The Impact of the Drying Process on the Antioxidant and Anti-Inflammatory Potential of Dried Ripe Coffee Cherry Pulp Soluble Powder.

Coffee fruit cascara, which is the skin and pulp of the coffee cherry, has been authorized as a novel food for commercialization in the European Union. The present research assessed the feasibility of using spray drying to produce a soluble powder called instant cascara (IC), employing sun-dried ripe coffee cherry pulp as a raw material. Although there were no significant differences (p > 0.05) in the overall antioxidant capacity between the freeze-dried and spray-dried samples, after an in vitro simulation of the digestion process, the spray-dried sample was significantly (p < 0.05) more antioxidant. Both samples reduced physiological intracellular ROS and significantly decreased (p < 0.05) the secretion of the pro-inflammatory factor NO. Alkaloids and phenolic compounds were detected in intestinal digests. In conclusion, spray drying is a good technique for producing IC as its use does not affect its properties and causes less environmental impact than freeze drying, as calculated by life cycle assessment. Sensory analysis did not show significant differences between the commercial beverage and the IC beverage in the adult population. IC at 10 mg/mL was significantly less accepted in adolescents than the commercial beverage. Future work will include the reformulation of the IC beverage at 10 mg/mL, which has antioxidant and anti-inflammatory potential, to increase its hedonic acceptance in all consumer segments.

Prognostic Significance of Heart Failure in Acute Pulmonary Embolism: A Comprehensive Assessment of 30-Day Outcomes.

INTRODUCTION: Patients with heart failure (HF) are known to have an increased risk of pulmonary embolism (PE), but there is limited evidence regarding the prognostic implications of HF in patients with acute PE and the relationship between PE prognosis and left ventricular ejection fraction (LVEF). The primary objective of this study was the development of a composite outcome (mortality, major bleeding, and recurrence) within the first 30 days. The secondary objective was to identify the role of LVEF in predicting the development of early complications in patients with both HF and reduced LVEF. MATERIAL AND METHODS: A prospective study was conducted at two tertiary hospitals between January 2012 and December 2022 to assess differences among patients diagnosed with acute PE based on the presence or absence of a history of HF. Cox regression models were employed to assess the impact of HF and reduced LVEF on the composite outcome at 30 days. RESULTS: Out of 1991 patients with acute symptomatic PE, 7.13% had a history of HF. Patients with HF were older and had more comorbidities. The HF group exhibited higher mortality (11.27% vs. 4.33%, p < 0.001) and a higher incidence of major bleeding (9.86% vs. 4.54%, p = 0.005). In the multivariate analysis, HF was an independent risk factor for the development of the composite outcome (HR 1.93; 95% CI 1.35-2.76). Reduced LVEF was independently associated with a higher risk of major bleeding (HR 3.44; 95% CI 1.34-8.81). CONCLUSION: In patients with acute pulmonary embolism, heart failure is independently associated with a higher risk of early complications. Additionally, heart failure with reduced LVEF is an independent risk factor for major bleeding.

Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to leukemia inhibitory factor.

STAT3 is a pleiotropic transcription factor overactivated in 70% of solid tumours. We have recently reported that inactivating mutations on residues susceptible to post-translational modifications (PTMs) in only one of the monomers (i.e. asymmetric) caused changes in the cellular distribution of STAT3 homodimers. Here, we used more controlled experimental conditions, i.e. without the interference of endogenous STAT3 (STAT3-/- HeLa cells) and in the presence of a defined cytokine stimulus (Leukemia Inhibitory Factor, LIF), to provide further evidence that asymmetric PTMs affect the nuclear translocation of STAT3 homodimers. Time-lapse microscopy for 20 min after LIF stimulation showed that S727 dephosphorylation (S727A) and K685 inactivation (K685R) slightly enhanced the nuclear translocation of STAT3 homodimers, while K49 inactivation (K49R) delayed STAT3 nuclear translocation. Our findings suggest that asymmetrically modified STAT3 homodimers could be a new level of STAT3 regulation and, therefore, a potential target for cancer therapy.

Antitumor Activity and Reductive Stress by Platinum(II) N-Heterocyclic Carbenes based on Guanosine.

Platinum(II) complexes bearing N-heterocyclic carbenes based guanosine and caffeine have been synthesized by unassisted C-H oxidative addition, leading to the corresponding trans-hydride complexes. Platinum guanosine derivatives bearing triflate as counterion or bromide instead of hydride as co-ligand were also synthesized to facilitate correlation between structure and activity. The hydride compounds show high antiproliferative activity against all cell lines (TC-71, MV-4-11, U-937 and A-172). Methyl Guanosine complex 3, bearing a hydride ligand, is up to 30 times more active than compound 4, with a bromide in the same position. Changing the counterion has no significant effect in antiproliferative activity. Increasing bulkiness at N7, with an isopropyl group (compound 6), allows to maintain the antiproliferative activity while decreasing toxicity for non-cancer cells. Compound 6 leads to an increase in endoplasmic reticulum and autophagy markers on TC71 and MV-4-11 cancer cells, induces reductive stress and increases glutathione levels in cancer cells but not in non-cancer cell line HEK-293.

Impact of emergency department management of isolated superficial vein thrombosis of the lower limbs: a secondary analysis of data from the ALTAMIRA study. / Impacto del manejo en urgencias en la evolución de los pacientes con trombosis venosa superficial aislada de miembros inferiores: subanálisis del estudio ALTAMIRA.

OBJECTIVES: To describe the management of superficial vein thrombosis (SVT) of the lower limbs in patients treated in Spanish hospital emergency departments (EDs). To evaluate the impact of ED management of venous thromboembolic complications on outcomes and to determine the characteristics of patients who develop complications. MATERIAL AND METHODS: The retrospective multicenter ALTAMIRA study (Spanish acronym for risk factors, complications, and assessment of Spanish ED management of SVT) used recorded data for consecutive patients with a diagnosis of isolated SVT treated in 18 EDs. We gathered data on symptomatic venous thromboembolic disease (deep vein thrombosis, pulmonary embolism, or the extension or recurrence of SVT), clinically significant bleeding, and 180-day mortality. Cox regression analysis was used to explore variables associated with complications. RESULTS: A total of 703 patients were included. Anticoagulation was prescribed for 84.1% of the patients for a median of 30 days (interquartile range, 15-42 days); 81.3% were treated with low molecular weight heparin. A prophylactic dose was prescribed for 48% and an intermediate therapeutic dose for 52%. Sixty-four patients (9.2%) developed symptomatic thromboembolic disease within 180 days, 12 (1.7%) experienced clinically significant bleeding, and 4 (0.6%) died. Complications developed later in patients receiving anticoagulant therapy than in those not taking an anticoagulant (66 vs 11 days , P=.009), and 76.6% of those developing complications were not on anticoagulant when symptoms appeared. A history of thromboembolic disease was associated with developing complications (adjusted hazard ratio, 2.20; 95% confidence interval, 1.34-3.62). CONCLUSION: ED treatment of SVT varies and is often suboptimal. The incidence of thromboembolic complications after SVT is high. Starting anticoagulation in the ED delays the development of complications. Patients with a history of thromboembolic disease are more at risk of complications.

OBJETIVO: Describir el manejo terapéutico de los pacientes con trombosis venosa superficial (TVS) aislada de miembros inferiores en servicios de urgencias hospitalarios (SUH) españoles. Evaluar el impacto del tratamiento instaurado en urgencias en la evolución, en términos de complicaciones de enfermedad tromboembólica venosa (ETV), y conocer las características de los pacientes que sufren complicaciones. METODO: El estudio multicentrico (18 SUH) ALTAMIRA (fActores de riesgo, compLicaciones y evaluación del manejo de la TVS de Miembros Inferiores en hospitales españoles atendidos en los seRvicios de urgenciAs) creó un cohorte retrospectivo de pacientes consecutivos con diagnóstico objetivo de TVS aislada. Se recogieron las complicaciones de ETV sintomáticas (trombosis venosa profunda, tromboembolia pulmonar y extensión o recurrencia de TVS), sangrados clínicamente relevantes y defunciones a 180 días. Se evaluaron las variables asociadas a las complicaciones mediante una regresión de Cox. RESULTADOS: Se incluyeron 703 pacientes. El 84,1% recibieron anticoagulación durante 30 días (rango intercuartil 15-42), 81,3% con heparina de bajo peso molecular (48% dosis profilácticas, 52% intermedias-terapéuticas). En 180 días, 64 pacientes (9,1%) tuvieron complicación de ETV, 12 (1,7%) tuvieron sangrado clínicamente relevante, y 4 fallecieron (0,6%). Los pacientes en que se instauró anticoagulación en urgencias tardaron más tiempo en desarrollar complicaciones (66 vs 11 días, p = 0,009). El 76,6% de los que se complicaron no estaban anticoagulados en ese momento. La ETV previa se asoció de forma independiente con el desarrollo de complicaciones (hazard ratio ajustada 2,20; intervalo de confianza del 95%: 1,34-3,62). CONCLUSIONES: El tratamiento en urgencias de la TVS aislada es heterogéneo y con frecuencia subóptimo. La incidencia de complicaciones de ETV es elevada. El tratamiento anticoagulante iniciado en urgencias supone un retraso en el desarrollo de complicaciones. Los pacientes con ETV previa tienen más riesgo de complicaciones.

Impacto del manejo en urgencias en la evolución de los pacientes con trombosis venosa superficial aislada de miembros inferiores: subanálisis del estudio ALTAMIRA / Impact of emergency department management of isolated superficial vein thrombosis of the lower limbs: a secondary analysis of data from the ALTAMIRA study

Objetivos: Describir el manejo terapéutico de los pacientes con trombosis venosa superficial (TVS) aislada de miembros inferiores en servicios de urgencias hospitalarios (SUH) españoles. Evaluar el impacto del tratamiento instaurado en urgencias en la evolución, en términos de complicaciones de enfermedad tromboembólica venosa (ETV), y conocer las características de los pacientes que sufren complicaciones. Métodos: Estudio de cohorte retrospectivo, multicéntrico (18 SUH), que incluyó pacientes consecutivos con diagnóstico objetivo de TVS aislada. Se recogieron las complicaciones de ETV sintomáticas (trombosis venosa profunda, tromboembolia pulmonar y extensión o recurrencia de TVS), sangrados clínicamente relevantes y defunciones a 180 días. Se evaluaron las variables asociadas a las complicaciones mediante una regresión de Cox. Resultados: Se incluyeron 703 pacientes. El 84,1% recibieron anticoagulación durante 30 días (rango intercuartil 15-42), 81,3% con heparina de bajo peso molecular (48% dosis profilácticas, 52% intermedias-terapéuticas). En 180 días, 64 pacientes (9,1 %) tuvieron complicación de ETV, 12 (1,7%) tuvieron sangrado clínicamente relevante, y 4 fallecieron (0,6 %). Los pacientes en que se instauró anticoagulación en urgencias tardaron más tiempo en desarrollar complicaciones (66 vs 11 días, p = 0,009). El 76,6% de los que se complicaron no estaban anticoagulados en ese momento. La ETV previa se asoció de forma independiente con el desarrollo de complicaciones (hazard ratio ajustada 2,20; intervalo de confianza del 95%: 1,34-3,62). (AU)

Objectives: To describe the management of superficial vein thrombosis (SVT) of the lower limbs in patients treated in Spanish hospital emergency departments (EDs). To evaluate the impact of ED management of venous thromboembolic complications on outcomes and to determine the characteristics of patients who develop complications.Methods: The retrospective multicenter ALTAMIRA study (Spanish acronym for risk factors, complications, and assessment of Spanish ED management of SVT) used recorded data for consecutive patients with a diagnosis of isolated SVT treated in 18 EDs. We gathered data on symptomatic venous thromboembolic disease (deep vein thrombosis, pulmonary embolism, or the extension or recurrence of SVT), clinically significant bleeding, and 180-day mortality. Cox regression analysis was used to explore variables associated with complications. Results: A total of 703 patients were included. Anticoagulation was prescribed for 84.1% of the patients for a median of 30 days (interquartile range, 15-42 days); 81.3% were treated with low molecular weight heparin. A prophylactic dose was prescribed for 48% and an intermediate therapeutic dose for 52%. Sixty-four patients (9.2%) developed symptomatic thromboembolic disease within 180 days, 12 (1.7%) experienced clinically significant bleeding, and 4 (0.6%) died. Complications developed later in patients receiving anticoagulant therapy than in those not taking an anticoagulant (66 vs 11 days , P=.009), and 76.6% of those developing complications were not on anticoagulant when symptoms appeared. A history of thromboembolic disease was associated with developing complications (adjusted hazard ratio, 2.20; 95% confidence interval, 1.34-3.62). (AU)

Differential Apoptotic Effects of Bee Product Mixtures on Normal and Cancer Hepatic Cells.

Most effective anticancer drugs normally generate considerable cytotoxicity in normal cells; therefore, the preferential activation of apoptosis in cancer cells and the reduction of toxicity in normal cells is a great challenge in cancer research. Natural products with selective anticancer properties used as complementary medicine can help to achieve this goal. The aim of the present study was to analyze the effect of the addition of bee products [propolis (PR) or royal jelly (RJ) or propolis and royal jelly (PR+RJ), 2-10%] to thyme (TH) and chestnut honeys (CH) on the differential anticancer properties, mainly the cytotoxic and pro-apoptotic effects, in normal and cancer hepatic cells. The cytotoxic effects of samples were analyzed using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (0-250 mg/mL) and the effects on apoptosis were analyzed using cell cycle analysis, TdT-dUTP terminal nick-end labeling (TUNEL) assay, DR5 (Death Receptor 5) and BAX (BCL-2-Associated X) activation, and caspases 8, 9, and 3 activities. Both honey samples alone and honey mixtures had no or very little apoptotic effect on normal cells. Antioxidant honey mixtures enhanced the apoptotic capacity of the corresponding honey alone via both extrinsic and intrinsic pathways. Of all the samples, chestnut honey enriched with 10% royal jelly and 10% propolis (sample 14, CH+10RJ+10PR) showed the highest apoptotic effect on tumor liver cells. The enrichment of monofloral honey with bee products could be used together with conventional anticancer treatments as a dietary supplement without side effects. On the other hand, it could be included in the diet as a natural sweetener with high added value.

Safety and efficacy of intra-arterial bone marrow mononuclear cell transplantation in patients with acute ischaemic stroke in Spain (IBIS trial): a phase 2, randomised, open-label, standard-of-care controlled, multicentre trial.

BACKGROUND: Pilot clinical trials have shown the safety of intra-arterial bone marrow mononuclear cells (BMMNCs) in stroke. However, the efficacy of different doses of intra-arterial BMMNCs in patients with acute stroke has not been tested in a randomised clinical trial. We aimed to show safety and efficacy of two different doses of autologous intra-arterial BMMNC transplantation in patients with acute stroke. METHODS: The IBIS trial was a multicentre phase 2, randomised, controlled, investigator-initiated, assessor-blinded, clinical trial, in four stroke centres in Spain. We included patients (aged 18-80 years) with a non-lacunar, middle cerebral artery ischaemic stroke within 1-7 days from stroke onset and with a National Institutes of Health Stroke Scale score of 6-20. We randomly assigned patients (2:1:1) with a computer-generated randomisation sequence to standard of care (control group) or intra-arterial injection of autologous BMMNCs at one of two different doses (2 × 106 BMMNCs/kg or 5 × 106 BMMNCs/kg). The primary efficacy outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days in the intention-to-treat population, comparing each BMMNC dose group and the pooled BMMNC group versus the control group. The primary safety endpoint was the proportion of serious adverse events. This trial was registered at ClinicalTrials.gov, NCT02178657 and is completed. FINDINGS: Between April 1, 2015, and May 20, 2021, we assessed 114 patients for eligibility. We randomly assigned 77 (68%) patients: 38 (49%) to the control group, 20 (26%) to the low-dose BMMNC group, and 19 (25%) the high-dose BMMNC group. The mean age of participants was 62·4 years (SD 12·7), 46 (60%) were men, 31 (40%) were women, all were White, and 63 (82%) received thrombectomy. The median NIHSS score before randomisation was 12 (IQR 9-15), with intra-arterial BMMNC injection done a median of 6 days (4-7) after stroke onset. The primary efficacy outcome occurred in 14 (39%) patients in the control group versus ten (50%) in the low-dose group (adjusted odds ratio 2·08 [95% CI 0·55-7·85]; p=0·28), eight (44%) in the high-dose group (1·89 [0·52-6·96]; p=0·33), and 18 (47%) in the pooled BMMNC group (2·22 [0·72-6·85]; p=0·16). We found no differences in the proportion of patients who had adverse events or dose-related events, but two patients had a groin haematoma after cell injection in the low-dose BMMNC group. INTERPRETATION: Intra-arterial BMMNCs were safe in patients with acute ischaemic stroke, but we found no significant improvement at 180 days on the mRS. Further clinical trials are warranted to investigate whether improvements might be possible at different timepoints. FUNDING: Instituto de Salud Carlos III co-funded by the European Regional Development Fund/European Social Fund, Mutua Madrileña, and the Regional Ministry of Health of Andalusia.

Protective Effect of Thyme and Chestnut Honeys Enriched with Bee Products against Benzo(a)pyrene-Induced DNA Damage.

The aim of the present study was to validate the cytotoxicity, genotoxicity, and preventive potential against benzo(a)pyrene (BaP)-induced DNA damage of nine samples of thyme and chestnut honeys enriched with bee products (royal jelly and propolis, 2-10%). Cell viability was determined by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay (0-250 mg/mL) to select nontoxic concentrations, and DNA damage (0.1-10 µg/mL) was evaluated by the alkaline single-cell gel electrophoresis or comet assay. Treatment with honey samples or royal jelly and propolis did not affect the viability of HepG2 cells up to 100 and 50 mg/mL, respectively. Treatment with 100 µM BaP significantly increased (p ≤ 0.001) the levels of the DNA strand breaks. None of the tested concentrations (0.1-10 µg/mL) of the honey samples (thyme and chestnut), royal jelly, and propolis caused DNA damage per se. All tested samples at all the concentrations used decreased the genotoxic effect of BaP. In addition, all mixtures of thyme or chestnut honeys with royal jelly or propolis showed a greater protective effect against BaP than the samples alone, being the thyme and chestnut honey samples enriched with 10% royal jelly and 10% propolis the most effective (70.4% and 69.4%, respectively). The observed protective effect may be associated with the phenolic content and antioxidant capacity of the studied samples. In conclusion, the thyme and chestnut honey samples enriched with bee products present potential as natural chemoprotective agents against the chemical carcinogen BaP.

Reducing Unnecessary Treatment of Bronchiolitis Across a Large Regional Health Service in Spain.

OBJECTIVES: A bronchiolitis integrated care pathway (BICP) proved useful in reducing the use of unnecessary medications at a local level. The aim of this study was to reduce overtreatment by scaling up the BICP across our regional health service in the 2019 and 2020 bronchiolitis season. METHODS: We conducted a quality improvement (QI) initiative in 115 primary care (PC) centers and 7 hospitals in the Basque Country, Spain, from October 2019 to March 2020. The primary outcome measure was the percentage of children prescribed salbutamol comparing the rate to that in the previous bronchiolitis season (October 2018-March 2019). Secondary outcomes were the use of other medications. Balancing measures were hospitalization and unscheduled return rates. RESULTS: We included 8153 PC visits, 3424 emergency department (ED) attendances, and 663 inpatient care episodes, of which 3817 (46.8%), 1614 (47.1%), and 328 (49.4%) occurred in the postintervention period, respectively. Salbutamol use decreased from 27.1% to 4.7%, 29.5% to 3.0%, and 44.4% to 3.9% (P < .001) in PC centers, Eds, and hospital wards, respectively. In PC, corticosteroid and antibiotic prescribing rates fell from 10.1% to 1.7% and 13.7% to 5.1%, respectively (P < .001). In EDs and hospital wards, epinephrine use rates fell from 14.2% to 4.2% (P < .001) and 30.4% to 19.8% (P = .001), respectively. No variations were noted in balancing measures. CONCLUSIONS: The scaling up of the BICP was associated with significant decreases in the use of medications in managing bronchiolitis across a regional health service without unintended consequences.

Enhancement of the Antioxidant Capacity of Thyme and Chestnut Honey by Addition of Bee Products.

Honey consumption and imports have increased in recent years, and it is considered by consumers to be a healthy alternative to more commonly used sweeteners. Honey contains a mixture of polyphenols and antioxidant compounds, and the botanical origin and geographical area of collection play an important role on its chemical composition. The present study investigated the physicochemical properties, total phenolic content and antioxidant capacity of Spanish thyme honey and chestnut honey, and their mixtures with royal jelly (2% and 10%) and propolis (2% and 10%). The analysis of the physicochemical parameters of both honey samples showed values within the established limits. Propolis showed the highest value of total phenolic content (17.21-266.83 mg GAE/100 g) and antioxidant capacity (DPPH, ORAC and ABTS assays; 0.63-24.10 µg eq. Tx/g, 1.61-40.82 µg eq. Tx/g and 1.89-68.54 µg eq. Tx/g, respectively), and significantly reduced ROS production in human hepatoma cells. In addition, mixtures of honey with 10% of propolis improved the results obtained with natural honey, increasing the value of total phenolic content and antioxidant capacity. A significant positive correlation was observed between total phenolic compounds and antioxidant capacity. Therefore, the antioxidant capacity could be attributed to the phenolic compounds present in the samples, at least partially. In conclusion, our results indicated that thyme and chestnut honey supplemented with propolis can be an excellent natural source of antioxidants and could be incorporated as a potential food ingredient with biological properties of technological interest, added as a preservative. Moreover, these mixtures could be used as natural sweeteners enriched in antioxidants and other bioactive compounds.

A proof of concept infant-microbiota associated rat model for studying the role of gut microbiota and alleviation potential of Cutibacterium avidum in infant colic.

Establishing the relationship between gut microbiota and host health has become a main target of research in the last decade. Human gut microbiota-associated animal models represent one alternative to human research, allowing for intervention studies to investigate causality. Recent cohort and in vitro studies proposed an altered gut microbiota and lactate metabolism with excessive H2 production as the main causes of infant colic. To evaluate H2 production by infant gut microbiota and to test modulation of gut colonizer lactose- and lactate-utilizer non-H2-producer, Cutibacterium avidum P279, we established and validated a gnotobiotic model using young germ-free rats inoculated with fecal slurries from infants younger than 3 months. Here, we show that infant microbiota-associated (IMA) rats inoculated with fresh feces from healthy (n = 2) and colic infants (n = 2) and fed infant formula acquired and maintained similar quantitative and qualitative fecal microbiota composition compared to the individual donor's profile. We observed that IMA rats excreted high levels of H2, which were linked to a high abundance of lactate-utilizer H2-producer Veillonella. Supplementation of C. avidum P279 to colic IMA rats reduced H2 levels compared to animals receiving a placebo. Taken together, we report high H2 production by infant gut microbiota, which might be a contributing factor for infant colic, and suggest the potential of C. avidum P279 in reducing the abdominal H2 production, bloating, and pain associated with excessive crying in colic infants.

Noncanonical activation of GLI signaling in SOX2+ cells drives medulloblastoma relapse.

SRY (sex determining region Y)-box 2 (SOX2)-labeled cells play key roles in chemoresistance and tumor relapse; thus, it is critical to elucidate the mechanisms propagating them. Single-cell transcriptomic analyses of the most common malignant pediatric brain tumor, medulloblastoma (MB), revealed the existence of astrocytic Sox2+ cells expressing sonic hedgehog (SHH) signaling biomarkers. Treatment with vismodegib, an SHH inhibitor that acts on Smoothened (Smo), led to increases in astrocyte-like Sox2+ cells. Using SOX2-enriched MB cultures, we observed that SOX2+ cells required SHH signaling to propagate, and unlike in the proliferative tumor bulk, the SHH pathway was activated in these cells downstream of Smo in an MYC-dependent manner. Functionally different GLI inhibitors depleted vismodegib-resistant SOX2+ cells from MB tissues, reduced their ability to further engraft in vivo, and increased symptom-free survival. Our results emphasize the promise of therapies targeting GLI to deplete SOX2+ cells and provide stable tumor remission.

Plasma D-dimer value corrected by inflammatory markers in patients with SARS-CoV-2 infection: Its prognostic value in the diagnosis of venous thromboembolism.

Introduction: D-dimer levels are elevated in COVID 19 and they correlate to the levels of other inflammatory markers such us ferritin, fibrinogen and C-reactive protein. It may be possible to correct D-dimer value in function of inflammatory markers, thus identifying patients at higher risk of venous thromboembolism (VTE). Our objectives are estimating a corrected value of plasma D-dimer as a linear function of ferritin, C-reactive protein and fibrinogen and stablishing a cut-off point of high probability of VTE. Patients and methods: Age and sex matched case-control study of all patients diagnosed with COVID 19 and VTE between March and May 2020 in a tertiary hospital in Madrid (Spain). Using linear regression, the best predictive model will be estimated and residual D-dimer values will be obtained and analyzed using ROC curves to determine its discriminative performance. Results: Thirty-eight cases and seventy-six controls were included. There was 63.2% of men and mean age was 68.2. D-dimer was best predicted by a linear model including fibrinogen, ferritin and C-reactive protein. Using residual values, the optimal cutoff point was 2165 ng/mL, with a sensitivity of 57.9% and specificity of 98.7%. Conclusion: It is possible to estimate a D-dimer corrected value in function of ferritin, C-reactive protein and fibrinogen. Using the observed and estimated value we can obtain a residual value that performs well as a screening method to detect patients who would benefit for further VTE diagnostic testing.

Introducción: El dímero-D está elevado en la COVID-19 y se correlacionan con los niveles de otros marcadores inflamatorios como ferritina, fibrinógeno y proteína C reactiva. Cabe la posibilidad de corregir el dímero-D en función de dichos marcadores inflamatorios, identificando así los pacientes con mayor riesgo de enfermedad tromboembólica venosa (ETV). Nuestros objetivos son estimar un valor corregido de dímero-D como función lineal de ferritina, proteína C reactiva y fibrinógeno, y establecer un punto de corte de alta probabilidad de ETV. Pacientes y métodos: Estudio de casos y controles emparejados por sexo y edad de todos los pacientes diagnosticados con COVID-19 y ETV entre marzo y mayo de 2020 en un hospital terciario de Madrid, España. Mediante regresión lineal, se estima el mejor modelo predictivo y se obtiene el valor residual de dímero-D. Este se analizará con curvas ROC para determinar su capacidad discriminativa. Resultados: Se incluyeron 38 casos y 76 controles. Había un 63,2% de varones y la edad media fue de 68,2 años. El valor de dímero-D fue predicho por un modelo que incluyó fibrinógeno, ferritina y proteína C reactiva. Usando los valores residuales, el punto de corte óptimo estimado de 2.165 ng/ml, con una sensibilidad del 57,9% y una especificidad del 98,7%. Conclusiones: Es posible estimar un valor corregido de dímero-D en función de ferritina, fibrinógeno y proteína C reactiva. Usando el valor observado y estimado podemos obtener un valor residual que funciona bien como método de cribado para detectar pacientes que podrían beneficiarse de más estudios diagnósticos de la ETV.

Calcium acts as a central player in melatonin antitumor activity in sarcoma cells.

PURPOSE: Chondrosarcoma and osteosarcoma are the most frequently occurring bone cancers. Although surgery and chemotherapy are currently clinically applied, improved treatment options are urgently needed. Melatonin is known to inhibit cell proliferation in both tumor types. Although the underlying mechanisms are not clear yet, calcium homeostasis has been reported to be a key factor in cancer biology. Here, we set out to investigate whether regulation of calcium by this indolamine may be involved in its antitumor effect. METHODS: Cell viability was measured using a MTT assay and flow cytometry was used to measure levels of cytosolic calcium, intracellular oxidants, mitochondrial membrane potential and cell cycle progression. Mitochondrial calcium was analyzed by fluorimetry. Cell migration was determined using a scratch wound-healing assay. Western blot analysis was used to assess the expression of proteins related to cell cycle progression, epithelial to mesenchymal transition (EMT), Ac-CoA synthesis and intracellular signaling pathways. RESULTS: We found that melatonin decreases cytosolic and mitochondrial Ca2+ levels, intracellular oxidant levels, mitochondrial function and the expression of the E1 subunit of the pyruvate dehydrogenase complex. These changes were found to be accompanied by decreases in cell proliferation, cell migration and EMT marker expression. The addition of CaCl2 prevented the changes mentioned above, while co-treatment with the calcium chelator BAPTA enhanced the effects. CONCLUSIONS: Our data indicate that regulation of calcium homeostasis is a key factor in the inhibition of cell proliferation and migration by melatonin. This effect should be taken into consideration in combined therapies with traditional or new antitumor compounds, since it may circumvent therapy resistance.

Plasma D-dimer value corrected by inflammatory markers in patients with SARS-CoV-2 infection: Its prognostic value in the diagnosis of venous thromboembolism / Valor del dímero-D corregido por marcadores inflamatorios en pacientes con infección por SARS-CoV-2 en el diagnóstico de enfermedad tromboembólica venosa

Introduction:D-dimer levels are elevated in COVID 19 and they correlate to the levels of other inflammatory markers such us ferritin, fibrinogen and C-reactive protein. It may be possible to correct D-dimer value in function of inflammatory markers, thus identifying patients at higher risk of venous thromboembolism (VTE). Our objectives are estimating a corrected value of plasma D-dimer as a linear function of ferritin, C-reactive protein and fibrinogen and stablishing a cut-off point of high probability of VTE.Patients and methods:Age and sex matched case-control study of all patients diagnosed with COVID 19 and VTE between March and May 2020 in a tertiary hospital in Madrid (Spain). Using linear regression, the best predictive model will be estimated and residual D-dimer values will be obtained and analyzed using ROC curves to determine its discriminative performance.Results:Thirty-eight cases and seventy-six controls were included. There was 63.2% of men and mean age was 68.2. D-dimer was best predicted by a linear model including fibrinogen, ferritin and C-reactive protein. Using residual values, the optimal cutoff point was 2165ng/mL, with a sensitivity of 57.9% and specificity of 98.7%.Conclusion:It is possible to estimate a D-dimer corrected value in function of ferritin, C-reactive protein and fibrinogen. Using the observed and estimated value we can obtain a residual value that performs well as a screening method to detect patients who would benefit for further VTE diagnostic testing.(AU)

Introducción:El dímero-D está elevado en la COVID-19 y se correlacionan con los niveles de otros marcadores inflamatorios como ferritina, fibrinógeno y proteína C reactiva. Cabe la posibilidad de corregir el dímero-D en función de dichos marcadores inflamatorios, identificando así los pacientes con mayor riesgo de enfermedad tromboembólica venosa (ETV). Nuestros objetivos son estimar un valor corregido de dímero-D como función lineal de ferritina, proteína C reactiva y fibrinógeno, y establecer un punto de corte de alta probabilidad de ETV.Pacientes y métodos:Estudio de casos y controles emparejados por sexo y edad de todos los pacientes diagnosticados con COVID-19 y ETV entre marzo y mayo de 2020 en un hospital terciario de Madrid, España. Mediante regresión lineal, se estima el mejor modelo predictivo y se obtiene el valor residual de dímero-D. Este se analizará con curvas ROC para determinar su capacidad discriminativa.Resultados:Se incluyeron 38 casos y 76 controles. Había un 63,2% de varones y la edad media fue de 68,2 años. El valor de dímero-D fue predicho por un modelo que incluyó fibrinógeno, ferritina y proteína C reactiva. Usando los valores residuales, el punto de corte óptimo estimado de 2.165ng/ml, con una sensibilidad del 57,9% y una especificidad del 98,7%.Conclusiones:Es posible estimar un valor corregido de dímero-D en función de ferritina, fibrinógeno y proteína C reactiva. Usando el valor observado y estimado podemos obtener un valor residual que funciona bien como método de cribado para detectar pacientes que podrían beneficiarse de más estudios diagnósticos de la ETV. (AU)

Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6Sacs-/-) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6Sacs-/- cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology.

Plasma D-dimer value corrected by inflammatory markers in patients with SARS-CoV-2 infection: Its prognostic value in the diagnosis of venous thromboembolism.

INTRODUCTION: D-dimer levels are elevated in COVID 19 and they correlate to the levels of other inflammatory markers such us ferritin, fibrinogen and C-reactive protein. It may be possible to correct D-dimer value in function of inflammatory markers, thus identifying patients at higher risk of venous thromboembolism (VTE). Our objectives are estimating a corrected value of plasma D-dimer as a linear function of ferritin, C-reactive protein and fibrinogen and stablishing a cut-off point of high probability of VTE. PATIENTS AND METHODS: Age and sex matched case-control study of all patients diagnosed with COVID 19 and VTE between March and May 2020 in a tertiary hospital in Madrid (Spain). Using linear regression, the best predictive model will be estimated and residual D-dimer values will be obtained and analyzed using ROC curves to determine its discriminative performance. RESULTS: Thirty-eight cases and seventy-six controls were included. There was 63.2% of men and mean age was 68.2. D-dimer was best predicted by a linear model including fibrinogen, ferritin and C-reactive protein. Using residual values, the optimal cutoff point was 2165ng/mL, with a sensitivity of 57.9% and specificity of 98.7%. CONCLUSION: It is possible to estimate a D-dimer corrected value in function of ferritin, C-reactive protein and fibrinogen. Using the observed and estimated value we can obtain a residual value that performs well as a screening method to detect patients who would benefit for further VTE diagnostic testing.

Reducing Unnecessary Treatments for Acute Bronchiolitis Through an Integrated Care Pathway.

OBJECTIVES: To analyze the impact of an integrated care pathway on reducing unnecessary treatments for acute bronchiolitis. METHODS: We implemented an evidence-based integrated care pathway in primary care (PC) centers and the referral emergency department (ED). This is the third quality improvement cycle in the management of acute bronchiolitis implemented by our research team. Family and provider experiences were incorporated by using design thinking methodology. A multifaceted plan that included several quality improvement initiatives was adopted to reduce unnecessary treatments. The primary outcome was the percentage of infants prescribed salbutamol. Secondary outcomes were prescribing rates of other medications. The main control measures were hospitalization and unscheduled return rates. Salbutamol prescribing rate data were plotted on run charts. RESULTS: We included 1768 ED and 1092 PC visits, of which 913 (51.4%) ED visits and 558 (51.1%) PC visits occurred in the postintervention period. Salbutamol use decreased from 7.7% (interquartile range [IQR] 2.8-21.4) to 0% (IQR 0-1.9) in the ED and from 14.1% (IQR 5.8-21.6) to 5% (IQR 2.7-8) in PC centers. In the ED, the overall epinephrine use rate fell from 9% (95% confidence interval [CI], 7.2-11.1) to 4.6% (95% CI, 3.4-6.1) (P < .001). In PC centers, overall corticosteroid and antibiotic prescribing rates fell from 3.5% (95% CI, 2.2-5.4) to 1.1% (95% CI, 0.4-2.3) (P =.007) and from 9.5% (95% CI; 7.3-12.3) to 1.7% (95% CI, 0.9-7.3) (P <.001), respectively. No significant variations were noted in control measures. CONCLUSIONS: An integrated clinical pathway that incorporates the experiences of families and clinicians decreased the use of medications in the management of bronchiolitis.

Part-time cancers and role of melatonin in determining their metabolic phenotype.

This brief review describes the association of the endogenous pineal melatonin rhythm with the metabolic flux of solid tumors, particularly breast cancer. It also summarizes new information on the potential mechanisms by which endogenously-produced or exogenously-administered melatonin impacts the metabolic phenotype of cancer cells. The evidence indicates that solid tumors may redirect their metabolic phenotype from the pathological Warburg-type metabolism during the day to the healthier mitochondrial oxidative phosphorylation on a nightly basis. Thus, they function as cancer cells only during the day and as healthier cells at night, that is, they are only part-time cancerous. This switch to oxidative phosphorylation at night causes cancer cells to exhibit a reduced tumor phenotype and less likely to rapidly proliferate or to become invasive or metastatic. Also discussed is the likelihood that some solid tumors are especially aggressive during the day and much less so at night due to the nocturnal rise in melatonin which determines their metabolic state. We further propose that when melatonin is used/tested in clinical trials, a specific treatment paradigm be used that is consistent with the temporal metabolic changes in tumor metabolism. Finally, it seems likely that the concurrent use of melatonin in combination with conventional chemotherapies also would improve cancer treatment outcomes.