mMSC/LXRα/GFP) exhibited significantly decreased adipogenesis compared with mMSCs overexpressing GFP alone (mMSC/GFP). Since Wnt/beta-catenin signaling is reported to inhibit adipogenesis, we further examined it. The LXR-null group showed significantly decreased Wnt expression accompanied by a decrease of cellular beta-catenin (vs WT). The mMSC/LXRα/GFP group exhibited significantly increased Wnt expression accompanied by an increase of cellular beta-catenin (vs mMSC/GFP). These data demonstrate that LXRα has an inhibitory effect on adipogenic differentiation in mMSCs with Wnt/beta-catenin signaling. These results provide important insights into the pathophysiology of obesity and obesity-related consequences such as metabolic syndrome and may identify potential therapeutic targets.
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Adipocitos/metabolismo , Adipogénesis/fisiología , Diferenciación Celular/fisiología , Receptores Nucleares Huérfanos/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animales , Células Cultivadas , Humanos , Receptores X del Hígado , Células Madre Mesenquimatosas/citología , Ratones , Receptores Nucleares Huérfanos/genética , Vía de Señalización Wnt/fisiologíaRESUMEN
BACKGROUND: Strategies for identifying normotensive patients with acute symptomatic PE at high risk of PE-related complications remain to be defined. METHODS: This prospective cohort study aimed to determine the role of plasma lactate levels in the risk assessment of normotensive patients with acute PE. Outcomes assessed over the 7â days after the diagnosis of PE included PE-related mortality and haemodynamic collapse, defined as need for cardiopulmonary resuscitation, systolic blood pressure <90â mmâ Hg for at least 15â min, need for catecholamine administration, or need for mechanical ventilation. RESULTS: Between December 2012 and January 2014, the study enrolled 496 normotensive outpatients with acute symptomatic PE. PE-related complications occurred in 20 (4.0%; 95% CI 2.5% to 6.2%) of the 496 patients. These patients had higher baseline lactate levels (median 2.66â mmol/L; IQR 1.56-5.96â mmol/L) than patients without complications (1.20â mmol/L; IQR 1.20-2.00â mmol/L) (p<0.001). Overall, 135 patients (27.2%) had plasma lactate ≥2â mmol/L. Fourteen (10.4%) of them had PE-related complications versus 6 of 361 patients with low lactate (negative predictive value 98.3%; p<0.001). Patients with elevated plasma lactate had an increased rate of PE-related complications (adjusted OR 5.3; 95% CI 1.9 to 14.4; p=0.001) compared with those with low lactate. The combination of elevated plasma lactate with markers of right ventricular dysfunction (by echocardiogram) and myocardial injury (by cardiac troponin) was a particularly useful prognostic indicator (positive predictive value 17.9%; 95% CI 6.1% to 36.9%). CONCLUSIONS: Plasma lactate represents a powerful predictor of short-term PE-related complications and may provide guidance for decision-making in PE care.
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Ácido Láctico/sangre , Embolia Pulmonar/diagnóstico , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Presión Sanguínea/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Embolia Pulmonar/sangre , Embolia Pulmonar/fisiopatología , Embolia Pulmonar/terapia , Medición de Riesgo/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Thrombocytopenia is the most common coagulation disorder in critically ill patients. No studies have investigated the epidemiology and clinical impact of this condition in emergency department (ED) patients. We aimed to investigate epidemiological features, incidence of bleeding, and diagnostic and therapeutic requirements of patients with thrombocytopenia admitted to the ED. METHODS: We performed a retrospective observational study enrolling all patients admitted to the medical-surgical ED of the "Città della Salute e della Scienza di Torino" Hospital with a platelet count <150×10(9) PLTs/L, during four non-consecutive months. There were no exclusion criteria. RESULTS: The study included 1218 patients. The percentage of patients with severe (<50×10(9) PLTs/L) or very severe (<20×10(9) PLTs/L) thrombocytopenia was about 12%. Thrombocytopenia associated with liver cirrhosis was the most represented etiology. On the contrary, the most frequent cause in patients with newly recognized low platelet count was disseminated intravascular coagulation/sepsis. The incidence of bleeding and hypovolemia, as well as the need of transfusional support and mechanical, surgical or endoscopic hemostasis progressively increased with the severity of thrombocytopenia. CONCLUSIONS: Our results suggest that the detection of a platelet count lower than 50×10(9) PLTs/L may help to identify patients with higher bleeding risk in the ED setting. Additional studies are required to evaluate whether, in this setting, thrombocytopenia may represent an independent risk factor for bleeding episodes and increased mortality.
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Transfusión Sanguínea , Servicio de Urgencia en Hospital , Hemorragia/complicaciones , Trombocitopenia/complicaciones , Trombocitopenia/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Trombocitopenia/diagnóstico , Adulto JovenRESUMEN
BACKGROUND: Thrombopoietin (TPO), a growth factor primarily involved in regulating thrombopoiesis, has been recently implicated in the pathogenesis of sepsis. TPO levels are, indeed, greatly increased in patients with sepsis compared to control subjects, and correlate with sepsis severity. The aim of this study was to evaluate TPO as predictive biomarker of sepsis and of sepsis severity in patients entering the emergency department (ED) with systemic inflammatory response syndrome (SIRS). METHODS: This was a prospective observational study. Ours is a sub-study of the 'Need-speed trial', a multi-center observational study involving six Italian centers affiliated to the GREAT Italian Network. TPO was measured by ELISA. RESULTS: We enrolled 13 patients with SIRS (6 with acute pancreatitis, 3 with acute heart failure, 1 with pulmonary embolism, and 3 with allergic reactions), and 40 patients with sepsis, eight of whom had severe sepsis and three septic shock. TPO was significantly higher in patients with sepsis than with SIRS. In addition, TPO was higher in patients with severe sepsis than with sepsis, and in patients with septic shock than with severe sepsis, although these differences did not reach the statistical significance. CONCLUSIONS: Our preliminary results suggest that TPO may have the potential to be considered a promising early biomarker for both the diagnosis of sepsis and the assessment of sepsis severity in patients with SIRS entering the ED.
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Servicio de Urgencia en Hospital , Sepsis/sangre , Sepsis/diagnóstico , Trombopoyetina/sangre , Anciano , Biomarcadores/sangre , Femenino , Humanos , MasculinoRESUMEN
Class I phosphoinositide 3-kinases (PI3Ks) are heterodimeric enzymes involved in signal transduction triggered by growth factors and G-protein-coupled receptors. The catalytic function of PI3Ks is well known to promote a wide variety of biological processes, including proliferation, survival and migration, but a new layer of complexity in the function of PI3Ks has recently emerged, indicating that these proteins function not only as kinases but also as scaffold proteins. Knockout mice that lack PI3K protein expression show a different phenotype from knock-in mice expressing PI3K mutants that have lost their kinase activity, providing evidence for this novel role of PI3Ks. We will discuss such findings, highlighting the crucial scaffold function of PI3Kgamma in cAMP homeostasis and PI3Kbeta in receptor recycling.
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Fosfatidilinositol 3-Quinasas/fisiología , Transducción de Señal/fisiología , Animales , Fosfatidilinositol 3-Quinasa Clase Ib , AMP Cíclico/metabolismo , Humanos , Isoenzimas/clasificación , Isoenzimas/genética , Isoenzimas/fisiología , Modelos Biológicos , Fosfatidilinositol 3-Quinasas/clasificación , Fosfatidilinositol 3-Quinasas/genética , Filogenia , Transducción de Señal/genéticaRESUMEN
BACKGROUND AND IMPORTANCE: The diagnostic accuracy of focused cardiac ultrasound (FoCUS) performed in patients presenting to the emergency department (ED) with chest pain is currently unknown. OBJECTIVE: The objective of this study was to assess the diagnostic accuracy of regional wall motion abnormalities detected with FoCUS for non-ST-elevation acute coronary syndrome (NSTE-ACS) diagnosis. DESIGN: A Single-center prospective observational study conducted in 2022 in the ED of the University Hospital Careggi, Italy. SETTING AND PARTICIPANTS: Adult patients presenting to the ED with acute nontraumatic chest pain were enrolled, irrespective of the presence of previous regional wall motion abnormalities. Patients with ST-segment elevation myocardial infarctions and patients with hemodynamic instability were excluded. FoCUS was performed at presentation by a trained ED physician. OUTCOME MEASURES AND ANALYSIS: The final diagnosis of NSTE-ACS vs. alternative diagnosis was adjudicated by an ED physician blinded to FoCUS results after a 30-day follow-up. To assess if regional wall motion abnormalities were an independent predictor of NSTE-ACS, a multivariable logistic regression model was built. Diagnostic performance measures were calculated. A sensitivity analysis considering only type-1 NSTEMIs (i.e. plaque rupture/thrombosis) was conducted. MAIN RESULTS: Among 686 patients, NSTE-ACS was adjudicated in 106 (15.5%) patients, 67 of which were NSTEMIs. A total of 87 (12.7%) patients had regional wall motion abnormalities detected by FoCUS, which were an independent predictor of NSTE-ACS in the multivariable logistic regression analysis. Regional wall motion abnormalities had a sensitivity of 42.5% (33.0-51.9), a specificity of 92.8% (90.6-94.9), a negative predictive value of 89.8% (87.4-92.2), and a positive predictive value of 51.7% (41.2-62.2), for NSTE-ACS. Results were consistent in the sensitivity analysis. CONCLUSIONS: In ED patients with chest pain and no ST elevation, the detection of regional wall motion abnormalities was a predictor of NSTE-ACS. Despite a high specificity, which indicated a possible role of FoCUS in the rule-in of NSTE-ACS, sensitivity was too low to allow a safe rule-out using FoCUS results alone.
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BACKGROUND AND AIMS: The diagnostic and prognostic performance of soluble Suppression of Tumorigenicity 2 (sST2) in suspected septic patients presenting to the Emergency Department (ED) is largely unknown. MATERIALS AND METHODS: Patients were included in this prospective study if there was high suspicion of sepsis. The plasma level of sST2 was measured during initial ED evaluation. Outcomes were the evaluation of (1) sST2 diagnostic performance (alone and in combination with procalcitonin [PCT]), and (2) sST2 ability to predict 30-day and 90-day all-cause mortality. RESULTS: Among 569 patients included, 481 (84.5 %) had sepsis or septic shock. Plasma sST2 levels were more elevated in septic patients (159 [71-331] vs 50 [31-103] ng/mL, P < 0.001). The AUC of sST2 for sepsis diagnosis was lower than the AUC of PCT (0.76 vs 0.85, P = 0.03). The best cut-off for sST2 was 61.7 ng/mL, with a sensitivity of 79.9 % and a specificity of 70.6 %. sST2 was able to correctly reclassify septic patients with PCT <0.5 (NRI 28.9 % [P = 0.02]). sST2 level was an independent predictor of 30-day mortality in a model including clinical variables (aHR 2.03 [1.24-3.33], C-index 0.69). CONCLUSION: sST2 could be a useful adjunct in diagnosing sepsis and in all-cause mortality prediction.
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Sepsis , Choque Séptico , Humanos , Estudios Prospectivos , Proteína 1 Similar al Receptor de Interleucina-1 , Biomarcadores , Choque Séptico/diagnóstico , Pronóstico , Polipéptido alfa Relacionado con Calcitonina , Carcinogénesis , Transformación Celular Neoplásica , Servicio de Urgencia en HospitalRESUMEN
BACKGROUND: In patients complaining common symptoms such as chest/abdominal/back pain or syncope, acute aortic syndromes (AAS) are rare underlying causes. AAS diagnosis requires urgent advanced aortic imaging (AAI), mostly computed tomography angiography. However, patient selection for AAI poses conflicting risks of misdiagnosis and overtesting. OBJECTIVES: We assessed the safety and efficiency of a diagnostic protocol integrating clinical data with point-of-care ultrasound (POCUS) and d-dimer (single/age-adjusted cutoff), to select patients for AAI. METHODS: This prospective study involved 12 Emergency Departments from 5 countries. POCUS findings were integrated with a guideline-compliant clinical score, to define the integrated pre-test probability (iPTP) of AAS. If iPTP was high, urgent AAI was requested. If iPTP was low and d-dimer was negative, AAS was ruled out. Patients were followed for 30 days, to adjudicate outcomes. RESULTS: Within 1979 enrolled patients, 176 (9 %) had an AAS. POCUS led to net reclassification improvement of 20 % (24 %/-4 % for events/non-events, P < 0.001) over clinical score alone. Median time to AAS diagnosis was 60 min if POCUS was positive vs 118 if negative (P = 0.042). Within 941 patients satisfying rule-out criteria, the 30-day incidence of AAS was 0 % (95 % CI, 0-0.41 %); without POCUS, 2 AAS were potentially missed. Protocol rule-out efficiency was 48 % (95 % CI, 46-50 %) and AAI was averted in 41 % of patients. Using age-adjusted d-dimer, rule-out efficiency was 54 % (difference 6 %, 95 % CI, 4-9 %, vs standard cutoff). CONCLUSIONS: The integrated algorithm allowed rapid triage of high-probability patients, while providing safe and efficient rule-out of AAS. Age-adjusted d-dimer maximized efficiency. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04430400.
RESUMEN
BACKGROUND: Phosphoinositide 3-kinase γ (PI3Kγ) signaling engaged by ß-adrenergic receptors is pivotal in the regulation of myocardial contractility and remodeling. However, the role of PI3Kγ in catecholamine-induced arrhythmia is currently unknown. METHODS AND RESULTS: Mice lacking PI3Kγ (PI3Kγ(-/-)) showed runs of premature ventricular contractions on adrenergic stimulation that could be rescued by a selective ß(2)-adrenergic receptor blocker and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, fluorescence resonance energy transfer probes revealed abnormal cAMP accumulation after ß(2)-adrenergic receptor activation in PI3Kγ(-/-) cardiomyocytes that depended on the loss of the scaffold but not of the catalytic activity of PI3Kγ. Downstream from ß-adrenergic receptors, PI3Kγ was found to participate in multiprotein complexes linking protein kinase A to the activation of phosphodiesterase (PDE) 3A, PDE4A, and PDE4B but not of PDE4D. These PI3Kγ-regulated PDEs lowered cAMP and limited protein kinase A-mediated phosphorylation of L-type calcium channel (Ca(v)1.2) and phospholamban. In PI3Kγ(-/-) cardiomyocytes, Ca(v)1.2 and phospholamban were hyperphosphorylated, leading to increased Ca(2+) spark occurrence and amplitude on adrenergic stimulation. Furthermore, PI3Kγ(-/-) cardiomyocytes showed spontaneous Ca(2+) release events and developed arrhythmic calcium transients. CONCLUSIONS: PI3Kγ coordinates the coincident signaling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia.
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Catecolaminas/toxicidad , Fosfatidilinositol 3-Quinasa Clase Ib/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Taquicardia Ventricular/enzimología , Taquicardia Ventricular/prevención & control , Animales , Animales Recién Nacidos , Biorretroalimentación Psicológica/fisiología , Señalización del Calcio/genética , Fosfatidilinositol 3-Quinasa Clase Ib/deficiencia , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Técnicas de Sustitución del Gen , Isoenzimas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Miocitos Cardíacos/enzimologíaRESUMEN
OBJECTIVE: Liver X receptors (LXRα, LXRß) are master regulators of cholesterol homeostasis. In the endothelium, perturbations of cell cholesterol have an impact on fundamental processes. We, therefore, assessed the effects of LXR activation on endothelial functions related to angiogenesis in vitro and in vivo. METHODS AND RESULTS: LXR agonists (T0901317, GW3965) blunted migration, tubulogenesis, and proliferation of human umbilical vein endothelial cells. By affecting endothelial cholesterol homeostasis, LXR activation impaired the compartmentation of vascular endothelial growth factor receptor-2 in lipid rafts/caveolae and led to defective phosphorylation and downstream signaling of vascular endothelial growth factor receptor-2 upon vascular endothelial growth factor-A stimulation. Consistently, the antiangiogenic actions of LXR agonists could be prevented by coadministration of exogenous cholesterol. LXR agonists reduced endothelial sprouting from wild-type but not from LXRα(-/-)/LXRß(-/-) knockout aortas and blunted the vascularization of implanted angioreactors in vivo. Furthermore, T0901317 reduced the growth of Lewis lung carcinoma grafts in mice by impairing angiogenesis. CONCLUSIONS: Pharmacological activation of endothelial LXRs reduces angiogenesis by restraining cholesterol-dependent vascular endothelial growth factor receptor-2 compartmentation and signaling. Thus, administration of LXR agonists could exert therapeutic effects in pathological conditions characterized by uncontrolled angiogenesis.
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Inhibidores de la Angiogénesis/farmacología , Células Endoteliales/efectos de los fármacos , Microdominios de Membrana/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Receptores Nucleares Huérfanos/agonistas , Receptores Nucleares Huérfanos/genética , Receptores Nucleares Huérfanos/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Benzoatos/farmacología , Bencilaminas/farmacología , Carcinoma Pulmonar de Lewis/irrigación sanguínea , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colesterol/metabolismo , Células Endoteliales/metabolismo , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Hidrocarburos Fluorados/farmacología , Receptores X del Hígado , Microdominios de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Nucleares Huérfanos/deficiencia , Fosforilación , Interferencia de ARN , Sulfonamidas/farmacología , Factores de Tiempo , Transfección , Carga Tumoral , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
INTRODUCTION: Sepsis, severe sepsis and septic shock are common conditions with high mortality. Their early diagnosis in the Emergency Department (ED) is one of the keys to improving survival. Procalcitonin (PCT) has been used as a biomarker in septic patients but has limited specificity and can be elevated in other scenarios of systemic inflammatory response syndrome (SIRS). Soluble CD14 (sCD14) or presepsin is the free fragment of a glycoprotein expressed on monocytes and macrophages. Preliminary reports suggest that levels of presepsin are significantly higher in septic patients than in healthy individuals. The aim of this study is to investigate the diagnostic and prognostic value of presepsin compared to PCT in people presenting at the ED with SIRS and suspected sepsis or septic shock. METHODS: This study was conducted in two major hospitals in Turin, Italy. One hundred six patients presenting to the EDs with suspected sepsis or septic shock were included, and another eighty-three patients affected by SIRS, but with no clinical evidence of infection, were recruited as controls. Blood samples were collected at first medical evaluation and for some patients after 24 and 72 h. The samples were analyzed using the PATHFAST Presepsin assay for sCD14, and commercial kits were used for other determinations (for example, PCT). Definitive diagnosis and survival rates were obtained afterward by analysis of digital medical records. RESULTS: Elevated concentrations of presepsin at presentation were observed in septic patients compared to control patients. The same trend was observed for mean values of PCT. Higher values of presepsin were observed in septic patients at presentation (time 0). The diagnostic accuracy of PCT was generally higher, and areas under the curve (AUCs) were 0.875 for PCT and 0.701 for presepsin. Mean presepsin values were significantly higher in nonsurvivor septic patients (60-day mortality) than in survivors. No significant correlation was noted between PCT and survival. CONCLUSIONS: In our experience, presepsin was useful in the early diagnosis of infection in a complex population of patients with SIRS, sepsis, severe sepsis and septic shock who presented to the ED. Presepsin showed a significant prognostic value, and initial values were significantly correlated with in-hospital mortality of patients affected by sepsis, severe sepsis or septic shock.