Major candidate variables to guide personalised treatment with steroids in critically ill patients with COVID-19: CIBERESUCICOVID study.

Purpose Although there is evidence supporting the benefits of corticosteroids in patients affected with severe coronavirus disease 2019 (COVID-19), there is little information related to their potential benefits or harm in some subgroups of patients admitted to the intensive care unit (ICU) with COVID-19. We aim to investigate to find candidate variables to guide personalized treatment with steroids in critically ill patients with COVID-19. Methods Multicentre, observational cohort study including consecutive COVID-19 patients admitted to 55 Spanish ICUs. The primary outcome was 90-day mortality. Subsequent analyses in clinically relevant subgroups by age, ICU baseline illness severity, organ damage, laboratory findings and mechanical ventilation were performed. High doses of corticosteroids (≥ 12 mg/day equivalent dexamethasone dose), early administration of corticosteroid treatment (< 7 days since symptom onset) and long term of corticosteroids (≥ 10 days) were also investigated. Results Between February 2020 and October 2021, 4226 patients were included. Of these, 3592 (85%) patients had received systemic corticosteroids during hospitalisation. In the propensity-adjusted multivariable analysis, the use of corticosteroids was protective for 90-day mortality in the overall population (HR 0.77 [0.65–0.92], p = 0.003) and in-hospital mortality (SHR 0.70 [0.58–0.84], p < 0.001). Significant effect modification was found after adjustment for covariates using propensity score for age (p = 0.001 interaction term), Sequential Organ Failure Assessment (SOFA) score (p = 0.014 interaction term), and mechanical ventilation (p = 0.001 interaction term). We observed a beneficial effect of corticosteroids on 90-day mortality in various patient subgroups, including those patients aged ≥ 60 years; those with higher baseline severity; and those receiving invasive mechanical ventilation at ICU admission. Early administration was associated with a higher risk of 90-day mortality in the overall population (HR 1.32 [1.14–1.53], p < 0.001). Long-term use was associated with a lower risk of 90-day mortality in the overall population (HR 0.71 [0.61–0.82], p < 0.001). No effect was found regarding the dosage of corticosteroids. Moreover, the use of corticosteroids was associated with an increased risk of nosocomial bacterial pneumonia and hyperglycaemia. Conclusion Corticosteroid in ICU-admitted patients with COVID-19 may be administered based on age, severity, baseline inflammation, and invasive mechanical ventilation. Early administration since symptom onset may prove harmful.post-print910 K

Methodology of a Large Multicenter Observational Study of Patients with COVID-19 in Spanish Intensive Care Units.

Introduction The COVID-19 pandemic created tremendous challenges for health-care systems. Intensive care units (ICU) were hit with a large volume of patients requiring ICU admission, mechanical ventilation, and other organ support with very high mortality. The Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CIBERES), a network of Spanish researchers to investigate in respiratory disease, commissioned the current proposal in response to the Instituto de Salud Carlos III (ISCIII) call. Methods CIBERESUCICOVID is a multicenter, observational, prospective/retrospective cohort study of patients with COVID-19 admitted to Spanish ICUs. Several work packages were created, including study population and ICU data collection, follow-up, biomarkers and miRNAs, data management and quality. Results This study included 6102 consecutive patients admitted to 55 ICUs homogeneously distributed throughout Spain and the collection of blood samples from more than 1000 patients. We enrolled a large population of COVID-19 ICU-admitted patients including baseline characteristics, ICU and MV data, treatments complications, and outcomes. The in-hospital mortality was 31%, and 76% of patients required invasive mechanical ventilation. A 3-6 month and 1 year follow-up was performed. Few deaths after 1 year discharge were registered. Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. These antibodies contribute to prevent systemic dissemination of SARS-CoV-2. The severity of COVID-19 impacts the circulating miRNA profile. Plasma miRNA profiling emerges as a useful tool for risk-based patient stratification in critically ill COVID-19 patients. Conclusions We present the methodology used in a large multicenter study sponsored by ISCIII to determine the short- and long-term outcomes in patients with COVID-19 admitted to more than 50 Spanish ICUs.post-print1142 K

Band gap alignment of structured microporous graphitic carbons by N doping and its influence on photocatalytic overall water splitting

[EN] Hydrogen generation from water using solar light could be a process of paramount importance in the forthcoming decarbonized society. This reaction requires efficient photocatalysts based on earthabundant elements. Metal-free carbon semiconducting materials are very appealing in this regard. This manuscript shows that N-doping is a convenient strategy to increase the photocatalytic activity of microporous graphitic carbons obtained from the pyrolysis of a-, b- and g-cyclodextrins. These (N)C carbons exhibit enhanced photocatalytic activity for H2 generation in the presence of methanol with respect to their undoped analogs. The optimal (N)C material (pore size, 0.65 nm) was the one derived from a-cyclodextrin at a N content of 3.1%, achieving a H2 productivity of 1.8 mmol g1 at 4 h in the presence of methanol. These materials also exhibit photocatalytic activity for overall water splitting, although with lower efficiency than for H2 generation in the presence of sacrificial electron donors. The present results illustrate the tuning of band alignment by N-doping in the graphitic matrixFinancial support by the Spanish Ministry of Science and Innovation (Severo Ochoa and CTQ2018-98237-CO2-1) and Generalitat Valenciana (Prometeo 2017-083) is gratefully acknowledged. AR and AP thanks the Spanish Ministry of Economy and Competitiveness for a postgraduate scholarship and a Ramon y Cajal research associate contract, respectively.Rendon-Patiño, A.; Torres-Martí, F.; Primo Arnau, AM.; García Gómez, H. (2022). Band gap alignment of structured microporous graphitic carbons by N doping and its influence on photocatalytic overall water splitting. Sustainable Energy & Fuels. 6(9):2170-2178. https://doi.org/10.1039/D2SE00078D217021786

Associations of residential greenspace exposure and fetal growth across four areas in Spain

An accumulating body of evidence has associated exposure to greenspace with improved birth outcomes, including higher birth weight and lower risk of low birth weight; however, evidence on such association with in-utero fetal growth is scarce. We explored the influence of maternal exposure to residential greenspace and fetal growth in four INMA (Infancia y Medio Ambiente) Spanish birth cohorts (2003-2008), with 2,465 participants. Residential greenspace was characterised by the Normalised Difference Vegetation Index (NDVI) average across 100 m, 300 m, and 500 m buffers around the residence. Repeated ultrasound measurements of the abdominal circumference (AC), biparietal diameter (BPD), femur length (FL), and estimated fetal weight (EFW) were used. We created customised-generalised least squares models to evaluate associations of residential greenspace exposure on each fetal growth parameter, controlled for the relevant confounders. There were associations be-tween the 500 m buffer and BPD, FL, and AC. We also found associations in the 300 m buffer and FL and AC. The associations in the 100 m buffer were null. Estimates were higher among participants with lower socioeconomic status. Mediation analyses found that air pollution might explain 15-37% of our associations. Mediation by physical activity was not observed. Greenspace exposure may be beneficial for fetal growth.We are grateful to all the participants for their generous collaboration. A full roster of the INMA Project founders can be found at: https://www.proyectoinma.org/proyecto-inma/financiadores/. Maria Torres Toda is funded by a PFIS (Contrato Predoctoral de Formación en Investigación en Salud) fellowship (FI17/00128) awarded by Instituto de Salud Carlos III. Maria Foraster is beneficiary of an AXA Research Fund grant. ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation and State Research Agency through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program

A Phase I-II multicenter trial with Avelumab plus autologous dendritic cell vaccine in pre-treated mismatch repair-proficient (MSS) metastatic colorectal cancer patients; GEMCAD 1602 study

[Background]: Immune check-point blockade (ICB) has shown clinical beneft in mismatch repair-defcient/microsatellite instability high metastatic colorectal cancer (mCRC) but not in mismatch repair-profcient/microsatellite stable patients. Cancer vaccines with autologous dendritic cells (ADC) could be a complementary therapeutic approach to ICB as this combination has the potential to achieve synergistic efects. [Methods]: This was a Phase I/II multicentric study with translational sub-studies, to evaluate the safety, pharmacodynamics and anti-tumor efects of Avelumab plus ADC vaccine in heavily pre-treated MSS mCRC patients. Primary objective was to determine the maximum tolerated dose and the efcacy of the combination. The primary end-point was 40% progressionfree survival at 6 months with a 2 Simon Stage. [Results]: A total of 28 patients were screened and 19 pts were included. Combined therapy was safe and well tolerated. An interim analysis (Simon design frst-stage) recommended early termination because only 2/19 (11%) patients were disease free at 6 months. Median PFS was 3.1 months [2.1–5.3 months] and overall survival was 12.2 months [3.2–23.2 months]. Stimulation of immune system was observed in vitro but not clinically. The evaluation of basal RNA-seq noted signifcant changes between pre and post-therapy liver biopsies related to lipid metabolism and transport, infammation and oxidative stress pathways. [Conclusions]: The combination of Avelumab plus ADC vaccine is safe and well tolerated but exhibited modest clinical activity. Our study describes, for the frst-time, a de novo post-therapy metabolic rewiring, that could represent novel immunotherapyinduced tumor vulnerabilities.The study was funded by grants from the FIS PI17/00732 from Instituto de Salud Carlos III, Premi Fi de Residència Emili Letang from Hospital Clínic Barcelona, Plan Nacional de I + D (PID-107139RB-C21 to DB-R and PID2020-115051RB-I00 to MC) and Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD). The study was funded with Grants from Catalan Agency for Management of University and Research Grants (AGAUR) (2014-SGR-474, 2017-SGR-1174 and 2017-SGR-1033), Fundació la Marató de TV3 (201330.10), Instituto de Salud Carlos III (PI13/01728 and PI19/00740) and Fundacion Olga Torres (Modalitat A. 2019/2020) to JM. IMMETCOLS signature is under patent protection (EP21382772.8.) This research was financially supported by GEMCAD and (OR Avelumab was provided) by Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: https://doi.org/10.13039/100009945) and Pfizer

Muscle patterns in singing. A pilot study

En estudios electromiográficos realizados previamente en diferentes cantantes, observamos cómo durante la emisión de la voz se producía la activación de los músculos espiradores y en paralelo se producía la contracción de los músculos intercostales externos, potentes inspiradores. Dadas estas observaciones, hemos realizado un estudio piloto con una cantante analizando el comportamiento conjunto de los músculos antes mencionados y del diafragma. Durante diferentes vocalizaciones hemos medido paralelamente la actividad muscular con electromiografía (EMG) y hemos observado el retorno diafragmático mediante ecografía. Los resultados apuntan a que el ascenso del diafragma está directamente relacionado con la nota emitida. Así, en el caso de una nota grave, el diafragma retorna lentamente acompañando el sonido. En el caso de las notas agudas, el diafragma se mantiene casi inmóvil durante la mayor parte de la emisión sonora y sólo al final de la vocalización se produce su ascenso de manera lenta. Se observa que durante la espiración en el canto, los músculos intercostales externos actúan elevando y fijando las costillas lo que impide el ascenso libre del diafragma, que se mantiene en tensión y se eleva de manera lenta y controlada gracias a la presión ejercida por los músculos del abdomen.In electromyographic studies previously executed in different singers, we observed how the activation of exhaling muscles was produced during the voice output, and how the contraction of the external intercostal muscles -powerful inspiratories- was produced in parallel. Given these observations, we conducted a pilot study with a female singer and analysed the behavior of all the aforementioned muscles and of the diaphragm. During different vocalisations, we have measured in parallel the muscle activity with electromyography (EMG) and have observed the diaphragmatic return by ultrasound. The results suggest that the rise of the diaphragm is directly related to the issued notes. Thus, in the case of a low note, the diaphragm returns slowly accompanying the sound. In the case of the high notes, the diaphragm remains almost immobile for most of the sound emission and his rise occurs slowly only at the end of the vocalisation. It is noted that during the expiration in singing, external intercostal muscles raise and fixe the ribs which prevents a free ascent of the diaphragm -which is held in tension and rised slowly and controllably thanks to the pressure exerted by the abdominal muscles.Facultad de Bellas Arte

Muscle patterns in singing. A pilot study

En estudios electromiográficos realizados previamente en diferentes cantantes, observamos cómo durante la emisión de la voz se producía la activación de los músculos espiradores y en paralelo se producía la contracción de los músculos intercostales externos, potentes inspiradores. Dadas estas observaciones, hemos realizado un estudio piloto con una cantante analizando el comportamiento conjunto de los músculos antes mencionados y del diafragma. Durante diferentes vocalizaciones hemos medido paralelamente la actividad muscular con electromiografía (EMG) y hemos observado el retorno diafragmático mediante ecografía. Los resultados apuntan a que el ascenso del diafragma está directamente relacionado con la nota emitida. Así, en el caso de una nota grave, el diafragma retorna lentamente acompañando el sonido. En el caso de las notas agudas, el diafragma se mantiene casi inmóvil durante la mayor parte de la emisión sonora y sólo al final de la vocalización se produce su ascenso de manera lenta. Se observa que durante la espiración en el canto, los músculos intercostales externos actúan elevando y fijando las costillas lo que impide el ascenso libre del diafragma, que se mantiene en tensión y se eleva de manera lenta y controlada gracias a la presión ejercida por los músculos del abdomen.In electromyographic studies previously executed in different singers, we observed how the activation of exhaling muscles was produced during the voice output, and how the contraction of the external intercostal muscles -powerful inspiratories- was produced in parallel. Given these observations, we conducted a pilot study with a female singer and analysed the behavior of all the aforementioned muscles and of the diaphragm. During different vocalisations, we have measured in parallel the muscle activity with electromyography (EMG) and have observed the diaphragmatic return by ultrasound. The results suggest that the rise of the diaphragm is directly related to the issued notes. Thus, in the case of a low note, the diaphragm returns slowly accompanying the sound. In the case of the high notes, the diaphragm remains almost immobile for most of the sound emission and his rise occurs slowly only at the end of the vocalisation. It is noted that during the expiration in singing, external intercostal muscles raise and fixe the ribs which prevents a free ascent of the diaphragm -which is held in tension and rised slowly and controllably thanks to the pressure exerted by the abdominal muscles.Facultad de Bellas Arte

Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection : A Spanish, Multicenter, Cohort Study

We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by inverse probability of the treatment weights (IPTW). Tocilizumab's effect in patients receiving steroids during the 48 h following inclusion was analysed. During the study period, 506 patients with severe COVID-19 fulfilled the inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days [interquartile range (IQR) 8-14]. Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls: 16.8% versus 31.5%, hazard ratio (HR) 0.514 [95% confidence interval (95% CI) 0.355-0.744], p < 0.001; weighted HR 0.741 (95% CI 0.619-0.887), p = 0.001. Tocilizumab treatment reduced mortality by 14.7% relative to no tocilizumab treatment [relative risk reduction (RRR) 46.7%]. We calculated a number necessary to treat of 7. Among patients treated with steroids, mortality was lower in those treated with tocilizumab than in those treated with steroids alone [10.9% versus 40.2%, HR 0.511 (95% CI 0.352-0.741), p = 0.036; weighted HR 0.6 (95% CI 0.449-0.804), p < 0.001] (interaction p = 0.094). These results show that survival of patients with severe COVID-19 is higher in those treated with tocilizumab than in those not treated and that tocilizumab's effect adds to that of steroids administered to non-intubated patients with COVID-19 during the first 48 h of presenting with respiratory failure despite oxygen therapy. Randomised controlled studies are needed to confirm these results. European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415 The online version of this article (10.1007/s40121-020-00373-8) contains supplementary material, which is available to authorized users

P53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis

Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy (CT) does not select previously resistant tumor populations but induces a quiescent state specifically to TP53 wildtype (WT) cancer cells, which is linked to the acquisition of a YAP1-dependent fetal phenotype. Cells displaying this phenotype exhibit high tumor-initiating and metastatic activity. Nuclear YAP1 and fetal traits are present in a proportion of tumors at diagnosis and predict poor prognosis in patients carrying TP53 WT CRC tumors. We provide data indicating the higher efficacy of CT together with YAP1 inhibitors for eradication of therapy resistant TP53 WT cancer cells. Together these results identify fetal conversion as a useful biomarker for patient prognosis and therapy prescription. The failure of chemotherapy in colorectal cancer is currently unclear. Here, the authors show that upon sub-lethal dose of chemotherapy wild-type p53 colorectal cancers acquire a quiescence-like phenotype and a YAP-dependent fetal-like intestinal stem cell state associated with a higher metastatic activity and poor prognosis in patients