Investigation of TNBC in vitro Antiproliferative Effects of Versatile Pirrolo[1,2-a]quinoxaline Compounds

he triple-negative breast cancer (TNBC) is characterized by a more aggressive nature and poorer prognosis, nowadays none pharmaceutical approach is still available. For this reason, the research of new active compounds and attractive targets represents an interesting field. In this context MDA- MB-231 cell line was selected to evaluate the antiproliferative effects of new [1,2-a]-pyrroloquinoxaline derivatives. The MTT assay revealed that the amine forms of synthesized molecules were more active compared to iminic ones at 72 h of incubation. The antiproliferative effect of the most promising compounds highlighted the formation of autophagic vacuoles

Epidemiology of Severe Sepsis in the Emergency Department and Difficulties in the Initial Assistance

BACKGROUND: The aim of this study was to determine the occurrence rate, demographics, clinical characteristics, and outcomes of patients with severe sepsis admitted to the emergency department. METHODS: A prospective study evaluating all patients admitted to the emergency department unit in a public hospital of tertiary complexity in a six-month period was conducted. During this period, the emergency team was trained to diagnose sepsis. Patients who met the diagnostic criteria for severe sepsis were followed until their discharge from the hospital. RESULTS: A total of 5,332 patients were admitted to the emergency department, and 342 met the criteria for severe sepsis/septic shock. The median (interquartile range) age of patients was 74 (65-84) years, and 52.1% were male. The median APACHE II and SOFA scores at diagnosis were 19 (15-25) and 5 (3-7), respectively. The median number of dysfunctional organ systems per patient was 2 (1-3). The median hospital length of stay was 10 (4.7-17) days, and the hospital mortality rate was 64%. Only 31% of the patients were diagnosed by the emergency department team as septic. About 33.5% of the 342 severe sepsis patients admitted to the emergency department were referred to an ICU, with a median time delay of 24 (12-48) hours. Training improved diagnosis and decreased the time delay for septic patients in arriving at the ICU. CONCLUSIONS: The occurrence rate of severe sepsis in the emergency department was 6.4%, and the rate of sepsis diagnosed by the emergency department team as well as the number of patients transferred to the ICU was very low. Educational campaigns are important to improve diagnosis and, hence, treatment of severe sepsis

Epidemiology of severe sepsis in the emergency department and difficulties in the initial assistance

BACKGROUND: The aim of this study was to determine the occurrence rate, demographics, clinical characteristics, and outcomes of patients with severe sepsis admitted to the emergency department. METHODS: A prospective study evaluating all patients admitted to the emergency department unit in a public hospital of tertiary complexity in a six-month period was conducted. During this period, the emergency team was trained to diagnose sepsis. Patients who met the diagnostic criteria for severe sepsis were followed until their discharge from the hospital. RESULTS: A total of 5,332 patients were admitted to the emergency department, and 342 met the criteria for severe sepsis/septic shock. The median (interquartile range) age of patients was 74 (65-84) years, and 52.1% were male. The median APACHE II and SOFA scores at diagnosis were 19 (15-25) and 5 (3-7), respectively. The median number of dysfunctional organ systems per patient was 2 (1-3). The median hospital length of stay was 10 (4.7-17) days, and the hospital mortality rate was 64%. Only 31% of the patients were diagnosed by the emergency department team as septic. About 33.5% of the 342 severe sepsis patients admitted to the emergency department were referred to an ICU, with a median time delay of 24 (12-48) hours. Training improved diagnosis and decreased the time delay for septic patients in arriving at the ICU. CONCLUSIONS: The occurrence rate of severe sepsis in the emergency department was 6.4%, and the rate of sepsis diagnosed by the emergency department team as well as the number of patients transferred to the ICU was very low. Educational campaigns are important to improve diagnosis and, hence, treatment of severe sepsis

MICA-129 dimorphism and soluble MICA are associated with the progression of multiple myeloma

Natural killer (NK) cells are immune innate effectors playing a pivotal role in the immunosurveillance of multiple myeloma (MM) since they are able to directly recognize and kill MM cells. In this regard, among activating receptors expressed by NK cells, NKG2D represents an important receptor for the recognition of MM cells, being its ligands expressed by tumor cells, and being able to trigger NK cell cytotoxicity. The MHC class I-related molecule A (MICA) is one of the NKG2D ligands; it is encoded by highly polymorphic genes and exists as membrane-bound and soluble isoforms. Soluble MICA (sMICA) is overexpressed in the serum of MM patients, and its levels correlate with tumor progression. Interestingly, a methionine (Met) to valine (Val) substitution at position 129 of the α2 heavy chain domain classifies the MICA alleles into strong (MICA-129Met) and weak (MICA-129Val) binders to NKG2D receptor. We addressed whether the genetic polymorphisms in the MICA-129 alleles could affect MICA release during MM progression. The frequencies of Val/Val, Val/Met, and Met/Met MICA-129 genotypes in a cohort of 137 MM patients were 36, 43, and 22%, respectively. Interestingly, patients characterized by a Val/Val genotype exhibited the highest levels of sMICA in the sera. In addition, analysis of the frequencies of MICA-129 genotypes among different MM disease states revealed that Val/Val patients had a significant higher frequency of relapse. Interestingly, NKG2D was downmodulated in NK cells derived from MICA-129Met/Met MM patients. Results obtained by structural modeling analysis suggested that the Met to Val dimorphism could affect the capacity of MICA to form an optimal template for NKG2D recognition. In conclusion, our findings indicate that the MICA-129Val/Val variant is associated with significantly higher levels of sMICA and the progression of MM, strongly suggesting that the usage of soluble MICA as prognostic marker has to be definitely combined with the patient MICA genotype

Conhecimento do enfermeiro para identificação precoce da Injúria Renal Aguda

OBJETIVO Avaliar o conhecimento do enfermeiro na identificação precoce da Injúria Renal Aguda (IRA) em Unidade de Terapia Intensiva, Unidade de Internação e Emergência. MÉTODO Estudo multicêntrico, prospectivo.Participaram do estudo 216 enfermeiros,por meio de questionário com 10 questões relacionadas à prevenção, ao diagnóstico e ao tratamento da IRA. RESULTADOS 57,2% não souberam identificar as manifestações clínicas da IRA, 54,6% não têm conhecimento da incidência de IRA em pacientes internados na UTI, 87,0% dos enfermeiros não souberam responder ao índice de mortalidade de IRA em pacientes internados na UTI, 67,1% responderam incorretamente que aumentos discretos da creatinina sérica não têm impacto na mortalidade, 66,8% responderam incorretamente à questão sobre as medidas de prevenção da IRA, 60,4% acertaram quando responderam que não é recomendada a utilização de diuréticos de alça na prevenção da IRA, 77,6% acertaram ao responder que IRA não caracteriza necessidade de hemodiálise e 92,5% disseram não conhecer a classificação AKIN. CONCLUSÃO Enfermeiros não têm conhecimento suficiente para a identificação precoce da IRA, mostrando a importância de programas de capacitação nesta área do conhecimento.OBJETIVO Evaluar el conocimiento del enfermero en la identificación precoz de la Insuficiencia Renal Aguda (IRA) en Unidad de Cuidados Intensivos, Unidad de Estancia Hospitalaria y Urgencias. MÉTODO Estudio multicéntrico, prospectivo.Participaron en el estudio 216 enfermeros, mediante cuestionario con 10 preguntas relacionadas con la prevención, el diagnóstico y el tratamiento de la IRA. RESULTADOS el 57,2% no supieron identificar las manifestaciones clínicas de la IRA, el 54,6% no tienen conocimiento de la incidencia de IRA en pacientes ingresados en la UCI, el 87,0% de los enfermeros no supieron responder al índice de mortalidad de IRA en pacientes ingresados en la UCI, el 67,1% respondieron incorrectamente que aumentos discretos de la creatinina sérica no tienen impacto en la mortalidad, el 66,8% respondieron incorrectamente a la pregunta acerca de las medidas de prevención a la IRA, el 60,4% acertaron cuando respondieron que no se recomienda la utilización de diuréticos de asa en la prevención de la IRA, el 77,6% acertaron al responder que la IRA no caracteriza necesidad de hemodiálisis y el 92,5% dijeron no conocer la clasificación AKIN. CONCLUSIÓN Enfermeros no tienen conocimiento suficiente para la identificación precoz de la IRA, mostrando la importancia de programas de capacitación en esa área del conocimiento.OBJECTIVE To evaluate the knowledgeof nurses on early identification of acute kidney injury (AKI) in intensive care, emergency and hospitalization units. METHOD A prospective multi-center study was conducted with 216 nurses, using a questionnaire with 10 questions related to AKI prevention, diagnosis, and treatment. RESULTS 57.2% of nurses were unable to identify AKI clinical manifestations, 54.6% did not have knowledge of AKI incidence in patients admitted to the ICU, 87.0% of the nurses did not know how to answer as regards the AKI mortality rate in patients admitted to the ICU, 67.1% answered incorrectly that slight increases in serum creatinine do not have an impact on mortality, 66.8% answered incorrectly to the question on AKI prevention measures, 60.4% answered correctly that loop diuretics for preventing AKI is not recommended, 77.6% answered correctly that AKI does not characterize the need for hemodialysis, and 92.5% said they had no knowledge of the Acute Kidney Injury Networkclassification. CONCLUSION Nurses do not have enough knowledge to identify early AKI, demonstrating the importance of qualification programs in this field of knowledge

Synthesis and evaluation of fluorimetric and colorimetric chemosensors for anions based on (oligo)thienyl-thiosemicarbazones

A family of heterocyclic thiosemicarbazone dyes (3a-d) containing thienyl groups has been synthesized, characterized and their chromo-fluorogenic response in acetonitrile in the presence of selected anions studied. Acetonitrile solutions of 3a-d show absorption bands in the 338-425 nm range which are modulated by the groups attached to the thiosemicarbazone moiety. The fluoride, chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulfate, nitrate, acetate and anions were used in the recognition studies. Only sensing features were observed for fluoride, cyanide, acetate and dihydrogen phosphate anions. Two different chromogenic responses were found, (i) a small shift of the absorption band due to coordination of the anions with the thiourea protons and (ii) the appearance of a new red shifted band due to deprotonation of the receptor. For the latter process changes in the color solutions from pale-yellow to orange-red were observed. Fluorescence studies showed a different emission behavior according to the number of thienyl rings in the π-conjugated bridges. Stability constants for the two processes (complex formation + deprotonation) for receptors 3a-d in the presence of fluoride and acetate anions were determined from spectrophotometric titrations using the HypSpec program. The interaction of 3d with fluoride was also studied through 1H NMR titrations. Semiempirical calculations to evaluate the hydrogen-donating ability of the receptors were also performed.Fundação para a Ciência e a Tecnologia (FCT) , Acções Integradas Luso-Espanholas/CRUP, Generalitat Valenci

The effect of excess fluid balance on the mortality rate of surgical patients: a multicenter prospective study

INTRODUCTION: In some studies including small populations of patients undergoing specific surgery, an intraoperative liberal infusion of fluids was associated with increasing morbidity when compared to restrictive strategies. Therefore, to evaluate the role of excessive fluid infusion in a general population with high-risk surgery is very important. The aim of this study was to evaluate the impact of intraoperative fluid balance on the postoperative organ dysfunction, infection and mortality rate. METHODS: We conducted a prospective cohort study during one year in four ICUs from three tertiary hospitals, which included patients aged 18 years or more who required postoperative ICU after undergoing major surgery. Patients who underwent palliative surgery and whose fluid balance could change in outcome were excluded. The calculation of fluid balance was based on preoperative fasting, insensible losses from surgeries and urine output minus fluid replacement intraoperatively. RESULTS: The study included 479 patients. Mean age was 61.2 ± 17.0 years and 8.8% of patients died at the hospital during the study. The median duration of surgery was 4.0 (3.2 to 5.5) h and the value of the Simplified Acute Physiology Score (SAPS) 3 score was 41.8 ± 14.5. Comparing survivors and non-survivors, the intraoperative fluid balance from non-survivors was higher (1,950 (1,400 to 3,400) mL vs. 1,400 (1,000 to 1,600) mL, P <0.001). Patients with fluid balance above 2,000 mL intraoperatively had a longer ICU stay (4.0 (3.0 to 8.0) vs. 3.0 (2.0 to 6.0), P <0.001) and higher incidence of infectious (41.9% vs. 25.9%, P = 0.001), neurological (46.2% vs. 13.2%, P <0.001), cardiovascular (63.2% vs. 39.6%, P <0.001) and respiratory complications (34.3% vs. 11.6%, P <0.001). In multivariate analysis, the fluid balance was an independent factor for death (OR per 100 mL = 1.024; P = 0.006; 95% CI 1.007 to 1.041). CONCLUSIONS: Patients with excessive intraoperative fluid balance have more ICU complications and higher hospital mortality

Lesão renal aguda após cirurgias não cardíacas: incidência e impacto das disfunções orgânicas extra-renais nos desfechos

Introdução: A permanência de pacientes em Unidades de Terapia Intensiva (UTI) é frequentemente complicada por Lesão Renal Aguda (LRA), principalmente em casos de sepse, baixo débito cardíaco e pós-operatório de grandes cirurgias. Objetivo: Avaliar a incidência, características, desenvolvimento de outras disfunções orgânicas, e desfechos de pacientes com LRA adquirida na UTI após cirurgias não cardíacas. Métodos: Estudo de coorte, prospectivo. Todos os pacientes internados consecutivamente nas UTIs após cirurgias não cardíacas nos meses de abril e maio de 2017 foram analisados quanto ao desenvolvimento ou não de LRA, de outras disfunções orgânicas e ao balanço hídrico. Resultados: A incidência de LRA foi de 16,2%. Os pacientes que desenvolveram LRA no pós-operatório eram mais graves, e diferiram quanto à necessidade de ventilação mecânica (60% vs. 11%, p < 0,001), uso de drogas vasoativas (82% vs. 44%, p = 0,021); presença de infecção (80% vs. 21%, p < 0,001), sepse ou choque séptico (50% vs. 9%, p < 0,001) e a outras complicações pós-operatórias (91% vs. 58%, p = 0,023). Outras disfunções de órgãos e sistemas foram mais fre-quentes nos pacientes com IRA (2 [2-3] vs. 1 [0-1], p < 0,001), particularmente disfunção gas-trointestinal (73% vs. 19%, p < 0,001) e cardiovascular (73% vs. 33%, p = 0,015). O número de pacientes com duas ou mais disfunções orgânicas aumentou de 21% para 82% em pacientes com LRA (RR 3,89, IC: 2,18 – 6,90, p < 0,001). O tempo de internação (13 ± 9 vs. 5 ± 6 dias, p < 0,001) e a mortalidade hospitalar (54,5% vs. 7%, p = 0,013) foram maiores nos pacientes com LRA. Conclusão: Entre pacientes com cirurgias não cardíacas e necessidade de UTI, a incidência de LRA é elevada e associada a complicações de outros sistemas, incluindo os sistemas neurológico, gastrointestinal, respiratório e cardiovascular; somandose a isso, balanço hídrico acumulado positivo, sepse e choque, maior tempo de internação e maiores taxas de mortalidade também foram encontrados nesses pacientes

Trajectories of Seroprevalence and Neutralizing Activity of Antibodies against SARS-CoV-2 in Southern Switzerland between July 2020 and July 2021: An Ongoing, Prospective Population-Based Cohort Study

OBJECTIVES: The COVID-19 pandemic continues, and evidence on infection- and vaccine-induced immunity is key. We assessed COVID-19 immunity and the neutralizing antibody response to virus variants across age groups in the Swiss population. STUDY DESIGN: We conducted a cohort study in representative community-dwelling residents aged five years or older in southern Switzerland (total population 353,343), and we collected blood samples in July 2020 (in adults only, N = 646), November-December 2020 (N = 1457), and June-July 2021 (N = 885). METHODS: We used a previously validated Luminex assay to measure antibodies targeting the spike (S) and the nucleocapsid (N) proteins of the virus and a high-throughput cell-free neutralization assay optimized for multiple spike protein variants. We calculated seroprevalence with a Bayesian logistic regression model accounting for the population's sociodemographic structure and the test performance, and we compared the neutralizing activity between vaccinated and convalescent participants across virus variants. RESULTS: The overall seroprevalence was 7.8% (95% CI: 5.4-10.4) by July 2020 and 20.2% (16.4-24.4) by December 2020. By July 2021, the overall seroprevalence increased substantially to 72.5% (69.1-76.4), with the highest estimates of 95.6% (92.8-97.8) among older adults, who developed up to 10.3 more antibodies via vaccination than after infection compared to 3.7 times more in adults. The neutralizing activity was significantly higher for vaccine-induced than infection-induced antibodies for all virus variants (all p values < 0.037). CONCLUSIONS: Vaccination chiefly contributed to the reduction in immunonaive individuals, particularly those in older age groups. Our findings on the greater neutralizing activity of vaccine-induced antibodies than infection-induced antibodies are greatly informative for future vaccination campaigns

Synthesis and evaluation of thiosemicarbazones functionalized with furyl moieties as new chemosensors for anion recognition

A family of heterocyclic thiosemicarbazone dyes (3a-f and 4) containing furyl groups were synthesized in good yields, characterized and their response in acetonitrile in the presence of selected anions was studied. Acetonitrile solutions of 3a-f and 4 show absorption bands in the 335-396 nm range which are modulated by the electron donor or acceptor strength of the heterocyclic systems appended to the thiosemicarbazone moiety. Fluoride, chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulphate, nitrate, acetate and cyanide anions, were used in recognition studies. From these anions, only sensing features were seen for fluoride, cyanide, acetate and dihydrogen phosphate. Two clearly different chromo-fluorogenic behaviours were observed, (i) a small shift of the absorption band due to the coordination of the anions with the thiourea protons and (ii) the appearance of a new red shifted band due to deprotonation. For the latter effect, a change in the colour solution from pale yellow to purple was observed. Fluorescence studies were also in agreement with the different effects observed in the UV/Vis titrations. In this case, hydrogen bonding interactions were visible through the enhancement of the emission band, whereas deprotonation induced the appearance of a new red-shifted emission. Logarithms of stability constants for the two processes (complex formation + deprotonation) for receptors 3a-f in the presence of fluoride and acetate anions were determined from spectrophotometric titrations using the HypSpec V1.1.18 program. Semi-empirical calculations to evaluate the hydrogen-donating ability of the receptors and a prospective electrochemical characterization of compound 3b in the presence of fluoride were also performed.Fundação para a Ciência e a Tecnologia (FCT), Acções Integradas Luso-espanholas/CRUP, Generalitat Valenciana