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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.)

Over the last decade, ultrasonography has taken on an increasingly important role in the daily management of critically patients and has recently been proposed as a means of measuring muscle volume and architecture. This study had two main aims: to monitor for the onset of muscle atrophy in mechanically ventilated pediatric patients during stays in a pediatric intensive care unit based on quadriceps femoris muscle thickness measurements and to study whether demographic and clinical variables have an impact on muscle loss in critically children. The study followed a prospective, observational, single-center design. The sample included all children admitted to our pediatric intensive care unit (PICU) who required mechanical ventilation for more than 48 h. Two trained clinicians measured the thickness of the quadriceps using a 12-MHz linear ultrasound transducer within 24 h of initiating invasive mechanical ventilation and again at 72 h, 1 week, and weekly thereafter until extubation. For the entire cohort, quadriceps femoris muscle thickness decreased by 4.67% on average (IQR = -13.4 to -0.59) between the first two assessments and 13% by the time of the final measurement (IQR = -24 to -0.5%) or 1.57%/day (p < 0.001). Approximately half of all the children (23/41; 56%) experienced muscle atrophy (defined a priori as a decrease in thickness of 10% or more). Bivariate analyses revealed that increasing age, being a child (vs. infant), cumulative energy and protein deficit, highest C-reactive protein value, exposure to neuromuscular blockers, and a longer stay in the PICU were all predictive of a greater decrease in thickness. In a multivariate model, exposure to neuromuscular blockers was linked with greater muscle loss.       Conclusion: In mechanically ventilated children, point-of-care ultrasonography can identify skeletal muscle atrophy. Muscle atrophy of limbs is strongly associated with the use of neuromuscular blockers. Ultrasound-based monitoring of the quadriceps femoris is a clinically useful tool for assessing muscle mass that can provide information on nutritional status and guide rehabilitation. What is Known: • ICU-acquired muscle atrophy is common and has a deleterious effect on adult outcomes. The prevalence and severity of muscular atrophy in critically ill children, however, are poorly understood. • Point-of-care ultrasonography has been put forward as an accurate, reliable method for monitoring variations in muscle mass.. What is New: • The quadriceps femoris muscle tends to suffer an intense loss of thickness early on in most critically ill children. • Quadriceps femoris ultrasound monitoring is a helpful tool for measuring muscle thickness and could lead to the development of novel therapies for critically ill children., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A 3-month-old male infant was admitted to our unit due to acute decompensation of chronic kidney disease of unknown etiology. Further investigation led to the diagnosis of primary hyperoxaluria type 1. As the patient did not recover, hemodialysis was initiated with a non-tunneled femoral catheter. A tunneled Hickman catheter was placed in the internal jugular vein. The patient experienced moderate intradialytic exit-site bleeding and catheter malfunction, which initially responded to pressure and postural changes. During the third session, the patient suffered cardiopulmonary arrest. After stabilization, a chest hematoma was identified. Fluoroscopy revealed a catheter breakage. Despite initial stabilization, the patient developed septic shock due to Pseudomonas aeruginosa and died several days later. Hemodialysis is sometimes necessary in children under 24 months with chronic kidney disease. Vascular access is a major challenge in these patients due to lack of appropriate catheter sizes and high complication rates. Hemodialysis catheter fracture is an uncommon complication, and diagnosis can be difficult when the breakage involves the subcutaneous segment. Persistent intradialytic bleeding and mechanical malfunction should raise suspicion of this complication and should elicit catheter revision under fluoroscopy. Without prompt diagnosis, catheter breakage may have fatal consequences, as in our case., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The COVID-19 pandemic exposed the health equity gap between and within countries. Western countries were the first to receive vaccines and mortality was higher among socially deprived, minority and indigenous populations. Surprisingly, many sub-Saharan countries reported low excess mortalities. These countries share experiences with community organization and participation in health. The aim of this article was to analyse if and how this central role of people can promote a successful pandemic response., Methods: This analysis was partly based on local and national experiences shared during an international and Latin American conference on person-and people-centred care in 2021. Additionally, excess mortality data and pandemic control-relevant data, as well as literature on the pandemic response of countries with an unexpected low excess mortality were consulted., Results: Togo, Mongolia, Thailand and Kenya had a seven times lower mean excess mortality for 2020 and 2021 than the United States of America. More successful pandemic responses were observed in settings with experience in managing epidemics like Ebola and HIV, well-established community networks, a national philosophy of mutual aid, financial government assistance, more human resources for primary care and paid community health workers., Discussion: Since trust in authorities and health needs vary greatly, local strategies are needed to complement national and international pandemic responses. Three key levers were identified to promote locally-tailored pandemic management: well-organized communities, community-oriented primary care, and health information systems. An organized community structure stems from a shared ethical understanding of humanity as being interconnected with each other and the environment. This structure facilitates mutual aid and participation in decision making. Community-oriented primary care includes attention for collective community health and ways to improve health from its roots. A health information system supports collective health and health equity analysis by presenting health needs stratified for social deprivation, ethnicity, and community circumstances., Conclusions: The difference in excess mortality between countries during the COVID-19 pandemic and various country experiences demonstrate the potential of the levers in promoting a more just and effective health emergency response. These same levers and strategies can promote more inclusive and socially just health systems., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: In renal transplant recipients, compliance with medical therapy is vital. Non-adherence is considered a risk factor for worst outcomes in kidney recipients, with attributed outcomes of 64% for graft loss and 80% for late acute rejection. Most literature defines adherence as self-based immunosuppression compliance but does not consider other relevant factors such as consult and procedure compliance. Therefore, this study aims to describe adherence prevalence in kidney transplant recipients and the factors related to non-adherence., Methods: This cross-sectional study included 1030 renal transplant patients followed by Colombiana de Trasplantes between January 2019 and July 2021. Sociodemographic and clinical variables were obtained based on clinical records. The mental-health group diagnosed holistic adherence in a semi-structured interview. The diagnosis considered medication intake failure, frequency and number of failures to medical controls or other procedures, suspicious non-adherence behaviors, and serum levels of immunosuppressants. A bivariate followed a descriptive analysis, and a forward logistic regression was performed for non-adherence., Results: Patients had a median of 47 years, and 58.1% were male. Non-adherence was presented in 30.7% of patients. The non-adherence patients were younger, with a higher prevalence of males, single, divided transplant care, had a longer time after transplantation, psychopathological diagnosis, and more reinforcement education by only nursing. Older age and multidisciplinary reinforcement education were protective factors. On the other hand, poor social support, psychopathology diagnosis, and longer time after transplant presented as non-adherence risk factors., Conclusion: Holistic non-adherence was diagnosed in approximately one-third of renal transplant recipients. Its definition included more than just medication non-compliance and could identify more non-adherent patients. Notably, there is a need to consider the related factors in the health follow-up and encourage future research in modifiable factor interventions aiming to increase adherence and achieve better outcomes for renal transplant patients., Competing Interests: The authors declare that there are no conflicts of interest in this work., (© 2023 Torres-Gutiérrez et al.)

Objective: To analyse the prognostic ability of the maximum standardised uptake value (SUV max ) on local disease control in patients with oropharyngeal carcinoma treated with radiotherapy., Material and Methods: Retrospective study of 105 patients with oropharyngeal carcinomas treated with radiotherapy, including chemo- and bio-radiotherapy, and who had a PET-CT scan prior to the start of treatment., Result: Patients with a SUV max value higher than 17.2 at the primary tumour site had a significantly higher risk of local recurrence. The 5-year local recurrence-free survival for patients with SUV max less than or equal to 17.2 (n = 71) was 86.5% (95% CI 78.2-94.7 %), and for patients with SUV max greater than 17.2 (n = 34) it was 55.8% (95% CI 36.0-75.6 %) (P = 0.0001). This difference in local control was maintained regardless of patients' HPV status. Specific survival was similarly lower for patients with a SUV greater than 17.2. The 5-year specific survival for patients with SUV max greater than 17.2 was 39.5% (95% CI: 20.6-58.3 %), significantly shorter than that of patients with SUV max equal to or less than 17.2, which was 77.3% (95% CI: 66.9-87.6 %) (P = 0.0001)., Conclusions: Patients with oropharyngeal carcinomas treated with radiotherapy with a SUV max greater than 17.2 at the level of the primary tumour site had a significantly higher risk of local recurrence., (Copyright © 2022 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Published by Elsevier España, S.L.U. All rights reserved.)

Individuals with pre-manifest and early symptomatic Huntington's disease (HD) have shown deficits in solving arithmetic word-problems. However, the neural correlates of these deficits in HD are poorly understood. We explored the structural (gray-matter volume; GMV) and metabolic (18F-FDG PET; SUVr) brain correlates of arithmetic performance using the recently developed HD-word problem arithmetic task (HD-WPA) in seventeen preHD and sixteen HD individuals. Symptomatic participants showed significantly lower scores in the HD-WPA than preHD participants. Lower performance in the HD-WPA was associated with reduced GMV in subcortical, medial frontal, and several posterior-cortical clusters in HD participants. No significant GMV loss was found in preHD participants. 18F-FDG data revealed a widespread pattern of hypometabolism in association with lower arithmetic performance in all participants. In preHD participants, this pattern was restricted to the ventrolateral and orbital prefrontal cortex, the insula, and the precentral gyrus. In HD participants, the pattern extended to several parietal-temporal regions. Word-problem solving arithmetic deficits in HD is subserved by a pattern of asynchronous metabolic and structural compromise across the cerebral cortex as a function of disease stage. In preHD individuals, arithmetic deficits were associated with prefrontal alterations, whereas in symptomatic HD patients, more severe arithmetic deficits are associated with the compromise of several frontal-subcortical and temporo-parietal regions. Our results support the hypothesis that cognitive deficits in HD are not exclusively dominated by frontal-striatal dysfunctions but also involve fronto-temporal and parieto-occipital damage., (© 2023 Wiley Periodicals LLC.)

The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-β 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-β 42/amyloid-β 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine., Competing Interests: O.B. reported receiving personal fees from ADx NeuroSciences outside the submitted work. H.Z. declares that he has served on scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside the submitted work. K.B. declares that he has served as a consultant, on advisory boards, or data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Pharmatrophix, Prothena, Roche Diagnostics and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside the submitted work. D.A. reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica and Esteve, outside the submitted work. A.L. has served as a consultant or on advisory boards for Fujirebio-Europe, Roche, Biogen and Nutricia, outside the submitted work. J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Novartis, Lundbeck, Roche, Fujirebio and Biogen, outside the submitted work. 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Before Euro-American settlement, many Native American nations intercropped maize ( Zea mays ), beans ( Phaseolus vulgaris ), and squash ( Cucurbita pepo ) in what is colloquially called the "Three Sisters." Here we review the historic importance and consequences of rejuvenation of Three Sisters intercropping (3SI), outline a framework to engage Native growers in community science with positive feedbacks to university research, and present preliminary findings from ethnography and a randomized, replicated 3SI experiment. We developed mutually beneficial collaborative research agendas with four Midwestern US Native American nations. Ethnographic data highlighted a culturally based respect for 3SI as living beings, the importance it holds for all cultural facets of these Native nations, and the critical impact the practice has on environmental sustainability. One concern expressed by Native growers during ethnographic research was improving soil health-part of the rationale for establishing the 3SI agronomic experiment. To address this, we collaboratively designed a 3SI experiment. After 1 year, 3SI increased short-term soil respiration by 24%, decreased salt-extractable nitrate by 54%, had no effect on soil microbial biomass (but increased its carbon-to-nitrogen ratio by 32%) compared to the average of monoculture crops. The overarching purpose of this collaborative project is to develop a deeper understanding of 3SI, its cultural importance to Native communities, and how reinvigorating the practice-and intercropping in general-can make agroecosystems more sustainable for people and the environment., (© The Author(s) 2022.)

Background: In recent years, neuroimaging with deep learning (DL) algorithms have made remarkable advances in the diagnosis of neurodegenerative disorders. However, applying DL in different medical domains is usually challenged by lack of labeled data. To address this challenge, transfer learning (TL) has been applied to use state-of-the-art convolution neural networks pre-trained on natural images. Yet, there are differences in characteristics between medical and natural images, also image classification and targeted medical diagnosis tasks. The purpose of this study is to investigate the performance of specialized and TL in the classification of neurodegenerative disorders using 3D volumes of 18F-FDG-PET brain scans., Results: Results show that TL models are suboptimal for classification of neurodegenerative disorders, especially when the objective is to separate more than two disorders. Additionally, specialized CNN model provides better interpretations of predicted diagnosis., Conclusions: TL can indeed lead to superior performance on binary classification in timely and data efficient manner, yet for detecting more than a single disorder, TL models do not perform well. Additionally, custom 3D model performs comparably to TL models for binary classification, and interestingly perform better for diagnosis of multiple disorders. The results confirm the superiority of the custom 3D-CNN in providing better explainable model compared to TL adopted ones., (© 2022. The Author(s).)

Although there is evidence that chemotherapy can have side effects on metabolism and brain function, there are few studies on the occurrence of these side effects with immunotherapy. The present study was conducted to assess whether brain metabolic changes occur in patients with malignant melanoma under immunotherapy. Thirty-nine patients after surgical intervention and with a diagnosis of malignant melanoma were retrospectively included and were divided into two groups: one group under the first-line therapy with anti-programmed cell death-1 ± anti-cytotoxic T lymphocyte antigen-4 monoclonal antibodies and the other group without any treatment after surgery, which served as a control. Basal and follow-up whole body and brain 2-[ 18 F]fluoro-2-deoxy-D-glucose ( 18 F]FDG) PET/computed tomography (CT) studies were performed. Changes in brain glucose metabolism after treatment initiation of the immunotherapy group were compared with the findings in the control group. In addition, longitudinal regression analysis to investigate whether the time under immunotherapy influenced the changes of brain metabolism was performed. None of the patients presented cognitive impairment or other neurological alterations between basal and follow-up brain [ 18 F]FDG PET/CT examinations. The statistical analysis revealed a significant relative SUV (SUVr)-loss in the left frontal region in patients of the immunotherapy group compared with the control group, with radjusted = -0.62 and P = 0.008. Severity of SUVr-loss was correlated with duration of treatment. Patients with disseminated malignant melanoma receiving immunotherapy may present a decrease of brain metabolism in the left frontal region, which is related with time-under-treatment, without any clinical evidence of neurological disorder., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Some oral lesions have been described in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); the possibility has been raised that the buccal lesions observed in patients with the coronavirus disease 2019 (COVID-19) are due to this virus and the patient's systemic condition. The aim of this review was to integrate the knowledge related to the oral lesions associated with COVID-19 and the participation of the buccal cavity in the establishment of immunity against SARS-CoV-2., Methods: A literature search on the manifestations of buccal lesions from the beginning of the pandemic until October 2021 was carried out by using the PubMed database. A total of 157 scientific articles were selected from the library, which included case reports and reports of lesions appearing in patients with COVID-19., Results: Oral lesions included erosions, ulcers, vesicles, pustules, plaques, depapillated tongue, and pigmentations, among others. The oral cavity is a conducive environment for the interaction of SARS-CoV-2 with the mucosal immune system and target cells; direct effects of the virus in this cavity worsen the antiviral inflammatory response of underlying oral disorders, immunodeficiencies, and autoimmunity primarily., Conclusions: The oral cavity is an accessible and privileged environment for the interaction of SARS-CoV-2 with the mucosal immune system and target cells; the direct effects of the virus in this cavity worsen the antiviral inflammatory response of underlying oral disorders, in particular those related to immunodeficiencies and autoimmunity.

Aim: to assess if the use of an audiovisual intervention in the uptake room and/or in the scanning room, could help to reduce anxiety during [18F]FDG PET/CT imaging., Methods: We prospectively studied 120 patients referred for [18F]FDG PET/CT imaging. Patients were allocated in 4 groups of 30 patients depending on the use of the audiovisual intervention: (1) no audiovisual intervention; (2) audiovisual intervention only in the uptake room; (3) audiovisual intervention only in the scanning room; (4) audiovisual intervention in the uptake and the scanning rooms. In order to measure the anxiety levels of the patients before and after the scan, all patients answered the State-Trait Anxiety Inventory (STAI)., Results: The anxiety status across typical situations on a daily basis (STAI-T) of the 4 groups of patients was comparable with no significant differences. The mean State Anxiety (STAI-S) sum-score at prescan and postscan among groups was: (1) 17.5±8.7 vs. 17.3±8.6, p=0.834; (2) 17.4±10.5 vs. 15.8±9.6, p=0.110; (3) 17.5±11.7 vs. 15.1±9.8, p= 0.013; (4) 17.4±9.7 vs. 14.9±8.1, p= 0.009. The percentage of patients with reduction of the STAI-S score among groups 1-4 was 17%, 47%, 50%, and 66%, respectively. The variation of the percentage of patients with lower scores after intervention among groups was statistically significant (p<0.001)., Conclusion: Audiovisual intervention decreases anxiety levels of patients referred for PET/CT imaging. The results of our study support a beneficial effect of the audiovisual intervention and its potential to alleviate the anxiety of oncological patients who undergo a PET/CT scan., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Autoimmune encephalitis are brain inflammatory processes that are classified into two main groups according to the underlying pathogenic mechanism: antibodies to intracellular antigens (paraneoplastic) and antibodies to extracellular or neuronal surface antigens. The clinical manifestations of autoimmune encephalitis are very varied and non-specific. Complementary tests included in its clinical diagnosis include determination of antibodies in serum or cerebrospinal fluid and magnetic resonance imaging (MRI). MRI may show characteristic patterns such as mesial temporal involvement, although in some cases it may be normal or non-specific. 18F-Fluorodeoxyglucose PET/CT (18F-FDG PET/CT) imaging may be helpful in cases of paraneoplastic autoimmune encephalitis to find the primary tumor. In autoimmune encephalitis mediated by antibodies to extracellular antigens, 18F-FDG PET/CT shows distinctive patterns that can aid clinical diagnosis. This continuing education aims to present in a clear and easy-to-understand way, the clinical features of autoimmune encephalitis, the difficulties in clinical diagnosis and the patterns seen on MRI and 18F-FDG PET/CT., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Background: The mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist., Methods: Changes in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects following the acute administration of salvinorin-A are reported. The study included 2 sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design., Results: The electroencephalography measures showed a marked increase in delta and gamma waves and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding single-photon emission computed tomography measures, significant decreases in regional cerebral blood flow were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant regional cerebral blood flow increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs but with an evidently dissociative nature. No dysphoric effects were reported., Conclusion: The salvinorin-A-mediated KOR agonism induced dramatic psychotomimetic effects along with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Purpose: The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer's disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model's performance to that of multiple expert nuclear medicine physicians' readers., Materials and Methods: Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer's disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model's performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention., Results: The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6-100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7-100) in AD, 71.4% (51.6-91.2) in MCI-AD, and 94.7% (90-99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders., Conclusion: Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus., (© 2021. The Author(s).)

Background and Aim of the Work: Expressive Writing (EW) is a useful tool for taking care of the person globally, and literature shows that self-care and self-awareness improve the coping skills of health professionals, positively increasing personal and professional satisfaction and reducing the negative aspects related to the profession, such as burnout. The objective of the research is to analyze the writings produced by healthcare professionals belonging to palliative care in a previous quantitative study to identify any changes between two sessions., Methods: It is a longitudinal qualitative research with an interpretative phenomenological methodology of analysis of documents written by professionals. The study included 50 expressive writings: 25 at Time 0 (T0) and 25 at Time 1 (T1). The analysis sample is composed of 25 professionals. All participants completed an Expressive Writing protocol homogeneous in procedure, mandate, and timing., Results: The study revealed a variation in contents from T0 to T1 highlighting both professional and intimate growth of the professionals. The practitioner appears more aware of working together to achieve a goal. Writing evolve as more spontaneous. Attention is focused on the relationship with the patient as an engine of personal and professional growth. The satisfaction is linked to the management of a complex case in its entirety., Conclusions: The investigated instrument resulted in a beneficial change in the healthcare professionals involved. Writing helps to find strategies to take care of the other, improves communication, favors the sharing of experience with the other, increasing the awareness of limitations and strengths.

Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs., (© 2021. The Author(s).)

Background: The interprofessional approach is part of the philosophy in palliative care, and its benefits are already documented. However, there are no evidence regarding the process through which the interprofessional team faces the process of the patient's end-of-life and how this experience might be of value for the team's development itself. The aim of this study was to analyse and understand the psychosocial processes that occurs when an interprofessional team accompanies patients and their families to death in palliative care, with the ultimate aim to develop a substantive theory to describe this phenomenon., Methods: A Grounded Theory method, as theorized by Strauss and Corbin, was adopted for this study. Data were collected through semi-structured interviews and then independently analysed using constant comparison analysis. Fourteen healthcare professionals - belonging to different disciplines (doctor, nurse coordinator, nurse, nurse assistant, psychologist) - were interviewed in a Northern Italy palliative care facility., Findings: The core category of this study was identified to be the process of accompaniment of the dying patient as an interprofessional ecosystem. Moreover, the results showed four main factors determining the development of the core psychosocial process: from professionals' 'Hidden Amazement' to 'Onerous Happiness' where 'Weaving of Professional Resources' and 'Work Meaning' are the underlying conditions to catalyse the process itself., Conclusion: Interprofessional care appears an essential value, which becomes the source of the team's strength when facing end-of-life experiences. Health policies and organisations should take the importance of the characteristics of the work environment more carefully. The meaning that professionals attribute to their work and to the team itself, indeed, it may have impact on the overall quality of care and contribute to sustain work engagement, even in stressful situations like end-of-life care., (© 2020 Nordic College of Caring Science.)

The immune microenvironment is a critical driver and regulator of leukemic progression and hematological disease. Recent investigations have demonstrated that multiple immune components play a central role in regulating hematopoiesis, and dysfunction at the immune cell level significantly contributes to neoplastic disease. Immune cells are acutely sensitive to remodeling by leukemic inflammatory cytokine exposure. Importantly, immune cells are the principal cytokine producers in the hematopoietic system, representing an untapped frontier for clinical interventions. Due to a proinflammatory cytokine environment, dysregulation of immune cell states is a hallmark of hematological disease and neoplasia. Malignant immune adaptations have profound effects on leukemic blast proliferation, disease propagation, and drug-resistance. Conversely, targeting the immune landscape to restore hematopoietic function and limit leukemic expansion may have significant therapeutic value. Despite the fundamental role of the immune microenvironment during the initiation, progression, and treatment response of hematological disease, a detailed examination of how leukemic cytokines alter immune cells to permit, promote, or inhibit leukemia growth is lacking. Here we outline an immune-based model of leukemic transformation and highlight how the profound effect of immune alterations on the trajectory of malignancy. The focus of this review is to summarize current knowledge about the impacts of pro- and anti-inflammatory cytokines on immune cells subsets, their modes of action, and immunotherapeutic approaches with the potential to improve clinical outcomes for patients suffering from hematological myeloid malignancies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Camacho, Kuznetsova and Welner.)

Introduction: Positron emission tomography (PET) amyloid quantification methods require magnetic resonance imaging (MRI) for spatial registration and a priori reference region to scale the images. Furthermore, different tracers have distinct thresholds for positivity. We propose the AMYQ index, a new measure of amyloid burden, to overcome these limitations., Methods: We selected 18F-amyloid scans from ADNI and Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) with the corresponding T1-MRI. A subset also had neuropathological data. PET images were normalized, and the AMYQ was calculated based on an adaptive template. We compared AMYQ with the Centiloid scale on clinical and neuropathological diagnostic performance., Results: AMYQ was related with amyloid neuropathological burden and had excellent diagnostic performance to discriminate controls from patients with Alzheimer's disease (AD) (area under the curve [AUC] = 0.86). AMYQ had a high agreement with the Centiloid scale (intraclass correlation coefficient [ICC] = 0.88) and AUC between 0.94 and 0.99 to discriminate PET positivity when using different Centiloid cutoffs., Discussion: AMYQ is a new MRI-independent index for standardizing and quantifying amyloid load across tracers., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We assessed the influence of education as a proxy of cognitive reserve and age on the dementia with Lewy bodies (DLB) metabolic pattern., Methods: Brain 18F-fluorodeoxyglucose positron emission tomography and clinical/demographic information were available in 169 probable DLB patients included in the European DLB-consortium database. Principal component analysis identified brain regions relevant to local data variance. A linear regression model was applied to generate age- and education-sensitive maps corrected for Mini-Mental State Examination score, sex (and either education or age)., Results: Age negatively covaried with metabolism in bilateral middle and superior frontal cortex, anterior and posterior cingulate, reducing the expression of the DLB-typical cingulate island sign (CIS). Education negatively covaried with metabolism in the left inferior parietal cortex and precuneus (making the CIS more prominent)., Discussion: These findings point out the importance of tailoring interpretation of DLB biomarkers considering the concomitant effect of individual, non-disease-related variables such as age and cognitive reserve., (© 2021 the Alzheimer's Association.)

Importance: Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ɛ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce., Objective: To investigate the association of the APOE ɛ4 allele with clinical and multimodal biomarkers of AD in adults with DS., Design, Setting, and Participants: This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ɛ4 allele carriers or noncarriers., Main Outcomes and Measures: Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18-labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ɛ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume., Results: Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ɛ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P = .56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ɛ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P = .02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ɛ4 allele carriers., Conclusions and Relevance: In this study, the APOE ɛ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS.

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73-0.87] and 0.92 [95% CI 0.89-0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS., (© 2021. The Author(s).)

Aim: To assess if digital PET/CT improves liver lesion detectability compared to analog PET/CT in patients with known or suspected liver metastases., Materials and Methods: We prospectively included 83 cancer patients, with one or more of these conditions: history of liver metastases, clinical risk of having liver metastases or presence of suspected liver metastases on the first of the two PET/CTs. All patients were consecutively scanned on each PET/CT on the same day after a single [18F]fluorodeoxyglucose dose injection. The order of acquisition was randomly assigned. Three nuclear medicine physicians assessed both PET/CTs by counting the foci of high uptake suspicious of liver metastases. Findings were correlated with appropriate reference standards; 19 patients were excluded from the analysis due to insufficient lesion nature confirmation. The final sample consisted of 64 patients (34 women, mean age 68 ± 12 years)., Results: As per-patient analysis, the mean number of liver lesions detected by the digital PET/CT (3.84 ± 4.25) was significantly higher than that detected by the analog PET/CT (2.91 ± 3.31); P < 0.001. Fifty-five patients had a positive PET/CT study for liver lesions. In 26/55 patients (47%), the digital PET/CT detected more lesions; 7/26 patients (27%) had detectable lesions only by the digital system and had <10 mm of diameter. Twenty-nine patients had the same number of liver lesions detected by both systems. In nine patients both PET/CT systems were negative for liver lesions., Conclusion: Digital PET/CT offers improved detectability of liver lesions over the analog PET/CT in patients with known or suspected liver metastases., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Approximately 20% of type 1 diabetes (T1D) patients have an impaired awareness of hypoglyceamia (IAH). IAH represents a risk factor for severe and recurrent hypoglycaemic events, which can lead to brain damage. Because no effective treatments are currently available to prevent IAH in this population, characterising the set of brain alterations associated with IAH may reveal novel preclinical diagnostic or therapeutic strategies. Using state-of-the art neuroimaging techniques, we compared 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake at rest between 10 T1D patients with IAH and nine patients with normal awareness of hypoglycaemia (NAH). T1D-IAH patients showed a pattern of increased FDG-PET uptake with respect to NAH patients (P < .05 corrected). Topographically, glucose metabolism was increased in the frontal and precuneus regions. Importantly, within the IAH group, this abnormal hypermetabolism correlated with IAH severity. This hypermetabolic state appeared to be unrelated to compensatory mechanisms as a result of reduced grey matter density or a neuroinflammatory state. We observed an abnormal increase in FDG-uptake in T1D patients with IAH in brain regions strongly related to cognition. Because this hypermetabolic state correlated with IAH severity, its biological characterisation could reveal new preventive or therapeutic strategies. A possible mechanism could be that glucose transport is increased in hypoglycaemia unawareness to compensate for recurrent hypoglycaemia, although this need to be confirmed in further research., (© 2020 British Society for Neuroendocrinology.)

Striatal dopamine transporter (DAT) uptake assessment through I 123 -Ioflupane Single-Pphoton Emission Computed Tomography (SPECT) provides valuable information about the dopaminergic denervation occurring in Parkinson's disease (PD). However, little is known about the clinical or biological relevance of extrastriatal DAT uptake in PD. Here, from the Parkinson's Progression Markers Initiative, we studied 623 participants (431 PD and 192 healthy controls) with available SPECT data. Even though striatal denervation was undoubtedly the imaging hallmark of PD, extrastriatal DAT uptake was also reduced in patients with PD. Topographically, widespread frontal but also temporal and posterior cortical regions showed lower DAT uptake in PD patients with respect to healthy controls. Importantly, a longitudinal voxelwise analysis confirmed an active one-year loss of extrastriatal DAT uptake within the PD group. Extrastriatal DAT uptake also correlated with the severity of motor symptoms, cognitive performance, and cerebrospinal fluid α-synuclein levels. In addition, we found an association between the Catechol-O-methyltransferase val 158 met genotype and extrastriatal DAT uptake. These results highlight the clinical and biological relevance of extrastriatal SPECT-DAT uptake in PD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The nonimmune roles of Tregs have been described in various tissues, including the BM. In this study, we comprehensively phenotyped marrow Tregs, elucidating their key features and tissue-specific functions. We show that marrow Tregs are migratory and home back to the marrow. For trafficking, marrow Tregs use S1P gradients, and disruption of this axis allows for specific targeting of the marrow Treg pool. Following Treg depletion, the function and phenotype of both mesenchymal stromal cells (MSCs) and hematopoietic stem cells (HSCs) was impaired. Transplantation also revealed that a Treg-depleted niche has a reduced capacity to support hematopoiesis. Finally, we found that marrow Tregs are high producers of IL-10 and that Treg-secreted IL-10 has direct effects on MSC function. This is the first report to our knowledge revealing that Treg-secreted IL-10 is necessary for stromal cell maintenance, and our work outlines an alternative mechanism by which this cytokine regulates hematopoiesis.

Background: Indocyanine green (ICG) fluorescence angiography (FA) was introduced to provide the real-time intraoperative evaluation of the vascular supply of anastomosis. However, further studies are required to evaluate its advantages in colorectal surgery and to know in which procedure this technology has more value. The aim of the present study is to assess the usefulness of the ICG-FA in the colorectal anastomosis evaluation and to evaluate where it is most useful depending on type of resection performed in terms of change of section line based on the ICG-FA and anastomotic leakage (AL) rates., Methods: This is a prospective study. From September 2014 to November 2018, all patients who underwent any colorectal surgical procedure with ICG-FA in our center were enrolled in the study. Based on the type of surgery, patients were grouped in 4 categories: Group A, right hemicolectomy; Group B, segmental resection of the splenic flexure; Group C, left hemicolectomy; and Group D, anterior resection of the rectum., Results: One-hundred-ninety-two unselected consecutive patients were enrolled: 67 in group A, 9 in B, 81 in C, and 35 in D. Change of section line based on ICG-FA occurred in 35 cases (18.2%): 4 in group A (6%), 1 in group B (11.1%), 21 in group C (25.9%), and 9 in group D (25.7%). ALs occurred in 5 patients (2.6%): 2 in group A (3%), 1 in C (1.2%), and 2 in D (5.7%)., Conclusions: ICG-FA leads to significantly more changes in the resection line in case of left hemicolectomy followed by anterior resection. FA is a promising optical imaging technique to reduce the AL incidence after colorectal procedures. To confirm this data, further studies with wider sample size and with an objective evaluation of the anastomotic perfusion are required.

Deep brain stimulation (DBS) has been found to be effective in treatment resistant neurological and psychiatric disorders. So far there has been only one completed trial in schizophrenia, in which seven treatment resistant patients received DBS in the subgenual anterior cingulate cortex (sgACC, N = 4) or the nucleus accumbens (NAc, N = 3); four met symptomatic response criteria over the trial period. Six patients underwent 18 F-FDG PET at baseline and after at least 6 months of stimulation. Individual patient analysis indicated that DBS to both the sgACC and NAc was associated with local and distant changes in glucose metabolism. Increments and decrements of brain activity were observed in regions that included the medial prefrontal cortex, the dorsolateral prefrontal cortex, the anterior cingulate cortex, the caudate nucleus, the NAc, the hippocampus and the thalamus. Increased activity appeared to be associated with clinical improvement. These preliminary findings suggest that DBS acts by modulating cerebral activity in the cortico-basal-thalamic-cortical circuit in patients with schizophrenia who show improvement in psychotic symptoms., Competing Interests: Declaration of competing interest All authors report no biomedical financial interest or potential conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Impulse control disorders (ICD) are a common and disrupting complication of Parkinson's disease (PD) treatment. Although their relationship with dopaminergic activity is well studied, their brain metabolic correlates are mostly unknown., Methods: In this work we studied brain metabolism using brain 18 F-FDG-PET. We performed a case-control study nested within a cohort of PD patients free of ICD at baseline to compare ICD patients right after ICD diagnosis and prior to any treatment modification with matched ICD-free patients. We also compared both PD groups with healthy controls., Results: When compared with ICD-free PD patients, PD patients with recently diagnosed ICD showed higher glucose metabolism in widespread areas comprising prefrontal cortices, both amygdalae and default mode network hubs (p < 0.05, corrected). When compared to healthy controls, they did not show hypermetabolism, and the only hypometabolic region was the right caudate. In turn, ICD-free patients showed diffuse hypometabolism when compared to healthy controls., Conclusion: Our results suggest brain metabolism is more preserved in PD patients with ICD than patients without ICD. This metabolic preservation could be related to ICD development.

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome., Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1-42 and 1-40 and their ratio (Aβ 1-42/1-40 ), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18 F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate., Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ 1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18 F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life., Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments., Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The healthcare professionals' specialized training has a positive impact on professional values, patient's outcome, and promotion of evidence-based practices. To raise the educational standard, the University of Parma has created Post Graduate Specializations which, in addition to learning sector-specific techniques and skills, include the acquisition of soft skills. Aim of the study is investigating the perception of the tutors dedicated to the organization, management, and teaching of the Post Graduate Specializations on the skills gained and the changes achieved in clinical practice, training, and research., Materials and Methods: Qualitative research was carried out through a semi-structured interview to 11 tutors who have been coordinating the Post Graduate Specializations., Results: The Qualitative analysis developed "thick" descriptions characterized by analytical density and interpretative richness. The emerging thematic nuclei were: General/unpredicted aspects, Professional empowerment, Satisfaction, Professional outcomes, Limits of the Post Graduate Specializations, and Development areas., Conclusions: We identified the most effective areas of the Post Graduate Specializations that emerged consistently from the interviews. We hypothesized that the values and mission the Scientific Board, are effectively lived and championed in the everyday activities of the Post Graduate Specializations. Some domains still need to be furtherly developed, as the professional record, the absence of a "follow up" relationship with former students, and the effective management of workload both for students and tutors. The rise of these limits, can be particularly fruitful, as it gives the chance to identify the development trajectory the post-graduate trainings should pursue to raise the standard of excellence.

The challenges in recapitulating in vivo human T cell development in laboratory models have posed a barrier to understanding human thymopoiesis. Here, we used single-cell RNA sequencing (sRNA-seq) to interrogate the rare CD34 + progenitor and the more differentiated CD34 - fractions in the human postnatal thymus. CD34 + thymic progenitors were comprised of a spectrum of specification and commitment states characterized by multilineage priming followed by gradual T cell commitment. The earliest progenitors in the differentiation trajectory were CD7 - and expressed a stem-cell-like transcriptional profile, but had also initiated T cell priming. Clustering analysis identified a CD34 + subpopulation primed for the plasmacytoid dendritic lineage, suggesting an intrathymic dendritic specification pathway. CD2 expression defined T cell commitment stages where loss of B cell potential preceded that of myeloid potential. These datasets delineate gene expression profiles spanning key differentiation events in human thymopoiesis and provide a resource for the further study of human T cell development., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Progressive supranuclear palsy (PSP) is rare neurodegenerative disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells. This disorder is underdiagnosed due to the overlap of the clinical syndrome with other related conditions. The clinical manifestations include cognitive impairment associated with behavioral changes, akinetic rigid syndrome, and prominent oculomotor dysfunction. We present the F-FDG and F-THK5351 PET images of a 71-year-old man diagnosed of probable PSP. This image highlights the hopeful results of the new tau-PET ligands radiotracers, because it allows to assess the distribution of tau-protein over time, closely associated with neurodegeneration in PSP.

The inclusion of 18 F-FDG PET as a biomarker in the diagnostic criteria of neurodegenerative diseases and its indication in the presurgical assessment for drug-resistant epilepsies allow to improve specificity of these diagnosis. The traditional interpretation of neurological PET studies has been performed qualitatively, although in the last decade, several quantitative evaluation methods have emerged. This technical development has become relevant in clinical practice, improving specificity, reproducibility and reducing the interrater reliability derived from visual analysis. In this article we update/review the main imaging processing techniques currently used. This may allow the Nuclear Medicine physician to know their advantages and disadvantages when including these procedures in daily clinical practice., (Copyright © 2020 Sociedad Española de Medicina Nuclear e Imagen Molecular. Publicado por Elsevier España, S.L.U. All rights reserved.)