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Abstract Bladder cancer (BCa) poses a significant health challenge, particularly affecting men with higher incidence and mortality rates. Addressing the need for improved predictive models in BCa treatment, this study introduces an innovative 3D in vitro patient-derived bladder cancer tumor model, utilizing decellularized pig bladders as scaffolds. Traditional 2D cell cultures, insufficient in replicating tumor microenvironments, have driven the development of sophisticated 3D models. The study successfully achieved pig bladder decellularization through multiple cycles of immersion in salt solutions, resulting in notable macroscopic and histological changes. This process confirmed the removal of cellular components while preserving the native extracellular matrix (ECM). Quantitative analysis demonstrated the efficacy of decellularization, with a remarkable reduction in DNA concentration, signifying the removal of over 95% of cellular material. In the development of the in vitro bladder cancer model, muscle invasive bladder cancer patients’ cells were cultured within decellularized pig bladders, yielding a three-dimensional cancer model. Optimal results were attained using an air–liquid interface technique, with cells injected directly into the scaffold at three distinct time points. Histological evaluations showcased characteristics resembling in vivo tumors derived from bladder cancer patients’ cells. To demonstrate the 3D cancer model’s effectiveness as a drug screening platform, the study treated it with Cisplatin (Cis), Gemcitabine (Gem), and a combination of both drugs. Comprehensive cell viability assays and histological analyses illustrated changes in cell survival and proliferation. The model exhibited promising correlations with clinical outcomes, boasting an 83.3% reliability rate in predicting treatment responses. Comparison with traditional 2D cultures and spheroids underscored the 3D model’s superiority in reliability, with an 83.3% predictive capacity compared to 50% for spheroids and 33.3% for 2D culture. Acknowledging limitations, such as the absence of immune and stromal components, the study suggests avenues for future improvements. In conclusion, this innovative 3D bladder cancer model, combining decellularization and patient-derived cells, marks a significant advancement in preclinical drug testing. Its potential for predicting treatment outcomes and capturing patient-specific responses opens new avenues for personalized medicine in bladder cancer therapeutics. Future refinements and validations with larger patient cohorts hold promise for revolutionizing BCa research and treatment strategies.

Abstract We present the discovery and characterization of a new multi-planetary system around the Sun-like star K2-360 (EPIC 201595106). K2-360 was first identified in K2 photometry as the host of an ultra-short-period (USP) planet candidate with a period of 0.88 d. We obtained follow-up transit photometry, confirming the star as the host of the signal. High precision radial velocity measurements from HARPS and HARPS-N confirm the transiting USP planet and reveal the existence of an outer (non-transiting) planet with an orbital period of $$\sim$$ ∼ 10 d. We measure a mass of $$7.67 \pm 0.75$$ 7.67 ± 0.75 $$M_{\oplus }$$ M ⊕ and a radius of $$1.57 \pm 0.08$$ 1.57 ± 0.08 $$R_{\oplus }$$ R ⊕ for the transiting planet, yielding a high mean density of $$11 \pm 2$$ 11 ± 2 g $$\hbox {cm}^{-3}$$ cm - 3 , making it the densest well-characterized USP super-Earth discovered to date. We measure a minimum mass of $$15.2 \pm 1.8$$ 15.2 ± 1.8 $$M_{\oplus }$$ M ⊕ for the outer planet, and explore a migration formation pathway via the von Zeipel–Kozai–Lidov (ZKL) mechanism and tidal dissipation.

Abstract This study explores a potential solution to the shortage of kidneys for transplantation in end-stage renal disease (ESRD). Currently, kidney transplantation stands as the optimal option, yet the scarcity of organs persists. Employing tissue engineering, researchers sought to assess the feasibility of generating kidneys for transplantation. Pig kidneys were utilized since they possess higher similarities to human kidneys. Cells were removed via decellularization, which maintains the organ’s microarchitecture. Subsequently, pig kidney cells and human red blood cells were perfused into the vacant kidney structure to reconstitute it. The methodologies employed showed promising results, suggesting a viable approach to increase the recellularization rate in whole pig kidneys. This proof-of-concept establishes a groundwork for potentially extending this technology to human kidneys, tackling the organ shortage, thus positively enhancing outcomes for ESRD patients by increasing the availability of transplantable organs.

El propósito del estudio fue describir las características clínicas, anatomopatológicas, tratamiento y supervivencia de los pacientes con cáncer de tiroides diferenciado. Se realizó un estudio de cohorte retrospectiva con datos de 150 pacientes de un hospital peruano entre los años 2010 al 2020. Se describieron las características y supervivencia (método de Kaplan-Meier). La media de edad fue 48,3 años, 130 (86,7%) fueron mujeres y el tipo histológico más frecuente fue el papilar 94,6%. El 74,2% tenían estadio TNM I, 70,7% tiroidectomía total y 68,7% recibió yodo radiactivo. La supervivencia global a los 5 años fue 89,3%, siendo menor en aquellos con estadio TNM IV y mayor en los que usaron yodo radiactivo. En conclusión, en un hospital de Cusco, el cáncer diferenciado de tiroides fue más frecuente en mujeres y la supervivencia fue menor en comparación con reportes de otros países.

Abstract The extended period of coexistence between Neanderthals and Homo sapiens in Europe coincided with the emergence of regionally distinctive lithic industries, signalling the onset of the Upper Palaeolithic. The Iberian Peninsula was on the periphery of pioneering Upper Palaeolithic developments, with archaeological remains primarily found in northern territories. We report the discovery of an initial Upper Palaeolithic lithic industry at Cueva Millán in the hinterlands of Iberia. This industry, termed here Arlanzian, not only represents the earliest and southernmost evidence of such industries in Iberia but also lacks a direct counterpart. However, it exhibits chronological and technological parallels with the lithic industries associated with the earliest expansion of Homo sapiens throughout Eurasia. We interpret this as potential evidence of its intrusive nature, but not necessarily associated with a migration event, as more complex scenarios derived from inter-population connectivity must be also considered. The biological identity of the Arlanzian makers remains unknown, but they coexisted with declining Neanderthal groups from neighbouring territories.

RESUMEN Objetivo: Valorar si en nuestra población los factores de riesgo cardiovascular (FRCV) se correlacionan con la severidad de la COVID-19 en pacientes hospitalizados. Material y Métodos: Estudio de cohortes retrospectivo de pacientes con COVID-19 ingresados entre los meses de abril y diciembre del 2020 en un centro terciario en el sur de España. Se valoró la asociación entre los FRCV y la severidad del SARS-COV2. Se consideró como COVID severo aquel que ingresó en la Unidad de Cuidados Intensivos (UCI) o que falleció. Resultados: Se analizaron 608 pacientes ingresados con diagnóstico de neumonía por COVID-19, la mediana de edad fue de 73 años (RIC: 64-81) años. Los pacientes fueron predominantemente varones (55,8%). La hipertensión arterial fue el FRCV más común (83,7%), seguido de la dislipemia (50,2%), diabetes (43,1%), obesidad (32,9%) y tabaquismo (15,6%). Durante la estancia un total del 25,8% de los pacientes tuvieron un pronóstico desfavorable: un 7,9% precisó ingreso en UCI y un 22,9% fallecieron. En el análisis multivariante resultaron variables independientes para padecer un COVID severo el género masculino (OR: 1,697; IC 95%: 1,138-2,532), la edad avanzada (OR: 1,697; IC 95%: 1,138-2,532), y la obesidad (OR: 1,634; IC95%: 1,370-1,947). Conclusión. Existe una gran prevalencia de FRCV en los pacientes ingresados por COVID 19 de nuestra población. La obesidad, junto con la edad avanzada y el género masculino se asocian con una mayor gravedad y mortalidad hospitalaria en los pacientes ingresados con SARS-CoV 2. ABSTRACT Objective: To assess whether cardiovascular risk factors (CVRF) are correlated with the severity of COVID-19 in hospitalized patients in our population. Material and Methods: Retrospective cohort study of patients with COVID-19 admitted between the months of April and December 2020 in a tertiary center in southern Spain. The association between CVRF and the severity of SARS-COV2 was assessed. Severe COVID was considered to be one who was admitted to the Intensive Care Unit (ICU) or who died. Results: 608 patients admitted with a diagnosis of COVID-19 pneumonia were analyzed, the median age was 73 years (IQR: 64-81) years. The patients were predominantly male (55.8%). Hypertension was the most common CVRF (83.7%), followed by dyslipidemia (50.2%), diabetes mellitus (43.1%), obesity (32.9%), and smoking (15.6%). During the stay, a total of 25.8% of the patients had an unfavorable prognosis: 22.9% died and 7.9% required admission in the ICU. In the multivariate analysis, significant independent variables were found for suffering from severe COVID: male sex (OR: 1,697; IC 95%: 1,138-2,532), age (OR: 1.697; CI 95%: 1,138-2,532), and obesity (OR: 1,634; 95% CI: 1,370-1,947). Conclusions: There is a high prevalence of CVRF in patients hospitalized for COVID 19 in our population. Obesity, along with older age and male gender, are associated with greater severity and hospital mortality in patients admitted with SARS-CoV-2

Abstract Spectral filters are fundamental building blocks in integrated photonics. Bragg grating filters have been demonstrated in silicon waveguides with a wide range of spectral responses and are suitable for wavelength division multiplexing applications. However, retrieving Bragg grating reflections typically requires external components such as fiber optic circulators. In this work, we develop fully integrated add-drop filters based on cladding-modulated Bragg gratings incorporated in a Mach–Zehnder interferometer configuration. We design complex spectral filtering devices with single and dual-band flat-top responses for the specified bandwidth. Additionally, we propose a novel design methodology which aims to minimize phase errors within the filters. We experimentally demonstrate add-drop filters with single-band and two-band rejection spectra at the datacom O-band, fabricated on a 220-nm thick silicon-on-insulator platform. Our results show an insertion loss below 1 dB and a crosstalk of around −20 dB at the channel center for a 4.5-nm wavelength grid and 3-nm wide channels.

Abstract Tritrichomonas foetus is a flagellated and anaerobic parasite able to infect cattle and felines. Despite its prevalence, there is no effective standardized or legal treatment for T. foetus-infected cattle; the vaccination still has limited success in mitigating infections and reducing abortion risk; and nowadays, the diagnosis of T. foetus presents important limitations in terms of sensitivity and specificity in bovines. Here, we characterize the plasma membrane proteome of T. foetus and identify proteins that are represented in different isolates of this protozoan. Additionally, we performed a bioinformatic analysis that revealed the antigenicity potential of some of those proteins. This analysis is the first study to identify common proteins at the plasma membrane of different T. foetus isolates that could be targets for alternative diagnostic or vaccine techniques in the future.

Mammalian sperm delve into the female reproductive tract to fertilize the female gamete. The available information about how sperm regulate their motility during the final journey to the fertilization site is extremely limited. In this work, we investigated the structural and functional changes in the sperm flagellum after acrosomal exocytosis (AE) and during the interaction with the eggs. The evidence demonstrates that the double helix actin network surrounding the mitochondrial sheath of the midpiece undergoes structural changes prior to the motility cessation. This structural modification is accompanied by a decrease in diameter of the midpiece and is driven by intracellular calcium changes that occur concomitant with a reorganization of the actin helicoidal cortex. Midpiece contraction occurs in a subset of cells that undergo AE, and live-cell imaging during in vitro fertilization showed that the midpiece contraction is required for motility cessation after fusion is initiated. These findings provide the first evidence of the F-actin network’s role in regulating sperm motility, adapting its function to meet specific cellular requirements during fertilization, and highlighting the broader significance of understanding sperm motility.

Summary: Background: Human immune responses to infection and vaccination are heterogenous, driven by multiple factors including genetics, environmental exposures and personal infection histories. For malaria caused by Plasmodium falciparum parasites, host factors that impact on humoral immunity are poorly understood. Methods: We investigated the role of latent cytomegalovirus (CMV) on the host immune response to malaria using samples obtained from individuals in previously conducted Phase 1 trials of blood stage P. falciparum Controlled Human Malaria Infection (CHMI) and in a MSP1 vaccine clinical trial. Induced antibody and functions of antibodies, as well as CD4 T cell responses were quantified. Findings: CMV seropositivity was associated with reduced induction of parasite specific antibodies following malaria infection and vaccination. During infection, reduced antibody induction was associated with modifications to the T -follicular helper (Tfh) cell compartment. CMV seropositivity was associated with a skew towards Tfh1 cell subsets before and after malaria infection, and reduced activation of Tfh2 cells. Protective Tfh2 cell activation was only associated with antibody development in individuals who were CMV seronegative, and a higher proportion of Tfh1 cells was associated with lower antibody development in individuals who were CMV seropositive. During MSP1 vaccination, reduced antibody induction in individuals who were CMV seropositive was associated with CD4 T cell expression of terminal differentiation marker CD57. Interpretation: These findings suggest that CMV seropositivity may be negatively associated with malaria antibody development. Further studies in larger cohorts, particularly in malaria endemic regions are required to investigate whether CMV infection may modify immunity to malaria gained during infection or vaccination in children. Funding: Work was funded by National Health and Medical Research Council of Australia, CSL Australia and Snow Medical Foundation. Funders had no role in data generation, writing of manuscript of decision to submit for publication.

Objetive. To identify the presence of the SARS-CoV-2 virus in wastewater from hospitals in Peru. Materials and methods. Water samples were collected from the effluents of nine hospitals in Peru during March and September 2022. SARS-CoV-2 was identified by using Illumina sequencing. Variant, lineage and clade assignments were carried out using the Illumina and Nextclado tools. We verified whether the SARS-CoV-2 variants obtained from wastewater were similar to those reported by the National Institute of Health of Peru from patients during the same period and region. Results. Eighteen of the 20 hospital wastewater samples (90%) provided sequences of sufficient quality to be classified as the Omicron variant according to the WHO classification. Among them, six (30%) were assigned by Nextclade to clades 21K lineage BA.1.1 (n=1), 21L lineage BA.2 (n=2), and 22B lineages BA.5.1 (n=2) and BA .5.5 (n=1). Conclusions. SARS-CoV-2 variants were found in hospital wastewater samples and were similar to those reported by the surveillance system in patients during the same weeks and geographic areas. Wastewater monitoring could provide information on the environmental and temporal variation of viruses such as SARS-CoV-2.

Abstract Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for treating cancers. This method consists in modifying the patients’ T-cells to directly target antigen-presenting cancer cells. One of the barriers to the development of this type of therapies, is target antigen heterogeneity. It is thought that intratumour heterogeneity is one of the leading determinants of therapeutic resistance and treatment failure. While understanding antigen heterogeneity is important for effective therapeutics, a good therapy strategy could enhance the therapy efficiency. In this work we introduce an agent-based model (ABM), built upon a previous ABM, to rationalise the outcomes of different CAR T-cells therapies strategies over heterogeneous tumour-derived organoids. We found that one dose of CAR T-cell therapy should be expected to reduce the tumour size as well as its growth rate, however it may not be enough to completely eliminate it. Moreover, the amount of free CAR T-cells (i.e. CAR T-cells that did not kill any cancer cell) increases as we increase the dosage, and so does the risk of side effects. We tested different strategies to enhance smaller dosages, such as enhancing the CAR T-cells long-term persistence and multiple dosing. For both approaches an appropriate dosimetry strategy is necessary to produce “effective yet safe” therapeutic results. Moreover, an interesting emergent phenomenon results from the simulations, namely the formation of a shield-like structure of cells with low antigen expression. This shield turns out to protect cells with high antigen expression. Finally we tested a multi-antigen recognition therapy to overcome antigen escape and heterogeneity. Our studies suggest that larger dosages can completely eliminate the organoid, however the multi-antigen recognition increases the risk of side effects. Therefore, an appropriate small dosages dosimetry strategy is necessary to improve the outcomes. Based on our results, it is clear that a proper therapeutic strategy could enhance the therapies outcomes. In that direction, our computational approach provides a framework to model treatment combinations in different scenarios and to explore the characteristics of successful and unsuccessful treatments.

Abstract* Background Digital addictions are a major problem worldwide, which has increased considerably during the COVID-19 pandemic. In this scenario, two important impact factors to explain this problem are stress and anxiety because of COVID-19. The objective of this research was to determine the impact of distress and anxiety due to COVID-19 on digital addictions. Methods cross-sectional, explanatory study. A total of 802 students from public and private universities residing in the city of Lima and Callao (Peru), with a mean age of 21.68 (SD = 3.11), selected by convenience sampling, participated in the study. The MULTICAGE CAD-4 questionnaire, the distress scale, and the COVID-19 worry scale were applied. Results two models examined with structural equation modeling showed good fit indices (CFI and TLI > .95, RMSEA and SRMR < .06). The first model shows that the latent variables distress and anxiety due to COVID-19 have direct effects on digital addictions as a general construct (R2 = 22%). The second model shows that the exogenous latent variables (stress and anxiety) have direct effects of different magnitudes on each digital technology, so the variance explained on smartphone addiction was higher (R2 = 25%) with respect to internet (R2 = 19%) and video game addiction (R2 = 6%). It was also found that for every male, there are two females with high levels of distress and anxiety. Regarding the problematic use of smartphones and internet, there is a prevalence of 40% regardless of sex; but as for the problematic use of video games, there is a marked difference between males (18.8%) and females (2.7%). Conclusion the distress and anxiety caused by COVID-19 have a direct impact in aggravating digital addictions.

El 9 de febrero de 2024 se cumplieron tres años desde que la vacuna de la empresa Sinopharm fue aplicada por primera vez en el Perú; los profesionales de la salud fueron el primer grupo poblacional en recibirla (1). Este hito ocurrió mientras los peruanos vivían en un contexto de imparable confusión y creciente temor ante el virus SARS-CoV-2, pero con la esperanza de que la ciencia, haciendo gala de sus herramientas, pudiera mostrar a la población la tan ansiada luz al final del túnel pandémico. En el Centro de Investigación de Virología de la Universidad de San Martín de Porres (CIV-USMP) se ha revisado información relevante, tanto a nivel nacional como internacional, y se ha reflexionado sobre los tres años transcurridos desde aquella primera dosis de la vacuna BBIBP-CorV de Sinopharm en nuestro país.

La viruela del simio es una enfermedad poco frecuente causada por el virus de la viruela del simio (MPXV). Este es un virus que puede ingresar al huésped a través de diferentes vías, como la orofaringe, la nasofaringe, rutas intradérmicas, entre otras. En el año 2022 se supo de un brote en el que el virus parecía tener mutaciones que le harían propagarse de manera más eficiente. Presentamos tres casos de viruela del simio en el seno de una familia de ocho miembros. El paciente 1, un hombre de 32 años, presentó una pápula debajo del ojo izquierdo, la cual fue eclosionada manualmente por su esposa; luego presentó endoftalmitis asociada a fiebre y cefalea, añadiéndose lesiones pruriginosas tipo vesiculares no dolorosas en extremidades y genitales. Finalmente, se le diagnosticó, clínicamente, infección por viruela del simio. La paciente 2, una mujer de 27 años (pareja del paciente 1), presentó lesiones vesiculares y pustulares en el tórax, las extremidades y la región anal seis días después de exposición por contacto estrecho con el paciente 1. Luego, se le adicionaron mialgias, fiebre y odinofagia, con resultado positivo a prueba molecular para MPXV. El paciente 3, un niño de ocho años, a los siete días del inicio de síntomas de la madre (paciente 2), presentó odinofagia, tinnitus, fiebre, adenopatía cervical y pápulas umbilicadas en el abdomen, el brazo izquierdo y el glúteo derecho, con resultado positivo a prueba molecular para MPXV. Los otros miembros de la familia no presentaron manifestaciones clínicas a pesar del contacto intrafamiliar prolongado de aproximadamente dos semanas con los pacientes, en el que compartieron áreas comunes y utensilios sin restricciones.

Objective. To obtain a comprehensive overview of organ donation, organ utilization, and discard in the entire donation process in Colombia. Methods. A retrospective study of 1 451 possible donors, distributed in three regions of Colombia, evaluated in 2022. The general characteristics, diagnosis, and causes of contraindication for potential donors were described. Results. Among the 1 451 possible donors, 441 (30.4%) fulfilled brain death criteria, constituting the potential donor pool. Families consented to organ donation in 141 medically suitable cases, while 60 instances utilized legal presumption, leading to 201 eligible donors (13.9%). Of those, 160 (11.0%) were actual donors (in whom operative incision was made with the intent of organ recovery or who had at least one organ recovered). Finally, we identified 147 utilized donors (10.1%) (from whom at least one organ was transplanted). Statistically significant differences were found between age, sex, diagnosis of brain death, and donor critical pathway between regions. A total of 411 organs were transplanted from 147 utilized donors, with kidneys being the most frequently procured and transplanted organs, accounting for 280 (68.1%) of the total. This was followed by 85 livers (20.7%), 31 hearts (7.5%), 14 lungs (3.4%), and 1 pancreas (0.2%). The discard rate of procured deceased donors was 8.1%. Conclusions. About one-tenth of donors are effectively used for transplantation purposes. Our findings highlight areas of success and challenges, providing a basis for future improvements in Colombia.

Abstract In this article, the Islamic gold coins collections of the University of Valencia is studied for the first time for its elemental composition and colorimetric properties. To that end, non-destructive elemental analysis using energy-dispersive X-ray fluorescence is applied to obtain the coins’ elemental profile. Additionally, the colour of the coins is assessed using smartphone-based colorimetry as an innovative non-invasive method. Results indicate that the Islamic coins could be attributed to Almoravids, and the gold origin could be the famous Sudanese gold, an ore which was valued all over the world. Also, the text found in the coins was translated and allowed to objectively identify the mint and year. Based on these results, it can be seen that the earliest coins struck in the Iberian Peninsula are characterised by slightly lower gold concentrations than the ones struck in the northern part of Africa, pointing towards a potential recycling of coins which already circulated in the area. In conclusion, this work provides new analytical insights into a peculiar and unique type of samples, allowing to draw some conclusions in terms of their origins and materials, and for the first time allows to characterise the chromatic coordinates of this type of samples.

Abstract Dopamine (DA) plays a critical role in striatal motor control. The drop in DA level within the dorsal striatum is directly associated with the appearance of motor symptoms in Parkinson’s disease (PD). The progression of the disease and inherent disruption of the DA neurotransmission has been closely related to accumulation of the synaptic protein α-synuclein. However, it is still unclear how α-synuclein affects dopaminergic terminals in different areas of dorsal striatum. Here we demonstrate that the overexpression of human α-synuclein (h-α-syn) interferes with the striatal DA neurotransmission in an age‐dependent manner, preferentially in the dorsolateral striatum (DLS) of PDGF-h-α-syn mice. While 3-month-old mice showed an increase at the onset of h-α-syn accumulation in the DLS, 12-month-old mice revealed a decrease in electrically-evoked DA release. The enhanced DA release in 3-month-old mice coincided with better performance in a behavioural task. Notably, DA amplitude alterations were also accompanied by a delay in the DA clearance independently from the animal age. Structurally, dopamine transporter (DAT) was found to be redistributed in larger DAT-positive clumps only in the DLS of 3- and 12-month-old mice. Together, our data provide new insight into the vulnerability of DLS and suggest DAT-related dysfunctionalities from the very early stages of h-α-syn accumulation.

Abstract Diversity of the naive T cell repertoire is maintained by competition for stimuli provided by self-peptides bound to major histocompatibility complexes (self-pMHCs). We extend an existing bi-variate competition model to a multi-variate model of the dynamics of multiple T cell clonotypes which share stimuli. In order to understand the late-time behaviour of the system, we analyse: (i) the dynamics until the extinction of the first clonotype, (ii) the time to the first extinction event, (iii) the probability of extinction of each clonotype, and (iv) the size of the surviving clonotypes when the first extinction event takes place. We also find the probability distribution of the number of cell divisions per clonotype before its extinction. The mean size of a new clonotype at quasi-steady state is an increasing function of the stimulus available to it, and a decreasing function of the fraction of stimuli it shares with other clonotypes. Thus, the probability of, and time to, extinction of a new clonotype entering the pool of T cell clonotypes is determined by the extent of competition for stimuli it experiences and by its initial number of cells.

Abstract Durum wheat cultivation in Mediterranean regions is threatened by abiotic factors, mainly related to the effects of climate change, and biotic factors such as the leaf rust disease. This situation requires an in-depth knowledge of how predicted elevated temperatures and [CO2] will affect durum wheat-leaf rust interactions. Therefore, we have characterised the response of one susceptible and two resistant durum wheat accessions against leaf rust under different environments in greenhouse assays, simulating the predicted conditions of elevated temperature and [CO2] in the far future period of 2070–2099 for the wheat growing region of Cordoba, Spain. Interestingly, high temperature alone or in combination with high [CO2] did not alter the external appearance of the rust lesions. However, through macro and microscopic evaluation, we found some host physiological and molecular responses to infection that would quantitatively reduce not only pustule formation and subsequent infection cycles of this pathogen, but also the host photosynthetic area under these predicted weather conditions, mainly expressed in the susceptible accession. Moreover, our results suggest that durum wheat responses to infection are mainly driven by temperature, being considered the most hampering abiotic stress. In contrast, leaf rust infection was greatly reduced when these weather conditions were also conducted during the inoculation process, resembling the effects of possible heat waves not only in disease development, but also in fungal germination and penetration success. Considering this lack of knowledge in plant-pathogen interactions combined with abiotic stresses, the present study is, to the best of our knowledge, the first to include the effects of the expected diurnal variation of maximum temperature and continuous elevated [CO2] in the durum wheat-leaf rust pathosystem.

Abstract The lumbopelvic muscle mechanical properties (MMPs) are clinically relevant, but their dependence on sex remains unknown. Therefore, this study aimed to identify if lumbopelvic MMPs depend on the sex in a young adult population. Thirty-five healthy nulliparous women and 35 healthy men were analyzed (age range: 18–50). Lumbopelvic MMPs, that is, tone, stiffness, elasticity, relaxation and creep, assessed with MyotonPRO®, and pelvic floor (PF) health questionnaires were compared between-sexes. Intra-group correlations between sociodemographic and clinical data, and MMPs were also determined. The MMPs of PF were different between healthy non-climacteric adults of both sexes, with women showing higher values of tone and stiffness and lower values of elasticity and viscoelastic properties than men (in all cases, p

Abstract Background Lung neuroendocrine neoplasms (LungNENs) comprise a heterogeneous group of tumors ranging from indolent lesions with good prognosis to highly aggressive cancers. Carcinoids are the rarest LungNENs, display low to intermediate malignancy and may be surgically managed, but show resistance to radiotherapy/chemotherapy in case of metastasis. Molecular profiling is providing new information to understand lung carcinoids, but its clinical value is still limited. Altered alternative splicing is emerging as a novel cancer hallmark unveiling a highly informative layer. Methods We primarily examined the status of the splicing machinery in lung carcinoids, by assessing the expression profile of the core spliceosome components and selected splicing factors in a cohort of 25 carcinoids using a microfluidic array. Results were validated in an external set of 51 samples. Dysregulation of splicing variants was further explored in silico in a separate set of 18 atypical carcinoids. Selected altered factors were tested by immunohistochemistry, their associations with clinical features were assessed and their putative functional roles were evaluated in vitro in two lung carcinoid-derived cell lines. Results The expression profile of the splicing machinery was profoundly dysregulated. Clustering and classification analyses highlighted five splicing factors: NOVA1, SRSF1, SRSF10, SRSF9 and PRPF8. Anatomopathological analysis showed protein differences in the presence of NOVA1, PRPF8 and SRSF10 in tumor versus non-tumor tissue. Expression levels of each of these factors were differentially related to distinct number and profiles of splicing events, and were associated to both common and disparate functional pathways. Accordingly, modulating the expression of NOVA1, PRPF8 and SRSF10 in vitro predictably influenced cell proliferation and colony formation, supporting their functional relevance and potential as actionable targets. Conclusions These results provide primary evidence for dysregulation of the splicing machinery in lung carcinoids and suggest a plausible functional role and therapeutic targetability of NOVA1, PRPF8 and SRSF10.

Introducción. La fibromialgia es una enfermedad crónica caracterizada por dolor musculoesquelético generalizado que puede producir deterioro en la capacidad cardiorrespiratoria; sin embargo, hasta la fecha no está claro cuál es el compromiso cardiorrespiratorio en los pacientes con esta condición. Objetivos. Determinar la capacidad cardiorrespiratoria de los pacientes con fibromialgia y analizar las diferencias con controles sanos. Métodos. Se realizó una búsqueda sistemática en las bases de datos PubMed, Web of Science, ScienceDirect, Redalyc, Scopus, Lilacs y Google Scholar. Se incluyeron estudios observacionales publicados en inglés, español y portugués que evaluaran la capacidad cardiorrespiratoria en pacientes con fibromialgia en comparación con sujetos sanos. La calidad metodológica se evaluó mediante la escala Newcastle-Ottawa. Bajo un modelo de efectos aleatorios, el tamaño del efecto combinado se calculó con la diferencia de medias estandarizadas y su intervalo de confianza del 95%; la heterogeneidad se analizó mediante la prueba I-cuadrado (I2). Se realizó análisis de subgrupos para evaluar la influenciadel tipo de prueba de ejercicio clínica utilizada. Resultados. Se incluyeron 14 estudios, con un total de 1.623 participantes (todos de sexo femenino), que cumplieron los criterios de inclusión. Se encontró una diferencia significativa en la distancia recorrida en la prueba de la caminata de seis minutos en mujeres con fibromialgia en comparación con mujeres sanas. Los estudios con ergoespirometría presentaron resultados no concluyentes. Conclusiones. Los pacientes con fibromialgia presentan una menor capacidad cardiorrespiratoria en la prueba de la caminata de seis minutos en comparación con los controles sanos. En este sentido, se necesitan investigaciones que permitan establecer métodos adecuados de medición de la aptitud cardiorrespiratoria que tengan en cuenta las condiciones particulares de los pacientes con esta enfermedad.

Introducción: se sabe poco de la relación de parámetros fisiológicos del sueño con la personalidad y el rendimiento académico en estudiantes universitarios. Objetivo: Explorar la relación entre sueño, cronotipo, ansiedad, personalidad, calidad de vida y rendimiento académico en adolescentes universitarios. Método: el estudio fue de corte cuantitativo, observacional transversal. Se exploró el rendimiento académico acumulado (RAA), los parámetros fisiológicos del sueño, índice de calidad de sueño, cronotipo, personalidad, ansiedad y calidad de vida en estudiantes universitarios. Se realizó comparación y regresión lineal múltiple. Resultados: en una muestra de 27 estudiantes universitarios, se encontraron: correlaciones significativas positivas entre RAA y sexo y duración del sueño; varianza para edad, del sueño, ansiedad, atención a normas y sensibilidad; efecto significativo en edad y desviación estándar del sueño, sobre la varianza del RAA (p=0,001) con 39,1% a 50,8% de causalidad (R2a=0,39; R2=0,51). Conclusiones: el RAA en jóvenes es moderado por la duración del sueño y de la actividad de sueño es sensible para identificar cambios significativos en el RAA. El índice de calidad de sueño, cronotipo, personalidad, ansiedad y calidad de vida no son susceptibles de identificar efectos significativos en el RAA en estudiantes.

Abstract Background The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the-art proton nuclear magnetic resonance spectrometry (1H-NMRS) metabolomics profiling, that androgen excess in women induces a certain masculinization of postprandial metabolism that is modulated by obesity. Materials and methods Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity. Patients were submitted to isocaloric separate glucose, lipid and protein oral challenges in alternate days and fasting and postprandial serum samples were submitted to 1H-NMRS metabolomics profiling for quantification of 36 low-molecular-weight polar metabolites. Results The largest postprandial changes were observed after glucose and protein intake, with lipid ingestion inducing smaller differences. Changes after glucose intake consisted of a marked increase in carbohydrates and byproducts of glycolysis, and an overall decrease in byproducts of proteolysis, lipolysis and ketogenesis. After the protein load, most amino acids and derivatives increased markedly, in parallel to an increase in pyruvate and a decrease in 3-hydroxybutyric acid and glycerol. Obesity increased β- and d-glucose and pyruvate levels, with this effect being observed mostly after glucose ingestion in women with PCOS. Regardless of the type of macronutrient, men presented increased lysine and decreased 3-hydroxybutyric acid. In addition, non-obese men showed increased postprandial β-glucose and decreased pyroglutamic acid, compared with non-obese control women. We observed a common pattern of postprandial changes in branched-chain and aromatic amino acids, where men showed greater amino acids increases after protein intake than control women and patients with PCOS but only within the non-obese participants. Conversely, this increase was blunted in obese men but not in obese women, who even presented a larger increase in some amino acids compared with their non-obese counterparts. Interestingly, regardless of the type of macronutrient, only obese women with PCOS showed increased leucine, lysine, phenylalanine and tryptophan levels compared with non-obese patients. Conclusions Serum 1H-NMRS metabolomics profiling indicated sexual dimorphism in the responses to oral macronutrient challenges, which were apparently driven by the central role of postprandial insulin effects with obesity, and to a lesser extent PCOS, exerting modifying roles derived from insulin resistance. Hence, obesity impaired metabolic flexibility in young adults, yet sex and sex hormones also influenced the regulation of postprandial metabolism. Graphical abstract

Abstract Shoreline position is a key parameter of a beach state, often used as a descriptor of the response of the system to changes in external forcing, such as sea-level rise. Changes in shoreline position are the result of coupled hydrodynamic and morphodynamic processes happening in the nearshore and acting at different temporal scales. Due to this complexity, methodologies aimed at reproducing shoreline evolution at decadal time scale require many simplifications. Simpler methods usually consider an equilibrium beach profile whose shape depends only on beach morphology, and whose location varies depending on incoming forcing. Here, we derive a general equation for shoreline evolution using equilibrium beach profiles. We particularize it based on several common assumptions, and evaluate changes on shoreline position caused by sea-level rise, combined with simultaneous wave and high-frequency sea-level forcing. We compare our model against other analytical equilibrium beach profile-based models and with a dynamic model explicitly computing sediment transport. Results indicate that: (i) it is necessary to consider the area of the emerged beach subject to marine forcing rather than focusing only on the submerged part, (ii) the rates of shoreline recession may change for narrow beaches, defined as those for which marine forcings act onto all of their aerial surface, and (iii) Bruun’s Rule can describe beach shoreline evolution, but the uncertainty in selecting the landward boundary of the active profile entails a huge uncertainty in the magnitude of shoreline evolution. This problematic uncertainty can be drastically reduced if instantaneous forcing conditions are used instead of the arbitrary emerged/submerged active profile boundaries typically defined by only one statistic parameter of extreme conditions.

Abstract Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units. Therefore, this review provides an introducing view on the structure and energy-related functions of mitochondria as well as their dynamics. In turn, we summarize current knowledge on how these features are deregulated in different neurodegenerative diseases, including frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich ataxia, Alzheimer´s disease, Parkinson´s disease, and Huntington’s disease. Finally, we analyzed current advances in mitochondrial transfer between diverse cell types that actively participate in neurodegenerative processes, and how they might be projected toward developing novel therapeutic strategies.

BackgroundWhile national adoption of universal HIV treatment guidelines has led to improved, timely uptake of antiretroviral therapy (ART), longer-term care outcomes are understudied. There is little data from real-world service delivery settings on patient attrition, viral load (VL) monitoring, and viral suppression (VS) at 24 and 36 months after HIV treatment initiation.Methods and findingsFor this retrospective cohort analysis, we used observational data from 25 countries in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium's Asia-Pacific, Central Africa, East Africa, Central/South America, and North America regions for patients who were ART naïve and aged ≥15 years at care enrollment between 24 months before and 12 months after national adoption of universal treatment guidelines, occurring 2012 to 2018. We estimated crude cumulative incidence of loss-to-clinic (CI-LTC) at 12, 24, and 36 months after enrollment among patients enrolling in care before and after guideline adoption using competing risks regression. Guideline change-associated hazard ratios of LTC at each time point after enrollment were estimated via cause-specific Cox proportional hazards regression models. Modified Poisson regression was used to estimate relative risks of retention, VL monitoring, and VS at 12, 24, and 36 months after ART initiation. There were 66,963 patients enrolling in HIV care at 109 clinics with ≥12 months of follow-up time after enrollment (46,484 [69.4%] enrolling before guideline adoption and 20,479 [30.6%] enrolling afterwards). More than half (54.9%) were females, and median age was 34 years (interquartile range [IQR]: 27 to 43). Mean follow-up time was 51 months (standard deviation: 17 months; range: 12, 110 months). Among patients enrolling before guideline adoption, crude CI-LTC was 23.8% (95% confidence interval [95% CI] 23.4, 24.2) at 12 months, 31.0% (95% CI [30.6, 31.5]) at 24 months, and 37.2% (95% [CI 36.8, 37.7]) at 36 months after enrollment. Adjusting for sex, age group, enrollment CD4, clinic location and type, and country income level, enrolling in care and initiating ART after guideline adoption was associated with increased hazard of LTC at 12 months (adjusted hazard ratio [aHR] 1.25 [95% CI 1.08, 1.44]; p = 0.003); 24 months (aHR 1.38 [95% CI 1.19, 1.59]; p < .001); and 36 months (aHR 1.34 [95% CI 1.18, 1.53], p < .001) compared with enrollment before guideline adoption, with no before-after differences among patients with no record of ART initiation by end of follow-up. Among patients retained after ART initiation, VL monitoring was low, with marginal improvements associated with guideline adoption only at 12 months after ART initiation. Among those with VL monitoring, VS was high at each time point among patients enrolling before guideline adoption (86.0% to 88.8%) and afterwards (86.2% to 90.3%), with no substantive difference associated with guideline adoption. Study limitations include lags in and potential underascertainment of care outcomes in real-world service delivery data and potential lack of generalizability beyond IeDEA sites and regions included in this analysis.ConclusionsIn this study, adoption of universal HIV treatment guidelines was associated with lower retention after ART initiation out to 36 months of follow-up, with little change in VL monitoring or VS among retained patients. Monitoring long-term HIV care outcomes remains critical to identify and address causes of attrition and gaps in HIV care quality.

Scientists and coaches seek effective ergogenic aids for performance improvement. Cyclists commonly use β-Alanine, which may enhance post-exercise recovery and physical performance. High-dose β-Alanine supplementation's impact on World Tour cyclists during a 7-day camp remains unstudied. This study aimed to analyse the effect of a high dose of β-alanine in World Tour cyclist during a 7-day camp. A double-blinded, randomised controlled trial was conducted. 11 cyclists were included in the final analysis: β-alanine supplementation (n = 5; VO2max: 67.6±1.6 ml/kg/min) and a placebo group (n = 6; VO2max: 68.0±2.4 ml/kg/min). The duration of the supplementation protocol was seven days with four daily intakes. The subjects commenced supplementation after the physical tests (immediately following the snack) and consumed the final intake after breakfast on the day of the final test (a total of 7 days and 3 additional doses, 31 servings in total; 5g per dosage; 155g the total cumulative amount). Before and after seven days of supplementation, the cyclists performed an uphill time trial. Blood lactate, heart rate and rating of perceived exertion were measured during test. β-alanine supplementation improved the relative mean power attained during the time-trial compared with the control group (Z = -2.008; p = 0.045; Δ = 0.060), as well as the time needed to complete this trial (Z = -2.373; p = 0.018). As for physiological and metabolic variables, no significant change was found. In conclusion, the present study supports the effectiveness of one-week high dose of β-alanine during a cycling training in World Tour cyclists to improve their uphill time-trial performance. In addition, it is important to highlight the potential role of β-alanine in improving recovery power. This aspect is particularly relevant in the context of a training camp, where fatigue levels can increase alongside training intensity. Trial registration: This study was registered in ClinicalTrials.gov: (identifier: NCT04427319).

El dengue es una infección viral transmitida a través del mosquito Aedes aegypti y presenta cuatro serotipos (DENV-1 a DENV-4). La enfermedad desencadena una variedad de manifestaciones clínicas, desde formas leves sin signos de alarma hasta formas graves, potencialmente mortales. Se presenta el caso de un niño de cinco años, procedente de la provincia del Callao, cuyos síntomas iniciales fueron fiebre, cefalea y malestar general. Al tercer día, el niño manifiestó dolor abdominal leve y vómitos escasos; posteriormente, distensión abdominal, ictericia y coluria. Fue hospitalizado en la unidad de cuidados intensivos pediátricos con deshidratación moderada, ictericia, edemas, abdomen distendido y doloroso, matidez desplazable, hígado a 2 cm debajo del reborde costal derecho y lúcido. Por exámenes complementarios, se evidenció falla hepática, hepatoesplenomegalia y derrame pleural en bases. Se diagnosticó dengue grave a través de una prueba de ELISA Ig M reactivo más sobreinfección por probable peritonitis bacteriana espontánea. Se inició el tratamiento con antibióticos, furosemida, plasma fresco congelado, crioprecipitado y metamizol. Al no observarse mejoría, se optimizó el diurético y se administró albúmina humana. Mostró mejoría con disminución de ascitis, edemas, ictericia y efusión pleural; también mejora del perfil hepático y de la coagulación, además de encontrarse afebril. Presentó inesperadamente dificultad respiratoria por insuficiencia cardiaca congestiva debido a miocardiopatía dilatada según ecocardiografía; se manejó con diuréticos. Fue dado de alta en estado afebril, sin edemas y con resolución de falla hepática y trastorno de coagulación.

Intolerance of Uncertainty (IU) is thought to lead to maladaptive behaviours and dysfunctional decision making, both in the clinical and healthy population. The seminal study reported by Luhmann and collaborators in 2011 showed that IU was negatively associated with choosing a delayed, but more certain and valuable, reward over choosing an immediate, but less certain and valuable, reward. These findings have been widely disseminated across the field of personality and individual differences because of their relevance to understand the role of IU in maladaptive behaviours in anxiety-related disorders. We conducted a study to replicate and extend Luhmann et al.'s results with a sample of 313 participants, which exceeded the size necessary (N = 266) to largely improve the statistical power of the original study by using the small telescopes approach. The results of our well powered study strongly suggest that the relationship between IU and the tendency to prefer an immediate, but less certain and less valuable reward is virtually negligible. Consequently, although this relationship cannot be definitely discarded, we conclude that it cannot be detected with Luhmann et al.'s (2011) decision-making task.

The transformation of the food and industrial agricultural production system into adaptative and sustainable systems capable of being productive within social, environmental, and economic limits is a crucial factor in reducing the risk to food security and to economic growth. However, the analysis structure of the effect of these variables in sustainable environments remains unknown, whereby the technology and processes are considered as variables of the equivalent critical level as those already described. The purpose of this study is to design a model that enables the characterisation of the agri-food sector based on the determination of sustainable variables from a sustainable and integral systemic approach. Tools, such as the viable system model, are employed to analyse the dynamics and generate the balanced scorecard, to which the items of learning and continuous improvement are added. Lastly, the impact of the principles of sustainability versus the variation of sustainability in the agri-food system is revealed, which is useful in determining the appropriate levels to guarantee a balance in the foundations of circularity. From a systemic approach, this model can be adopted by agronomists and scientists to design alternative strategies for the management of food sustainability.

To control the SARS-CoV-2 pandemic, healthcare systems have focused on ramping up their capacity for epidemiological surveillance through viral whole genome sequencing. In this paper, we tested the performance of two protocols of SARS-CoV-2 nucleic acid enrichment, an amplicon enrichment using different versions of the ARTIC primer panel and a hybrid-capture method using KAPA RNA Hypercap. We focused on the challenge of the Omicron variant sequencing, the advantages of automated library preparation and the influence of the bioinformatic analysis in the final consensus sequence. All 94 samples were sequenced using Illumina iSeq 100 and analysed with two bioinformatic pipelines: a custom-made pipeline and an Illumina-owned pipeline. We were unsuccessful in sequencing six samples using the capture enrichment due to low reads. On the other hand, amplicon dropout and mispriming caused the loss of mutation G21987A and the erroneous addition of mutation T15521A respectively using amplicon enrichment. Overall, we found high sequence agreement regardless of method of enrichment, bioinformatic pipeline or the use of automation for library preparation in eight different SARS-CoV-2 variants. Automation and the use of a simple app for bioinformatic analysis can simplify the genotyping process, making it available for more diagnostic facilities and increasing global vigilance.

BackgroundEvidence regarding differences in survival associated with the site of metastasis in triple-negative breast cancer (TNBC) remains limited. Our aim was to analyze the overall survival (OS), distant relapse free survival (DRFS), and survival since the diagnosis of the relapse (MS), according to the side of metastasis.MethodsThis was a retrospective study of TNBC patients with distant metastases at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru) from 2000 to 2014. Prognostic factors were determined by multivariate Cox regression analysis.ResultsIn total, 309 patients were included. Regarding the type of metastasis, visceral metastasis accounted for 41% and the lung was the most frequent first site of metastasis (33.3%). With a median follow-up of 10.2 years, the 5-year DRFS and OS were 10% and 26%, respectively. N staging (N2-N3 vs. N0, HR = 1.49, 95%CI: 1.04-2.14), metastasis in visceral sites (vs. bone; HR = 1.55, 95%CI: 0.94-2.56), the central nervous system (vs. bone; HR = 1.88, 95% CI: 1.10-3.22), and multiple sites (vs. bone; HR = 2.55, 95%CI:1.53-4.25) were prognostic factors of OS whereas multiple metastasis (HR = 2.30, 95% CI: 1.42-3.72) was a predictor of MS. In terms of DRFS, there were no differences according to metastasis type or solid organ.ConclusionTNBC patients with multiple metastasis and CNS metastasis have an increased risk of death compared to those with bone metastasis in terms of OS and MS.

Abstract Sarcomas constitute a heterogeneous group of rare and difficult-to-treat tumors that can affect people of all ages, representing one of the most common forms of cancer in childhood and adolescence. Little is known about the molecular entities involved in sarcomagenesis. Therefore, the identification of processes that lead to the development of the disease may uncover novel therapeutic opportunities. Here, we show that the MEK5/ERK5 signaling pathway plays a critical role in the pathogenesis of sarcomas. By developing a mouse model engineered to express a constitutively active form of MEK5, we demonstrate that the exclusive activation of the MEK5/ERK5 pathway can promote sarcomagenesis. Histopathological analyses identified these tumors as undifferentiated pleomorphic sarcomas. Bioinformatic studies revealed that sarcomas are the tumors in which ERK5 is most frequently amplified and overexpressed. Moreover, analysis of the impact of ERK5 protein expression on overall survival in patients diagnosed with different sarcoma types in our local hospital showed a 5-fold decrease in median survival in patients with elevated ERK5 expression compared with those with low expression. Pharmacological and genetic studies revealed that targeting the MEK5/ERK5 pathway drastically affects the proliferation of human sarcoma cells and tumor growth. Interestingly, sarcoma cells with knockout of ERK5 or MEK5 were unable to form tumors when engrafted into mice. Taken together, our results reveal a role of the MEK5/ERK5 pathway in sarcomagenesis and open a new scenario to be considered in the treatment of patients with sarcoma in which the ERK5 pathway is pathophysiologically involved.

Abstract Background Anti-CGRP monoclonal antibodies have shown notable effectiveness and tolerability in migraine patients; however, data on their use in elderly patients is still lacking, as clinical trials have implicit age restrictions and real-world evidence is scarce. In this study, we aimed to describe the safety and effectiveness of erenumab, galcanezumab and fremanezumab in migraine patients over 65 years old in real-life. Methods In this observational real-life study, a retrospective analysis of prospectively collected data from 18 different headache units in Spain was performed. Migraine patients who started treatment with any anti-CGRP monoclonal antibody after the age of 65 years were included. Primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and medication intake frequencies by months 3 and 6, response rates, changes in patient-reported outcomes and reasons for discontinuation. As a subanalysis, reduction in monthly migraine days and proportion of adverse effects were also compared among the three monoclonal antibodies. Results A total of 162 patients were included, median age 68 years (range 65–87), 74.1% women. 42% had dyslipidaemia, 40.3% hypertension, 8% diabetes, and 6.2% previous cardiovascular ischaemic disease. The reduction in monthly migraine days at month 6 was 10.1 ± 7.3 days. A total of 25.3% of patients presented adverse effects, all of them mild, with only two cases of blood pressure increase. Headache and medication intake frequencies were significantly reduced, and patient-reported outcomes were improved. The proportions of responders were 68%, 57%, 33% and 9% for reductions in monthly migraine days ≥ 30%, ≥ 50%, ≥ 75% and 100%, respectively. A total of 72.8% of patients continued with the treatment after 6 months. The reduction in migraine days was similar for the different anti-CGRP treatments, but fewer adverse effects were detected with fremanezumab (7.7%). Conclusions Anti-CGRP mAbs are safe and effective treatments in migraine patients over 65 years old in real-life clinical practice. Graphical Abstract

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been and remains one of the major challenges modern society has faced thus far. Over the past few months, large amounts of information have been collected that are only now beginning to be assimilated. In the present work, the existence of residual information in the massive numbers of rRT-PCRs that tested positive out of the almost half a million tests that were performed during the pandemic is investigated. This residual information is believed to be highly related to a pattern in the number of cycles that are necessary to detect positive samples as such. Thus, a database of more than 20,000 positive samples was collected, and two supervised classification algorithms (a support vector machine and a neural network) were trained to temporally locate each sample based solely and exclusively on the number of cycles determined in the rRT-PCR of each individual. Overall, this study suggests that there is valuable residual information in the rRT-PCR positive samples that can be used to identify patterns in the development of the SARS-CoV-2 pandemic. The successful application of supervised classification algorithms to detect these patterns demonstrates the potential of machine learning techniques to aid in understanding the spread of the virus and its variants.

Abstract Background The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the art proton nuclear magnetic resonance spectroscopy metabolomics profiling, that androgen excess in women induces also a certain masculinization of intermediate metabolism that is modulated by obesity. Methods Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected in order to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity defined by a body mass index ≥ 30 kg/m2. Subjects maintained the same diet unrestricted in carbohydrates for 3 days before sampling and maintained their lifestyle and exercise patterns prior and during the study. Plasma samples were submitted to proton nuclear magnetic resonance spectroscopy metabolomics profiling. Results Obesity associated a metabolomics profile mainly characterized by increased branched chain and aromatic aminoacids. Regardless of obesity, this unfavorable profile also characterized men as compared with control women, and was shared by women with PCOS. Notably, the negative impact of obesity on metabolomics profile was restricted to women, with obese men showing no further deterioration when compared with their non-obese counterparts. Conclusions Serum metabolomics profiling by proton nuclear magnetic resonance spectroscopy reveals sexual dimorphism, and masculinization of intermediate metabolism in women with PCOS, further suggesting a role for sex and sex hormones in the regulation of intermediate metabolism.

ABSTRACTObjectives: The COVID-19 pandemic and resultant lockdown and containment measures have instigated substantial changes in our daily lives and have affected many people’s mental health. This paper reports two studies exploring gender-based differences with regard to the impact of COVID-related confinement on individuals’ self-efficacy to regulate negative emotions (RESE-NE) and anxiety.Methods: Study 1 (cross-sectional; 269 participants; 52% women) explored the evolution of RESE-NE and anxiety. To this end, participants assessed their status at two time points: a retrospective assessment of the period before confinement in Spain, and a current assessment during confinement. Study 2 (longitudinal; 114 participants; 72.2% women) explored the evolution of the variables by adding a post-confinement time point and analyzed the mediating role of RESE-NE in the positivity–anxiety and resilience–anxiety relationships.Results: The results confirmed that: (a) RESE-NE decreased and anxiety increased more among women than among men during confinement (Study 1); (b) women recovered their pre-pandemic levels of mental health more slowly than did men following confinement; and (c) the mediating role of RESE-NE could be observed in the two relationships under analysis.Conclusion: In practical terms, the research highlights the need to pay special attention to women undergoing mental health interventions related to the COVID-19 pandemic, as well as to the differential burden that the pandemic may entail for men and women and to the contrasting social roles traditionally attributed to them. From the gender differences identified, it is possible to infer how stereotypes and social roles influence the behavior and mental health of men and women, leading them to cope differently with stressful situations such as confinement.

Introduction The expansion of higher education is a worldwide phenomenon. To our knowledge, there are no studies analyzing the trends in demands of enrollment in health-related studies in Spain. Therefore, the objective was to analyze the change in demand (the number of requests for enrollment divided by the number of offered places) for undergraduate health-related studies in Spain during the period 2015–2021 as well as compare the change by region in the pre (2015–2019) and pandemic (2020–2021) period. Methods This is an observational (ecological type) study with temporal series analyses using data from public (non-for-profit) higher education institutions from the Integrated University Information System. For the analysis by region, we calculated the demand of all twelve undergraduate health-related degrees and the percentages of change between both periods using the Wilcoxon test. The Joinpoint Regression program was used to analyze the trends in demand for each degree during the 7-year period. Results Significant (p < 0.001) increases in demand during the pandemic period were observed in all regions. During the pandemic, medicine, biomedicine, nursing, odontology and pharmacy presented a higher demand in comparison with data collected before the pandemic started. In contrast, this pattern was not confirmed in the following cases: physiotherapy, occupational therapy, podiatry, psychology, social work, human nutrition and dietetics. By regions, Navarra, Asturias, and La Rioja presented the most drastic changes. In regions with the biggest number of universities, such as Catalonia, Andalusia and Madrid, the change observed was smaller.

Objective. The aim of this study was to establish normative values for the Voice Symptom Scale (VoiSS) in the Spanish community population (without voice problems), using a sample from a large area of southeastern Spain. Method. The sample consisted of 115 adults from ages 16 to 87, 60 of whom were women and 55 were men. Participants included the family members of patients who attended the Otorhinolaryngology (ENT) and Speech Therapy Clinic at a referral hospital in the region of Murcia, Spain, and some of the clinic’s staff. All the participants reported never having suffered from any voice disorder before. Results. The normative values obtained in this study for the VoiSS were 14.61 (SD=8.18) for the total score, 7.57 (SD = 5.42) for the Impairment subscale, 1.04 (SD = 1.65) for the Emotional subscale, and 5.99 (SD = 3.61) for the Physical subscale. The percentile values were also obtained for the VoiSS scale and for its three subscales. Conclusions. This study presents normative values for the VoiSS scale that have not previously been obtained in Spain. These values can be used as a reference to detect possible voice disorders.

Background: The objective of this study was to estimate the prevalence of adolescent pregnancy among sexually active adolescents, and identify the factors associated with this problem. Methods: A population-based analytical cross-sectional study was conducted using pooled data from the Demographic and Family Health Surveys of Peru, 2015-2019. A total sample of 8850 adolescent girls aged 12 to 19 years who reported a history of sexual intercourse were included. To identify factors related to adolescent pregnancy, the study employed adjusted prevalence ratios (aPR) with 95% confidence intervals (95% CI). The aPR were obtained from a multivariable logistic regression model. Results: The prevalence of adolescent pregnancy among sexually active adolescents in Peru was 30.9% (95%CI: 29.4–32.4%). In the multivariable analysis; being 17-19 years (aPR: 1.48; 95%CI :1.33–1.64), being married or cohabitant (aPR: 4.01; 95%CI: 3.48–4.61) and belonging to the Quechua ethnicity group (aPR: 1.16; 95%CI: 1.07–1.25), were associated with a higher prevalence. Conversely, the following factors were associated with a lower prevalence of pregnancy: being employed (aPR: 0.81; 95%CI: 0.76–0.86), being currently studying (aPR: 0.43; 95%CI: 0.38–0.49), belonging to the second (aPR: 0.91; 95%CI: 0.85–0.97), third (aPR: 0.81; 95%CI: 0.74–0.89), fourth (aPR: 0.79; 95%CI: 0.69–0.91) and fifth (aPR: 0.59; 95%CI: 0.47–0.75) wealth quintile, initiating sexual relations in middle adolescente (aPR: 0.76; 95%CI: 0.69–0.83) or late adolescence (aPR: 0.40; 95%CI: 0.35–0.46), perceiving a future pregnancy as a problem (aPR: 0.77; 95%CI: 0.72–0.83) and having knowledge of the moment in the cycle when pregnancy can occur (aPR: 0.84; 95%CI: 0.77–0.92) Conclusions: Approximately three out of ten adolescents who initiated a sexual life had at least one pregnancy. Age, marital status, employment, education, wealth, ethnicity, age at first intercourse, knowledge of when in the cycle she may become pregnant, and perception of future pregnancy were associated with adolescent pregnancy

Objectives This study evaluated the feasibility of exercising into pain in rotator cuff related shoulder pain (RCRSP), data collection procedures, feedback from physiotherapists and patients, and clinically important changes in patient-reported outcome measures (PROMs).Design Unblinded non-randomised single-group study.Setting Physiotherapy clinic in Belgium.Participants Twelve patients with unilateral RCRSP for minimum 3 months, aged 18–65 years.Interventions Twelve weeks of four individualised exercises, with nine physiotherapist-led sessions with pain ratings 4–7 out of 10 on a verbal Numeric Pain Rating Scale for 9 weeks and then pain ratings 0–2 for 3 weeks. Every physiotherapy session included 15 min of manual therapy. Non-supervised exercises were: 2×/week in weeks with physiotherapy session, 3×/week in weeks without physiotherapy session.Outcome measures Primary: adherence, where patients were considered adherent with 78% (7/9 sessions) attendance for supervised sessions and 81% (22/27 sessions) completion for non-supervised exercises, and Shoulder Pain and Disability Index (SPADI); secondary: fear-avoidance behaviour, fear of pain, physical outcomes (strength, range of motion, scapular dyskinesis); others: ultrasound (US) imaging outcomes (acromionhumeral distance, supraspinatus tendon thickness, occupation ratio), global perceived effect (GPE). PROMs were collected via online survey, except for the GPE (via closed envelope). US measures were taken after physical measures.Results Adherence and adverse effects were analysed in patients who had the possibility to attend minimum seven supervised sessions (n=8): 88% of them adhered to supervised sessions, 50% to non-supervised exercises; none of them withdrew from the study, three of them obtained individual clinically important improvements in SPADI score above 20 points. The measurement protocol of physical and ultrasonographic outcomes took around 60 min.Conclusions Adherence to supervised sessions was satisfactory, the adherence to non-supervised exercises must be improved. Data collection procedures were feasible to perform, but some changes are recommended.Trial registration number NCT04154345.

Con el objetivo de describir las características clínicas y epidemiológicas de los pacientes fallecidos por dengue durante el 2017 en Piura, se realizó un estudio retrospectivo de revisión de 24 historias clínicas. El 67% de los casos fueron mujeres y tres (12,5%) estaban embarazadas. La diabetes (12,5%) y la hipertensión (16,7%) fueron las comorbilidades más frecuentes. Sólo en el 12,5% se reportó dengue previo. El tiempo transcurrido desde asistencia sanitaria hasta la muerte fue de 4,10 (DE: 5,34) días. Se hicieron transfusiones de glóbulos rojos en el 45,8% de los casos, plasma en el 25%, plaquetas en el 16,8% y crioprecipitado en el 16,8%. También fueron frecuentes la terapia con ristaloides (91,7%) y el tratamiento con fármacos vasoactivos (70,8%). En conclusión, la mortalidad del dengue grave fue mayoritaria en las mujeres adultas y el tiempo de atención desde el primer establecimiento de salud hasta una unidad especializada fue prolongada.

Abstract Iberian hare populations have suffered severe declines during recent decades in Spain. Between 1970 and 1990s, a rapid increase in irrigation crop surface in NW Spain (Castilla-y-León region) was followed by a common vole massive range expansion and complete colonization of lowland irrigated agricultural landscapes from mountainous habitats. The subsequent large cyclic fluctuations in abundance of colonizing common voles have contributed to a periodic amplification of Francisella tularensis, the etiological agent that causes human tularemia outbreaks in the region. Tularemia is a fatal disease to lagomorphs, so we hypothesize that vole outbreaks would lead to disease spill over to Iberian hares, increasing prevalence of tularemia and declines among hare populations. Here we report on the possible effects that vole abundance fluctuations and concomitant tularemia outbreaks had on Iberian hare populations in NW Spain. We analysed hare hunting bag data for the region, which has been recurrently affected by vole outbreaks between 1996 and 2019. We also compiled data on F. tularensis prevalence in Iberian hares reported by the regional government between 2007 and 2016. Our results suggest that common vole outbreaks may limit the recovery of hare populations by amplifying and spreading tularemia in the environment. The recurrent rodent-driven outbreaks of tularemia in the region may result in a "disease pit" to Iberian hares: at low host densities, the rate of population growth in hares is lower than the rate at which disease-induced mortality increases with increased rodent host density, therefore, keeping hare populations on a low-density equilibrium. We highlight future research needs to clarify tularemia transmission pathways between voles and hares and confirm a disease pit process.

Abstract This study investigated the intra-rater reliability of a novice ultrasound (US) examiner and the inter-rater reliability of two examiners (novice, expert) in the measures of coracohumeral distance at rest (CHD) and at 60° of elevation without (CHD60) or with weights (CHD60w), tendon thickness of the long head of the biceps (LHB) and subscapularis (SCP). Twenty-one patients with subacromial pain syndrome (SAPS) and 20 asymptomatic participants were included. Intra and inter-rater reliability were tested with intraclass-correlation-coefficient (ICC), differences between raters were analyzed with Bland–Altman plots. Intra-rater reliability for CHD, CHD60 and CHD60w was excellent (ICC = 0.97–0.98) in asymptomatic participants, and good-to-excellent (0.88–0.93) in SAPS, while intra-rater reliability for LHB and SCP was good-to-excellent in asymptomatic participants (0.88–0.97) and in SAPS (0.90–0.92). Inter-rater reliability for CHD, CHD60 and CHD60w was moderate-to-good (0.70–0.90) in asymptomatic participants and good (0.85–0.87) in SAPS, in contrast inter-rater reliability for LHB and SCP was poor in asymptomatic participants (0.10–0.46) and poor-to-moderate (0.49–0.61) in SAPS. Bland–Altman plots revealed systematic and/or proportional bias for tendons’ thickness. A novice showed good-to-excellent intra-rater reliability in all US measures, whereas in comparison to an expert a novice can measure reliably CHD, CHD60 and CHD60w, but not LHB and SCP, where more training is recommended.

Abstract Background C3G is a guanine nucleotide exchange factor (GEF) that activates Rap1 to promote cell adhesion. Resting C3G is autoinhibited and the GEF activity is released by stimuli that signal through tyrosine kinases. C3G is activated by tyrosine phosphorylation and interaction with Crk adaptor proteins, whose expression is elevated in multiple human cancers. However, the molecular details of C3G activation and the interplay between phosphorylation and Crk interaction are poorly understood. Methods We combined biochemical, biophysical, and cell biology approaches to elucidate the mechanisms of C3G activation. Binding of Crk adaptor proteins to four proline-rich motifs (P1 to P4) in C3G was characterized in vitro using isothermal titration calorimetry and sedimentation velocity, and in Jurkat and HEK293T cells by affinity pull-down assays. The nucleotide exchange activity of C3G over Rap1 was measured using nucleotide-dissociation kinetic assays. Jurkat cells were also used to analyze C3G translocation to the plasma membrane and the C3G-dependent activation of Rap1 upon ligation of T cell receptors. Results CrkL interacts through its SH3N domain with sites P1 and P2 of inactive C3G in vitro and in Jurkat and HEK293T cells, and these sites are necessary to recruit C3G to the plasma membrane. However, direct stimulation of the GEF activity requires binding of Crk proteins to the P3 and P4 sites. P3 is occluded in resting C3G and is essential for activation, while P4 contributes secondarily towards complete stimulation. Tyrosine phosphorylation of C3G alone causes marginal activation. Instead, phosphorylation primes C3G lowering the concentration of Crk proteins required for activation and increasing the maximum activity. Unexpectedly, optimal activation also requires the interaction of CrkL-SH2 domain with phosphorylated C3G. Conclusion Our study revealed that phosphorylation of C3G by Src and Crk-binding form a two-factor mechanism that ensures tight control of C3G activation. Additionally, the simultaneous SH2 and SH3N interaction of CrkL with C3G, required for the activation, reveals a novel adaptor-independent function of Crk proteins relevant to understanding their role in physiological signaling and their deregulation in diseases. Video abstract

Abstract Soil contamination by Pb can result from different anthropogenic sources such as lead-based paints, gasoline, pesticides, coal burning, mining, among others. This work aimed to evaluate the potential of P-loaded biochar (Biochar-based slow-release P fertilizer) to remediate a Pb-contaminated soil. In addition, we aim to propose a biomonitoring alternative after soil remediation. First, rice husk-derived biochar was obtained at different temperatures (450, 500, 550, and 600 °C) (raw biochars). Then, part of the resulting material was activated. Later, the raw biochars and activated biochars were immersed in a saturated KH2PO4 solution to produce P-loaded biochars. The ability of materials to immobilize Pb and increase the bioavailability of P in the soil was evaluated by an incubation test. The materials were incorporated into doses of 0.5, 1.0, and 2.0%. After 45 days, soil samples were taken to biomonitor the remediation process using two bioindicators: a phytotoxicity test and enzyme soil activity. Activated P-loaded biochar produced at 500 °C has been found to present the best conditions for soil Pb remediation. This material significantly reduced the bioavailability of Pb and increased the bioavailability of P. The phytotoxicity test and the soil enzymatic activity were significantly correlated with the decrease in bioavailable Pb but not with the increase in bioavailable P. Biomonitoring using the phytotoxicity test is a promising alternative for the evaluation of soils after remediation processes.

Abstract Negative attitudes and prejudices towards people with a mental disorder are common across cultures and societies. The stigma associated with mental illness leads to a lower quality of life, given the discrimination and social exclusion suffered by people with this type of disorder. In the field of health, research has shown that doctors and nurses also manifest these types of stigmatizing behaviors and attitudes. The present study aims to create and apply an educational escape room for the purpose of training nursing students in mental health, promoting positive attitudes towards people who have a mental disorder. To do so, a pre-post study was conducted with an experimental group and a control group to determine whether the escape room was effective for the modification of stigmatizing behaviors compared to transmissive lecture class, and a third measurement was made at 6 months only to the experimental group to evaluate whether the changes produced by the escape room were maintained in the long term. The results indicate that the students participating in the study obtained better scores in sensitization and these remain better over time. It is concluded that the escape room used is suitable for the training and sensitization of future nursing professionals in the field of mental health, facilitating the learning of knowledge and positive attitudes towards severe mental disorder.