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Background: There is scarcity of data on the incidence and factors associated with the occurrence of ocular lesions in critically ill children., Aim: Test the applicability and utility of an ocular assessment scale and to identify risk factors of ocular lesions., Study Design: Prospective observational study. A tertiary care medical-surgical Paediatric Intensive Care Unit. 194 children without previous ocular disease who stayed in the Paediatric Intensive Care Unit for more than 48 h. An ocular lesions risk scale was designed including risk factors lagophthalmos, eye dryness, conjunctival hyperemia, slow blinking, intubation, sedation, relaxation, face mask and hemodynamic instability. Patients were classified as high-, medium-, and low-risk patients. Corneal lesions were examined by fluorescein staining according to their risk and were confirmed by an ophthalmologist., Results: 76 patients were examined with fluorescein staining. Thirty-two ocular lesions were detected by nursing staff, 26 confirmed by the ophthalmologist. 53.6% of the high-risk patients developed a corneal lesion. Univariate analysis revealed an association between ocular damage and all factors included in the scale, except for face mask. In the multivariate analysis, ocular lesions were associated with lagophthalmos, hyperemia, invasive mechanical ventilation and inotropic support., Conclusions: The scale was useful to detect corneal lesions in critically ill children. The identification of risk factors will enable the development of measures to reduce the incidence of ocular lesions., Relevance for Clinical Practice: A new, non-validated scale allowed staff to detect eye injuries, study this problem and improve future prevention., (© 2023 The Authors. Nursing in Critical Care published by John Wiley & Sons Ltd on behalf of British Association of Critical Care Nurses.)

Background: Platelets are essential for hemostasis and thrombosis and play vital roles during metastatic cancer progression and infection. Hallmarks of platelet function are activation, cytoskeletal rearrangements, and the degranulation of their cellular contents upon stimulation. While α-granules and dense granules are the most studied platelet secretory granules, the dense tubular system (DTS) also functions as a secretory system for vascular thiol isomerases. However, how DTS cargo is packaged and transported from megakaryocytes (MKs) to platelets is poorly understood., Objectives: To underpin the mechanisms responsible for DTS cargo transport and leverage those for therapeutic protein packaging into platelets., Methods: A retroviral expression system combined with immunofluorescence confocal microscopy was employed to track protein DTS cargo protein disulfide isomerase fused to enhanced green fluorescent protein (eGFP-PDI) during platelet production. Murine bone marrow transplantation models were used to determine the release of therapeutic proteins from platelets., Results: We demonstrated that the endoplasmic reticulum retrieval motif Lys-Asp-Glu-Leu (KDEL) located at the C-terminus of protein disulfide isomerase was essential for the regular transport of eGFP-PDI-containing granules. eGFP-PDI ΔKDEL , in which the retrieval signal was deleted, was aberrantly packaged, and its expression was upregulated within clathrin-coated endosomes. Finally, we found that ectopic transgenic proteins, such as tissue factor pathway inhibitor and interleukin 2, can be packaged into MKs and proplatelets by adding a KDEL retrieval sequence., Conclusion: Our data corroborate the DTS as a noncanonical secretory system in platelets and demonstrate that in vitro-generated MKs and platelets may be used as a delivery system for transgenic proteins during cellular therapy., Competing Interests: Declaration of competing interests J.E.I. has a financial interest in and is a founder of Stellular Bio, a biotechnology company focused on making donor-independent platelet-like cells at scale, and Spry Bio. Boston Children’s Hospital manages the interests of J.E.I.. R.F. is a founder of and consultant for Platelet Diagnostics. Beth Israel Deaconess Medical Center manages the interests of R.F.. All other authors declare no competing financial interests., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Introduction: In Down syndrome (DS), white matter hyperintensities (WMHs) are highly prevalent, yet their topography and association with sociodemographic data and Alzheimer's disease (AD) biomarkers remain largely unexplored., Methods: In 261 DS adults and 131 euploid controls, fluid-attenuated inversion recovery magnetic resonance imaging scans were segmented and WMHs were extracted in concentric white matter layers and lobar regions. We tested associations with AD clinical stages, sociodemographic data, cerebrospinal fluid (CSF) AD biomarkers, and gray matter (GM) volume., Results: In DS, total WMHs arose at age 43 and showed stronger associations with age than in controls. WMH volume increased along the AD continuum, particularly in periventricular regions, and frontal, parietal, and occipital lobes. Associations were found with CSF biomarkers and temporo-parietal GM volumes., Discussion: WMHs increase 10 years before AD symptom onset in DS and are closely linked with AD biomarkers and neurodegeneration. This suggests a direct connection to AD pathophysiology, independent of vascular risks., Highlights: White matter hyperintensities (WMHs) increased 10 years before Alzheimer's disease symptom onset in Down syndrome (DS). WMHs were strongly associated in DS with the neurofilament light chain biomarker. WMHs were more associated in DS with gray matter volume in parieto-temporal areas., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Narrowing, trauma, tumors, and systemic diseases can cause esophageal dysfunction. Severe cases resist traditional surgery, leading to long-term gastrostomy or jejunostomy tubes, affecting patients negatively. No established surgery ensures both airway and oral function with proper speech. This article introduces the oral-vestibule-enteral anastomosis (OVEA) technique, targeting patients with compromised epiglottic closure competence and loss of cervical esophagus, where conventional methods fall short., Methods: Technique description study evaluated in 13 patients in a single tertiary referral center in Mexico City treated with OVEA from January 1990 to July 2023., Results: Of the 13 patients (69% male; mean age, 37.14 ± 12.907 years), preoperative conditions included a mean body mass index of 17.78 ± 2.66 kg/m 2 , 46% with previous abdominal surgeries, and 31% with a smoking history. After OVEA, complications affected 46%, primarily pneumonia (23%), abscess formations (15%), intestinal necrosis (8%), and airway fistula (8%). Reoperation was needed in 38%, addressing functionality loss, necrosis, stenosis, and jawbone remodeling. No fatalities occurred within the first 6 months after surgery; 84% had successful gastrostomy tube removal, and 8% retained a tracheostomy tube. Currently 13 patients (92%) use the OVEA as their main enteral route of feeding., Conclusion: The OVEA technique seems promising for cases involving esophageal loss or impaired epiglottic function, enhancing patients' quality of life by enabling oral feeding and restoring regular eating habits. Further research should focus on long-term results and identifying optimal candidates for this innovative surgical method., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Objective: Preclinical research implicates hypothalamic inflammation (HI) in obesity and type 2 diabetes pathophysiology. However, their pathophysiological relevance and potential reversibility need to be better defined. We sought to evaluate the effect of bariatric surgery (BS) on radiological biomarkers of HI and the association between the severity of such radiological alterations and post-BS weight loss (WL) trajectories. The utility of cerebrospinal fluid large extracellular vesicles (CSF-lEVs) enriched for microglial and astrocyte markers in studying HI was also explored., Research Design and Methods: We included 72 individuals with obesity (20 with and 52 without type 2 diabetes) and 24 control individuals. Participants underwent lumbar puncture and 3-T MRI at baseline and 1-year post-BS. We assessed hypothalamic mean diffusivity (MD) (higher values indicate lesser microstructural integrity) and the volume of the whole and main hypothalamic subregions. CSF-lEVs enriched for glial and astrocyte markers were determined by flow cytometry., Results: Compared with control group, the obesity and type 2 diabetes groups showed a larger volume and higher MD in the hypothalamic tubular inferior region, the area encompassing the arcuate nucleus. These radiological alterations were positively associated with baseline anthropometric and metabolic measures and improved post-BS. A larger baseline tubular inferior hypothalamic volume was independently related to lesser WL 1 and 2 years after BS. CSF-lEVs did not differ among groups and were unrelated to WL trajectories., Conclusions: These findings suggest HI improvement after BS and may support a role for HI in modulating the WL response to these interventions., (© 2024 by the American Diabetes Association.)

Megakaryocytes (MKs) produce platelets, and like other hematopoietic progenitors they are involved in homeostatic aspects of their bone marrow niche. MKs release and endocytose various factors, such as platelet factor 4 (PF4/CXCL4). Here we show that the intra-α-granular proteoglycan, serglycin (SRGN) plays a key role in this process by retaining PF4 and perhaps other factors during MK maturation. Immature, SRGN-/- MKs released ~80% of their PF4 and conditioned media from these cells negatively affected wild-type MK differentiation in vitro. This was replicated in wild-type MKs, by treatment with the polycation surfen, a known inhibitor of glycosaminoglycan/protein interactions. In vivo, SRGN-/- mice had an interstitial accumulation of PF4, TGFβ-1, IL-1β, and TNF-α in their bone marrow and increased numbers of immature MKs, consistent with their mild thrombocytopenia. SRGN-/- mice also had reduced numbers of hematopoietic stem cells and multipotent progenitors, reduced laminin, and increased collagen I deposition. These findings demonstrate that MKs depend on SRGN and its charged glycosaminoglycans to balance the distribution of PF4 and perhaps other factors between their α-granules and their adjacent extracellular spaces. Disrupting this balance negatively affects MK development and bone marrow microenvironment homeostasis., (Copyright © 2024 American Society of Hematology.)

Malignant pleural effusion (MPE) has become an increasingly prevalent complication in oncological patients, negatively impacting their quality of life and casting a shadow over their prognosis. Owing to the pathophysiological mechanisms involved and the heterogeneous nature of the underlying disease, this entity is both a diagnostic and therapeutic challenge. Advances in the understanding of MPE have led to a shift in the treatment paradigm towards a more personalized approach. This article provides a comprehensive review and update on the pathophysiology of MPE and describes the diagnostic tools and the latest advances in the treatment of this complex clinical entity., (© 2024 Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Published by Elsevier España, S.L.U.)

Purpose: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA)., Methods: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level., Results: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R 2  = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912)., Conclusion: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset., (© 2023. The Author(s).)

Abstract: Megakaryocytes (MKs) generate thousands of platelets over their lifespan. The roles of platelets in infection and inflammation has guided an interest to the study of extramedullary thrombopoiesis and therefore MKs have been increasingly reported within the spleen and lung. However, the relative abundance of MKs in these organs compared to the bone marrow and the scale of their contribution to the platelet pool in a steady state remain controversial. We investigated the relative abundance of MKs in the adult murine bone marrow, spleen, and lung using whole-mount light-sheet and quantitative histological imaging, flow cytometry, intravital imaging, and an assessment of single-cell RNA sequencing (scRNA-seq) repositories. Flow cytometry revealed significantly higher numbers of hematopoietic stem and progenitor cells and MKs in the murine bone marrow than in spleens or perfused lungs. Two-photon intravital and light-sheet microscopy, as well as quantitative histological imaging, confirmed these findings. Moreover, ex vivo cultured MKs from the bone marrow subjected to static or microfluidic platelet production assays had a higher capacity for proplatelet formation than MKs from other organs. Analysis of previously published murine and human scRNA-seq data sets revealed that only a marginal fraction of MK-like cells can be found within the lung and most likely only marginally contribute to platelet production in the steady state., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose of Review: Single-cell RNA sequencing studies have revealed transcriptional heterogeneity within the megakaryocytic lineage and the identified unique subsets. In this review, we discuss the functional and phenotypic plasticity of these subpopulations as well as the impacts on health and disease., Recent Findings: Megakaryocytes (MKs) can be transcriptionally categorized into platelet generating, niche supporting, immune, and cycling cells, which are distinguished by their unique gene expression patterns and cellular markers. Additionally, a significant population of these cells has been established to reside in the nonhematopoietic tissues and they display enhanced immune-related characteristics. Combined with the location in which the megakaryocytes exist, these cells can play unique roles dictated by their current environment and biological needs, including responding to changes in pathogen exposure., Summary: Advances in megakaryocyte research has elucidated the existence of multiple subpopulations of MKs that serve different functions. These subpopulations implicate a greater potential for MKs to be regulators of health and suggest new avenues for treatments and therapies in related diseases., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)