Etiology and Prognosis of Pneumonia in Patients with Solid Tumors: A Prospective Cohort of Hospitalized Cases.

BACKGROUND: Data on the incidence, etiology, and prognosis of non-ventilator-associated pneumonia in hospitalized patients with solid tumors are scarce. We aimed to study the characteristics of non-ventilator-associated pneumonia in hospitalized patients with solid tumors. MATERIALS AND METHODS: This was a prospective noninterventional cohort study of pneumonia in patients hospitalized in an oncology ward in a tertiary teaching hospital. Pneumonia was defined according to the American Thoracic Society criteria. Patients were followed for 1 month after diagnosis or until discharge. Survivors were compared with nonsurvivors. RESULTS: A total of 132 episodes of pneumonia were diagnosed over 1 year (9.8% of admissions to the oncology ward). They were health care-related (67.4%) or hospital-acquired pneumonia (31.8%). Lung cancer was the most common malignancy. An etiology was established in 48/132 episodes (36.4%). Knowing the etiology led to changes in antimicrobial therapy in 58.3%. Subsequent intensive care unit admission was required in 10.6% and was linked to inappropriate empirical therapy. Ten-day mortality was 24.2% and was significantly associated with hypoxia (odds ratio [OR], 2.1). Thirty-day mortality was 46.2%. The independent risk factors for 30-day mortality were hypoxia (OR, 3.3), hospital acquisition (OR, 3.1), and a performance status >1 (OR, 2.6). Only 40% of patients who died within 30 days were terminally ill. CONCLUSION: Pneumonia is a highly prevalent condition in hospitalized patients with solid tumors, even with nonterminal disease. Etiology is diverse, and poor outcome is linked to inappropriate empirical therapy. Efforts to get the empirical therapy right and reach an etiological diagnosis to subsequently de-escalate are warranted. IMPLICATIONS FOR PRACTICE: The present study shows that pneumonia is a prevalent infectious complication in patients admitted to oncology wards, with a very high mortality, even in non-terminally ill patients. Etiology is diverse, and etiological diagnosis is reached in fewer than 40% of cases in nonintubated patients. Intensive care unit admission, a marker of poor outcome, is associated with inappropriate empirical therapy. These results suggest that, to improve prognosis, a more precise and appropriate antimicrobial empirical therapy for pneumonia in patients with solid tumors is necessary, together with an effort to reach an etiological diagnosis to facilitate subsequent de-escalation.

Involvement of stanniocalcins in the deregulation of glycaemia in obese mice and type 2 diabetic patients.

Stanniocalcins are expressed in the pancreas tissue, and it was suggested a direct correlation between circulating insulin and STC2 concentrations in human. Here, we show a significant correlation between STC1 and both glycaemia and glycosylated haemoglobin among DM2 patients, while DM2 patients who present the greatest glycosylated haemoglobin values exhibited the lowest STC2 expression. However, treatment of patients with antiglycaemic drugs does not significantly modify the expression of both STCs. On the other hand, STC2-/- mice that exhibited neonatal and adult overweight further presented deregulated glycaemia when they were feed with a hypercaloric diet (breeding pellet, BP). This alteration is more evident at the early stages of the animal life. Deregulated glycaemia in these mice was confirmed using glucose oral test. In addition, STC2-/- mice present enhanced pancreas size; thus, the histological analysis reveals that WT mice respond to BP diet by increasing the size of the pancreatic islets through inducing cell division, and STC2-/- mice lack this compensatory mechanism. Contrary, BP fed STC2-/- mice show enhanced number of islets but of similar size than those fed with regular pellet. Histopathological analysis demonstrates tissue structure disruption and erythrocytes infiltrations in STC2-/- mice, possibly due to the stress evoked by the BP diet. Finally, enhanced glucagon immunostaining was observed in the islet of STC2-/- mice, and the glucagon ELISA assay confirmed the increase in the circulating glucagon. Summarizing, we present evidence of the role of STCs, mainly STC2, as a possible early marker during development of diabetes mellitus.

Apelin: an antithrombotic factor that inhibits platelet function.

Apelin peptide and its receptor APJ are directly implicated in various physiological processes ranging from cardiovascular homeostasis to immune signaling. Here, we show that apelin is a key player in hemostasis with an ability to inhibit thrombin- and collagen-mediated platelet activation. Mice lacking apelin displayed a shorter bleeding time and a prothrombotic profile. Their platelets exhibited increased adhesion and a reduced occlusion time in venules, and displayed a higher aggregation rate after their activation by thrombin compared with wild-type platelets. Consequently, human and mouse platelets express apelin and its receptor APJ. Apelin directly interferes with thrombin-mediated signaling pathways and platelet activation, secretion, and aggregation, but not with ADP and thromboxane A2-mediated pathways. IV apelin administration induced excessive bleeding and prevented thrombosis in mice. Taken together, these findings suggest that apelin and/or APJ agonists could potentially be useful adducts in antiplatelet therapies and may provide a promising perspective for patients who continue to display adverse thrombotic events with current antiplatelet therapies.

Concatemerization increases the inhibitory activity of short, cell-penetrating, cationic and tryptophan-rich antifungal peptides.

There are short cationic and tryptophan-rich antifungal peptides such as the hexapeptide PAF26 (RKKWFW) that have selective toxicity and cell penetration properties against fungal cells. This study demonstrates that concatemeric peptides with tandem repeats of the heptapeptide PAF54 (which is an elongated PAF26 sequence) show increased fungistatic and bacteriostatic activities while maintaining the absence of hemolytic activity of the monomer. The increase in antimicrobial activity of the double-repeated PAF sequences (diPAFs), compared to the nonrepeated PAF, was higher (4-8-fold) than that seen for the triple-repeated sequences (triPAFs) versus the diPAFs (2-fold). However, concatemerization diminished the fungicidal activity against quiescent spores of the filamentous fungus Penicillium digitatum. Peptide solubility and sensitivity to proteolytic degradation were affected by the design of the concatemers: incorporation of the AGPA sequence hinge to separate PAF54 repeats increased solubility while the C-terminal addition of the KDEL sequence decreased in vitro stability. These results led to the design of the triPAF sequence PAF102 of 30 amino acid residues, with increased antimicrobial activity and minimal inhibitory concentration (MIC) value of 1-5 µM depending on the fungus. Further characterization of the mode-of-action of PAF102 demonstrated that it colocalizes first with the fungal cell wall, it is thereafter internalized in an energy dependent manner into hyphal cells of the filamentous fungus Fusarium proliferatum, and finally kills hyphal cells intracellularly. Therefore, PAF102 showed mechanistic properties against fungi similar to the parental PAF26. These observations are of high interest in the future development of PAF-based antimicrobial molecules optimized for their production in biofactories.

Use of an endoscopy face mask in patients with gastric distention undergoing noninvasive ventilation for acute respiratory failure: a comparative case study report.

We describe the use of an endoscopy face mask with a perforated membrane, which allows a nasogastric tube for continuous noninvasive ventilation in acute hypercapnic respiratory failure, in 2 patients who developed gastric distention. This interface was able to avoid most nonintentional leaks through the mask, as compared with a conventional approach, improving ventilation efficiency. To our knowledge, this is the first case report of an endoscopy face mask used in noninvasive ventilation for this specific side effect.

Differences between the first and the second wave of critically ill COVID-19 patients admitted to the intensive care units.

Background: To compare the demographic characteristics and prognosis of patients admitted to the intensive care unit (ICU) for coronavirus disease 2019 (COVID-19) pneumonia during the first wave (March-July) versus those admitted during the second wave (August-December). Methods: Prospective, observational, descriptive cohort-study including patients admitted to the ICU for COVID-19 pneumonia during the first wave (March-July 2020) or the second wave (August-December). The demographic characteristics, comorbidities, treatments, complications, and mortality in both pandemic waves were studied. Results: A total of 72 patients were included: Twenty-six admitted during the first wave and 46 during the second wave. Men were predominant in both waves: 61.5% versus 73.9%. The most frequently associated comorbidities in both periods were: arterial hypertension 65.4% versus 65.2%, diabetes mellitus 46.2% versus 34.8% and overweight, measured as (body mass index), 29.13 ± 3.38 versus 28.98 ± 4.25. More patients received noninvasive mechanical ventilation prior to invasive ventilation during the second wave (P < 0.01); the incidence of atelectasis and bronchial obstruction were lower during the second wave (P < 0.01 and P = 0.055 respectively); no further differences were observed in the occurrence of other complications. Conclusions: No significant differences were observed between the first and the second wave in the demographic characteristics or comorbidities of admitted patients. Blood hypertension, diabetes and overweight were remarkable risk factors. Improving our knowledge of the complications, these patients tend to develop was essential to reduce some of them, such as endotracheal tube obstruction or atelectasis, and to promote the use of noninvasive ventilation therapies.

[Aspiration thrombectomy for acute pulmonary embolism with an intermediate-high risk]. / Trombectomía mecánica en la tromboembolia pulmonar aguda de riesgo intermedio-alto.

INTRODUCTION AND PURPOSE: The treatment of acute pulmonary embolism (PE) with an intermediate-high risk of mortality at 30 days is still not well defined, recommending the latest clinical guidelines of the European Society of Cardiology 2019 exclusively anticoagulant treatment, reducing the indication for mechanical thrombectomy to high-risk patients or intermediate-high risk patients with poor hemodynamic evolution. Our purpose is to determine the safety and efficacy of aspiration thrombectomy in intermediate-high risk patients with PE and to analyze possible differences in these results between hemodynamically unstable patients (massive PE) and hemodynamically stable patients (submassive PE). METHODS: We analyzed all patients who underwent aspiration thrombectomy for PE at our tertiary university hospital during a 34-month period. We compared echocardiographic parameters (right ventricular diameter, tricuspid plane annular plane systolic excursion (TAPSE), S' wave, and pulmonary hypertension), respiratory parameters (PaO2/FiO2 ratio), and clinical parameters recorded before and 24h after the procedure. We also analyzed bleeding complications and mortality. RESULTS: In the 42 patients included (16 with massive PE and 26 with submassive PE), aspiration thrombectomy resulted in significant improvements in right ventricular diameter, TAPSE, S' wave, andPaO2/FiO2 ratio. Of the 8 patients administered fibrinolysis, 4 developed bleeding complications. Only one direct complication of the procedure was observed (pulmonary artery rupture). Eight patients died in the acute phase. CONCLUSIONS: Aspiration thrombectomy for PE is safe and effective, significantly improving respiratory and hemodynamic parameters in the first 24h after the procedure with a low rate of complications compared to fibrinolysis.

Platelet Functions are Decreased in Obesity and Restored after Weight Loss: Evidence for a Role of the SERCA3-Dependent ADP Secretion Pathway.

In obesity, platelets are described as hyperactive, mainly based on increased platelet size and presence of pro-thrombotic plasmatic molecules. We explored platelet functions, including calcium signalling in obesity, and the effect of weight loss. We included 40 obese patients (women with body mass index [BMI] of ≥ 35 kg/m2) who were to undergo gastric bypass surgery and 40 healthy lean subjects (women with BMI of < 25 kg/m2) as a control group. Approximately 1 year after surgery, the obese patients lost weight (75% had a BMI < 35 kg/m2). They were explored a second time with the same healthy control for the same platelet experiments. Compared with controls, obese patients' platelets displayed reduced sensitivity to thrombin (aggregation EC50 increased by 1.9 ± 0.3-fold, p = 0.005) and a lower Ca2+ response (70 ± 7% decrease, p < 10-4). In 17 pairs of patients, we performed additional experiments: in obese patients' platelets, thrombin-induced αIIbß3 activation was significantly lower (p = 0.003) and sarco-endoplasmic reticulum Ca2+ATPase (SERCA3) expression was decreased (48 ± 6% decrease, p < 10-4). These differences were abolished after weight loss. Interestingly, pharmacological inhibition of SERCA3 activity in control group's platelets mimicked similar alterations than in obese patients' platelets and was associated with defective adenosine diphosphate (ADP) secretion. Addition of ADP to agonist restored platelet functions in obese patients and in SERCA3-inhibited control platelets (five experiments) confirming the direct involvement of the SERCA3-dependent ADP secretion pathway. This is the first study demonstrating that platelets from obese patients are hypo-reactive, due to a deficiency of SERCA3-dependent ADP secretion. Weight loss restores SERCA3 activity and subsequent calcium signalling, αIIbß3 activation, platelet aggregation and ADP secretion.

Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer.

Proprotein convertases (PC) activate precursor proteins that play crucial roles in various cancers. In this study, we investigated whether PC enzyme activity is required for expression of the checkpoint protein programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTL) in colon cancer. Although altered expression of the PC secretory pathway was observed in human colon cancers, only furin showed highly diffuse expression throughout the tumors. Inhibition of PCs in T cells using the general protein-based inhibitor α1-PDX or the pharmacologic inhibitor Decanoyl-Arg-Val-Lys-Arg-chloromethylketone repressed PD-1 and exhausted CTLs via induction of T-cell proliferation and apoptosis inhibition, which improved CTL efficacy against microsatellite instable and microsatellite stable colon cancer cells. In vivo, inhibition of PCs enhanced CTL infiltration in colorectal tumors and increased tumor clearance in syngeneic mice compared with immunodeficient mice. Inhibition of PCs repressed PD-1 expression by blocking proteolytic maturation of the Notch precursor, inhibiting calcium/NFAT and NF-κB signaling, and enhancing ERK activation. These findings define a key role for PCs in regulating PD-1 expression and suggest targeting PCs as an adjunct approach to colorectal tumor immunotherapy. SIGNIFICANCE: Protein convertase enzymatic activity is required for PD-1 expression on T cells, and inhibition of protein convertase improves T-cell targeting of microsatellite instable and stable colorectal cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/5008/F1.large.jpg.

Efecto hipoglicemiante de la NeuroEPO en ratas con y sin diabetes mellitus / Hypoglycemic effect of NeuroEPO in diabetic and non-diabetic rats

RESUMEN Introducción: La NeuroEPO es una variante no-hematopoyética de la eritropoyetina recombinante humana, que pudiera tener efecto hipoglicemiante. Objetivo: Evaluar la influencia de la NeuroEPO sobre la glicemia de ratas con diabetes mellitus y ratas no-diabéticas. Material y Métodos: Se realizaron experimentos en ratas Wistar con diabetes inducida por estreptozotocina, con y sin tratamiento con insulina, y en ratas no-diabéticas con una sobrecarga de glucosa. En cada experimento, un grupo recibió una inyección subcutánea de NeuroEPO (0,5 mg/kg) y otro el vehículo, y se determinó la glicemia durante 120 minutos. Se realizaron comparaciones mediante análisis de varianza de una y dos vías, seguidas por la prueba de Bonferroni. Las diferencias se consideraron significativas con valores de p < 0,05. Resultados: En las ratas diabéticas sin tratamiento con insulina, los niveles de glicemia del grupo con NeuroEPO disminuyeron de forma significativa. En las ratas no-diabéticas que recibieron NeuroEPO y una sobrecarga de glucosa, la glicemia fue similar al grupo control. En las ratas diabéticas que recibieron NeuroEPO e insulina la reducción de la glicemia fue mayor que en el grupo que solo recibió insulina. Conclusiones: La NeuroEPO tiene un efecto hipoglicemiante en ratas diabéticas, por un mecanismo insulinotrópico que muestra sinergismo con la insulina en el tratamiento de la hiperglicemia. Sin embargo, la NeuroEPO no influye en la tolerancia a la glucosa de ratas no-diabéticas, al menos de forma inmediata. Es necesario profundizar en los mecanismos mediante los cuales la NeuroEPO puede reducir la hiperglicemia, y la influencia de esta sustancia en condiciones de normoglicemia.

ABSTRACT Introduction: NeuroEPO is a non-hematopoietic variant of human recombinant erythropoietin, which may have a hypoglycemic effect. Objectives: To evaluate the influence of NeuroEPO on glycemia in diabetic and non-diabetic rats. Material and Methods: The experiments were conducted in Wistar rats with streptozotocin-induced diabetes with and without insulin treatment, and in non-diabetic rats with glucose overload. In each experiment, one group received a subcutaneous injection of NeuroEPO (0.5 mg/kg) and the other group received a vehicle. Glycemia was determined in 120 min. Comparisons were made using one-and two-way analysis of variance, followed by the Bonferroni test. The differences were considered significant with p values < 0,05. Results: In diabetic rats without insulin treatment, glycemic levels decreased significantly in the group that received NeuroEPO. In nondiabetic rats that received NeuroEPO and a glucose overload, glycemia was similar to that in the control group. In diabetic rats that received NeuroEPO and insulin, the glycemia reduction was greater than in the group that only received insulin. Conclusions: NeuroEPO has a hypoglycemic effect in diabetic rats due to an insulinotropic mechanism that shows synergism with insulin in the treatment of hyperglycemia. However, NeuroEPO does not influence the glucose tolerance in non-diabetic rats, at least immediately. It is necessary to delve into the mechanisms by which NeuroEPO can reduce hyperglycemia and the influence of this substance under conditions of normoglycemia.

COMMUNI-CARE: Assessment tool for reactions and behaviours of patients with dementia in a multisensory stimulation environment.

BACKGROUND: The 'Snoezelen' is an approach based on stimulation and sensory stimulation proposals, giving priority to the notion of caretaking. The aim of this paper is to present the creation and validation of the COMMUNI-CARE scale. This is a new tool that allows for an evaluation of the psycho-emotional well-being that the patient with dementia shows in a 'Snoezelen' multisensory stimulation environment. METHODS: In total 429 evaluations in 143 multisensory stimulation interventions were made using the COMMUNI-CARE scale, in 16 patients between 53 and 85 years of age, diagnosed with moderate to severe dementia. The goal was to evaluate the psycho-emotional well-being the patients present. RESULTS: The tool's internal consistency showed a Crombach alpha of 0.90. The concurrent validity between the COMMUNI-CARE scale and the Clinical Global Impression (CGI) was of r = -0.961. The Kappa index used to determine the reliability between evaluators was of K = 0.87. CONCLUSIONS: The COMMUNI-CARE scale fulfills the basic principles of classic psychometrics of construct, and criterion validity and reliability. It does so while showing a clear idea, through its five subscales (anxiety, communication, pleasure, adaptation to the surroundings and affection), of the degree of well-being that the patient with dementia shows during such interventions. This scale embodies, through psychometrics, a very subjective human experience with a tool unavailable to date.

Endobronchial cryotherapy for a mycetoma.

Mycetoma is defined as a fungus ball that fills a preexisting lung cavity, most frequently being of tuberculous or sarcoid etiology. The most frequently isolated fungus is the species of Aspergillus, but other fungi such as Fusarium or Zygomycetes can also be present. Most patients lack symptoms. However, presentation may also be with hemoptysis, which can be massive and life-threatening. We describe the case of a 50-year-old man with a history of prior pulmonary tuberculosis, with recurrent episodes of cough and hemoptysis. He was diagnosed to have mycetoma in the left upper lobe cavity. The mycetoma was extracted through bronchoscopy under general anesthesia using a cryoprobe. Treatment was completed with amphotericin B instilled in the cavity and the patient was placed on oral itraconazole. This is the first case report to date in which cryotherapy was used to remove a mycetoma.

Study of the rheological properties of a fermentation broth of the fungus Beauveria bassiana in a bioreactor under different hydrodynamic conditions.

Fermentation with filamentous fungi in a bioreactor is a complex dynamic process that is affected by flow conditions and the evolution of the rheological properties of the medium. These properties are mainly affected by the biomass concentration and the morphology of the fungus. In this work, the rheological properties of a fermentation with the fungus Beauveria bassiana under different hydrodynamic conditions were studied and the rheological behavior of this broth was simulated through a mixture of carboxymethyl cellulose sodium and cellulose fibers (CMCNa-SF). The bioreactor was a 10 L CSTR tank operated at different stir velocities. Rheological results were similar at 100 and 300 rpm for both systems. However, there was a significant increase in the viscosity accompanied by a change in the consistence index, calculated according to the power law model, for both systems at 800 rpm. The systems exhibited shear-thinning behavior at all stir velocities, which was determined with the power law model. The mixing time was observed to increase as the cellulose content in the system increased and, consequently, the efficiency of mixing diminished. These results are thought to be due to the rheological and morphological similarities of the two fungal systems. These results will help in the optimization of scale-up production of these fungi.

Trombectomía mecánica en la tromboembolia pulmonar aguda de riesgo intermedio-alto / Aspiration thrombectomy for acute pulmonary embolism with an intermediate-high risk

Introducción y objetivo:El tratamiento de la tromboembolia pulmonar (TEP) aguda con riesgo de mortalidad intermedio-alto a los 30 días, sigue sin estar bien definido, recomendándose por las últimas guías clínicas de la European Society of Cardiology2019 el tratamiento anticoagulante exclusivamente, reduciendo la indicación de trombectomía mecánica a pacientes de riesgo alto o pacientes con riesgo intermedio-alto con mala evolución hemodinámica. Nuestro objetivo fue comprobar la mejoría ecocardiográfica, respiratoria y hemodinámica en las primeras horas de los pacientes sometidos a trombectomía mecánica con tromboembolia pulmonar de riesgo intermedio-alto.Material y métodos:Se analizó la evolución cardíaca por ecocardiografía (diámetro de ventrículo derecho, TAPSE, Onda S e hipertensión pulmonar), hemodinámica, respiratoria y clínica de los pacientes en las primeras 24 horas tras trombectomía mecánica por aspiración, así como las complicaciones hemorrágicas y mortalidad del procedimiento.Resultados:Se llevaron a cabo 42 trombectomías mecánicas, 16 con inestabilidad hemodinámica (TEP masivo) y 26 estables hemodinámicamente (TEP submasivo). Se obtuvo mejoría (p<0,05) en el diámetro de ventrículo derecho, TAPSE, Onda S y presión arterial oxígeno/fracción inspiratoria de oxígeno (PaFi). Ocho pacientes recibieron tratamiento fibrinolítico, presentando 4 de ellos (50%) complicaciones hemorrágicas. Solo un paciente presentó complicación directa por el procedimiento (rotura arteria pulmonar). Ocho pacientes fallecieron en la fase aguda de la enfermedad.Conclusiones:La trombectomía mecánica por aspiración es una técnica segura y efectiva, observando una mejoría de la situación respiratoria, hemodinámica y ecocardiográfica de los pacientes en las primeras 24 horas postprocedimiento con baja tasa de complicaciones frente al tratamiento fibrinolítico. (AU)

Introduction and purpose:The treatment of acute pulmonary embolism (PE) with an intermediate-high risk of mortality at 30 days is still not well defined, recommending the latest clinical guidelines of the European Society of Cardiology 2019 exclusively anticoagulant treatment, reducing the indication for mechanical thrombectomy to high-risk patients or intermediate-high risk patients with poor hemodynamic evolution. Our purpose is to determine the safety and efficacy of aspiration thrombectomy in intermediate-high risk patients with PE and to analyze possible differences in these results between hemodynamically unstable patients (massive PE) and hemodynamically stable patients (submassive PE).Methods:We analyzed all patients who underwent aspiration thrombectomy for PE at our tertiary university hospital during a 34-month period. We compared echocardiographic parameters (right ventricular diameter, tricuspid plane annular plane systolic excursion (TAPSE), S′ wave, and pulmonary hypertension), respiratory parameters (PaO2/FiO2 ratio), and clinical parameters recorded before and 24h after the procedure. We also analyzed bleeding complications and mortality.Results:In the 42 patients included (16 with massive PE and 26 with submassive PE), aspiration thrombectomy resulted in significant improvements in right ventricular diameter, TAPSE, S′ wave, andPaO2/FiO2 ratio. Of the 8 patients administered fibrinolysis, 4 developed bleeding complications. Only one direct complication of the procedure was observed (pulmonary artery rupture). Eight patients died in the acute phase.Conclusions:Aspiration thrombectomy for PE is safe and effective, significantly improving respiratory and hemodynamic parameters in the first 24h after the procedure with a low rate of complications compared to fibrinolysis. (AU)