Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination.

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination in male and female mice. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.

Swallowed topical corticosteroids for eosinophilic esophagitis: Utilization and real-world efficacy from the EoE CONNECT registry.

BACKGROUND: Swallowed topical corticosteroids (tC) are common therapy for patients with eosinophilic esophagitis (EoE). Widely heterogeneous results have occurred due to their active ingredients, formulations and doses. OBJECTIVE: To assess the effectiveness of topical corticosteroid therapy for EoE in real-world practice. METHODS: Cross-sectional study analysis of the multicentre EoE CONNECT registry. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom scores; histological remission was defined as a peak eosinophil count below 15 per high-power field. The effectiveness in achieving clinico-histological remission (CHR) was compared for the main tC formulations. RESULTS: Overall, data on 1456 prescriptions of tC in monotherapy used in 866 individual patients were assessed. Of those, 904 prescriptions with data on formulation were employed for the induction of remission; 234 reduced a previously effective dose for maintenance. Fluticasone propionate formulations dominated the first-line treatment, while budesonide was more common in later therapies. A swallowed nasal drop suspension was the most common formulation of fluticasone propionate. Doses ≥0.8 mg/day provided a 65% CHR rate and were superior to lower doses. Oral viscous solution prepared by a pharmacist was the most common prescription of budesonide; 4 mg/day provided no benefit over 2 mg/day (CHR rated being 72% and 80%, respectively). A multivariate analysis revealed budesonide orodispersible tablets as the most effective therapy (OR 18.9, p < 0.001); use of higher doses (OR 4.3, p = 0.03) and lower symptom scores (OR 0.9, p = 0.01) were also determinants of effectiveness. CONCLUSION: Reduced symptom severity, use of high doses, and use of budesonide orodispersible tablets particularly were all independent predictors of tC effectiveness.

Glial cell alterations in diabetes-induced neurodegeneration.

Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration.

Vacunación contra el SARS-CoV-2 en pacientes paraguayos con artritis reumatoide

Introducción: La vacunación en poblaciones expuestas a mayor riesgo de enfermedad grave y muerte consecuentes a la infección por SARS-CoV-2, ha generado un gran impacto en la salud pública mundial. Indudablemente, el beneficio ha sido evidenciado mayormente en personas con comorbilidades crónicas, donde la artritis reumatoide (AR) juega un rol importante. Objetivo: Analizar la vacunación contra Sars-CoV-2 en pacientes paraguayos con AR, durante la pandemia COVID-19. Métodos: Se realizó un estudio multicéntrico, en el que se analizó transversalmente a una cohorte de pacientes con AR, durante el periodo de octubre a diciembre del año 2022. Para el estudio se registraron variables clínico-epidemiológicas y relacionadas con la vacunación (i.e. acceso a la vacunación, tipo, número de dosis). Se realizó un análisis descriptivo de las variables con el software R-4.3.2. Resultados: Se incluyeron 568 pacientes, 84,1% eran mujeres, con un promedio de edad de 55,5±13,9 años. El 88,7% (504) pacientes, recibieron al menos una dosis de vacuna contra SARS-CoV-2. 85% (483) recibieron dos dosis, mientras que el 60,9% (344) pacientes recibieron el primer refuerzo, y 21,2% el segundo refuerzo. Conclusiones: En esta serie de pacientes paraguayos con AR el porcentaje de vacunación contra SARS-CoV-2 fue más elevado que el registrado en la población general del país. Esto podría estar relacionado con la prioridad de esta población para acceder a las vacunas y a la insistencia de sus médicos en completar el esquema de vacunación.

Introduction: Vaccination in populations exposed to increased risk of severe disease and death consequent to SARS-CoV-2 infection has generated a major impact on global Public Health. Certainly, the benefit has been evidenced mostly in people with chronic comorbidities, where rheumatoid arthritis (RA) plays an important role. Objective: To analyze vaccination against Sars-CoV-2 in paraguayan patients with rheumatoid arthritis (RA) during the COVID19 pandemic. Methods: A multicenter study was carried out, in which a cohort of patients with RA was analyzed cross-sectionally, during the period from October to December 2022. For the study, clinical-epidemiological and vaccination-related variables were recorded (i.e. access to vaccination, type, number of doses). A descriptive analysis of the variables was carried out with the R-4.3.2 software. Results: 568 patients were included, 84.1% were female, with an average age of 55.5±13.9 years. 88.7% (504) patients received at least one dose of SARS-CoV-2 vaccine, 85% (483) received two doses, while 60.9% (344) patients received the first booster, and 21.2% the second booster. Conclusions: In this series of Paraguayan patients with RA the percentage of vaccination against SARS-CoV-2 was higher than that registered in the general population of the country. This could be related to the priority of this population to access vaccines and the insistence of their physicians to complete the vaccination schedule.

METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer.

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translation control and tumour biology.

Tubulointerstitial nephritis and uveitis syndrome and SARS-CoV-2 infection in an adolescent: just a coincidence in time?

BACKGROUND: Despite recent well-established kidney tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), usually presenting as acute kidney injury (AKI), there are few published cases with SARS-CoV-2-related tubulointerstitial nephritis (TIN). We report an adolescent with TIN and delayed association with uveitis (TINU syndrome), where SARS-CoV-2 spike protein was identified in kidney biopsy. CASE-DIAGNOSIS/TREATMENT: A 12-year-old girl was assessed for a mild elevation of serum creatinine detected during the evaluation of systemic manifestations including asthenia, anorexia, abdominal pain, vomiting, and weight loss. Data of incomplete proximal tubular dysfunction (hypophosphatemia and hypouricemia with inappropriate urinary losses, low molecular weight proteinuria, and glucosuria) were also associated. Symptoms had initiated after a febrile respiratory infection with no known infectious cause. After 8 weeks, the patient tested positive in PCR for SARS-CoV-2 (Omicron variant). A subsequent percutaneous kidney biopsy revealed TIN and immunofluorescence staining with confocal microscopy detected the presence of SARS-CoV-2 protein S within the kidney interstitium. Steroid therapy was started with gradual tapering. Ten months after onset of clinical manifestations, as serum creatinine remained slightly elevated and kidney ultrasound showed mild bilateral parenchymal cortical thinning, a second percutaneous kidney biopsy was performed, without demonstrating acute inflammation or chronic changes, but SARS-CoV-2 protein S within the kidney tissue was again detected. At that moment, simultaneous routine ophthalmological examination revealed an asymptomatic bilateral anterior uveitis. CONCLUSIONS: We present a patient who was found to have SARS-CoV-2 in kidney tissue several weeks following onset of TINU syndrome. Although simultaneous infection by SARS-CoV-2 could not be demonstrated at onset of symptoms, since no other etiological cause was identified, we hypothesize that SARS-CoV-2 might have been involved in triggering the patient's illness.

Adipose tissue plasticity in pheochromocytoma patients suggests a role of the splicing machinery in human adipose browning.

Adipose tissue from pheochromocytoma patients acquires brown fat features, making it a valuable model for studying the mechanisms that control thermogenic adipose plasticity in humans. Transcriptomic analyses revealed a massive downregulation of splicing machinery components and splicing regulatory factors in browned adipose tissue from patients, with upregulation of a few genes encoding RNA-binding proteins potentially involved in splicing regulation. These changes were also observed in cell culture models of human brown adipocyte differentiation, confirming a potential involvement of splicing in the cell-autonomous control of adipose browning. The coordinated changes in splicing are associated with a profound modification in the expression levels of splicing-driven transcript isoforms for genes involved in the specialized metabolism of brown adipocytes and those encoding master transcriptional regulators of adipose browning. Splicing control appears to be a relevant component of the coordinated gene expression changes that allow human adipose tissue to acquire a brown phenotype.

Nutritional Assessment and Support in Children with Chronic Kidney Disease: The Benefits of Working with a Registered Dietitian.

BACKGROUND: An unbalanced dietary pattern, characterized by high animal protein content: may worsen metabolic control, accelerate renal deterioration and consequently aggravate the stage of the chronic kidney disease (CKD) in pediatric patients with this condition. AIM: to assess the effect of a registered dietitian (RD) intervention on the CKD children's eating habits. METHODS: Anthropometric and dietetic parameters, obtained at baseline and 12 months after implementing healthy eating and nutrition education sessions, were compared in 16 patients (50% girls) of 8.1 (1-15) years. On each occasion, anthropometry, 3-day food records and a food consumption frequency questionnaire were carried out. The corresponding relative intake of macro- and micronutrients was contrasted with the current advice by the European Food Safety Authority (EFSA) and with consumption data obtained using the Spanish dietary guidelines. Student's paired t-test, Wilcoxon test and Mc Nemar test were used. RESULTS: At Baseline 6% were overweight, 69% were of normal weight and 25% were underweight. Their diets were imbalanced in macronutrient composition. Following nutritional education and dietary intervention 63%, 75% and 56% met the Dietary Reference Values requirements for fats, carbohydrates and fiber, respectively, but not significantly. CKD children decreased protein intake (p < 0.001), increased dietary fiber intake at the expense of plant-based foods consumption (p < 0.001) and a corresponding reduction in meat, dairy and processed food intake was noticed. There were no changes in the medical treatment followed or in the progression of the stages. CONCLUSIONS: RD-led nutrition intervention focused on good dieting is a compelling helpful therapeutic tool to improve diet quality in pediatric CKD patients.

Emotional processing in patients with single brain damage in the right hemisphere.

BACKGROUND: The interest in the relationship between brain damage and social cognition has increased in recent years. The objectives of the present study were the following: (1) to evaluate and compare emotional facial recognition and subjective emotional experience in patients who have suffered a single ischemic stroke in the right hemisphere (RH) and in healthy people, (2) to analyze the relationship between both variables in both groups of subjects, and (3) to analyze the association between the cerebral location of the stroke and these two variables. METHODS: Emotional facial recognition and the subjective emotional experience of 41 patients who had suffered a single ischemic stroke in the RH and 45 volunteers without previous cerebrovascular pathology were evaluated. RESULTS: Brain damaged patients performed lower in facial emotional recognition and had a less intense subjective emotional response to social content stimuli compared to healthy subjects. Likewise, among patients with RH ischemic stroke, we observed negative associations between facial recognition of surprise and reactivity to unpleasant images, and positive associations between recognition of disgust and reactivity to pleasant images. Finally, patients with damage in the caudate nucleus of the RH presented a deficit in the recognition of happiness and sadness, and those with damage in the frontal lobe exhibited a deficit in the recognition of surprise, compared to those injured in other brain areas. CONCLUSIONS: Emotional facial recognition and subjective emotional experience are affected in patients who have suffered a single ischemic stroke in the RH. Professionals caring for stroke patients should improve their understanding of the general condition of affected persons and their environment, assess for risk of depression, and facilitate their adaptation to work, family, and social environments.

Ammonium effects on oxidative stress, telomere length, and locomotion across life stages of an anuran from habitats with contrasting land-use histories.

Understanding the mechanistic implications behind wildlife responses to global changes is a central topic in eco-evolutionary research. In particular, anthropic pollution is known to impact wild populations across the globe, which may have even stronger consequences for species with complex life cycles. Among vertebrates, amphibians represent a paradigmatic example of metamorphosis, and their characteristics make them highly vulnerable to pollution. Here, we tested for differences in the redox status, telomere length, and locomotor performance across life stages of green frogs (Pelophylax perezi) from agrosystem and natural habitats, both constitutively and in response to an experimental ammonium exposure (10 mg/L). We found that larvae from the agrosystem constitutively showed an enhanced redox status (better antioxidant balance against H2O2, lower lipid peroxidation) but shorter telomeres as compared to larvae from the natural environment. The larval redox response to ammonium was, overall, similar in both habitats. In contrast, after metamorphosis, the redox status of individuals from the natural habitat seemed to cope better with ammonium exposure (denoted by lower lipid peroxidation), and differences between habitats in telomere length were no longer present. Intriguingly, while the swimming performance of larvae did not correlate with individual's physiology, metamorphs with lower glutathione reductase activity and longer telomeres had a better jumping performance. This may suggest that locomotor performance is both traded off with the production of reactive oxygen species and potentiated directly by longer telomeres or indirectly by the mechanisms that buffer their shortening. Overall, our study suggests that contrasting land-use histories can drive divergence in physiological pathways linked to individual health and lifespan. Since this pattern was life-stage dependent, divergent habitat conditions can have contrasting implications across the ontogenetic development of species with complex life cycles.

Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis: Predictive Factors and Long-Term Step-Down Efficacy.

OBJECTIVES: To assess the short- and long-term efficacy of proton pump inhibitor (PPI) therapy for pediatric eosinophilic esophagitis (EoE) in real-world practice with a step-down strategy, and to evaluate factors predictive of PPI responsiveness. METHODS: We collected data regarding the efficacy of PPIs during this cross-sectional analysis of the prospective nationwide RENESE registry. Children with EoE treated with PPI monotherapy were included. Histological remission was defined as a peak eosinophilic count of <15 eosinophils (eos)/high-power field (hpf). Factors associated with PPI responsiveness were identified using multivariate logistic regression analysis. RESULTS: After induction therapy, histological and clinico-histological remission were observed in 51.4% (n = 346) and 46.5% of children, respectively. Normal endoscopic appearance of the esophagus was associated with a higher possibility [odds ratio (OR), 9.20; 95% confidence interval (CI), 2.10-40.16], and fibrostenotic phenotype was associated with a lower possibility (OR, 0.36; 95% CI, 0.18-0.74) of histological remission. Long-term therapy with a step-down strategy effectively maintained histological remission in 68.5% and 85.3% of children at 7 months (n = 108) and 16 months (n = 34), respectively. Complete initial histological remission (≤5 eos/hpf) was associated with a higher possibility of sustained histological remission (OR, 5.08; 95% CI, 1.75-14.68). Adverse events were infrequent and mild. CONCLUSIONS: We confirmed the efficacy of PPIs for a large cohort of children with EoE with sustained histological remission using a step-down strategy. Children with fibrostenotic phenotypes are less likely to respond to induction therapy. Furthermore, patients with complete initial histological remission are more likely to experience long-term histological remission.

Immune-stem cell crosstalk in the central nervous system: how oligodendrocyte progenitor cells interact with immune cells.

The interaction between immune and stem cells has proven essential for homeostasis and regeneration in a wide range of tissues. However, because the central nervous system was long considered an immune-privileged organ, its immune-stem cell axis was not deeply investigated until recently. Research has shown that oligodendrocyte progenitor cells (OPCs), a highly abundant population of adult brain stem cells, establish bidirectional interactions with the immune system. Here, we provide an overview of the interactions that OPCs have with tissue-resident and recruited immune cells, paying particular attention to the role they play in myelin regeneration and neuroinflammation. We highlight the described role of OPCs as key active players in neuroinflammation, overriding the previous concept that OPCs are mere recipients of immune signals. Understanding the mechanisms behind this bidirectional interaction holds great potential for the development of novel therapeutic approaches limiting neuroinflammation and promoting myelin repair. A better understanding of the central nervous system's immune-stem cell axis will also be key for tackling two important features shared across neurodegenerative diseases, neuroinflammation and myelin loss.

Differences between childhood- and adulthood-onset eosinophilic esophagitis: An analysis from the EoE connect registry.

BACKGROUND: Direct comparisons of childhood- and adulthood-onset eosinophilic esophagitis (EoE) are scarce. AIM: To compare disease characteristics, endoscopic and histological features, allergic concomitances and therapeutic choices across ages. METHODS: Cross-sectional analysis of the EoE CONNECT registry. RESULTS: The adulthood-onset cohort (those diagnosed at ≥18y) comprised 1044 patients and the childhood-onset cohort (patients diagnosed at <18 y), 254. Vomiting, nausea, chest and abdominal pain, weight loss, slow eating and food aversion were significantly more frequent in children; dysphagia, food bolus impaction and heartburn predominated in adults. A family history of EoE was present in 16% of pediatric and 8.2% of adult patients (p<0.001). Concomitant atopic diseases did not vary across ages. Median±IQR diagnostic delay (years) from symptom onset was higher in adults (2.7 ± 6.1) than in children (1 ± 2.1; p<0.001). Esophageal strictures and rings predominated in adults (p<0.001), who underwent esophageal dilation more commonly (p = 0.011). Inflammatory EoE phenotypes were more common in children (p = 0.001), who also presented higher eosinophil counts in biopsies (p = 0.015) and EREFS scores (p = 0.017). Despite PPI predominating as initial therapy in all cohorts, dietary therapy and swallowed topical corticosteroids were more frequently prescribed in children (p<0.001). CONCLUSIONS: Childhood-onset EoE has differential characteristics compared with adulthood-onset, but similar response to treatment.

Is Activation the Active Ingredient of Transdiagnostic Therapies? A Randomized Clinical Trial of Behavioral Activation, Acceptance and Commitment Therapy, and Transdiagnostic Cognitive-Behavioral Therapy for Emotional Disorders.

Studying the usefulness of contextual and cognitive transdiagnostic therapies calls for an analysis of both their differential efficacy and their specificity when acting on the transdiagnostic conditions on which they focus. This controlled trial compares the post-treatment and 3- and 6-month follow-up effects of Behavioral Activation (BA), Acceptance and Commitment Therapy (ACT) and Cognitive-Behavioral Transdiagnostic Therapy (TD-CBT) on emotional symptomatology, and analyses the role played by Experiential Avoidance, Cognitive Fusion, Activation and Emotion Regulation in the clinical change. One hundred twenty-eight patients who fulfilled diagnostic criteria for anxiety and/or depression (intention-to-treat sample) were randomly assigned to three experimental group-treatment conditions (BA, n = 34; ACT, n = 27; TD-CBT n = 33) and one control group (WL, n = 34). Ninety-nine (77.34%) completed the treatment (per-protocol sample). In the post-treatment, all therapies reduced anxiety and depression symptomatology. In the follow-ups, the reduction in emotional symptomatology was greater in the condition which produced greater and more prolonged effects on Activation. Activation appears to be the principal condition in modifying all the transdiagnostic patterns and BA was the most efficacious and specific treatment. The trial was registered at ClinicalTrials.gov NCT04117464. Raw data are available online http://dx.doi.org/10.17632/krj3w2hfsj.1.

Type I interferon subtypes differentially activate the anti-leukaemic function of natural killer cells.

Natural killer (NK) cells have an intrinsic ability to detect and eliminate leukaemic cells. Cellular therapies using cytokine-activated NK cells have emerged as promising treatments for patients with advanced leukaemia. However, not all patients respond to current NK cell therapies, and thus improvements in efficacy are required. Type I interferons (IFN-I) are a family of potent immunomodulatory cytokines with a known ability to modulate NK cell responses against cancer. Although the human IFN-I family comprises 16 distinct subtypes, only IFNα2 has been widely explored as an anti-cancer agent. Here, we investigated the individual immunomodulatory effects each IFNα subtype and IFNß had on NK cell functionality to determine whether a particular subtype confers enhanced effector activity against leukaemia. Importantly, IFNα14 and IFNß were identified as superior activators of NK cell effector function in vitro. To test the ability of these subtypes to enhance NK cell activity in vivo, IFN-I stimulation was overlaid onto a standard ex vivo expansion protocol to generate NK cells for adoptive cell therapy. Interestingly, infusion of NK cells pre-activated with IFNα14, but not IFNß, significantly prolonged survival in a preclinical model of leukaemia compared to NK cells expanded without IFN-I. Collectively, these results highlight the diverse immunomodulatory potencies of individual IFN-I subtypes and support further investigation into the use of IFNα14 to favourably modulate NK cells against leukaemia.

Long-term sex-dependent inflammatory response of adult frogs to ammonium exposure during the larval stage.

Among others, the global change involves a worldwide increase in cropland area, with the concomitant rise in nitrogenous fertilizer supplementation and species range alterations, including parasites and pathogens. As most animals rely on their immune systems against these infectious agents, studying the potential effects of nitrogenous compounds on animal immune response is vital to understand their susceptibility to infections under these altered circumstances. Being subjected to an alarming process of global declines, amphibians are the object of particular attention, given their sensitivity to these compounds, especially to ammonium. Moreover, whereas adults can actively avoid polluted patches, larvae are confined within their waterbodies, thus exposed to contaminants in it. In this work, we test whether chronic exposure to a sublethal dose of ammonium during the larval stage of Pelophylax perezi frogs, released from all contamination after metamorphosis, leads to impaired inflammatory response to phytohemagglutinin in adults. We also test whether such a response differs between agrosystem individuals as compared with conspecifics from natural habitats. We found negative carryover effects of chronic exposure of larvae to ammonium on adult inflammatory response, which could imply a greater susceptibility to pathogens and parasites. However, this damage is only true for males, which, according to the immunocompetence handicap hypothesis, could be a consequence of a testosterone-triggered impairment of male immune function. In disagreement with our prediction, however, we detected no differences in the inflammatory response of agrosystem frogs to phytohemagglutinin as compared with natural habitat conspecifics.

Characterization of Eosinophilic Esophagitis From the European Pediatric Eosinophilic Esophagitis Registry (pEEr) of ESPGHAN.

OBJECTIVES: Few pediatric data on phenotypic aspects of eosinophilic esophagitis (EoE) are available. The pEEr registry was developed to prospectively characterize children with EoE from Europe and Israel. METHODS: pEEr is an ongoing prospective registry enrolling children with esophageal eosinophilia (≥15 eos/HPF). Anonymized data were collected from 19 pediatric centers. Data regarding demographics, clinical manifestations, endoscopy, histology, and therapies were collected. RESULTS: A total of 582 subjects (61% male) were analyzed. The median age at diagnosis was 10.5 years [interquartile range (IQR): 5.7-17.7], whereas the age at symptom onset was 9.2 years (IQR: 4.3-16.4), resulting in a median diagnostic delay of 1.2 years (IQR: 0.7-2.3). The diagnostic delay was longer below age <6 years. Shorter diagnostic delays were associated with the presence of food allergy or a family history for EoE. Symptoms varied by age with dysphagia and food impaction more common in adolescents, while vomiting and failure to thrive more common in younger children ( P < 0.001). Among endoscopic findings, esophageal rings were more common in adolescents, whereas exudates were more frequent in younger children( P < 0.001). Patients who responded to proton pump inhibitors (PPIs) were more likely to be older, males, and less often presented severe endoscopic findings. Patients unresponsive to PPIs received topical steroids (40%), elimination diet (41%), or a combined therapy (19%). CONCLUSIONS: EoE findings vary according to age in pediatric EoE. Young children are commonly characterized by non-specific symptoms, atopic dermatitis, food allergy, and inflammatory endoscopic lesions. Adolescents usually have dysphagia or food impaction, fibrostenotic lesions, and a better PPI response.