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Summary: Background: Due to its late stage of diagnosis lung cancer is the commonest cause of death from cancer in the UK. Existing epidemiological risk models in clinical usage, which have Positive Predictive Values (PPV) of less than 10%, do not consider the temporal relations expressed in sequential electronic health record (EHR) data. We aimed to build a model for lung cancer early detection in primary care using machine learning with deep ‘transformer’ models on EHR data to learn from these complex sequential ‘care pathways’. Methods: We split the Whole Systems Integrated Care (WSIC) dataset into 70% training and 30% validation. Within the training set we created a case–control study with lung cancer cases and control cases of ‘other’ cancers or respiratory conditions or ‘other’ non cancer conditions. Based on 3,303,992 patients from January 1981 to December 2020 there were 11,847 lung cancer cases. 5789 cases and 7240 controls were used for training and 50,000 randomly selected patients out of the whole validation population of 368,906 for validation. GP EHR data going back three years from the date of diagnosis less the most recent one months were semantically pre-processed by mapping from more than 30,000 terms to 450. Model building was performed using ALBERT with a Logistic Regression Classifier (LRC) head. Clustering was explored using k-means. An additional regression model alone was built on the pre-processed data as a comparator. Findings: Our model achieved an AUROC of 0.924 (95% CI 0.921–0.927) with a PPV of 3.6% (95% CI 3.5–3.7) and Sensitivity of 86.6% (95% CI 85.3–87.8) based on the three year's data prior to diagnosis less the immediate month before index diagnosis. The comparator regression model achieved a PPV of 3.1% (95% CI 3.0–3.1) and AUROC of 0.887 (95% CI 0.884–0.889). We interpreted our model using cluster analysis and have identified six groups of patients exhibiting similar lung cancer progression patterns and clinical investigation patterns. Interpretation: Capturing temporal sequencing between cancer and non-cancer pathways to diagnosis enables much more accurate models. Future work will focus on external dataset validation and integration into GP clinical systems for evaluation. Funding: Cancer Research UK.

Summary: Background: Symptom fluctuations within and between individuals with long COVID are widely reported, but the extent to which severity varies following different types of activity and levels of exertion, and the timing of symptoms and recovery, have not previously been quantified. We aimed to characterise timing, severity, and nature of symptom fluctuations in response to effortful physical, social and cognitive activities, using Ecological Momentary Assessments. Methods: We recorded activity, effort, and severity of 8 core symptoms every 3 h for up to 24 days, in cohorts from both clinic and community settings. Symptom severities were jointly modelled using autoregressive and moving average processes. Findings: Consent was received from 376 participants providing ≥1 week's measurements (273 clinic-based, 103 community-based). Severity of all symptoms was elevated 30 min after all categories of activity. Increased effort was associated with increased symptom severity. Fatigue severity scores increased by 1.8/10 (95% CI: 1.6–1.9) following the highest physical exertions and by 1.5 (1.4–1.7) following cognitive efforts. There was evidence of only mild delayed fatigue 3 h (0.3, 0.2–0.5) or one day later (0.2, 0.0– 0.5). Fatigue severity increased as the day progressed (1.4, 1.0–1.7), and cognitive dysfunction was 0.2 lower at weekends (0.1–0.3). Interpretation: Cognitive, social, self-care and physical activities all triggered increased severity across every symptom, consistent with associated common pathways as potential therapeutic targets. Clear patterns of symptom fluctuations emerged that support more targeted self-management. Funding: National Institute for Health and Care Research.

Cooperative phenomena constitute important mechanisms to explain the magnetic properties of the perovskite manganites REMnO3, in which the rare-earth and/or Mn is partially replaced by divalent elements. In this way, the manganese ion changes its valence state (Mn3+ Mn4+), triggering strong magnetic interactions. In this work we describe the case of GdCoxMn1-xO3 (0.0 ≤ x ≤ 1.0) for which the antiferromagnetic interaction between the Gd sublattice and the Mn/Co network leads to a reversal of the magnetic moment at low temperature. No inversion is observed for the LaCoxMn1-xO3 series, in which the ordering temperature may attain a maximum of 235 K for LaCo0.50Mn0.50O3, while it is only 120 K for similar Co/Mn ratio in the case of GdCo0.50Mn0.50O3. Magnetic properties are described in terms of two regimes: one, for x < 0.5, when Co substitutes Mn in the GdMnO3 manganite and another one, for x > 0.5, when Mn substitutes Co in the GdCoO3 cobaltite, while the magnetic interactions are maximized at x(Co) = 0.50. This hypothesis is discussed in terms of the respective oxidation states of both manganese (Mn3+ / Mn4+) and cobalt (Co2+ / Co3+).El fenómeno cooperativo constituye un importante mecanismo para explicar las propiedades magnéticas de las perovskitas manganitas TRMnO3, en las que el catión de tierra rara, TR, y/o el catión Mn3+ son parcialmente reemplazados por cationes divalentes. Por esta vía el ión de manganeso cambia de estado de valencia (Mn3+ Mn4+), generando fuertes interacciones magnéticas. En el presente trabajo se describe el caso de las soluciones sólidas GdCoxMn1-xO3 (0.0 ≤ x ≤ 1.0) para las que la interacción antiferromagnética entre la subred del Gd3+ y la red Mn/Co lleva a una inversión del momento magnético a baja temperatura. No se ha observado inversión para la serie LaCoxMn1-xO3, en que la temperatura de orden puede alcanzar un máximo de 235K para LaCo0.50Mn0.50O3, mientras que en el caso de GdCo0.50Mn0.50O3, en que sí se observa inversión, la temperatura de orden es sólo de 120 K para una razón Co/Mn similar. Las propiedades magnéticas se describen en términos de dos regímenes diferentes: uno, para x < 0.5, cuando Co sustituye al Mn en la manganita GdMnO3 y otro, para x > 0.5, cuando Mn sustituye a Co en la cobaltita GdCoO3. Las interacciones magnéticas se maximizan a x(Co) = 0.50. Esta hipótesis se discute en términos de los respectivos estados de oxidación de ambos cationes: manganeso (Mn3+ / Mn4+) y cobalto (Co2+ / Co3+).

Partial substitution of Mn by a divalent metal in rare-earth manganites REMexMn1 xO3 results in the simultaneous presence of Mn3+ and Mn4+. The RE sublattice has its own properties and can interact with the local field imposed by the ferromagnetic Mn network. Its orientation differs depending on the RE nature, adopting a parallel direction with respect to the local field, or it may align in opposite direction, resulting in uncompensated antiferromagnetic structure. For divalent elements (e.g., Ni2+), the solid solution is limited to RENi2+0.5Mn4+0.5O3 ; at this frontier composition, the ferromagnetic superexchange Ni2+-O-Mn4+ interactions are optimized. For Me = Co, this limit can be extended, meaning that part of cobalt takes a 3+ state ; in this case, presence of Co3+ modifies the magnetic coupling, leading to qualitatively different behaviours during the ZFC/FC cycles. In this work, we have chosen the specific composition REMe0.50Mn0.50O3 for which the strongest magnetic interactions are expected, emphasizing the results obtained for Me = Ni and Co and comparing various rare-earth elements (RE = Y, La, Pr, Nd, Eu, Gd and Er). As expected from the general behaviour of the series (RE,Ca)MnO3, we find that in the RE(Mn,Me)O3, the larger the RE ionic radius, the highest the transition temperature, reaching 235 K in LaCo0.50Mn0.50O3 compared to 68 K in ErCo0.50Mn0.50O3.La sustitución parcial de Mn por un catión divalente en manganitas de tierras raras TRMexMn1 xO3 induce la presencia simultánea de Mn3+ y Mn4+. La subred TR tiene sus propiedades intrínsecas y puede interactuar con el campo local impuesto por la red ferromagnética del Mn. Su orientación difiere dependiendo de la naturaleza de la TR, adoptando una dirección paralela con respecto al campo local, o puede alinearse en sentido opuesto, produciendo una estructura antiferromagnética no compensada. Para cationes divalentes (Ni2+), la solución sólida está limitada a TRNi2+0.5Mn4+0.5O3; en este límite, las interacciones de supercanje Ni2+-O-Mn4+ se optimizan. Para Me = Co el límite se amplía a causa de que el cobalto puede tomar el estado 3+; en este caso, la presencia de Co3+ modifica el acoplamiento magnético llevando a comportamientos cualitativamente diferentes durante los ciclos ZFC/FC. En el presente trabajo se ha escogido la composición específica TRMe0.50Mn0.50O3 para la cual se esperan las interacciones magnéticas más intensas, remarcando los resultados obtenidos para Me = Ni y Co y comparando varios elementos de tierras raras (TR = Y, La, Pr, Nd, Eu, Gd y Er). Como se esperaba de acuerdo con el comportamiento general de las soluciones sólidas (TR,Ca)MnO3, se ha hallado que en las series TR(Mn,Me)O3, cuanto mayor es el radio iónico de la TR mayor es la temperatura de transición, alcanzando 235 K para composiciones LaCo0.50Mn0.50O3 frente a 68 K para ErCo0.50Mn0.50O3.

Introduction and aim: A large number of patients with autoimmune hepatitis (AH) seek information about their disease on the Internet. The reliability, comprehensiveness, and quality of said information in Spanish has not been studied. Our aim was to describe the characteristics of the information about AH on YouTube®. Methods: An analytic observational study evaluated videos in Spanish about AH available on YouTube®, describing their general characteristics, viewer engagement, and information sources. Standardized tools were utilized to analyze reliability (DISCERN), comprehensiveness, and overall quality (Global Quality Score [GQS]). Results: One hundred videos were included, 93% of which provided information from healthcare professionals (group 1), and 7% of which reflected patient opinions (group 2). There were differences in the median reliability (DISCERN 4 vs 2, p ≤ 0.05) and comprehensiveness (4 vs 2, p ≤ 0.05) scores between groups, but equal overall quality (GQS 3 vs 2, p = 0.2). Reliability (DISCERN 4; RIC 3–4) and comprehensiveness (4.5; IQR 3–5) were higher in videos by professional organizations, compared with those by independent users, healthcare information websites, and for-profit organizations (DISCERN 3; IQR 2.5–3.5) (p

Introduction and aim: The majority of patients with inflammatory bowel disease (IBD) seek information about their disease on the Internet. The reliability, comprehensiveness, and quality of said information in Spanish has not previously been studied. Materials and methods: An analytic observational study was conducted that included YouTube® videos on IBD available in Spanish, describing general characteristics, engagement, and sources. Standard tools for evaluating reliability (DISCERN), comprehensiveness, and overall quality (Global Quality Score, GQS) were employed. Results: One hundred videos were included. Eighty-eight videos consisted of information produced by healthcare professionals (group 1) and 12 included patient opinions (group 2). There were no differences in the median scores for reliability (DISCERN 3 vs 3, p = 0.554) or comprehensiveness (3 vs 2.5, p = 0.768) between the two groups, but there was greater overall quality in the group 2 videos (GQS 3 vs 4, p = 0.007). Reliability was higher for the videos produced by professional organizations (DISCERN 4; IQR 3–4), when compared with healthcare information websites and for-profit agencies (DISCERN 3; IQR 2.5–3.5) (p

Extracellular histone proteins in the blood indicate a heightened risk of morbidity after trauma or in major illnesses such as sepsis. We present the development of an aptasensor for histone detection with an extended gate field-effect transistor (EGFET) configuration, which benefits from low power consumption, rapid response, and compatibility with miniaturized gold electrodes. Histones have a high isoelectric point and charge density, which cause them to physically adsorb to non-specific elements of the sensor that have available electrostatic charges. To combat this, the sensing surface is formed with a thiol-modified, high-affinity and histone-specific RNA aptamer sequence and by co-immobilizing with poly(ethylene glycol) methyl ether thiol (PEG) as a blocking agent. Surface plasmon resonance (SPR) is used to analyze aptamer and PEG immobilization strategies, confirm histone binding, and calculate kinetic binding constants. Through comparison of different blocking agents and time-dependent preparation, the ideal equilibrium dissociation constant (KD) is estimated to be below 200 pM, which is the upper range of extracellular histone concentrations in critically ill patients with high mortality. The EGFET sensitivity of the optimized aptasensor is 6.65 mV/decade concentration change for histone H4 with a physiologically relevant 5 pM limit of detection. Selectivity tests with 100 nM bovine serum albumin (BSA) demonstrate a signal response that is 13-fold smaller than for histones. This EGFET aptasensor platform is suitable for future point-of-care monitoring of histone levels in critically ill patients, thus permitting the early detection of increased risk and the need for more aggressive interventional measures to prevent mortality.

Summary: A signal mixer facilitates rich computation, which has been the building block of modern telecommunication. This frequency mixing produces new signals at the sum and difference frequencies of input signals, enabling powerful operations such as heterodyning and multiplexing. Here, we report that a neuron is a signal mixer. We found through ex vivo and in vivo whole-cell measurements that neurons mix exogenous (controlled) and endogenous (spontaneous) subthreshold membrane potential oscillations, producing new oscillation frequencies, and that neural mixing originates in voltage-gated ion channels. Furthermore, we demonstrate that mixing is evident in human brain activity and is associated with cognitive functions. We found that the human electroencephalogram displays distinct clusters of local and inter-region mixing and that conversion of the salient posterior alpha-beta oscillations into gamma-band oscillations regulates visual attention. Signal mixing may enable individual neurons to sculpt the spectrum of neural circuit oscillations and utilize them for computational operations.

Objective: The liver releases glucose into the blood using the glucose-6-phosphatase (G6Pase) system, a multiprotein complex located in the endoplasmic reticulum (ER). Here, we show for the first time that the G6Pase system is also expressed in hypothalamic tanycytes, and it is required to regulate energy balance. Methods: Using automatized qRT-PCR and immunohistochemical analyses, we evaluated the expression of the G6Pase system. Fluorescent glucose analogue (2-NBDG) uptake was evaluated by 4D live-cell microscopy. Glucose release was tested using a glucose detection kit and high-content live-cell analysis instrument, Incucyte s3. In vivo G6pt knockdown in tanycytes was performed by AAV1-shG6PT-mCherry intracerebroventricular injection. Body weight gain, adipose tissue weight, food intake, glucose metabolism, c-Fos, and neuropeptide expression were evaluated at 4 weeks post-transduction. Results: Tanycytes sequester glucose-6-phosphate (G6P) into the ER through the G6Pase system and release glucose in hypoglycaemia via facilitative glucose transporters (GLUTs). Strikingly, in vivo tanycytic G6pt knockdown has a powerful peripheral anabolic effect observed through decreased body weight, white adipose tissue (WAT) tissue mass, and strong downregulation of lipogenesis genes. Selective deletion of G6pt in tanycytes also decreases food intake, c-Fos expression in the arcuate nucleus (ARC), and Npy mRNA expression in fasted mice. Conclusions: The tanycyte-associated G6Pase system is a central mechanism involved in controlling metabolism and energy balance.

Precise monitoring of insect floral visitors and their relationship with floral resources throughout the flowering season provides baseline information to help us understand long-term changes in plant-pollinator interactions and improve pollinator conservation strategies. Pan traps are one of the methods most used for monitoring insect floral visitors and several studies have already linked the abundance and richness of these floral visitors with floral resources. However, less research has been conducted into the effectiveness of pan traps for monitoring phenological changes in the floral visitor community with regard to floral resources. We used pan traps to study the species composition and the abundance of insect floral visitors and their relationship with flower richness in a coastal forest throughout the entire flowering season for two consecutive years. Captures were confirmed to be floral visitors through field survey studies. Pan traps were effective for revealing changes in the abundance and species composition of floral visitor communities during and between years that correlated with changes in floral richness and species composition. Changes in floral visitor abundance showed a different bias in their association with floral richness. Thus, while Hymenoptera and Diptera abundance tended to be negatively correlated with floral richness, Coleoptera abundance tended to be positively correlated, although such correlations could change from year to year. There were two significantly different groups of flowering plant and floral visitor species: one in spring and the other in summer. Each period was characterized by unique overlap between some floral visitors and their floral resources, suggesting that to monitor floral visitors effectively both communities need to be considered. Interestingly, the floral phenology in this coastal forest extended longer than that of more inland communities, so reliable monitoring of floral visitors throughout the floral season may help us to better understand the role of coastal plant communities in the stabilization of the pollinator networks of more inland communities. Overall, phenology patterns need to be taken into account for pan trapping to become an effective methodology for monitoring floral visitor communities, considering both intra-year (spring and summer communities) and inter-year variations.

BabiaXR is a toolset for conducting experiments about 3D data visualizations in extended reality (XR) in the browser. BabiaXR provides both components for building complex data visualizations, and for easily transforming them into scenes suitable for running experiments with subjects. For data visualization, it provides components to retrieve, filter, select, and visualize data. To facilitate empirical experiments with human subjects, it provides components for showing information to subjects, controlling their interaction with data, and recording their reactions. This enables the easy transformation of a certain data visualization scene into an experiment directly usable by subjects. BabiaXR is extensible, based on the A-Frame JavaScript framework for XR. As such, it is easily composable with other A-Frame components, and complex data visualization scenes can be created by using only HTML constructs. BabiaXR can be used in any XR device supporting WebXR, and with limited capabilities also in desktop and mobile devices.

Bumblebees are key pollinators, but their global decline is being driven by factors such as invasive species. Bombus terrestris has invaded many countries, displacing and competing with native bumblebees for resources throughout many different habitats, which causes native populations to decline. In the Chilean highlands, Bombus funebris—a Chilean species under threat—shares its habitat with B. terrestris, suggesting that the two species could be competing for resources (e.g., flowers or habitats) within this ecosystem. However, an information gap in this regard prevents us from proposing conservation measures. Our goals were (1) to assess overlapping distribution between native and invasive Bombus species, (2) to determine any niche overlap in the use of flowers between the two bumblebee species, and (3) to document the predictors that influence their abundance. We conducted a survey in northern Chile between 2017 and 2019 with different latitudinal and altitudinal sampling points to count bumblebees and record their interaction with flowers, both in natural and perturbed habitats. We analyzed their overlapping distribution using the chi-square test and evaluated the use of floral resources and their overlap niche through an interaction network analysis. Predictors and bumblebee abundance were associated with a general linear mixed model. We found the distribution of both bumblebees overlapped by 94.3 %, whereas the overlap niche index (NO) for the common use of flowers was high between B. terrestris and B. funebris (NO = 0.78). The abundance of both bumblebee species was associated with the use of natural scrubland in the highlands. Our results suggest that both species are likely to have a competitive dynamic for floral resources in the high Andean scrubland. As such, we propose implementing an export ban on invasive bumblebee species, coordinating measures between bordering countries, removing any remaining B. terrestris populations, and restoring native flora to attract native pollinators and to provide and manage pollination services in the Chilean highlands.

Summary: Climate change is one of several drivers of recurrent outbreaks and geographical range expansion of infectious diseases in Europe. We propose a framework for the co-production of policy-relevant indicators and decision-support tools that track past, present, and future climate-induced disease risks across hazard, exposure, and vulnerability domains at the animal, human, and environmental interface. This entails the co-development of early warning and response systems and tools to assess the costs and benefits of climate change adaptation and mitigation measures across sectors, to increase health system resilience at regional and local levels and reveal novel policy entry points and opportunities. Our approach involves multi-level engagement, innovative methodologies, and novel data streams. We take advantage of intelligence generated locally and empirically to quantify effects in areas experiencing rapid urban transformation and heterogeneous climate-induced disease threats. Our goal is to reduce the knowledge-to-action gap by developing an integrated One Health—Climate Risk framework.

Summary: Background: The incidence of endometrial cancer is increasing worldwide. While delays in diagnosis reduce survival, case molecular misclassification might be associated with under- and over-treatment. The objective of this study was to evaluate genetic alterations to detect and molecularly classify cases of endometrial cancer using non-invasive samples. Methods: Consecutive patients with incident endometrial cancer (N = 139) and controls (N = 107) from a recent Spanish case–control study were included in this analysis. Overall, 339 cervicovaginal samples (out of which 228 were clinician-collected and 111 were self-collected) were analysed using a test based on next-generation sequencing (NGS), which targets 47 genes. Immunohistochemical markers were evaluated in 133 tumour samples. A total of 159 samples were used to train the detection algorithm and 180 samples were used for validation. Findings: Overall, 73% (N = 94 out of 129 clinician-collected samples, and N = 66 out of 90 self-collected samples) of endometrial cancer cases had detectable mutations in clinician-collected and self-collected samples, while the specificity was 80% (79/99) for clinician-collected samples and 90% (19/21) for self-collected samples. The molecular classifications obtained using tumour samples and non-invasive gynaecologic samples in our study showed moderate-to-good agreement. The molecular classification of cases of endometrial cancer into four groups using NGS of both clinician-collected and self-collected cervicovaginal samples yielded significant differences in disease-free survival. The cases with mutations in POLE had an excellent prognosis, whereas the cases with TP53 mutations had the poorest clinical outcome, which is consistent with the data on tumour samples. Interpretation: This study classified endometrial cancer cases into four molecular groups based on the analysis of cervicovaginal samples that showed significant differences in disease-free survival. The molecular classification of endometrial cancer in non-invasive samples may improve patient care and survival by indicating the early need for aggressive surgery, as well as reducing referrals to highly specialized hospitals in cancers with good prognosis. Validation in independent sets will confirm the potential for molecular classification in non-invasive samples. Funding: This study was funded by a competitive grant from Instituto de Salud Carlos III through the projects PI19/01835, PI23/00790, and FI20/00031, CIBERESP CB06/02/0073 and CIBERONC CB16/12/00231, CB16/12/00234 (Co-funded by European Regional Development Fund. ERDF: A way to build Europe). Samples and data were provided by Biobank HUB-ICO-IDIBELL, integrated into the Spanish Biobank Network, and funded by the Instituto de Salud Carlos III (PT20/00171) and by Xarxa de Bancs de Tumors de Catalunya (XBTC) sponsored by Pla Director d’Oncologia de Catalunya. This work was supported in part by the AECC, Grupos estables (GCTRA18014MATI). It also counts with the support of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Generalitat de Catalunya, and grants to support the activities of research groups 2021SGR01354 and 2021SGR1112.

Resumen: La colitis ulcerativa (CU) es una enfermedad crónica de etiología desconocida, incurable, su curso clínico es intermitente, caracterizado por periodos de remisión y recaídas, su prevalencia e incidencia mundial ha venido incrementando. En esta actualización participaron profesionales de la salud, tomadores decisiones y un representante de los pacientes. Todos los involucrados declararon sus conflictos de interés. Se formularon preguntas clínicas contestables y se graduaron los desenlaces. La pesquisa de la información se realizó en Medline/PubMed, Embase, Epistemonikos y LILACS. La búsqueda también abarcó fuentes de literatura gris y se actualizó el 30 de noviembre de 2020 sin restricciones por fecha o idioma. Se implementó la aproximación Grading of Recommendations Assessment, Development and Evaluation (GRADE) para establecer la calidad de la evidencia y la fuerza de las recomendación. Se realizó consenso formal implementando la metodología RAND/UCLA. El documento fue objeto de revisión por pares. Se presenta aquí la versión corta de la Guía de Práctica Clínica para el Tratamiento de la Colitis Ulcerativa en Población Adulta, junto con la evidencia de apoyo y las recomendaciones respectivas. En CU leve a moderada, la budesonida MMX es una opción en caso de falla a 5-ASA, y antes de usar esteroides sistémicos. En CU moderada a severa, infliximab y adalimumab, vedolizumab, ustekinumab y tofacitinib pueden ser usados como terapia de primera línea. En caso de falla a anti-TNF, los mejores resultados son con ustekinumab y tofacitinib. En pacientes con reservoritis refractaria a antibióticos, el tratamiento de elección son los anti-TNF. Abstract: Ulcerative colitis (US) is a chronic disease of unknown etiology. It is incurable and its clinical course is intermittent, characterized by periods of remission and relapse. The prevalence and incidence of the disease has been increasing worldwide. The update presented herein includes the participation of healthcare professionals, decision-makers, and a representative of the patients, all of whom declared their conflicts of interest. Answerable clinical questions were formulated, and the outcomes were graded. The information search was conducted on the Medline/PubMed, Embase, Epistemonikos, and LILACS databases, and covered grey literature sources, as well. The search was updated on November 30, 2020, with no restrictions regarding date or language. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification system was implemented to establish the strength of the recommendation and quality of evidence. A formal consensus was developed, based on the RAND/UCLA methodology and the document was peer reviewed. The short version of the Clinical Practice Guidelines for the Treatment of Ulcerative Colitis in the Adult Population is presented herein, together with the supporting evidence and respective recommendations. In mild-to-moderate UC, budesonide MMX is an option when treatment with 5-ASA fails, and before using systemic steroids. In moderate-to-severe UC, infliximab, adalimumab, vedolizumab, ustekinumab, and tofacitinib can be used as first-line therapy. If there is anti-TNF therapy failure, ustekinumab and tofacitinib provide the best results. In patients with antibiotic-refractory pouchitis, anti-TNFs are the treatment of choice.

Ulcerative colitis (US) is a chronic disease of unknown etiology. It is incurable and its clinical course is intermittent, characterized by periods of remission and relapse. The prevalence and incidence of the disease has been increasing worldwide. The update presented herein includes the participation of healthcare professionals, decision-makers, and a representative of the patients, all of whom declared their conflicts of interest. Answerable clinical questions were formulated, and the outcomes were graded. The information search was conducted on the Medline/PubMed, Embase, Epistemonikos, and LILACS databases, and covered grey literature sources, as well. The search was updated on November 30, 2020, with no restrictions regarding date or language. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification system was implemented to establish the strength of the recommendation and quality of evidence. A formal consensus was developed, based on the RAND/UCLA methodology and the document was peer reviewed. The short version of the Clinical Practice Guidelines for the Treatment of Ulcerative Colitis in the Adult Population is presented herein, together with the supporting evidence and respective recommendations. In mild-to-moderate UC, budesonide MMX is an option when treatment with 5-ASA fails, and before using systemic steroids. In moderate-to-severe UC, infliximab, adalimumab, vedolizumab, ustekinumab, and tofacitinib can be used as first-line therapy. If there is anti-TNF therapy failure, ustekinumab and tofacitinib provide the best results. In patients with antibiotic-refractory pouchitis, anti-TNFs are the treatment of choice. Resumen: La colitis ulcerativa (CU) es una enfermedad crónica de etiología desconocida, incurable, su curso clínico es intermitente, caracterizado por periodos de remisión y recaídas, su prevalencia e incidencia mundial ha venido incrementando. En esta actualización participaron profesionales de la salud, tomadores decisiones y un representante de los pacientes. Todos los involucrados declararon sus conflictos de interés. Se formularon preguntas clínicas contestables y se graduaron los desenlaces. La pesquisa de la información se realizó en Medline/PubMed, Embase, Epistemonikos y LILACS. La búsqueda también abarcó fuentes de literatura gris y se actualizó el 30 de noviembre de 2020 sin restricciones por fecha o idioma. Se implementó la aproximación GRADE (Grading of Recommendations Assessment, Development and Evaluation) para establecer la calidad de la evidencia y la fuerza de las recomendación. Se realizó consenso formal implementando la metodología RAND/UCLA. El documento fue objeto de revisión por pares. Se presenta aquí la versión corta de La Guía de Práctica Clínica para el Tratamiento de la Colitis Ulcerativa en Población Adulta, junto con la evidencia de apoyo y las recomendaciones respectivas. En CU leve a moderada, la budesonida MMX es una opción en caso de falla a 5-ASA, y antes de usar esteroides sistémicos. En colitis ulcerativa moderada a severa, infliximab y adalimumab, vedolizumab, ustekinumab y tofacitinib pueden ser usado como terapia de primera línea. En caso de falla a anti-TNFs, los mejores resultados son con ustekinumab y tofacitinib. En pacientes con reservoritis refractaria a antibióticos, el tratamiento de elección son los anti-TNFs.

Intro: Understanding infectious disease transmission dynamics is key to optimising infection prevention and control (IPC) strategies. Yet, standard epidemiological modelling tools do not fully utilise large datasets of time- evolving spatial interactions, which could lead to improved descriptions of complex transmission dynamics, as exhibited by multi-drug resistant organisms (MDRO). Here, we showcase an approach accounting for spatial-temporal dynamics using machine learning and graph theory to characterize nosocomial MDRO transmission. Methods: We performed a retrospective cohort study using all inpatient admissions to a 1200-bed Singaporean hospital from 2018-01-01 to 2021-12-31. We employ a graph-based machine learning methodology to learn transmission dynamics using spatial-temporal patient interactions. Taking Methicillin-resistant Staphylococcus aureus (MRSA) as a proof-of-principle, we examine the real-world efficacy using routine surveillance and clinical cultures obtained during acute care. Findings: There were 149,352 inpatient admissions and 3.21 million contact-interactions during the study period; 7,753 (5.2%) of these patients tested positive for MRSA, with 1,585 (1.1%;) being likely hospital acquisitions. The probability of onward transmission was largest on the day a culture-positive result was reported (11.2% of all transmissions). However, high onward-transmission persisted beyond (weighted-mean 7.8 days). Through spatial-temporal analsysis, we found hospital rooms with comparatively high acquisition-rates (36/665 wards accounting for 50.2% of hospital-acquisitions); these hotspots were found to be central in network of patient transfers, and interconnected with each other. Conclusion: With extensive and detailed datasets becoming available, new methodologies that leverage their size and detail can provide insights into transmission processes. Here, we demonstrated their use to learn the transmission dynamics of an MDRO and showed their ability to make inferences on spatial-temporal profiles of transmission. Furthering this research, we will engineer spatial-temporal features to predict pathogen transmission dynamics and expand to additional MDROs.

Intro: Controlling the spread of infectious diseases requires correctly targeting preventative resources. When poorly deployed, these resources are misspent and have an inefficient impact. In a dynamic environment where sources of outbreaks are ever-changing, how to optimally deploy these resources is difficult to identify and can moreover change over time. In addressment, we outline and test network-driven framework that accounts for underlying patient mobility, and outbreak dynamics in hospitals to predict the temporal and spatial arrival of carbapenemase-producing Enterobacteriaceae (CPE) outbreaks. Methods: We reconstructed CPE-outbreaks using a novel formulation based on transmission-dynamics, contact-interactions, and microbiology data. For each outbreak, we then examine their spatial evolution and, using background hospital population movement (entire patient population from Imperial College Healthcare NHS Trust between 2018-08-17 and 2022-02-03), we predict the arrival times of new CPE cases across wards. Findings: The background mobility-network contained ward-transitions from 181,512 patients (178 wards). Based on the construction, the network comprises a single giant component and acts as a medium for disease transmission. For the results of a fitted regression predicting outbreak arrival, we included locational attributes, in addition to network distances. Overall, we found that effective distance (a graphbased path measure shown previously epidemiologically predictive) contained unique predictive power compared to edge weight. However, the effective distance could be complemented by information regarding patient demographics (Age and Sex) of patient transfers; their predictive power is suggestive of specific sub-population mobility as more important drivers of CPE. Conclusion: We investigated a network-driven framework showing the potential to anticipate arrival-times of hospital CPE outbreaks. In including additional information, we also showed how specific hospital population movements were key drivers of CPE. In furthering our results, we next plan to investigate additional diseases, validate our findings beyond our current dataset, and explore further locational attributes.

The development of biofunctional non-dairy beverages with probiotics and prebiotics is a challenge and a frontier goal prompted by current consumers demand of health promoting foods, in particular from those with dietary restrictions related to dairy products. This study aimed to evaluate the survival of two commercially available probiotic strains, Lactobacillus rhamnosus LGG® and Lactobacillus paracasei (Lactobacillus casei 431), in a commercial sterile purple pitaya juice during storage at 5 °C. Additionally, the prebiotic effect of inulin (6.25 mg/ml) on the survival of L. rhamnosus, the most promising strain, was assessed. Physicochemical parameters such as betalain and soluble solids contents, pH, and color were also monitored during storage. Populations of L. rhamnosus and L. paracasei decreased from 11 to 7 log CFU/ml after 12 ± 1 and 0.93 ± 0.05 d, respectively. No changes on the individual betalain contents, as well as for total betalain concentrations (28 ± 3 μg/ml) were observed after probiotic inoculation nor during storage for all experimental trials and regardless of the strain evaluated (P 0.05) influence the survival kinetics of L. rhamnosus in the juice during storage and the juice color, pH and soluble solids content remained unaffected as well. Purple pitaya juice represents therefore a promising non-dairy food matrix for probiotics delivery.

Resumen: Introducción: La enfermedad inflamatoria intestinal (EII) es una entidad crónica e incurable. La Pan American Crohn's and Colitis Organisation (PANCCO) tiene como objetivo generar concientización sobre la EII, con especial énfasis en Latinoamérica, y el Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) tiene por objetivo primordial procurar la homologación de criterios clínico-terapéuticos para el diagnóstico y tratamiento de la EII. Objetivo: Realizar un consenso para la evaluación de los criterios de aprobación que debe cumplir una Clínica de Atención Integral de pacientes con EII a nivel latinoamericano para ser considerada un centro de excelencia. Material y métodos: Se contó con la participación de 14 expertos clínicos especialistas en gastroenterología, con amplia experiencia clínica de varios años en el manejo de la atención a numerosos pacientes con EII, así como también aquellos que tuvieran la formación de alta especialidad en EII. Todos pertenecientes a 11 países latinoamericanos: Argentina, Brasil, Colombia, Ecuador, Guatemala, México, Perú, Puerto Rico, República Dominicana, Uruguay y Venezuela, en donde tienen clínicas de EII; así mismo, también participó un experto de España como apoyo metodológico, representante de GETECCU.El consenso consistió de 52 enunciados divididos en tres secciones: 1) Indicadores de estructura; 2) Indicadores de proceso y 3) Indicadores de resultados. Se aplicó el método de panel Delphi. Resultados: El consenso latinoamericano muestra los indicadores de calidad que debe cumplir una Clínica de Atención Integral de pacientes con EII para ser considerada un centro de excelencia teniendo en cuenta las necesidades de nuestra región. Conclusiones: Es el primer consenso latinoamericano realizado de manera conjunta por la PANCCO y GETECCU para presentar los estándares para aprobar centros de excelencia en la atención de pacientes con EII. Abstract: Introduction: Inflammatory bowel disease (IBD) is a chronic and incurable entity. The aim of the Pan American Crohn's and Colitis Organisation (PANCCO) is to create awareness of IBD, with special emphasis on Latin America, and the primary objective of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU, the Spanish acronym) is to obtain the accreditation of the clinical and therapeutic criteria for the diagnosis and treatment of IBD. Aim: To carry out a consensus for evaluating the approval criteria that a Comprehensive Care Clinic for Latin American IBD patients must meet, to be considered a center of excellence. Materials and methods: Fourteen clinical experts participated in the consensus. They were made up of specialists in gastroenterology, with broad clinical experience, spanning several years, in managing the care of a large number of patients with IBD, as well as advanced specialists in IBD. Thirteen of the participants came from 11 Latin American countries (Argentina, Brazil, Colombia, Dominican Republic, Ecuador, Guatemala, Mexico, Peru, Puerto Rico, Uruguay, and Venezuela) that have IBD clinics. An expert from Spain, representing the GETECCU, provided the methodologic support.The consensus consisted of 52 statements divided into three sections: 1) Structure indicators, 2) Process indicators, and 3) Result indicators. The Delphi panel method was applied. Results: The present Latin American consensus describes the quality indicators that a Comprehensive Care Clinic for IBD patients must meet, to be considered a center of excellence, taking into account the needs of our region. Conclusions: This is the first Latin American consensus, jointly carried out by the PANCCO and GETECCU, to present accreditation standards for centers of excellence in the care of patients with IBD.

Introduction: Inflammatory bowel disease (IBD) is a chronic and incurable entity. The aim of the Pan American Crohn's and Colitis Organisation (PANCCO) is to create awareness of IBD, with special emphasis on Latin America, and the primary objective of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU, the Spanish acronym) is to obtain the accreditation of the clinical and therapeutic criteria for the diagnosis and treatment of IBD. Aim: To carry out a consensus for evaluating the approval criteria that a Comprehensive Care Clinic for Latin American IBD patients must meet, to be considered a center of excellence. Materials and methods: Fourteen clinical experts participated in the consensus. They were made up of specialists in gastroenterology, with broad clinical experience, spanning several years, in managing the care of a large number of patients with IBD, as well as advanced specialists in IBD. Thirteen of the participants came from 11 Latin American countries (Argentina, Brazil, Colombia, Dominican Republic, Ecuador, Guatemala, Mexico, Peru, Puerto Rico, Uruguay, and Venezuela) that have IBD clinics. An expert from Spain, representing the GETECCU, provided the methodologic support.The consensus consisted of 52 statements divided into three sections: 1) Structure indicators, 2) Process indicators, and 3) Result indicators. The Delphi panel method was applied. Results: The present Latin American consensus describes the quality indicators that a Comprehensive Care Clinic for IBD patients must meet, to be considered a center of excellence, taking into account the needs of our region. Conclusions: This is the first Latin American consensus, jointly carried out by the PANCCO and GETECCU, to present accreditation standards for centers of excellence in the care of patients with IBD. Resumen: Introducción: La enfermedad inflamatoria intestinal (EII) es una entidad crónica e incurable. La Pan American Crohn's and Colitis Organisation (PANCCO) tiene como objetivo generar concientización sobre la EII, con especial énfasis en Latinoamérica, y el Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) tiene por objetivo primordial procurar la homologación de criterios clínico-terapéuticos para el diagnóstico y tratamiento de la EII. Objetivo: Realizar un consenso para la evaluación de los criterios de aprobación que debe cumplir una Clínica de Atención Integral de pacientes con EII a nivel latinoamericano para ser considerada un centro de excelencia. Material y métodos: Se contó con la participación de 14 expertos clínicos especialistas en gastroenterología, con amplia experiencia clínica de varios años en el manejo de la atención a numerosos pacientes con EII, así como también aquellos que tuvieran la formación de alta especialidad en EII. Todos pertenecientes a 11 países latinoamericanos: Argentina, Brasil, Colombia, Ecuador, Guatemala, México, Perú, Puerto Rico, República Dominicana, Uruguay y Venezuela, en donde tienen clínicas de EII; así mismo, también participó un experto de España como apoyo metodológico, representante de GETECCU.El consenso consistió de 52 enunciados divididos en tres secciones: 1) Indicadores de estructura; 2) Indicadores de proceso y 3) Indicadores de resultados. Se aplicó el método de panel Delphi. Resultados: El consenso latinoamericano muestra los indicadores de calidad que debe cumplir una Clínica de Atención Integral de pacientes con EII para ser considerada un centro de excelencia teniendo en cuenta las necesidades de nuestra región. Conclusiones: Es el primer consenso latinoamericano realizado de manera conjunta por la PANCCO y GETECCU para presentar los estándares para aprobar centros de excelencia en la atención de pacientes con EII.

Summary: Background: Improvements in the early diagnosis of dengue are urgently needed, especially in resource-limited settings where the distinction between dengue and other febrile illnesses is crucial for patient management. Methods: In this prospective, observational study (IDAMS), we included patients aged 5 years and older with undifferentiated fever at presentation from 26 outpatient facilities in eight countries (Bangladesh, Brazil, Cambodia, El Salvador, Indonesia, Malaysia, Venezuela, and Viet Nam). We used multivariable logistic regression to investigate the association between clinical symptoms and laboratory tests with dengue versus other febrile illnesses between day 2 and day 5 after onset of fever (ie, illness days). We built a set of candidate regression models including clinical and laboratory variables to reflect the need of a comprehensive versus parsimonious approach. We assessed performance of these models via standard measures of diagnostic values. Findings: Between Oct 18, 2011, and Aug 4, 2016, we recruited 7428 patients, of whom 2694 (36%) were diagnosed with laboratory-confirmed dengue and 2495 (34%) with (non-dengue) other febrile illnesses and met inclusion criteria, and were included in the analysis. 2703 (52%) of 5189 included patients were younger than 15 years, 2486 (48%) were aged 15 years or older, 2179 (42%) were female and 3010 (58%) were male. Platelet count, white blood cell count, and the change in these variables from the previous day of illness had a strong association with dengue. Cough and rhinitis had strong associations with other febrile illnesses, whereas bleeding, anorexia, and skin flush were generally associated with dengue. Model performance increased between day 2 and 5 of illness. The comprehensive model (18 clinical and laboratory predictors) had sensitivities of 0·80 to 0·87 and specificities of 0·80 to 0·91, whereas the parsimonious model (eight clinical and laboratory predictors) had sensitivities of 0·80 to 0·88 and specificities of 0·81 to 0·89. A model that includes laboratory markers that are easy to measure (eg, platelet count or white blood cell count) outperformed the models based on clinical variables only. Interpretation: Our results confirm the important role of platelet and white blood cell counts in diagnosing dengue, and the importance of serial measurements over subsequent days. We successfully quantified the performance of clinical and laboratory markers covering the early period of dengue. Resulting algorithms performed better than published schemes for distinction of dengue from other febrile illnesses, and take into account the dynamic changes over time. Our results provide crucial information needed for the update of guidelines, including the Integrated Management of Childhood Illness handbook. Funding: EU's Seventh Framework Programme. Translations: For the Bangla, Bahasa Indonesia, Portuguese, Khmer, Spanish and Vietnamese translations of the abstract see Supplementary Materials section.

Early childhood caries (ECC) are an oral health problem worldwide in children under 6 years of age. This disease of rapid development has a multifactorial etiology, and one of the possible risk factors is developmental defects of enamel (DDE), such as hypoplasia and opacities. The aim of this systematic review was to evaluate the association between DDE and ECC in children under 6 years of age. An electronic search was conducted until March 2022 using Medline (PubMed), Scopus, Science-Direct, LILACS, Web of Science, Cochrane Library, EBSCO-Host, EMBASE, and Google Scholar and complemented with a manual search, with no restrictions on language or date of publication. Longitudinal studies of children under 6 years of age with primary dentition were included. A total of 1158 studies were found, of which 651 records were reviewed by title and abstract, and 24 articles were selected for full-text evaluation. Finally, nine studies that met the selection criteria were included in the qualitative synthesis. Study quality and certainty were assessed using the Newcastle-Ottawa scale and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Three cohort studies of good quality were included in the meta-analysis. A risk associated with DDE (RR = 1.94; 95% CI: 1.52–2.49) and a risk associated with enamel hypoplasia (RR = 5.45; 95% CI: 1.84–16.14) were found. The results for diffuse opacity (RR = 1.21; 95% CI: 0.18–8.15) and demarcated opacity (RR = 1.26; 95% CI: 0.43–3.65) were not significant. GRADE analysis presented low and very low certainty of evidence. It was concluded that there is an association between DDE and ECC. However, the results should be interpreted with caution because of the limitations of the study.The protocol for this study has been registered in PROSPERO under identification number CRD42021238919.

Background: The small intestine is one of the most sensitive organs to ischemia. L-arginine has been shown to reduce damage from ischemia and reperfusion injury. We hypothesize that explanted intestinal segments from rats will demonstrate reduced susceptibility to ischemic injury when perfused with l-arginine. Methods: 45 small intestinal segments were harvested from male Sprague-Dawley rats and connected to an ex vivo intestinal perfusion device. Ischemic damage was induced by perfusing the extraluminal side with Ringer-HEPES buffer saturated with 100% N2. All segments were then perfused intraluminally with and without l-arginine. We conducted a set of experiments with intraluminal perfusion with both l-arginine and N-nitroarginine methyl ester (L-NAME), an inhibitor of the nitric oxide – arginine pathway. Control segments were perfused extraluminally under non-ischemic conditions and intraluminally with and without l-arginine. The intraluminal perfusate contained FITC-inulin, and the fluorescence signal of FITC-inulin was measured to calculate average fluid secretion, which directly corresponds to the extent of ischemic injury. Results: Intestinal segments perfused with l-arginine had significantly decreased secretion over time in comparison to intestinal segments perfused without l-arginine (p

Xanthophyllomyces dendrorhous is a basidiomycete yeast that produces carotenoids, mainly astaxanthin. Astaxanthin is an organic pigment of commercial interest due to its antioxidant and coloring properties. X. dendrorhous has a functional SREBP pathway, and the Sre1 protein is the SREBP homolog in this yeast. However, how sterol regulatory element (Sre)1 promotes the biosynthesis of sterols and carotenoids in X. dendrorhous is unknown. In this work, comparative RNA-sequencing analysis between modified X. dendrorhous strains that have an active Sre1 protein and the WT was performed to identify Sre1-dependent genes. In addition, Sre1 direct target genes were identified through ChIP combined with lambda exonuclease digestion (ChIP-exo) assays. SRE motifs were detected in the promoter regions of several Sre1 direct target genes and were consistent with the SREs described in other yeast species. Sre1 directly regulates genes related to ergosterol biosynthesis as well as genes related to the mevalonate (MVA) pathway, which synthesizes the building blocks of isoprenoids, including carotenoids. Two carotenogenic genes, crtE and crtR, were also identified as Sre1 direct target genes. Thus, carotenogenesis in X. dendrorhous is regulated by Sre1 through the regulation of the MVA pathway and the regulation of the crtE and crtR genes. As the crtR gene encodes a cytochrome P450 reductase, Sre1 regulates pathways that include cytochrome P450 enzymes, such as the biosynthesis of carotenoids and sterols. These results demonstrate that Sre1 is a sterol master regulator that is conserved in X. dendrorhous.

Xanthophyllomyces dendrorhous is a basidiomycete yeast known as a natural producer of astaxanthin, a carotenoid of commercial interest because of its antioxidant properties. Recent studies indicated that X. dendrorhous has a functional SREBP pathway involved in the regulation of isoprenoid compound biosynthesis, which includes ergosterol and carotenoids. SREBP is a major regulator of sterol metabolism and homeostasis in mammals; characterization in fungi also provides information about its role in the hypoxia adaptation response and virulence. SREBP protease processing is required to activate SREBP pathway functions in fungi. Here, we identified and described the STP1 gene, which encodes a metallopeptidase of the M50 family involved in the proteolytic activation of the transcription factor Sre1 of the SREBP pathway, in X. dendrorhous. We assessed STP1 function in Δstp1 strains derived from the wild-type and a mutant of ergosterol biosynthesis that overproduces carotenoids and sterols. Bioinformatic analysis of the deduced protein predicted the presence of characteristic features identified in homologs from mammals and fungi. The Δstp1 mutation decreased yeast growth in the presence of azole drugs and reduced transcript levels of Sre1-dependent genes. This mutation also negatively affected the carotenoid- and sterol-overproducing phenotype. Western blot analysis demonstrated that Sre1 was activated in the yeast ergosterol biosynthesis mutant and that the Δstp1 mutation introduced in this strain prevented Sre1 proteolytic activation. Overall, our results demonstrate that STP1 encodes a metallopeptidase involved in proteolytic activation of Sre1 in X. dendrorhous, contributing to our understanding of fungal SREBP pathways.

Purpose: Contact tracing is a crucial tool in infection prevention and control (IPC), which aims to identify outbreaks and prevent onward transmission. What constitutes a contact is typically based on strict binary criteria (i.e., being at a location at the same time). Missing data, indirect contacts and background sources can however substantially alter contact-tracing investigations. Here, we present StEP, a Spatial-temporal Epidemiological Proximity model that accounts for imperfect data by introducing a network-based notion of contact based on spatial-temporal proximity derived from background flows of patient movement. Methods & Materials: We showcase StEP by analysing outbreaks of multidrug-resistant bacteria and COVID-19 within a large hospital Trust in London (UK).StEP utilises spatial-temporal patient trajectories and the background hospital movement flows to recover enhanced contact networks. Firstly, we study a well-characterised outbreak of carbapenemase-producing Enterobacteriaceae (CPE) involving 116 hospitalised patients where genetic sequencing is used to learn model parameters. Secondly, our trained model is deployed in an unsupervised manner on three unseen outbreaks involving 867 patients of related CPE-types. Thirdly, we test application to an altogether novel pathogen by analysing a hospital outbreak of COVID-19 among 90 hospital patients, and demonstrate the power of StEP when characterising newly emerging diseases, even when there is a lack of sequencing data. Results: In addition to recovering core contact structures, StEP identifies missing contacts that link seemingly unconnected infection clusters, revealing a larger extent of transmission than conventional methods. Via genomic analyses we confirm that the additional contacts detected through StEP lead to improved alignment to the plasmid phylogeny (the major outbreak driving force). Hence the StEP contact network is most aligned to the transmission structure. Conclusion: By considering spatial-temporal information in a continuous manner, StEP tackles several challenges associated with traditional contact-tracing. StEP allows both direct and indirect contacts as possible routes of disease transmission and is tuneable to a pathogen's epidemiological characteristics. Such flexible use of heterogeneous data in uncertain situations can significantly enhance IPC.

Purpose: Predicting healthcare-acquired infections (HAIs) has the potential to revolutionise the prevention and control of transmissible infections. Existing prediction models for HAIs, however, fail to capture fully the contact-driven nature of infectious diseases. Here, we investigate the epidemiological predictivity of patient contact patterns through a forecasting model for hospital-onset COVID-19 infection (HOCI). Methods & Materials: Our cohort comprises all patient admissions at a large London NHS Trust between 1/04/2020 and 1/04/2021. For patients, we consider (i) their hospital pathway, (ii) patient contacts, and (iii) date of COVID-19 infection. We consider rolling 14-day windows and forecast patient infection over the subsequent 7 days. Over each window, we construct a patient contact network and compute network features that capture contact centrality. We then combine network features, hospital environmental variables and patient clinical data to predict subsequent infections. Results: A total of 51,157 patient admissions/episodes were observed during the study. Across all models, we find that contact-network features showed the highest performance (0.91 AUC-ROC). A reduced model with the six most predictive variables was almost as predictive and contained five features from patient contact (including direct contact with and network proximity to infectious cases) and only one environmental variable (length of stay). Conclusion: Our results reveal that the number of direct contacts and network proximity to infectious patient(s) are highly predictive of HOCI. Such contact-based risk factors are easily extracted from routinely collected electronic health records providing a highly accessible route to improve personalised disease prognostics in future models.

Digital active disturbance rejection controllers (DADRC) have a wide scope as they have inherent advantages such as: easy hardware implementation, the entire system's mathematical model it is not necessary, is a linear controller dealing with uncertainty and is intended to ensure that energy savings are achieved. This document provides a procedure for designing a DADRC for a dc motor drive from the perspective of a Generalized Proportional Integral observer and differential flatness. The angular speed of a dc motor drive is the main purpose of the controller. The proposed DADRC was implemented using floating point operations on a field programmable gate array Artix-7™ using a Nexys 4 board. The system is subject to current demands, parameter variations, dc power supply changes and external load torque variations. The coupling of buck converter and dc motor resulting in external and internal disturbances that are actively counteracts the linear controller, as shown in the results.

This data article describes the dataset of the International COVID-19 Impact on Parental Engagement Study (ICIPES). ICIPES is a collaborative effort of more than 20 institutions to investigate the ways in which, parents and caregivers built capacity engaged with children's learning during the period of social distancing arising from global COVID-19 pandemic. A series of data were collected using an online survey conducted in 23 countries and had a total sample of 4,658 parents/caregivers. The description of the data contained in this article is divided into two main parts. The first part is a descriptive analysis of all the items included in the survey and was performed using tables and figures. The second part refers to the construction of scales. Three scales were constructed and included in the dataset: ‘parental acceptance and confidence in the use of technology’, ‘parental engagement in children's learning’ and ‘socioeconomic status’. The scales were created using Confirmatory Factor Analysis (CFA) and Multi-Group Confirmatory Analysis (MG-CFA) and were adopted to evaluate their cross-cultural comparability (i.e., measurement invariance) across countries and within sub-groups. This dataset will be relevant for researchers in different fields, particularly for those interested in international comparative education.

Resumen: La contaminación del planeta alcanza también al ecosistema de la lactancia, uno de los más íntimos e inviolables que nos liga como especie animal al resto de los mamíferos. Las madres lactantes pueden estar preocupadas sobre si la calidad de su leche será la adecuada para su bebé y si los contaminantes medioambientales, a través del trabajo, la dieta y el envasado, pueden afectar a su hijo desfavorablemente. La leche materna es fuente de exposición a contaminantes medioambientales, y al mismo tiempo contrabalancea muchos de los efectos de estas exposiciones. Un enfoque basado en los principios de realidad y precaución de la salud medioambiental para evitar, reducir o eliminar la producción y el uso de sustancias químicas nocivas durante el embarazo y la lactancia aseguran a la descendencia una mejor salud humana y del planeta. Abstract: The pollution of the planet also reaches the breastfeeding ecosystem, one of the most intimate and inviolable that links us as an animal species to the rest of mammals. Nursing mothers may be concerned about whether the quality of their milk will be adequate for their baby and whether environmental pollutants through work, diet, and storing may adversely affect their child. Breast milk is a source of exposure to environmental pollutants, and at the same time it counteracts much of the effects of these exposures. An approach based on the principles of reality and precaution of environmental health to avoid, reduce or eliminate the production and use of harmful chemicals during pregnancy and lactation would improve the human and planetary health for the offspring.

The pollution of the planet also reaches the breastfeeding ecosystem, one of the most intimate and inviolable that links us as an animal species to the rest of mammals. Nursing mothers may be concerned about whether the quality of their milk will be adequate for their baby and whether environmental pollutants through work, diet, and storing may adversely affect their child. Breast milk is a source of exposure to environmental pollutants, and at the same time it counteracts much of the effects of these exposures. An approach based on the principles of reality and precaution of environmental health to avoid, reduce or eliminate the production and use of harmful chemicals during pregnancy and lactation would improve the human and planetary health for the offspring. Resumen: La contaminación del planeta alcanza también al ecosistema de la lactancia, uno de los más íntimos e inviolables que nos liga como especie animal al resto de los mamíferos. Las madres lactantes pueden estar preocupadas sobre si la calidad de su leche será la adecuada para su bebé y si los contaminantes medioambientales, a través del trabajo, la dieta y el envasado, pueden afectar a su hijo desfavorablemente. La leche materna es fuente de exposición a contaminantes medioambientales, y al mismo tiempo contrabalancea muchos de los efectos de estas exposiciones. Un enfoque basado en los principios de realidad y precaución de la salud medioambiental para evitar, reducir o eliminar la producción y el uso de sustancias químicas nocivas durante el embarazo y la lactancia aseguran a la descendencia una mejor salud humana y del planeta.

Under physiological conditions, vitamin C is the main antioxidant found in the central nervous system and is found in two states: reduced as ascorbic acid (AA) and oxidized as dehydroascorbic acid (DHA). However, under pathophysiological conditions, AA is oxidized to DHA. The oxidation of AA and subsequent production of DHA in neurons are associated with a decrease in GSH concentrations, alterations in glucose metabolism and neuronal death. To date, the endogenous molecules that act as intrinsic regulators of neuronal necroptosis under conditions of oxidative stress are unknown. Here, we show that treatment with AA regulates the expression of pro- and antiapoptotic genes. Vitamin C also regulates the expression of RIPK1/MLKL, whereas the oxidation of AA in neurons induces morphological alterations consistent with necroptosis and MLKL activation. The activation of necroptosis by AA oxidation in neurons results in bubble formation, loss of membrane integrity, and ultimately, cellular explosion. These data suggest that necroptosis is a target for cell death induced by vitamin C. Keywords: Vitamin C, Ascorbic acid, Dehydroascorbic acid, Necroptosis, Neuronal death, Live cell microscopy

Instrumental assessments and sensory tests were performed to evaluate the effects of diet and postmortem ageing time (1, 7 and 21 days) on beef quality. A total of 48 Friesian calves were randomly allocated to four dietary treatments: control, whole linseed (10% linseed), conjugated linoleic acid (CLA) (2% protected CLA), and whole linseed+CLA (10% linseed and 2% protected CLA). Animals were slaughtered at 458±16.6 kg live weight and 11 months of age. Ageing was more significant than diet on most instrumental parameters. Meat from linseed enriched diets had greater drip loss (P⩽0.001) and intramuscular fat (P⩽0.01) than meat from animals fed CLA. Beef aged for 7 and 21 days had lower cooking losses (P⩽0.01) and shear force (P⩽0.001) than beef aged for 1 day. Lightness was affected only by display time. The addition of CLA in the diet increased hue and yellowness, whereas the inclusion of linseed decreased these values, as well as increased redness. Linseed in the diet decreased fat odour (P⩽0.05), but increased beef (P⩽0.01) and liver (P⩽0.05) flavours. Meat aged for 21 days was significantly more rancid (P⩽0.001), even under vacuum storage. Several organoleptic properties were improved with the inclusion of linseed in the diet, whereas they remained unaffected by the inclusion of CLA.

The important influence that incremental innovation has, both on the organization’s results and on the development of disruptive innovations in a synergistic relationship of positive sum, makes it necessary to deepen its study. In the context of absorptive capacity, this paper aims to contribute to the construction of a specific model of routines for more efficient exploitation. The empirical study was carried out in a sample of Spanish manufacturing companies of the PITEC Panel. The results show the superiority of the market as a source of knowledge compared to other sources with more complex knowledge, but not adjusted to the needs of a minor improvement. In addition, the management of external knowledge is a process whose phases are interrelated, so the routines and resources used must contribute to enriching the external knowledge previously acquired and not be redundant. Therefore, that would mean an inefficient allocation of resources for obtaining and exploiting continuous innovation.

Background. Hepatitis A is the most common type of viral hepatitis in Mexico. The change of hepatitis A epidemiology in Mexico from high to intermediate endemicity leads to increasing susceptible adults for severe illness. Objective. To describe the clinical characteristics and hospital outcome of adult patients with acute hepatitis A infection, and determine risk factor for mortality.Material and methods. This is a retrospective observational, multicentre study in Mexico City and in Guatemala City. All inhospital patients were followed until discharge or death. Risk factors for death/acute liver failure were identified.Results. Forty seven patients were analyzed, sixty percent were male, the prodrome phase was from 3 to 30 days. The three most common symptoms were fever, malaise and jaundice, with 87%, 74% and 62% respectively. The incidence of patients who were treated with antibiotics before hospital admission was up to 34%. Unnecessary imaging studies and out of guidelines drugs were used. Presence of encephalopathy, leukocytes > 19,000/mL, blood urea nitrogen > 36 mg/dL, creatinine > 2 mg/dL, albumin < 2.5 mg/dL andtotal bilirubin > 9.6 mg/dL, are predictors of mortality. Serum creatinine > 2 mg/dL has the best sensibility and specificity for predicting fulminant hepatitis/death.Conclusion. Acute hepatitis A infection in adults is associated some unnecessary diagnostic and therapeutic approach. Could be associated with fulminant hepatitis, and a creatinine value > 2 mg/dL is the best predictor for fulminant hepatitis and death.

In the present report, we have described venous outflow banding as a technique to assist with maturation of a percutaneous arteriovenous fistula (pAVF) without sacrificing potential target veins for future access. A 47-year-old obese man had undergone pAVF creation between the right ulnar vessels with coil embolization of the brachial vein. Follow-up imaging demonstrated the median cubital vein briskly filling the cephalic and basilic veins. The basilic vein was banded with the patient under local anesthesia successfully. Banding of the superficial veins provides an alternative after creation of a pAVF to preserve veins that could be used as conduits for future access.

Summary: Background: Global sustainability is an enmeshed system of complex socioeconomic, climatological, and ecological interactions. The numerous objectives of the UN's Sustainable Development Goals (SDGs) and the Paris Agreement have various levels of interdependence, making it difficult to ascertain the influence of changes to particular indicators across the whole system. In this analysis, we aimed to detect and rank the complex interlinkages between objectives of sustainability agendas. Methods: We developed a method to find interlinkages among the 17 SDGs and climate change, including non-linear and non-monotonic dependences. We used time series of indicators defined by the World Bank, consisting of 400 indicators that measure progress towards the 17 SDGs and an 18th variable (annual average temperatures), representing progress in the response to the climate crisis, from 2000 to 2019. This method detects significant dependencies among the time evolution of the objectives by using partial distance correlations, a non-linear measure of conditional dependence that also discounts spurious correlations originating from lurking variables. We then used a network representation to identify the most important objectives (using network centrality) and to obtain nexuses of objectives (defined as highly interconnected clusters in the network). Findings: Using temporal data from 181 countries spanning 20 years, we analysed dependencies among SDGs and climate for 35 country groupings based on region, development, and income level. The observed significant interlinkages, central objectives, and nexuses identified varied greatly across country groupings; however, SDG 17 (partnerships for the goals) and climate change ranked as highly important across many country groupings. Temperature rise was strongly linked to urbanisation, air pollution, and slum expansion (SDG 11), especially in country groupings likely to be worst affected by climate breakdown, such as Africa. In several country groupings composed of developing nations, we observed a consistent nexus of strongly interconnected objectives formed by SDG 1 (poverty reduction), SDG 4 (education), and SDG 8 (economic growth), sometimes incorporating SDG 5 (gender equality), and SDG 16 (peace and justice). Interpretation: The differences across groupings emphasise the need to define goals in accordance with local circumstances and priorities. Our analysis highlights global partnerships (SDG 17) as a pivot in global sustainability efforts, which have been strongly linked to economic growth (SDG 8). However, if economic growth and trade expansion were repositioned as a means instead of an end goal of development, our analysis showed that education (SDG 4) and poverty reduction (SDG 1) become more central, thus suggesting that these could be prioritised in global partnerships. Urban livelihoods (SDG 11) were also flagged as important to avoid replicating unsustainable patterns of the past. Funding: Engineering and Physical Sciences Research Council, UK Research and Innovation.

Cytochrome P450s (P450s) are heme-containing proteins involved in several cellular functions, including biosynthesis of steroidal hormones, detoxification of xenobiotic compounds, among others. Damage response protein 1 (Dap1) has been described as a positive regulator of P450s through protein-protein interactions in organisms such as Schizosaccharomyces pombe. Three P450s in the carotenogenic yeast Xanthophyllomyces dendrorhous have thus far been characterized: Cyp51 and Cyp61, which are involved in ergosterol biosynthesis, and CrtS (astaxanthin synthase), which is involved in biosynthesis of the carotenoid astaxanthin. In this work, we describe the X. dendrorhous DAP1 gene, deletion of which affected yeast pigmentation by decreasing the astaxanthin fraction and increasing the β-carotene (a substrate of CrtS) fraction, which is consistent with the known role of CrtS. We found that the proportion of ergosterol was also decreased in the Δdap1 mutant. However, even though the fractions of the end products of these two pathways (the synthesis of carotenoids and sterols) were decreased in the Δdap1 mutant, the transcript levels of genes from the P450 systems involved were higher than those in the wild-type strain. We demonstrate that Dap1 coimmunoprecipitates with these three P450s, suggesting that Dap1 interacts with these three proteins. We propose that Dap1 regulates the synthesis of astaxanthin and ergosterol in X. dendrorhous, probably by regulating the P450s involved in both biosynthetic pathways at the protein level. This work suggests a new role for Dap1 in the regulation of carotenoid biosynthesis in X. dendrorhous.

Resumen: Desde la publicación en 2008 de las guías de diagnóstico y tratamiento de la enfermedad diverticular del colon de la Asociación Mexicana de Gastroenterología ha habido avances significativos en el conocimiento de esta enfermedad. Se realizó una revisión sistemática de la literatura en PubMed de enero de 2008 a julio de 2018 con el fin de revisar y actualizar las guías 2008 y proporcionar nuevas recomendaciones basadas en la evidencia. Se incluyeron todas las publicaciones en español e inglés, de alta calidad. Se redactaron los enunciados, que fueron votados utilizando el método Delphi. Se estableció la calidad de la evidencia y la fuerza de las recomendaciones según el sistema GRADE para cada enunciado. Cuarenta y tres enunciados fueron finalmente votados y calificados. Se informan nuevos datos sobre definición, clasificación, epidemiología, fisiopatología y factores de riesgo. Se revisó con especial énfasis la utilidad de la tomografía computarizada y de la colonoscopia, así como los métodos endoscópicos para el control de la hemorragia. Se discutió sobre el tratamiento ambulatorio de la diverticulitis no complicada, el papel de la rifaximina y la mesalazina, en el manejo de la diverticulitis aguda complicada tanto en sus alternativas mínimamente invasivas hasta las opciones quirúrgicas con énfasis en sus indicaciones, limitaciones y contraindicaciones. Los nuevos enunciados proporcionan directrices basadas en la evidencia actualizada. Se presentan la discusión, el grado y la fuerza de la recomendación de cada uno de ellos. Abstract: Since the publication of the 2008 guidelines on the diagnosis and treatment of diverticular disease of the colon by the Asociación Mexicana de Gastroenterología, significant advances have been made in the knowledge of that disease. A systematic review of articles published in the medical literature from January 2008 to July 2018 was carried out to revise and update the 2008 guidelines and provide new evidence-based recommendations. All high-quality articles in Spanish and English published within that time frame were included. The final versions of the 43 statements accepted in the three rounds of voting, utilizing the Delphi method, were written, and the quality of evidence and strength of the recommendations were established for each statement, utilizing the GRADE system. The present consensus contains new data on the definition, classification, epidemiology, pathophysiology, and risk factors of diverticular disease of the colon. Special emphasis is given to the usefulness of computed tomography and colonoscopy, as well as to the endoscopic methods for controlling bleeding. Outpatient treatment of uncomplicated diverticulitis is discussed, as well as the role of rifaximin and mesalazine in the management of complicated acute diverticulitis. Both its minimally invasive alternatives and surgical options are described, stressing their indications, limitations, and contraindications. The new statements provide guidelines based on updated scientific evidence. Each statement is discussed, and its quality of evidence and the strength of the recommendation are presented. Palabras clave: Divertículos, Diverticulitis, México, Colon, Enfermedad, Consenso, Keywords: Diverticula, Diverticulitis, Mexico, Colon, Disease, Consensus

Since the publication of the 2008 guidelines on the diagnosis and treatment of diverticular disease of the colon by the Asociación Mexicana de Gastroenterología, significant advances have been made in the knowledge of that disease. A systematic review of articles published in the medical literature from January 2008 to July 2018 was carried out to revise and update the 2008 guidelines and provide new evidence-based recommendations. All high-quality articles in Spanish and English published within that time frame were included. The final versions of the 43 statements accepted in the three rounds of voting, utilizing the Delphi method, were written, and the quality of evidence and strength of the recommendations were established for each statement, utilizing the GRADE system. The present consensus contains new data on the definition, classification, epidemiology, pathophysiology, and risk factors of diverticular disease of the colon. Special emphasis is given to the usefulness of computed tomography and colonoscopy, as well as to the endoscopic methods for controlling bleeding. Outpatient treatment of uncomplicated diverticulitis is discussed, as well as the role of rifaximin and mesalazine in the management of complicated acute diverticulitis. Both its minimally invasive alternatives and surgical options are described, stressing their indications, limitations, and contraindications. The new statements provide guidelines based on updated scientific evidence. Each statement is discussed, and its quality of evidence and the strength of the recommendation are presented. Resumen: Desde la publicación en 2008 de las guías de diagnóstico y tratamiento de la enfermedad diverticular del colon de la Asociación Mexicana de Gastroenterología ha habido avances significativos en el conocimiento de esta enfermedad. Se realizó una revisión sistemática de la literatura en PubMed de enero de 2008 a julio de 2018 con el fin de revisar y actualizar las guías 2008 y proporcionar nuevas recomendaciones basadas en la evidencia. Se incluyeron todas las publicaciones en español e inglés, de alta calidad. Se redactaron los enunciados, que fueron votados utilizando el método Delphi. Se estableció la calidad de la evidencia y la fuerza de las recomendaciones según el sistema GRADE para cada enunciado. Cuarenta y tres enunciados fueron finalmente votados y calificados. Se informan nuevos datos sobre definición, clasificación, epidemiología, fisiopatología y factores de riesgo. Se revisó con especial énfasis la utilidad de la tomografía computarizada y de la colonoscopia, así como los métodos endoscópicos para el control de la hemorragia. Se discutió sobre el tratamiento ambulatorio de la diverticulitis no complicada, el papel de la rifaximina y la mesalazina, en el manejo de la diverticulitis aguda complicada tanto en sus alternativas mínimamente invasivas hasta las opciones quirúrgicas con énfasis en sus indicaciones, limitaciones y contraindicaciones. Los nuevos enunciados proporcionan directrices basadas en la evidencia actualizada. Se presentan la discusión, el grado y la fuerza de la recomendación de cada uno de ellos. Keywords: Diverticula, Diverticulitis, Mexico, Colon, Disease, Consensus, Palabras clave: Divertículos, Diverticulitis, México, Colon, Enfermedad, Consenso

Forestry plantations of Pinus radiata, managed through clearcutting method, would offer resistance to the movement of native fauna among remnants of native forest. In this study, we evaluate the possibilities of establishing connectivity corridors for native fauna in a forest landscape dominated by P. radiata, focusing on seven species with some level of specialisation in the use of different land covers and that exhibit different movement strategies. We sampled presences and abundances using several types of sampling to determine the abundance and crossing edge probabilities for the ground-dwelling beetle Ceroglossus chilensis; the mesocarnivores Conepatus chinga, Lycalopex culpaeus and Leopardus guigna; the terrestrial frogs Eupsophus septentrionalis and Pleuroderma thaul, and the understory bird Pteroptochos castaneus. We use species distribution modelling and circuit theory to calculate connectivity for each species. Finally, a spatial priorization approach was applied to obtain two scenarios of least-cost corridors. The results show that species with more specific requirements such as L. guigna, P. castaneus, P. thaul and E. septentrionalis, are unlikely to move through clear cuttings and young plantations, but their movement is possible through adult pine plantations with understory. For species that are habitat generalists such as C. chinga and L. culpaeus plantations were suitable for movement. The management of forest plantations should use multi-taxa assessments in the design of biological corridors that allow the connection of forest fragments.

Background: Microglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but the molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration are unclear. We recently identified microglial contributions to the homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap and stabilize neuronal synapses, but whether PNNs are altered in AD remains controversial. Methods: Extensive histological analysis was performed on male and female 5xFAD mice at 4, 8, 12, and 18 months of age to assess plaque burden, microgliosis, and PNNs. Findings were validated in postmortem AD tissue. The role of neuroinflammation in PNN loss was investigated via LPS treatment, and the ability to prevent or rescue disease-related reductions in PNNs was assessed by treating 5xFAD and 3xTg-AD model mice with colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia. Findings: Utilizing the 5xFAD mouse model and human cortical tissue, we report that PNNs are extensively lost in AD in proportion to plaque burden. Activated microglia closely associate with and engulf damaged nets in the 5xFAD brain, and inclusions of PNN material are evident in mouse and human microglia, while aggrecan, a critical PNN component, deposits within human dense-core plaques. Disease-associated reductions in parvalbumin (PV)+ interneurons, frequently coated by PNNs, are preceded by PNN coverage and integrity impairments, and similar phenotypes are elicited in wild-type mice following microglial activation with LPS. Chronic pharmacological depletion of microglia prevents 5xFAD PNN loss, with similar results observed following depletion in aged 3xTg-AD mice, and this occurs despite plaque persistence. Interpretation: We conclude that phenotypically altered microglia facilitate plaque-dependent PNN loss in the AD brain. Funding: The NIH (NIA, NINDS) and the Alzheimer's Association.

The NADPH oxidase reaction produces protons. In the case of the NADPH oxidase, NOX2, activity depends on secretion of these protons and is inhibited by blockade of the voltage-gated proton channel (Hv1). Duox1 and Duox2 activities similarly produce intracellular protons but synthesize hydrogen peroxide directly instead of superoxide. Hv1 contributes to acid secretion in some epithelia that express Duox. To test the hypothesis that Duox activity is also sensitive to Hv1 channel blockers, Duox was assayed in the presence of either Zn2+ or 5-chloro-2-guanidinobenzimidazole (ClGBI). Both compounds inhibited Duox activity in normal human bronchial epithelial cells but with an IC50 over 10-fold higher than that reported for Hv1 (IC50 Zn2+ = 0.68 mM; IC50 ClGBI = 0.07–0.14 mM). Homogenized HEK293T cells expressing either Duox1 or Duox2 showed similar IC50 values for ClGBI suggesting these compounds inhibit the enzymes through alternate mechanisms independent of Hv1 proton secretion. Inclusion of superoxide dismutase did not restore Duox hydrogen peroxide synthesis. Addition of nigericin to eliminate any possible transmembrane pH gradients in intracellular membrane-localized Duox did not alter activity in HEK293T homogenates. Extracellular Zn2+ blocked intracellular Ca2+ increases needed for Duox activity. Together the data suggest that Duox enzyme activities in epithelia are inhibited by compounds that block Hv1 but inhibition occurs through Hv1-independent mechanisms and support the idea that Hv1 is not required for Duox activity. Keywords: Duox, Hv1, Zinc, Bronchial epithelium

Objectives: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). Methods: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2–7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. Results: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. Conclusions: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD. Keywords: PTP1B, Steatosis, Steatohepatitis, Inflammation, Oval cells

Introduction: Evidence of a concentration of cigarette advertising in predominantly low-income, non-White neighborhoods underscores the need to examine retail marketing and promotions for novel tobacco products like little cigars and cigarillos (LCCs). We sought to investigate neighborhood racial/ethnic disparities in LCC marketing at retail, including availability, advertising, price promotions, and product placement in Los Angeles, California. Methods: Between January 2016 and April 2017, community health workers (n = 19) conducted in-person observational audits from tobacco retail stores (n = 679) located in zip codes with a high percentage of non-Hispanic White (n = 196), Black (n = 194), Hispanic/Latino (n = 189), or Korean American (n = 100) residents. To account for clustering effect of zip codes, multilevel modeling approach for a dichotomized outcome was conducted to evaluate the association between racial/ethnic neighborhood sample and dependent variables. Results: Stores located in zip codes with a high percentage of non-Hispanic Blacks had more than eight times higher odds of selling LCCs (OR = 8.10; 95% CI = 3.10–21.11 vs. non-Hispanic White), more than five times higher odds of selling flavored LCCs (OR = 5.20; 95% CI = 2.33–11.61 vs. non-Hispanic White), and more than six times higher odds of displaying storefront exterior LCC signage (OR = 6.03; 95% CI = 2.93–12.40 vs. non-Hispanic White). Stores in Hispanic/Latino and Korean American communities had about three times higher odds of selling LCCs (OR = 3.02; 95% CI = 1.15–7.93 vs. non-Hispanic White; OR = 2.99; 95% CI = 1.33–6.71 vs. non-Hispanic White). Conclusions: LCCs are heavily marketed in retail establishments in Los Angeles, with disproportionate targeting of predominantly non-White neighborhoods, especially stores in neighborhoods with a higher proportion of African Americans. Local, state, and federal flavor restrictions, minimum pack size standards, preventive messages, and campaigns could counter the influence of LCC marketing in retail establishments. Keywords: Little cigars/cigarillos, Retail marketing, Racial/ethnic neighborhoods