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Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF6, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.
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Apoptose , Morte Celular Autofágica , Neoplasias Hepáticas , Células-Tronco Neoplásicas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Humanos , Apoptose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Células Hep G2 , Morte Celular Autofágica/efeitos dos fármacos , Tiazolidinas/farmacologia , Animais , Camundongos , Movimento Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/químicaRESUMO
OBJECTIVE: To describe the development and implementation of a comprehensive in situ simulation-based curriculum for anesthesia residents. DESIGN: This is a prospective study. SETTING: This study was conducted at a university hospital. PARTICIPANTS: This single-center prospective study included all 53 anesthesia residents enrolled in the anesthesia residency program. INTERVENTIONS: Introduction of a routine, high-fidelity, in situ simulation program that incorporates short sessions to train residents in the necessary skill sets and decision-making processes required in the operating room. MEASUREMENTS AND MAIN RESULTS: Our team conducted 182 individual 15-minute simulation sessions over 3 months during regular working hours. All 53 residents in our program actively participated in the simulations. Most residents engaged in at least 3 sessions, with an average participation rate of 3.4 per resident (range, 1-6 sessions). Residents completed an online anonymous survey, with a response rate of 71.7% (38 of 53 residents) over the 3-month period. The survey aimed to assess their overall impression and perceived contribution of this project to their training. CONCLUSIONS: Our proposed teaching method can bridge the gap in resident training and enhance their critical reasoning to manage diverse clinical situations they may not experience during their residency.
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Cancer stem cells (CSCs) are defined as a rare population of cancer cells related to tumor initiation and maintenance. These cells are primarily responsible for tumor growth, invasion, metastasis, recurrence, and resistance to chemotherapy. In this paper, we demonstrated the ability of Ru(II)-based complexes containing 2-thiouracil derivatives with the chemical formulas trans-[Ru(2TU)(PPh3)2(bipy)]PF6 (1) and trans-[Ru(6m2TU)(PPh3)2(bipy)]PF6 (2) (where 2TU = 2-thiouracil and 6m2TU = 6-methyl-2-thiouracil) to suppress liver CSCs by targeting NF-κB and Akt/mTOR signaling. Complexes 1 and 2 displayed potent cytotoxic effects on cancer cell lines and suppressed liver CSCs from HepG2 cells. Increased phosphatidylserine exposure, loss of mitochondrial transmembrane potential, increased PARP (Asp214) cleavage, DNA fragmentation, chromatin condensation and cytoplasmic shrinkage were detected in HepG2 cells treated with these complexes. Mechanistically, complexes 1 and 2 target NF-κB and Akt/mTOR signaling in HepG2 cells. Cell motility inhibition was also detected in HepG2 cells treated with these complexes. Complexes 1 and 2 also inhibited tumor progression in mice with HepG2 cell xenografts and exhibited tolerable systemic toxicity. Taken together, these results indicate that these complexes are new anti-HCC drug candidates that can suppress liver CSCs.
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Coronavirus disease 2019 (COVID-19) is often linked to a broad range of opportunistic bacterial and fungal infections. The second wave of the COVID-19 pandemic has witnessed an unprecedented surge in mucormycosis cases, predominantly in India, while the disease remained relatively rare in Europe. The authors describe the case of a 62-year-old female patient admitted to the hospital for consolidation therapy with chemotherapy as a part of the treatment protocol for acute myeloid leukemia. During hospitalization, she was diagnosed with nosocomial COVID-19, which later progressed to respiratory deterioration. COVID-19 with bacterial superinfection was presumed, leading to the initiation of empirical antibiotic therapy. A bronchoscopy was performed several days later due to a lack of improvement, revealing an infection by the Rhizopus microsporus complex. Despite antifungal treatment, the patient experienced an unfavorable clinical course and ultimately died. Given the high index of suspicion required to diagnose pulmonary mucormycosis, which can lead to delays in appropriate treatment and increase the burden of disease, the authors are aiming to enhance its awareness.
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OBJECTIVES: To investigate whether implementation of a multidisciplinary protocol for ruptured abdominal aortic aneurysm (rAAA) management reduces rates of adverse complications. DESIGN: A retrospective before-after study. SETTING: A tertiary-care academic hospital. PARTICIPANTS: Adult patients who underwent open or endovascular rAAA repair; data were stratified into before-protocol implementation (group 1: 2015-2018) and after-protocol implementation (group 2: 2019-2022) groups. INTERVENTION: The protocol details the workflow for vascular surgery, anesthesia, emergency department, and operating room staff for a rAAA case; training was accomplished through yearly workshops. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality. Secondary outcomes included all-cause morbidity and other major complications. Differences in postoperative complication rates between groups were assessed using Pearson's χ2 test. Of the 77 patients included undergoing rAAA repair, 41 (53.2%) patients were in group 1, and 36 (46.8%) patients were in group 2. Patients in group 2 had a significantly shorter median time to incision (1.0 v 0.7 hours, p = 0.022) and total procedure time (180.0 v 160.5 minutes, p = 0.039) for both endovascular and open repair. After protocol implementation, patients undergoing endovascular repair exhibited significantly lower rates of mortality (46.2% v 20.0%, p = 0.048), all-cause morbidity (65.4% v 44.0%, p = 0.050), and renal complications (15.4% v 0.0%, p = 0.036); patients undergoing open repair for a rAAA exhibited significantly lower rates of mortality (53.3% v 27.3%, p = 0.018) and bowel ischemia (26.7% v 0.0%, p = 0.035). CONCLUSIONS: Implementation of a multidisciplinary protocol for the management of a rAAA may reduce rates of adverse complications and improve the quality of care.
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Aneurisma da Aorta Abdominal , Ruptura Aórtica , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Estudos Retrospectivos , Estudos Controlados Antes e Depois , Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/efeitos adversos , Procedimentos Endovasculares/métodos , Resultado do Tratamento , Ruptura Aórtica/cirurgia , Complicações Pós-Operatórias/etiologia , Fatores de RiscoRESUMO
Anesthesia for major head and neck surgery is historically heavily reliant on opioids with deleterious consequences. We reported a case of a patient with a history of heroin abuse submitted to a tongue carcinoma excision, followed by free-flap reconstruction under opioid-free anesthesia. We used a propofol total intravenous anesthesia and perfusions of ketamine, dexmedetomidine, lidocaine, and magnesium sulfate for analgesia, complemented by boluses of dexamethasone, acetaminophen, parecoxib, and metamizole. Hemodynamic needs of the procedure were addressed by titrating perfusions of sodium nitroprusside or dobutamine. The patient was weaned from the ventilator at the end of the surgery. Surgical outcomes were achieved and opioid-free analgesia allowed early reestablishment of bodily functions without compromise of adequate pain control. Anesthesia protocols for free-flap surgery still lack scientific evidence, especially in the context of substance abuse: opioid-sparing approaches seem a viable option, which requires further studies and familiarity by health care professionals.
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Tuberculous lymphadenitis (TBL) is one of the most common presentations of extrapulmonary tuberculosis (EPTB). The particularity of this presentation is the difficulty in establishing a definitive diagnosis, as clinical manifestations and imaging may be unspecific. We describe a case of tuberculous cervical lymphadenitis in a young male from Pakistan, a high-burden tuberculosis country. We intend to raise awareness of this entity, given the high index of suspicion required to diagnose it, which can lead to delays in appropriate treatment, potentially increasing the morbidity and mortality of affected patients. Increased awareness is especially important in immigrants, in whom tuberculosis cases continue to increase, exposing the need for easy and equitable access to healthcare. A brief review of the subject is also presented.
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Simulation-based training is an essential component in the education of transthoracic echocardiography (TTE). Nevertheless, current TTE teaching methods may be subject to certain limitations. Hence, the authors in this study aimed to invent a novel TTE training system employing three-dimensional (3D) printing technology to teach the basic principles and psychomotor skills of TTE imaging more intuitively and understandably. This training system comprises a 3D-printed ultrasound probe simulator and a sliceable heart model. The probe simulator incorporates a linear laser generator to enable the visualization of the projection of the ultrasound scan plane in a 3D space. By using the probe simulator in conjunction with the sliceable heart model or other commercially available anatomic models, trainees can attain a more comprehensive understanding of probe motion and related scan planes in TTE. Notably, the 3D-printed models are portable and low-cost, suggesting their potential utility in various clinical scenarios, particularly for just-in-time training.
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Ecocardiografia , Coração , Humanos , Ecocardiografia/métodos , Ultrassonografia , Coração/diagnóstico por imagem , Modelos Anatômicos , Impressão TridimensionalRESUMO
Osteosarcoma is a highly malignant bone tumor derived from mesenchymal cells that contains self-renewing cancer stem cells (CSCs), which are responsible for tumor progression and chemotherapy resistance. Understanding the signaling pathways that regulate CSC self-renewal and survival is crucial for developing effective therapies. The Notch, Hedgehog, and Wnt/ß-Catenin developmental pathways, which are essential for self-renewal and differentiation of normal stem cells, have been identified as important regulators of osteosarcoma CSCs and also in the resistance to anticancer therapies. Targeting these pathways and their interactions with embryonic markers and the tumor microenvironment may be a promising therapeutic strategy to overcome chemoresistance and improve the prognosis for osteosarcoma patients. This review focuses on the role of Notch, Hedgehog, and Wnt/ß-Catenin signaling in regulating CSC self-renewal, pluripotency, and chemoresistance, and their potential as targets for anti-cancer therapies. We also discuss the relevance of embryonic markers, including SOX-2, Oct-4, NANOG, and KLF4, in osteosarcoma CSCs and their association with the aforementioned signaling pathways in overcoming drug resistance.
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Neoplasias Ósseas , Osteossarcoma , Animais , Humanos , beta Catenina/metabolismo , Neoplasias Ósseas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Neoplásicas/metabolismo , Osteossarcoma/metabolismo , Microambiente Tumoral , Via de Sinalização Wnt , Receptores Notch/metabolismo , Proteínas Hedgehog/metabolismoRESUMO
Biliary ascariasis is rare in non-endemic areas. This infection is associated with severe complications of the biliary tract, which can become a medical emergency. Treatment with oral anthelmintics is often effective, but, in some cases, surgery is required. We describe an unusual case of ultrasound diagnosis of biliary ascariasis in the gallbladder in a patient who, besides residing in a low-prevalence area of the infection, did not present with biliary tract manifestations. We intend to raise awareness of this clinical entity in non-endemic areas, where this diagnosis is not usually considered. A brief review of the subject is also presented.
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Background and Aim: Aeromonas are Gram-negative rods known to cause a spectrum of diseases. Inflammatory bowel disease (IBD) is an idiopathic complex condition resulting from interaction of multiple factors. Aeromonas infection in association with IBD is still largely unknown. We aim to look for the significance of Aeromonas infection and for significant differences between IBD and non-IBD patients. Methods: A retrospective observational analysis was performed of all patients positive for Aeromonas in stool cultures, during a 10-year period, from a tertiary and university hospital. Results: Fifty patients were included, 56% male with a mean age of 42.1 years. Thirty-eight (76%) were non-IBD and 12 (24%) IBD patients. IBD patients were more frequently under immunosuppressors. Two patients were asymptomatic and 44% developed mild, 44% moderate, and 16.7% severe infection. The main strains isolated were Aeromonas hydrophila/caviae. Bacterial co-isolation was found in 4 non-IBD and histological findings of cytomegalovirus in 2 IBD patients. Non-IBD patients presented more frequently with fever and IBD patients with bloody diarrhea and abdominal pain. There was higher tendency for severe infection rate in IBD patients with higher antimicrobial therapy use. Steroids were exclusively used in the IBD group. From IBD, 4 patients had the diagnosis of ulcerative colitis and 9 of Crohn's disease with colonic involvement. Of these patients, 5 received IBD diagnosis after the acute episode of Aeromonas infection. Conclusions: Clinical presentation of Aeromonas infection differs between IBD and non-IBD patients. Non-IBD patients had milder severity of infection with less use of antibiotics. Aeromonas infection seems to greatly contribute to IBD manifestation.
Introdução: A etiologia da Doença Inflamatória Intestinal (DII) é complexa e resultante da interação de diversos fatores, nomeadamente microbiológicos. A infeção por Aeromonas caracteriza-se por um espectro alargado de manifestações clínicas. O papel da infeção por Aeromonas na DII não está caracterizado. Objetivos: Avaliar o significado da infeção por Aeromonas na DII e as diferenças com a infeção em doentes não-DII. Métodos: avaliação retrospetiva e observacional de todos os doentes com isolamento microbiológico de Aeromonas em amostras fecais num período de 10 anos, num hospital terciário. Resultados: foram avaliados 50 doentes, 56% do sexo masculino, com idade média de 42.1 anos. Doze (24%) com diagnóstico de DII e trinta e oito (76%) não-DII. Os doentes com DII encontravam-se mais frequentemente sob imunossupressão. Dois doentes foram assintomáticos, 44% desenvolveram doença ligeira, 44% moderada e 16.7% severa, havendo maior tendência para infeção severa nos DII. Os doentes não-DII apresentaram mais frequentemente febre e os DII diarreia sanguinolenta e dor abdominal. O uso de antimicrobianos foi superior no grupo DII e a utilização de corticoesteroides foi exclusiva nestes doentes. Isolamento concomitante de outros agentes microbiológicos ocorreu em 4 doentes não-DII e 2 com DII tinham histologia compatível com infeção por Citomegalovírus. Da população DII, 4 eram Colite Ulcerosa e 9 Doença de Crohn com envolvimento cólico. Destes, 5 receberam o diagnóstico após a infeção por Aeromonas. Conclusão: A apresentação clínica da infeção por Aeromonas foi distinta entre as populações DII e não-DII, sendo que os doentes DII apresentaram doença mais severa e maior utilização de antimicrobianos. A infeção na DII ocorreu essencialmente em doentes com envolvimento cólico.
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PURPOSE: Polidocanol foam sclerotherapy (SP) versus doppler-guided hemorrhoidal artery ligation with recto-anal repair (HAL-RAR) in the treatment of hemorrhoidal disease (HD) was analyzed. METHODS: A prospective, randomized study including patients with HD grades II and III was performed. Participants were randomly assigned (1:1) into SP or HAL-RAR, during a recruitment period between September 2019 and February 2020. Therapeutic success (Sodergren's and bleeding scores) was the primary outcome. Other outcomes evaluated included complications and implication in the professional life. Efficacy and safety outcomes were evaluated during the 8 weeks after surgery or the final SP session. RESULTS: Forty-six patients were allocated either to SP (n=22) or HAL-RAR (n=24). Most patients achieved therapeutic success (SP 100% vs. HAL-RAR 90.9%, p=0.131). Complete success was higher in the SP group (91.7% vs. 68.2%, p=0.045) and SP patients had less complications (25% vs. 68.2%, p=0.003). HAL-RAR had a greater negative impact on work activity of the patient. CONCLUSION: SP was more effective and safer than HAL-RAR. SP patients had less impact on their work activity. Clinical trials identifier NCT04675177.
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Hemorroidas , Humanos , Hemorroidas/cirurgia , Polidocanol/uso terapêutico , Escleroterapia , Estudos Prospectivos , Projetos Piloto , ArtériasRESUMO
OBJECTIVES: Identifying the prevalence of palliative care (PC) needs among patients who die at the emergency department (ED) and to assess symptom control and aggressiveness of care. METHODS: We conducted a decedent cohort study of adults deceased at the ED of a Portuguese teaching hospital in 2016. PC needs were identified using the National Hospice Organization terminality criteria and comorbidities measurement by the Charlson's Index. RESULTS: 384 adults died at the ED (median age 82 (IQR 72-89) years) and 78.4% (95% CI 73.9% to 82.2%) presented PC needs. Only 3.0% (n=9) were referred to the hospital PC team. 64.5%, 38.9% and 57.5% experienced dyspnoea, pain and confusion, respectively. Dyspnoea was commonly medicated (92%), against 56% for pain and 8% for confusion. Only 6.3% of the patients were spared from aggressive interventions, namely blood collection (86.0%) or intravenous fluid therapy (63.5%). The burden of aggressive interventions was similar between those with or without withhold cardiopulmonary resuscitation order (median 3 (2-4) vs 3 (2-5)), p=0.082. CONCLUSIONS: Nearly four out of five adults who died at the ED had PC needs at the time of admission. Most experienced poor symptom control and care aggressiveness in their last hours of life and were mostly unknown to the PC team. The findings urge improvements in the care provided to patients with PC needs at the ED, focusing on patient well-being and increased PC referral.
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Hospitais para Doentes Terminais , Medicina Paliativa , Adulto , Humanos , Idoso de 80 Anos ou mais , Estudos de Coortes , Cuidados Paliativos , Serviço Hospitalar de Emergência , Dor , Dispneia/terapiaRESUMO
Mycobacterium szulgai is a slow-growing nontuberculous mycobacterium (NTM). It was first described in 1972 and is responsible for less than 0.2% of all NTM infections. The most common presentation resembles pulmonary tuberculosis, but it may also present as an extrapulmonary disease. It primarily affects individuals with underlying lung disease or immunocompromising conditions. The increasing use of tumor necrosis factor-alpha inhibitors, such as adalimumab, is associated with an increased risk of serious infections. We report a case of Mycobacterium szulgai infection in a 23-year-old woman with a history of childhood pneumonia and Crohn's disease on adalimumab.
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Osteosarcoma is amongst the most prevalent bone sarcomas and majorly afflicts children and adolescents. Therapeutic regimens based on the triad of doxorubicin, cisplatin and methotrexate have been used as the state-of-the-art approach to clinical treatment and management, with no significant improvements in the general outcomes since their inception in the early 1970s. This fact raises the following problematic questions: Why do some patients still relapse despite an initial good response to therapy? Why do nearly 30% of patients not respond to neoadjuvant therapies? Does residual persistent disease contribute to relapses and possible metastatic dissemination? Accumulating evidence suggests that chemoresistant cancer stem cells may be the major culprits contributing to those challenging clinical outcomes. Herein, we revisit the maneuvers that cancer stem cells devise for eluding cell killing by the classic cytotoxic therapies used in osteosarcoma, highlighting studies that demonstrate the complex crosstalk of signaling pathways that cancer stem cells can recruit to become chemoresistant.
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Neoplasias Ósseas , Osteossarcoma , Adolescente , Neoplasias Ósseas/metabolismo , Criança , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Osteossarcoma/metabolismo , Transdução de SinaisRESUMO
Background: This study's primary aim was to determine how training programs use simulation-based medical education (SBME), because SBME is linked to superior clinical performance. Methods: An anonymous 10-question survey was distributed to anesthesiology residency program directors across the United States. The survey aimed to assess where and how SBME takes place, which resources are available, frequency of and barriers to its use, and perceived utility of a dedicated departmental education laboratory. Results: The survey response rate was 30.4% (45/148). SBME typically occurred at shared on-campus laboratories, with residents typically participating in SBME 1 to 4 times per year. Frequently practiced skills included airway management, trauma scenarios, nontechnical skills, and ultrasound techniques (all ≥ 77.8%). Frequently cited logistical barriers to simulation laboratory use included COVID-19 precautions (75.6%), scheduling (57.8%), and lack of trainers (48.9%). Several respondents also acknowledged financial barriers. Most respondents believed a dedicated departmental education laboratory would be a useful or very useful resource (77.8%). Conclusion: SBME is a widely incorporated activity but may be impeded by barriers that our survey helped identify. Barriers can be addressed by departmental education laboratories. We discuss how such laboratories increase capabilities to support structured SBME events and how costs can be offset. Other academic departments may also benefit from establishing such laboratories.
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OBJECTIVE: To establish agreement among nationwide experts through a Delphi process on the key components of perioperative ultrasound and the recommended minimum number of examinations that should be performed by a resident upon graduation. DESIGN: A prospective cross-sectional study. SETTING: A survey on multiinstitutional academic medical centers. PARTICIPANTS: Anesthesiology residency program directors and/or experts in perioperative ultrasound. INTERVENTIONS: A list of components and examinations recommended for anesthesiology resident training in perioperative ultrasound was developed based on guidelines and 2 survey rounds among a steering committee of 10 experts. A questionnaire asking for a rating of each component on a 5-point Likert scale subsequently was sent to an expert panel of 120 anesthesiology residency program directors across the United States. An agreement of at least 70% of participants, rating a component as 4 or 5, was compulsory to list a component as essential for anesthesiology resident training in perioperative ultrasound. MEASUREMENTS AND MAIN RESULTS: The nationwide survey's response rate was 62.5%, and agreement was reached after 2 Delphi rounds. The final list included 44 essential components for basic ultrasound physics and knobology, cardiac ultrasound, lung ultrasound, and ultrasound-guided vascular access. Agreement was not reached for abdominal ultrasound, gastric ultrasound, and ultrasound-guided airway assessment. Agreement for the recommended minimum number of examinations that should be performed by a resident upon graduation included 50 each for transthoracic and transesophageal echocardiography, and 20 each for lung ultrasound, ultrasound-guided central line, and ultrasound-guided arterial line placements. CONCLUSIONS: The recommendations outlined in this survey can be used to establish standardized training for perioperative ultrasound by anesthesiology residency programs.
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Anestesiologia , Internato e Residência , Anestesiologia/educação , Competência Clínica , Estudos Transversais , Humanos , Estudos Prospectivos , Estados UnidosRESUMO
High quality feedback on resident clinical performance is pivotal to growth and development. Therefore, a reliable means of assessing faculty feedback is necessary. A feedback assessment instrument would also allow for appropriate focus of interventions to improve faculty feedback. We piloted an assessment of the interrater reliability of a seven-item feedback rating instrument on faculty educators trained via a three-workshop frame-of-reference training regimen. The rating instrument's items assessed for the presence or absence of six feedback traits: actionable, behavior focused, detailed, negative feedback, professionalism / communication, and specific; as well as for overall utility of feedback with regard to devising a resident performance improvement plan on an ordinal scale from 1 to 5. Participants completed three cycles consisting of one-hour-long workshops where an instructor led a review of the feedback rating instrument on deidentified feedback comments, followed by participants independently rating a set of 20 deidentified feedback comments, and the study team reviewing the interrater reliability for each feedback rating category to guide future workshops. Comments came from four different anesthesia residency programs in the United States; each set of feedback comments was balanced with respect to utility scores to promote participants' ability to discriminate between high and low utility comments. On the third and final independent rating exercise, participants achieved moderate or greater interrater reliability on all seven rating categories of a feedback rating instrument using Gwet's agreement coefficient 1 for the six feedback traits and using intraclass correlation for utility score. This illustrates that when this instrument is utilized by trained, expert educators, reliable assessments of faculty-provided feedback can be made. This rating instrument, with further validity evidence, has the potential to help programs reliably assess both the quality and utility of their feedback, as well as the impact of any educational interventions designed to improve feedback.
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Acute myeloid leukemia (AML) is the most lethal form of leukemia. Standard anti-AML treatment remains almost unchanged for decades. Tingenone (TG) and 22-hydroxytingenone (22-HTG) are quinonemethide triterpenes found in the Amazonian plant Salacia impressifolia (Celastraceae), with cytotoxic properties in different histological types of cancer cells. In the present work, we investigated the anti-AML action mechanism of TG and 22-HTG in the AML HL-60 cell line. Both compounds exhibited potent cytotoxicity in a panel of cancer cell lines. Mechanistic studies found that TG and 22-HTG reduced cell growth and caused the externalization of phosphatidylserine, the fragmentation of internucleosomal DNA and the loss of mitochondrial transmembrane potential in HL-60 cells. In addition, pre-incubation with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, prevented TG- and 22-HTG-induced apoptosis, indicating cell death by apoptosis via a caspase-dependent pathway. The analysis of the RNA transcripts of several genes indicated the interruption of the cellular antioxidant system, including the downregulation of thioredoxin, as a target for TG and 22-HTG. The application of N-acetyl-cysteine, an antioxidant, completely prevented apoptosis induced by TG and 22-HTG, indicating activation of the apoptosis pathway mediated by oxidative stress. Moreover, TG and 22-HTG induced DNA double-strand break and phosphorylation of JNK2 (T183/Y185) and p38α (T180/Y182), and co-incubation with SP 600125 (JNK/SAPK inhibitor) and PD 169316 (p38 MAPK inhibitor) partially prevented apoptosis induced by TG and 22-HTG. Together, these data indicate that TG and 22-HTG are new candidate for anti-AML therapy targeting thioredoxin.
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Leucemia Mieloide Aguda/tratamento farmacológico , Tiorredoxinas/genética , Triterpenos/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Mieloide Aguda/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Salacia/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Readmission to the Intensive Care Unit (ICU) is associated with a high risk of in-hospital mortality and higher health care costs. Previously published tools to predict ICU readmission in surgical ICU patients have important limitations that restrict their clinical implementation. We sought to develop a clinically intuitive score that can be implemented to predict readmission to the ICU after surgery or trauma. We designed the score to emphasize modifiable predictors. METHODS: In this retrospective cohort study, we included surgical patients requiring critical care between June 2015 and January 2019 at Beth Israel Deaconess Medical Center, Harvard Medical School, MA, USA. We used logistic regression to fit a prognostic model for ICU readmission from a priori defined, widely available candidate predictors. The score performance was compared with existing prediction instruments. RESULTS: Of 7,126 patients, 168 (2.4%) were readmitted to the ICU during the same hospitalization. The final score included 8 variables addressing demographical factors, surgical factors, physiological parameters, ICU treatment and the acuity of illness. The maximum score achievable was 13 points. Potentially modifiable predictors included the inability to ambulate at ICU discharge, substantial positive fluid balance (>5 liters), severe anemia (hemoglobin <7 mg/dl), hyperglycemia (>180 mg/dl), and long ICU length of stay (>5 days). The score yielded an area under the receiver operating characteristic curve of 0.78 (95% CI 0.74-0.82) and significantly outperformed previously published scores. The performance of the underlying model was confirmed by leave-one-out cross-validation. CONCLUSION: The RISC-score is a clinically intuitive prediction instrument that helps identify surgical ICU patients at high risk for ICU readmission. The simplicity of the score facilitates its clinical implementation across surgical divisions.