Efficacy and Safety of Dupilumab for the Treatment of Severe Atopic Dermatitis in Clinical Practice: A Single Center Experience / Eficacia y seguridad de dupilumab para el tratamiento de la dermatitis atópica grave en la práctica clínica: experiencia en un centro terciario

Background Dupilumab is a new targeted therapy for severe atopic dermatitis (AD) with limited real-world evidence. Objective Explore our experience with dupilumab for AD in clinical practice at a tertiary care center. Material and method Unicentric observational retrospective study including adult and pediatric patients with severe AD receiving dupilumab between December 2017 and December 2021. The Eczema Area and Severity Index (EASI) score, Pruritus Numerical Rating Scale (P-NRS) and Sleep disturbance Numerical Rating Scale (S-NRS) were recovered to assess severity and response. Results Fifty-nine patients received dupilumab: 52, 48, 26 and 13 patients reached 6, 12, 24 and 36 months of treatment, respectively. The EASI-75 response rates were 94.2%, 95.8%, 92.3% and 100% at months 6, 12, 24 and 36. The EASI-90 response rates were 63.5%, 72.9%, 84.6% and 92.3% at months 6, 12, 24 and 36. The EASI <7 response rates were 92.3%, 91.7%, 88.5% and 100% at months 6, 12, 24 and 36. The P-NRS ≥4 reduction rates were 86%, 87.5%, 92.3% and 100% at months 6, 12, 24 and 36. The S-NRS ≥4 reduction rates were 82.7%, 85.4%, 100% and 100% at months 6, 12, 24 and 36. Adverse events were mild and occurred in 20.3% of patients, all of them adults. Conclusion Our findings support dupilumab's favorable efficacy and tolerability profile in clinical practice. Dupilumab offers a rapid and sustained response, regardless of combined therapy. Longer follow-ups are still required to adequately assess its performance (AU)

Antecedentes Dupilumab es una nueva terapia dirigida para la dermatitis atópica (DA) grave con una evidencia en la vida real aún limitada. Objetivo Explorar nuestra experiencia con dupilumab para la DA en práctica clínica en un centro terciario. Material y método Estudio observacional retrospectivo y unicéntrico que incluye pacientes adultos y pediátricos con DA grave en tratamiento con dupilumab entre diciembre de 2017 y diciembre de 2021. La gravedad y la respuesta se evaluaron con las escalas Eczema Area and Severity Index (EASI), Pruritus Numerical Rating Scale y Sleep Disturbance Numerical Rating Scale. Resultado Cincuenta y nueve pacientes recibieron dupilumab: 52, 48, 26 y 13 pacientes alcanzaron los 6, 12, 24 y 36 meses de tratamiento, respectivamente. La tasa de EASI-75 fue del 94,2; 95,8; 92,3 y 100% a los 6, 12, 24 y 36 meses, respectivamente. La tasa de EASI-90 fue del 63,5; 72,9; 84,6 y 92,3% a los 6, 12, 24 y 36 meses, respectivamente. La tasa de EASI <7 fue del 92,3; 91,7; 88,5 y 100% a los 6, 12, 24 y 36 meses, respectivamente. La Pruritus Numerical Rating Scale ≥4 fue del 86; 87,5; 92,3 y 100% a los 6, 12, 24 y 36 meses, respectivamente. La tasa de reducción Sleep Disturbance Numerical Rating Scale ≥4 fue del 82,7; 85,4; 100 y 100% a los 6, 12, 24 y 36 meses, respectivamente. Los eventos adversos fueron leves y ocurrieron en el 20,3% de los pacientes, todos adultos. Conclusión Nuestros hallazgos apoyan el perfil favorable de eficacia y tolerabilidad de dupilumab en práctica clínica real. Dupilumab ofrece una respuesta rápida y mantenida, independientemente del uso de terapia combinada. Se requieren seguimientos más prolongados para evaluar su funcionamiento a largo plazo (AU)

[Artículo traducido]Eficacia y seguridad de dupilumab para el tratamiento de la dermatitis atópica grave en la práctica clínica: experiencia en un centro terciario / Efficacy and Safety of Dupilumab for the Treatment of Severe Atopic Dermatitis in Clinical Practice: A Single Center Experience

Antecedentes Dupilumab es una nueva terapia dirigida para la dermatitis atópica (DA) grave con una evidencia en la vida real aún limitada. Objetivo Explorar nuestra experiencia con dupilumab para la DA en práctica clínica en un centro terciario. Material y método Estudio observacional retrospectivo y unicéntrico que incluye pacientes adultos y pediátricos con DA grave en tratamiento con dupilumab entre diciembre de 2017 y diciembre de 2021. La gravedad y la respuesta se evaluaron con las escalas Eczema Area and Severity Index (EASI), Pruritus Numerical Rating Scale y Sleep Disturbance Numerical Rating Scale. Resultados Cincuenta y nueve pacientes recibieron dupilumab: 52, 48, 26 y 13 pacientes alcanzaron los 6, 12, 24 y 36 meses de tratamiento, respectivamente. La tasa de EASI-75 fue del 94,2; 95,8; 92,3 y 100% a los 6, 12, 24 y 36 meses, respectivamente. La tasa de EASI-90 fue del 63,5; 72,9; 84,6 y 92,3% a los 6, 12, 24 y 36 meses, respectivamente. La tasa de EASI <7 fue del 92,3; 91,7; 88,5 y 100% a los 6, 12, 24 y 36 meses, respectivamente. La Pruritus Numerical Rating Scale ≥4 fue del 86; 87,5; 92,3 y 100% a los 6, 12, 24 y 36 meses, respectivamente. La tasa de reducción Sleep Disturbance Numerical Rating Scale ≥4 fue del 82,7; 85,4; 100 y 100% a los 6, 12, 24 y 36 meses, respectivamente. Los eventos adversos fueron leves y ocurrieron en el 20,3% de los pacientes, todos adultos. Conclusión Nuestros hallazgos apoyan el perfil favorable de eficacia y tolerabilidad de dupilumab en práctica clínica real. Dupilumab ofrece una respuesta rápida y mantenida, independientemente del uso de terapia combinada. Se requieren seguimientos más prolongados para evaluar su funcionamiento a largo plazo (AU)

Background Dupilumab is a new targeted therapy for severe atopic dermatitis (AD) with limited real-world evidence. Objective Explore our experience with dupilumab for AD in clinical practice at a tertiary care center. Material and method Unicentric observational retrospective study including adult and pediatric patients with severe AD receiving dupilumab between December 2017 and December 2021. The Eczema Area and Severity Index (EASI) score, Pruritus Numerical Rating Scale (P-NRS) and Sleep disturbance Numerical Rating Scale (S-NRS) were recovered to assess severity and response. Results Fifty-nine patients received dupilumab: 52, 48, 26 and 13 patients reached 6, 12, 24 and 36 months of treatment, respectively. The EASI-75 response rates were 94.2%, 95.8%, 92.3% and 100% at months 6, 12, 24 and 36. The EASI-90 response rates were 63.5%, 72.9%, 84.6% and 92.3% at months 6, 12, 24 and 36. The EASI <7 response rates were 92.3%, 91.7%, 88.5% and 100% at months 6, 12, 24 and 36. The P-NRS ≥4 reduction rates were 86%, 87.5%, 92.3% and 100% at months 6, 12, 24 and 36. The S-NRS ≥4 reduction rates were 82.7%, 85.4%, 100% and 100% at months 6, 12, 24 and 36. Adverse events were mild and occurred in 20.3% of patients, all of them adults. Conclusion Our findings support dupilumab's favorable efficacy and tolerability profile in clinical practice. Dupilumab offers a rapid and sustained response, regardless of combined therapy. Longer follow-ups are still required to adequately assess its performance (AU)

Efficacy and Safety of Dupilumab for the Treatment of Severe Atopic Dermatitis in Clinical Practice: A Single Center Experience. / [Artículo traducido]Eficacia y seguridad de dupilumab para el tratamiento de la dermatitis atópica grave en la práctica clínica: experiencia en un centro terciario.

BACKGROUND: Dupilumab is a new targeted therapy for severe atopic dermatitis (AD) with limited real-world evidence. OBJECTIVE: Explore our experience with dupilumab for AD in clinical practice at a tertiary care center. MATERIAL AND METHOD: Unicentric observational retrospective study including adult and pediatric patients with severe AD receiving dupilumab between December 2017 and December 2021. The Eczema Area and Severity Index (EASI) score, Pruritus Numerical Rating Scale (P-NRS) and Sleep disturbance Numerical Rating Scale (S-NRS) were recovered to assess severity and response. RESULTS: Fifty-nine patients received dupilumab: 52, 48, 26 and 13 patients reached 6, 12, 24 and 36 months of treatment, respectively. The EASI-75 response rates were 94.2%, 95.8%, 92.3% and 100% at months 6, 12, 24 and 36. The EASI-90 response rates were 63.5%, 72.9%, 84.6% and 92.3% at months 6, 12, 24 and 36. The EASI <7 response rates were 92.3%, 91.7%, 88.5% and 100% at months 6, 12, 24 and 36. The P-NRS ≥4 reduction rates were 86%, 87.5%, 92.3% and 100% at months 6, 12, 24 and 36. The S-NRS ≥4 reduction rates were 82.7%, 85.4%, 100% and 100% at months 6, 12, 24 and 36. Adverse events were mild and occurred in 20.3% of patients, all of them adults. CONCLUSION: Our findings support dupilumab's favorable efficacy and tolerability profile in clinical practice. Dupilumab offers a rapid and sustained response, regardless of combined therapy. Longer follow-ups are still required to adequately assess its performance.

Efficacy and Safety of Dupilumab for the Treatment of Severe Atopic Dermatitis in Clinical Practice: A Single Center Experience.

BACKGROUND: Dupilumab is a new targeted therapy for severe atopic dermatitis (AD) with limited real-world evidence. OBJECTIVE: Explore our experience with dupilumab for AD in clinical practice at a tertiary care center. MATERIAL AND METHOD: Unicentric observational retrospective study including adult and pediatric patients with severe AD receiving dupilumab between December 2017 and December 2021. The Eczema Area and Severity Index (EASI) score, Pruritus Numerical Rating Scale (P-NRS) and Sleep disturbance Numerical Rating Scale (S-NRS) were recovered to assess severity and response. RESULTS: Fifty-nine patients received dupilumab: 52, 48, 26 and 13 patients reached 6, 12, 24 and 36 months of treatment, respectively. The EASI-75 response rates were 94.2%, 95.8%, 92.3% and 100% at months 6, 12, 24 and 36. The EASI-90 response rates were 63.5%, 72.9%, 84.6% and 92.3% at months 6, 12, 24 and 36. The EASI <7 response rates were 92.3%, 91.7%, 88.5% and 100% at months 6, 12, 24 and 36. The P-NRS ≥4 reduction rates were 86%, 87.5%, 92.3% and 100% at months 6, 12, 24 and 36. The S-NRS ≥4 reduction rates were 82.7%, 85.4%, 100% and 100% at months 6, 12, 24 and 36. Adverse events were mild and occurred in 20.3% of patients, all of them adults. CONCLUSION: Our findings support dupilumab's favorable efficacy and tolerability profile in clinical practice. Dupilumab offers a rapid and sustained response, regardless of combined therapy. Longer follow-ups are still required to adequately assess its performance.

A deep learning approach to the automatic detection of alignment errors in cryo-electron tomographic reconstructions.

Electron tomography is an imaging technique that allows for the elucidation of three-dimensional structural information of biological specimens in a very general context, including cellular in situ observations. The approach starts by collecting a set of images at different projection directions by tilting the specimen stage inside the microscope. Therefore, a crucial preliminary step is to precisely define the acquisition geometry by aligning all the tilt images to a common reference. Errors introduced in this step will lead to the appearance of artifacts in the tomographic reconstruction, rendering them unsuitable for the sample study. Focusing on fiducial-based acquisition strategies, this work proposes a deep-learning algorithm to detect misalignment artifacts in tomographic reconstructions by analyzing the characteristics of these fiducial markers in the tomogram. In addition, we propose an algorithm designed to detect fiducial markers in the tomogram with which to feed the classification algorithm in case the alignment algorithm does not provide the location of the markers. This open-source software is available as part of the Xmipp software package inside of the Scipion framework, and also through the command-line in the standalone version of Xmipp.

Pharmacogenetic biomarkers for secukinumab response in psoriasis patients in real-life clinical practice.

BACKGROUND: Prediction of the response to a biological treatment in psoriasis patients would allow efficient treatment allocation. OBJECTIVE: To identify polymorphisms associated with secukinumab response in psoriasis patients in a daily practice setting. METHODS: We studied 180 SNPs in patients with moderate-to-severe plaque psoriasis recruited from 15 Spanish hospitals. Treatment effectiveness was evaluated by absolute PASI ≤3 and ≤1 at 6 and 12 months. Individuals were genotyped using a custom Taqman array. Multiple logistic regression models were generated. Sensitivity, specificity and area under the curve (AUC) were analysed. RESULTS: A total of 173 patients were studied at 6 months, (67% achieved absolute PASI ≤ 3 and 65% PASI ≤ 1) and 162 at 12 months (75% achieved absolute PASI ≤ 3 and 64% PASI ≤ 1). Multivariable analysis showed the association of different sets of SNPs with the response to secukinumab. The model of absolute PASI≤3 at 6 months showed best values of sensitivity and specificity. Four SNPs were associated with the capability of achieving absolute PASI ≤ 3 at 6 months. rs1801274 (FCGR2A), rs2431697 (miR-146a) and rs10484554 (HLCw6) were identified as risk factors for failure to achieve absolute PASI≤3, while rs1051738 (PDE4A) was protective. AUC including these genotypes, weight of patients and history of biological therapy was 0.88 (95% CI 0.83-0.94), with a sensitivity of 48.6% and specificity of 95.7% to discriminate between both phenotypes. CONCLUSION: We have identified a series of polymorphisms associated with the response to secukinumab capable of predicting the potential response/non-response to this drug in patients with plaque psoriasis.

A new algorithm for particle weighted subtraction to decrease signals from unwanted components in single particle analysis.

Single particle analysis (SPA) in cryo-electron microscopy (cryo-EM) is highly used to obtain the near-atomic structure of biological macromolecules. The current methods allow users to produce high-resolution maps from many samples. However, there are still challenging cases that require extra processing to obtain high resolution. This is the case when the macromolecule of the sample is composed of different components and we want to focus just on one of them. For example, if the macromolecule is composed of several flexible subunits and we are interested in a specific one, if it is embedded in a viral capsid environment, or if it has additional components to stabilize it, such as nanodiscs. The signal from these components, which in principle we are not interested in, can be removed from the particles using a projection subtraction method. Currently, there are two projection subtraction methods used in practice and both have some limitations. In fact, after evaluating their results, we consider that the problem is still open to new solutions, as they do not fully remove the signal of the components that are not of interest. Our aim is to develop a new and more precise projection subtraction method, improving the performance of state-of-the-art methods. We tested our algorithm with data from public databases and an in-house data set. In this work, we show that the performance of our algorithm improves the results obtained by others, including the localization of small ligands, such as drugs, whose binding location is unknown a priori.

Local defocus estimation in single particle analysis in cryo-electron microscopy.

Single Particle analysis (SPA) aims to determine the three-dimensional structure of proteins and macromolecular complexes. The current state of the art has allowed us to achieve near-atomic and even atomic resolutions. To obtain high-resolution structures, a set of well-defined image processing steps is required. A critical one is the estimation of the Contrast Transfer Function (CTF), which considers the sample defocus and aberrations of the microscope. Defocus is usually globally estimated; in this case, it is the same for all the particles in each micrograph. But proteins are ice-embedded at different heights, suggesting that defocus should be measured in a local (per particle) manner. There are four state-of-the-art programs to estimate local defocus (Gctf, Relion, CryoSPARC, and Xmipp). In this work, we have compared the results of these software packages to check whether the resolution improves. We have used the Scipion framework and developed a specific program to analyze local defocus. The results produced by different programs do not show a clear consensus using the current test datasets in this study.

Scipion Flexibility Hub: an integrative framework for advanced analysis of conformational heterogeneity in cryoEM.

Understanding how structure and function meet to drive biological processes is progressively shifting the cryoEM field towards a more advanced analysis of macromolecular flexibility. Thanks to techniques such as single-particle analysis and electron tomography, it is possible to image a macromolecule in different states, information that can subsequently be extracted through advanced image-processing methods to build a richer approximation of a conformational landscape. However, the interoperability of all of these algorithms remains a challenging task that is left to users, preventing them from defining a single flexible workflow in which conformational information can be addressed by different algorithms. Therefore, in this work, a new framework integrated into Scipion is proposed called the Flexibility Hub. This framework automatically handles intercommunication between different heterogeneity software, simplifying the task of combining the software into workflows in which the quality and the amount of information extracted from flexibility analysis is maximized.

ZART: A Novel Multiresolution Reconstruction Algorithm with Motion-blur Correction for Single Particle Analysis.

One of the main purposes of CryoEM Single Particle Analysis is to reconstruct the three-dimensional structure of a macromolecule thanks to the acquisition of many particle images representing different poses of the sample. By estimating the orientation of each projected particle, it is possible to recover the underlying 3D volume by multiple 3D reconstruction methods, usually working either in Fourier or in real space. However, the reconstruction from the projected images works under the assumption that all particles in the dataset correspond to the same conformation of the macromolecule. Although this requisite holds for some macromolecules, it is not true for flexible specimens, leading to motion-induced artefacts in the reconstructed CryoEM maps. In this work, we introduce a new Algebraic Reconstruction Technique called ZART, which is able to include continuous flexibility information during the reconstruction process to improve local resolution and reduce motion blurring. The conformational changes are modelled through Zernike3D polynomials. Our implementation allows for a multiresolution description of the macromolecule adapting itself to the local resolution of the reconstructed map. In addition, ZART has also proven to be a useful algorithm in cases where flexibility is not so dominant, as it improves the overall aspect of the reconstructed maps by improving their local and global resolution.

Estimating conformational landscapes from Cryo-EM particles by 3D Zernike polynomials.

The new developments in Cryo-EM Single Particle Analysis are helping us to understand how the macromolecular structure and function meet to drive biological processes. By capturing many states at the particle level, it is possible to address how macromolecules explore different conformations, information that is classically extracted through 3D classification. However, the limitations of classical approaches prevent us from fully understanding the complete conformational landscape due to the reduced number of discrete states accurately reconstructed. To characterize the whole structural spectrum of a macromolecule, we propose an extension of our Zernike3D approach, able to extract per-image continuous flexibility information directly from a particle dataset. Also, our method can be seamlessly applied to images, maps or atomic models, opening integrative possibilities. Furthermore, we introduce the ZART reconstruction algorithm, which considers the Zernike3D deformation fields to revert particle conformational changes during the reconstruction process, thus minimizing the blurring induced by molecular motions.

Modificación de la prevalencia de genotipos del virus del papiloma humano en los condilomas acuminados tras la instauración de la vacuna profiláctica / Changes in the Prevalence of Human Papillomavirus Genotypes in Genital Warts Since the Introduction of Prophylactic Vaccines

Introducción El condiloma acuminado está causado por el virus del papiloma humano (VPH), cuyos genotipos se han descrito tradicionalmente como de bajo y alto riesgo (AR) oncogénico. Clásicamente, los genotipos más frecuentes son el 6, el 11, el 16 y el 18, incluidos en las dos primeras vacunas desarrolladas. Nuestro objetivo es valorar cambios en la prevalencia de estos genotipos tras 10 años desde la instauración de la vacuna profiláctica en nuestro medio. Material y métodos Se trata de un estudio observacional descriptivo retrospectivo realizado en la UITS de un Servicio de Dermatología entre enero de 2016 y junio de 2019, seleccionando posteriormente a los pacientes diagnosticados de condilomas acuminados. Resultados Se han diagnosticado 362 pacientes con condilomas acuminados, realizándose genotipado en 212 pacientes (58,6%). Se han detectado 32 genotipos distintos, siendo los más frecuentes el 6, el 11, el 16 y el 42. En el 93,9% la detección de VPH fue positiva, detectándose hasta 299 genotipos, lo que corresponde a 1,5 por paciente. En el 26,6% de pacientes se detectaron más de un genotipo distinto de VPH. En el 24,1% se detectó al menos un genotipo de AR. No se observó asociación estadísticamente significativa entre la presencia de un genotipo de AR y las variables estudiadas. En el 91,4% de las lesiones se aisló al menos uno de los cuatro genotipos cubiertos por las dos primeras vacunas desarrolladas. Conclusiones La prevalencia de los genotipos de VPH incluidos en las dos primeras vacunas profilácticas desarrolladas ha disminuido. La implicación de al menos uno de los cuatro genotipos más frecuentes se ha mantenido estable con respecto a hace 10 años. Las infecciones por múltiples genotipos y la presencia de al menos un genotipo de AR oncogénico ha aumentado ligeramente (AU)

Background and objective Genital warts are caused by the human papillomavirus (HPV), whose genotypes have traditionally been classified as low risk or high risk (oncogenic). The first 2 prophylactic vaccines included the most common genotypes at the time: HPV-6, HPV-11, HPV-16, and HPV-18. The aim of this study was to evaluate the prevalence of HPV types in our setting 10 years after the introduction of HPV vaccines. Material and methods Descriptive, observational, retrospective study of patients diagnosed with genital warts at the sexually transmitted infection unit of a dermatology department between January 2016 and June 2019. Results In total, 362 patients were diagnosed with genital warts during the study period, and 212 (58.6%) underwent genotyping. Thirty-two distinct HPV types were observed, the most common being HPV-6, HPV-11, HPV-16, and HPV-42. HPV DNA was detected in 93.9% of the samples analyzed, and there were 299 genotypes (mean, 1.5 per patient). Overall, 26.6% of patients had more than a single HPV genotype, while 24.1% had at least 1 high-risk type. No significant associations were found between the presence of high-risk HPV types and any of the study variables. At least 2 of the 4 HPV types targeted in the original vaccines were detected in 94.1% of lesions. Conclusions Compared to 10 years ago, the prevalences of HPV types included in the first 2 prophylactic vaccines have decreased, while the proportion of patients with at least 1 of the 4 most common types has remained unchanged. We also observed a slight increase in infections with multiple HPV types or at least 1 high-risk type (AU)

[Translated article] Changes in the Prevalence of Human Papillomavirus Genotypes in Genital Warts Since the Introduction of Prophylactic Vaccines / Modificación de la prevalencia de genotipos del virus del papiloma humano en los condilomas acuminados tras la instauración de la vacuna profiláctica

Background and objective Genital warts are caused by the human papillomavirus (HPV), whose genotypes have traditionally been classified as low risk or high risk (oncogenic). The first 2 prophylactic vaccines included the most common genotypes at the time: HPV-6, HPV-11, HPV-16, and HPV-18. The aim of this study was to evaluate the prevalence of HPV types in our setting 10 years after the introduction of HPV vaccines. Material and methods Descriptive, observational, retrospective study of patients diagnosed with genital warts at the sexually transmitted infection unit of a dermatology department between January 2016 and June 2019. Results In total, 362 patients were diagnosed with genital warts during the study period, and 212 (58.6%) underwent genotyping. Thirty-two distinct HPV types were observed, the most common being HPV-6, HPV-11, HPV-16, and HPV-42. HPV DNA was detected in 93.9% of the samples analyzed, and there were 299 genotypes (mean, 1.5 per patient). Overall, 26.6% of patients had more than a single HPV genotype, while 24.1% had at least 1 high-risk type. No significant associations were found between the presence of high-risk HPV types and any of the study variables. At least 2 of the 4 HPV types targeted in the original vaccines were detected in 94.1% of lesions. Conclusions Compared to 10 years ago, the prevalences of HPV types included in the first 2 prophylactic vaccines have decreased, while the proportion of patients with at least 1 of the 4 most common types has remained unchanged. We also observed a slight increase in infections with multiple HPV types or at least 1 high-risk type (AU)

Introducción El condiloma acuminado está causado por el virus del papiloma humano (VPH), cuyos genotipos se han descrito tradicionalmente como de bajo y alto riesgo (AR) oncogénico. Clásicamente, los genotipos más frecuentes son el 6, el 11, el 16 y el 18, incluidos en las dos primeras vacunas desarrolladas. Nuestro objetivo es valorar cambios en la prevalencia de estos genotipos tras 10 años desde la instauración de la vacuna profiláctica en nuestro medio. Material y métodos Se trata de un estudio observacional descriptivo retrospectivo realizado en la UITS de un Servicio de Dermatología entre enero de 2016 y junio de 2019, seleccionando posteriormente a los pacientes diagnosticados de condilomas acuminados. Resultados Se han diagnosticado 362 pacientes con condilomas acuminados, realizándose genotipado en 212 pacientes (58,6%). Se han detectado 32 genotipos distintos, siendo los más frecuentes el 6, el 11, el 16 y el 42. En el 93,9% la detección de VPH fue positiva, detectándose hasta 299 genotipos, lo que corresponde a 1,5 por paciente. En el 26,6% de pacientes se detectaron más de un genotipo distinto de VPH. En el 24,1% se detectó al menos un genotipo de AR. No se observó asociación estadísticamente significativa entre la presencia de un genotipo de AR y las variables estudiadas. En el 91,4% de las lesiones se aisló al menos uno de los cuatro genotipos cubiertos por las dos primeras vacunas desarrolladas. Conclusiones La prevalencia de los genotipos de VPH incluidos en las dos primeras vacunas profilácticas desarrolladas ha disminuido. La implicación de al menos uno de los cuatro genotipos más frecuentes se ha mantenido estable con respecto a hace 10 años. Las infecciones por múltiples genotipos y la presencia de al menos un genotipo de AR oncogénico ha aumentado ligeramente (AU)

Performance of Coronary Artery Calcium Testing in Patients With Severe Psoriasis: Risk Assessment and Reclassification Potential in a Low Cardiovascular Risk Population / Realización del examen de calcio en los pacientes con psoriasis severa: evaluación del riesgo y potencial de reclasificación en una población de riesgo cardiovascular bajo

Background Patients with severe psoriasis have an increased cardiovascular (CV) risk and prevalence of subclinical coronary artery disease (CAD). Coronary artery calcium (CAC) testing can detect subclinical CAD and improve cardiovascular risk assessment beyond clinical scores. Objectives Evaluate the presence and magnitude of subclinical CAD determined by CAC score among the different ESC/EAS CV risk categories, as well as the potential for risk reclassification, in patients with severe psoriasis from a low CV risk population. Methods Unicentric cross-sectional study in 111 patients with severe chronic plaque psoriasis from a low CV risk population in the Mediterranean region. Patients were classified into four CV risk categories according to the ESC/EAS guideline recommendations and HeartScore/SCORE calibrated charts. Patients underwent coronary computed tomography to determine their CAC scores. Patients in the moderate-risk category with a CAC score of ≥100 were considered to be reclassified as recommended by the 2019 ESC/EAS guidelines. Reclassification was also considered for patients in the low-risk category with a CAC score>0. Results Presence of subclinical CAD was detected in 46 (41.4%) patients. These accounted for 86.2% of patients in high/very-high-risk categories and 25.6% of patients in non-high-risk categories. Fourteen (17.1%) of the patients in non-high-risk categories were reclassifiable due to their CAC score. This percentage was higher (25%) when considering the moderate-risk category alone and lower (13.8%) in the low-risk category. Age was the only variable associated with presence of subclinical CAD and reclassification. Conclusions Over 40% of patients with severe psoriasis from a low-risk region and up to 25% of those in non-high-risk categories have subclinical CAD (AU)

Antecedentes Los pacientes con psoriasis severa tienen riesgo cardiovascular (CV) incrementado, así como prevalencia de la enfermedad de las arterias coronarias (EAC) subclínica. El examen de calcio en las arterias coronarias (CAC) puede detectar la EAC subclínica y mejorar la evaluación del riesgo CV más allá de las puntuaciones clínicas. Objetivos Evaluar la presencia y magnitud de la EAC subclínica determinadas mediante la puntuación CAC entre las diferentes categorías de riesgo CV de ESC/EAS, así como el potencial de reclasificación del riesgo, en pacientes con psoriasis severa, procedentes de una población de riesgo CV bajo. Métodos Estudio transversal unicéntrico de 111 pacientes con psoriasis crónica en placa procedentes de una población de bajo riesgo CV de la región mediterránea. Los pacientes fueron clasificados en cuatro categorías de riesgo CV conforme a las recomendaciones de la guía ESC/EAS y la tabla de calibración HeartScore/SCORE. Se realizó a los pacientes una tomografía computarizada para determinar sus puntuaciones CAC. Se consideró que los pacientes de la categoría de riesgo moderado con una puntuación CAC≥100 debían ser reclasificados, conforme a las guías ESC/EAS de 2019. También se reconsideró la reclasificación para aquellos pacientes de la categoría de riesgo bajo con una puntuación CAC>0. Resultados La presencia de EAC subclínica fue detectada en 46 pacientes (41,4%), que representaron el 86,2% de los pacientes incluidos en las categorías de riesgo alto/muy alto, y el 25,6% de los pacientes de las categorías de riesgo no alto. Catorce pacientes (17,1%) de las categorías de riesgo no alto no fueron reclasificables debido a su puntuación CAC. Este porcentaje fue más alto (25%) al considerar la categoría de riesgo moderado en solitario, y más bajo (13,8%) en la categoría de riesgo bajo. La edad fue la única variable asociada a la presencia de EAC subclínica y reclasificación (AU)

[Artículo traducido] Realización del examen de calcio en los pacientes con psoriasis severa: evaluación del riesgo y potencial de reclasificación en una población de riesgo cardiovascular bajo / Performance of Coronary Artery Calcium Testing in Patients With Severe Psoriasis: Risk Assessment and Reclassification Potential in a Low Cardiovascular Risk Population

Antecedentes Los pacientes con psoriasis severa tienen riesgo cardiovascular (CV) incrementado, así como prevalencia de la enfermedad de las arterias coronarias (EAC) subclínica. El examen de calcio en las arterias coronarias (CAC) puede detectar la EAC subclínica y mejorar la evaluación del riesgo CV más allá de las puntuaciones clínicas. Objetivos Evaluar la presencia y magnitud de la EAC subclínica determinadas mediante la puntuación CAC entre las diferentes categorías de riesgo CV de ESC/EAS, así como el potencial de reclasificación del riesgo, en pacientes con psoriasis severa, procedentes de una población de riesgo CV bajo. Métodos Estudio transversal unicéntrico de 111 pacientes con psoriasis crónica en placa procedentes de una población de bajo riesgo CV de la región mediterránea. Los pacientes fueron clasificados en cuatro categorías de riesgo CV conforme a las recomendaciones de la guía ESC/EAS y la tabla de calibración HeartScore/SCORE. Se realizó a los pacientes una tomografía computarizada para determinar sus puntuaciones CAC. Se consideró que los pacientes de la categoría de riesgo moderado con una puntuación CAC≥100 debían ser reclasificados, conforme a las guías ESC/EAS de 2019. También se reconsideró la reclasificación para aquellos pacientes de la categoría de riesgo bajo con una puntuación CAC>0. Resultados La presencia de EAC subclínica fue detectada en 46 pacientes (41,4%), que representaron el 86,2% de los pacientes incluidos en las categorías de riesgo alto/muy alto, y el 25,6% de los pacientes de las categorías de riesgo no alto. Catorce pacientes (17,1%) de las categorías de riesgo no alto no fueron reclasificables debido a su puntuación CAC. Este porcentaje fue más alto (25%) al considerar la categoría de riesgo moderado en solitario, y más bajo (13,8%) en la categoría de riesgo bajo. La edad fue la única variable asociada a la presencia de EAC subclínica y reclasificación (AU)

Background Patients with severe psoriasis have an increased cardiovascular (CV) risk and prevalence of subclinical coronary artery disease (CAD). Coronary artery calcium (CAC) testing can detect subclinical CAD and improve cardiovascular risk assessment beyond clinical scores. Objectives Evaluate the presence and magnitude of subclinical CAD determined by CAC score among the different ESC/EAS CV risk categories, as well as the potential for risk reclassification, in patients with severe psoriasis from a low CV risk population. Methods Unicentric cross-sectional study in 111 patients with severe chronic plaque psoriasis from a low CV risk population in the Mediterranean region. Patients were classified into four CV risk categories according to the ESC/EAS guideline recommendations and HeartScore/SCORE calibrated charts. Patients underwent coronary computed tomography to determine their CAC scores. Patients in the moderate-risk category with a CAC score of ≥100 were considered to be reclassified as recommended by the 2019 ESC/EAS guidelines. Reclassification was also considered for patients in the low-risk category with a CAC score>0. Results Presence of subclinical CAD was detected in 46 (41.4%) patients. These accounted for 86.2% of patients in high/very-high-risk categories and 25.6% of patients in non-high-risk categories. Fourteen (17.1%) of the patients in non-high-risk categories were reclassifiable due to their CAC score. This percentage was higher (25%) when considering the moderate-risk category alone and lower (13.8%) in the low-risk category. Age was the only variable associated with presence of subclinical CAD and reclassification. Conclusions Over 40% of patients with severe psoriasis from a low-risk region and up to 25% of those in non-high-risk categories have subclinical CAD (AU)

Image processing tools for the validation of CryoEM maps.

The number of maps deposited in public databases (Electron Microscopy Data Bank, EMDB) determined by cryo-electron microscopy has quickly grown in recent years. With this rapid growth, it is critical to guarantee their quality. So far, map validation has primarily focused on the agreement between maps and models. From the image processing perspective, the validation has been mostly restricted to using two half-maps and the measurement of their internal consistency. In this article, we suggest that map validation can be taken much further from the point of view of image processing if 2D classes, particles, angles, coordinates, defoci, and micrographs are also provided. We present a progressive validation scheme that qualifies a result validation status from 0 to 5 and offers three optional qualifiers (A, W, and O) that can be added. The simplest validation state is 0, while the most complete would be 5AWO. This scheme has been implemented in a website https://biocomp.cnb.csic.es/EMValidationService/ to which reconstructed maps and their ESI can be uploaded.

BIPSPI+: Mining Type-Specific Datasets of Protein Complexes to Improve Protein Binding Site Prediction.

Computational approaches for predicting protein-protein interfaces are extremely useful for understanding and modelling the quaternary structure of protein assemblies. In particular, partner-specific binding site prediction methods allow delineating the specific residues that compose the interface of protein complexes. In recent years, new machine learning and other algorithmic approaches have been proposed to solve this problem. However, little effort has been made in finding better training datasets to improve the performance of these methods. With the aim of vindicating the importance of the training set compilation procedure, in this work we present BIPSPI+, a new version of our original server trained on carefully curated datasets that outperforms our original predictor. We show how prediction performance can be improved by selecting specific datasets that better describe particular types of protein interactions and interfaces (e.g. homo/hetero). In addition, our upgraded web server offers a new set of functionalities such as the sequence-structure prediction mode, hetero- or homo-complex specialization and the guided docking tool that allows to compute 3D quaternary structure poses using the predicted interfaces. BIPSPI+ is freely available at https://bipspi.cnb.csic.es.

ScipionTomo: Towards cryo-electron tomography software integration, reproducibility, and validation.

Image processing in cryogenic electron tomography (cryoET) is currently at a similar state as Single Particle Analysis (SPA) in cryogenic electron microscopy (cryoEM) was a few years ago. Its data processing workflows are far from being well defined and the user experience is still not smooth. Moreover, file formats of different software packages and their associated metadata are not standardized, mainly since different packages are developed by different groups, focusing on different steps of the data processing pipeline. The Scipion framework, originally developed for SPA (de la Rosa-Trevín et al., 2016), has a generic python workflow engine that gives it the versatility to be extended to other fields, as demonstrated for model building (Martínez et al., 2020). In this article, we provide an extension of Scipion based on a set of tomography plugins (referred to as ScipionTomo hereafter), with a similar purpose: to allow users to be focused on the data processing and analysis instead of having to deal with multiple software installation issues and the inconvenience of switching from one to another, converting metadata files, managing possible incompatibilities, scripting (writing a simple program in a language that the computer must convert to machine language each time the program is run), etcetera. Additionally, having all the software available in an integrated platform allows comparing the results of different algorithms trying to solve the same problem. In this way, the commonalities and differences between estimated parameters shed light on which results can be more trusted than others. ScipionTomo is developed by a collaborative multidisciplinary team composed of Scipion team engineers, structural biologists, and in some cases, the developers whose software packages have been integrated. It is open to anyone in the field willing to contribute to this project. The result is a framework extension that combines the acquired knowledge of Scipion developers in close collaboration with third-party developers, and the on-demand design of functionalities requested by beta testers applying this solution to actual biological problems.

Changes in the Prevalence of Human Papillomavirus Genotypes in Genital Warts Since the Introduction of Prophylactic Vaccines. / Modificación de la prevalencia de genotipos del virus del papiloma humano en los condilomas acuminados tras la instauración de la vacuna profiláctica.

BACKGROUND AND OBJECTIVE: Genital warts are caused by the human papillomavirus (HPV), whose genotypes have traditionally been classified as low risk or high risk (oncogenic). The first 2 prophylactic vaccines included the most common genotypes at the time: HPV-6, HPV-11, HPV-16, and HPV-18. The aim of this study was to evaluate the prevalence of HPV types in our setting 10 years after the introduction of HPV vaccines. MATERIAL AND METHODS: Descriptive, observational, retrospective study of patients diagnosed with genital warts at the sexually transmitted infection unit of a dermatology department between January 2016 and June 2019. RESULTS: In total, 362 patients were diagnosed with genital warts during the study period, and 212 (58.6%) underwent genotyping. Thirty-two distinct HPV types were observed, the most common being HPV-6, HPV-11, HPV-16, and HPV-42. HPV DNA was detected in 93.9% of the samples analyzed, and there were 299 genotypes (mean, 1.5 per patient). Overall, 26.6% of patients had more than a single HPV genotype, while 24.1% had at least 1 high-risk type. No significant associations were found between the presence of high-risk HPV types and any of the study variables. At least 2 of the 4 HPV types targeted in the original vaccines were detected in 94.1% of lesions. CONCLUSIONS: Compared to 10 years ago, the prevalences of HPV types included in the first 2 prophylactic vaccines have decreased, while the proportion of patients with at least 1 of the 4 most common types has remained unchanged. We also observed a slight increase in infections with multiple HPV types or at least 1 high-risk type.

Cryo-Electron Microscopy: The field of 1,000+ methods.

Cryo-Electron Microscopy (CryoEM) is currently a well-established method to elucidate a biological macromolecule's three-dimensional (3D) structure. Its success is due to technological and methodological advances in several fronts: sample preparation, electron optics and detection, image acquisition, image processing, and map interpretation. The first methods started in the late 1960s and, since then, new methods on all fronts have continuously been published, maturating the field as we know it now. In terms of publications, we can distinguish several periods, witnessing a substantial acceleration of methodological publications in recent years, pointing out to an increased interest in the domain. On the other hand, this accelerated increase of methods development may confuse practitioners about which method they should be using (and how) and highlight the importance of paying attention to establishing best practices for methods reporting and usage. In this paper, we analyze the trends identified in over 1,000 methodological papers. Our focus is primarily on computational image processing methods. However, our list also covers some aspects of sample preparation and image acquisition. Several interesting ideas stem out from this study: (1) Single Particle Analysis (SPA) has largely accelerated in the last decade and sample preparation methods in the last five years; (2) Electron Tomography is not yet in a rapidly growing phase, but it is foreseeable that it will soon be; (3) the work horses of SPA are 3D classification, 3D reconstruction, and 3D alignment, and there have been many papers on these topics, which are not considered to be solved yet, but ever improving; and (4) since the resolution revolution, atomic modelling has also caught on as a hot topic.