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Vaikunthavasan Thiruchenthooran,1 Marta Espina,2,3 Marta Świtalska,4 Lorena Bonilla-Vidal,2,3 Joanna Wietrzyk,4 Maria Luisa Garcia,2,3 Eliana B Souto,5 Elena Sánchez-López,2,3,6,* Anna Gliszczyńska1,* 1Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Wrocław, Poland; 2Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain; 3Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain; 4Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland; 5Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; 6Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain*These authors contributed equally to this workCorrespondence: Anna Gliszczyńska; Elena Sánchez-López, Email anna.gliszczynska@upwr.edu.pl; esanchezlopez@ub.eduPurpose: The anticancer potential of indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, in vivo, and in clinical trials is well known and widely reported in the literature, along with their side effects, which are mainly observed in the gastrointestinal tract. Here, we present a strategy for the application of the old drug indomethacin as an anticancer agent by encapsulating it in nanostructured lipid carriers (NLC). We describe the production method of IND-NLC, their physicochemical parameters, and the results of their antiproliferative activity against selected cancer cell lines, which were found to be higher compared to the activity of free indomethacin.Methods: IND-NLC were fabricated using the hot high-pressure homogenization method. The nanocarriers were physicochemically characterized, and their biopharmaceutical behaviour and therapeutic efficacy were evaluated in vitro.Results: Lipid nanoparticles IND-NLC exhibited a particle size of 168.1 nm, a negative surface charge (– 30.1 mV), low polydispersity index (PDI of 0.139), and high encapsulation efficiency (over 99%). IND-NLC were stable for over 60 days and retained integrity during storage at 4 °C and 25 °C. The potential therapeutic benefits of IND-NLC were screened using in vitro cancer models, where nanocarriers with encapsulated drug effectively inhibited the growth of breast cancer cell line MDA-MB-468 at dosage 15.7 μM.Conclusion: We successfully developed IND-NLC for delivery of indomethacin to cancer cells and confirmed their antitumoral efficacy in in vitro studies. The results suggest that indomethacin encapsulated in lipid nanoparticles possesses high anticancer potential. Moreover, the presented strategy is highly promising and may offer a new alternative for future therapeutic drug innovations. Keywords: lipid nanoparticles, indomethacin, antitumoral activity, tumor-targeting

BackgroundNo definitive, antemortem diagnostic test for canine degenerative myelopathy (DM) is available. Phosphorylated neurofilament heavy (pNF-H) is a promising biomarker for nervous system diseases.Hypothesis/objectiveCerebrospinal fluid (CSF) and serum pNF-H is a detectable biological marker for diagnosis of canine DM.AnimalsFifty-three DM-affected, 27 neurologically normal, 7 asymptomatic at-risk, and 12 DM mimic dogs.MethodsArchived CSF and serum pNF-H concentrations were determined by a commercially available ELISA. A receiver-operating characteristic (ROC) curve was generated with CSF values.ResultsCompared with old control dogs, median CSF pNF-H concentration was increased in all stages of DM; old dogs 5.1 ng/mL (interquartile range [IQR] 1.4-9.3) versus DM stage 1 23.9 ng/mL (IQR 20.8-29.6; P < .05) versus DM stage 2 36.8 ng/mL (IQR 22.9-51.2; P < .0001) versus DM stage 3 25.2 ng/mL (IQR 20.2-61.8; P < .001) versus DM stage 4 38.0 ng/mL (IQR 11.6-59.9; P < .01). Degenerative myelopathy stage 1 dogs had increased median CSF pNF-H concentrations compared with asymptomatic, at-risk dogs (3.4 ng/mL [IQR 1.5-10.9; P < .01]) and DM mimics (6.6 ng/mL [IQR 3.0-12.3; P < .01]). CSF pNF-H concentration >20.25 ng/mL was 80.4% sensitive (confidence interval [CI] 66.09-90.64%) and 93.6% specific (CI 78.58-99.21%) for DM. Area under the ROC curve was 0.9467 (CI 0.92-0.9974). No differences in serum pNF-H concentration were found between control and DM-affected dogs.Conclusions and clinical importancepNF-H concentration in CSF is a sensitive biomarker for diagnosis of DM. Although there was high specificity for DM in this cohort, further study should focus on a larger cohort of DM mimics, particularly other central and peripheral axonopathies.

Charcot-Marie-Tooth (CMT) is the most common inherited peripheral neuropathy, affecting approximately 2.8 million people. The CMT leads to distal neuropathy that is characterized by reduced motor nerve conduction velocity, ataxia, muscle atrophy and sensory loss. We generated a mouse model of CMT type 2E (CMT2E) expressing human neurofilament light E396K (hNF-LE396K ), which develops decreased motor nerve conduction velocity, ataxia and muscle atrophy by 4 months of age. Symptomatic hNF-LE396K mice developed phenotypes that were consistent with proprioceptive sensory defects as well as reduced sensitivity to mechanical stimulation, while thermal sensitivity and auditory brainstem responses were unaltered. Progression from presymptomatic to symptomatic included a 50% loss of large diameter sensory axons within the fifth lumbar dorsal root of hNF-LE396K mice. Owing to proprioceptive deficits and loss of large diameter sensory axons, we analyzed muscle spindle morphology in presymptomatic and symptomatic hNF-LE396K and hNF-L control mice. Muscle spindle cross-sectional area and volume were reduced in all hNF-LE396K mice analyzed, suggesting that alterations in muscle spindle morphology occurred prior to the onset of typical CMT pathology. These data suggested that CMT2E pathology initiated in the muscle spindles altering the proprioceptive sensory system. Early sensory pathology in CMT2E could provide a unifying hypothesis for the convergence of pathology observed in CMT.

Maria Luz Garcia-Garcia,1 Ersilia Gonzalez-Carrasco,2 Teresa Bracamonte,1 Mar Molinero,3 Francisco Pozo,3 Inmaculada Casas,3 Cristina Calvo4 1Pediatrics Department, Severo Ochoa University Hospital, Fundación IDIPHISA, Alfonso X El Sabio University Madrid, Spain. Translational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain; 2Department, Severo Ochoa University Hospital, Fundación IDIPHISA. Alfonso X El Sabio University, Madrid, Spain; 3Respiratory Virus and Influenza Unit, National Microbiology Center (ISCIII), Madrid, Spain; 4Pediatric Infectious Diseases Department, Fundación IdiPaz, Translational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain. TEDDY Network (European Network of Excellence for Pediatric Clinical Research), Italy. La Paz University Hospital, Madrid, SpainCorrespondence: Maria Luz Garcia-Garcia Email marialuz.hso@gmail.comBackground: Premature birth is associated with increased susceptibility for viral infections and chronic airway morbidity. Preterm children, even moderate and late, may be at risk for short- and long-term respiratory morbidities.Objective: Our main goal was to compare the burden of two conditions, severe bronchiolitis and prematurity (early and moderate-late), on asthma development at 6– 9 years.Patients and Methods: A retrospective cohort of all preterm (< 37weeks gestational age) and full-term children hospitalized for bronchiolitis, with current age between 6 and 9 years, was created. A second cohort was made up of preterm children, without admission for bronchiolitis, randomly chosen from the hospital premature births database. Prevalence and risk factors for asthma were analysed. Parents completed the International Study of Asthma and Allergies in Childhood (ISAAC) Questionnaire for asthma symptoms for children 6– 7 years. Lung function and aeroallergen sensitization were evaluated.Results: Of the 480 selected children, 399 could be contacted and agreed to participate: 133 preterm and 114 full-term cases with admission for bronchiolitis and 146 preterm control children without admission for bronchiolitis. The frequency of current asthma at 6– 9 years was higher in preterm cases (27%) compared with full-term-cases (15%) and preterm controls (14%) (p=0.04). Among hospitalized-bronchiolitis children, prematurity (p=0.04), rhinovirus infection (p=0.03), viral coinfection (p=0.04) and paternal asthma (p=0.003) were risk factors for asthma at 6– 9 years. Among premature children, with and without bronchiolitis admission, the risk factors for asthma at 6– 9 years were admission for bronchiolitis (p=0.03) and aeroallergen sensitisation (p=0.01). Moderate and late preterm children without admission for bronchiolitis showed similar prevalence of current asthma than full-term ones, previously admitted for bronchiolitis.Conclusion: Preterm birth is an important early life risk factor for asthma in childhood. The addition of other risk factors, such as severe bronchiolitis, especially by rhinovirus or viral coinfections, are associated with even higher risk for subsequent asthma.Keywords: asthma, wheezing, prematurity, bronchiolitis, rhinovirus, respiratory syncytial virus

The PREVIA study was designed to investigate the role of montelukast, a leukotriene receptor antagonist, in the prevention of viral-induced asthma exacerbations in children aged 2 to 5 years with a history of intermittent asthma symptoms. The study was a 12-month multicenter, double-blind, parallel-group study of patients with asthma exacerbations associated with respiratory infections and minimal symptoms between episodes. Patients were randomized to receive oral montelukast 4 or 5 mg (depending on age) (n = 278) or placebo (n = 271) once per day for 12 months. Caregivers recorded children's symptoms, beta-agonist use, and health care resource use in a diary card. Over 12 months of therapy, montelukast significantly reduced the rate of asthma exacerbations by 31.9% compared with placebo. The average rate of exacerbation episodes per patient was 1.60 episodes per year on montelukast compared with 2.34 episodes on placebo. Montelukast also delayed the median time to first exacerbation by approximately 2 months (p = 0.024), and the rate of inhaled corticosteroid courses (p = 0.027) compared with placebo. Montelukast effectively reduced asthma exacerbations in 2- to 5-year-old patients with intermittent asthma over 12 months of treatment and was generally well tolerated. [ABSTRACT FROM AUTHOR]

This article looks at the conceptualization and practice of interdisciplinary community collaboration and development (ICCD) in Israel and the US. It is based on the work of two interdisciplinary professional groups which were initiated by social workers-one in Israel and one in the US. This article presents a mapping of key issues and concepts, including distinguishing between mono-, multi-, and inter-, trans-disciplinary and inter-perspectives. The article addresses the issues of multiple professional identities, identification of a common core knowledge base and skills among disciplinary specializations for community development practice, and an understanding of inter-organizational perspectives. A qualitative methodology was used to conduct a content analysis of data from dialogues among professional practitioners in the Israeli and the US groups. Despite differences in the purpose, frequency and intensity of the two forums, there is an underlying belief in the importance of these discussions and in the commitment to interdisciplinary practice. Both groups believe that multiple types of expertise are needed, alongside new models of both inter-organizational and interdisciplinary relationships as well as professional-community interactions. Recommendations include the need for further examination of interdisciplinary community collaboration and development. [ABSTRACT FROM AUTHOR]

Delayed-rectifier K+ currents (I(DR)) in pancreatic beta-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K+ channel, K(V)2.1, is expressed in beta-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of I(DR) in rodent beta-cells. A novel peptidyl inhibitor of K(V)2.1/K(V)2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration approximately 1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to beta-cell physiology. In mouse beta-cells, GxTX-1 inhibits 90% of I(DR) and, as for K(V)2.1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the beta-cell action potential, enhances glucose-stimulated intracellular calcium oscillations, and enhances insulin secretion from mouse pancreatic islets in a glucose-dependent manner. These data point to a mechanism for specific enhancement of glucose-dependent insulin secretion by applying blockers of the beta-cell I(DR), which may provide advantages over currently used therapies for the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]

To assess whether infants hospitalized after an apparently life-threatening event had an associated respiratory virus infection, we analyzed nasopharyngeal aspirates from 16 patients. Nine of 11 infants with positive virus results were infected by rhinoviruses. We detected the new genogroup of rhinovirus C in 6 aspirates. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To compare antibody responses and side-effects of aerosolized and injected measles vaccines after revaccination of children enrolling in elementary schools. METHODS: Vaccines for measles (Edmonston-Zagreb) or measles-rubella (Edmonston-Zagreb with RA27/3) were given by aerosol or injection to four groups of children. An additional group received Schwarz measles vaccine by injection. These five groups received vaccines in usual standard titre doses. A sixth group received only 1000 plaque-forming units of Edmonston-Zagreb vaccine by aerosol. The groups were randomized by school. Concentrations of neutralizing antibodies were determined in blood specimens taken at baseline and four months after vaccination from randomized subgroups (n = 28-31) of children in each group. FINDINGS: After baseline antibody titres were controlled for, the frequencies of fourfold or greater increases in neutralizing antibodies did not differ significantly between the three groups that received vaccine by aerosol (range 52%-64%), but they were significantly higher than those for the three groups that received injected vaccine (range 4%-23%). Mean increases in titres and post-vaccination geometric mean titres paralleled these findings. Fewer side-effects were noted after aerosol than injection administration of vaccine. CONCLUSION: Immunogenicity of measles vaccine when administered by aerosol is superior to that when the vaccine is given by injection. This advantage persists with aerosolized doses less than or equal to one-fifth of usual injected doses. The efficacy and cost-effectiveness of measles vaccination by aerosol should be further evaluated in mass campaigns. Copyright © 2002 World Health Organization [ABSTRACT FROM AUTHOR]

The focus on energy efficiency to move towards a more sustainable use of resources has intensified efforts to minimize friction and wear in mechanical systems, which account for 23% of the world's energy consumption. In this study, polyoxometalate ionic liquids (POM-ILs) are introduced as environmentally acceptable lubricant additives, for their potential friction-reducing and anti-wear (AW) properties. These compounds, characterized by their complex structures and tunable properties, have been investigated for their tribological performance across base fluids of varying polarities. Their performance has been compared against zinc dialkyldithiophosphate (ZDDP), a standard AW additive. Our findings demonstrate that POM-ILs exhibit promising friction-reducing and AW capabilities, comparable to traditional additives. The efficacy of POM-ILs was found to be highly dependent on the base fluid used, with significant variations observed in their ability to interact with stainless steel surfaces. Adsorption studies confirmed strong adsorption of POM-ILs onto stainless steel, with notable influence from the base fluid. Advanced characterization techniques revealed the formation of a predominantly oxide-rich tribofilm on the metal surface, as a result of POM-IL decomposition and reaction with the metal. POM-ILs show significant potential as lubricant additives, with their structural versatility offering a promising path for future greener developments in tribology., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

This study explores the interactions of the cis -[Ru(phen) 2 (Apy) 2 ] 2+ complex (RuApy, phen = 1,10-phenanthroline, Apy = 3,4-aminopyridine) with model lipid membranes to explain the role this complex plays in mitigating Aβ toxicity in PC12 neuronal cells. Fluorescence quenching, surface pressure isotherms in Langmuir monolayers, and infrared reflection-absorption analyses revealed that the positively charged RuApy interacts with the phosphate headgroups of monolayers, indirectly affecting ester carbonyl groups through hydrogen bonding with the amino group of the pyridine ligand of RuApy. These results offer a scenario for the protective effect of RuApy against Aβ toxicity in neuronal cells in which these interactions shield the electrostatic interactions of Aβ with lipid membranes, preserving membrane integrity and mitigating the deleterious influence of Aβ. This opens new avenues for antiamyloid strategies, focusing on compounds that prevent salt-bridge formation between bilayer membranes and amyloid proteins, aiding in the rational design of effective antiamyloid agents for therapeutic application.

Sepsis is a dysregulated systemic inflammatory response to an infection, which can lead to multiple organ dysfunction syndrome that includes the kidney. Leukocyte recruitment is an important process of the host immune defense in response to sepsis. Endothelial cells (EC) actively regulate leukocyte recruitment by expressing adhesion molecules following the activation of dedicated intracellular signal transduction pathways. Previous studies reported that the expression of adhesion molecules was associated with the activation of endothelial nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 and mitogen-activated protein kinase (MAPK) c-Jun pathways in vitro in response to conditions that mimic processes that occur in inflammation. This study aimed to investigate the spatiotemporal patterns of leukocyte recruitment, expression of adhesion molecules, and endothelial nuclear p65 and c-Jun localization in renal microvascular beds of septic mice. Here, we used a cecal ligation and puncture (CLP) sepsis mouse model and RT-qPCR and immunohistochemical staining. We showed that neutrophils, macrophages, and T lymphocytes were all present in the kidney, yet only neutrophils accumulated in a spatiotemporally discernible pattern, mainly in glomeruli at 4 h after CLP sepsis initiation. E-selectin, not vascular cell adhesion molecule-1 (VCAM-1), was expressed in glomeruli at the same time point. In a subset of mice at 72 h after CLP sepsis started, VCAM-1 expression was prominent in glomerular EC, which was not related to changes in mmu-microRNA(miR)-126a-3p levels, a short noncoding microRNA previously shown to inhibit the translation of VCAM-1 mRNA into protein. Nuclear localization of p65 and c-Jun occurred in EC of all microvascular segments at 4 and 7 h after CLP sepsis initiation. In summary, sepsis-induced recruitment of neutrophils, E-selectin expression, and NF-κB p65 and MAPK c-Jun pathway activation coincided in glomeruli at the early stage of the disease. In the other microvascular beds, sepsis led to NF-κB p65 and MAPK c-Jun pathway activation with limited expression of E-selectin and no association with VCAM-1 expression or leukocyte recruitment., Competing Interests: Conflict of interest statement. The authors declare that there is no conflict of interest in this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Access to healthcare data for secondary use in clinical research is often restricted due to privacy concerns or business interests, hindering comprehensive analysis across patient pathways. The Smart FOX project seeks to address this challenge by developing concepts, methods, and tools to facilitate citizen/patient-driven donations of health data for clinical research. Leveraging the groundwork, laid by the national Electronic Health Record implementation in Austria (called ELGA), Smart FOX aims to harness structured datasets from ELGA for research purposes through an opt-in approach. With funding secured from the Austrian Research Promotion Agency, the project embarks on innovative solutions encompassing governance frameworks, community engagement, and technical infrastructure. The Smart FOX consortium, comprising key stakeholders across various healthcare-associated domains, will evaluate these efforts through demonstrators focusing on clinical registries, patient-generated data, and recruitment services. The project targets to accompany the development of future data donation infrastructure while ultimately advancing clinical research efficiency and bolstering Austria's preparedness for the European Health Data Space. This paper presents the first systematic evaluation of the technical concept and proposal for the federated system architecture of the Austrian Health Data Donation Space, which is the socio-technical goal of Smart FOX.

Introduction: Moderate-to-late preterm infants constitute the majority within the preterm infant population. Most research on preterm infants has focused on very preterm children, often treating moderate-to-late preterm infants as similar to full-term infants. Our objective was to compare clinical, respiratory, cardio-metabolic and neurodevelopmental outcomes in adolescents aged 12-15 years born moderate and late preterm with a control group of the same age born full-term., Methods: Observational cross-sectional study, comparing moderate-to-late preterm (32-36 +6 weeks' gestational age) with full-term adolescents (37-41 +6 weeks' gestational age; 75 each group). Perinatal and neonatal history were collected as well as data on respiratory evolution (ISAAC questionnaire for asthma symptoms for adolescents 13-14 years), anthropometric values, learning difficulties, behavioral test (screening questionnaire for high-performance autism spectrum disorder and evaluation test for attention deficit hyperactivity disorder), skin prick test, pulmonary function test, echocardiogram and blood pressure. A blood test with metabolic profile was conducted., Results: Moderate-to-late preterm adolescents had more current asthma [ p  = 0.008, OR3 (95% CI 1.26-7.14)] and longer duration of combined treatments to control asthma (inhaled corticosteroids and anti-leukotrienes; p  = 0.048). Forced vital capacity <80% was detected more often in moderate-to-late preterm patients ( p  = 0.013). When assessing right ventricle, moderate-to-late preterm adolescents showed better tricuspid annular plane systolic excursion z-score ( p  = 0.003), shortening fraction ( p  < 0.001) and E/A ratio z-score ( p  = 0.002). Regarding left ventricular assessment, moderate-to-late preterm group had smaller ventricle diastolic diameter ( p  = 0.04) and lower posterior wall z-score values ( p  = 0.037). They also showed a better S'wave z-score ( p  = 0.027), E wave ( p  = 0.005), E/A ratio ( p  = 0.003) and a higher septal myocardial performance index z-score ( p  = 0.025). Moderate-to-late preterm adolescents presented lower weight z-score ( p  = 0.039), body mass index z-score ( p  = 0.013), Waterlow weight index ( p  = 0.006) and higher undernutrition index [ p  = 0.04; OR 1.4 (95% CI 1-1.9)]. Although there were no differences in neurodevelopmental survey or behavioral tests., Conclusion: Our findings underscore the importance of extended follow-up for this predominant group of premature infants to identify potential respiratory, cardiac and anthropometric issues that may emerge in the future., 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 © 2024 Alonso-Lopez, Arroyas, Beato, Ruiz-Gonzalez, Olabarrieta and Garcia-Garcia.)

Background: Sepsis is an uncontrolled systemic inflammatory response to an infection that can result in acute failure of the function of the lung called acute respiratory distress syndrome. Leukocyte recruitment is an important hallmark of acute lung failure in patients with sepsis. Endothelial cells (EC) participate in this process by facilitating tethering, rolling, adhesion, and transmigration of leukocytes via adhesion molecules on their cell surface. In in vivo studies, endothelial nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 and mitogen-activated protein kinase (MAPK) c-Jun intracellular signal transduction pathways were reported to regulate the expression of adhesion molecules., Methods: Mice underwent cecal ligation and puncture (CLP) to induce polymicrobial sepsis and were sacrificed at different time points up to 72 h after sepsis onset. Immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses were used to determine the kinetics of nuclear localization of p65 and c-Jun in EC, expression and location of adhesion molecules E-selectin and vascular cell adhesion molecule 1 (VCAM-1). Furthermore, the extent and location of leukocyte recruitment were assessed based on Ly6G staining of neutrophils, cluster determinant (CD) 3 staining of T lymphocytes, and CD68 staining of macrophages., Results: In all pulmonary microvascular beds, we identified p65 and c-Jun nuclear accumulation in a subset of endothelial cells within the first 24 h after CLP-sepsis initiation. E-selectin protein was expressed in a subset of microvessels at 4 and 7 h after sepsis initiation, while VCAM-1 was expressed in a scattered pattern in alveolar tissue and microvessels, without discernible changes during sepsis development. CLP-induced sepsis predominantly promoted the accumulation of neutrophils and T lymphocytes 4 and 7 h after disease onset. Neutrophil accumulation occurred in all pulmonary microvascular beds, while T lymphocytes were present in alveolar tissue and postcapillary venules. Taken together, nuclear localization of p65 and c-Jun in EC and neutrophil recruitment could be associated with induced E-selectin expression in the pulmonary microvessels in CLP-septic mice at the early stage of the disease. In alveolar capillaries, on the other hand, activation of these molecular pathways and leukocyte accumulation occurred in the absence of E-selectin or VCAM-1., Conclusions: Endothelial activation and leukocyte recruitment in sepsis-induced lung injury are regulated by multiple, heterogeneously controlled mechanisms, which vary depending on the type of microvascular bed involved.

Background: COVID-19 lung sequelae can impact the course of patient lives. We investigated the evolution of pulmonary abnormalities in post-COVID-19 patients 18-24 months after hospital discharge., Methods: A cohort of COVID-19 patients admitted to the Hospital das Clínicas da Faculdade de Medicina da USP in São Paulo, Brazil, between March and August of 2020, were followed-up 6-12 months after hospital discharge. A subset of patients with pulmonary involvement and chest computed tomography (CT) scans were eligible to participate in this second follow-up (18-24 months). Data was analyzed in an ambidirectional manner, including retrospective data from the hospitalization, and from the first follow-up (6-12 months after discharge), and compared with the prospective data collected in this new follow-up., Findings: From 348 patients eligible, 237 (68%) participated in this follow-up. Among participants, 139 (58%) patients presented ground-glass opacities and reticulations, and 80 (33%) presented fibrotic-like lesions (traction bronchiectasis and architectural distortion). Five (2%) patients improved compared to the 6-12-month assessment, but 20 (25%) of 80 presented worsening of lung abnormalities. For those with relevant assessments on both occasions, comparing the CT findings between this follow-up with the previous assessment, there was an increase in patients with architectural distortion (43 [21%] of 204 vs 57 [28%] of 204, p = 0.0093), as well as in traction bronchiectasis (55 [27%] of 204 vs 69 [34%] of 204, p = 0.0043). Patients presented a persistent functional impairment with demonstrated restrictive pattern in both follow-ups (87 [42%] of 207 vs 91 [44%] of 207, p = 0.76), as well as for the reduced diffusion capacity (88 [42%] of 208 vs 87 [42%] of 208, p = 1.0). Length of hospitalization (OR 1.04 [1.01-1.07], p = 0.0040), invasive mechanical ventilation (OR 3.11 [1.3-7.5] p = 0.011), patient's age (OR 1.03 [1.01-1.06] p = 0.0074 were consistent predictors for development of fibrotic-like lung lesions in post-COVID-19 patients., Interpretation: Post-COVID-19 lung sequelae can persist and progress after hospital discharge, suggesting airways involvement and formation of new fibrotic-like lesions, mainly in patients who were in intensive care unit (ICU)., Funding: São Paulo Research Foundation (22/01769-5) and Instituto Todos pela Saúde (C1721)., Competing Interests: We declare no competing interests., (© 2024 The Authors.)

Background: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus., Methods: In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m 2 docetaxel and 40 mg per m 2 cisplatin on day 1 and 1200 mg per m 2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants., Findings: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths., Interpretation: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies., Funding: GERCOR, Roche., Competing Interests: Declaration of interests Genentech provided atezolizumab for the study. SK reports consultancy, advisory roles, and honoraria from Amgen, BeiGene, Boehringer Ingelheim, Merck, MSD, Pfizer, and Servier; and research funding from Boehringer Ingelheim, Bristol Myers Squibb, Novartis, and Roche. FG reports consultancy for Roche, MSD, Merck Serono, Brenus, Engetix, and Odimma; research grants from AstraZeneca, Roche Genentech, Amgen, XBiotech, and Springworks; and travel or accommodation from Amgen, MSD, Roche, and Servier. CdlF reports honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Incyte Biosciences, Ipsen, Lilly, Merck Serono, MSD, Pierre Fabre Oncologie, Pfizer, Roche, Sanofi-Aventis, and Servier. ES reports consultancy, advisory roles, and honoraria from Amgen, Astellas, BeiGene, Bristol Myers Squibb, Daichi, Merck, MSD, Pierre Fabre, and Servier; and travel or accommodation from Bristol Myers Squibb, MSD, Pierre Fabre, and Servier. DT reports consulting or advisory board fees from AstraZeneca, Sanofi, Amgen, MSD, BMS, Roche, Servier, and Pierre Fabre; and research funding from Pierre Fabre and Sandoz. OB reports honoraria for speaker or advisory roles from Astellas, Merck Serono, Amgen, Servier, Pierre Fabre, Apmonia Therapeutics, Deciphera, and MSD. DV reports consulting fees from Apmonia Therapeutics, Cellprothera, Novartis, Incyte, Veracyte, and Lysarc. FB reports honoraria for speaker or advisory roles from Astellas, Servier, Incyte, Pierre Fabre, BMS, AstraZeneca, Owkin, and MSD. JT reports honoraria for speaker or advisory roles from Astellas, Roche, Merck Serono, Amgen, Servier, Pierre Fabre, BMS, AstraZeneca, Novartis, Takeda, and MSD. MBA reports honoraria for speaker or advisory roles from Bayer, Incyte, Deciphera, Merck, Servier, BMS, Pierre Fabre, and Amgen. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: The COVID-19 pandemic has prompted global research efforts to reduce infection impact, highlighting the potential of cross-disciplinary collaboration to enhance research quality and efficiency., Methods: At the FMUSP-HC academic health system, we implemented innovative flow management routines for collecting, organizing and analyzing demographic data, COVID-related data and biological materials from over 4,500 patients with confirmed SARS-CoV-2 infection hospitalized from 2020 to 2022. This strategy was mainly planned in three areas: organizing a database with data from the hospitalizations; setting-up a multidisciplinary taskforce to conduct follow-up assessments after discharge; and organizing a biobank. Additionally, a COVID-19 curated collection was created within the institutional digital library of academic papers to map the research output., Results: Over the course of the experience, the possible benefits and challenges of this type of research support approach were identified and discussed, leading to a set of recommended strategies to enhance collaboration within the research institution. Demographic and clinical data from COVID-19 hospitalizations were compiled in a database including adults and a minority of children and adolescents with laboratory confirmed COVID-19, covering 2020-2022, with approximately 350 fields per patient. To date, this database has been used in 16 published studies. Additionally, we assessed 700 adults 6 to 11 months after hospitalization through comprehensive, multidisciplinary in-person evaluations; this database, comprising around 2000 fields per subject, was used in 15 publications. Furthermore, thousands of blood samples collected during the acute phase and follow-up assessments remain stored for future investigations. To date, more than 3,700 aliquots have been used in ongoing research investigating various aspects of COVID-19. Lastly, the mapping of the overall research output revealed that between 2020 and 2022 our academic system produced 1,394 scientific articles on COVID-19., Discussion: Research is a crucial component of an effective epidemic response, and the preparation process should include a well-defined plan for organizing and sharing resources. The initiatives described in the present paper were successful in our aim to foster large-scale research in our institution. Although a single model may not be appropriate for all contexts, cross-disciplinary collaboration and open data sharing should make health research systems more efficient to generate the best evidence., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ritto, de Araujo, de Carvalho, De Souza, Favaretto, Saboya, Garcia, Kulikowski, Kallás, Pereira, Cobello Junior, Silva, Abdalla, Segurado, Sabino, Ribeiro Junior, Francisco, Miethke-Morais, Levin, Sawamura, Ferreira, Silva, Mauad, Gouveia, Letaif, Bego, Battistella, Duarte, Seelaender, Marchini, Forlenza, Rocha, Mendes-Correa, Costa, Cerri, Bonfá, Chammas, de Barros Filho and Busatto Filho.)

Leukemia cutis is a term used to describe cutaneous manifestations of leukemic infiltration of the skin and portends a poor prognosis. Cutaneous involvement by hematopoietic/lymphoid tumors can occur before, concurrently, or after the initial diagnosis. Early involvement of dermatologists and timely biopsies play a crucial role in achieving a prompt diagnosis. Prior reports of acute myeloid leukemia have revealed a strong association between the cup-like nuclear morphology observed in bone marrow specimens and concurrent mutations of NPM1 and FLT3-ITD. In cutaneous tissue sections of leukemia cutis, folded or indented nuclei may represent the "cup-like" counterpart previously described in bone marrow specimens. Recognizing this morphological feature could aid in identifying this molecular subtype of leukemia cutis. In this study, we present a case of leukemia cutis in a 63-year-old female with AML and NPM1 and FLT3-ITD mutations, demonstrating scattered indented/folded nuclei., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of "local" when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation., Competing Interests: Declaration of interests K.G.A. has received consulting fees on SARS-CoV-2 and the COVID-19 pandemic., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Self-management interventions (SMIs) may be promising in the treatment of Diabetes Mellitus Type 2 (T2DM). However, accurate comparisons of their relative effectiveness are challenging, partly due to a lack of clarity and detail regarding the intervention content being evaluated. This study summarizes intervention components and characteristics in randomized controlled trials (RCTs) related to T2DM using a taxonomy for SMIs as a framework and identifies components that are insufficiently incorporated into the design of the intervention or insufficiently reported. Following evidence mapping methodology, we searched MEDLINE, CINAHL, Embase, Cochrane, and PsycINFO from 2010 to 2018 for randomized controlled trials (RCTs) on SMIs for T2DM. We used the terms 'self-management', 'adult' and 'T2DM' for content. For data extraction, we used an online platform based on the taxonomy for SMIs. Two independent reviewers assessed eligible references; one reviewer extracted data, and a second checked accuracy. We identified 665 RCTs for SMIs (34% US, 21% Europe) including 164,437 (median 123, range 10-14,559) adults with T2DM. SMIs highly differed in design and content, and characteristics such as mode of delivery, intensity, location and providers involved were poorly described. The majority of interventions aimed to improve clinical outcomes like HbA1c (83%), weight (53%), lipid profile (45%) or blood pressure (42%); 27% (also) targeted quality of life. Improved knowledge, health literacy, patient activation or satisfaction with care were hardly used as outcomes (<16%). SMIs most often used education (98%), self-monitoring (56%), goal-setting (48%) and skills training (42%) to improve outcomes. Management of emotions (17%) and shared decision-making (5%) were almost never mentioned. Although diabetes is highly prevalent in some minority groups, in only 13% of the SMIs, these groups were included. Our findings highlight the large heterogeneity that exists in the design of SMIs for T2DM and the way studies are reported, making accurate comparisons of their relative effectiveness challenging. In addition, SMIs pay limited attention to outcomes other than clinical, despite the importance attached to these outcomes by patients. More standardized and streamlined research is needed to better understand the effectiveness and cost-effectiveness of SMIs of T2DM and benefit patient care.

Small-bowel diverticulosis is rare. We report the case of a male with an acute abdomen secondary to an ileal diverticulum. A 46-year-old male complained of progressive abdominal pain over 24 hours of evolution in the left flank. On physical examination, we found abdominal pain in the left flank and mesogastrium, tenderness, and signs of peritonitis. The simple abdominal CT showed a heterogeneous tubular image in the small bowel. We performed a diagnostic laparoscopy and found a normal cecal appendix. There was no free abdominal fluid or adhesions, and the colon was without diverticula. We found a single diverticulum of 4 cm in length and 2 cm in diameter in the small intestine and therefore converted the procedure to a laparotomy. We performed a bowel resection including the diverticulum and intestinal anastomosis. The patient reported remission of symptoms after surgery., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Suro Santos et al.)

Background There is limited evidence on the potential negative metabolic health impacts of prolonged and uninterrupted sedentary bouts in structurally disadvantaged youth. This study investigated associations between sedentary bout variables and metabolic health markers in the Hispanic Community Health Study/SOL Youth (Study of Latino Youth). Methods and Results SOL Youth was a population-based cohort of 1466 youth (age range, 8-16 years; 48.5% female); 957 youth were included in the analytic sample based on complete data. Accelerometers measured moderate-to-vigorous physical activity (MVPA), total sedentary time, and sedentary bout patterns (daily time spent in sedentary bouts ≥30 minutes, median sedentary bout duration, and number of daily breaks from sedentary time). Clinical measures included body mass index, waist circumference, fasting glucose, glycated hemoglobin, fasting insulin, and the homeostasis model assessment of insulin resistance. After adjusting for sociodemographics, total sedentary time, and MVPA, longer median bout durations and fewer sedentary breaks were associated with a greater body mass index percentile (b bouts =0.09 and b breaks =-0.18), waist circumference (b bouts =0.12 and b breaks =-0.20), and fasting insulin (b bouts =0.09 and b breaks =-0.21). Fewer breaks were also associated with a greater homeostasis model assessment of insulin resistance (b=-0.21). More time in bouts lasting ≥30 minutes was associated with a greater fasting glucose (b=0.18) and glycated hemoglobin (b=0.19). Conclusions Greater accumulation of sedentary time in prolonged and uninterrupted bouts had adverse associations with adiposity and glycemic control over and above total sedentary time and MVPA. Findings suggest interventions in Hispanic/Latino youth targeting both ends of the activity spectrum (more MVPA and less prolonged/uninterrupted sedentary patterns) may provide greater health benefits than those targeting only MVPA.

For more than three decades, major efforts in sampling and analyzing tree diversity in South America have focused almost exclusively on trees with stems of at least 10 and 2.5 cm diameter, showing highest species diversity in the wetter western and northern Amazon forests. By contrast, little attention has been paid to patterns and drivers of diversity in the largest canopy and emergent trees, which is surprising given these have dominant ecological functions. Here, we use a machine learning approach to quantify the importance of environmental factors and apply it to generate spatial predictions of the species diversity of all trees (dbh ≥ 10 cm) and for very large trees (dbh ≥ 70 cm) using data from 243 forest plots (108,450 trees and 2832 species) distributed across different forest types and biogeographic regions of the Brazilian Amazon. The diversity of large trees and of all trees was significantly associated with three environmental factors, but in contrasting ways across regions and forest types. Environmental variables associated with disturbances, for example, the lightning flash rate and wind speed, as well as the fraction of photosynthetically active radiation, tend to govern the diversity of large trees. Upland rainforests in the Guiana Shield and Roraima regions had a high diversity of large trees. By contrast, variables associated with resources tend to govern tree diversity in general. Places such as the province of Imeri and the northern portion of the province of Madeira stand out for their high diversity of species in general. Climatic and topographic stability and functional adaptation mechanisms promote ideal conditions for species diversity. Finally, we mapped general patterns of tree species diversity in the Brazilian Amazon, which differ substantially depending on size class., (© 2023 John Wiley & Sons Ltd.)

The impact of obesity upon bone metabolism is controversial since both beneficial or harmful effects have been reported. Bone remodeling is modulated by the central nervous system through cytokines, hormones and neuromodulators. The present study aimed to evaluate the effects evoked by bilateral retroperitoneal white adipose tissue (rWAT) denervation (Dnx) upon bone mineral metabolism and remodeling in an experimental model of obesity in rats. Male Wistar rats were fed during 18 weeks with high-fat diet (HFD) or standard diet (SD) as controls, and rWAT Dnx or Sham surgery was performed at the 14th week. Biochemical and hormonal parameters, bone histomorphometry, rWAT and hypothalamus protein and gene expression were analyzed. The HFD group presented decreased bone formation parameters, increased serum and bone leptin and FGF23, increased serum and hypothalamic neuropeptide Y (NPY) and decreased serum 1,25-dihydroxyvitamin D 3 and PTH. After rWAT Dnx, bone markers and histomorphometry showed restoration of bone formation, and serum and hypothalamic NPY decreased, without alteration in leptin levels. The present study shows that the denervation of rWAT improved bone formation in obese rats mediated by a preferential reduction in neurohormonal actions of NPY, emphasizing the relevance of the adipose tissue-brain-bone axis in the control of bone metabolism in obesity.

The coronavirus disease (COVID-19) pandemic leveraged telemedicine worldwide mainly due to the need for social distancing, patient safety, and infection prevention. The Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) was a key reference site in the treatment of COVID-19 severe cases in the country. To continue patient's health care, it became necessary to increase the number of teleconsultations and standardize it institutionally. Herein, we briefly described how the HCFMUSP improved the teleconsultation health care service during the COVID-19 pandemic, highlighting the implementation of important innovations and the throughout standardization process, including patients and professional workflow. We also detailed the methodology used to implement or improve teleconsultation in a medical/multidisciplinary specialty at HCFMUSP. All these efforts made the HCFMUSP reach the goal of converting 15% of all face-to-face consultations into teleconsultations only in 2021. In addition, there were more than 370,000 teleconsultations until the end of 2022. Our experience has shown that having a supporting team, a digital certification process, and the data integration were key factors toward the successful implementation of the teleconsultation services. We believe that progressing toward teleconsultation will improve the population covered by health care services in Brazil, as well as contribute to a reduction of waiting time, and solving costs to health care institutions and patients. We expect this report of our experience in teleconsultation implementation could inspire and guide other health care institutions in the development of telemedicine., Competing Interests: No conflict of interest is declared., (© Paula Gobi Scudeller et al., 2023; Published by Mary Ann Liebert, Inc.)

Structural metastability of viral capsids is pivotal for viruses to survive in harsh environments and to undergo timely conformational changes required for cell entry. Mammalian orthoreovirus (reovirus) is a model to study capsid metastability. Following initial disassembly of the reovirus particle mediated by proteases, a metastable intermediate called the infectious subvirion particle (ISVP) is generated. Using a σ1 monoreassortant virus, we recently showed that σ1 properties affect its encapsidation on particles and the metastability of ISVPs. How metastability is impacted by σ1 and whether the lower encapsidation level of σ1 is connected to this property is unknown. To define a correlation between encapsidation of σ1 and ISVP stability, we generated mutant viruses with single amino acid polymorphisms in σ1 or those that contain chimeric σ1 molecules composed of σ1 portions from type 1 and type 3 reovirus strains. We found that under most conditions where σ1 encapsidation on the particle was lower, ISVPs displayed lower stability. Characterization of mutant viruses selected for enhanced stability via a forward genetic approach also revealed that in some cases, σ1 properties influence stability without influencing σ1 encapsidation. These data indicate that σ1 can also influence ISVP stability independent of its level of incorporation. Together, our work reveals an underappreciated effect of the σ1 attachment protein on the properties of the reovirus capsid. IMPORTANCE Reovirus particles are comprised of eight proteins. Among them, the reovirus σ1 protein functions engages cellular receptors. σ1 also influences the stability of an entry intermediate called ISVP. Here, we sought to define the basis of the link between σ1 properties and stability of ISVPs. Using variety of mutant strains, we determined that when virus preparations contain particles with a high amount of encapsidated σ1, ISVP stability is higher. Additionally, we identified portions of σ1 that impact its encapsidation and consequently the stability of ISVPs. We also determined that in some cases, σ1 properties alter stability of ISVPs without affecting encapsidation. This work highlights that proteins of these complex particles are arranged in an intricate, interconnected manner such that changing the properties of these proteins has a profound impact on the remainder of the particle., Competing Interests: The authors declare no conflict of interest.