Childhood-Onset Non-Infectious Uveitis in the "Biologic Era". Results From Spanish Multicenter Multidisciplinary Real-World Clinical Settings.

OBJECTIVE: To characterize and describe clinical experience with childhood-onset non-infectious uveitis. STUDY DESIGN: A multicenter retrospective multidisciplinary national web-based registry of 507 patients from 21 hospitals was analyzed. Cases were grouped as immune disease-associated (IMDu), idiopathic (IDIu) or ophthalmologically distinct. Characteristics of juvenile idiopathic arthritis-associated (non-HLA-B27-related) uveitis (JIAu), IDIu, and pars planitis (PP) were compared. RESULTS: IMDu (62.3%) and JIAu (51.9%) predominated in young females; and IDIu (22.7%) and PP (13.6%) in older children, without sex imbalance. Ocular complications occurred in 45.3% of cases (posterior synechiae [28%], cataracts [16%], band keratopathy [14%], ocular hypertension [11%] and cystoid macular edema [10%]) and were associated with synthetic (86%) and biologic (65%) disease-modifying antirheumatic drug (DMARD) use. Subgroups were significantly associated (p < 0.05) with different characteristics. JIAu was typically anterior (98%), insidious (75%), in ANA-positive (69%), young females (82%) with fewer complications (31%), better visual outcomes, and later use of uveitis-effective biologics. In contrast, IDIu was characteristically anterior (87%) or panuveitic (12.1%), with acute onset (60%) and more complications at onset (59%: synechiae [31%] and cataracts [9.6%]) and less DMARD use, while PP is intermediate, and was mostly bilateral (72.5%), persistent (86.5%) and chronic (86.8%), with more complications (70%; mainly posterior segment and cataracts at last visit), impaired visual acuity at onset, and greater systemic (81.2%), subtenon (29.1%) and intravitreal (10.1%) steroid use. CONCLUSION: Prognosis of childhood uveitis has improved in the "biologic era," particularly in JIAu. Early referral and DMARD therapy may reduce steroid use and improve outcomes, especially in PP and IDIu.

Exploring the geometry of the bifurcation sets in parameter space.

By studying a nonlinear model by inspecting a p-dimensional parameter space through ( p - 1 ) -dimensional cuts, one can detect changes that are only determined by the geometry of the manifolds that make up the bifurcation set. We refer to these changes as geometric bifurcations. They can be understood within the framework of the theory of singularities for differentiable mappings and, in particular, of the Morse Theory. Working with a three-dimensional parameter space, geometric bifurcations are illustrated in two models of neuron activity: the Hindmarsh-Rose and the FitzHugh-Nagumo systems. Both are fast-slow systems with a small parameter that controls the time scale of a slow variable. Geometric bifurcations are observed on slices corresponding to fixed values of this distinguished small parameter, but they should be of interest to anyone studying bifurcation diagrams in the context of nonlinear phenomena.

Development of a Six-Degree-of-Freedom Analog 3D Tactile Probe Based on Non-Contact 2D Sensors.

In this paper, a six-degree-of-freedom analog tactile probe with a new, simple, and robust mechanical design is presented. Its design is based on the use of one elastomeric ring that supports the stylus carrier and allows its movement inside a cubic measuring range of ±3 mm. The position of the probe tip is determined by three low-cost, noncontact, 2D PSD (position-sensitive detector) sensors, facilitating a wider application of this probe to different measuring systems compared to commercial ones. However, several software corrections, regarding the size and orientation of the three LED light beams, must be carried out when using these 2D sensors for this application due to the lack of additional focusing or collimating lenses and the very wide measuring range. The development process, simulation results, correction models, experimental tests, and calibration of this probe are presented. The results demonstrate high repeatability along the X-, Y-, and Z-axes (2.0 µm, 2.0 µm, and 2.1 µm, respectively) and overall accuracies of 6.7 µm, 7.0 µm, and 8.0 µm, respectively, which could be minimized by more complex correction models.

Alteration of Gut Microbiota Composition in the Progression of Liver Damage in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex disorder whose prevalence is rapidly growing in South America. The disturbances in the microbiota-gut-liver axis impact the liver damaging processes toward fibrosis. Gut microbiota status is shaped by dietary and lifestyle factors, depending on geographic location. We aimed to identify microbial signatures in a group of Chilean MASLD patients. Forty subjects were recruited, including healthy controls (HCs), overweight/obese subjects (Ow/Ob), patients with MASLD without fibrosis (MASLD/F-), and MASLD with fibrosis (MASLD/F+). Both MASLD and fibrosis were detected through elastography and/or biopsy, and fecal microbiota were analyzed through deep sequencing. Despite no differences in α- and ß-diversity among all groups, a higher abundance of Bilophila and a lower presence of Defluviitaleaceae, Lachnospiraceae ND3007, and Coprobacter was found in MASLD/F- and MASLD/F+, compared to HC. Ruminococcaceae UCG-013 and Sellimonas were more abundant in MASLD/F+ than in Ow/Ob; both significantly differed between MASLD/F- and MASLD/F+, compared to HC. Significant positive correlations were observed between liver stiffness and Bifidobacterium, Prevotella, Sarcina, and Acidaminococcus abundance. Our results show that MASLD is associated with changes in bacterial taxa that are known to be involved in bile acid metabolism and SCFA production, with some of them being more specifically linked to fibrosis.

Models Used by Nurse Case Managers in Different Autonomous Communities in Spain: A Scoping Review.

(1) Background: The role of the nurse case manager is unknown to the population. The main objective is to analyze the existing differences within the national territory in order to make known the situation in Spain with a view to the recognition of its functions and the creation of the professional profile in an equal manner. (2) Methods: A scoping review was conducted in order to achieve the main aim. Selected articles were subjected to a critical reading, and the levels of evidence and grades of recommendation of the Joanna Briggs Institute were verified. The search field was limited to the last ten years. (3) Results: Case management models are heterogeneous in different autonomous communities in Spain. Case nurse management is qualified for high-complexity patients, follow up on chronic patients, and coordinate health assistance. (4) Conclusions: It concludes that nursing's role is crucial in the field of case management, being required in the follow-up of chronic patients of high complexity. Despite the proven health benefits, efficacy, and efficiency of case management, there are many heterogeneous models that coexist in Spain. This involves a restriction in the development of a nursing career because of the lack of a definition of its functions and competences.

Parenting practices and interventions during the COVID-19 pandemic lockdown: an exploratory cross-sectional study of caregivers in Brazil, Mexico, and the United States.

INTRODUCTION: The COVID-19 pandemic led countries' governments to rapidly establish lockdowns and social distancing, which altered family routines and the quality of family relationships worldwide. OBJECTIVES: This exploratory cross-sectional study aimed to identify the impacts of the social distancing and lockdown in parenting practices of caregivers from Brazil, Mexico, and the USA, and to analyze the continuity of parenting intervention support for children and their families at the beginning of the pandemic in these countries. METHODS: The sample consisted of 704 caregivers of children (286 from Brazil, 225 from Mexico, and 193 from the USA) who answered an online survey about parenting practices before/after quarantine, caregiver/child routines, feelings related to quarantine, changes in everyday life since the beginning of the COVID-19 pandemic, contact with health professionals, and sources of parenting information. RESULTS: Data indicate that caregivers from the three countries experienced similar parenting practices during this time, and did not report significant changes before and after the lockdown. They sought information about parenting predominantly via social media. Those receiving previous mental health care perceived the transition from in-person to telehealth services during the pandemic as feasible and acceptable. CONCLUSION: This study will be helpful for clinicians and parents to contextualize their practices amid long-standing effects that the COVID-19 pandemic can have on children and their families during and post-pandemic from multiple cultural backgrounds.

Persistent Monkeypox-Associated Keratouveitis in a Post-LASIK Cornea: A Case Report With Flap Removal.

PURPOSE: This study aimed to report a case of persistent keratouveitis associated with mpox virus infection in an immunocompetent patient with a history of laser-assisted in situ keratomileusis (LASIK), leading to the need for flap removal. METHODS: A comprehensive literature review was conducted, and a detailed case report was presented. RESULTS: A 44-year-old immunocompetent male patient with a history of LASIK and HIV infection presented with conjunctival and corneal lesions indicative of mpox infection. Despite initial topical treatment, the condition worsened, leading to severe epithelial and stromal keratitis with anterior chamber inflammation. Polymerase chain reaction testing confirmed the presence of mpox virus in conjunctival, corneal, and aqueous humor samples. The patient underwent various treatments, including tecovirimat, oral and topical corticosteroids, and topical trifluridine, and eventually flap removal with amniotic membrane application. Subsequent polymerase chain reaction testing of the aqueous humor yielded negative results, and the cornea gradually reepithelialized without inflammation. After 8 months, the patient's eye remained stable, with a central stromal scar. CONCLUSIONS: This case highlights the rare occurrence of mpox-associated keratouveitis and emphasizes the challenges faced in its management. The successful outcome achieved through a combination of antiviral therapy, antiinflammatories, and surgical intervention underscores the importance of a multidisciplinary approach in managing such cases.

Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell-Associated Pathogenicity in Chronic Intestinal Inflammation.

BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell-induced murine colitis models. RESULTS: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 ß, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 ß pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell-driven chronic intestinal inflammation.

Tesis doctorales españolas de ciencias de la salud en materia de género (1976-2022) / Spanish doctoral thesis in health sci-ences on gender subjects (1976-2022)

Objetivo principal: analizar cuantitativamente la producción de las tesis doctorales en materia sanitaria relacionadas con el género en España. Metodología: síntesis cuantitativa de indicadores de productividad de las tesis doctorales conseguidas en la base de datos española TESEO y defendidas en Universidades españolas entre 1976 y 2022. Los análisis empleados han sido descriptivos y el cálculo de predicción se basó en la metodología del modelo Holt-Winters. Resultados principales: el 18,75% de las tesis defendidas pertenecen a una Universidad de Madrid. El 75% de ellas son defendidas por graduados en Medicina. La temática de las tesis es en el 25% la violencia de género. El 87,5% son doctoras, pero solamente el 44% de las mujeres dirigen tesis. La predicción para los futuros 24 años indica que se generará alrededor de 1 tesis al año. Conclusión principal: la investigación española en tesis doctorales clínicas de género es escasa y masculinizada.(AU)

Main objective: to quantitatively analyze the production of gender-related doctoral theses in health in Spain. Methodology: quantitative synthesis of productivity indicators of the doctoral theses obtained in the Spanish TESEO database and defended in Spanish Universities between 1976 and 2022. The analyzes used have been descriptive and the prediction calculation was based on the methodology of the Holt- Winters. Main results: 18.75% of the theses defended belong to a University of Madrid. 75% of them are defended by graduates in Medicine. The theme of the theses is gender violence in 25%. 87.5% are doctors, but only 44% of women direct theses. The prediction for the future 24 years indicates that around 1 thesis will be generated per year. Main conclusion: Spanish research in gender clinical doctoral theses is scarce and masculinized.(AU)

Hematoma subcapsular esplénico espontáneo y mononucleosis infecciosa: una asociación de interés para el cirujano

La rotura espontánea de bazo es una complicación infrecuente pero muy grave de la mononucleosis infecciosa. Dada la urgencia con la que suele presentarse tal situación, la esplenectomía suele ser la opción quirúrgica más utilizada. Presentamos el caso de un paciente en el que con el diagnóstico de rotura esplénica espontánea se somete a laparoscopia diagnóstica en la que se consigue la preservación del bazo con buena evolución clínica. A la luz de este paciente, consideramos que, en caso de estabilidad clínica y hematomas subcapsulares de bazo, la laparoscopia con preservación esplénica es una opción viable y con buenos resultados. (provisto por Infomedic International)

Spontaneous rupture of the spleen is a rare but very serious complication of infectious mononucleosis. Given the urgency with which such a situation usually presents, splenectomy is usually the most used surgical option. We present the case of a patient diagnosed with spontaneous splenic rupture who underwent diagnostic laparoscopy in which spleen preservation was achieved with good clinical evolution. In the light of this patient, we consider that, in the case of clinical stability and subcapsular haematomas of the spleen, laparoscopy with splenic preservation is a viable option with good results. (provided by Infomedic International)

"Direct and indirect impacts of the COVID-19 pandemic on operational conduct of pediatric vaccine clinical trials".

The coronavirus 2019 (COVID-19) pandemic, as well as the resulting public health measures, impacted many aspects of society. The conduct of important pediatric vaccine trials was among these. Analyzing data from six ongoing non-COVID-19 pediatric vaccine trials we aimed to assess the operational impact of the COVID-19 pandemic using descriptive analyses. We identified multiple operational disruptions in trial conduct. Additionally, we identified higher percentages of missed routine vaccinations than investigational vaccines throughout the observation period. Overall, the impact of the COVID-19 pandemic was most apparent early in the pandemic period while adaptations to the pandemic were developed; however, some disruptions persisted throughout the observation period. Pediatric vaccine clinical trials are critical to developing new and/or improved vaccines for the pediatric population. Continued evaluation of the impacts of COVID-19 on pediatric vaccine clinical trials is warranted.

The Chlamydia effector CpoS modulates the inclusion microenvironment and restricts the interferon response by acting on Rab35.

The obligate intracellular bacterium Chlamydia trachomatis inserts a family of inclusion membrane (Inc) proteins into the membrane of its vacuole (the inclusion). The Inc CpoS is a critical suppressor of host cellular immune surveillance, but the underlying mechanism remained elusive. By complementing a cpoS mutant with various natural orthologs and variants of CpoS, we linked distinct molecular interactions of CpoS to distinct functions. Unexpectedly, we found CpoS to be essential for the formation of inclusion membrane microdomains that control the spatial organization of multiple Incs involved in signaling and modulation of the host cellular cytoskeleton. While the function of CpoS in microdomains was uncoupled from its role in the suppression of host cellular defenses, we found the ability of CpoS to interact with Rab GTPases to be required not only for the manipulation of membrane trafficking, such as to mediate transport of ceramide-derived lipids (sphingolipids) to the inclusion, but also for the inhibition of Stimulator of interferon genes (STING)-dependent type I interferon responses. Indeed, depletion of Rab35 phenocopied the exacerbated interferon responses observed during infection with CpoS-deficient mutants. Overall, our findings highlight the role of Inc-Inc interactions in shaping the inclusion microenvironment and the modulation of membrane trafficking as a pathogenic immune evasion strategy. IMPORTANCE Chlamydia trachomatis is a prevalent bacterial pathogen that causes blinding ocular scarring and urogenital infections that can lead to infertility and pregnancy complications. Because Chlamydia can only grow within its host cell, boosting the intrinsic defenses of human cells may represent a novel strategy to fight pathogen replication and survival. Hence, CpoS, a Chlamydia protein known to block host cellular defenses, or processes regulated by CpoS, could provide new opportunities for therapeutic intervention. By revealing CpoS as a multifunctional virulence factor and by linking its ability to block host cellular immune signaling to the modulation of membrane trafficking, the present work may provide a foundation for such rationale targeting and advances our understanding of how intracellular bacteria can shape and protect their growth niche.

Long-term antibody titers variation in unvaccinated patients receiving convalescent plasma or placebo for severe SARS-CoV-2 pulmonary infection.

BACKGROUND: Convalescent plasma (CP) became a prominent treatment in the early stages of the SARS-CoV-2 pandemic. In Argentina, a randomized clinical trial was executed to compare the use of CP in inpatients with severe COVID-19 pneumonia versus placebo. No differences in clinical outcomes or overall mortality between groups were observed. We conducted a cohort study in outpatients enrolled in the trial to describe long-term antibody titer variations between CP and placebo recipients. METHODS: Patients' total SARS-CoV-2 IgG antibodies against spike protein were collected 3, 6 and 12 months after hospital discharge from August 2020 to December 2021. In addition, reinfections, deaths and vaccination status were retrieved. Statistical analysis was performed using antibody geometric mean titers (GMT). All estimations were made considering the date of the trial infusion (placebo or CP) as time 0. RESULTS: From the 93 patients included in the follow-up, 64 had received CP and 29 placebo. We excluded all 12-month measurements because they were collected after the patients' vaccination date. At 90 days post-infusion, patients had an antibody GMT of 8.1 (IQR 7.4-8.1) in the CP group and 8.8 (IQR 8.1-9.1) in the placebo group. At 180 days, both groups had a GMT of 8.1 (IQR 7.4-8.1). No statistical differences in GMT were found between CP and placebo groups at 90 days (p = 0.12) and 180 days (p = 0.25). No patients registered a new COVID-19 infection; one died in the CP group from an ischemic stroke. CONCLUSIONS: No differences were observed in long-term antibody titers in unvaccinated patients that received CP or placebo after severe COVID-19 pneumonia.

Changing biosynthesis of terpenoid percursors in rice through synthetic biology.

Many highly valued chemicals in the pharmaceutical, biotechnological, cosmetic, and biomedical industries belong to the terpenoid family. Biosynthesis of these chemicals relies on polymerization of Isopentenyl di-phosphate (IPP) and/or dimethylallyl diphosphate (DMAPP) monomers, which plants synthesize using two alternative pathways: a cytosolic mevalonic acid (MVA) pathway and a plastidic methyleritritol-4-phosphate (MEP) pathway. As such, developing plants for use as a platform to use IPP/DMAPP and produce high value terpenoids is an important biotechnological goal. Still, IPP/DMAPP are the precursors to many plant developmental hormones. This creates severe challenges in redirecting IPP/DMAPP towards production of non-cognate plant metabolites. A potential solution to this problem is increasing the IPP/DMAPP production flux in planta. Here, we aimed at discovering, understanding, and predicting the effects of increasing IPP/DMAPP production in plants through modelling. We used synthetic biology to create rice lines containing an additional ectopic MVA biosynthetic pathway for producing IPP/DMAPP. The rice lines express three alternative versions of the additional MVA pathway in the plastid, in addition to the normal endogenous pathways. We collected data for changes in macroscopic and molecular phenotypes, gene expression, isoprenoid content, and hormone abundance in those lines. To integrate the molecular and macroscopic data and develop a more in depth understanding of the effects of engineering the exogenous pathway in the mutant rice lines, we developed and analyzed data-centric, line-specific, multilevel mathematical models. These models connect the effects of variations in hormones and gene expression to changes in macroscopic plant phenotype and metabolite concentrations within the MVA and MEP pathways of WT and mutant rice lines. Our models allow us to predict how an exogenous IPP/DMAPP biosynthetic pathway affects the flux of terpenoid precursors. We also quantify the long-term effect of plant hormones on the dynamic behavior of IPP/DMAPP biosynthetic pathways in seeds, and predict plant characteristics, such as plant height, leaf size, and chlorophyll content from molecular data. In addition, our models are a tool that can be used in the future to help in prioritizing re-engineering strategies for the exogenous pathway in order to achieve specific metabolic goals.

Rho-associated protein kinase 1 inhibition in hepatocytes attenuates nonalcoholic steatohepatitis.

BACKGROUND: NASH is the progressive form of NAFLD characterized by lipotoxicity, hepatocyte injury, tissue inflammation, and fibrosis. Previously, Rho-associated protein kinase (ROCK) 1 has been implicated in lipotoxic signaling in hepatocytes in vitro and high-fat diet-induced lipogenesis in vivo. However, whether ROCK1 plays a role in liver inflammation and fibrosis during NASH is unclear. Here, we hypothesized that pathogenic activation of ROCK1 promotes murine NASH pathogenesis. METHODS AND RESULTS: Patients with NASH had increased hepatic ROCK1 expression compared with patients with fatty liver. Similarly, hepatic ROCK1 levels and activity were increased in mice with NASH induced by a western-like diet that is high in fat, fructose, and cholesterol (FFC). Hepatocyte-specific ROCK1 knockout mice on the FFC diet displayed a decrease in liver steatosis, hepatic cell death, liver inflammation, and fibrosis compared with littermate FFC-fed controls. Mechanistically, these effects were associated with a significant attenuation of myeloid cell recruitment. Interestingly, myeloid cell-specific ROCK1 deletion did not affect NASH development in FFC-fed mice. To explore the therapeutic opportunities, mice with established NASH received ROCKi, a novel small molecule kinase inhibitor of ROCK1/2, which preferentially accumulates in liver tissue. ROCK inhibitor treatment ameliorated insulin resistance and decreased liver injury, inflammation, and fibrosis. CONCLUSIONS: Genetic or pharmacologic inhibition of ROCK1 activity attenuates murine NASH, suggesting that ROCK1 may be a therapeutic target for treating human NASH.

Interleukin-21 Drives a Hypermetabolic State and CD4+ T Cell-associated Pathogenicity in Chronic Intestinal Inflammation.

BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease (IBD); however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing Seahorse XF analyzer. We utilized Crohn's disease single-cell RNA sequencing dataset to infer therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically-modified Tregs in CD4+ T cell-induced murine colitis models. RESULTS: Mitochondria-endoplasmic reticulum (ER) appositions, known to mediate pyruvate entry into mitochondria via VDAC1, are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate (MePyr) supplementation. Notably, IL-21 diminished mitochondria-ER appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 ß (GSK3ß), a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. MePyr and GSK3ß pharmacologic inhibitor (LY2090314) reversed IL-21-induced metabolic rewiring and inflammatory state. Moreover, IL-21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS: IL-21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL-21-induced metabolism in Tregs may mitigate CD4+ T cell-driven chronic intestinal inflammation.

mRNA-1273 SARS-CoV-2 vaccine in recently transplanted allogeneic hematopoietic cell transplant recipients: Dynamics of cellular and humoral immune responses and booster effect.

Allogeneic hematopoietic stem cell transplant (HCT) recipients are at high risk of severe COVID-19 despite vaccination. Little is known about cellular response to SARS-CoV-2 vaccine in this population, especially in recently transplanted patients (RTP). In this single-center study we examined cellular and humoral response to the mRNA-1273 (Spikevax®) vaccine in recently transplanted patients (RTP, n = 49), and compared them to long-term transplanted patients (LTTP, n = 19) and healthy controls (n = 20) at three different timepoints: one and three months after the second dose (T1 and T2, respectively, 28 days apart), and one month after the third dose (T3). Controls did not receive a third dose. RTPs showed lower IgG anti-S1 titers than healthy controls at both T1 (mean 0.50 vs 0.94 arbitrary units -AU-, p < 0.0001) and T2 (0.37 vs 0.79 AU, p < 0.0001). They also presented lower titers than LTTPs at T1 (0.50 vs 0.66, p = 0.01), but no differences at T2 (0.37 vs 0.40 AU, p = 0.55). The rate of positive T-cell responses was lower in RTPs than in controls at both T1 and T2 (61.2 % vs 95 %, p = 0.007; 59.2 % vs 100 %, p = 0.001, respectively), but without statistically significant differences between transplanted groups. At T3 no differences were seen between RTPs and LTTPs as well, neither in IgG antibodies (p = 0.82) nor in cellular responses (p = 0.15), although a third dose increased the rate of positive cellular and humoral responses in approximately 50 % of recently transplanted patients. However, active immunosuppressive treatment severely diminished their chances to produce an adequate response.

The gut-derived metabolites as mediators of the effect of healthy nutrition on the brain.

Nutrition is now well recognized to be an environmental factor which positively or negatively influences the risk to develop neurological and psychiatric disorders. The gut microbiota has recently been shown to be an important actor mediating the relationship between environmental factors, including nutrition, and brain function. While its composition has been widely studied and associated with the risk of brain diseases, the mechanisms underlying the relationship between the gut and brain diseases remain to be explored. The wide range of bioactive molecules produced by the gut microbiota, called gut-derived metabolites (GDM), represent new players in the gut to brain interactions and become interesting target to promote brain health. The aim of this narrative review is to highlight some GDMs of interest that are produced in response to healthy food consumption and to summarize what is known about their potential effects on brain function. Overall, GDMs represent future useful biomarkers for the development of personalized nutrition. Indeed, their quantification after nutritional interventions is a useful tool to determine individuals' ability to produce microbiota-derived bioactive compounds upon consumption of specific food or nutrients. Moreover, GDMs represent also a new therapeutic approach to counteract the lack of response to conventional nutritional interventions.

Detection and genetic characterization of enteric viruses in diarrhoea outbreaks from swine farms in Spain.

BACKGROUND: The aim of this work was to study the prevalence and distribution of Porcine astrovirus (PAstV), Porcine kobuvirus (PKoV), Porcine torovirus (PToV), Mammalian orthoreovirus (MRV) and Porcine mastadenovirus (PAdV) as well as their association with widely recognized virus that cause diarrhoea in swine such as coronavirus (CoVs) and rotavirus (RVs) in diarrhoea outbreaks from Spanish swine farms. Furthermore, a selection of the viral strains was genetically characterized. RESULTS: PAstV, PKoV, PToV, MRV and PAdV were frequently detected. Particularly, PAstV and PKoV were detected in almost 50% and 30% of the investigated farms, respectively, with an age-dependent distribution; PAstV was mainly detected in postweaning and fattening pigs, while PKoV was more frequent in sucking piglets. Viral co-infections were detected in almost half of the outbreaks, combining CoVs, RVs and the viruses studied, with a maximum of 5 different viral species reported in three investigated farms. Using a next generation sequencing approach, we obtained a total of 24 ARN viral genomes (> 90% genome sequence), characterizing for first time the full genome of circulating strains of PAstV2, PAstV4, PAstV5 and PToV on Spanish farms. Phylogenetic analyses showed that PAstV, PKoV and PToV from Spanish swine farms clustered together with isolates of the same viral species from neighboring pig producing countries. CONCLUSIONS: Although further studies to evaluate the role of these enteric viruses in diarrhoea outbreaks are required, their wide distribution and frequent association in co-infections cannot be disregard. Hence, their inclusion into routine diagnostic panels for diarrhoea in swine should be considered.