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Resumen: La medicina ha evolucionado en positivo a lo largo de mi vida profesional. Es actualmente más resolutiva y respetuosa y menos invasiva que hace unas décadas. La prueba de ello es que la esperanza de vida ha aumentado y la salud general de la población es claramente mejor. No obstante, parece que hay cierta discordancia entre estos datos objetivos y la autopercepción de la salud por parte de una buena parte de la población. Se apuntan diversas posibles causas, entre las que destaca la progresiva tecnificación de la medicina a costa, frecuentemente, de una pérdida de valores humanísticos de la profesión. A partir de estas premisas se reflexiona acerca de posibles acciones encaminadas a paliar este problema. Abstract: Medicine has evolved positively throughout my professional life. It is currently more decisive and respectful, and less invasive than a few decades ago. The proof of this is that life expectancy has increased and the general health of the population is clearly better. However, there seems to be some discrepancy between these objective data and the self-perception of health by a large part of the population. Various possible causes are pointed out, among which stands out the progressive technification of medicine at the cost, frequently, of a loss of humanistic values of the profession. From these premises, we ponder on possible actions aimed at alleviating this problem.

Abstract 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.

IntroductionThis was an ambispective cohort study evaluating the prognostic significance of lymphocytic foci and its lymphoid composition in minor salivary gland biopsy (MSGB) for short-term disease flare and severity in Sjögren’s syndrome (SS).MethodsThe inclusion criteria comprised individuals meeting the ACR/EULAR 2016 criteria who underwent MSGB with an infiltration of more than 50 lymphocytes and received clinical diagnosis between September 2017 and December 2018. Patients with inadequate biopsy samples were excluded. The number of lymphocytic foci and their lymphoid composition in MSGB were assessed using immunofluorescence staining. Major organ damage and improvements in the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) were measured. Statistical analyses, including Cox and linear regressions, were conducted.ResultsA total of 78 patients with at least one lymphocytic focus were included in the study. The presence of higher T-cell counts in lymphocytic foci in MSGB was associated with severe disease flare, and a logarithmic transformation of T-cell count indicated increased risk (HR 1.96, 95% CI 0.91-4.21). Improvements in the ESSDAI were associated with higher total lymphocyte count and T- and B-cell numbers in the lymphoid composition of the lymphocytic foci. Seropositive patients exhibited higher T CD4+ cell numbers. Correlation analysis showed negative associations between age and lymphocytic foci and the T-cell count. Positive correlations were observed between antinuclear antibody (ANA) titers and total lymphocyte numbers.DiscussionPatients with a higher number of T cells in the lymphocytic infiltrates of lymphocytic foci may have a two-fold risk of severe disease flare. The number of B cells and T CD4+ cells in the lymphocytic infiltrates of lymphocytic foci showed a weak but positive relation with the ESSDAI improvement during follow-up. Age and seropositivity appeared to influence the lymphoid composition of the lymphocytic foci.

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.

Abstract The main goal of the H2020-CARAMEL project is to address the cybersecurity gaps introduced by the new technological domains adopted by modern vehicles applying, among others, advanced Artificial Intelligence and Machine Learning techniques. As a result, CARAMEL enhances the protection against threats related to automated driving, smart charging of Electric Vehicles, and communication among vehicles or between vehicles and the roadside infrastructure. This work focuses on the latter and presents the CARAMEL architecture aiming at assessing the integrity of the information transmitted by vehicles, as well as at improving the security and privacy of communication for connected and autonomous driving. The proposed architecture includes: (1) multi-radio access technology capabilities, with simultaneous 802.11p and LTE-Uu support, enabled by the connectivity infrastructure; (2) a MEC platform, where, among others, algorithms for detecting attacks are implemented; (3) an intelligent On-Board Unit with anti-hacking features inside the vehicle; (4) a Public Key Infrastructure that validates in real-time the integrity of vehicle’s data transmissions. As an indicative application, the interaction between the entities of the CARAMEL architecture is showcased in case of a GPS spoofing attack scenario. Adopted attack detection techniques exploit robust in-vehicle and cooperative approaches that do not rely on encrypted GPS signals, but only on measurements available in the CARAMEL architecture.

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.

Objective: We set out to analyze the incidence and predictive factors of pulmonary embolism (PE) in hospitalized patients with Covid-19.Methods: We prospectively collected data from all consecutive patients with laboratory-confirmed Covid-19 admitted to the Hospital de la Santa Creu i Sant Pau, a university hospital in Barcelona, between March 9 and April 15, 2020. Patients with suspected PE, according to standardized guidelines, underwent CT pulmonary angiography (CTPA).Results: A total of 1,275 patients with Covid-19 were admitted to hospital. CTPA was performed on 76 inpatients, and a diagnosis of PE was made in 32 (2.6% [95%CI 1.7–3.5%]). Patients with PE were older, and they exhibited lower PaO2:FiO2 ratios and higher levels of D-dimer and C-reactive protein (CRP). They more often required admission to ICU and mechanical ventilation, and they often had longer hospital stays, although in-hospital mortality was no greater than in patients without PE. High CRP and D-dimer levels at admission (≥150 mg/L and ≥1,000 ng/ml, respectively) and a peak D-dimer ≥6,000 ng/ml during hospital stay were independent factors associated with PE. Prophylactic low molecular weight heparin did not appear to prevent PE. Increased CRP levels correlated with increased D-dimer levels and both correlated with a lower PaO2:FiO2.Conclusions: The 2.6% incidence of PE in Covid-19 hospitalized patients is clearly high. Higher doses of thromboprophylaxis may be required to prevent PE, particularly in patients at increased risk, such as those with high levels of CRP and D-dimer at admission. These findings should be validated in future studies.

Summary: The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once. These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop. Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1–7)/Mas1R axis. The viral feedback loop includes evading the host's innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response. The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm. Downregulation of the ACE2/Ang-(1–7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS. The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop. The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.

Systemic sclerosis is a disease where microcirculation damage is critical in their beginning and vascular complications have similar pathogenic findings. Digital ulcers are a frequent complication in systemic sclerosis patients and pulmonary hypertension is one of the leading causes of death. The use of bosentan has been shown to be useful for the treatment of pulmonary arterial hypertension and to prevent new digital ulcers. However, is unknown if bosentan can prevent pulmonary hypertension. Our objective was to determine if bosentan is useful to prevent pulmonary hypertension in SSc patients. A retrospective study in 237 systemic sclerosis patients with digital ulcers history treated or not with bosentan to prevent it was made. We analyzed the occurrence of pulmonary hypertension defined by an echocardiogram pulmonary arterial pressure > 40 mmHg in the entire cohort. Demographic, clinical, and treatment variables were recorded for all patients. Statistical significance was denoted by p values < 0.05. Fifty-nine patients were treated with bosentan a median of 34 months. 13.8% of treated patients had pulmonary hypertension vs 23.7% of untreated patients (p 0.13) during the follow up. In multivariate analysis patients not treated with bosentan had 3.9fold-increased risk of pulmonary hypertension compared with patients under bosentan treatment (p < 0.02). Moreover the percentage carbon monoxide diffusing capacity (DLCO) in bosentan treated patients did not decrease from baseline to the end of follow-up (61.8±14% vs 57±20.1%, p = 0.89). We concluded that Systemic sclerosis patients with digital ulcers treated with bosentan seems to have less risk to develop pulmonary hypertension and to stabilize DLCO.

Introducción: La asignatura de fisiopatología y semiología clínica, correspondiente a la antigua patología general, se sigue impartiendo en la mayoría de facultades españolas con un formato muy clásico. Los alumnos suelen ir recopilando información a lo largo del curso para estudiarla y memorizarla al acercarse los exámenes. Con el objetivo de estimular un estudio más activo y continuado, presentamos una experiencia docente basada en la resolución voluntaria de casos clínicos de pequeño formato al finalizar cada uno de los bloques temáticos de la asignatura. Material y métodos: Los alumnos dispusieron, después de cada bloque temático, de unos 7-8 casos clínicos (53 a lo largo del curso) que debían resolver en el plazo de 15 días. Tras este período los profesores facilitamos unos comentarios y reflexiones respecto a cada caso para que los alumnos se autoevaluasen. El hecho de resolver los mini-casos no se tuvo en cuenta en la evaluación final de la asignatura. Resultados: Los alumnos que resolvieron más asiduamente los casos planteados obtuvieron mejores notas (8,0 ± 1,2 versus 6,8 ± 1,3; p

Resumen: La metodología docente de muchas asignaturas debe ser replanteada. En un entorno donde los médicos disponen de mucha información de acceso inmediato en formatos diversos, la memorización de conceptos expuestos en clases magistrales seguida de una evaluación mediante pruebas de respuesta múltiple es claramente obsoleta. El aprendizaje debería fundamentarse en un trabajo activo por parte del estudiante, basado en la resolución de situaciones que simulen lo que en el futuro se encontrará en el trabajo clínico cotidiano. En este contexto, y conscientes de la enorme dificultad que representa un cambio de este calado, se comenta el interés de ensayar nuevas experiencias docentes, como la que se expone en este mismo número de Educación Médica. Solo una participación más activa de los estudiantes en su aprendizaje, en la que los profesores se conviertan en acompañantes más que en protagonistas, puede garantizar la formación que deseamos que alcancen los médicos del siglo xxi. Abstract: The teaching methodology of many subjects must be rethought. In an environment where physicians have a lot of immediate access information in different formats, the memorization of concepts exposed in classical lectures followed by a multiple-choice test is clearly obsolete. The process of learning should be based on an active work by the student based on the resolution of situations that simulate what in the future will be found in the daily clinical work. In this context and aware of the enormous difficulty of a change of this depth, the interest of rehearsing new teaching experiences such as the one discussed in this same issue of Educación Médica is discussed. Only a more active participation of the students in their learning, in which the teachers become companions rather than protagonists, can guarantee the training that we want the doctors of the XXI century to achieve. Palabras clave: Educación médica, Experiencia docente, Aprendizaje activo, Fisiopatología, Semiología clínica, Patología general, Keywords: Medical education, Teaching experience, Active learning, Pathophysiology, Clinical semiotics, General pathology

Energy-efficient communication is one of the main concerns of wireless sensor networks nowadays. A commonly employed approach for achieving energy efficiency has been the use of duty-cycled operation of the radio, where the node’s transceiver is turned off and on regularly, listening to the radio channel for possible incoming communication during its on-state. Nonetheless, such a paradigm performs poorly for scenarios of low or bursty traffic because of unnecessary activations of the radio transceiver. As an alternative technology, Wake-up Radio (WuR) systems present a promising energy-efficient network operation, where target devices are only activated in an on-demand fashion by means of a special radio signal and a WuR receiver. In this paper, we analyze a novel wake-up radio approach that integrates both data communication and wake-up functionalities into one platform, providing a reconfigurable radio operation. Through physical experiments, we characterize the delay, current consumption and overall operational range performance of this approach under different transmit power levels. We also present an actual single-hop WuR application scenario, as well as demonstrate the first true multi-hop capabilities of a WuR platform and simulate its performance in a multi-hop scenario. Finally, by thorough qualitative comparisons to the most relevant WuR proposals in the literature, we state that the proposed WuR system stands out as a strong candidate for any application requiring energy-efficient wireless sensor node communications.

Femoral neck geometry parameters are believed to be as good as bone mineral density as independent factors in predicting hip fracture risk. This study was conducted to analyze the roles of genetic and environmental factors in femoral properties measured in a sample of Spanish families with osteoporotic fractures and extended genealogy. The "Genetic Analysis of Osteoporosis (GAO) Project" involved 11 extended families with a total number of 376 individuals. We studied three categorical phenotypes of particular clinical interest and we used a Hip structural analysis based on DXA to analyze 17 strength and geometrical phenotypes of the hip. All the femoral properties had highly significant heritability, ranging from 0.252 to 0.586. The most significant correlations were observed at the genetic level (ρG). Osteoporotic fracture status (Affected 2) and, particularly, low bone mass and osteoporotic condition (Affected 3) had the highest number of significant genetic correlations with diverse femoral properties. In conclusion, our findings suggest that a relatively simple and easy to use method based on DXA studies can provide useful data on properties of the Hip in clinical practice. Furthermore, our results provide a strong motivation for further studies in order to improve the understanding of the pathophysiological mechanism underlying bone architecture and the genetics of osteoporosis.

Wireless Sensor Networks (WSNs) are attracting more and more interest since they offer a low-cost solution to the problem of providing a means to deploy large sensor networks in a number of application domains. We believe that a crucial aspect to facilitate WSN diffusion is to make them interoperable with external IP networks. This can be achieved by using the 6LoWPAN protocol stack. 6LoWPAN enables the transmission of IPv6 packets over WSNs based on the IEEE 802.15.4 standard. IPv6 packet size is considerably larger than that of IEEE 802.15.4 data frame. To overcome this problem, 6LoWPAN introduces an adaptation layer between the network and data link layers, allowing IPv6 packets to be adapted to the lower layer constraints. This adaptation layer provides fragmentation and header compression of IP packets. Furthermore, it also can be involved in routing decisions. Depending on which layer is responsible for routing decisions, 6LoWPAN divides routing in two categories: mesh under if the layer concerned is the adaptation layer and route over if it is the network layer. In this paper we analyze different routing solutions (route over, mesh under and enhanced route over) focusing on how they forward fragments. We evaluate their performance in terms of latency and energy consumption when transmitting IP fragmented packets. All the tests have been performed in a real 6LoWPAN implementation. After consideration of the main problems in forwarding of mesh frames in WSN, we propose and analyze a new alternative scheme based on mesh under, which we call controlled mesh under.

Altered mitochondrial DNA (mtDNA) levels have been associated with common diseases in humans. We investigated the genetic mechanism that controls mtDNA levels using genome-wide linkage analyses in families from the Genetic Analysis of Idiopathic Thrombophilia Project (GAIT). We measure mtDNA levels by quantitative real-time PCR in 386 subjects from 21 extended Spanish families. A variance component linkage method using 485 microsatellites was conducted to evaluate linkage and to detect quantitative trait loci (QTLs) involved in the control of mtDNA levels. The heritalibility of mtDNA levels was 0.33 (p=1.82e-05). We identified a QTL on Chromosome 2 (LOD=2.21) using all of the subjects, independently on their sex. When females and males were analysed separately, three QTLs were identified. Females showed the same QTL on Chromosome 2 (LOD=3.09), indicating that the QTL identified in the analysis using all of the subjects was a strong female QTL, and another one on Chromosome 3 (LOD=2.67), whereas in males a QTL was identified on Chromosome 1 (LOD=2.81). These QTLs were fine-mapped to find associations with mtDNA levels. The most significant SNP association was for the rs10888838 on Chromosome 1 in males. This SNP mapped to the gene MRPL37, involved in mitochondrial protein translation. The rs2140855 on Chromosome 2 showed association in the analysis using all of the subjects. It was near the gene CMPK2, which encodes a mitochondrial enzyme of the salvage pathway of deoxyribonucleotide synthesis. Our results provide evidence of a sex-specific genetic mechanism for the control of mtDNA levels and provide a framework to identify new genes that influence mtDNA levels.