Transcultural adaptation and validation of IMPACT-III and IMPACT-III-P in Spanish families: a multicenter study from SEGHNP.

IMPACT-III and IMPACT-III-P are health-related quality of life (HRQoL) questionnaires for patients with pediatric inflammatory bowel disease (p-IBD) and their parents/caregivers. We aimed to perform a transcultural adaptation and validation for the Spanish context. Translation, back-translation, and evaluation of the questionnaires were performed by an expert committee and 12 p-IBD families. We recruited p-IBD patients aged 10-17 and their parents/caregivers. Utility, content, and face validity were considered. Validation was performed with Cronbach's alpha coefficient and varimax rotation. We confirmed the adequacy of the factor analysis using Kaiser-Meyer-Olkin (KMO) and Bartlett's sphericity tests. A confirmatory factor analysis was performed using the following goodness indexes: chi-square, Normed Fit Index (NFI), Root Mean Square Error of Approximation index (RMSEA), Standardized Root Mean Square Residual (SRMR), and Comparative Fit Index (CFI). The correlation coefficient between IMPACT-III and IMPACT-III-P was analyzed. We included 370 patients and 356 parents/caregivers (37 hospitals). Both questionnaires had good content and face validity and were considered user-friendly. The KMO measure (0.8998 and 0.9228, respectively) and Bartlett's sphericity test (p-value < 0.001 for both) confirmed the adequacy of the factor analysis. The 4-factor model, complying with Kaiser's criterion, explained 89.19% and 88.87% of the variance. Cronbach's alpha (0.9123 and 0.9383) indicated excellent internal consistency. The CFA showed an adequate fit (NFI 0.941 and 0.918, RMSEA 0.048 and 0.053, SRMR 0.037 and 0.044, and CFI 0.879 and 0.913). The correlation coefficient was excellent (0.92). CONCLUSION: The SEGHNP versions of IMPACT-III and IMPACT-III-P are valid and reliable instruments for Spanish p-IBD families. WHAT IS KNOWN: • IMPACT-III and parent-proxy IMPACT-III (IMPACT-III-P) are useful questionnaires for assessing health-related quality of life (HRQoL) in pediatric inflammatory bowel disease (p-IBD) patients and their parents/caregivers and have been translated and validated in several countries. • To date, no transcultural adaptation and validation of these questionnaires have been published for Spanish patients with p-IBD and their families. WHAT IS NEW: • This is the first transcultural adaptation and validation of IMPACT-III and IMPACT-III-P for Spanish p-IBD families. • These are valid and reliable instruments for assessing HRQoL in Spanish families of patients with p-IBD.

Is There an Over-Indication for Elective Tracheostomy in Patients With Oral Cavity Cancer?

OBJECTIVES: Temporary tracheostomies (TT) are often used in oral oncologic surgery to secure the postoperative airway. Our primary objective was to determine if there was an over-indication for elective tracheostomy in our population. If so, our secondary objective was to ascertain which patients could have possibly avoided TT. MATERIALS AND METHODS: We performed a retrospective study of patients with oral and oropharyngeal squamous cell carcinoma in which resection with curative intent and TT were performed. Variables collected included demographics, comorbidities, and complications. Additionally, we retrospectively applied the Cameron and TRACHY tracheostomy scoring systems to evaluate overall tracheostomy recommendations. RESULTS: A total of 116 elective tracheostomies were performed between January 2019 and December 2020. According to the Cameron and TRACHY scoring systems, recommendations for tracheostomy coincided in only 54.3% and 45.7%, respectively. Tumor anatomy and type of reconstruction were associated with less time until decannulation. Additionally, in patients without TT recommendation determined by both scores with tumor anatomy and location, as well as T and N stages were also associated with less time until decannulation. CONCLUSION: There appears to be an over-indication for elective tracheostomy in our patients with oral cavity and oropharyngeal cancer. The patients that could have potentially avoided elective TT were those with lateral anatomy, without flap or with fasciocutaneous flap, location in the mandibular alveolus or anterior tongue, as well as N0/N1 and T1/T2 patients.

Impact of IL6R genetic variants on treatment efficacy and toxicity response to sarilumab in rheumatoid arthritis.

BACKGROUND: Sarilumab, an IL-6 receptor antagonist, is a first-line biologic disease-modifying anti-rheumatic drug for rheumatoid arthritis. The identification of genetic biomarkers as predictors of response to sarilumab could allow for a personalized treatment strategy to improve clinical outcomes. METHODS: We conducted a retrospective cohort study of 62 patients treated with sarilumab to determine whether single-nucleotide polymorphisms (SNP) in the IL6R gene could predict efficacy and toxicity responses. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples obtained from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Treatment response was assessed six months after treatment initiation. Satisfactory response was based on EULAR criteria. Low disease activity was determined according to DAS28 and CDAI and quantitative improvements in DAS28 and CDAI scores. RESULTS: Three SNPs (rs4845625, rs4329505 and rs11265618) were significantly associated with response outcomes. All of the SNPs, except for rs12083537, had at least one significant association with dyslipidemia or hepatotoxicity. CONCLUSIONS: These findings support the potential clinical value of SNPs, particularly rs4845625, as potentially useful biomarkers to predict response to sarilumab in patients with RA.

Integrins Can Act as Suppressors of Ras-Mediated Oncogenesis in the Drosophila Wing Disc Epithelium.

Cancer is the second leading cause of death worldwide. Key to cancer initiation and progression is the crosstalk between cancer cells and their microenvironment. The extracellular matrix (ECM) is a major component of the tumour microenvironment and integrins, main cell-ECM adhesion receptors, are involved in every step of cancer progression. However, accumulating evidence has shown that integrins can act as tumour promoters but also as tumour suppressor factors, revealing that the biological roles of integrins in cancer are complex. This incites a better understating of integrin function in cancer progression. To achieve this goal, simple model organisms, such as Drosophila, offer great potential to unravel underlying conceptual principles. Here, we find that in the Drosophila wing disc epithelium the ßPS integrins act as suppressors of tumours induced by a gain of function of the oncogenic form of Ras, RasV12. We show that ßPS integrin depletion enhances the growth, delamination and invasive behaviour of RasV12 tumour cells, as well as their ability to affect the tumour microenvironment. These results strongly suggest that integrin function as tumour suppressors might be evolutionarily conserved. Drosophila can be used to understand the complex tumour modulating activities conferred by integrins, thus facilitating drug development.

Apnea or cyanosis as COVID-19 initial presentation in newborns.

INTRODUCTION: The clinical manifestation of coronavirus disease 2019 (COVID-19) infection in newborns varies from asymptomatic infection to severe illness. Apnea or cyanosis as the earliest symptoms is rarely mentioned. The aim of this study is to describe the characteristics of newborns with COVID-19 infection admitted to the neonatal intensive care unit considering cyanosis or apnea as a form of presentation. METHODOLOGY: This is a descriptive observational study with retrospectively collected data. All neonates under 30 days old and preterm infants with corrected gestational age of 44 weeks who had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with a positive antigen or reverse transcriptase polymerase chain reaction (RT-PCR) test and who were attended to between March 2020 and March 2022 were included. RESULTS: During the two years of the study, 410 patients were admitted to the neonatal unit. Twenty-six patients (6.3%) presented with confirmed SARS-CoV-2 infection. The main clinical characteristic at admission was apnea in 55% and cyanosis in 45%. Of the 11 patients admitted with this presentation, eight were diagnosed with COVID-19 acute upper respiratory disease, and three met the definition of COVID-19 bronchiolitis. A large proportion of the patients had a mild infection (65%, n = 17), 31% (n = 8) had a severe infection and only one patient had a critical infection, accounting for 4%. CONCLUSIONS: Apnea and cyanosis can be a manifestation of SARS-CoV-2 infection in newborns, which suggests the need to include it in the diagnostic workup as other viral respiratory infections.

The role of epidemic spreading in seizure dynamics and epilepsy surgery.

Epilepsy surgery is the treatment of choice for drug-resistant epilepsy patients, but only leads to seizure freedom for roughly two in three patients. To address this problem, we designed a patient-specific epilepsy surgery model combining large-scale magnetoencephalography (MEG) brain networks with an epidemic spreading model. This simple model was enough to reproduce the stereo-tactical electroencephalography (SEEG) seizure propagation patterns of all patients (N = 15), when considering the resection areas (RA) as the epidemic seed. Moreover, the goodness of fit of the model predicted surgical outcome. Once adapted for each patient, the model can generate alternative hypothesis of the seizure onset zone and test different resection strategies in silico. Overall, our findings indicate that spreading models based on patient-specific MEG connectivity can be used to predict surgical outcomes, with better fit results and greater reduction on seizure propagation linked to higher likelihood of seizure freedom after surgery. Finally, we introduced a population model that can be individualized by considering only the patient-specific MEG network, and showed that it not only conserves but improves the group classification. Thus, it may pave the way to generalize this framework to patients without SEEG recordings, reduce the risk of overfitting and improve the stability of the analyses.

Drosophila as Model System to Study Ras-Mediated Oncogenesis: The Case of the Tensin Family of Proteins.

Oncogenic mutations in the small GTPase Ras contribute to ~30% of human cancers. However, tissue growth induced by oncogenic Ras is restrained by the induction of cellular senescence, and additional mutations are required to induce tumor progression. Therefore, identifying cooperating cancer genes is of paramount importance. Recently, the tensin family of focal adhesion proteins, TNS1-4, have emerged as regulators of carcinogenesis, yet their role in cancer appears somewhat controversial. Around 90% of human cancers are of epithelial origin. We have used the Drosophila wing imaginal disc epithelium as a model system to gain insight into the roles of two orthologs of human TNS2 and 4, blistery (by) and PVRAP, in epithelial cancer progression. We have generated null mutations in PVRAP and found that, as is the case for by and mammalian tensins, PVRAP mutants are viable. We have also found that elimination of either PVRAP or by potentiates RasV12-mediated wing disc hyperplasia. Furthermore, our results have unraveled a mechanism by which tensins may limit Ras oncogenic capacity, the regulation of cell shape and growth. These results demonstrate that Drosophila tensins behave as suppressors of Ras-driven tissue hyperplasia, suggesting that the roles of tensins as modulators of cancer progression might be evolutionarily conserved.

Benefits of Paediatric to Adult Transition Programme in Inflammatory Bowel Disease: The BUTTERFLY Study of GETECCU and SEGHNP.

(1) Background: Transition is a planned movement of paediatric patients to adult healthcare systems, and its implementation is not yet established in all inflammatory bowel disease (IBD) units. The aim of the study was to evaluate the impact of transition on IBD outcomes. (2) Methods: Multicentre, retrospective and observational study of IBD paediatric patients transferred to an adult IBD unit between 2017-2020. Two groups were compared: transition (≥1 joint visit involving the gastroenterologist, the paediatrician, a programme coordinator, the parents and the patient) and no-transition. Outcomes within one year after transfer were analysed. The main variable was poor clinical outcome (IBD flare, hospitalisation, surgery or any change in the treatment because of a flare). Predictive factors of poor clinical outcome were identified with multivariable analysis. (3) Results: A total of 278 patients from 34 Spanish hospitals were included. One hundred eighty-five patients (67%) from twenty-two hospitals (65%) performed a structured transition. Eighty-nine patients had poor clinical outcome at one year after transfer: 27% in the transition and 43% in the no-transition group (p = 0.005). One year after transfer, no-transition patients were more likely to have a flare (36% vs. 22%; p = 0.018) and reported more hospitalisations (10% vs. 3%; p = 0.025). The lack of transition, as well as parameters at transfer, including IBD activity, body mass index < 18.5 and corticosteroid treatment, were associated with poor clinical outcome. One patient in the transition group (0.4%) was lost to follow-up. (4) Conclusion: Transition care programmes improve patients' outcomes after the transfer from paediatric to adult IBD units. Active IBD at transfer impairs outcomes.

Tau protein spreads through functionally connected neurons in Alzheimer's disease: a combined MEG/PET study.

Recent studies on Alzheimer's disease (AD) suggest that tau proteins spread through the brain following neuronal connections. Several mechanisms could be involved in this process: spreading between brain regions that interact strongly (functional connectivity); through the pattern of anatomical connections (structural connectivity); or simple diffusion. Using magnetoencephalography (MEG), we investigated which spreading pathways influence tau protein spreading by modelling the tau propagation process using an epidemic spreading model. We compared the modelled tau depositions with 18F-flortaucipir PET binding potentials at several stages of the AD continuum. In this cross-sectional study, we analysed source-reconstructed MEG data and dynamic 100-min 18F-flortaucipir PET from 57 subjects positive for amyloid-ß pathology [preclinical AD (n = 16), mild cognitive impairment (MCI) due to AD (n = 16) and AD dementia (n = 25)]. Cognitively healthy subjects without amyloid-ß pathology were included as controls (n = 25). Tau propagation was modelled as an epidemic process (susceptible-infected model) on MEG-based functional networks [in alpha (8-13 Hz) and beta (13-30 Hz) bands], a structural or diffusion network, starting from the middle and inferior temporal lobe. The group-level network of the control group was used as input for the model to predict tau deposition in three stages of the AD continuum. To assess performance, model output was compared to the group-specific tau deposition patterns as measured with 18F-flortaucipir PET. We repeated the analysis by using networks of the preceding disease stage and/or using regions with most observed tau deposition during the preceding stage as seeds. In the preclinical AD stage, the functional networks predicted most of the modelled tau-PET binding potential, with best correlations between model and tau-PET [corrected amplitude envelope correlation (AEC-c) alpha C = 0.584; AEC-c beta C = 0.569], followed by the structural network (C = 0.451) and simple diffusion (C = 0.451). Prediction accuracy declined for the MCI and AD dementia stages, although the correlation between modelled tau and tau-PET binding remained highest for the functional networks (C = 0.384; C = 0.376). Replacing the control-network with the network from the preceding disease stage and/or alternative seeds improved prediction accuracy in MCI but not in the dementia stage. These results suggest that in addition to structural connections, functional connections play an important role in tau spread, and highlight that neuronal dynamics play a key role in promoting this pathological process. Aberrant neuronal communication patterns should be taken into account when identifying targets for future therapy. Our results also suggest that this process is more important in earlier disease stages (preclinical AD/MCI); possibly, in later stages, other processes may be influential.

María Narcisa Isacia Agramonte Jiménez, primera mujer dentista en Lajas, Cienfuegos / María Narcisa Isacia Agramonte Jiménez, first woman dentist in Lajas, Cienfuegos

Introducción: Numerosas mujeres han contribuido al desarrollo de la estomatología en Cuba y en Cienfuegos. Sin embargo, en este sentido, existen escasas fuentes locales que aborden el accionar de las féminas. Objetivo: Profundizar en la vida y obra de la Dra. María Narcisa Isacia Agramonte Jiménez, de manera que se puedan rescatar elementos de la evolución histórica de la estomatología cienfueguera. Métodos: Se realizó una investigación de tipo histórico-biográfica en el período de octubre del 2016 a diciembre del 2020. Como forma de reseñar la historia se emplearon las memorias. Los métodos utilizados fueron analítico-sintético y deductivo-inductivo; y los submétodos empleados fueron el cronológico, la numismática, la diplomática y la iconografía. Para recolectar datos se emplearon técnicas de la investigación histórica: la revisión documental y las entrevistas. Como fuentes primarias de la investigación se consultaron documentos histórico-legales en el Registro del Estado Civil (2), y en la Universidad de La Habana (1), así como entrevistas orales a profundidad (13), con testimonios de informantes clave. Se realizó una búsqueda bibliográfica, con cuatro referencias de artículos y libros. Resultados: María Narcisa Isacia Agramonte Jiménez fue la primera mujer lajera dentista -negra además-, graduada en 1944, de clase media. Tuvo un accionar revolucionario notorio, posterior a 1959. Se destaca la donación de todos sus instrumentos al policlínico "Manuel Piti Fajardo" de Cruces, del cual fue dentista fundadora. Conclusiones: La vocación de la primera dentista lajera por la pedagogía y su compromiso con la causa revolucionaria fueron elementos de vital importancia en el desarrollo de la estomatología crucense(AU)

Introduction: Numerous women have contributed to the development of stomatology in Cuba and in Cienfuegos. However, in this sense, few local sources broach the lives of these women. Objective: To deepen in the life and work of Dr. María Narcisa Isacia Agramonte Jiménez, so that elements of the historical evolution of Cienfuegos stomatology can be rescued. Methods: A historical-biographical research was carried out from October 2016 to December 2020. Memoirs were used as a way of reviewing the history. The methods used were analytical-synthetic and deductive-inductive; and the sub-methods employed were chronological, numismatic, diplomatic and iconographic. Historical research techniques were used to collect data: documentary review and interviews. As primary sources of the research, historical-legal documents were consulted at the Civil Status Registry (2), and at the University of Havana (1), as well as oral interviews (13), with testimonies of key informants. A bibliographic search was carried out, with four references of articles and books. Results: María Narcisa Isacia Agramonte Jiménez was the first middle class female dentist from Lajas -also black-, graduated in 1944. She had an active revolutionary presence, after 1959. The donation of all her dental equipment to the "Manuel Piti Fajardo" polyclinic in Cruces, of which she was the founding dentist, stands out. Conclusions: The vocation of the first dentist from La Paz for pedagogy and her commitment to the revolutionary cause were elements of vital importance in the development of stomatology in Cruces(AU)

Dra. Mercedes Verónica Diego Cobelo en la historia de la Estomatología cienfueguera

Muchas son las mujeres que han contribuido al desarrollo de la Estomatología en Cuba. En Cienfuegos, se encuentra entre las más destacadas en dicho ámbito, la Dra. Mercedes Verónica Diego Cobelo, personalidad que este artículo se propone abordar mediante la descripción de los acontecimientos significativos de su vida y obra, pasando por su trayectoria en el plano estudiantil, laboral y político. Se realizó una investigación histórica, en el periodo de octubre a diciembre de 2016. Como forma de reseñar la historia se emplearon las memorias; así como los métodos analítico-sintético y deductivo-inductivo. Se emplearon técnicas de la investigación histórica: revisión documental; y entrevistas orales a profundidad con testimonio de la propia Mercedes, como fuente primaria de obtención de la información. Es considerada iniciadora de la docencia estomatológica y médica media en la provincia de Cienfuegos desde 1970, al participar en la inauguración de los servicios estomatológicos de todos sus municipios, además de ser elegida presidenta provincial de la Sociedad Cubana de Salud Pública. El estudio evidencia la trascendencia de su labor en el establecimiento de los servicios estomatológicos en Cienfuegos, su entrega a la docencia desde su etapa estudiantil, y la vinculación íntegra a la obra revolucionaria en todos los ámbitos.

There are many women who have contributed to the development of Stomatology in Cuba. In Cienfuegos, one of the most prominent in this field is Dr. Mercedes Verónica Diego Cobelo, a personality that this article intends to address through the description of the significant events of her life and work, going through her career in the student, labor and political fields. A historical research was carried out, from October to December 2016. As a way of reviewing the history, her memories were used; as well as the analytic-synthetic and deductive-inductive methods. Historical research techniques were used: documentary review; and in-depth oral interviews with testimony from Mercedes herself, as the primary source for obtaining the information. She is considered the initiator of stomatology and medical education in Cienfuegos province since 1970, by participating in the inauguration of the stomatology services of all its municipalities, in addition to being elected provincial president of the Cuban Society of Public Health. The study evidences the transcendence of her work in the establishment of stomatological services in Cienfuegos, her dedication to teaching from her student stage, and the integral link to the revolutionary work in all areas.

Real-world use of once-weekly semaglutide in patients with type 2 diabetes at an outpatient clinic in Spain.

Objectives: To investigate the use of once-weekly semaglutide in a real population of people with type 2 diabetes mellitus (T2DM) in three Spanish hospitals. Method: An observational, retrospective and multicenter clinical study was designed that included 166 participants with T2DM, distinguishing between a group naïve to GLP-1RA (n=72) and another switching from another GLP-1RA (n=94), all managed in the outpatient clinical setting. The primary endpoint was the change in HbA1c from baseline to the end of the study. The secondary endpoints included changes in body weight and the proportion of people with T2DM, achieving HbA1c <7.0% and body weight loss >5%. Results: After 24 months of follow-up, the reductions in HbA1c were -0.91 ± 0.7% (p<0.001) in the total cohort, -1.13 ± 1.38% (p<0.019) for GLP-1RA-naïve participants, and -0.74 ± 0.9% (p<0.023) for GLP-1RA-experienced participants. Body weight reductions were -12.42 ± 9.1% in GLP-1RA-naïve participants vs. -7.65 ± 9.7% in GLP-1RA-experienced participants (p<0.001). In the total cohort, 77.1% reached the objective of an HbA1c level <7%, and 12.7% reached between 7.1% and 7.5%. Additionally, 66.9% achieved a weight reduction ≥5%. Of all cohort, 90% received 1 mg of semaglutide once a week. The reported adverse events were consistent with the known safety profile of semaglutide. Conclusions: In routine clinical practice in Spain, the use of semaglutide once a week was associated with statistically significant and clinically relevant improvements in HbA1c and body weight in a wide range of adults with T2DM, without notable adverse effects, which supports real-world use.

Role of IL6R Genetic Variants in Predicting Response to Tocilizumab in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response.

The dual action of glioma-derived exosomes on neuronal activity: synchronization and disruption of synchrony.

Seizures represent a frequent symptom in gliomas and significantly impact patient morbidity and quality of life. Although the pathogenesis of tumor-related seizures is not fully understood, accumulating evidence indicates a key role of the peritumoral microenvironment. Brain cancer cells interact with neurons by forming synapses with them and by releasing exosomes, cytokines, and other small molecules. Strong interactions among neurons often lead to the synchronization of their activity. In this paper, we used an in vitro model to investigate the role of exosomes released by glioma cell lines and by patient-derived glioma stem cells (GSCs). The addition of exosomes released by U87 glioma cells to neuronal cultures at day in vitro (DIV) 4, when neurons are not yet synchronous, induces synchronization. At DIV 7-12 neurons become highly synchronous, and the addition of the same exosomes disrupts synchrony. By combining Ca2+ imaging, electrical recordings from single neurons with patch-clamp electrodes, substrate-integrated microelectrode arrays, and immunohistochemistry, we show that synchronization and de-synchronization are caused by the combined effect of (i) the formation of new neuronal branches, associated with a higher expression of Arp3, (ii) the modification of synaptic efficiency, and (iii) a direct action of exosomes on the electrical properties of neurons, more evident at DIV 7-12 when the threshold for spike initiation is significantly reduced. At DIV 7-12 exosomes also selectively boost glutamatergic signaling by increasing the number of excitatory synapses. Remarkably, de-synchronization was also observed with exosomes released by glioma-associated stem cells (GASCs) from patients with low-grade glioma but not from patients with high-grade glioma, where a more variable outcome was observed. These results show that exosomes released from glioma modify the electrical properties of neuronal networks and that de-synchronization caused by exosomes from low-grade glioma can contribute to the neurological pathologies of patients with brain cancers.

Krebs von den Lungen-6 glycoprotein circulating levels are not useful as prognostic marker in COVID-19 pneumonia: A large prospective cohort study.

Coronavirus disease 2019 (COVID-19) has rapidly expanded worldwide. Currently, there are no biomarkers to predict respiratory worsening in patients with mild to moderate COVID-19 pneumonia. Small studies explored the use of Krebs von de Lungen-6 circulating serum levels (sKL-6) as a prognostic biomarker of the worsening of COVID-19 pneumonia. We aimed at a large study to determine the prognostic value of sKL-6 in predicting evolving trends in COVID-19. We prospectively analyzed the characteristics of 836 patients with COVID-19 with mild lung disease on admission. sKL-6 was obtained in all patients at least at baseline and compared among patients with or without respiratory worsening. The receiver operating characteristic curve was used to find the optimal cutoff level. A total of 159 (19%) patients developed respiratory worsening during hospitalization. Baseline sKL-6 levels were not higher in patients who had respiratory worsening (median {IQR} 315.5 {209-469} vs. 306 {214-423} U/ml p = 0.38). The last sKL-6 and the change between baseline and last sKL-6 were higher in the respiratory worsening group (p = 0.02 and p < 0.0001, respectively). The best sKL-6 cutoff point for respiratory worsening was 497 U/ml (area under the curve 0.52; 23% sensitivity and 85% specificity). sKL-6 was not found to be an independent predictor of respiratory worsening. A conditional inference tree (CTREE) was not useful to discriminate patients at risk of worsening. We found that sKL-6 had a low sensibility to predict respiratory worsening in patients with mild-moderate COVID-19 pneumonia and may not be of use to assess the risk of present respiratory worsening in inpatients with COVID-19 pneumonia.

Effects of Fe and Mn Deficiencies on the Root Protein Profiles of Tomato (Solanum lycopersicum) Using Two-Dimensional Electrophoresis and Label-Free Shotgun Analyses.

Iron (Fe) and manganese (Mn) are two essential elements for plants that compete for the same uptake transporters and show conflicting interactions at the regulatory level. In order to understand the differential response to both metal deficiencies in plants, two proteomic techniques (two-dimensional gel electrophoresis and label-free shotgun) were used to study the proteome profiles of roots from tomato plants grown under Fe or Mn deficiency. A total of 119 proteins changing in relative abundance were confidently quantified and identified, including 35 and 91 in the cases of Fe deficiency and Mn deficiency, respectively, with 7 of them changing in both deficiencies. The identified proteins were categorized according to function, and GO-enrichment analysis was performed. Data showed that both deficiencies provoked a common and intense cell wall remodelling. However, the response observed for Fe and Mn deficiencies differed greatly in relation to oxidative stress, coumarin production, protein, nitrogen, and energy metabolism.

René Laurentino Miní Rodríguez Cobre y Carlos Manuel Miní Llorens, primeros dentistas en Lajas, Cienfuegos

RESUMEN Numerosas hechos y personalidades han formado parte de la evolución histórica de la Estomatología en Cienfuegos. El presente artículo tiene el objetivo de describir los acontecimientos significativos de la vida y obra de los doctores René Laurentino Miní Rodríguez Cobre y Carlos Manuel Miní Llorens. Se realizó una investigación de tipo histórica, mediante técnicas como la revisión documental y entrevistas orales a profundidad, con testimonios de informantes claves como fuente primaria de obtención de la información. También se consultaron documentos históricos legales. René Miní, una vez graduado en Estados Unidos, regresó a su natal Lajas para ejercer en ella como el primer dentista oficial. Dicho legado fue asumido por su hijo, continuador de la labor paterna, graduado de la Universidad de La Habana. Permanecieron en Cuba hasta 1972, cuando emigró a España toda la familia. El estudio de la vida y obra de estos profesionales de la Estomatología permitió conocer y patentar datos históricos acerca de los inicios de esta en Cienfuegos, especialmente en Lajas. Ambos pusieron a disposición de la población lo más avanzado en esta rama de la ciencia para inicios del siglo XX.

ABSTRACT Many events and personalities have been part of the Stomatology historical evolution in Cienfuegos. This article aims to describe the significant events in life and work of René Laurentino Miní Rodríguez Cobre and Carlos Manuel Miní Llorens doctors. A historical research was carried out, using techniques such as documentary review and in-depth oral interviews, with testimonies from key informants as the primary source for obtaining information. Historical legal documents were also consulted. René Miní, once graduated in the United States, returned to his native Lajas to practice there as the first official dentist. Said legacy was assumed by his son, follower of his father's work, graduated from the Havana University. They remained in Cuba until 1972, when the whole family emigrated to Spain. The study of the life and work of these Stomatology professionals allowed knowing and patenting historical data about the beginnings of this in Cienfuegos, especially in Lajas. Both made available to the population the most advanced in this branch of science at the beginning of the 20th century.

Epidemic models characterize seizure propagation and the effects of epilepsy surgery in individualized brain networks based on MEG and invasive EEG recordings.

Epilepsy surgery is the treatment of choice for drug-resistant epilepsy patients. However, seizure-freedom is currently achieved in only 2/3 of the patients after surgery. In this study we have developed an individualized computational model based on MEG brain networks to explore seizure propagation and the efficacy of different virtual resections. Eventually, the goal is to obtain individualized models to optimize resection strategy and outcome. We have modelled seizure propagation as an epidemic process using the susceptible-infected (SI) model on individual brain networks derived from presurgical MEG. We included 10 patients who had received epilepsy surgery and for whom the surgery outcome at least one year after surgery was known. The model parameters were tuned in in order to reproduce the patient-specific seizure propagation patterns as recorded with invasive EEG. We defined a personalized search algorithm that combined structural and dynamical information to find resections that maximally decreased seizure propagation for a given resection size. The optimal resection for each patient was defined as the smallest resection leading to at least a 90% reduction in seizure propagation. The individualized model reproduced the basic aspects of seizure propagation for 9 out of 10 patients when using the resection area as the origin of epidemic spreading, and for 10 out of 10 patients with an alternative definition of the seed region. We found that, for 7 patients, the optimal resection was smaller than the resection area, and for 4 patients we also found that a resection smaller than the resection area could lead to a 100% decrease in propagation. Moreover, for two cases these alternative resections included nodes outside the resection area. Epidemic spreading models fitted with patient specific data can capture the fundamental aspects of clinically observed seizure propagation, and can be used to test virtual resections in silico. Combined with optimization algorithms, smaller or alternative resection strategies, that are individually targeted for each patient, can be determined with the ultimate goal to improve surgery outcome. MEG-based networks can provide a good approximation of structural connectivity for computational models of seizure propagation, and facilitate their clinical use.

Real-World Treatment Patterns and Clinical Outcomes of Baricitinib in Rheumatoid Arthritis Patients in Spain: Results of a Multicenter, Observational Study in Routine Clinical Practice (The ORBIT-RA Study).

INTRODUCTION: Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved to treat rheumatoid arthritis (RA). This study aimed to investigate patients' characteristics, prescription patterns, effectiveness, and treatment persistence in patients receiving baricitinib in real-world practice in Spain. METHODS: This retrospective longitudinal cohort study conducted in five rheumatology units included adults with RA initiating baricitinib (Sep-2017-May-19) with at least a 6-month-follow-up. Demographic/clinical characteristics, prescription patterns, and changes in disease activity and pain level were collected until treatment discontinuation/end of follow-up. Treatment persistence was estimated by Kaplan-Meier methods. RESULTS: Data from 182 patients were included (mean (SD)): 83.5% women, 62.2 (12.3) years, body mass index 26.8 (5.1), disease duration 13.2 (10.8) years and Charlson Comorbidity Index score 2.4 (2.0). All patients had received at least one conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) before starting baricitinib and 78.0% at least one biologic disease-modifying anti-rheumatic drugs (bDMARD). Furthermore, 90.1% started with baricitinib 4 mg/day; 43.4% in monotherapy. One hundred and twelve (61.5%) of patients continued baricitinib at data collection time; mean persistence was 14.1 (0.5) months. Overall treatment persistence was 79.7/64.8/59.1% at 6/12/18 months. Seventy (38.5%) patients discontinued baricitinib during follow-up due to loss of efficacy (68.6%) or adverse events (18.6%). In those patients with available scores at the different observed cut-off points, remission or low disease activity was reported in 71.6 and 76.3% of patients at 6/12 months at any index: Disease Activity Score 28 joints using erythrocyte sedimentation rate (DAS28-ESR) (73.1 and 73.5%), Simplified Disease Activity Index (SDAI) (62.4 and 75.0%), and Clinical Disease Activity Index (CDAI) (66.7 and 78.1%). Good or moderate European League Against Rheumatism (EULAR)-response was noted in 80.0 and 78.2% of patients, respectively. Improvement from baseline in pain (Visual Analog Scale) was 2.5 cm and 3.0 cm at 6/12 months, respectively. CONCLUSIONS: This Spanish cohort of patients treated with baricitinib had a long-standing and refractory disease. Nevertheless, high persistence and improvements in disease activity and pain were found at 6 and 12 months after treatment initiation, independently of the composite disease activity measure used, reinforcing the effectiveness of baricitinib in routine clinical practice.