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Cardiac arrest is a hyper-acute condition with a high mortality that requires rapid diagnostics and treatment. As such, point-of-care ultrasound (POCUS) has become a valuable tool in the assessment of these patients. While transthoracic echocardiography (TTE) is the more conventional modality used to find reversible causes of cardiac arrest, transoesophageal echocardiography (TOE) has been increasingly utilised due to its superior image quality, continuous imaging, and ability to be operated away from the patient's chest. TOE also has a number of applications in the aftermath of cardiac arrest, such as during the initiation of extracorporeal cardiopulmonary resuscitation (ECPR) and the subsequent monitoring of extracorporeal membranous oxygenation (ECMO). As TOE has evolved, multiple variations have been developed with different utilities. In this article, we will review the evidence supporting the use of TOE in cardiac arrest and where the different forms of TOE can be applied to evaluate the cardiac arrest patient in a timely and accurate manner.
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OBJECTIVE: APPEASE is a phase I study to assess the safety, dosing, and efficacy of rivoceranib (a selective, small-molecule inhibitor of VEGFR2) in combination with pembrolizumab. We aimed to treat patients with metastatic malignancies who have progressed through at least first-line therapy, with pembrolizumab 200 mg every 3 weeks, as well as escalating doses of rivoceranib until disease progression or unacceptable toxicity. RESULTS: Five patients were enrolled on the starting dose of rivoceranib 300 mg once daily. There were no dose-limiting toxicities observed in combination with pembrolizumab. The dose of rivoceranib was not escalated due to study closure. We note a treatment related grade 3 adverse event (AE) rate of 40%, predominantly in urothelial cancer patients, with no deaths related to treatment related AEs. The disease control rate was 75% (3 of 4) and the median progression free survival (PFS) was 3.6 months. Tumor shrinkage was noted in patients who were previously progressing on pembrolizumab alone. Apatinib 300 mg is safe and demonstrates anti-tumor activity in advanced solid tumors in combination with pembrolizumab. Further dose escalation and efficacy need to be investigated in larger disease-specific patient populations. TRIAL REGISTRATION NUMBER: Clinical trial registration number: NCT03407976. Date of registration: January 17, 2018.
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Antineoplásicos Imunológicos , Neoplasias , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológicoRESUMO
FUSIC haemodynamics (HD) - the latest Focused Ultrasound in Intensive Care (FUSIC) module created by the Intensive Care Society (ICS) - describes a complete haemodynamic assessment with ultrasound based on ten key clinical questions: 1. Is stroke volume abnormal? 2. Is stroke volume responsive to fluid, vasopressors or inotropes? 3. Is the aorta abnormal? 4. Is the aortic valve, mitral valve or tricuspid valve severely abnormal? 5. Is there systolic anterior motion of the mitral valve? 6. Is there a regional wall motion abnormality? 7. Are there features of raised left atrial pressure? 8. Are there features of right ventricular impairment or raised pulmonary artery pressure? 9. Are there features of tamponade? 10. Is there venous congestion? FUSIC HD is the first system of its kind to interrogate major cardiac, arterial and venous structures to direct time-critical interventions in acutely unwell patients. This article explains the rationale for this accreditation, outlines the training pathway and summarises the ten clinical questions. Further details are included in an online supplementary appendix.
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OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: classical and basal-like. The classical subtype is characterised by a more favourable prognosis and better response to chemotherapy than the basal-like subtype. The classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor hepatocyte nuclear factor 4 α (HNF4α). The objective of this study is to evaluate the role of HNF4α, SIX4 and SIX1 in regulating the growth and molecular subtype of PDAC. DESIGN: We manipulate the expression of HNF4α, SIX4 and SIX1 in multiple in vitro and in vivo PDAC models. We determine the consequences of manipulating these genes on PDAC growth, differentiation and molecular subtype using functional assays, gene expression analysis and cross-species comparisons with human datasets. RESULTS: We show that HNF4α restrains tumour growth and drives tumour cells toward an epithelial identity. Gene expression analysis of murine models and human tumours shows that HNF4α activates expression of genes associated with the classical subtype. HNF4α also directly represses SIX4 and SIX1, two mesodermal/neuronal lineage specifiers expressed in the basal-like subtype. Finally, SIX4 and SIX1 drive proliferation and regulate differentiation in HNF4α-negative PDAC. CONCLUSION: Our data show that HNF4α regulates the growth and molecular subtype of PDAC by multiple mechanisms, including activation of the classical gene expression programme and repression of SIX4 and SIX1, which may represent novel dependencies of the basal-like subtype.
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Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Fator 4 Nuclear de Hepatócito/genética , Proteínas de Homeodomínio/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Transativadores/genética , Neoplasias PancreáticasAssuntos
Betacoronavirus , Infecções por Coronavirus/diagnóstico por imagem , Lesão Pulmonar/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Medicina de Precisão/métodos , Respiração Artificial/métodos , COVID-19 , Infecções por Coronavirus/fisiopatologia , Humanos , Lesão Pulmonar/fisiopatologia , Lesão Pulmonar/prevenção & controle , Pandemias , Pneumonia Viral/fisiopatologia , SARS-CoV-2RESUMO
Pancreatic islets regulate glucose homeostasis through coordinated actions of hormone-secreting cells. What underlies the function of the islet as a unit is the close approximation and communication among heterogeneous cell populations, but the structural mediators of islet cellular cross talk remain incompletely characterized. We generated mice specifically lacking ß-cell primary cilia, a cellular organelle that has been implicated in regulating insulin secretion, and found that the ß-cell cilia are required for glucose sensing, calcium influx, insulin secretion, and cross regulation of α- and δ-cells. Protein expression profiling in islets confirms perturbation in these cellular processes and reveals additional targets of cilia-dependent signaling. At the organism level, the deletion of ß-cell cilia disrupts circulating hormone levels, impairs glucose homeostasis and fuel usage, and leads to the development of diabetes. Together, these findings demonstrate that primary cilia not only orchestrate ß-cell-intrinsic activity but also mediate cross talk both within the islet and from islets to other metabolic tissues, thus providing a unique role of cilia in nutrient metabolism and insight into the pathophysiology of diabetes.
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Cílios/metabolismo , Diabetes Mellitus/patologia , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Animais , Cálcio/metabolismo , Comunicação Celular/fisiologia , Cílios/genética , Cílios/patologia , Diabetes Mellitus/genética , Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Feminino , Células Secretoras de Glucagon/metabolismo , Humanos , Secreção de Insulina , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/fisiologiaRESUMO
AIMS: To examine the effects of a high-fat-diet (HFD) on monogenic neonatal diabetes, without the confounding effects of compensatory hyperinsulinaemia. METHODS: Mice expressing KATP channel gain-of-function (KATP -GOF) mutations, which models human neonatal diabetes, were fed an HFD. RESULTS: Surprisingly, KATP -GOF mice exhibited resistance to HFD-induced obesity, accompanied by markedly divergent blood glucose control, with some KATP -GOF mice showing persistent diabetes (KATP -GOF-non-remitter [NR] mice) and others showing remission of diabetes (KATP -GOF-remitter [R] mice). Compared with the severely diabetic and insulin-resistant KATP -GOF-NR mice, HFD-fed KATP -GOF-R mice had lower blood glucose, improved insulin sensitivity, and increased circulating plasma insulin and glucagon-like peptide-1 concentrations. Strikingly, while HFD-fed KATP -GOF-NR mice showed increased food intake and decreased physical activity, reduced whole body fat mass and increased plasma lipids, KATP -GOF-R mice showed similar features to those of control littermates. Importantly, KATP -GOF-R mice had restored insulin content and ß-cell mass compared with the marked loss observed in both HFD-fed KATP -GOF-NR and chow-fed KATP -GOF mice. CONCLUSION: Together, our results suggest that restriction of dietary carbohydrates and caloric replacement by fat can induce metabolic changes that are beneficial in reducing glucotoxicity and secondary consequences of diabetes in a mouse model of insulin-secretory deficiency.
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Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Experimental/genética , Dieta Hiperlipídica , Mutação com Ganho de Função , Células Secretoras de Insulina/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Feminino , Técnicas de Introdução de Genes , Resistência à Insulina/genética , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , Especificidade de Órgãos/genética , Indução de RemissãoRESUMO
ATP-sensitive potassium channels (KATP channels) are critical nutrient sensors in many mammalian tissues. In the pancreas, KATP channels are essential for coupling glucose metabolism to insulin secretion. While orthologous genes for many components of metabolism-secretion coupling in mammals are present in lower vertebrates, their expression, functionality and ultimate impact on body glucose homeostasis are unclear. In this paper, we demonstrate that zebrafish islet ß-cells express functional KATP channels of similar subunit composition, structure and metabolic sensitivity to their mammalian counterparts. We further show that pharmacological activation of native zebrafish KATP using diazoxide, a specific KATP channel opener, is sufficient to disturb glucose tolerance in adult zebrafish. That ß-cell KATP channel expression and function are conserved between zebrafish and mammals illustrates the evolutionary conservation of islet metabolic sensing from fish to humans, and lends relevance to the use of zebrafish to model islet glucose sensing and diseases of membrane excitability such as neonatal diabetes.