Injectable Hydrogels for Nervous Tissue Repair-A Brief Review.

The repair of nervous tissue is a critical research field in tissue engineering because of the degenerative process in the injured nervous system. In this review, we summarize the progress of injectable hydrogels using in vitro and in vivo studies for the regeneration and repair of nervous tissue. Traditional treatments have not been favorable for patients, as they are invasive and inefficient; therefore, injectable hydrogels are promising for the treatment of damaged tissue. This review will contribute to a better understanding of injectable hydrogels as potential scaffolds and drug delivery system for neural tissue engineering applications.

Legionnaires Disease in Solid Organ Transplant Recipients: A Decade-Long Nationwide Study in France.

BACKGROUND: Legionnaires disease (LD) is a rare, life-threatening opportunistic bacterial infection that poses a significant risk to patients with impaired cell-mediated immunity such as solid organ transplant recipients. However, the epidemiologic features, clinical presentation, and outcomes of LD in this population are poorly described. RESEARCH QUESTION: What are the clinical manifestations, radiologic presentation, risk factors for severity, treatment, and outcome of LD in solid organ transplant recipients? STUDY DESIGN AND METHODS: In this 10-year multicenter retrospective cohort study in France, where LD notification is mandatory, patients were identified by hospital discharge databases. Diagnosis of LD relied on positive culture findings from any respiratory sample, positive urinary antigen test (UAT) results, positive specific serologic findings, or a combination thereof. Severe LD was defined as admission to the ICU. RESULTS: One hundred one patients from 51 transplantation centers were eligible; 64 patients (63.4%) were kidney transplant recipients. Median time between transplantation and LD was 5.6 years (interquartile range, 1.5-12 years). UAT results were positive in 92% of patients (89/97). Among 31 patients with positive culture findings in respiratory samples, Legionella pneumophila serogroup 1 was identified in 90%. Chest CT imaging showed alveolar consolidation in 98% of patients (54 of 57), ground-glass opacity in 63% of patients (36 of 57), macronodules in 21% of patients (12 of 57), and cavitation in 8.8% of patients (5 of 57). Fifty-seven patients (56%) were hospitalized in the ICU. In multivariate analysis, severe LD was associated with negative UAT findings at presentation (P = .047), lymphopenia (P = .014), respiratory symptoms (P = .010), and pleural effusion (P = .039). The 30-day and 12-month mortality rates were 8% (8 of 101) and 20% (19 of 97), respectively. In multivariate analysis, diabetes mellitus was the only factor associated with 12-month mortality (hazard ratio, 3.2; 95% OR, 1.19-8.64; P = .022). INTERPRETATION: LD is a late and severe complication occurring in solid organ transplant recipients that may present as pulmonary nodules on which diabetes impacts its long-term prognosis.

Domestic Animal Models of Central Nervous System Tumors: Focus on Meningiomas.

Intracranial primary tumors (IPTs) are aggressive forms of malignancies that cause high mortality in both humans and domestic animals. Meningiomas are frequent adult IPTs in humans, dogs, and cats, and both benign and malignant forms cause a decrease in life quality and survival. Surgery is the primary therapeutic approach to treat meningiomas, but, in many cases, it is not resolutive. The chemotherapy and targeted therapy used to treat meningiomas also display low efficacy and many side effects. Therefore, it is essential to find novel pharmacological approaches to increase the spectrum of therapeutic options for meningiomas. This review analyzes the similarities between human and domestic animal (dogs and cats) meningiomas by evaluating the molecular and histological characteristics, diagnosis criteria, and treatment options and highlighting possible research areas to identify novel targets and pharmacological approaches, which are useful for the diagnosis and therapy of this neoplasia to be used in human and veterinary medicine.

Qualitative Analysis of the Content Validity of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) in Schizophrenia: A Multi-Stakeholder Perspective.

The US Food and Drug Agency (FDA) requires clinical trials targeting cognitive impairment associated with schizophrenia (CIAS) to demonstrate the functional relevance of cognitive improvements by employing a functional co-primary measure. Although quantitative evidence supports the suitability of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) for this purpose, FDA guidelines for qualification of clinical outcome assessments require evidence of content validity, defined as qualitative evidence that key stakeholders view the measure as relevant and important. To collect this important qualitative data, semi-structured interviews were conducted with outpatients with schizophrenia (n = 24), caregivers (n = 12), and professional peer support specialists (n = 12) to elicit their views about the definition and importance of functional independence, the importance of the functional domains assessed by the VRFCAT (meal planning, using transportation, handling money, shopping), and the relevance of the VRFCAT tasks to these domains. Qualitative thematic analyses revealed consistent themes across groups in defining functional independence, including performing instrumental self-care, financial, and social tasks; making decisions autonomously; and not depending on others to carry out daily activities. There were, however, notable differences in their views regarding the importance of and barriers to functional independence. All groups viewed the VRFCAT as assessing skill domains that are central to independent functioning and, with some minor differences, the VRFCAT tasks were viewed as relevant and meaningful examples of the domains. These qualitative results provide converging evidence that key stakeholders view the VRFCAT as a content-valid measure.

Acute Chagas Disease Presenting as Preseptal Cellulitis.

Chagas disease, also known as American trypanosomiasis, is caused by Trypanosoma cruzi, a parasite transmitted by hematophagous triatomine insects (subfamily Triatominae) belonging to the Reduviidae family, order Hemiptera. Infection occurs through contact with the feces of the infected vector at the site of its bite or on intact mucosa. [Pediatr Ann. 2023;52(10):e394-e397.].

Self-regulation learning as active inference: dynamic causal modeling of an fMRI neurofeedback task.

Introduction: Learning to self-regulate brain activity by neurofeedback has been shown to lead to changes in the brain and behavior, with beneficial clinical and non-clinical outcomes. Neurofeedback uses a brain-computer interface to guide participants to change some feature of their brain activity. However, the neural mechanism of self-regulation learning remains unclear, with only 50% of the participants succeeding in achieving it. To bridge this knowledge gap, our study delves into the neural mechanisms of self-regulation learning via neurofeedback and investigates the brain processes associated with successful brain self-regulation. Methods: We study the neural underpinnings of self-regulation learning by employing dynamical causal modeling (DCM) in conjunction with real-time functional MRI data. The study involved a cohort of 18 participants undergoing neurofeedback training targeting the supplementary motor area. A critical focus was the comparison between top-down hierarchical connectivity models proposed by Active Inference and alternative bottom-up connectivity models like reinforcement learning. Results: Our analysis revealed a crucial distinction in brain connectivity patterns between successful and non-successful learners. Particularly, successful learners evinced a significantly stronger top-down effective connectivity towards the target area implicated in self-regulation. This heightened top-down network engagement closely resembles the patterns observed in goal-oriented and cognitive control studies, shedding light on the intricate cognitive processes intertwined with self-regulation learning. Discussion: The findings from our investigation underscore the significance of cognitive mechanisms in the process of self-regulation learning through neurofeedback. The observed stronger top-down effective connectivity in successful learners indicates the involvement of hierarchical cognitive control, which aligns with the tenets of Active Inference. This study contributes to a deeper understanding of the neural dynamics behind successful self-regulation learning and provides insights into the potential cognitive architecture underpinning this process.

Sub-MIC antibiotics influence the microbiome, resistome and structure of riverine biofilm communities.

The effects of sub-minimum inhibitory concentrations (sub-MICs) of antibiotics on aquatic environments is not yet fully understood. Here, we explore these effects by employing a replicated microcosm system fed with river water where biofilm communities were continuously exposed over an eight-week period to sub-MIC exposure (1/10, 1/50, and 1/100 MIC) to a mix of common antibiotics (ciprofloxacin, streptomycin, and oxytetracycline). Biofilms were examined using a structure-function approach entailing microscopy and metagenomic techniques, revealing details on the microbiome, resistome, virulome, and functional prediction. A comparison of three commonly used microbiome and resistome databases was also performed. Differences in biofilm architecture were observed between sub-MIC antibiotic treatments, with an overall reduction of extracellular polymeric substances and autotroph (algal and cyanobacteria) and protozoan biomass, particularly at the 1/10 sub-MIC condition. While metagenomic analyses demonstrated that microbial diversity was lowest at the sub-MIC 1/10 antibiotic treatment, resistome diversity was highest at sub-MIC 1/50. This study also notes the importance of benchmarking analysis tools and careful selection of reference databases, given the disparity in detected antimicrobial resistance genes (ARGs) identity and abundance across methods. Ultimately, the most detected ARGs in sub-MICs exposed biofilms were those that conferred resistance to aminoglycosides, tetracyclines, ß-lactams, sulfonamides, and trimethoprim. Co-occurrence of microbiome and resistome features consistently showed a relationship between Proteobacteria genera and aminoglycoside ARGs. Our results support the hypothesis that constant exposure to sub-MICs antibiotics facilitate the transmission and promote prevalence of antibiotic resistance in riverine biofilms communities, and additionally shift overall microbial community metabolic function.

Eculizumab as a therapeutic approach for severe crescentic recurrence of immunoglobulin A nephropathy after kidney transplantation.

Crescentic forms of immunoglobulin A nephropathy (IgAN) are rare but can be associated with rapid kidney failure and a high rate of end-stage renal disease despite immunosuppression therapy. Complement activation has emerged as a key driver of glomerular injury in IgAN. Therefore, complement inhibitors may be a rational treatment option in patients unresponsive to first-line immunosuppressive therapy. Here, we describe the case of a 24-year-old woman presenting with crescentic IgAN recurrence a few months after living kidney transplantation. Considering the dramatic graft failure accompanied by malignant hypertension and thrombotic microangiopathy features worsening after a first-line of high-dose steroids and 3 sessions of plasma exchanges, eculizumab was started as a rescue therapy. For the first time, the clinical response to eculizumab was highly successful, with a complete graft recovery without any relapse after 1 year of treatment. Further clinical studies are strongly needed to specify which patients might benefit from terminal complement blockade.

Lipid Metabolism Reprogramming and Trastuzumab Resistance in Breast Cancer Cell Lines Overexpressing the ERBB2 Membrane Receptor.

Trastuzumab (Tz), an antibody targeting ERBB2, has significantly improved the prognosis for breast cancer (BCa) patients with overexpression of the ERBB2 receptor. However, Tz resistance poses a challenge to patient outcomes. Numerous mechanisms have been suggested to contribute to Tz resistance, and this study aimed to uncover shared mechanisms in in vitro models of acquired BCa Tz resistance. Three widely used ERBB2+ BCa cell lines, adapted to grow in Tz, were examined. Despite investigating potential changes in phenotype, proliferation, and ERBB2 membrane expression in these Tz-resistant (Tz-R) cell lines compared to wild-type (wt) cells, no common alterations were discovered. Instead, high-resolution mass spectrometry analysis revealed a shared set of differentially expressed proteins (DEPs) in Tz-R versus wt cells. Bioinformatic analysis demonstrated that all three Tz-R cell models exhibited modulation of proteins associated with lipid metabolism, organophosphate biosynthesis, and macromolecule methylation. Ultrastructural examination corroborated the presence of altered lipid droplets in resistant cells. These findings strongly support the notion that intricate metabolic adaptations, including lipid metabolism, protein phosphorylation, and potentially chromatin remodeling, may contribute to Tz resistance. The detection of 10 common DEPs across all three Tz-resistant cell lines offers promising avenues for future therapeutic interventions, providing potential targets to overcome Tz resistance and potentially improve patient outcomes in ERBB2+ breast cancer.

Porous Chitosan Hydrogels Produced by Physical Crosslinking: Physicochemical, Structural, and Cytotoxic Properties.

Chitosan hydrogels are biomaterials with excellent potential for biomedical applications. In this study, chitosan hydrogels were prepared at different concentrations and molecular weights by freeze-drying. The chitosan sponges were physically crosslinked using sodium bicarbonate as a crosslinking agent. The X-ray spectroscopy (XPS and XRD diffraction), equilibrium water content, microstructural morphology (confocal microscopy), rheological properties (temperature sweep test), and cytotoxicity of the chitosan hydrogels (MTT assay) were investigated. XPS analysis confirmed that the chitosan hydrogels obtained were physically crosslinked using sodium bicarbonate. The chitosan samples displayed a semi-crystalline nature and a highly porous structure with mean pore size between 115.7 ± 20.5 and 156.3 ± 21.8 µm. In addition, the chitosan hydrogels exhibited high water absorption, showing equilibrium water content values from 23 to 30 times their mass in PBS buffer and high thermal stability from 5 to 60 °C. Also, chitosan hydrogels were non-cytotoxic, obtaining cell viability values ≥ 100% for the HT29 cells. Thus, physically crosslinked chitosan hydrogels can be great candidates as biomaterials for biomedical applications.

Evaluation of the Biological Properties of an Optimized Extract of Polygonum cuspidatum Using Ultrasonic-Assisted Extraction.

Phytochemicals are natural compounds found in plants that have potential health benefits such as antioxidants, anti-inflammatory and anti-cancer properties, and immune reinforcement. Polygonum cuspidatum Sieb. et Zucc. is a source rich in resveratrol, traditionally consumed as an infusion. In this study, P. cuspidatum root extraction conditions were optimized to increase antioxidant capacity (DPPH, ABTS+), extraction yield, resveratrol concentration, and total polyphenolic compounds (TPC) via ultrasonic-assisted extraction using a Box-Behnken design (BBD). The biological activities of the optimized extract and the infusion were compared. The optimized extract was obtained using a solvent/root powder ratio of 4, 60% ethanol concentration, and 60% ultrasonic power. The optimized extract showed higher biological activities than the infusion. The optimized extract contained 16.6 mg mL-1 resveratrol, high antioxidant activities (135.1 µg TE mL-1 for DPPH, and 230.4 µg TE mL-1 for ABTS+), TPC (33.2 mg GAE mL-1), and extraction yield of 12.4%. The EC50 value (effective concentration 50) of the optimized extract was 0.194 µg mL-1, which revealed high cytotoxic activity against the Caco-2 cell line. The optimized extract could be used to develop functional beverages with high antioxidant capacity, antioxidants for edible oils, functional foods, and cosmetics.

Gender Differences in Routine Health Maintenance Examinations Before and During the COVID-19 Pandemic.

PURPOSE: Adolescent and young adult (AYA) males historically have lower healthcare utilization than their female peers. METHODS: Electronic health record data from an Adolescent/Young Adult Medicine outpatient practice were reviewed to assess gender differences in routine health maintenance examinations before and during the COVID-19 pandemic. RESULTS: Routine health maintenance examinations decreased for both males and females during the pandemic. However, a two-proportion z-test demonstrated that established male patients were statistically less likely (p < .01) to have a routine health maintenance examination from December 2020 to December 2021 than their female counterparts. DISCUSSION: AYA males are at a higher risk for persistent disengagement in healthcare and exacerbates future gender gaps in healthcare utilization. Primary care providers need to focus efforts on re-engaging all young people in preventive care, with specific efforts tailored to AYA males.

Fraisinib: a calixpyrrole derivative reducing A549 cell-derived NSCLC tumor in vivo acts as a ligand of the glycine-tRNA synthase, a new molecular target in oncology.

Background and purpose: Lung cancer is the leading cause of death in both men and women, constituting a major public health problem worldwide. Non-small-cell lung cancer accounts for 85%-90% of all lung cancers. We propose a compound that successfully fights tumor growth in vivo by targeting the enzyme GARS1. Experimental approach: We present an in-depth investigation of the mechanism through which Fraisinib [meso-(p-acetamidophenyl)-calix(4)pyrrole] affects the human lung adenocarcinoma A549 cell line. In a xenografted model of non-small-cell lung cancer, Fraisinib was found to reduce tumor mass volume without affecting the vital parameters or body weight of mice. Through a computational approach, we uncovered that glycyl-tRNA synthetase is its molecular target. Differential proteomics analysis further confirmed that pathways regulated by Fraisinib are consistent with glycyl-tRNA synthetase inhibition. Key results: Fraisinib displays a strong anti-tumoral potential coupled with limited toxicity in mice. Glycyl-tRNA synthetase has been identified and validated as a protein target of this compound. By inhibiting GARS1, Fraisinib modulates different key biological processes involved in tumoral growth, aggressiveness, and invasiveness. Conclusion and implications: The overall results indicate that Fraisinib is a powerful inhibitor of non-small-cell lung cancer growth by exerting its action on the enzyme GARS1 while displaying marginal toxicity in animal models. Together with the proven ability of this compound to cross the blood-brain barrier, we can assess that Fraisinib can kill two birds with one stone: targeting the primary tumor and its metastases "in one shot." Taken together, we suggest that inhibiting GARS1 expression and/or GARS1 enzymatic activity may be innovative molecular targets for cancer treatment.

Two calix[4]pyrroles as potential therapeutics for castration-resistant prostate cancer.

Macrocyclic compounds meso-(p-acetamidophenyl)-calix[4]pyrrole and meso-(m-acetamidophenyl)-calix[4]pyrrole have previously been reported to exhibit cytotoxic properties towards lung cancer cells. Here, we report pre-clinical in vitro and in vivo studies showing that these calixpyrrole derivatives can inhibit cell growth in both PC3 and DU145 prostatic cancer cell lines. We explored the impact of these compounds on programmed cell death, as well as their ability to inhibit cellular invasion. In this study we have demonstrated the safety of these macrocyclic compounds by cytotoxicity tests on ex-vivo human peripheral blood mononuclear cells (PBMCs), and by in vivo subcutaneous administration. Preliminary in vivo tests demonstrated no hepato-, no nephro- and no genotoxicity in Balb/c mice compared to controls treated with cisplatin. These findings suggest these calixpyrroles might be novel therapeutic tools for the treatment of prostate cancer and of particular interest for the treatment of androgen-independent castration-resistant prostate cancer.

Prediction of Vaccine Response and Development of a Personalized Anti-SARS-CoV-2 Vaccination Strategy in Kidney Transplant Recipients: Results from a Large Single-Center Study.

Kidney transplant recipients (KTRs) displays marked inter-individual variations in magnitude of immune responses to anti-SARS-CoV-2 vaccination. The aim of this large single-center study was to identify the predictive factors for serological response to the mRNA-1273 vaccine in KTRs. We also devised a score to optimize prediction with the goal of implementing a personalized vaccination strategy. The study population consisted of 564 KTRs who received at least two doses of the mRNA-1273 vaccine. Anti-RBD IgG titers were quantified one month after each vaccine dose and until six months thereafter. A third dose vaccine was given when the antibody titer after the second dose was <143 BAU/mL. A score to optimize prediction of vaccine response was devised using the independent predictors identified in multivariate analysis. The seropositivity rate after the second dose was 46.6% and 22.2% of participants were classified as good responders (titers ≥ 143 BAU/mL). On analyzing the 477 patients for whom serology testing was available after the second or third dose, the global seropositivity rate was 69% (good responders: 46.3%). Immunosuppressive drugs, graft function, age, interval from transplantation, body mass index, and sex were associated with vaccine response. The devised score was strongly associated with the seropositivity rate (AUC = 0.752, p < 0.0001) and the occurrence of a good antibody response (AUC = 0.785, p < 0.0001). Notably, antibody titers declined over time both after the second and third vaccine doses. In summary, a high burden of comorbidities and immunosuppression was correlated with a weaker antibody response. A fourth vaccine dose and/or pre-exposure prophylaxis with monoclonal antibodies should be considered for KTRs who remain unprotected.

Sexual violence experiences among adolescent and young adult males: a review to empower healthcare providers.

PURPOSE OF REVIEW: Despite 3-17% of adolescent and young adult males (AYAMs) experiencing sexual violence, there is a paucity of information regarding their sexual violence experiences leaving them vulnerable to dangerous and detrimental sequelae. RECENT FINDINGS: There is underreporting and under-discussion of AYAMs' experiences of sexual violence, with disclosure influenced by societal perceptions of male sexuality, shame, and fear of discrimination. AYAMs experience sexual violence from individuals known to them, with many experiencing physical violence, threats, coercion, and electronic harassment. Intersectionality, previous traumas, inappropriate childhood exposures to sexually explicit situations, select online media consumption, and adverse childhood experiences (ACEs) increase the risk of sexual violence. AYAMs who experience sexual violence are at increased risk of re-victimization, perpetrating sexual violence, experiencing bodily harm, contracting sexually transmitted infections (STIs), and experiencing internalizing and externalizing symptoms, which can lead to significant morbidity and mortality. Research on male-specific protective and resilience factors is scarce and represents an ongoing need. SUMMARY: After reviewing AYAMs' experiences of sexual violence, including risk and protective factors, media influences, detrimental sequelae, and resilience factors, we provide a screening framework to empower the healthcare provider (HCP) to champion tailored prevention, screening, intervention, and advocacy efforts to support AYAMs.