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We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Motor learning principles guide treatment of childhood apraxia of speech (CAS). Previous studies found children to benefit from higher-intensity conditions; however, they did not control for the total amount of therapy time. The aims of the article are to examine the effects of high versus low treatment frequency in intervention for CAS in German-speaking children. An alternating single-subject design with multiple baselines was applied to compare frequent, short sessions with fewer, longer sessions in terms of speech production accuracy in four children with CAS while keeping the total therapy time constant. We administered a version of integral stimulation treatment. Despite inter-individual differences, changes under both treatment conditions showed similar positive trajectories for all four children. Untreated control targets also improved across participants and conditions. Maintenance and generalization to untreated targets were observed two weeks and three months post treatment, independent of treatment intensity. Our results show no significant advantage of more intensive treatment when the total therapy time is held constant. This study contributes to the evidence base for the use of integral stimulation in treating children with CAS, and in particular those who speak languages other than English.

We evaluated how the gender composition of top-cited authors within different subfields of research has evolved over time. We considered 9,071,122 authors with at least 5 full papers in Scopus as of September 1, 2022. Using a previously validated composite citation indicator, we identified the 2% top-cited authors for each of 174 science subfields (Science-Metrix classification) in 4 separate publication age cohorts (first publication pre-1992, 1992 to 2001, 2002 to 2011, and post-2011). Using NamSor, we assigned 3,784,507 authors as men and 2,011,616 as women (for 36.1% gender assignment uncertain). Men outnumbered women 1.88-fold among all authors, decreasing from 3.93-fold to 1.36-fold over time. Men outnumbered women 3.21-fold among top-cited authors, decreasing from 6.41-fold to 2.28-fold over time. In the youngest (post-2011) cohort, 32/174 (18%) subfields had > = 50% women, 97/174 (56%) subfields had > = 30% women, and 3 subfields had =

Abstract We introduce a novel agent‐based model for simulating interactions between migrating barchan dunes. A new two‐flank representation of barchans allows modeling of bedform asymmetries that are intrinsic to collision dynamics but have not been explored before. Although simple compared with real‐world barchans or those in continuum and cellular automata simulations, all known barchan behaviors emerge from the rules of our model. In particular, the two mechanisms for asymmetry growth in bimodal winds are observed and qualitatively agree with existing theories. We also reproduce the emergence of calving and all types of collisions that have been reported in reductionist models, water‐tank experiments, and field observations. The computational efficiency of the new model, compared with continuum simulations, enables the simulation of large swarms of dunes while maintaining the complex phenomenology of these bedforms, some of which has been lacking in previous agent‐based models.

Introducción: El trasplante renal es el tratamiento de elección de la enfermedad renal en etapa terminal (ERT). Desde marzo de 2020, la actividad de trasplantes en México se ha visto afectada debido a la pandemia de COVID-19. Objetivo: Determinar el impacto en la mortalidad de pacientes en lista de espera (LE) para trasplante renal de donante cadavérico en un hospital de referencia en Yucatán, por suspensión de actividades debido a la pandemia. Material y métodos: Pacientes > 18 años en LE para trasplante renal en este hospital. En caso de muerte de un paciente, se investigó la causa, especialmente si estaba asociada a COVID-19. Un valor de p de dos colas ≤ 0.05 se consideró significativo en todos los análisis. Resultados: La razón de probabilidad de muerte por COVID-19 en un paciente con ERT en la LE en 2020 fue OR = 5.04 (IC 95%: 1.65-7.14, p = 0.023). La razón de probabilidad de morir con ERT en la LE con retraso en las consultas de seguimiento fue de OR = 6.59 (IC 95%: 2.7-16.28, p = 0.008). Conclusión: La probabilidad de muerte de un paciente con ERT en la LE con retraso en las consultas de seguimiento y retención del trasplante es estadísticamente más alta que la probabilidad de muerte por COVID-19.

IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare kidney disease caused by dysregulation of the complement alternative pathway. The complement dysregulation specifically leads to damage to the glomerular endothelium. To further understand aHUS pathophysiology, we validated an ex vivo model for measuring complement deposition on both control and patient human glomerular microvascular endothelial cells (GMVECs).MethodsEndothelial cells were incubated with human test sera and stained with an anti-C5b-9 antibody to visualize and quantify complement depositions on the cells with immunofluorescence microscopy.ResultsFirst, we showed that zymosan-activated sera resulted in increased endothelial C5b-9 depositions compared to normal human serum (NHS). The levels of C5b-9 depositions were similar between conditionally immortalized (ci)GMVECs and primary control GMVECs. The protocol with ciGMVECs was further validated and we additionally generated ciGMVECs from an aHUS patient. The increased C5b-9 deposition on control ciGMVECs by zymosan-activated serum could be dose-dependently inhibited by adding the C5 inhibitor eculizumab. Next, sera from five aHUS patients were tested on control ciGMVECs. Sera from acute disease phases of all patients showed increased endothelial C5b-9 deposition levels compared to NHS. The remission samples showed normalized C5b-9 depositions, whether remission was reached with or without complement blockage by eculizumab. We also monitored the glomerular endothelial complement deposition of an aHUS patient with a hybrid complement factor H (CFH)/CFH-related 1 gene during follow-up. This patient had already chronic kidney failure and an ongoing deterioration of kidney function despite absence of markers indicating an aHUS flare. Increased C5b-9 depositions on ciGMVECs were observed in all samples obtained throughout different diseases phases, except for the samples with eculizumab levels above target. We then tested the samples on the patient’s own ciGMVECs. The C5b-9 deposition pattern was comparable and these aHUS patient ciGMVECs also responded similar to NHS as control ciGMVECs.DiscussionIn conclusion, we demonstrate a robust and reliable model to adequately measure C5b-9-based complement deposition on human control and patient ciGMVECs. This model can be used to study the pathophysiological mechanisms of aHUS or other diseases associated with endothelial complement activation ex vivo.

Factor I (FI) is an essential regulator of the complement system. Together with co-factors, FI degrades C3b, which inhibits further complement activation. Genetic mutations in FI are associated with pathological conditions like age-related macular degeneration and atypical hemolytic uremic syndome. Here, we evaluated eight recombinant FI genetic variants found in patients. We assessed FI’s co-factor activity in the presence of two co-factors; Factor H and soluble CR1. Different analytical assays were employed; SDS-PAGE to evaluate the degradation of C3b, ELISA to measure the generation of fluid phase iC3b and the degradation of surface-bound C3b using a novel Luminex bead-based assay. We demonstrate that mutations in the FIMAC and SP domains of FI led to significantly reduced protease activity, whereas the two analyzed mutations in the LDLRA2 domain did not result in any profound changes in FI’s function. The different assays employed displayed a strong positive correlation, but differences in the activity of the genetic variants Ile55Phe and Gly261Asp could only be observed by combining different methods and co-factors for evaluating FI activity. In conclusion, our results provide a new perspective regarding available diagnostic tools for assessing the impact of mutations in FI.

Summary: Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016–2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92–5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07–7.59), Group A streptococcus (OR 2.73, 95% CI 1.13–6.09) and E. coli (OR 2.7, 95% CI 1.02–6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11–0.46), influenza B (OR 0.12, 95% CI 0.02–0.37) and RSV (OR 0.16, 95% CI: 0.06–0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23–0.72) and EBV (OR 0.71, 95% CI 0.56–0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics. Funding: EU Horizon 2020 grant 668303.

We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non-HLA antibodies (>1.5 fold, P 1R) with an area under the curve of 0.87 (P

The infectious disease coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization in March 2020. The impact of COVID-19 on solid organ transplantations, including heart transplantation, is currently unclear. Many transplant programs have been forced to swiftly re-evaluate and adapt their practices, leading to a marked decrease in transplants performed. This trend has been due to various factors, including increased donor COVID-19 screening scrutiny and recipient waiting list management in anticipation of COVID-19 critical care surge capacity planning. In the face of these unknown variables, determining when and how to proceed with transplantation in our population of patients with end-stage cardiomyopathies is challenging. Here, we describe our center's experience with orthotopic heart transplantation (OHT) in one of the country's pandemic epicenters, where we performed eight OHTs in the first 2 months after community spread began in late February 2020.

Abstract Background Little is known about the association between juvenile idiopathic arthritis (JIA) and autoimmune thyroid disease (AITD) and therefore there are no indications for AITD screening in this population, which is possible using standard blood tests. The objective of this study is to determine the prevalence and predictors of symptomatic AITD in JIA patients from the international Pharmachild registry. Methods Occurrence of AITD was determined from adverse event forms and comorbidity reports. Associated factors and independent predictors for AITD were determined using univariable and multivariable logistic regression analyses. Results The prevalence of AITD after a median observation period of 5.5 years was 1.1% (96/8965 patients). Patients who developed AITD were more often female (83.3% vs. 68.0%), RF positive (10.0% vs. 4.3%) and ANA positive (55.7% vs. 41.5%) than patients who did not. AITD patients were furthermore older at JIA onset (median 7.8 years vs. 5.3 years) and had more often polyarthritis (40.6% vs. 30.4%) and a family history of AITD (27.5% vs. 4.8%) compared to non-AITD patients. A family history of AITD (OR = 6.8, 95% CI: 4.1 – 11.1), female sex (OR = 2.2, 95% CI: 1.3 – 4.3), ANA positivity (OR = 2.0, 95% CI: 1.3 – 3.2) and older age at JIA onset (OR = 1.1, 95% CI: 1.1 – 1.2) were independent predictors of AITD on multivariable analysis. Based on our data, 16 female ANA positive JIA patients with a family history of AITD would have to be screened during ±5.5 years using standard blood tests to detect one case of AITD. Conclusions This is the first study to report independent predictor variables for symptomatic AITD in JIA. Female ANA positive JIA patients with positive family history are at increased risk of developing AITD and thus might benefit from yearly serological screening.

The growing complexity and interdisciplinary nature of Materials Science research demand efficient data management and exchange through structured knowledge representation. Domain-Level Ontologies (DLOs) for Materials Science have emerged as a valuable tool for describing materials properties, processes, and structures, enabling effective data integration, interoperability, and knowledge discovery. However, the harmonization of DLOs, and, more generally, the establishment of fully interoperable multi-level ecosystems, remains a challenge due to various factors, including the diverse landscape of existing ontologies. This work provides, for the first time in literature, a comprehensive overview of the state-of-the-art of DLOs for Materials Science, reviewing more than 40 DLOs and highlighting their main features and purposes. Furthermore, an alignment methodology including both manual and automated steps, making use of Top-Level Ontologies’ (TLO) capability of promoting interoperability, and revolving around the engineering of FAIR standalone entities acting as minimal data pipelines (“bridge concepts”), is presented. A proof of concept is also provided. The primary aspiration of this undertaking is to make a meaningful contribution towards the establishment of a unified ontology framework for Materials Science, facilitating more effective data integration and fostering interoperability across Materials Science subdomains.

Individuals with an upper motor neuron syndrome, e.g., stroke survivors, may have a pathological increase of passive ankle stiffness due to spasticity, that impairs ankle function and activities such as walking. To improve mobility, walking aids such as ankle-foot orthoses and orthopaedic shoes are prescribed. However, these walking aids generally limit the range of motion (ROM) of the foot and may therewith negatively influence activities that require a larger ROM. Here we present a new ankle-foot orthosis “Hermes”, and its first experimental results from four hemiparetic chronic stroke patients. Hermes was designed to facilitate active ankle dorsiflexion by mechanically compensating the passive ankle stiffness using a negative-stiffness mechanism. Four levels of the Hermes’ stiffness compensation (0%, 35%, 70% and 100%) were applied to evaluate active ROM in a robotic ankle manipulator and to test walking feasibility on an instrumented treadmill, in a single session. The robotic tests showed that Hermes successfully compensated the ankle joint stiffness in all four patients and improved the active dorsiflexion ROM in three patients. Three patients were able to walk with Hermes at one or more Hermes’ stiffness compensation levels and without reducing their preferred walking speeds compared to those with their own walking aids. Despite a small sample size, the results show that Hermes holds great promise to support voluntary ankle function and to benefit walking and daily activities.

Abstract Background Health inequities lead to low rates of cancer screening in certain populations, such as low-income and ethnic minority groups. Different interventions to address this have been developed with mixed results. However, interventions are not always developed in collaboration with the people they target. The aim of our article is to present the viewpoint of patients, survivors, advocates, and lay persons on interventions to increase cancer screening from a health inequity perspective. Methods We prepared talking points to guide discussions between coauthors, who included representatives from nine patient and survivor advocacy groups, organizations working for citizen/patient empowerment, and health equity experts. Perspectives and opinions were first collected through video conferencing meetings and a first draft of the paper was prepared. All authors, read through, revised, and discussed the contents to reach an agreement on the final perspectives to be presented. Results Several themes were identified: it is important to not view screening as a discrete event; barriers underlying an individual’s access and willingness to undergo screening span across a continuum; individually tailored interventions are likely to be more effective than a one-size fits-all approach because they may better accommodate the person’s personal beliefs, knowledge, behaviors, and preferences; targeting people who are unknown to medical services and largely unreachable is a major challenge; including professional patient advocacy groups and relevant lay persons in the cocreation of interventions at all stages of design, implementation, and evaluation is essential along with relevant stakeholders (healthcare professionals, researchers, local government and community organizations etc). Conclusions Interventions to address cancer screening inequity currently do not adequately solve the issue, especially from the viewpoint of patients, survivors, and lay persons. Several core pathways should be focused on when designing and implementing interventions: advancing individually tailored interventions; digital tools and social media; peer-based approaches; empowerment; addressing policy and system barriers; better design of interventions; and collaboration, including the involvement of patients and patient advocacy organizations.

Introduction: Burnout syndrome is defined as that condition characterized by emotional exhaustion, depersonalization and low personal fulfillment at work. Objective: To identify if the mean scores of emotional fatigue, depersonalization and self-realization were different based on the sociodemographic variables of the nursing staff of the Elvia Carrillo Puerto Regional Hospital during the COVID-19 pandemic in 2020. Methodology: Observational and cross-sectional study. The Maslach Burnout In-ventory questionnaire was applied to 229 nurses from Mérida, Yucatán, México selected by quotas. Results: The means of emotional fatigue, depersonalization and self-realization were 15.27 (SD: 11.4), 4.85 (SD: 4.8) and 37.4 (SD: 7.7); depersonalization showed significant differences by level of education and type of contract; self-realization and emotional fatigue showed significant differences due to the number of jobs; fatigue, depersonalization and self-realization had differences when grouped based on marital status. Conclusion: Separated people, with three or more jobs, temporary contract and with a high level of educational training showed higher scores in the burnout syndrome indicators

Abstract Background Regardless of injury prevention and outreach efforts, there continue to be low rates of adherence with the American Academy of Pediatrics (AAP) safe sleep recommendations. Media is an important tool for parental education and may influence risk perception and caregiver choices. Due to media reports potentially serving as an opportunity for shaping social norms, caregiver education and injury prevention, an evaluation was undertaken to evaluate Georgia local news reporting of sudden unexpected infant death (SUID) as compared to drownings, homicides, and firearm injuries. Our objective was to evaluate incident and racial discrepancies in Georgia news media reporting of SUID as compared to other pediatric injury deaths. Results Despite its high incidence, SUID was far less commonly mentioned in the news media, with only 1.9% (10/525) mentioned as compared to 8.1% of drownings (17/211), 11.4% (74/649) of MVC’s, 14.7% (59/402) of homicides between ages 1–18, 20% (11/55) of fire-related deaths and 25% (15/59) of homicides under age one (infant homicides). Across SUID and homicide, deaths of White infants were reported in the news media at 2.5 times the rate of Black infants. Conclusion Despite SUID being a leading cause of infant death, it is infrequently mentioned in the news media. When mentioned, the news media are more likely to highlight the deaths of White infants as compared to Black infants, though the incidence rate of SUID is higher in Black infants as compared to White.

Societal Impact Statement Combining natural and social science approaches to conduct archeological research on wooden cultural relics is important for exploring major aspects of ancient civilizations. The Forbidden City in Beijing, China, is the largest existing wooden palace complex in the world. We examined ancient DNA of imperial wood “Nanmu” specimens taken from representative structural components of the Forbidden City, in order to provide a new perspective on the long‐standing dispute about its species. This allowed us to accurately identify and properly restore these wooden artifacts and improved our understanding of the past interactions between plant distribution, forest resources, and human activities. Summary Exploring the life styles and production methods of past generations using plant resources can help us to improve our understanding of human civilization. Nanmu, known for its high wood quality, was exclusively used for imperial palace construction in the 15th–19th centuries in China, yet its species has been a subject of long‐standing debate. Here, we revisit this unresolved problem, using morphology and ancient DNA (aDNA) to analyze 21 centuries‐old Nanmu specimens sampled from representative palaces of the Forbidden City. Cytochemical staining demonstrated that endogenous aDNA sporadically occurs in the wood ray parenchyma cells of Nanmu specimens. High‐quality plastid genomes were retrieved from archeological woods for the first time via an aDNA capture method, with 90%–100% coverage (137,663–152,805 bp) and sequence depths of 27.05‐ to 1409.94‐fold. Utilizing these ancient genomes, our results demonstrate that Phoebe zhennan and Phoebe hui are most likely the main species of Nanmu in the Forbidden City. This finding diverges from the prevailing view that Nanmu encompasses woods from the whole genus Phoebe and even its close relative Machilus. It also shows that stringent criteria were used when selecting construction materials for the Forbidden City. By combining morphological traits with aDNA analyses, we provide a new solution for identifying the species of timber used for ancient architecture, and we increase our understanding of the way in which forest resources were recognized and utilized by our ancestors despite the lack of a plant taxonomic framework in ancient times.

Abstract Aims Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease. HCM is an important cause of sudden cardiac death and may also lead to outflow tract obstruction and heart failure. Disease severity is highly variable and risk stratification remains limited. Therefore, we aimed to review current knowledge of prognostic blood‐based biomarkers in HCM. Methods and results A systematic literature search was performed on PubMed, Embase, and the Cochrane library to identify studies assessing plasma or serum biomarkers for outcomes involving malignant ventricular arrhythmia, outflow tract obstruction, and heart failure. Risk of bias was assessed using the QUIPS tool. Meta‐analyses were performed using the random effects method. A total of 26 unique cohort studies assessing 42 biomarkers were identified. Overall risk of bias was moderate. Thirty‐two biomarkers were significantly associated to an HCM outcome in at least one study (nine biomarkers in at least two studies). In pooled analyses, cardiovascular mortality was predicted by N‐terminal prohormone of brain natriuretic peptide (hazard ratio [HR] 5.38 per log[pg/mL], 95% confidence interval [CI] 2.07–14.03, P

Parkinson’s disease (PD) is one of the most frequent neurological diseases affecting millions of people worldwide. While the majority of PD cases are of unknown origin (idiopathic), about 5%–10% are familial and linked to mutations in different known genes. However, there are also people with a genetic predisposition to PD who do not develop the disease. To elucidate factors leading to the manifestation of PD we compared the occurrence of single nucleotide polymorphisms (SNPs) in various cytochrome P450 (P450) genes in people with a genetic predisposition and suffering from PD (GPD) to that of people, who are genetically predisposed, but show no symptoms of the disease (GUN). We used the PPMI (Parkinson’s Progression Markers Initiative) database and the gene sequences of all 57 P450s as well as their three redox partners. Corresponding odds ratios (OR) and confidence intervals (CI) were calculated to assess the incidence of the various SNPs in the two groups of individuals and consequently their relation to PD. We identified for the first time SNPs that are significantly (up to 10fold!) over- or under-represented in GPD patients compared to GUN. SNPs with OR > 5 were found in 10 P450s being involved in eicosanoid, vitamin A and D metabolism as well as cholesterol degradation pointing to an important role of endogenous factors for the manifestation of PD clinical symptoms. Moreover, 12 P450s belonging to all P450 substrate classes as well as POR have SNPs that are significantly under-represented (OR < 0.2) in GPD compared to GUN, indicating a protective role of those SNPs and the corresponding P450s regarding disease advancement. To the best of our knowledge our data for the first time demonstrate an association between known PD predisposition genes and SNPs in other genes, shown here for different P450 genes and for their redox partner POR, which promote the manifestation of the disease in familial PD. Our results thus shed light onto the pathogenesis of PD, especially the switch from GUN to GPD and might further help to advance novel strategies for preventing the development or progression of the disease.

Summary: Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection.

Introducción: La neoplasia vulvar intraepitelial es poco frecuente; sin embargo, es necesario destacar que en los últimos años su incidencia ha aumentado de manera significativa en las pacientes más jóvenes, debido al aumento de la infección genital por el virus de papiloma humano. Objetivo: Describir la intervención quirúrgica de vulvectomía parcial en una paciente con cáncer de vulva, haciendo una valoración fundamentada en la teoría de Déficit de Autocuidado de Dorothea Orem, con un enfoque en el Proceso de Atención de Enfermería, durante el perioperatorio. Material y métodos: Estudio de caso observacional, transversal y descriptivo, enfocado en una paciente que se seleccionó en una institución de salud pública de segundo nivel de atención de la ciudad de Mérida, Yucatán, México. Resultados: Las intervenciones de enfermería fueron realizadas satisfactoriamente, por lo cual, la paciente tuvo un perioperatorio y una estadía hospitalaria sin complicaciones. Discusión: La modificación en el estilo de vida tras el diagnóstico de la patología vulvar en la paciente de estudio, nos demuestra que puede ser prevenida aplicando los métodos de autocuidado descritos por Dorothea Orem. Conclusión: La enfermera quirúrgica tiene un rol importante; en el preoperatorio, ayudando a la paciente a manejar sus sentimientos y brindándole información de su padecimiento y futura cirugía, en el transoperatorio evitando daños y vigilando que se realice una cirugía segura, en el posoperatorio, realizando una valoración para evitar riesgos que puedan prolongar su estadía hospitalaria.

IntroductionObesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking.MethodsIn this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. First, HFD-fed 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology.ResultsWe show that chow-fed Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with C57BL/6J controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis in Ldlr-/-.Leiden mice. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed Ldlr-/-.Leiden mice, indicating alteration of microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In addition, NGS data of hippocampi from Ldlr-/-.Leiden mice showed that HFD feeding affected multiple molecular pathways relative to chow-fed controls: HFD notably inactivated synaptogenesis and activated neuroinflammation pathways. The anti-C5 treatment restored the HFD-induced effect on molecular pathways to a large extent.ConclusionThis study shows that the Ldlr-/-.Leiden mouse model is suitable to study brain histopathology and associated biological processes in a context of obesity and provides evidence of the potential therapeutic value of anti-complement therapy against obesity-induced neuroinflammation.

Background Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI.Methods We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508) or nivolumab and ipilimumab (INITIATE, NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis.Results We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.

The oncoprotein c-Myc is often overexpressed in triple negative breast cancer and has a role in tumor progression and resistance to therapy. Here the authors show that elevated MYC expression is correlated with low immune infiltration, diminished MHC-I pathway expression and that CpG/aOX40 treatment could overcome resistance to PD-L1 blockade in MYC-high breast tumors.

Abstract A revision of the popular equation of Richardson and Zaki (1954a, Transactions of the Institute of Chemical Engineering, 32, 35–53) for the hindered settling of suspensions of non‐cohesive particles in fluids is proposed, based on 548 data sets from a broad range of scientific disciplines. The new hindered settling equation enables predictions of settling velocity for a wide range of particle sizes and densities, and liquid densities and viscosities, but with a focus on sediment particles in water. The analysis of the relationship between hindered settling velocity and particle size presented here shows that the hindered settling effect increases as the particle size decreases, for example, a 50% reduction in settling velocity is reached for 0.025 mm silt and 4 mm pebbles at particle concentrations of 13% and 25% respectively. Moreover, hindered settling starts to influence the settling behaviour of sediment particles at volumetric concentrations of merely a few per cent. For example, the particle settling velocity in flows that carry 5% silt is reduced by at least 22%. These observations suggest that hindered settling greatly increases the efficiency of natural flows to transport sediment particles, but also particulate carbon and pollutants, such as plastics, over large distances.

Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule-associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.