Phase II Clinical Trial of Pembrolizumab and Chemotherapy Reveals Distinct Transcriptomic Profiles by Radiologic Response in Metastatic Triple-Negative Breast Cancer.

PURPOSE: A single arm, phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple-negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, overall survival (OS), and identify pathologic and transcriptomic correlates of response to therapy. PATIENTS AND METHODS: Patients with ≤2 prior therapies for metastatic disease were treated with CNP regardless of tumor programmed cell death-ligand 1 status. Core tissue biopsies were obtained prior to treatment initiation. ORR was assessed using a binomial distribution. Survival was analyzed via the Kaplan-Meier method. Bulk RNA sequencing was employed for correlative studies. RESULTS: Thirty patients were enrolled. The ORR was 48.0%: 2 (7%) complete responses (CR), 11 (41%) partial responses (PR), and 8 (30%) stable disease (SD). The median DOR for patients with CR or PR was 6.4 months [95% confidence interval (CI), 4-8.5 months]. For patients with CR, DOR was >24 months. Overall median PFS and OS were 5.8 (95% CI, 4.7-8.5 months) and 13.4 months (8.9-17.3 months), respectively. We identified unique transcriptomic landscapes associated with each RECIST category of radiographic treatment response. In CR and durable PR, IGHG1 expression was enriched. IGHG1high tumors were associated with improved OS (P = 0.045) and were concurrently enriched with B cells and follicular helper T cells, indicating IGHG1 as a promising marker for lymphocytic infiltration and robust response to chemo-immunotherapy. CONCLUSIONS: Pretreatment tissue sampling in mTNBC treated with CNP reveals transcriptomic signatures that may predict radiographic responses to chemo-immunotherapy.

Preventable incidence cases from non-communicable diseases attributable to insufficient physical activity in Chile.

OBJECTIVES: Lack of sufficient physical activity (PA) has been associated with an increased risk of several non-communicable diseases (NCDs) and all-cause mortality. This study aimed to estimate the number of preventable incidence cases of NCDs attributable to insufficient PA in the Chilean population. STUDY DESIGN: Comparative risk assessment modelling study. METHODS: This study examined data from 5834 participants aged ≥20 years from the Chilean National Survey (2016-2017). PA was assessed by the Global Physical Activity Questionnaire (GPAQ), and metabolic equivalent of tasks (METs) were assigned according to PA intensity. Estimated incidence cases of NCDs in Chile in 2019 were obtained from the Global Burden of Disease study. Relative risks for breast cancer, colon cancer, ischaemic heart disease, diabetes and stroke were obtained from a published meta-analysis and applied to the prevalence of insufficient PA estimates through the potential impact fraction equation. RESULTS: High levels of PA (≥8000 MET-min/week) could potentially avoid more than 22,000 (64.6 %) incidence NCD cases, ranging from 498 (10.1 %) preventable cases of breast cancer to 5629 (14.7 %) cases of diabetes. Other modelled scenarios also showed to reduce the incidence cases of all five NCDs but to a lesser extent; where at least PA recommendation was achieved, preventable NCDs were reduced by 6522 cases (18.7 %), and where a 10 % relative reduction in insufficient PA level in the population was achieved, preventable NCDs were reduced by 651 (1.8 %) cases. CONCLUSIONS: The study results provide estimates for the incidence cases of preventable NCDs attributable to insufficient PA, highlighting the important role of PA in NCD prevention in Chile.

Clinical and Immunologic Features of Germline Pathogenic Variant-Positive Patients with Melanoma.

PURPOSE: Malignant melanoma represents the most lethal skin cancer with germline predispositions thought to comprise 10% to 15% of all melanoma cases. No studies to date examine the immunologic features that may differentiate survival differences between germline pathogenic variant (gPV)-positive patients with melanoma from gPV-negative patients with melanoma. EXPERIMENTAL DESIGN: Adult patients with melanoma and clinical characteristics suggesting hereditary predisposition to cancer were prospectively recruited to undergo germline testing and flow cytometric analysis of peripheral immune suppressor cells. RESULTS: In this cohort, gPV-positive patients (n = 72) had a significantly improved melanoma-specific survival (MSS) compared with gPV-negative patients (n = 411; HRadj, 0.32; 95% CI, 0.13-0.82; P = 0.01). These survival improvements among gPV-positive patients were most apparent among cutaneous melanoma subtypes (HRadj, 0.12; 95% CI, 0.016-0.86; P = 0.03) and numerically improved in later-stage (IIB-IV) patients (HRadj, 0.34; 95% CI, 0.10-1.11; P = 0.06). Further, gPV-positive patients had a significantly lower level of total circulating PMN-MDSC compared with gPV-negative patients (P = 0.01), which was most apparent in those diagnosed with later stages (IIB-IV) of melanoma (P = 0.009). Finally, a significant upregulation of inflammatory transcriptome signatures in later-stage gPV-positive patients (n = 21) was observed in comparison with gPV-negative patients (n = 173) in the cutaneous melanoma cohort (SKCM) of The Cancer Genome Atlas (TCGA). CONCLUSIONS: gPV-positive patients with melanoma exhibit improved MSS in addition to reduced peripheral PMN-MDSC and an enhanced inflammatory microenvironment.

Immunotherapy with IL12 and PD1/CTLA4 inhibition is effective in advanced ovarian cancer and associates with reversal of myeloid cell-induced immunosuppression.

The tumor microenvironment (TME) in ovarian cancer (OC) is characterized by immune suppression, due to an abundance of suppressive immune cells populations. To effectively enhance the activity of immune checkpoint inhibition (ICI), there is a need to identify agents that target these immunosuppressive networks while promoting the recruitment of effector T cells into the TME. To this end, we sought to investigate the effect of the immunomodulatory cytokine IL12 alone or in combination with dual-ICI (anti-PD1 + anti-CTLA4) on anti-tumor activity and survival, using the immunocompetent ID8-VEGF murine OC model. Detailed immunophenotyping of peripheral blood, ascites, and tumors revealed that durable treatment responses were associated with reversal of myeloid cell-induced immune suppression, which resulted in enhanced anti-tumor activity by T cells. Single cell transcriptomic analysis further demonstrated striking differences in the phenotype of myeloid cells from mice treated with IL12 in combination with dual-ICI. We also identified marked differences in treated mice that were in remission compared to those whose tumors progressed, further confirming a pivotal role for the modulation of myeloid cell function to allow for response to immunotherapy. These findings provide the scientific basis for the combination of IL12 and ICI to improve clinical response in OC.

Implementación del análisis modal de fallos y efectos en una Unidad de Radiofarmacia Hospitalaria / Implementation of the failure modes and effects analysis in a Hospital Radiopharmacy Unit

Objetivo El objetivo de este estudio es la implementación en una Unidad de Radiofarmacia Hospitalaria de una metodología de análisis de riesgos para poder identificar de forma proactiva los posibles modos de fallo y priorizar medidas correctivas. Material y métodos Mediante el análisis modal de fallos y efectos (AMFE) se identificaron los posibles modos de fallo de cada una de las etapas de los procesos de prescripción, preparación y administración de los radiofármacos de diagnóstico y de terapia. A partir de las variables de severidad, probabilidad y detectabilidad se cuantificó el riesgo mediante el número de prioridad de riesgo (NPR) para cada modo de fallo, subproceso y tipo de radiofármaco. Se establecieron medidas de mejora y se calculó la reducción en el NPR. Resultados Se identificaron 96 modos de fallos (58 para los radiofármacos de diagnóstico y 38 para los de terapia). La identificación biunívoca del paciente con el radiofármaco es el modo de fallo con mayor NPR (60) y el subproceso de marcaje celular el que presenta mayor riesgo (NPR 286). Como resultado de las medidas de mejora se disminuyó el NPR global en un 22% para los radiofármacos de diagnóstico y 20% para los de terapia. Esta reducción sería del 46 y el 31%, respectivamente, si se implantara un software de radiofarmacia y tecnología de código de barras en la administración. Conclusiones La aplicación de la metodología AMFE como herramienta de análisis de riesgos permite identificar los puntos críticos de los procesos relacionados con los radiofármacos y priorizar medidas para disminuir el riesgo (AU)

Aim The aim of this study is the implementation in a Hospital Radiopharmacy Unit of a risk analysis methodology in order to proactively identify possible failure modes and prioritize corrective measures. Materials and methods By means of the failure modes and effects analysis (FMEA), the possible failure modes of each of the stages of the processes of prescription, preparation, and administration of radiopharmaceuticals for diagnostic and therapy were identified. From the variables of severity, probability and detectability, the risk was quantified using the Risk Priority Number (RPN) for each failure mode, sub-process, and type of radiopharmaceutical. Improvement measures were established and the reduction in the RPN value was calculated. Result A total of 96 failure modes were identified (58 for diagnostic radiopharmaceuticals and 38 for therapy). Biunivocal identification of the patient with the radiopharmaceutical is the failure mode with the highest RPN (60) and the radiolabeling cell sub-process the one that has the highest risk (RPN 286). As a result of the improvement measures, the overall RPN was reduced by 22% for diagnostic radiopharmaceuticals and 20% for therapy. This reduction would be 46% and 31% respectively if radiopharmacy software and a barcode technology in the administration were implemented. Conclusions The application of the FMEA methodology as a risk analysis tool allows to identify the critical points of the processes related to radiopharmaceuticals and prioritize measures to reduce the risk (AU)

Old is new again: emergence of thromboembolic complications in cancer patients on immunotherapy.

Cancer immunotherapy has emerged as one of the most important new treatments for cancer in many years, moving rapidly to front-line therapy for several cancers. Cancer immunotherapy is based on treatment with immune checkpoint inhibitors (ICI), which are monoclonal antibodies directed toward immunoregulatory proteins including PD-1, PD-L1 and CTLA-4. ICI inhibit interactions between these proteins and their ligands, disabling physiologic immune regulatory networks and enhancing anti-tumor immunity. However, since the immune response cannot be directed specifically to the tumor, ICI are associated with immune-related adverse events (irAEs) resulting from immune-mediated attack of normal tissues. We and others have reported a high incidence of thrombosis in patients treated with ICI, which may approach 20%. Given the rapidly increasing use of ICIs, it is clear that ICI-Associated Thrombosis (IAT) is a major emerging clinical problem. However, there is a remarkable knowledge gap concerning mechanisms of IAT. IAT may be a composite irAE resulting from activation of blood and vascular cells, leading to thromboinflammation. Cancer itself is an inflammatory disorder, and inducing further inflammation through ICI administration may stimulate procoagulant activity by multiple cell types. Moreover, some blood and vascular cells express ICI target proteins. Here, we review the results of several studies describing the clinical manifestations of IAT, as well as our recent studies demonstrating that elevated levels of myeloid derived suppressor cells and inflammatory cytokines may serve as biomarkers of IAT. It is hoped that the concepts reviewed here may stimulate further research into this important clinical problem.

Método para establecer la reserva funcional de la velocidad de marcha en una muestra de adultas mayores autosuficientes chilenas: la relevancia del estímulo / Method to establish the functional reserve of gait speed in a sample of self-reliant older Chilean women: The relevance of the stimulus

Antecedentes y objetivo: El envejecimiento como proceso complejo y multifactorial involucra cambios multisistémicos asociados al rendimiento físico con pérdida de funcionalidad, tal como la velocidad de marcha y su reserva. El estudio estableció el método que mejor evidencia la reserva funcional de velocidad de marcha (RFVM) según la incorporación de estímulos en mujeres adultas mayores (AM). Material y método: Estudio observacional analítico con muestra conformada por 30AM de entre 65-69años, autosuficientes sin riesgo, normopeso y sin sospecha de depresión, controladas en Centro Comunitario de Salud Familiar y Centro de Salud Familiar de Talca. La velocidad de marcha (VM) fue medida a través de tres métodos: M1 (marcha habitual), M2 (marcha máxima) y M3 (marcha máxima con estímulos), para posteriormente calcular la RFVM en las AM. El ejercicio se ejecutó en una pista de 10m que incluía 2m de aceleración, 2m de desaceleración y 6m centrales para medir el tiempo en segundos que demoraba en recorrerlos. Resultados: Las medias de velocidades de la muestra en los métodos habitual, máxima y máxima con estímulo fueron de 1,17, 1,38 y 1,57m/s, respectivamente; las reservas funcionales (RF) resultantes entre las diferencias de los métodos fueron: RF-A (M2−M1) 0,26m/s; RF-B (M3−M1) 0,45m/s y RF-C (M2−M3) 0,19m/s; para la mayoría de los casos y según orden correspondiente, las diferencias estadísticas fueron significativas. Conclusión: El método que mejor evidenció la RFVM fue a través de las diferencias de medias entre M3 y M1, siendo una forma objetiva de verificar esta dimensión del movimiento humano como expresión de funcionalidad de las AM. (AU)

Background and objective: Aging as a complex and multifactorial process involves multisystemic changes associated with physical performance with loss of functionality such as walking speed and reserve. The study established the method that best evidences the functional reserve (FR) of walking speed (FRWS) according to the incorporation of stimuli in older adults (OAs). Material and method: Analytical observational study with a sample made up of 30OAs between 65 and 69years, self-administered without risk, normal weight and without suspicion of depression, controlled in Centro Comunitario de Salud Familiar and Centro de Salud Familiar of Talca. The walking speed (WS) was measured by three methods: M1 (usual gait), M2 (maximum gait) and M3 (maximum gait with stimuli); to later calculate the FRWS in the AO, executed on a 10m track that included 2m acceleration, 2m deceleration and 6m centrals to measure the time in seconds it took to travel them. Results: The mean velocities of the sample in the usual, maximum and maximum stimulated methods were 1.17, 1.38 and 1.57m/s respectively; the resulting FRs between the method differences: FR-A (M2−M1) 0.26m/s; FR-B (M3−M1) 0.45m/s and FR-C (M2−M3) 0.19m/s, for most of the cases and according to the corresponding order, the statistical differences were significant. Conclusion: The method that best evidenced the FRWS was through the differences in means between M3 and M1, being an objective way to verify this dimension of human movement as an expression of OA functionality. (AU)

Implementation of the failure modes and effects analysis in a Hospital Radiopharmacy Unit.

AIM: The aim of this study is the implementation in a Hospital Radiopharmacy Unit of a risk analysis methodology in order to proactively identify possible failure modes and prioritize corrective measures. MATERIALS AND METHODS: By means of the failure modes and effects analysis (FMEA), the possible failure modes of each of the stages of the processes of prescription, preparation, and administration of radiopharmaceuticals for diagnostic and therapy were identified. From the variables of severity, probability and detectability, the risk was quantified using the Risk Priority Number (RPN) for each failure mode, sub-process, and type of radiopharmaceutical. Improvement measures were established and the reduction in the RPN value was calculated. RESULTS: A total of 96 failure modes were identified (58 for diagnostic radiopharmaceuticals and 38 for therapy). Biunivocal identification of the patient with the radiopharmaceutical is the failure mode with the highest RPN (60) and the radiolabeling cell sub-process the one that has the highest risk (RPN 286). As a result of the improvement measures, the overall RPN was reduced by 22% for diagnostic radiopharmaceuticals and 20% for therapy. This reduction would be 46% and 31% respectively if radiopharmacy software and a barcode technology in the administration were implemented. CONCLUSIONS: The application of the FMEA methodology as a risk analysis tool allows to identify the critical points of the processes related to radiopharmaceuticals and prioritize measures to reduce the risk.

A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients.

Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS "CD8+ TOXPHOS cells." We validated that higher levels of OXPHOS in tumor- and peripheral blood-derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients.

Immunobiology of Melanoma.

Despite the ability of immune-based interventions to dramatically increase the survival of patients with melanoma, a significant subset fail to benefit from this treatment, underscoring the need for accurate means to identify the patient population likely to respond to immunotherapy. Understanding how melanoma evades natural or manipulated immune responses could provide the information needed to identify such resistant individuals. Efforts to address this challenge are hampered by the vast immune diversity characterizing tumor microenvironments that remain largely understudied. It is thus important to more clearly elucidate the complex interactions that take place between the tumor microenvironment and host immune system.

[Predictive models of gestational diabetes, a new prediction mode]. / Modelos predictivos de diabetes gestacional, un nuevo modelo de predicción.

OBJECTIVES: Recognized the value of gestational diabetes (GD) as a health problem, our aim in this work has been to analyze the diagnostic performance of the different today's existing criteria (GEDE, O'Sullivan and Carpenter) after the overload of 100 g of glucose and revise how to increase its efficiency. MATERIALS AND METHODS: We carried out a description of all the variables. In the analytical phase of the work, we used Pearson's Chi square to see if there were differences in the percentage of cases collected in each health center and the proportions contrast test to study the differences between the experimental prevalence. We completed binary logistic regression models using as result variable having or not having gestational diabetes (yes/no) and as predictors the four measurements of the curve with 100 g of glucose overload. To decide which model was better, the stepwise backward-forward analysis and the surface of the ROC curve generated by each of them were considered. RESULTS: We obtained a sample of 170 pregnant women from six different Primary Care Area of Seville health centers who had shown a positive O'Sullivan test with a median age of 35 years. There were significant differences in the prevalence proportions according to the criteria used: GEDE/O'Sullivan p < 0.001; GEDE/Carpenter p < 0.001. Logistic models with three and four predictor variables were equal in discriminatory diagnostic capacity when the GEDE criteria were used (area under the ROC curve = 0.96, 95% CI: 0.93-0.98). The back-forward stepwise analysis stayed with the three-variable model as the most parsimonious. The same did not occur when applying the other two criteria. CONCLUSIONS: Regarding an observational design, we state that there are significant differences in the prevalence proportions observed according to the criteria applied (p < 0.001) and we can also support that using the GEDE criteria, the taking of the third hour could be dispensed with, based on Bayesian criteria and the application of the ROC curve analysis.

Increased Incidence of Venous Thromboembolism with Cancer Immunotherapy.

BACKGROUND: Cancer immunotherapy is associated with several immune-related adverse events, but the relationship between immunotherapy and venous thromboembolism has not been thoroughly studied. METHODS: We conducted a retrospective cohort study of 1,686 patients who received immunotherapy for a variety of malignancies to determine the incidence of venous thromboembolism and the impact of venous thromboembolism on survival. To examine the potential role of inflammation in venous thromboembolism, we also profiled immune cells and plasma cytokines in blood samples obtained prior to initiation of immunotherapy in a sub-cohort of patients treated on clinical trials who subsequently did (N = 15), or did not (N = 10) develop venous thromboembolism. FINDINGS: Venous thromboembolism occurred while on immunotherapy in 404/1686 patients (24%) and was associated with decreased overall survival [HR=1.22 (95% CI 1.06-1.41), p<0.008]. Patients that developed venous thromboembolism had significantly higher pretreatment levels of myeloid-derived suppressor cells (5.382 ± 0.873 vs. 3.341 ± 0.3402, mean ± SEM; p=0.0045), interleukin 8 (221.2 ± 37.53 vs. 111.6 ± 25.36, mean ± SEM; p=0.016), and soluble vascular cell adhesion protein 1 (1210 ± 120.6 vs. 895.5 ± 53.34, mean ± SEM; p=0.0385). CONCLUSIONS: These findings demonstrate that venous thromboembolism is an underappreciated and important immune-related adverse event associated with cancer immunotherapy, and may implicate an interleukin 8 and myeloid-derived suppressor cell-driven pathway in pathogenesis.

Complicaciones neurológicas en pacientes críticos por SARS-CoV-2 / Neurological complications in critical patients with COVID-19

INTRODUCCIÓN: Nos proponemos analizar las complicaciones neurológicas de los pacientes con infección grave por SARS-CoV-2 que han requerido ingreso en unidad de cuidados intensivos (UCI). PACIENTES Y MÉTODOS: Estudio descriptivo retrospectivo, observacional, de pacientes consecutivos ingresados en UCI por infección respiratoria grave por SARS-CoV-2 desde el 1 de abril hasta el 1 de junio de 2020. RESULTADOS: Registramos 30 pacientes con síntomas neurológicos, 21 hombres (72,40%), edad media: 57,41 años ± 11,61 desviación estándar (DE). Estancia media en UCI: 18,83 ± 14,33 DE. A nivel sindrómico: 28 pacientes (93,33%) con síndrome confusional agudo, 15 (50%) con patología neuromuscular, 5 (16,66%) con cefalea, 4 (13,33%) con patología cerebrovascular y 4 (13,33%) con encefalopatías/encefalitis. Punción lumbar normal en 6 pacientes (20%). La RMN craneal o TAC craneal mostró alteraciones en 20 casos (66,6%). Se realizó EEG en todos los pacientes (100%), alterado en 8 pacientes (26,66%). En 5 de los 15 pacientes con miopatía clínica se ha podido confirmar con ENMG. Hemos encontrado relación entre la mayor edad y los días de ingreso en UCI (p = 0,002; IC95%: 4,032-6,022; OR: 3,594). CONCLUSIONES: La infección grave por COVID-19 afecta mayoritariamente a hombres, similar a lo descrito en otras series. La mitad de nuestros pacientes presenta una miopatía aguda, y casi la totalidad de los pacientes salen de la UCI con síndromes confusionales agudos que evolucionan a una resolución completa, sin correlacionarse con los resultados del EEG o de pruebas de neuroimagen. La mayor edad se asocia con un mayor número de días de estancia en UCI

INTRODUCTION: We analysed the neurological complications of patients with severe SARS-CoV-2 infection who required intensive care unit (ICU) admission. PATIENTS AND METHODS: We conducted a retrospective, observational, descriptive study of consecutive patients admitted to the ICU due to severe respiratory symptoms secondary to SARS-CoV-2 infection between 1 April and 1 June 2020. RESULTS: We included 30 patients with neurological symptoms; 21 were men (72.40%), and mean age (standard deviation [SD]) was 57.41 years (11.61). The mean duration of ICU stay was 18.83 days (14.33). The neurological conditions recorded were acute confusional syndrome in 28 patients (93.33%), neuromuscular disease in 15 (50%), headache in 5 (16.66%), cerebrovascular disease in 4 (13.33%), and encephalopathies/encephalitis in 4 (13.33%). CSF analysis results were normal in 6 patients (20%). Brain MRI or head CT showed alterations in 20 patients (66.6%). EEG was performed in all patients (100%), with 8 (26.66%) showing abnormal findings. In 5 of the 15 patients with clinical myopathy, diagnosis was confirmed with electroneuromyography. We found a correlation between older age and duration of ICU stay (P = .002; 95%CI: 4.032-6.022; OR: 3,594). CONCLUSIONS: Severe COVID-19 mainly affects men, as observed in other series. Half of our patients presented acute myopathy, and almost all patients left the ICU with acute confusional syndrome, which fully resolved; no correlation was found with EEG or neuroimaging findings. Older age is associated with longer ICU stay

Correlaciones de biomarcadores del primer trimestre con el peso fetal y con el peso materno en embarazadas con diabetes gestacional

Dada la importancia obstétrica y metabólica de la Diabetes Gestacional, hemos querido estudiar las correlaciones de los biomarcadores de primer trimestre con el peso fetal en las 20 semanas y con el de la madre en las 28 semanas para embarazadas con y sin diabetes gestacional, en una investigación desarrollada en atención primaria. Se trata de un estudio de casos y controles. Las variables cuantitativas analizadas han sido: PAPPA (Pregnancy Associated Plasma Protein A) (mU/ml), Betahidroxicoriónica (ngrs/ml), TSH (pUI/ml) y T4 libre (ngrs/dl) a las 12 semanas, peso fetal a las 20 semanas y peso materno en kilogramos a las 28 semanas. Como variable complementaria descriptiva hemos utilizado la edad en años de la gestante. Se han muestreado seis centros de salud del Distrito Sanitario de Atención Primaria de Sevilla (España). Utilizamos la regresión lineal simple por el método de los mínimos cuadrados y la técnica de suavización denominada LOESS (Locally Weighted Scatterplot Smoothing). Destacamos sobre todas las demás, las correlaciones inversas y las líneas de mínimos cuadrados de las variables PAPPA y TSH en las 12 semanas de gestación, y las correlaciones entre peso fetal a las 20 semanas con Betahidroxicoriónica y con PAPP-A. La más importante es la primera por el cambio y la magnitud de la R2 de Pearson (+0,10) en gestantes con diabetes gestacional. Hemos encontrado un cambio ostensible en la correlación de la PAPP-A con la TSH en las gestantes con Diabetes Gestacional. El intervalo de confianza superior del coeficiente de correlación llega a alcanzar +0,3. Una posible explicación fisiopatológica para esta correlación encontrada en nuestro trabajo podría ser la acción de la TSH sobre los factores de crecimiento similares a insulina en células osteoblásticas humanas.

Given the obstetric and metabolic importance of Gestational Diabetes, we wanted to study the correlations of the first trimester biomarkers with the weight of the fetus at 20 weeks and with that of the mother at 28 weeks of gestation for pregnant women with and without gestational diabetes in a research carried out in primary care. This is an observational study of cases and controls. The quantitative variables analyzed were: PAPPA (Pregnancy Associated Plasma Protein A) (mU / ml), Betahydroxychorionic (ngrs / ml), TSH (pUI / ml) and free T4 (ngrs / dl) at 12 weeks, fetal weight at 20 weeks and maternal weight in kilograms at 28 weeks. As a descriptive balancing variable, we have used the age of the pregnant woman in years. Six health centers of the Primary Healthcare District of Seville (Spain) have been sampled. We applied simple linear regression using the least squares method and the smoothing technique called LOESS (Locally Weighted Scatterplot Smoothing). A finding was highlighted above all the others, the inverse correlations and the least squares lines of the PAPP-A and TSH variables at 12 weeks of gestation, and the correlations between fetal weight at 20 weeks with Betahydroxychorionic and with PAPPA. The most important is the first because of the change and the magnitude of Pearson's R2 (+0.10) in pregnant women with gestational diabetes. We have found a noticeable change in the correlation of PAPPA with TSH in pregnant women with Gestational Diabetes. The upper confidence interval of the Pearson correlation coefficient reaches +0.3. A possible pathophysiological explanation for this correlation found in our work could be the action of TSH on insulin-like growth factors in human osteoblastic cells

Neurological complications in critical patients with COVID-19. / Complicaciones neurológicas en pacientes críticos por SARS-CoV-2.

INTRODUCTION: We analysed the neurological complications of patients with severe SARS-CoV-2 infection who required intensive care unit (ICU) admission. PATIENTS AND METHODS: We conducted a retrospective, observational, descriptive study of consecutive patients admitted to the ICU due to severe respiratory symptoms secondary to SARS-CoV-2 infection between 1 April and 1 June 2020. RESULTS: We included 30 patients with neurological symptoms; 21 were men (72.40%), and mean age (standard deviation [SD]) was 57.41 years (11.61). The mean duration of ICU stay was 18.83 days (14.33). The neurological conditions recorded were acute confusional syndrome in 28 patients (93.33%), neuromuscular disease in 15 (50%), headache in 5 (16.66%), cerebrovascular disease in 4 (13.33%), and encephalopathies/encephalitis in 4 (13.33%). CSF analysis results were normal in 6 patients (20%). Brain MRI or head CT showed alterations in 20 patients (66.6%). EEG was performed in all patients (100%), with 8 (26.66%) showing abnormal findings. In 5 of the 15 patients with clinical myopathy, diagnosis was confirmed with electroneuromyography. We found a correlation between older age and duration of ICU stay (P=.002; 95%CI: 4.032-6.022; OR: 3,594). CONCLUSIONS: Severe COVID-19 mainly affects men, as observed in other series. Half of our patients presented acute myopathy, and almost all patients left the ICU with acute confusional syndrome, which fully resolved; no correlation was found with EEG or neuroimaging findings. Older age is associated with longer ICU stay.

The immunology of renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and comprises several subtypes with unique characteristics. The most common subtype (~70% of cases) is clear-cell RCC. RCC is considered to be an immunogenic tumour but is known to mediate immune dysfunction in large part by eliciting the infiltration of immune-inhibitory cells, such as regulatory T cells and myeloid-derived suppressor cells, into the tumour microenvironment. Several possible mechanisms have been proposed to explain how these multiple tumour-infiltrating cell types block the development of an effective anti-tumour immune response, including inhibition of the activity of effector T cells and of antigen presenting cells via upregulation of suppressive factors such as checkpoint molecules. Targeting immune suppression using checkpoint inhibition has resulted in clinical responses in some patients with RCC and combinatorial approaches involving checkpoint blockade are now standard of care in patients with advanced RCC. However, a substantial proportion of patients do not benefit from checkpoint blockade. The identification of reliable biomarkers of response to checkpoint blockade is crucial to facilitate improvements in the clinical efficacy of these therapies. In addition, there is a need for the development of other immune-based strategies that address the shortcomings of checkpoint blockade, such as adoptive cell therapies.

Mass Transfer and Colour Analysis during Vacuum Frying of Colombian Coastal Carimañola.

This study is aimed at analysing the effect of vacuum frying on the kinetic parameters of mass transfer, the CIE L ∗ a ∗ b ∗ colour parameters of the Carimañola. For the kinetic analysis, the moisture and oil content were measured by means of an experimental design consisting of two factors: frying time with seven levels (60, 120, 180, 240, 300, 420, and 540 s) and frying temperature with three levels (120, 130, and 140°C). The diffusivity coefficient, the moisture transfer rate, and the oil adsorption rate, with their respective activation energies, were calculated. For the colour analysis, the reflectance technique was used to determine the colour coordinates of the CIE L ∗ a ∗ b ∗ space, and the general colour change was calculated (ΔE). Concerning the kinetics, the increase in temperature and frying time reduced the moisture content, while the oil content decreased with the increase in temperature and increases with frying time. The diffusivity ranged from 1, 238 × 10-6 m2/s at 120°C to 2, 84 × 10-6 m2/s at 140°C. The mass transfer coefficients for moisture ranged from 2 × 10-4 m/s at 120°C to 4 × 10-4 m/s at 140°C. The values of the oil uptake rate were from 0.0022 s-1 at 120°C to 0.0018 s-1 at 140°C. Finally, the luminosity parameter shows a decrease with the increase in temperature, although the first 240 s shows a rise and then begins to decrease. Vacuum frying allowed Carimañolas to be obtained with a lower oil and moisture content, with an appropriate colouring, eye-catching and visually attractive to consumers.

[Neurological complications in critical patients with COVID-19]. / Complicaciones neurológicas en pacientes críticos por SARS-CoV-2.

Introduction: We analysed the neurological complications of patients with severe SARS-CoV-2 infection who required intensive care unit (ICU) admission. Patients and methods: We conducted a retrospective, observational, descriptive study of consecutive patients admitted to the ICU due to severe respiratory symptoms secondary to SARS-CoV-2 infection between 1 April and 1 June 2020. Results: We included 30 patients with neurological symptoms; 21 were men (72.40%), and mean age (standard deviation [SD]) was 57.41 years (11.61). The mean duration of ICU stay was 18.83 days (14.33). The neurological conditions recorded were acute confusional syndrome in 28 patients (93.33%), neuromuscular disease in 15 (50%), headache in 5 (16.66%), cerebrovascular disease in 4 (13.33%), and encephalopathies/encephalitis in 4 (13.33%). CSF analysis results were normal in 6 patients (20%). Brain MRI or head CT showed alterations in 20 patients (66.6%). EEG was performed in all patients (100%), with 8 (26.66%) showing abnormal findings. In 5 of the 15 patients with clinical myopathy, diagnosis was confirmed with electroneuromyography. We found a correlation between older age and duration of ICU stay (P = .002; 95% CI: 4.032-6.022; OR: 3,594). Conclusions: Severe COVID-19 mainly affects men, as observed in other series. Half of our patients presented acute myopathy, and almost all patients left the ICU with acute confusional syndrome, which fully resolved; no correlation was found with EEG or neuroimaging findings. Older age is associated with longer ICU stay.

Fístula orbitaria supratroclear secundaria a la realización de un bloqueo para anestesia en una cirugía de catarata / Orbital supratrochlear fistula secondary to anaesthetic block in cataract surgery

Presentamos un caso de una mujer con antecedente de bloqueo peribulbar derecho previo a cirugía de cataratas que a los pocos días presenta una fístula arteriovenosa intraorbitaria supratroclear derecha. Se resuelve sin secuelas a los 3 meses mediante la realización de masajes carotídeos homolaterales intermitentes. Es la primera vez que se describe una fístula arteriovenosa intraorbitaria de localización supratroclear. Solo se han descrito 8 casos de fístula arteriovenosa intraorbitaria postraumáticas y solo uno fue después de anestesia peribulbar

A case is described of a woman with history of right peribulbar nerve block prior to cataract surgery that, within a few days, presented with a trochlear intraorbital arteriovenous fistula. This was resolved without sequelae after three months by performing intermittent homolateral carotid massages. This is the first case of supratrochlear intraorbital arteriovenous fistula. There are only 8 cases reported of traumatic intraorbital arteriovenous fistula, and only one was with post-peribulbar anaesthesia

Mediators of Inflammation-Driven Expansion, Trafficking, and Function of Tumor-Infiltrating MDSCs.

Myeloid-derived suppressor cells (MDSC) are induced by and accumulate within many histologically distinct solid tumors, where they promote disease by secreting angiogenic and immunosuppressive molecules. Although IL1ß can drive the generation, accumulation, and functional capacity of MDSCs, the specific IL1ß-induced inflammatory mediators contributing to these activities remain incompletely defined. Here, we identified IL1ß-induced molecules that expand, mobilize, and modulate the accumulation and angiogenic and immunosuppressive potencies of polymorphonuclear (PMN)-MDSCs. Unlike parental CT26 tumors, which recruited primarily monocytic (M)-MDSCs by constitutively expressing GM-CSF- and CCR2-directed chemokines, IL1ß-transfected CT26 produced higher G-CSF, multiple CXC chemokines, and vascular adhesion molecules required for mediating infiltration of PMN-MDSCs with increased angiogenic and immunosuppressive properties. Conversely, CT26 tumors transfected with IL1ß-inducible molecules could mobilize PMN-MDSCs, but because they lacked the ability to upregulate IL1ß-inducible CXCR2-directed chemokines or vascular adhesion molecules, additional PMN-MDSCs could not infiltrate tumors. IL1ß-expressing CT26 increased angiogenic and immunosuppressive factors of tumor-infiltrating MDSCs, as did CT26 tumors individually transfected with G-CSF, Bv8, CXCL1, or CXCL5, demonstrating that mediators downstream of IL1ß could also modulate MDSC functional activity. Translational relevance was indicated by the finding that the same growth factors, cytokines, chemokines, and adhesion molecules responsible for the mobilization and recruitment of PMN-MDSCs into inflammatory CT26 murine tumors were also coordinately upregulated with increasing IL1ß expression in human renal cell carcinoma tumors. These studies demonstrated that IL1ß stimulated the components of a multifaceted inflammatory program that produces, mobilizes, chemoattracts, activates, and mediates the infiltration of PMN-MDSCs into inflammatory tumors to promote tumor progression.