Multifactoral immune modulation potentiates durable remission in multiple models of aggressive malignancy.

Tumors typically lack canonical danger signals required to activate adaptive immunity and also frequently employ substantial immunomodulatory mechanisms that downregulate adaptive responses and contribute to escape from immune surveillance. Given the variety of mechanisms involved in shielding tumors from immune recognition, it is not surprising that single-agent immunomodulatory approaches have been largely unsuccessful in generating durable antitumor responses. Here we report a unique combination of immunomodulatory and cytostatic agents that recondition the tumor microenvironment and eliminate complex and/or poor-prognosis tumor types including the non-immunogenic 4T-1 model of TNBC, the aggressive MOC-2 model of HNSCC, and the high-risk MYCN-amplified model of neuroblastoma. A course of therapy optimized for TNBC cured a majority of tumors in both ectopic and orthotopic settings and eliminated metastatic spread in all animals tested at the highest doses. Immune responses were transferable between therapeutic donor and naïve recipient through adoptive transfer, and a sizeable abscopal effect on distant, untreated lesions could be demonstrated experimentally. Similar results were observed in HNSCC and neuroblastoma models, with characteristic remodeling of the tumor microenvironment documented in all model systems. scRNA-seq analysis implicated upregulation of innate immune responses and antigen presentation in tumor cells and the myeloid cell compartment as critical early events. This analysis also highlighted the potential importance of the autonomic nervous system in the governance of inflammatory processes. The data indicate that the targeting of multiple pathways and mechanisms of action can result in substantial synergistic antitumor effects and suggest follow-up in the neoadjuvant setting may be warranted.

Exploration of low-frequency allelic variants of SARS-CoV-2 genomes reveals coinfections in Mexico occurred during periods of VOCs turnover.

A total of 14 973 alleles in 29 661 sequenced samples collected between March 2021 and January 2023 by the Mexican Consortium for Genomic Surveillance (CoViGen-Mex) and collaborators were used to construct a thorough map of mutations of the Mexican SARS-CoV-2 genomic landscape containing Intra-Patient Minor Allelic Variants (IPMAVs), which are low-frequency alleles not ordinarily present in a genomic consensus sequence. This additional information proved critical in identifying putative coinfecting variants included alongside the most common variants, B.1.1.222, B.1.1.519, and variants of concern (VOCs) Alpha, Gamma, Delta, and Omicron. A total of 379 coinfection events were recorded in the dataset (a rate of 1.28 %), resulting in the first such catalogue in Mexico. The most common putative coinfections occurred during the spread of Delta or after the introduction of Omicron BA.2 and its descendants. Coinfections occurred constantly during periods of variant turnover when more than one variant shared the same niche and high infection rate was observed, which was dependent on the local variants and time. Coinfections might occur at a higher frequency than customarily reported, but they are often ignored as only the consensus sequence is reported for lineage identification.

The ecto-enzyme CD38 modulates CD4 T cell immunometabolic responses and participates in HIV pathogenesis.

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4 T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after TCR-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular NAD and NMN concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the OCR/ECAR ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ectoCD38 catalytic activity in memory CD4 T cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous pro-inflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morpho-functionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4 T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.

Artificial intelligence-powered discovery of small molecules inhibiting CTLA-4 in cancer.

BACKGROUND/OBJECTIVES: Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4. SUBJECTS/METHODS: In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the hits molecules with biochemical, biophysical, immunological, and experimental animal assays. RESULTS: The primary hits obtained from the virtual screening were successfully validated in vitro and in vivo. We then optimized lead compounds and obtained inhibitors (inhibitory concentration, 1 micromole) that disrupted the CTLA-4/CD80 interaction without degrading CTLA-4. CONCLUSIONS: Several compounds inhibited tumor development prophylactically and therapeutically in syngeneic and CTLA-4-humanized mice. Our findings support using AI-based frameworks to design small molecules targeting immune checkpoints for cancer therapy.

An amplicon-based protocol for whole-genome sequencing of human respiratory syncytial virus subgroup A.

It is convenient to study complete genome sequences of human respiratory syncytial virus (hRSV) for ongoing genomic characterization and identification of highly transmissible or pathogenic variants. Whole genome sequencing of hRSV has been challenging from respiratory tract specimens with low viral loads. Herein, we describe an amplicon-based protocol for whole genome sequencing of hRSV subgroup A validated with 24 isolates from nasopharyngeal swabs and infected cell cultures, which showed cycle threshold (Ct) values ranging from 10 to 31, as determined by quantitative reverse-transcription polymerase chain reaction. MinION nanopore generated 3200 to 5400 reads per sample to sequence over 93% of the hRSV-A genome. Coverage of each contig ranged from 130× to 200×. Samples with Ct values of 20.9, 25.2, 27.1, 27.7, 28.2, 28.8, and 29.6 led to the sequencing of over 99.0% of the virus genome, indicating high genome coverage even at high Ct values. This protocol enables the identification of hRSV subgroup A genotypes, as primers were designed to target highly conserved regions. Consequently, it holds potential for application in molecular epidemiology and surveillance of this hRSV subgroup.

Highly deformable and strongly magnetic semi-interpenetrating hydrogels based on alginate or cellulose.

The effective implementation of many of the applications of magnetic hydrogels requires the development of innovative systems capable of withstanding a substantial load of magnetic particles to ensure exceptional responsiveness, without compromising their reliability and stability. To address this challenge, double-network hydrogels have emerged as a promising foundation, thanks to their extraordinary mechanical deformability and toughness. Here, we report a semi-interpenetrating polymer networks (SIPNs) approach to create diverse magnetic SIPNs hydrogels based on alginate or cellulose, exhibiting remarkable deformability under certain stresses. Achieving strong responsiveness to magnetic fields is a key objective, and this characteristic is realized by the incorporation of highly magnetic iron microparticles at moderately large concentrations into the polymer network. Remarkably, the SIPNs hydrogels developed in this research accommodate high loadings of magnetic particles without significantly compromising their physical properties. This feature is essential for their use in applications that demand robust responsiveness to applied magnetic fields and overall stability, such as a hydrogel luminescent oxygen sensor controlled by magnetic fields that we designed and tested as proof-of-concept. These findings underscore the potential and versatility of magnetic SIPNs hydrogels based on carbohydrate biopolymers as fundamental components in driving the progress of advanced hydrogels for diverse practical implementations.

Real-World Effectiveness and Safety of SDZ ETN, an Etanercept Biosimilar, in Patients with Rheumatic Diseases: Final Results from Multi-Country COMPACT Study.

INTRODUCTION: COMPACT, a non-interventional study, evaluated the persistence, effectiveness, safety and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA), axial-spondyloarthritis (axSpA) or psoriatic arthritis (PsA) treated with SDZ ETN (etanercept [ETN] biosimilar) in Europe and Canada. METHODS: Patients (aged ≥ 18 years) who have been treated with SDZ ETN were categorised on the basis of prior treatment status (groups A-D): patients in clinical remission or with low disease activity under treatment with reference ETN or biosimilar ETN and switched to SDZ ETN; patients who received non-ETN targeted therapies and switched to SDZ ETN; biologic-naïve patients who started SDZ ETN after conventional therapy failure; or disease-modifying anti-rheumatic drug (DMARD)-naïve patients with RA considered suitable for treatment initiation with a biologic and started on treatment with SDZ ETN. The primary endpoint was drug persistence, defined as time from study enrolment until discontinuation of SDZ ETN treatment. RESULTS: Of the 1466 patients recruited, 844 (57.6%) had RA, 334 (22.8%) had axSpA and 288 (19.6%) had PsA. Patients had an ongoing SDZ ETN treatment at the time of enrolment for an observed average of 138 days (range 1-841); 22.7% of patients discontinued SDZ ETN through 12 months of study observation. Overall, all the patients receiving SDZ ETN showed good treatment persistence at 12 months with discontinuation rates of 15.2%, 25.7% and 27.8% in groups A, B and C, respectively. Across all patient groups, no major differences were observed in the disease activity and PRO scores between baseline and month 12. Injection-site reactions were low across the treatment groups. CONCLUSION: These results support the effectiveness and safety of SDZ ETN treatment in patients with RA, axSpA or PsA in real-life conditions. The treatment persistence rates observed were consistent with previously published reports of patients treated with reference or other biosimilar ETN. No new safety signals were identified.

Quality indicators and satisfaction with care in patients with systemic lupus erythematosus.

Grading the quality of care in patients with systemic lupus erythematosus and determining its relationship with care satisfaction may recognize gaps that could lead to better clinical practice. Eighteen quality indicators (QIs) were recently developed and validated for patients with SLE based on the 2019 EULAR management recommendations. Few studies have analyzed the relationship between quality of care and care satisfaction in patients with lupus. This was a cross-sectional study. We included patients at least 18 years old who met the EULAR/ACR 2019 classification criteria for SLE. We interviewed patients and retrieved data from medical records to assess their compliance with a set of 18 EULAR-based QIs. We calculated each QI fulfillment as the proportion of fulfilled QI divided by the number of eligible patients for each indicator. Care satisfaction was evaluated with the satisfaction domain of LupusPRO version 1.7. Spearman correlation coefficient was used to determine the relationship between quality of care and care satisfaction. Seventy patients with a median age of 33 (IQR 23-48) were included, 90% were women. Overall adherence was 62.29%. The median care satisfaction was 100. Global adherence to the 18-QIs and the care satisfaction score revealed no correlation (r = 0.064, p = 0.599). Higher QI fulfillment was found in the group with remission versus the moderate-high activity group (p = 0.008). In our study, SLE patients in remission had higher fulfillment of quality indicators. We found no correlation between the quality of care and satisfaction with care.

Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases.

The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.

Conocimiento de la enfermedad venosa crónica en los profesionales sanitarios en España / Knowledge of chronic venous disease among healthcare professionals in Spain

Introducción La enfermedad venosa crónica (EVC) está catalogada como la enfermedad vascular más prevalente en el ser humano. Se ha asociado con un aumento de la incidencia de enfermedades cardiovasculares y es un fuerte predictor de mortalidad por todas las causas, suponiendo un problema de salud pública de primera magnitud. El objetivo de este estudio fue analizar las actuaciones en el manejo de la EVC en la práctica clínica diaria de los profesionales sanitarios en España. Material y métodos Estudio observacional, descriptivo y transversal con recogida de datos a través de una encuesta de opinión de 22 preguntas cumplimentadas electrónicamente a través de un formulario Google® para profesionales implicados en la atención a la enfermedad venosa crónica. Se analizaron 300 encuestas. Las variables cuantitativas se representaron con medias y desviación estándar y las cualitativas con porcentajes e intervalos de confianza. Resultados Analizadas 300 encuestas; 65,3% eran mujeres. La franja de edad más participativa fue la de mayores de 55 años; 85% de los encuestados consideraba que la EVC es una enfermedad infradiagnosticada e infratratada, con un impacto negativo añadido en lo que se refería al seguimiento durante la pandemia de COVID-19, ya que 91,7% consideraba que no había sido el adecuado. Cuarenta y siete por ciento de los participantes no conocía la clasificación CEAP y 56,3% tampoco la Escala de Severidad Clínica Venosa (VCSS); 92,7% de facultativos prescribía medias de compresión y 74,7% fármacos flebotónicos. La hidrosmina era el fármaco venoactivo más conocido y prescrito (51,7%); 73% de los galenos reconocía no utilizar ningún algoritmo o protocolo para el diagnóstico, tratamiento y seguimiento de la EVC en su práctica clínica habitual y 91% afirmaba que no se les formaba en sus centros de trabajo (AU)

Introduction Chronic venous disease (CVD) is classified as the most prevalent vascular disease in humans. It has been associated with an increased incidence of cardiovascular diseases and is a strong predictor of all-cause mortality, representing a public health problem of the first magnitude. The objective of this study was to analyze the actions in the management of CVD in the daily clinical practice of health professionals in Spain. Material and methods Observational, descriptive and cross-sectional study with data collection through an opinion survey of 22 questions completed electronically through a Google® form for professionals involved in chronic venous disease care. Three hundred surveys were analyzed. The quantitative variables were represented with means and standard deviation and the qualitative ones with percentages and confidence intervals. Results Three hundred surveys analyzed. 65.3% were women. The most participatory age group was over 55 years of age. 85% of those surveyed considered that CVD is an underdiagnosed and undertreated disease, with an added negative impact in terms of follow-up during the Covid-19 pandemic, since 91.7% considered that it had not been adequate. 47% of the participants did not know the CEAP classification and 56.3% did not know the venous clinical severity scale (VCSS). 92.7% of physicians prescribed compression stockings and 74.7% phlebotonic drugs. Hidrosmine was the best known and most prescribed venoactive drug (51.7%). 73% of the doctors recognized that they did not use any algorithm or protocol for the diagnosis, treatment and monitoring of CVD in their usual clinical practice and 91% stated that they were not trained in their workplaces (AU)

Fabrication and Actuation of Magnetic Shape-Memory Materials.

Soft actuators are deformable materials that change their dimensions or shape in response to external stimuli. Among the various stimuli, remote magnetic fields are one of the most attractive forms of actuation, due to their ease of use, fast response, and safety in biological systems. Composites of magnetic particles with polymer matrices are the most common materials for magnetic soft actuators. In this paper, we demonstrate the fabrication and actuation of magnetic shape-memory materials based on hydrogels containing field-structured magnetic particles. These actuators are formed by placing the pregel dispersion into a mold of the desired on-field shape and exposing it to a homogeneous magnetic field until the gel point is reached. At this point, the material may be removed from the mold and fully gelled in the desired off-field shape. The resultant magnetic shape-memory material then transitions between these two shapes when it is subjected to successive cycles of a homogeneous magnetic field, acting as a large deformation actuator. For actuators that are planar in the off-field state, this can result in significant bending to return to the on-field state. In addition, it is possible to make shape-memory materials that twist under the application of a magnetic field. For these torsional actuators, both experimental and theoretical results are given.

Endocarditis infecciosa en pacientes pediátricos de Andalucía (España), 2008-2020 / Infective endocarditis in paediatric patients from Andalusia (Spain), 2008-2020

Introducción: La endocarditis infecciosa (EI) pediátrica es un cuadro grave con mortalidad significativa. La información en España es limitada y procede de series de casos de centros únicos. El objetivo fue describir la epidemiología, la clínica, la microbiología y los resultados de la EI pediátrica en Andalucía. Pacientes y métodos: Estudio descriptivo observacional retrospectivo multicéntrico de pacientes <18años con diagnóstico de EI en 6 hospitales andaluces durante el periodo 2008-2020. Resultados: Se identificaron 44 episodios de EI (41 pacientes) con mediana de edad de 103 meses (RIQ 37-150 meses). Las cardiopatías congénitas (CC) fueron el principal factor predisponente, presente en 34 casos (77%). Un total de 21 (48%) episodios de EI ocurrieron en pacientes con material protésico. Estos tuvieron una mayor tasa de CC (p=0,002) y disfunción orgánica (p=0,04) que aquellos con válvula nativa. La fiebre fue un síntoma prácticamente universal asociada con insuficiencia cardíaca en el 23% de los episodios. Staphylococcus aureus (25%), estafilococos coagulasa negativos (18%) y Streptococcus viridans (14%) fueron los microorganismos aislados con mayor frecuencia y tres (7%) pacientes portadores de catéter venoso central tuvieron una infección fúngica. Se observaron complicaciones tromboembólicas en el 30% de los episodios, y tuvieron requerimientos quirúrgicos el 48% de casos. La mortalidad fue del 9%. El material protésico y la PCR >140mg/l fueron predictores independientes de EI complicada. Conclusiones: Los hallazgos del estudio subrayan la elevada morbilidad de la EI pediátrica. La información generada podría favorecer la identificación de los perfiles epidemiológicos y clínicos de los niños con EI y formas complicadas.(AU)

Introduction: Paediatric infective endocarditis (IE) is a serious condition associated with significant mortality. Information in Spain is limited and comes from case series from single centres. The aim was to describe the epidemiology, clinical features, microbiology and outcome of paediatric IE in Andalusia. Patients and methods: Multi-centre descriptive observational retrospective study of patients <18years old with a diagnosis of IE who were admitted to six Andalusian hospitals during 2008-2020. Results: 44 episodes of IE (41 patients) with a median age of 103months (IQR 37-150 months) were identified. Congenital heart disease (CHD) was the main predisposing factor, identified in 34 cases (77%). A total of 21 (48%) episodes of IE occurred in patients with prosthetic material. These had higher rate of CHD (P=.002) and increased end organ dysfunction (P=.04) compared to those with native valve. Fever was an almost universal symptom, associated in 23% of the episodes with heart failure. Staphylococcus aureus (25%) followed by coagulase-negative staphylococci (18%) and Streptococcus viridans (14%) were the most frequently isolated microorganisms, and three (7%) patients with central venous catheters had a fungal infection. Thromboembolic events were observed in 30% of the episodes, surgical intervention was required in 48% of cases. Mortality rate was 9%. Prosthetic material and CRP >140mg/L were independent predictors of complicated IE. Conclusions: Our findings emphasise the high morbidity of paediatric IE. The information provided could be useful for the identification of epidemiological and clinical profiles of children with IE and complicated forms.(AU)

Psoas muscle analysis as a surrogate marker of sarcopenia and frailty: A multicenter analysis of predictive capacities over short- and long-term outcomes after abdominal aortic aneurysm repair.

OBJECTIVES: Several predictive models exist for estimating the postoperative risks of abdominal aortic aneurysm (AAA) repair, although no particular tool has seen widespread use. We present the results of a multicenter, historic cohort study comparing the predictive capacity of the psoas muscle area (PMA), radiodensity (PMD), and lean muscle area (LMA) as surrogate markers of sarcopenia, over short- and long-term outcomes after AAA repair, compared to the mFI-5 and American Society of Anesthesiologists (ASA) scales. METHODS: Retrospective review was conducted of all consecutive AAA elective repair cases (open or endovascular) in three tertiary-care centers from 2014 to 2019. Cross-sectional PMA, PMD, and LMA at the mid-body of the L3 vertebra were measured by two independent operators in the preoperative computed tomography. Receiver operating characteristic (ROC) curves were used to determine optimal cutoff values. Bivariate analysis, logistic regression, and Cox's proportional hazards models were built to examine the relationship between baseline variables and postoperative mortality, long-term mortality, and complications. RESULTS: 596 patients were included (mean age 72.7 ± 8 years, 95.1% male, 66.9% EVAR). Perioperative mortality was 2.3% (EVAR 1.2% vs open repair 4.6%, p = .015), and no independent predictors could be identified in the multivariate analysis. Conversely, an age over 74 years old (OR 1.84 95%CI 1.25-2.70), previous heart diseases (OR 1.62 95%CI 1.13-2.32), diabetes mellitus (OR 1.61 95%CI 1.13-2.32), and a PMD value over 66 HU (OR 0.58 95%CI 0.39-0.84) acted as independent predictors of long-term mortality in the Cox's proportional hazards model. Heart diseases (congestive heart failure or coronary artery disease), serum creatinine levels over 1.05 mg/dL, and an aneurysm diameter over 60 mm were independent predictors of major complications. CONCLUSION: Surrogate markers of sarcopenia had a poor predictive profile for postoperative mortality after AAA repair in our sample. However, PMD stood out as an independent predictor of long-term mortality. This finding can guide future research and should be confirmed in larger datasets.