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Understanding the complexity of the long-lived HIV reservoir during antiretroviral therapy (ART) remains a considerable impediment in research towards a cure for HIV. To address this, we developed a single-cell strategy to precisely define the unperturbed peripheral blood HIV-infected memory CD4+ T cell reservoir from ART-treated people living with HIV (ART-PLWH) via the presence of integrated accessible proviral DNA in concert with epigenetic and cell surface protein profiling. We identified profound reservoir heterogeneity within and between ART-PLWH, characterized by new and known surface markers within total and individual memory CD4+ T cell subsets. We further uncovered new epigenetic profiles and transcription factor motifs enriched in HIV-infected cells that suggest infected cells with accessible provirus, irrespective of reservoir distribution, are poised for reactivation during ART treatment. Together, our findings reveal the extensive inter- and intrapersonal cellular heterogeneity of the HIV reservoir, and establish an initial multiomic atlas to develop targeted reservoir elimination strategies.

The HIV reservoir is largely composed of latently infected memory CD4 + T cells that persist during antiretroviral therapy and constitute a major barrier toward HIV eradication. In particular, CD4 + T follicular helper cells have been demonstrated as key targets for viral replication and persistence under ART.

Objectif : Évaluer l’implémentation d’une pratique quotidienne de cohérence cardiaque chez des patients opérés pour une carcinose péritonéale. Matériel et méthode : Étude pilote monocentrique, ouverte, contrôlée, randomisée non comparative, incluant 20 patients en soins courants vs 40 patients formés à la cohérence cardiaque avec biofeedback et guide respiratoire pour une pratique au domicile enregistrée. Résultats attendus : Adhésion satisfaisante au programme, pouvant caractériser les éléments favorisant son implémentation avant et après chirurgie et évaluation de son impact sur l’anxiété. Perspectives : Efficacité à déterminer pour transférer ce soin de support.

Objectives This document presents the fundamentals of speech audiometry in noise, general requirements for implementation and criteria for choice among the tests available in French according to the health-professional's needs. Material and methods The recommendations are based on a systematic analysis of the literature carried out by a multidisciplinary group of doctors, audiologists and audioprosthetists from all over France. They are graded A, B, C or expert opinion according to decreasing level of scientific evidence. Results Eight tests of speech audiometry in noise can be used in France. Conclusion To be complete, evaluation of hearing status requires testing understanding of speech in noise. The examination must begin with a minimum of two measurements familiarizing the subject with the test procedure. For initial diagnosis, adaptive procedures establishing the 50% speech reception threshold (SRT50) in noise are to be preferred in order to obtain a rapid and standardized measurement of perception of speech in noise. When the aim is to measure real-life speech comprehension, tests based on sentences, cocktail-party noise and free-field stimulation are to be preferred. Prosthetic gain is evaluated exclusively in free field. This is the only way to evaluate the contribution of binaurality and to measure perception in noise in an environment as close as possible to real life. In order to avoid acoustic interference in free field, at least five loudspeakers should be used, in particular for evaluating the effectiveness of directional microphones, CROS devices enabling sounds picked up in the damaged ear to be rerouted to the functional ear, or bimodal fitting (i.e., when hearing is enabled by two modalities: for example, hearing aid for one ear, cochlear implant for the other).

Local and environmental governance is crucial for contending with the complex problems of land-use systems and socio-ecological conflicts that bedevil progress toward sustainable development. The community-based governance (CBG) framework is a practical instrument designed to identify collective problems, source the appropriate institutions and articulate joint solutions. It uses community perspectives to construct local and environmental governance models. Through a literature review, two expert workshops and 37 applied questionnaires, a bottom-up CBG model that could enhance environmental and local governance in a post-conflict era for two Colombian administrative departments is developed. Strengthening law enforcement, supporting sustainable land-use systems and promoting education are integral to a participatory-led approach to socio-ecological conflict prevention and resolution. The results are instructive for other communities and regions facing persistent conflict.

espanolLas cuernas de ciervo pueden usarse como un indice de calidad individual, tanto en contextos ecologicos como productivos. Por lo general, la calidad de las cuernas se mide solo por sus caracteristicas biometricas, como la longitud, la asimetria o el peso, mientras que las caracteristicas mecanicas normalmente no pueden medirse sin destruir la cuerna y, por lo tanto, sin perder el valor comercial de los trofeos. En este trabajo medimos la velocidad de transmision de ultrasonidos en distintas secciones de cuernas de desmogue de ciervo iberico (Cervus elaphus hispanicus), junto con la densidad y la resistencia a la traccion. Encontramos que el valor de la velocidad depende de la seccion de la cuerna y de la direccion de propagacion. En relacion con las secciones de las cuernas, las velocidades mas bajas se obtuvieron en el tronco medio y las mas altas, en las luchaderas. Los resultados fueron similares con respecto a la densidad y la resistencia a la traccion indirecta, probablemente debido a la diferencia de funcionalidad de las distintas secciones de cuerna. La densidad fue la principal causa de la variabilidad en la velocidad de los ultrasonidos. El tiempo transcurrido entre el desmogue y la medicion afecto a la densidad mas que a la velocidad de los ultrasonidos. La resistencia a la traccion indirecta mostro una relacion curvilinea de desaceleracion con la velocidad de los ultrasonidos. Analizamos las aplicaciones de la velocidad de los ultrasonidos como herramienta no invasiva para medir la densidad y las caracteristicas fisicas de las cuernas y de sus secciones, asi como su posible utilidad como indice de la calidad. EnglishDeer antlers can be used as an index of individual performance both in ecological and productive contexts. Their quality is often measured only by their biometrical features, such as size, asymmetry or weight. Mechanic characteristics cannot normally be measured without destroying the antler and hence losing the commercial value of the trophies. Here, we studied ultrasonic velocities, density, and tensile strength across various sections of cast antlers of Iberian red deer (Cervus elaphus hispanicus). We found that the speed value depended on the section of the antler and the propagation direction. For antler sections, velocities were lower for mid–beam and highest for brow tine. Results were similar for density and indirect tensile strength, probably related to differences in functionality among antler sections. Density explained most of the variability of ultrasound–speed. The time elapsed from antler shed affected density more than ultrasound speed. The indirect tensile strength showed a non–linear, decelerating relationship with ultrasound speed. We discuss the applications of ultrasound speed as a non–invasive tool to measure density and physical properties of antlers and antler sections, and their potential use as an index of quality.

Global population immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is accumulating through heterogeneous combinations of infection and vaccination. Vaccine distribution in low- and middle-income countries has been variable and reliant on diverse vaccine platforms. We studied B-cell immunity in Mexico, a middle-income country where five different vaccines have been deployed to populations with high SARS-CoV-2 incidences. Levels of antibodies that bound a stabilized prefusion spike trimer, neutralizing antibody titers, and memory B-cell expansion correlated with each other across vaccine platforms. Nevertheless, the vaccines elicited variable levels of B-cell immunity, and the majority of recipients had undetectable neutralizing activity against the recently emergent omicron variant. SARS-CoV-2 infection, experienced before or after vaccination, potentiated B-cell immune responses and enabled the generation of neutralizing activity against omicron and SARS-CoV for all vaccines in nearly all individuals. These findings suggest that broad population immunity to SARS-CoV-2 will eventually be achieved but by heterogeneous paths.

CD4 T cells are key mediators of adaptive immune responses during infection and vaccination. Within secondary lymphoid organs, helper CD4 T cells, particularly those residing in germinal centers known as follicular helper T cells (Tfh), provide critical help to B-cells to promote their survival, isotype switching and selection of high affinity memory B-cells. On the other hand, the important role of Tfh cells for the maintenance of HIV reservoir is well documented. Thus, interrogating and better understanding the tissue specific micro-environment and immune subsets that contribute to optimal Tfh cell differentiation and function is important for designing successful prevention and cure strategies. Here, we describe the development and optimization of eight multispectral confocal microscopy immunofluorescence panels designed for in depth characterization and immune-profiling of relevant immune cells in formalin-fixed paraffin-embedded human lymphoid tissue samples. We provide a comprehensive library of antibodies to use for the characterization of CD4+ T-cells -including Tfh and regulatory T-cells- as well as CD8 T-cells, B-cells, macrophages and dendritic cells and discuss how the resulting multispectral confocal datasets can be quantitatively dissected using the HistoCytometry pipeline to collect information about relative frequencies and immune cell spatial distributions. Cells harboring actively transcribed virus are analyzed using an in-situ hybridization assay for the characterization of HIV mRNA positive cells in combination with additional protein markers (multispectral RNAscope). The application of this methodology to lymphoid tissues offers a means to interrogate multiple relevant immune cell targets simultaneously at increased resolution in a reproducible manner to guide CD4 T-cell studies in infection and vaccination.

Summary Background Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer‐prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders. Objectives To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC. Methods We conducted RNA‐Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies. Results Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA‐Seq data. In addition, enzyme‐linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB. Conclusions Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury‐sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development.Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix‐synthetic capacity.This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor‐β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention.It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB., Linked Comment: https://doi.org/10.1111/bjd.18104. https://doi.org/10.1111/bjd.18271 available online

Cutaneous squamous cell carcinoma (cSCC) is the leading cause of death in patients with recessive dystrophic epidermolysis bullosa (RDEB). We provide the management and prognosis of cSCC in RDEB patients at a Spanish reference center. We retrospectively included patients with RDEB attended in La Paz University Hospital from November 1988 to October 2018. Fourteen patients developed at least one cSCC. Tumors were predominantly well differentiated. Nearly half of the tumors have recurred. Median time to first recurrence was 23.4 months (95% CI: 17.2–29.5). Five patients have developed distant metastases. Median overall survival (mOS) was 136.5 months since the diagnosis of the first cSCC (95% CI: 30.6–242.3). When distant metastases occurred, mOS was 6.78 months (95% CI: 1.94–11.61). cSCC is a life-threatening complication of RDEB patients. Although tumors are usually well differentiated, they tend to relapse. This is the first Spanish report of cSCC arising in RDEB patients.

tIn a contemporary context of major health challenges, the market of digital technologies has increasingly developed in past years. This article aims to explore main profiles of use in relation to connected objects and health apps, as well as attitudes related to uses, non-uses and contexts of use. Therefore, our objective is to contribute to the scientific debate by proposing an empirical study in psychology that focusses on the perspectives of consumers and non-consumers of these technologies in the French-speaking part of Switzerland. Todo this, a survey was conducted among participants of a large publich ealth exhibition (n = 760). According to our results, the majority of respondents declare not having a connected object/health app and a third of non-users does not intend to acquire such techno-logies. Also, there is a trend among younger generations to have a connected object/health app. Concerning the contexts of use, such technologies are employed to self-track physical activity and eating practices. The degree of satisfaction of such use is rather high. Given these results, our analyses point out a divide within our sample, between individuals who seem resistant and declare not willing to have this kind of technology and those who use it in the long run.These results cast new light upon concrete uses and contexts of use among consumers and non-consumers of connected objects/healthapps beyond techno-scientific promises that prevail today in ours societies.

The FAIR Principles are a set of recommendations that aim to underpin knowledge discovery and integration by making the research outcomes Findable, Accessible, Interoperable and Reusable. These guidelines encourage the accurate recording and exchange of structured data, coupled with contextual information about their creation, expressed in domain-specific standards and machine readable formats. This paper analyses the potential support to FAIRness of the openEHR e-health standard, by theoretically assessing the compliance with each of the 15 FAIR principles of a hypothetical Clinical Data Repository (CDR) developed according to the openEHR specifications. Our study highlights how the openEHR approach, thanks to its computable semantics-oriented design, is inherently FAIR-enabling and is a promising implementation strategy for creating FAIR-compliant CDRs.

The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method for intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two HIV-1 regions to distinguish genomically intact proviruses against a large background of defective ones, and its application has yielded insights into HIV-1 persistence. Reports of assay failures however, attributed to HIV-1 polymorphism, have recently emerged. Here, we describe a diverse North American cohort of people with HIV-1 subtype B, where the IPDA yielded a failure rate of 28% due to viral polymorphism. We further demonstrate that within-host HIV-1 diversity can lead the IPDA to underestimate intact reservoir size, and provide examples of how this phenomenon could lead to erroneous interpretation of clinical trial data. While the IPDA represents a major methodological advance, HIV-1 diversity should be addressed before its widespread adoption as a principal readout in HIV-1 remission trials., The intact proviral DNA assay quantifies the genomically intact HIV reservoir, but assay failure due to HIV-1 polymorphism has been observed. Here, the authors report a 28% failure rate in a cohort of people with HIV-1, and note within-host HIV-1 diversity as a further challenge to IPDA accuracy.

Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up. © 2021, The Author(s).

Background: Ischemia-reperfusion injury in free flaps is associated with tissue damage and is one of the main factors causing flap failure in reconstructive microsurgery. The aim of this study is to assess whether any ischemia-reperfusion injury takes place during a microsurgical flap reconstruction as seen through the levels of malondialdehyde (MDA) and superoxide dismutase, biomarkers of oxidative stress, and to analyze the effect of lidocaine in this process. Methods: Twenty-four patients operated for immediate breast reconstruction using the Deep Inferior Epigastric Perforator free flap technique were divided into two groups: one group was treated with a lidocaine intravenous perfusion and the other group with a saline perfusion. MDA and superoxide dismutase (SOD) levels were measured at several points before, during, and after surgery. Background: Ischemia-reperfusion injury in free flaps is associated with tissue damage and is one of the main factors causing flap failure in reconstructive microsurgery. The aim of this study is to assess whether any ischemia-reperfusion injury takes place during a microsurgical flap reconstruction as seen through the levels of malondialdehyde (MDA) and superoxide dismutase, biomarkers of oxidative stress, and to analyze the effect of lidocaine in this process. Methods: Twenty-four patients operated for immediate breast reconstruction using the Deep Inferior Epigastric Perforator free flap technique were divided into two groups: one group was treated with a lidocaine intravenous perfusion and the other group with a saline perfusion. MDA and superoxide dismutase (SOD) levels were measured at several points before, during, and after surgery. Results: There was an increase in MDA levels in both groups, but the lidocaine group experienced a decrease during reperfusion. On the other hand, we observed a rise in SOD levels in both groups, but a decrease during reperfusion in the placebo group. However, these differences between groups were not statistically significant. Conclusions: The decreased SOD activity and increased MDA content in our research prove a redox imbalance and high reactive oxygen species levels in flaps, indicating that tissues experience ischemia-reperfusion injury during microsurgical reconstruction. Lidocaine may have a protective effect in free flap surgery, but our results were not statistically significant, so further studies will be required. (c) 2020 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

A warming climate poses a fundamental problem for embryos that develop within eggs because their demand for oxygen (O 2 ) increases much more rapidly with temperature than their capacity for supply, which is constrained by diffusion across the egg surface. Thus, as temperatures rise, eggs may experience O 2 limitation due to an imbalance between O 2 supply and demand. Here, we formulate a mathematical model of O 2 limitation and experimentally test whether this mechanism underlies the upper thermal tolerance in large aquatic eggs. Using Chinook salmon ( Oncorhynchus tshawytscha ) as a model system, we show that the thermal tolerance of eggs varies systematically with features of the organism and environment. Importantly, this variation can be precisely predicted by the degree to which these features shift the balance between O 2 supply and demand. Equipped with this mechanistic understanding, we predict and experimentally confirm that the thermal tolerance of these embryos in their natural habitat is substantially lower than expected from laboratory experiments performed under normoxia. More broadly, our biophysical model of O 2 limitation provides a mechanistic explanation for the elevated thermal sensitivity of fish embryos relative to other life stages, global patterns in egg size and the extreme fecundity of large teleosts.

Opening Paragraph (serves as abstract for submission) and BodyThe Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a precise and scalable method for intact HIV reservoir quantification1. This duplexed droplet digital PCR (ddPCR) assay simultaneously targets the HIV Packaging Signal (Ψ) and the Rev Responsive Element (RRE) within Envelope (env) to distinguish genomically intact proviruses against a large background of defective ones2. The IPDA requires less time, resources, and biological material than the gold standard for replication-competent HIV reservoir measurement, the Quantitative Viral Outgrowth Assay (QVOA)3, and is being adopted in research and clinical studies4–7. In our cohort of HIV-1 subtype B-infected individuals from North America however, the IPDA yielded a 28% failure rate due to HIV polymorphism. We further demonstrate that within-host HIV diversity can lead the IPDA to underestimate intact HIV reservoir size, which could negatively impact clinical trial results interpretation. While the IPDA represents an important methodological advance, HIV diversity should be addressed before its widespread adoption.

The integration of HIV DNA into the host genome contributes to lifelong infection in most individuals. Few studies have examined integration in lymphoid tissue, where HIV predominantly persists before and after antiretroviral treatment (ART). Of particular interest is whether integration site distributions differ between infection stages with paired blood and tissue comparisons. Here, we profiled HIV integration site distributions in sorted memory, tissue-resident, and/or follicular helper CD4+ T cell subsets from paired blood and lymphoid tissue samples from acute, chronic, and ART-treated individuals. We observed minor differences in the frequency of nonintronic and nondistal intergenic sites, varying with tissue and residency phenotypes during ART. Genomic and epigenetic annotations were generally similar. Clonal expansion of cells marked by identical integration sites was detected, with increased detection in chronic and ART-treated individuals. However, overlap between or within CD4+ T cell subsets or tissue compartments was only observed in 8 unique sites of the 3540 sites studied. Together, these findings suggest that shared integration sites between blood and tissue may, depending on the tissue site, be the exception rather than the rule and indicate that additional studies are necessary to fully understand the heterogeneity of tissue-sequestered HIV reservoirs., Deep characterization of HIV integration sites between tissue and blood compartments at multiple infection stages reveals a partitioning of integration sites between and within compartments.

Background: According to the International Study of Asthma and Allergies in Childhood (ISAAC) methodology, in 2003, the prevalence of asthma symptoms in children 6–7 years old and adolescents 13–14 years old was 11.6% and 13.7%, respectively. Since then, the number of asthma cases has increased worldwide. The study was conducted in several districts in northern Mexico City to evaluate the prevalence of asthma in these age groups and examine possible risk factors. The data were compared to the 2003 results from the same area. Methods: This was a comparative cross-sectional study following the official Global Asthma Network (GAN) methodology. The parents or guardians of participants completed a questionnaire that explored demographics, asthma symptoms, diagnoses, and possible risk factors. Central tendency measurements were determined for statistical analysis and chi-squared distribution for possible risk factors. Results: A total of 2515 children aged 6–7 years and 3375 adolescents aged 13–14 years participated in the study. Compared to the ISAAC results, we found a greater prevalence of wheezing in both children (at some time in life, 19.2% vs. 27.1%; over the last year, 6.8% vs. 10.6%) and adolescents (at some time in life, 16.9% vs. 19.7%), and for children with an asthma diagnosis (4.5% vs. 5.1%). For both groups, the most common risk factor associated with wheezing was the presence of rhinitis symptoms. Conclusions: Asthma symptoms are highly prevalent in Mexico City, occurring in almost 20% of adolescents. Compared to a decade ago, there was a 7.9% increase in the prevalence of asthma symptoms in children. Almost half of the children and adolescents presenting with symptoms had experienced more than four episodes per year. However, less than 50% of children and adolescents with asthma symptoms had been diagnosed with this disorder, suggesting under-diagnosis. Keywords: Asthma, Atopic allergic diseases, Wheezing, Rhinitis, Risk factors, ISAAC, GAN

The functional properties of circulating CD8+ T cells have been associated with immune control of HIV. However, viral replication occurs predominantly in secondary lymphoid tissues, such as lymph nodes (LNs). We used an integrated single-cell approach to characterize effective HIV-specific CD8+ T cell responses in the LNs of elite controllers (ECs), defined as individuals who suppress viral replication in the absence of antiretroviral therapy (ART). Higher frequencies of total memory and follicle-homing HIV-specific CD8+ T cells were detected in the LNs of ECs compared with the LNs of chronic progressors (CPs) who were not receiving ART. Moreover, HIV-specific CD8+ T cells potently suppressed viral replication without demonstrable cytolytic activity in the LNs of ECs, which harbored substantially lower amounts of CD4+ T cell–associated HIV DNA and RNA compared with the LNs of CPs. Single-cell RNA sequencing analyses further revealed a distinct transcriptional signature among HIV-specific CD8+ T cells from the LNs of ECs, typified by the down-regulation of inhibitory receptors and cytolytic molecules and the up-regulation of multiple cytokines, predicted secreted factors, and components of the protein translation machinery. Collectively, these results provide a mechanistic framework to expedite the identification of novel antiviral factors, highlighting a potential role for the localized deployment of noncytolytic functions as a determinant of immune efficacy against HIV.

Objectives To evaluate changes in retinal layers of the macula (mRLs) using OCT posterior pole program (PPP) in primary open-angle glaucoma (POAG). Material and methods The study included 128 patients with POAG and 103 healthy controls who had PPP maps (macular grid 8 × 8) drawn by SD-OCT. Only one eye per patient was studied. The 9 mRLs were automatically segmented by prototype software, obtaining: a macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform + nuclear layer, photoreceptor layer, retinal pigment epithelium (RPE), outer retina and RPE + outer retina. Thickness values were obtained on 64 cells of the grid for each mRL, and mean thickness of superior and inferior hemispheres were calculated. Comparisons of mean thickness of these hemispheres and thickness of each cell between groups were determined. Differences in the cell by cell comparisons were represented quantitatively by heat maps for each mRL. Results Photoreceptors and RPE were found in POAG group when comparing thickness of hemispheres, thinning of mRNFL, GCL, IPL, and thickening of INL. Heat maps showed symmetrical thinning patters between superior and inferior hemispheres in inner retinal layers (except for INL) and asymmetrical thickening patters in outer retinal layers in GPAA group. Conclusions There are thickness changes in all mRLs in POAG, when studied by PPP. Thinning of inner layers (except for INL), and thickening of outer layers in POAG show different symmetry patterns in relation to horizontal meridian.

espanolObjetivos Evaluar los cambios de las capas retinianas maculares (CRM) usando el programa de OCT de polo posterior (PP) en el glaucoma primario de angulo abierto (GPAA). Material y metodos Ciento veintiocho pacientes con GPAA y 103 controles sanos con mapas de PP (rejilla macular 8 × 8) obtenidos mediante SD-OCT fueron incluidos. Solo un ojo por paciente fue considerado. Entonces 9 CRM se segmentaron automaticamente mediante un software prototipo obteniendo: capas de fibras nerviosas maculares, capa de celulas ganglionares (GCL), plexiforme interna, nuclear interna (INL), plexiforme + nuclear externa, capa de fotorreceptores, epitelio pigmentario de la retina (RPE) y retina externa completa. Se obtuvieron los valores de grosor de las 64 celdas de la rejilla para cada una de las CRM y se calcularon los grosores promedio de los hemisferios superior e inferior. Se realizo una comparacion de los grosores promedio de dichos hemisferios y de los grosores celda a celda entre los 2 grupos. Las diferencias en comparaciones celda a celda fueron representadas mediante mapas de calor para cada CRM. Resultados Al comparar los grosores de los hemisferios se encontraron adelgazamientos en capas de fibras nerviosas maculares, capa de celulas ganglionares y plexiforme interna y engrosamientos en INL, fotorreceptores y RPE en GPAA. Los mapas de calor mostraron patrones de adelgazamiento simetricos entre ambos hemisferios (superior e inferior) en capas de la retina interna (excepto INL) y patrones de engrosamiento asimetricos en las CRM externas en GPAA. Conclusiones Existen patrones de cambio en el grosor en todas las CRM en el GPAA estudiadas mediante el programa PP. Los adelgazamientos de las capas internas (excepto INL) y los engrosamientos de las externas en el GPAA presentan diferentes patrones de simetria respecto al meridiano horizontal. EnglishObjectives To evaluate changes in retinal layers of the macula (mRLs) using OCT posterior pole program (PPP) in primary open-angle glaucoma (POAG). Material and methods The study included 128 patients with POAG and 103 healthy controls who had PPP maps (macular grid 8 × 8) drawn by SD-OCT. Only one eye per patient was studied. The 9 mRLs were automatically segmented by prototype software, obtaining: a macular retinal nerve fibre layer (mRNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform + nuclear layer, photoreceptor layer, retinal pigment epithelium (RPE), outer retina and RPE + outer retina. Thickness values were obtained on 64 cells of the grid for each mRL, and mean thickness of superior and inferior hemispheres were calculated. Comparisons of mean thickness of these hemispheres and thickness of each cell between groups were determined. Differences in the cell by cell comparisons were represented quantitatively by heat maps for each mRL. Results Photoreceptors and RPE were found in POAG group when comparing thickness of hemispheres, thinning of mRNFL, GCL, IPL, and thickening of INL. Heat maps showed symmetrical thinning patters between superior and inferior hemispheres in inner retinal layers (except for INL) and asymmetrical thickening patters in outer retinal layers in GPAA group. Conclusions There are thickness changes in all mRLs in POAG, when studied by PPP. Thinning of inner layers (except for INL), and thickening of outer layers in POAG show different symmetry patterns in relation to horizontal meridian.

Resumen La epidermolisis bullosa (EB), enfermedad genetica de fragilidad mucocutanea rara y devastadora, es clinica y geneticamente heterogenea. Se caracteriza por la aparicion de ampollas inducidas por contacto/friccion o de forma espontanea. La EB se clasifica en 4 tipos: simple, juntural, distrofica y sindrome de Kindler y en 30 subtipos. Esta genodermatosis esta causada por defectos en proteinas implicadas en la adhesion dermoepidermica, con al menos 19 genes caracterizados hasta el momento y mas de 1.000 mutaciones identificadas, que explican la complejidad de su diagnostico. El diagnostico molecular de la EB es el ultimo paso de un proceso laborioso que se inicia con la recogida de una historia clinica detallada y la toma de una biopsia cutanea, que incluya una zona de despegamiento entre la dermis y la epidermis inducida, en el momento de la recoleccion. Dicho despegamiento permite establecer el plano de rotura por mapeo antigenico y, en el mejor de los casos, un unico gen candidato en el que realizar la busqueda de las mutaciones patogenicas. Finalizado el diagnostico molecular, se esta en condiciones de ofrecer al paciente un asesoramiento genetico adecuado (patron de herencia, riesgo de recurrencia y opciones de diagnostico prenatal y preimplantacional) y los consecuentes programas preventivos, asi como un pronostico clinico razonable que facilite su acceso a opciones terapeuticas y de rehabilitacion especificas. Por ultimo, el diagnostico molecular es imprescindible para la participacion de los pacientes en ensayos clinicos, de gran importancia en una enfermedad como la EB, que no tiene cura. El objetivo de la presente guia es difundir el procedimiento de diagnostico de la EB tal y como se esta llevando a cabo en nuestro laboratorio y, asi, evitar diagnosticos clinicos suboptimos o incompletos. Las recomendaciones recogidas son fruto de nuestra experiencia de mas de 10 anos de diagnostico molecular de EB en Espana.

Epidermolysis bullosa (EB) is a rare genetic disease that causes mucocutaneous fragility. It comprises a clinically and genetically heterogeneous group of disorder characterized by spontaneous or contact/friction–induced blistering. EB is classified into 4 types–simplex, junctional, dystrophic, and Kindler syndrome–and 30 subtypes. The disease is caused by defects in proteins implicated in dermal-epidermal adhesion. At least 19 genes have been characterized and more than 1000 mutations identified, thus rendering diagnosis complex. Molecular diagnosis of EB is the last stage of a laborious process that starts with a detailed clinical history compilation and careful procurement of a skin fresh biopsy that includes an area where the epidermis detaches from the dermis. The detachment area makes it possible to establish the cleavage plane by antigen mapping and, in the best scenario, to identify a single candidate gene to search for pathogenic mutations. The results of the molecular diagnosis enable the physician to provide appropriate genetic counseling (inheritance pattern, risk of recurrence, and options for prenatal and preimplantation diagnosis) and implement subsequent preventive programs, as well as to establish a reasonable clinical prognosis facilitating access to specific therapy and rehabilitation. Lastly, molecular diagnosis is essential for the participation of patients in clinical trials, a critical issue given the current incurable status of EB. The present guidelines aim to disseminate the procedure for diagnosing EB in our laboratory and thus avoid suboptimal or incomplete clinical diagnoses. The recommendations we provide are the result of more than 10 years’ experience in the molecular diagnosis of EB in Spain.

In recent years, research and technology made considerable progress in increasing the speed and the safety of the entire digitization process of ancient collections. Despite this, imaging ancient, fragile or un-opened documents remains a formidable challenge. We employ an alternate digitization technique for handwritten documents, exploiting x-ray tomography: Virtual X-ray Reading. Thanks to the high penetration of x-rays, we can acquire 3-dimensional (3D) tomographic images of a multi-page document without opening it. The x-ray contrast necessary for the readability is produced by the chemical composition and the consequent strong x-ray absorption of the iron gall inks - largely used for European handwritten documents. We present the development of this technology, from the chemical investigations of the inks to the tomography of an unopened Venetian testament and of an 18th century, 200-page, handwritten book.

Background Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. Patients and methods We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. Results We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P = 0.003), but not to FOLFOX (P = 0.911) and FOLFIRI + Bevacizumab (P = 0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). Conclusions Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.

Resume Avec l’avenement d’Internet et la democratisation des telephones portables dits intelligents, l’usage des objets connectes relies a des applications specifiques devient de plus en plus courant. Cet usage permet la captation d’etats physiologiques et corporels, ainsi que leur transformation en donnees biometriques, lesquelles sont ensuite interpretees et partagees par les usagers de ces technologies afin de suivre et/ou de controler leurs propres pratiques de sante au quotidien. L’objectif de cet article est de dresser une revue de la litterature anglophone et francophone au sein de ce champ en pleine expansion. Notre analyse permet de degager deux grandes tendances de la recherche actuelle en sante digitale, independamment du domaine disciplinaire et de l’origine. L’une est definie par son enthousiasme plus ou moins affirme, et surtout, par son espoir a l’egard des nouvelles technologies de sante et de leurs promesses. L’autre est caracterisee par son attitude critique face au developpement de ces technologies, pouvant se traduire dans certains cas par une attitude de mise en garde concernant des phenomenes de surveillance et de risque. La discussion porte sur une reflexion approfondie des caracteristiques definissant chacune de ces tendances, en identifiant les questionnements que souleve cette revue de la litterature au sein de la psychologie. Enfin, notre conclusion met en evidence des perspectives de recherche future.

Impaired immunity is a common symptom of aging and advanced Human Immunodeficiency Virus type 1 (HIV-1) disease. In both diseases, a decline in lymphocytic function and cellularity leads to ineffective adaptive immune responses to opportunistic infections and vaccinations. Furthermore, despite sustained myeloid cellularity there is a background of chronic immune activation and a decrease in innate immune function in aging. In HIV-1 disease, myeloid cellularity is often more skewed than in normal aging, but similar chronic activation and innate immune dysfunction typically arise. Similarities between aging and HIV-1 infection have led to several investigations into HIV-1-mediated aging of the immune system. In this article, we review various studies that report alterations of leukocyte number and function during aging, and compare those alterations with those observed during progressive HIV-1 disease. We pay particular attention to changes within lymphoid tissue microenvironments and how histoarchitectural changes seen in these two diseases affect immunity. As we review various immune compartments including peripheral blood as well as primary and secondary lymphoid organs, common themes arise that help explain the decline of immunity in the elderly and in HIV-1-infected individuals with advanced disease. In both conditions, lymphoid tissues often show signs of histoarchitectural deterioration through fat accumulation and/or fibrosis. These structural changes can be attributed to a loss of communication between leukocytes and the surrounding stromal cells that produce the extracellular matrix components and growth factors necessary for cell migration, cell proliferation, and lymphoid tissue function. Despite the common general impairment of immunity in aging and HIV-1 progression, deterioration of immunity is caused by distinct mechanisms at the cellular and tissue levels in these two diseases.

HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination., The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia. IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.

Inhaled therapy is considered the cornerstone of asthma treatment. However, despite being the ideal form of drug delivery, it is recognized that only 70% of patients have an adequate attachment to their treatment and only 39-67% of physicians can explain the optimal inhaler technique. Inhaled therapy has very specific characteristics. Pulmonary deposit of an inhaled medication through the respiratory tract is more complex than when administered orally and depends on several factors inherent to both the medication and the administration. For successful inhaled therapy, the drug needs to be converted into particles of an appropriate size, which can enter beyond the oropharynx and larynx, and be deposited in the lungs. There are multiple devices for the administration of drugs in the lower respiratory tract, each one with a similar efficacy as long as it is used with the correct technique. The decision of which device should be used is made based on the age of the patient, the ability to coordinate between the inhalation and activation of the device, and the presence of acute symptoms. The choice of the device must be evaluated individually.La terapia inhalada se considera la piedra angular del manejo del asma. Sin embargo, a pesar de ser la forma ideal de administración de estos medicamentos, solamente el 70% de los pacientes cumple el tratamiento adecuadamente y sólo del 39 al 67% de los médicos conocen y pueden explicar de forma adecuada las distintas técnicas de inhalación. La terapia inhalada tiene características muy particulares. El depósito pulmonar de un medicamento inhalado a través del tracto respiratorio es más complejo que cuando se administra por vía oral, y varía dependiendo de varios factores, tanto inherentes al medicamento como a la forma de administrarlo. Para que la terapia inhalada sea exitosa, se requiere que se generen partículas del medicamento de un tamaño apropiado que penetren más allá de la orofaringe y la laringe, y que puedan depositarse en los pulmones. Existen múltiples dispositivos para la administración de medicamentos en la vía respiratoria baja. Cada uno ha probado tener una eficacia similar, siempre y cuando se utilicen con la técnica correcta. La decisión para su uso se realiza con base en la edad del paciente, la capacidad de coordinar entre la inhalación y la activación del dispositivo y la presencia de síntomas agudos. La elección del dispositivo a utilizar siempre deberá hacerse de forma conjunta, evaluando pros y contras de cada uno de los dispositivos y siempre de forma individualizada.

Asthma and allergic rhinitis frequently appear together Otitis media, upper respiratory tract infections and sinusitis are frequent comorbidities of allergic rhinoconjunctivitis Persistent allergic rhinitis is defined as having symptoms for more than 4 days a week and for over 4 weeks