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ContextTreatment options for central precocious puberty (CPP) are important for individualization of therapy.ObjectiveWe evaluated the efficacy and safety of 6-month 45-mg leuprolide acetate (LA) depot with intramuscular administration.MethodsLA depot was administered at weeks 0 and 24 to treatment-naïve (n = 27) or previously treated (n = 18) children with CPP in a phase 3, multicenter, single-arm, open-label study (NCT03695237). Week 24 peak-stimulated luteinizing hormone (LH) suppression (

AbstractAltered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here, we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the BMP type I receptor ACVR1 (ACVR1 R206H ), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although patients with FOP can harbor pathological lesions in the peripheral and central nervous system, their etiology and clinical impact are unclear. Quantitative sensory testing of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major effect of ACVR1 R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells, both intracellular and extracellular electrophysiology analyses of the ACVR1 R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1 R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.

ABSTRACT The injectisome encoded by Salmonella pathogenicity island 2 (SPI-2) had been thought to translocate 28 effectors. Here, we used a proteomic approach to characterize the secretome of a clinical strain of invasive non-typhoidal Salmonella enterica serovar Enteritidis that had been mutated to cause hyper-secretion of the SPI-2 injectisome effectors. Along with many known effectors, we discovered the novel SseM protein. sseM is widely distributed among the five subspecies of Salmonella enterica, is found in many clinically relevant serovars, and is co-transcribed with pipB2, a SPI-2 effector gene. The translocation of SseM required a functional SPI-2 injectisome. Following expression in human cells, SseM interacted with five components of the dystrophin-associated protein complex (DAPC), namely, β-2-syntrophin, utrophin/dystrophin, α-catulin, α-dystrobrevin, and β-dystrobrevin. The interaction between SseM and β-2-syntrophin and α-dystrobrevin was verified in Salmonella Typhimurium-infected cells and relied on the postsynaptic density-95/discs large/zonula occludens-1 (PDZ) domain of β-2-syntrophin and a sequence corresponding to a PDZ-binding motif (PBM) in SseM. A ΔsseM mutant strain had a small competitive advantage over the wild-type strain in the S. Typhimurium/mouse model of systemic disease. This phenotype was complemented by a plasmid expressing wild-type SseM from S. Typhimurium or S. Enteritidis and was dependent on the PBM of SseM. Therefore, a PBM within a Salmonella effector mediates interactions with the DAPC and modulates the systemic growth of bacteria in mice. Furthermore, the ΔsseM mutant strain displayed enhanced replication in bone marrow-derived macrophages, demonstrating that SseM restrains intracellular bacterial growth to modulate Salmonella virulence.IMPORTANCEIn Salmonella enterica, the injectisome machinery encoded by Salmonella pathogenicity island 2 (SPI-2) is conserved among the five subspecies and delivers proteins (effectors) into host cells, which are required for Salmonella virulence. The identification and functional characterization of SPI-2 injectisome effectors advance our understanding of the interplay between Salmonella and its host(s). Using an optimized method for preparing secreted proteins and a clinical isolate of the invasive non-typhoidal Salmonella enterica serovar Enteritidis strain D24359, we identified 22 known SPI-2 injectisome effectors and one new effector—SseM. SseM modulates bacterial growth during murine infection and has a sequence corresponding to a postsynaptic density-95/discs large/zonula occludens-1 (PDZ)-binding motif that is essential for interaction with the PDZ-containing host protein β-2-syntrophin and other components of the dystrophin-associated protein complex (DAPC). To our knowledge, SseM is unique among Salmonella effectors in containing a functional PDZ-binding motif and is the first bacterial protein to target the DAPC.

Antecedentes: La prevalencia de desnutrición en niños con cáncer oscila entre el 10.8 y el 76% acorde al estadio de enfermedad y a los parámetros para evaluarlo. Objetivo: Evaluar el estado de nutrición a través de la prevalencia de bajo peso y baja talla y su relación con la edad en niños y adolescentes con diagnóstico de cáncer en el tercer nivel de atención. Material y métodos: Pacientes ingresados entre 2018 y 2023 al Centro Oncológico Pediátrico del Centro Médico ABC. Variables dependientes: bajo peso para la edad, bajo peso para talla y baja talla. La independiente: tipo de cáncer. Se estimaron prevalencias, se aplica la prueba de U Mann Whitney y se calcularon OR. El nivel de significancia estadística de < 0.05. Resultados: La muestra es de 80 niños y adolescentes. El 58.75% (n = 47) son del sexo masculino. El 68.8% (55) son casos con tumores sólidos y el 31.3% (25), neoplasias hematológicas. Las prevalencias de bajo peso, bajo peso para talla y baja talla: 33.8%, 30% y 13.8%. En el grupo de niños de 10 años y menos la mediana del percentil peso/talla es inferior a la del grupo de mayores de 10 años (p = 0.017). Los niños con bajo peso tienen 12,750 veces más riesgo de tener baja talla (IC95%: 2.513-64.655). Conclusión: La prevalencia de bajo peso y baja talla en niños y adolescentes con cáncer al momento del diagnóstico es elevada. Es importante diseñar estrategias para optimizar el tratamiento y el pronóstico del paciente.

Abstract Antimicrobial resistant Salmonella enterica serovar Concord (S. Concord) is known to cause severe gastrointestinal and bloodstream infections in patients from Ethiopia and Ethiopian adoptees, and occasional records exist of S. Concord linked to other countries. The evolution and geographical distribution of S. Concord remained unclear. Here, we provide a genomic overview of the population structure and antimicrobial resistance (AMR) of S. Concord by analysing genomes from 284 historical and contemporary isolates obtained between 1944 and 2022 across the globe. We demonstrate that S. Concord is a polyphyletic serovar distributed among three Salmonella super-lineages. Super-lineage A is composed of eight S. Concord lineages, of which four are associated with multiple countries and low levels of AMR. Other lineages are restricted to Ethiopia and horizontally acquired resistance to most antimicrobials used for treating invasive Salmonella infections in low- and middle-income countries. By reconstructing complete genomes for 10 representative strains, we demonstrate the presence of AMR markers integrated in structurally diverse IncHI2 and IncA/C2 plasmids, and/or the chromosome. Molecular surveillance of pathogens such as S. Concord supports the understanding of AMR and the multi-sector response to the global AMR threat. This study provides a comprehensive baseline data set essential for future molecular surveillance.

BackgroundThe developmental fates of offspring have the potential to be influenced by the identity of their care-givers and by the nature of the care that they receive. In animals that exhibit both parental and alloparental care, such as the annually eusocial insects, the influence of care-giver identity can be directly assessed to yield mechanistic and evolutionary insights into the origins and elaboration of brood care. Here, we performed a comparative investigation of maternal and worker brood care in bumble bees, a pollinator group where mothers (queens) rear the first offspring in the nest, and then daughters (workers) assume this role upon their emergence. Specifically, we compared the effects of queen and worker brood care on offspring development and also offspring performance, for a set of traits related to sensory biology, learning, and stress resistance.ResultsWe found that queen-reared workers were smaller-bodied than worker-reared offspring, suggesting that bumble bee queens influence body size determination in their offspring. We also found that queen-reared workers were more resistant to starvation, which might be beneficial for early nesting success. These maternal influences could not be explained by feeding rate, given that we detected a similar offspring feeding frequency in both queens and workers.ConclusionBumble bee queens have a unique influence on the development of the first offspring in the nest, which they rear, relative to worker-reared workers. We propose that bumble bee brood care has been shaped by a suite of evolutionary and ecological factors, which might include a maternal influence on traits that promote survival of incipient colonies.

Antecedentes: La educación médica puede dificultar que los estudiantes realicen acciones para mejorar su salud. Objetivo: Evaluar la influencia del contexto universitario en los comportamientos de autocuidado y la calidad de vida. Material y métodos: Se empleó un enfoque de métodos mixtos, combinando encuestas para evaluar el autocuidado y la calidad de vida, con entrevistas en profundidad para explorar influencias culturales y percepciones. Se llevaron a cabo análisis estadísticos y codificación de datos cualitativos; los métodos se integraron a través del análisis de redes. Resultados: Las puntuaciones de autocuidado superaron los 50 puntos y las de calidad de vida, los 60 puntos. El contexto de los estudiantes de medicina está moldeado por motivaciones, expectativas, habilidades y metas que influyen en la formación de la identidad y contribuyen a la profesión médica. Conclusiones: Existe una conexión positiva entre prácticas de autocuidado y la calidad de vida; sin embargo, el estrés académico pueden interrumpir potencialmente las rutinas de autocuidado. Además, se destaca la asociación entre la obesidad y la afectación en la calidad de vida, lo que enfatiza la necesidad de acciones de promoción de la salud.

This article presents findings from a Youth Participatory Action Research (YPAR) study on the experiences of six undocumented college students at a community college in the Midwest United States. We focused on two main research questions: What are some of the key developmental experiences of undocumented youth? What is the impact of these experiences on the students' identity and sense of belonging in educational spaces, especially as they transition to college? The findings illustrate the experiences of the six participant coresearchers (PCRs) as they navigated the messy, fragile, and shifting nature of belonging. A common thread in their narratives was the recurrence across their young lives of moments of dislocation (or "being-out-of-place") associated with their undocumented status. These moments of dislocation barred these undocumented students from fully inhabiting both educational and noneducational spaces; in addition, they affected their ability to develop a sense of belonging as they transitioned to the college environment. Dislocation entails a degree of vulnerability and liminality that is not necessarily encompassed in current models of student development theory, nor considered in institutional support structures created with majority-population students in mind. We argue that institutional agents require sensitivity to the multiple types of dislocation that undocumented youth may experience within and beyond educational settings.

Maria Luisa Somoza1 &ast;, Natalia Pérez-Sánchez2 &ast;, Isabel Torres-Rojas,1 Laura Martín-Pedraza,3 Natalia Blanca-López,1 Laura Victorio Puche,4 Eva Abel Fernández González,5 José Damián López Sánchez,6 Javier Fernández-Sánchez,7,8 Enrique Fernández-Caldas,5,9 Mayte Villalba,10 Francisco Javier Ruano,1 José Antonio Cornejo-García11 &ast;, Gabriela Canto1,12 &ast;, Miguel Blanca3 &#x002A1Allergy Department, Infanta Leonor University Hospital, Madrid, Spain; 2Allergy Department, Hospital Regional Universitario de Málaga, Málaga-IBIMA (FIMABIS), Málaga, Spain; 3Allergy Department, Fundación para la Investigación e Innovación Biomédica (FIIB) de los Hospitales Universitarios Infanta Leonor y Sureste, Madrid, Spain; 4Allergy Department, Morales Meseguer General University Hospital, Murcia, Spain; 5R&D Department, Inmunotek Laboratories, Madrid, Spain; 6Allergy Department, Virgen de la Arrixaca Clinical University Hospital, Murcia, Spain; 7Allergy Department, General University Hospital of Alicante- ISABIAL, Alicante, Spain; 8Clinical Medicine Department, Miguel Hernandez University, Alicante, Spain; 9Division of Allergy and Immunology, University of South Florida College of Medicine, Tampa, FL, USA; 10Department of Biochemistry and Molecular Biology, Universidad Complutense de Madrid, Madrid, Spain; 11Instituto de Investigación Biomédica de Málaga-IBIMA (FIMABIS), Málaga, Spain; 12School of Medicine, Universidad Complutense de Madrid, Madrid, Spain&ast;These authors contributed equally to this workCorrespondence: Maria Luisa Somoza, Email mlsomoza@yahoo.comBackground: Allergy can start at early ages, with genetic and environmental factors contributing to its development.Aim: The study aimed to describe the pattern of sensitisation and allergy in children and adolescents of Spanish versus Moroccan ancestry but born in the same rural area of Spain.Methods: Participants were children and adolescents (3– 19 years) of Spanish or Moroccan descent, born in Blanca, Murcia (Spain). A detailed questionnaire was completed, and skin prick tests were performed to assess reactions to the most prevalent pollen allergens (O. europaea, P. pratense, S. kali, C. arizonica, P. acerifolia, A. vulgaris and P. judaica) plus molecular components Ole e 1 and Ole e 7. The association with ancestry was verified by studying participants’ parents.Results: The study included 693 participants: 48% were aged 3– 9 years and 52%, 10– 19 years; 80% were of Spanish descent and 20% of Moroccan descent. Sensitisation to Olea europaea, Phleum pratense, Salsola kali and Cupressus arizonica were slightly higher in the Spanish group. The only significant differences were observed in sensitisation to Ole e 1 (p=0.02). Rhinitis, conjunctivitis, and rhinitis plus asthma were significantly higher in the Spanish group (p=0.03, p=0.02, p=0.007, respectively). The sensitisation pattern differed between Spanish and Moroccan parents, and between Moroccan parents and their children, but not between Spanish parents and their children.Conclusion: Both environment and ancestry may influence sensitisation and symptoms. Although the environment seems to have a stronger influence, other factors may contribute to the differences in prevalence and in the clinical entities in people of Spanish versus Moroccan descent.Keywords: ancestry, pollen sensitisation, children/adolescents, olive tree pollen, molecular components, respiratory allergy

El soporte nutricional (SN) en pacientes adultos que reciben terapia de oxigenación por membrana extracorpórea (ECMO, extracorporeal membrane oxygenation) es controvertido. Si bien existen guías para el SN en pacientes pediátricos con ECMO, en adultos no se cuenta con estos lineamientos para el uso, tipo, ruta y momento de la terapia nutricional. En pacientes críticamente enfermos es bien sabido que la nutrición enteral (NE) temprana es beneficiosa, no obstante existe la posibilidad de que en pacientes con ECMO la NE temprana condicione complicaciones gastrointestinales. Asimismo, no se han establecido metas calóricas, proteicas y dosis o tipos de micronutrimentos que usar para esta población en específico, siendo un reto para el clínico encargado de brindar el SN. Aunado a esto los pacientes con ECMO son algunos de los más gravemente enfermos en las unidades de cuidados intensivos, donde la desnutrición se asocia con una mayor morbilidad y mortalidad. En cuanto al uso de nutrición parenteral (NP), no se tiene descrito si implica riesgo de falla en el circuito al momento de introducir lípidos al oxigenador. Por lo anterior es imperativa una correcta evaluación e intervención nutricional específica, realizada por expertos en el tema para mejorar el pronóstico y la calidad de vida en esta población, siendo un objetivo primordial en los cuidados de los pacientes adultos que reciben terapia de ECMO.

BackgroundInflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear.MethodsWe examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-β activated kinase 1 (TAK1), and NF-κB pathways.ResultsFOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-κB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-β production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages.ConclusionsAbnormal ACVR1 activity causes a proinflammatory state via increased NF-κB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification.

Abstract We have developed an efficient and inexpensive pipeline for streamlining large-scale collection and genome sequencing of bacterial isolates. Evaluation of this method involved a worldwide research collaboration focused on the model organism Salmonella enterica, the 10KSG consortium. Following the optimization of a logistics pipeline that involved shipping isolates as thermolysates in ambient conditions, the project assembled a diverse collection of 10,419 isolates from low- and middle-income countries. The genomes were sequenced using the LITE pipeline for library construction, with a total reagent cost of less than USD$10 per genome. Our method can be applied to other large bacterial collections to underpin global collaborations.

ABSTRACT Salmonella enterica serovar Enteritidis is one of the most commonly reported serovars of nontyphoidal Salmonella causing human disease and is responsible for both gastroenteritis and invasive nontyphoidal Salmonella (iNTS) disease worldwide. Whole-genome sequence (WGS) comparison of Salmonella Enteritidis isolates from across the world has identified three distinct clades, global epidemic, Central/East African, and West African, all of which have been implicated in epidemics: the global epidemic clade was linked to poultry-associated gastroenteritis, while the two African clades were related to iNTS disease. However, the distribution and epidemiology of these clades across Africa are poorly understood because identification of these clades currently requires whole-genome sequencing capacity. Here, we report a sensitive, time- and cost-effective real-time PCR assay capable of differentiating between the Salmonella Enteritidis clades to facilitate surveillance and to inform public health responses. The assay described here is limited to previously confirmed S. Enteritidis isolates. IMPORTANCE Challenges in the diagnosis and treatment of invasive Salmonella Enteritidis bloodstream infections in sub-Saharan Africa are responsible for a case fatality rate of approximately 15%. It is important to identify distinct clades of S. Enteritidis in diagnostic laboratories in the African setting to determine the different health outcomes associated with particular outbreaks. Here, we describe the development of a high-quality molecular classification assay for clade typing of S. Enteritidis that is ideal for use in public health laboratories in resource-limited settings.

BackgroundNon-integrating episomal vectors have become an important tool for induced pluripotent stem cell reprogramming. The episomal vectors carrying the "Yamanaka reprogramming factors" (Oct4, Klf, Sox2, and L-Myc + Lin28) are critical tools for non-integrating reprogramming of cells to a pluripotent state. However, the reprogramming process remains highly stochastic, and is hampered by an inability to easily identify clones that carry the episomal vectors.MethodsWe modified the original set of vectors to express spectrally separable fluorescent proteins to allow for enrichment of transfected cells. The vectors were then tested against the standard original vectors for reprogramming efficiency and for the ability to enrich for stoichiometric ratios of factors.ResultsThe reengineered vectors allow for cell sorting based on reprogramming factor expression. We show that these vectors can assist in tracking episomal expression in individual cells and can select the reprogramming factor dosage.ConclusionsTogether, these modified vectors are a useful tool for understanding the reprogramming process and improving induced pluripotent stem cell isolation efficiency.

Hay condiciones que resultan en la obstrucción o lesión del sistema linfático y que llevan a una filtración de la linfa a las cavidades subyacentes, dando lugar al llenado del espacio peritoneal, condicionando la aparición de ascitis quilosa (AQ). Las causas principales en adultos son las lesiones quirúrgicas, obstrucción, compresión extrínseca del sistema linfático, infección, cirrosis, enfermedades inflamatorias y tumores benignos o malignos. Existen diversos métodos diagnósticos como la paracentesis, citología del líquido ascítico, biopsia peritoneal, laparoscopia, así como estudios de imagen para complementar el diagnóstico.

Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment.sup.1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis.sup.3-5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions.sup.1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8.sup.+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions. Single-cell RNA sequencing and imaging of macrophages in human non-small cell lung cancer and in a mouse model of lung adenocarcinoma show that tissue-resident macrophages have a key role in early tumour progression., Author(s): María Casanova-Acebes [sup.1] [sup.2] [sup.3] [sup.19] , Erica Dalla [sup.4] [sup.5] [sup.6] [sup.7] , Andrew M. Leader [sup.1] [sup.2] [sup.3] , Jessica LeBerichel [sup.1] [sup.2] [sup.3] , Jovan Nikolic [...]

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