Radiomic-based nonlinear supervised learning classifiers on non-contrast CT to predict functional prognosis in patients with spontaneous intracerebral hematoma.

PURPOSE: To evaluate if nonlinear supervised learning classifiers based on non-contrast CT can predict functional prognosis at discharge in patients with spontaneous intracerebral hematoma. METHODS: Retrospective, single-center, observational analysis of patients with a diagnosis of spontaneous intracerebral hematoma confirmed by non-contrast CT between January 2016 and April 2018. Patients with HIE > 18 years and with TCCSC performed within the first 24 h of symptom onset were included. Patients with secondary spontaneous intracerebral hematoma and in whom radiomic variables were not available were excluded. Clinical, demographic and admission variables were collected. Patients were classified according to the Modified Rankin Scale (mRS) at discharge into good (mRS 0-2) and poor prognosis (mRS 3-6). After manual segmentation of each spontaneous intracerebral hematoma, the radiomics variables were obtained. The sample was divided into a training and testing cohort and a validation cohort (70-30% respectively). Different methods of variable selection and dimensionality reduction were used, and different algorithms were used for model construction. Stratified 10-fold cross-validation were performed on the training and testing cohort and the mean area under the curve (AUC) were calculated. Once the models were trained, the sensitivity of each was calculated to predict functional prognosis at discharge in the validation cohort. RESULTS: 105 patients with spontaneous intracerebral hematoma were analyzed. 105 radiomic variables were evaluated for each patient. P-SVM, KNN-E and RF-10 algorithms, in combination with the ANOVA variable selection method, were the best performing classifiers in the training and testing cohort (AUC 0.798, 0.752 and 0.742 respectively). The predictions of these models, in the validation cohort, had a sensitivity of 0.897 (0.778-1;95%CI), with a false-negative rate of 0% for predicting poor functional prognosis at discharge. CONCLUSION: The use of radiomics-based nonlinear supervised learning classifiers are a promising diagnostic tool for predicting functional outcome at discharge in HIE patients, with a low false negative rate, although larger and balanced samples are still needed to develop and improve their performance.

Clasificadores de aprendizaje supervisado no lineales basados en radiómica de la TC cerebral sin contraste para predecir el pronóstico funcional en pacientes con hematoma intracerebral espontáneo / Radiomic-based nonlinear supervised learning classifiers on non-contrast CT to predict functional prognosis in patients with spontaneous intracerebral hematoma

Objetivo: Evaluar si clasificadores de aprendizaje supervisado no lineales basados en radiómica de la TC cerebral sin contraste (TCCSC) pueden predecir el pronóstico funcional al alta en pacientes con hematoma intracerebral espontáneo (HIE). Material y método: Análisis observacional retrospectivo y unicéntrico de pacientes con diagnóstico de HIE confirmado por TCCSC entre enero de 2016 y abril de 2018. Se incluyeron pacientes con HIE >18años y con TCCSC realizado dentro de las primeras 24horas del inicio de los síntomas. Se excluyeron los HIE secundarios y en los que no se disponía de las variables de radiómica. Se recogieron datos clínicos, demográficos y variables al ingreso. Los pacientes se clasificaron según la Escala Modificada de Rankin (mRS) al alta en buen (mRS0-2) y mal pronóstico (mRS3-6). Tras la segmentación manual de la TCCSC de cada HIE se obtuvieron las variables de radiómica. La muestra se dividió en una cohorte de entrenamiento y prueba y otra cohorte de validación (70-30%, respectivamente). Se usaron diferentes métodos de selección de variables y reducción de dimensionalidad, así como diferentes algoritmos para la construcción del modelo. Se realizaron 10 iteraciones de validación cruzada estratificada en la cohorte de entrenamiento y prueba y se calculó la media de los valores de área bajo la curva (AUC). Una vez entrenados los modelos, se calculó la sensibilidad de cada uno para predecir el pronóstico funcional al alta en la cohorte de validación. Resultados: Se analizaron 105 pacientes con HIE. Se evaluaron 105 variables de radiómica de cada paciente. Los algoritmos P-SVM, KNN-E y RF-10, en combinación con el método de selección de variables ANOVA, fueron los clasificadores con mejor rendimiento en la cohorte de entrenamiento y prueba (AUC: 0,798, 0,752 y 0,742, respectivamente)...(AU)

Purpose: To evaluate if nonlinear supervised learning classifiers based on non-contrast cerebral CT can predict functional prognosis at discharge in patients with spontaneous intracerebral hematoma (HIE). Methods: Retrospective, single-center, observational analysis of patients with a diagnosis of spontaneous intracerebral hematoma confirmed by non-contrast CT between January 2016 and April 2018. Patients with HIE >18years and with non-contrast CT performed within the first 24hours of symptom onset were included. Patients with secondary spontaneous intracerebral hematoma and in whom radiomic variables were not available were excluded. Clinical, demographic and admission variables were collected. Patients were classified according to the Modified Rankin Scale (mRS) at discharge into good (mRS0-2) and poor prognosis (mRS3-6). After manual segmentation of each spontaneous intracerebral hematoma, the radiomics variables were obtained. The sample was divided into a training and testing cohort and a validation cohort (70-30%, respectively). Different methods of variable selection and dimensionality reduction were used, and different algorithms were used for model construction. Stratified 10-fold cross-validation were performed on the training and testing cohort and the mean area under the curve (AUC) were calculated. Once the models were trained, the sensitivity of each was calculated to predict functional prognosis at discharge in the validation cohort. Results: 105 patients with spontaneous intracerebral hematoma were analyzed. 105 radiomic variables were evaluated for each patient. P-SVM, KNN-E and RF-10 algorithms, in combination with the ANOVA variable selection method, were the best performing classifiers in the training and testing cohort (AUC: 0.798, 0.752 and 0.742, respectively)...(AU)

SQ HDM sublingual immunotherapy tablet for the treatment of HDM allergic rhinitis and asthma improves subjective sleepiness and insomnia: an exploratory analysis of the real-life CARIOCA study.

BACKGROUND AND OBJECTIVE: There are still gaps in the knowledge regarding the effectiveness of house dust mite (HDM) sublingual immunotherapy (SLIT) on allergic rhinitis (AR) and asthma (AA)-associated sleep disorders. A non-interventional study was conducted to assess the effect of the Standardized quality (SQ) HDM SLIT-tablet on safety and symptoms in adults with HDM respiratory allergies. The aim was to describe the status of insomnia and daytime sleepiness in AR and/or AA patients treated with the SQ HDM SLIT-tablet. METHODS: This was a 12-month multicenter, longitudinal and prospective study. Participants started the SQ HDM SLIT-tablet for moderate-to-severe HDM AR, persistent despite the use of symptom-relieving medication; or HDM AA not well controlled by inhaled corticosteroids and associated with mild-to-severe HDM AR. Sleep symptoms were measured using the Insomnia Severity Index (ISI) questionnaire and the Epworth Sleepiness Scale (ESS). RESULTS: A total of 1,526 adult patients were enrolled and 1,483 were included in the analysis. At baseline, 41.5% of patients reported sleep disorders: 77.0% of them had insomnia and 28.9% suffered from excessive daytime sleepiness. Insomnia was significantly more frequent among patients with uncontrolled AR (83.1%) than those with controlled AR (52.6%) (p<0.0001). Over time, 48.3% and 59.7% of patients reported an improvement greater than the minimal clinically important difference on the ISI and ESS scales respectively. CONCLUSION: In patients with HDM AR and/or asthma associated sleep disorders, an improvement in subjective insomnia and sleepiness was observed after one year of treatment with the SQ HDM SLIT-tablet in a real-life setting.

Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination.

Since the emergence of SARS-CoV-2, vaccines targeting COVID-19 have been developed with unprecedented speed and efficiency. CoronaVac, utilising an inactivated form of the COVID-19 virus and the mRNA26 based Pfizer/BNT162b2 vaccines are widely distributed. Beyond the ability of vaccines to induce production of neutralizing antibodies, they might lead to the generation of antibodies attenuating the disease by recruiting cytotoxic and opsonophagocytic functions. However, the Fc-effector functions of vaccine induced antibodies are much less studied than virus neutralization. Here, using systems serology, we follow the longitudinal Fc-effector profiles induced by CoronaVac and BNT162b2 up until five months following the two-dose vaccine regimen. Compared to BNT162b2, CoronaVac responses wane more slowly, albeit the levels remain lower than that of BNT162b2 recipients throughout the entire observation period. However, mRNA vaccine boosting of CoronaVac responses, including response to the Omicron variant, induce significantly higher peak of antibody functional responses with increased humoral breadth. In summary, we show that vaccine platform-induced humoral responses are not limited to virus neutralization but rather utilise antibody dependent effector functions. We demonstrate that this functionality wanes with different kinetics and can be rescued and expanded via boosting with subsequent homologous and heterologous vaccination.

Difficult withdrawal of an inferior vena cava filter: Technical considerations and associated variables.

OBJECTIVE: To analyse the efficacy of the procedure for withdrawing an inferior vena cava (IVC) filter and the clinical and radiological factors associated with difficult withdrawal. MATERIAL AND METHODS: This retrospective observational study included patients who underwent IVC filter withdrawal at a single centre between May 2015 and May 2021. We recorded demographic, clinical, procedural, and radiological variables: type of IVC filter, angle with the IVC > 15°, hook against the wall, and legs embedded in the IVC wall > 3 mm. The efficacy variables were fluoroscopy time, success of IVC filter withdrawal, and number of attempts to withdraw the filter. The safety variables were complications, surgical removal, and mortality. The main variable was difficult withdrawal, defined as more than 5 min fluoroscopy or more than 1 attempt at withdrawal. RESULTS: A total of 109 patients were included; withdrawal was considered difficult in 54 (49.5%). Three radiological variables were more common in the difficult withdrawal group: hook against the wall (33.3% vs. 9.1%; p = 0.027), embedded legs (20.4% vs. 3.6%; p = 0.008), and >45 days since IVC filter placement (51.9% vs. 25.5%; p = 0.006). These variables remained significant in the subgroup of patients with OptEase IVC filters; however, in the group of patients with Celect IVC filters, only the inclination of the IVC filter >15 ° was significantly associated with difficult withdrawal (25% vs 0%; p = 0.029). CONCLUSION: Difficult withdrawal was associated with time from IVC placement, embedded legs, and contact between the hook and the wall. The analysis of the subgroups of patients with different types of IVC filters found that these variables remained significant in those with OptEase filters; however, in those with cone-shaped devices (Celect), the inclination of the IVC filter >15° was significantly associated with difficult withdrawal.

Retirada difícil de filtro de vena cava inferior (FVCI). Consideraciones técnicas y variables asociadas / Difficult withdrawal of an inferior vena cava filter: technical considerations and associated variables

Objetivo: Analizar la eficacia del procedimiento de retirada de los filtros de la vena cava inferior (FVCI), así como los factores clínico-radiológicos asociados a una retirada difícil. Material y método: Estudio retrospectivo, observacional y unicéntrico de pacientes tratados mediante retirada de FVCI entre mayo del 2015 y mayo del 2021. Se recogieron variables clínico-demográficas, del procedimiento y radiológicas: tipo de FVCI, angulación respecto a la vena cava inferior (VCI) >15°, gancho contra la pared y patas del dispositivo incrustadas en la pared de VCI> 3mm. Las variables de eficacia fueron: tiempo de fluoroscopia, éxito en la retirada del FVCI y número de intentos hasta la retirada. Como variables de seguridad: presencia de complicaciones, retirada quirúrgica y mortalidad. La variable principal fue la retirada difícil, definida como más de 5min de fluoroscopia o más de un intento de retirada. Resultados: Se incluyó a 109 pacientes, 54 (49,5%) fueron considerados retirada difícil. Las variables radiológicas gancho contra la pared (33,3% vs. 9,1%; p=0,027), patas incrustadas (20,4% vs. 3,6%; p=0,008) y> 45 días desde la colocación (51,9% vs. 25,5%; p=0,006) fueron significativamente más frecuentes en el grupo de retirada difícil. Estas variables mantienen la asociación al analizar los FVCI Optease®. En los FVCI Celect® solo se asoció con retirada difícil la inclinación del FVCI> 15° (25% vs. 0%; p=0,029).Conclusión: Se ha encontrado asociación entre una retirada difícil y las siguientes variables: tiempo desde colocación del FVCI, patas incrustadas y contacto del gancho con la pared de VCI. Al analizar según el tipo de FVCI, estas variables se mantienen en el tipo Optease®, en cambio, la inclinación de más de 15° dificulta la retirada de los dispositivos de morfología cónica (Celect®).(AU)

Objective: To analyze the efficacy of the procedure for withdrawing an inferior vena cava (IVC) filter and the clinical and radiological factors associated with difficult withdrawal. Material and methods: This retrospective observational study included patients who underwent IVC filter withdrawal at a single center between May 2015 and May 2021. We recorded demographic, clinical, procedural, and radiological variables: type of IVC filter, angle with the IVC> 15°, hook against the wall, and legs embedded in the IVC wall> 3mm. The efficacy variables were fluoroscopy time, success of IVC filter withdrawal, and number of attempts to withdraw the filter. The safety variables were complications, surgical removal, and mortality. The main variable was difficult withdrawal, defined as more than 5minutes fluoroscopy or more than 1 attempt at withdrawal. Results: A total of 109 patients were included; withdrawal was considered difficult in 54 (49.5%). Three radiological variables were more common in the difficult withdrawal group: hook against the wall (33.3% vs. 9.1%; p=0.027), embedded legs (20.4% vs. 3.6%; p=0.008), and>45 days since IVC filter placement (51.9% vs. 25.5%; p=0.006). These variables remained significant in the subgroup of patients with OptEase IVC filters; however, in the group of patients with Celect IVC filters, only the inclination of the IVC filter>15° was significantly associated with difficult withdrawal (25% vs 0%; p=0.029). Conclusion: Difficult withdrawal was associated with time from IVC placement, embedded legs, and contact between the hook and the wall. The analysis of the subgroups of patients with different types of IVC filters found that these variables remained significant in those with OptEase filters; however, in those with cone-shaped devices (Celect), the inclination of the IVC filter>15° was significantly associated with difficult withdrawal.(AU)

[Impact of the "daily huddle" on the safety of pediatric hospitalized patients]. / Impacto de los «daily huddle¼ en la seguridad del paciente pediátrico hospitalizado.

INTRODUCTION: In 2017, the Joint Commission proposed daily meetings called "huddle" as an indicator of quality of care. They are brief daily meetings of the multidisciplinary team, where security problems of the last 24h are shared and risks are anticipated. The objectives were to describe the most frequent safety events in Pediatric wards, implement improvements in patient safety, improve team communication, implement international safety protocols, and measure the satisfaction of the staff involved. MATERIAL AND METHODS: Prospective, longitudinal and analytical design (June 2020-February 2022), with previous educational intervention. Safety incidents, data related to unequivocal identification, allergy and pain records, data from the Scale for the Early Detection of Deficiencies (SAPI) and the Scale for the Secure Transmission of Information (SBAR) were collected. The degree of satisfaction of the professionals was evaluated. RESULTS: Three hundred forty-eight security incidents were recorded. Medication prescription or administration errors stood out (n=103). Drug prescription or administration errors stood out (n=103), especially those related to high-risk medication: acetaminophen (n=14) (×10 doses of acetaminophen; n=6), insulin (n=6), potassium (n=5) and morphic (n=5). An improvement was observed in the pain record; 5% versus 80% (P<.01), in the SAPI registry 5% versus 70% (P<.01), in SBAER scale 40% vs 100% (P<.01), in unequivocal identification of the patient 80% versus 100%; (P<.01) and in the application of analgesic techniques 60% versus 85% (P=.01). In the survey of professionals, a degree of satisfaction of 8 (7-9.5)/10 was obtained. CONCLUSIONS: Huddles made it possible to learn about security events in our environment and increase the safety of hospitalized patients, and improved communication and the relationship of the multidisciplinary team.

Beneficial effect of TLR4 blockade by a specific aptamer antagonist after acute myocardial infarction.

Experimental evidence indicates that the control of the inflammatory response after myocardial infarction is a key strategy to reduce cardiac injury. Cellular damage after blood flow restoration in the heart promotes sterile inflammation through the release of molecules that activate pattern recognition receptors, among which TLR4 is the most prominent. Transient regulation of TLR4 activity has been considered one of the potential therapeutic interventions with greater projection towards the clinic. In this regard, the characterization of an aptamer (4FT) that acts as a selective antagonist for human TLR4 has been investigated in isolated macrophages from different species and in a rat model of cardiac ischemia/reperfusion (I/R). The binding kinetics and biological responses of murine and human macrophages treated with 4FT show great affinity and significant inhibition of TLR4 signaling including the NF-κB pathway and the LPS-dependent increase in the plasma membrane currents (Kv currents). In the rat model of I/R, administration of 4FT following reoxygenation shows amelioration of cardiac injury function and markers, a process that is significantly enhanced when the second dose of 4FT is administered 24 h after reperfusion of the heart. Parameters such as cardiac injury biomarkers, infiltration of circulating inflammatory cells, and the expression of genes associated with the inflammatory onset are significantly reduced. In addition, the expression of anti-inflammatory genes, such as IL-10, and pro-resolution molecules, such as resolvin D1 are enhanced after 4FT administration. These results indicate that targeting TLR4 with 4FT offers new therapeutic opportunities to prevent cardiac dysfunction after infarction.

Técnicas de radiología intervencionista para el manejo del sangrado uterino anormal (SUA) / Interventional radiology techniques for the management of abnormal uterine bleeding (AUB)

El sangrado uterino anormal (SUA) es una de las patologías ginecológicas más comunes en mujeres en edad reproductiva. El sistema de clasificación de la Federación Internacional de Ginecología y Obstetricia (PALM-COEIN) armoniza las definiciones de los síntomas de hemorragia normal y anormal y clasifica las posibles causas subyacentes en causas estructurales y no estructurales. El objetivo de este manuscrito es revisar el diagnóstico radiológico de cada una de las causas estructurales de sangrado uterino anormal, examinar las indicaciones de las técnicas de radiología vascular intervencionista en el manejo del SUA y conocer el procedimiento de embolización de arterias uterinas, así como sus posibles complicaciones y contraindicaciones.(AU)

Abnormal uterine bleeding is one of the most common gynaecological pathologies in women of reproductive age. The classification system of the International Federation of Gynaecology and Obstetrics (PALM-COEIN) harmonizes the definitions of normal and abnormal bleeding symptoms and classifies possible underlying causes as structural and non-structural. The aim of this manuscript is to review the radiological diagnosis of each of the structural causes of abnormal uterine bleeding, to examine the indications for interventional vascular radiology techniques in the treatment of abnormal uterine bleeding, and to learn about the uterine artery embolization procedure, as well as its possible complications and contraindications.(AU)

Waning and boosting of functional humoral immunity to SARS-CoV-2.

Since the emergence of the SARS-CoV-2 virus, we have witnessed a revolution in vaccine development with the rapid emergence and deployment of both traditional and novel vaccine platforms. The inactivated CoronaVac vaccine and the mRNA-based Pfizer/BNT162b2 vaccine are among the most widely distributed vaccines, both demonstrating high, albeit variable, vaccine effectiveness against severe COVID-19 over time. Beyond the ability of the vaccines to generate neutralizing antibodies, antibodies can attenuate disease via their ability to recruit the cytotoxic and opsinophagocytic functions of the immune response. However, whether Fc-effector functions are induced differentially, wane with different kinetics, and are boostable, remains unknown. Here, using systems serology, we profiled the Fc-effector profiles induced by the CoronaVac and BNT162b2 vaccines, over time. Despite the significantly higher antibody functional responses induced by the BNT162b2 vaccine, CoronaVac responses waned more slowly, albeit still found at levels below those present in the systemic circulation of BNT162b2 immunized individuals. However, mRNA boosting of the CoronaVac vaccine responses resulted in the induction of significantly higher peak antibody functional responses with increased humoral breadth, including to Omicron. Collectively, the data presented here point to striking differences in vaccine platform-induced functional humoral immune responses, that wane with different kinetics, and can be functionally rescued and expanded with boosting.

Malos resultados y complicaciones en el uso de ondas de choque focales y ondas de presión radial en patología musculoesquelética / Poor results and complications in the use of focused shockwaves and radial pressure waves in musculoskeletal pathology

La aplicación de ondas de choque focales y de ondas de presión radial en patología musculoesquelética ha tenido un gran desarrollo y difusión en la última década. Si bien la mayoría de las publicaciones han resaltado su seguridad y eficacia, no están exentas de malos resultados y complicaciones. Esta revisión analiza las principales causas de los malos resultados, efectos adversos y complicaciones, haciendo énfasis en su prevención.(AU)

The application of focused shockwaves and radial pressure waves in musculoskeletal pathology has had a great development in the last decade. Although most of the publications have highlighted their safety and efficacy, poor results and complications can occur. This review analyzes the main causes of its poor results, adverse effects, and complications, emphasizing their prevention.(AU)

Suicide-related thoughts and behavior and suicide death trends during the COVID-19 in the general population of Catalonia, Spain.

The COVID-19 pandemic is expected to increase suicidal behavior. However, data available to date are inconsistent. This study examines suicidal thoughts and behaviors and suicide trends in 2020 relative to 2019 as an approximation to the impact of the pandemic on suicidal behavior and death in the general population of Catalonia, Spain. Data on suicide-related thoughts and behaviors (STBs) and suicidal mortality were obtained from the Catalonia Suicide Risk Code (CSRC) register and the regional police, respectively. We compared the monthly crude incidence of STBs and suicide mortality rates of 2020 with those of 2019. Joinpoint regression analysis was used to assess changes in trends over time during the studied period. In 2020, 4,263 consultations for STBs and 555 suicide deaths were registered in Catalonia (approx. 7.5 million inhabitants). Compared to 2019, in 2020 STBs rates decreased an average of 6.3% (incidence rate ratio, IRR=0.94, 95% CI 0,90-0,98) and overall suicide death rates increased 1.2% (IRR=1.01, 95% CI 0.90-1.13). Joinpoint regression results showed a substantial decrease in STBs rates with a monthly percent change (MPC) of -22.1 (95% CI: -41.1, 2.9) from January-April 2020, followed by a similar increase from April-July 2020 (MPC=24.7, 95% CI: -5.9, 65.2). The most restrictive measures implemented in response to the COVID-19 pandemic reduced consultations for STBs, suggesting that the "stay at home" message may have discouraged people from contacting mental health services. STBs and mortality should continue to be monitored in 2021 and beyond to understand better the mid-to-long term impact of COVID-19 on suicide trends.

[Poor results and complications in the use of focused shockwaves and radial pressure waves in musculoskeletal pathology]. / Malos resultados y complicaciones en el uso de ondas de choque focales y ondas de presión radial en patología musculoesquelética.

The application of focused shockwaves and radial pressure waves in musculoskeletal pathology has had a great development in the last decade. Although most of the publications have highlighted their safety and efficacy, poor results and complications can occur. This review analyzes the main causes of its poor results, adverse effects, and complications, emphasizing their prevention.

COVID-19 mRNA vaccine and antibody response in lactating women: a prospective cohort study.

BACKGROUND: Immunological protection via breastfeeding is well known. The immunological profile of human milk changes during lactation. No clinical trials have been conducted in lactating women with the newest mRNA vaccines against SARS- CoV-2. A Few studies have shown the presence of antibodies in breastmilk after vaccination. The aim of this work is to study possible antibodies transfer via breastmilk and also the immunological characteristics of lactating women compared to non-lactating women, after using the BNT162b2 Pfizer vaccine. METHODS: This is a prospective cohort study with a convenience homogenous sample of 24 healthcare workers (14 lactating and 10 non-lactating women) enrolled at the time of COVID-19 vaccination. Clinical data was registered in a questionnaire. Titers of SARS-CoV-2 spike IgG, IgA and IgM were quantified in post vaccination blood and human milk. Antibody quantification was performed by an in-house ELISA to SARS-CoV-2 trimeric spike protein. RESULTS: All women showed immunity after vaccination with positive antibodies for IgM, IgA and IgG antibodies. The dominant serum antibody response was IgG. Modest levels of antibodies in breastmilk of lactating mothers were observed in this study, especially IgG in 42.9%. There was a moderate association between higher titers of IgG and a longer duration of breastfeeding (R= 0.55, p=0.041). CONCLUSIONS: Evidence of antibody transfer in human milk after COVID-19 vaccination is scarce. The presence of antibodies in human milk is reported, but immunization through breastfeeding is still to be established.

Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study.

First-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.

Polyhydroxyalkanoates production from fermented domestic wastewater using phototrophic mixed cultures.

Phototrophic mixed cultures (PMC) have been found to be a promising technology to produce polyhydroxyalkanoates (PHA), however, work performed thus far has focussed mainly on the use of synthetic feedstocks and operational conditions that differ from those expectable in full-scale processes. The goals of this work were to study, for the first time, the capability of PMCs to produce PHA using real fermented domestic wastewater as feedstock under mixing/light/temperature conditions that are naturally found in outdoor open systems. Various operational strategies were evaluated in this study to increase PHA productivity, namely the poly(3-hydroxybutyric-co-3-hydroxyvaleric) copolymer (PHBV) by PMC systems. Two lab-scale photobioreactors were operated in parallel, with transient illumination (12 h light/12 h dark) and subjected to feedstock fluctuations under two culture selection strategies that best suit the oxidative conditions of high rate algal ponds (HRAPs) which are commonly applied in wastewater treatment plants (WWTP). Under a permanent carbon feast regime (selection strategy 1), the PMC became highly enriched in phototrophic purple bacteria (PPB), and two complementary conditions that can improve the selection of PHA accumulating bacteria were discovered: phosphate cycling, where 20% PHA/VSS (86HB:14HV in a C-mol basis) with a light phase productivity of 0.23 g PHA/L•d_light phase was attained; and transitioning from selection under low organic loading rate (OLR) to high OLR where 17.6% PHA/VSS (60HB:40HV in C base) with a light phase productivity of 0.18 g PHA/L•d_light phase was achieved. Under a feast and famine regime (selection strategy 2), a PMC consortium of microalgae and PPB was obtained, and a multiple pulse feeding strategy during the first hours of the light phase in the selector reactor led to a 26.1% PHA/VSS (36HB:64HV in C base) content, with a productivity of 0.26 g PHA/L•d_light phase and 0.52 g PHA/L•d_feast phase. An accumulation test under higher light intensity led to 30.8% PHA/VSS (85HB:15HV on a C-mol basis) with a productivity of 2.67 g PHA/L•d, along the 8 h of accumulation.