Correlation between systemic allergen desensitisation and long-term asthma protection in mice following intravenous administration of the live tuberculosis vaccine MTBVAC.

BACKGROUND: MTBVAC is a live attenuated tuberculosis vaccine, currently undergoing phase III evaluation for tuberculosis prevention. In previous preclinical studies, we found that local pulmonary administration of MTBVAC via the intranasal route had a strong therapeutic effect against asthma. This effect correlated with the abrogation of allergen-specific Th2 response in the lungs. METHODS: Using different mouse models of asthma, we investigated the effect of MTBVAC administered by intravenous (IV) route and its potential as immunotherapeutic agent to induce desensitisation of allergen-specific responses at a systemic level. We explored the effects of this process in the efficacy against airway hyperresponsiveness (AHR) induced by exposure to different allergens. FINDINGS: IV MTBVAC was highly efficient at reducing AHR induced by different allergens. Additionally, IV MTBVAC was found to be well-tolerated, being progressively eliminated from the different organs analysed. From a mechanistic standpoint, we observed that MTBVAC intravenous, but not intranasal, impaired allergen-specific Th2 response in both lungs and spleen. This reduction at a systemic level correlated with long-term therapeutic protection against allergen exposure. Our results also revealed differential immunological mechanisms governing systemic and local pulmonary allergen desensitisation processes. Notably, in a cohort of patients with asthma sensitive to house dust mite (HDM), in vitro incubation of peripheral blood mononuclear cells (PBMCs) with MTBVAC prevented allergen-specific production of Th2 cytokines IL-4 and IL-5. INTERPRETATION: Altogether, our results suggest that intravenous MTBVAC could be a plausible allergen desensitising approach for treatment of asthma, and could provide long-term protection against allergen exposure. FUNDING: MCIN/AEI/10.13039/501100011033 [grants number RTI2018-097625-B-I00 and PID2022-138624OB-I00]; Consorcio Centro de Investigación Biomédica en Red- (Groups CB06/06/0020 and CB06/06/0013), Instituto de Salud Carlos III.

Protective effect of modified lange "second position" for developing avascular necrosis following closed reduction for developmental dysplasia of the hip.

BACKGROUND: Developmental Dysplasia of the Hip (DDH) is a condition affecting hip joint development in children, presenting multiple manifestations. Immobilization methods to ensure hip concentricity, such as the human position and modified Lange position, vary in effectiveness and risks, especially avascular necrosis. The purpose of this study was to identify whether closed reduction (CR), with two different immobilization techniques, is effective in avoiding complications such as residual hip dysplasia (RHD), re-dislocation, and Avascular Necrosis (AVN). METHODS: A total of 66 patients with DDH (84 hips) were treated with two different techniques of immobilization (groups A and B); the mean age at the time of reduction was 8 (6-13) months. The rates of RHD, Re-dislocation, and AVN were determined with a minimum follow-up of 48 months in both techniques. RESULTS: The Chi-square analysis conducted across the study groups unveiled that patients in Group B demonstrated a protective effect against AVN compared to those in Group A (OR: 0.248, 95% CI: 0.072-0.847, p = 0.026). However, no statistically significant differences were found between the groups concerning RHD (p = 0.563) and re-dislocation (p = 0.909). CONCLUSIONS: After the initial Human Position immobilization, the second cast with the modified Lange "second position" demonstrated a protective effect compared with maintaining the Human Position immobilization throughout the immobilization period, reducing the likelihood of AVN development in patients undergoing closed reduction for developmental dysplasia of the hip.

Long noncoding RNA MALAT1 in dermatologic disorders: a comprehensive review.

Dermatologic disorders, affecting the integumentary system, involve diverse molecular mechanisms such as cell proliferation, apoptosis, inflammation and immune responses. Long noncoding RNAs, particularly Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1), are crucial regulators of gene expression. MALAT1 influences inflammatory responses, immune cell function and signaling pathways, impacting various physiological and pathological processes, including dermatologic disorders. Dysregulation of MALAT1 is observed in skin conditions like psoriasis, atopic dermatitis and systemic lupus erythematosus. However, its precise role remains unclear. This review consolidates knowledge on MALAT1's impact on skin biology and pathology, emphasizing its potential diagnostic and therapeutic implications in dermatologic conditions.

[Box: see text].

Research to Confront Climate Change Complexity: Intersectionality, Integration, and Innovative Governance.

Climate impacts increasingly unfold in interlinked systems of people, nature, and infrastructure. The cascading consequences are revealing sometimes surprising connections across sectors and regions, and prospects for climate responses also depend on complex, difficult-to-understand interactions. In this commentary, we build on the innovations of the United States Fifth National Climate Assessment to suggest a framework for understanding and responding to complex climate challenges. This approach involves: (a) integration of disciplines and expertise to understand how intersectionality shapes complex climate impacts and the wide-ranging effects of climate responses, (b) collaborations among diverse knowledge holders to improve responses and better encompass intersectionality, and (c) sustained experimentation with and learning about governance approaches capable of handling the complexity of climate change. Together, these three pillars underscore that usability of climate-relevant knowledge requires transdisciplinary coordination of research and practice. We outline actionable steps for climate research to incorporate intersectionality, integration, and innovative governance, as is increasingly necessary for confronting climate complexity and sustaining equitable, ideally vibrant climate futures.

SEOM-GEMCAD-TTD clinical guidelines for the management of hepatocarcinoma patients (2023).

Hepatocellular carcinoma (HCC) is the most common primary malignancy in the liver and is the third cause of cancer-related death worldwide. Surveillance with abdominal ultrasound should be offered to individuals at high risk for developing HCC. Accurate diagnosis, staging, and liver function are crucial when determining the optimal therapeutic approach. The BCLC staging system is widely endorsed in Western countries. Managing this pathology requires a multidisciplinary, personalized approach, generally with a multimodal strategy. Surgery remains the only curative option, albeit local and systemic therapy may also increase survival when surgery is not suitable. In advanced disease, systemic treatment should be offered to patients with ECOG/PS 0-1 and Child-Pugh class A.

Malnutrition: muscle wasting, inflammation, RDW, and their relation with adverse outcomes.

OBJECTIVE: The objective of the study was to explore red cell distribution width (RDW) as a surrogate marker of inflammation, alone and in conjunction with muscle wasting to predict malnutrition-related adverse outcomes. METHODS: This was a single-center observational study including adult hospitalized patients. Demographic variables, malnutrition criteria, and RDW were captured within 24 hours of hospital admission. Correlation tests and regression models were performed between these variables (RDW and muscle wasting) and adverse outcomes (in-hospital mortality and unplanned transfer to critical care areas (CCA). RESULTS: Five hundred and forty-five patients were included in the final analysis. Muscle wasting showed an independent association with adverse outcomes in every regression model tested. RDW alone showed fair predictive performance for both outcomes' significance and the adjusted model with muscle wasting showed association only for unplanned transfer to CCA. CONCLUSION: RDW did not improve the prediction of adverse outcomes compared to muscle wasting assessed by physical examination and simple indexes for acute and chronic inflammation. Malnourished patients presented higher RDW values showing a possible metabolic profile (higher inflammation and lower muscle). It is still unknown whether nutrition support can influence RDW value over time as a response marker or if RDW can predict who may benefit the most from nutritional support.

OBJETIVO: Explorar el ancho de distribución eritrocitaria (ADE) como un marcador subrogado de inflamación, individualmente y en conjunto con el desgaste muscular, para predecir resultados adversos asociados a la desnutrición. MÉTODO: Estudio unicéntrico, observacional, incluyendo pacientes adultos hospitalizados. Se capturaron variables demográficas, criterios de desnutrición y el ADE en las primeras 24 horas de ingreso. Se realizaron pruebas de correlación y modelos de regresión entre dichas variables (ADE y desgaste) y resultados adversos (mortalidad hospitalaria y traslado no planeado a áreas críticas). RESULTADOS: Se incluyeron 545 pacientes. El desgaste muscular mostró asociación independiente con los resultados adversos en cada modelo. El ADE individualmente mostró un desempeño aceptable para la predicción de ambos resultados, y en modelos ajustados con desgaste muscular mostró asociación únicamente con traslado no planeado a áreas críticas. CONCLUSIONES: El ADE no mejoró la predicción de resultados adversos comparado con el desgaste muscular por exploración física e índices simples de inflamación. Los pacientes con desnutrición presentaron mayores valores de ADE, mostrando un posible perfil metabólico (mayor inflamación y menos músculo). Aún se desconoce si el soporte nutricional puede influenciar el ADE como un marcador de respuesta o si puede predecir una respuesta favorable al soporte nutricional.

Low-dose M.tb infection but not BCG or MTBVAC vaccination enhances heterologous antibody titres in non-human primates.

Introduction: Mycobacteria are known to exert a range of heterologous effects on the immune system. The mycobacteria-based Freund's Complete Adjuvant is a potent non-specific stimulator of the immune response used in immunization protocols promoting antibody production, and Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccination has been linked with decreased morbidity and mortality beyond the specific protection it provides against tuberculosis (TB) in some populations and age groups. The role of heterologous antibodies in this phenomenon, if any, remains unclear and under-studied. Methods: We set out to evaluate antibody responses to a range of unrelated pathogens following infection with Mycobacterium tuberculosis (M.tb) and vaccination with BCG or a candidate TB vaccine, MTBVAC, in non-human primates. Results: We demonstrate a significant increase in the titer of antibodies against SARS-CoV-2, cytomegalovirus, Epstein-Barr virus, tetanus toxoid, and respiratory syncytial virus antigens following low-dose aerosol infection with M.tb. The magnitude of some of these responses correlated with TB disease severity. However, vaccination with BCG administered by the intradermal, intravenous or aerosol routes, or intradermal delivery of MTBVAC, did not increase antibody responses against unrelated pathogens. Discussion: Our findings suggest that it is unlikely that heterologous antibodies contribute to the non-specific effects of these vaccines. The apparent dysregulation of B cell responses associated with TB disease warrants further investigation, with potential implications for risk of B cell cancers and novel therapeutic strategies.

All-photonic kinase inhibitors: light-controlled release-and-report inhibition.

Light-responsive molecular tools targeting kinases affords one the opportunity to study the underlying cellular function of selected kinases. In efforts to externally control lymphocyte-specific protein tyrosine kinase (LCK) activity, the development of release-and-report LCK inhibitors is described, in which (i) the release of the active kinase inhibitor can be controlled externally with light; and (ii) fluorescence is employed to report both the release and binding of the active kinase inhibitor. This introduces an unprecedented all-photonic method for users to both control and monitor real-time inhibitory activity. A functional cellular assay demonstrated light-mediated LCK inhibition in natural killer cells. The use of coumarin-derived caging groups resulted in rapid cellular uptake and non-specific intracellular localisation, while a BODIPY-derived caging group predominately localised in the cellular membrane. This concept of release-and-report inhibitors has the potential to be extended to other biorelevant targets where both spatiotemporal control in a cellular setting and a reporting mechanism would be beneficial.

Membrane Fluctuation Model for Understanding the Effect of Receptor Nanoclustering on the Activation of Natural Killer Cells through Biomechanical Feedback.

We investigated the role of ligand clustering and density in the activation of natural killer (NK) cells. To that end, we designed reductionist arrays of nanopatterned ligands arranged with different cluster geometries and densities and probed their effects on NK cell activation. We used these arrays as an artificial microenvironment for the stimulation of NK cells and studied the effect of the array geometry on the NK cell immune response. We found that ligand density significantly regulated NK cell activation while ligand clustering had an impact only at a specific density threshold. We also rationalized these findings by introducing a theoretical membrane fluctuation model that considers biomechanical feedback between ligand-receptor bonds and the cell membrane. These findings provide important insight into NK cell mechanobiology, which is fundamentally important and essential for designing immunotherapeutic strategies targeting cancer.

Generation of human alveolar epithelial type I cells from pluripotent stem cells.

Alveolar epithelial type I cells (AT1s) line the gas exchange barrier of the distal lung and have been historically challenging to isolate or maintain in cell culture. Here, we engineer a human in vitro AT1 model system via directed differentiation of induced pluripotent stem cells (iPSCs). We use primary adult AT1 global transcriptomes to suggest benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, enriched in these cells. Next, we generate iPSC-derived alveolar epithelial type II cells (AT2s) and find that nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier producing characteristic extracellular matrix molecules and secreted ligands. Our results provide an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s.

Photoswitchable optoelectronic properties of 2D MoSe2/diarylethene hybrid structures.

The ability to modulate optical and electrical properties of two-dimensional (2D) semiconductors has sparked considerable interest in transition metal dichalcogenides (TMDs). Herein, we introduce a facile strategy for modulating optoelectronic properties of monolayer MoSe2 with external light. Photochromic diarylethene (DAE) molecules formed a 2-nm-thick uniform layer on MoSe2, switching between its closed- and open-form isomers under UV and visible irradiation, respectively. We have discovered that the closed DAE conformation under UV has its lowest unoccupied molecular orbital energy level lower than the conduction band minimum of MoSe2, which facilitates photoinduced charge separation at the hybrid interface and quenches photoluminescence (PL) from monolayer flakes. In contrast, open isomers under visible light prevent photoexcited electron transfer from MoSe2 to DAE, thus retaining PL emission properties. Alternating UV and visible light repeatedly show a dynamic modulation of optoelectronic signatures of MoSe2. Conductive atomic force microscopy and Kelvin probe force microscopy also reveal an increase in conductivity and work function of MoSe2/DAE with photoswitched closed-form DAE. These results may open new opportunities for designing new phototransistors and other 2D optoelectronic devices.

Plasma miR-150-5p in Renal Transplant Recipients with Acute Antibody-Mediated Rejection.

Background: Rejection continues to be the main cause of renal graft loss. Currently, the gold standard for diagnosis is an allograft biopsy; however, because it is time-consuming, costly, and invasive, the pursuit of novel biomarkers has gained interest. Variation in the expressions of miRNAs is currently considered a probable biomarker for the diagnosis of acute rejection. This study aimed to determine whether miR-150-5p in serum is related to microvascular damage in patients with acute antibody-mediated rejection (ABMR). Methods: A total of 27 patients who underwent renal transplantation (RT) with and without ABMR were included in the study. We performed the quantification of hsa-miR-150-5p, hsa-miR-155, hsa-miR-21, hsa-miR-126, and hsa-miR-1 in plasma by RT-qPCR. The expressions between the groups and their correlations with the histological characteristics of the patients with ABMR were also investigated. Results: miR-150-5p significantly increased in the plasma of patients with rejection (p < 0.05), and the changes in miR-150-5p were directly correlated with microvascular inflammation in the allograft biopsies. Clinical utility was determined by ROC analysis with an area under the curve of 0.873. Conclusions: Our results show that the patients with RT with ABMR exhibited increased expression of miR-150-5p compared to patients without rejection, which could have clinical consequences, as well as probable utility in the diagnosis of ABMR, and bioinformatics may help in unraveling the molecular mechanisms underlying ABMR conditions.

A Novel Approach for Colloidal Lithography: From Dry Particle Assembly to High-Throughput Nanofabrication.

We introduce a novel approach for colloidal lithography based on the dry particle assembly into a dense monolayer on an elastomer, followed by mechanical transfer to a substrate of any material and curvature. This method can be implemented either manually or automatically and it produces large area patterns with the quality obtained by the state-of-the-art colloidal lithography at a very high throughput. We first demonstrated the fabrication of nanopatterns with a periodicity ranging between 200 nm and 2 µm. We then demonstrated two nanotechnological applications of this approach. The first one is antireflective structures, fabricated on silicon and sapphire, with different geometries including arrays of bumps and holes and adjusted for different spectral ranges. The second one is smart 3D nanostructures for mechanostimulation of T cells that are used for their effective proliferation, with potential application in cancer immunotherapy. This new approach unleashes the potential of bottom-up nanofabrication and paves the way for nanoscale devices and systems in numerous applications.

LncRNA MALAT1 in Keratinocyte function: A review of recent advances.

Keratinocytes, the principal epidermal cells, play a vital role in maintaining the structural integrity and functionality of the skin. Beyond their protective role, keratinocytes are key contributors to the process of wound healing, as they migrate to injury sites, proliferate, and generate new layers of epidermis, facilitating tissue repair and remodeling. Moreover, keratinocytes actively participate in the skin's immune responses, expressing pattern recognition receptors (PRRs) to detect microbial components and interact with immune cells to influence adaptive immunity. Keratinocytes express a diverse repertoire of signaling pathways, transcription factors, and epigenetic regulators to regulate their growth, differentiation, and response to environmental cues. Among these regulatory elements, long non-coding RNAs (lncRNAs) have emerged as essential players in keratinocyte biology. LncRNAs, including MALAT1, play diverse roles in gene regulation and cellular processes, influencing keratinocyte proliferation, differentiation, migration, and response to environmental stimuli. Dysregulation of specific lncRNAs such as MALAT1 can disrupt keratinocyte homeostasis, leading to impaired differentiation, compromised barrier integrity, and contributing to the pathogenesis of various skin disorders. Understanding the intricate interplay between lncRNAs and keratinocytes offers promising insights into the molecular underpinnings of skin health and disease, with potential implications for targeted therapies and advancements in dermatological research. Hence, our objective is to provide a comprehensive summary of the available knowledge concerning keratinocytes and their intricate relationship with MALAT1.

Modulating the properties and structure of lignins produced by alkaline delignification of sugarcane bagasse pretreated with two different mineral acids at pilot-scale.

Sugarcane bagasse was pretreated with dilute phosphoric acid or sulfuric acid to facilitate cellulose hydrolysis and lignin extraction. With phosphoric acid, only 8 % of the initial cellulose was lost after delignification, whereas pretreatment with sulfuric acid resulted in the solubilization of 38 % of the initial cellulose. After enzymatic hydrolysis, the process using phosphoric acid produced approximately 35 % more glucose than that using sulfuric acid. In general, the lignins showed 95-97 % purity (total lignin, w/w), an average molar mass of 9500-10,200 g mol-1, a glass transition temperature of 140-160 °C, and a calorific value of 25 MJ kg-1. Phosphoric acid lignin (PAL) was slightly more polar than sulfuric acid lignin (SAL). PAL had 13 % more oxidized units and 20 % more OH groups than SAL. Regardless of the acid used, the lignins shared similar properties, but differed slightly in the characteristics of their functional groups and chemical bonds. These findings show that pretreatment catalyzed with either of the two acids resulted in lignin with sufficiently good characteristics for use in industrial processes.

[Incidence and causes of hospitalization in patients with transthyretin (ATTR-CA) and light chain (AL-CA) cardiac amyloidosis]. / Incidencia y causas de hospitalización en pacientes con amiloidosis cardiaca por transtiretina (AC-ATTR) y por cadenas ligeras (AC-AL).

INTRODUCTION AND OBJETIVES: Cardiac amyloidosis (CA) is a disorder associated with high number of hospital admissions. Given the scarce information available, we propose an analysis of the incidence and causes of hospitalization in this disease. MATERIAL AND METHODS: One hundred and forty-three patients [128 by transthyretin (ATTR-CA) and 15 by light chains (AL-CA)] included in Registro de Amiloidosis Cardiaca de Galicia (AMIGAL) were evaluated, including all hospitalizations. RESULTS: During a median follow-up of 959 days there were 179 unscheduled hospitalizations [incidence rate (IR) 512.6 admissions per 1000 patients-year], most common due to cardiovascular reasons (n=109, IR 312.2). Most frequent individual cause of hospitalization was heart failure (n=87, TI 249.2). AL-CA was associated with a higher IR of unscheduled hospitalizations than ATTR-CA (IR 781 vs. 483.2; HR 1.62; p=0,029) due to non-cardiovascular admissions (IR 376 vs. 181.2; HR 2.07; p=0.027). Unscheduled admission-free survival at 1 and 3 years in AL-CA was inferior than in ATTR-CA (46.7% and 20.0% vs. 73.4% and 35.2%, respectively; p=0.021). CONCLUSIONS: CA was associated with high incidence of hospitalizations, being heart failure the most frequent individual cause; unscheduled admission-free survival in AL-CA was lower than in ATTR-CA due mostly to non-cardiovascular admissions.

Wound Bed Preparation 2024: Delphi Consensus on Foot Ulcer Management in Resource-Limited Settings.

GENERAL PURPOSE: To review a practical and scientifically sound application of the wound bed preparation model for communities without ideal resources. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and registered nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Summarize issues related to wound assessment.2. Identify a class of drugs for the treatment of type II diabetes mellitus that has been shown to improve glycemia, nephroprotection, and cardiovascular outcomes.3. Synthesize strategies for wound management, including treatment in resource-limited settings.4. Specify the target time for edge advancement in chronic, healable wounds.

Chronic wound management in low-resource settings deserves special attention. Rural or underresourced settings (ie, those with limited basic needs/healthcare supplies and inconsistent availability of interprofessional team members) may not have the capacity to apply or duplicate best practices from urban or abundantly-resourced settings. The authors linked world expertise to develop a practical and scientifically sound application of the wound bed preparation model for communities without ideal resources. A group of 41 wound experts from 15 countries reached a consensus on wound bed preparation in resource-limited settings. Each statement of 10 key concepts (32 substatements) reached more than 88% consensus. The consensus statements and rationales can guide clinical practice and research for practitioners in low-resource settings. These concepts should prompt ongoing innovation to improve patient outcomes and healthcare system efficiency for all persons with foot ulcers, especially persons with diabetes.