Re-evaluation of shellac (E 904) as a food additive and a new application on the extension of use of shellac (E 904) in dietary foods for special medical purposes.

The present opinion deals with the re-evaluation of shellac (E 904) when used as a food additive and with the new application on the extension of use of shellac (E 904) in dietary foods for special medical purposes. The Panel derived an acceptable daily intake (ADI) of 4 mg/kg body weight (bw) per day for wax-free shellac (E 904) produced by physical decolouring, based on a NOAEL of 400 mg/kg bw per day and applying an uncertainty factor of 100. The Panel concluded that the ADI of 4 mg/kg bw per day should be considered temporary for wax-free shellac (E 904) produced by chemical bleaching, while new data are generated on the identity and levels of the organochlorine impurities in E 904. This ADI is not applicable for wax-containing shellac as a food additive. For several age groups, the ADI was exceeded at the 95th percentile in the non-brand-loyal exposure assessment scenario and maximum level exposure assessment scenario. Considering the low exceedance and the fact that both the exposure estimation and the toxicological evaluation of shellac were conservative, the panel concluded that the calculated exceedance of the ADI does not indicate a safety concern. The Panel recommended to the European Commission separating specifications for E 904 depending on the manufacturing process, chemical bleaching and physical decolouring, because they result in different impurities; revising the definition of the food additive to include a description of each manufacturing process; deleting information on wax-containing shellac from the EU specifications; revising the acid value for wax-free shellac produced by chemical bleaching; lowering the maximum limit for lead; to consider introducing limits for other toxic elements potentially present in shellac; including a maximum limit for chloroform and total inorganic chloride in the EU specification for shellac produced by chemical bleaching.

Flavouring Group Evaluation 80, Revision 2 (FGE.80Rev2): Consideration of alicyclic, alicyclic-fused and aromatic-fused ring lactones evaluated by the JECFA (61st and 82nd meetings) structurally related to an aromatic lactone evaluated in FGE.27.

The EFSA Panel on Food Additives and Flavourings was requested to evaluate 14 flavouring substances assigned to the Flavouring Group Evaluation 80 (FGE.80), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Thirteen substances have already been considered in FGE.80 and its revision and in FGE.96 [FL-no: 10.005, 10.024, 10.025, 10.050, 10.061, 10.069, 10.070, 10.072, 10.169, 13.009, 13.012, 13.161 and 16.055]. The remaining flavouring substance 3a,4,5,7a-tetrahydro-3,6-dimethylbenzofuran-2(3H)-one [FL-no: 10.057] has been cleared with respect to genotoxicity in FGE.217Rev3 and it is considered in this revision 2 of FGE.80. The substance [FL-no: 10.057] was evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, threshold of toxicological concern (TTC) and available data on metabolism and toxicity. The Panel concluded that [FL-no: 10.057] does not give rise to safety concerns at its levels of dietary intake, when estimated on the basis of the 'Maximised Survey-derived Daily Intake' (MSDI) approach. Besides the safety assessment of the flavouring substance, the specifications for the material of commerce have also been considered and the information provided was complete for [FL-no: 10.057]. However, for the flavouring substance [FL-no: 10.057] in the present revision and for eight substances evaluated in previous revisions, the 'modified Theoretical Added Maximum Daily Intakes' (mTAMDIs) values are above the TTC for their structural class (III). For four substances previously evaluated in FGE.80Rev1 and in FGE.96, use levels are still needed to calculate the mTAMDI estimates. Therefore, in total for 13 flavouring substances, data on uses and use levels should be provided to finalise their safety evaluations. For [FL-no: 10.050, 10.069 and 13.161], information on the composition of stereoisomeric mixtures is needed.

Proton pump inhibitor effect on esophageal protein signature of eosinophilic esophagitis, prediction, and evaluation of treatment response.

BACKGROUND: Recently, we have identified a dysregulated protein signature in the esophageal epithelium of eosinophilic esophagitis (EoE) patients including proteins associated with inflammation and epithelial barrier function; however, the effect of proton pump inhibitor (PPI) treatment on this signature is unknown. Herein, we used a proteomic approach to investigate: (1) whether PPI treatment alters the esophageal epithelium protein profile observed in EoE patients and (2) whether the protein signature at baseline predicts PPI response. METHODS: We evaluated the protein signature of esophageal biopsies using a cohort of adult EoE (n = 25) patients and healthy controls (C) (n = 10). In EoE patients, esophageal biopsies were taken before (pre) and after (post) an 8-week PPI treatment, determining the histologic response. Eosinophil count PostPPI was used to classify the patients: ≥15 eosinophils/hpf as non-responders (non-responder) and < 15 eosinophils/hpf as responders (R). Protein signature was determined and differentially accumulated proteins were characterized to identify altered biological processes and signaling pathways. RESULTS: Comparative analysis of differentially accumulated proteins between groups revealed common signatures between three groups of patients with inflammation (responder-PrePPI, non-responder-PrePPI, and non-responder-PostPPI) and without inflammation (controls and responder-PostPPI). PPI therapy almost reversed the EoE specific esophageal protein signature, which is enriched in pathways associated with inflammation and epithelial barrier function, in responder-PostPPI. Furthermore, we identified a set of candidate proteins to differentiate responder-PrePPI and non-responder-PrePPI EoE patients before treatment. CONCLUSION: These findings provide evidence that PPI therapy reverses the alterations in esophageal inflammatory and epithelial proteins characterizing EoE, thereby providing new insights into the mechanism of PPI clinical response. Interestingly, our results also suggest that PPI response could be predicted at baseline in EoE.

Dynamin-2 mutations linked to neonatal-onset centronuclear myopathy impair exocytosis and endocytosis in adrenal chromaffin cells.

Dynamins are large GTPases whose primary function is not only to catalyze membrane scission during endocytosis but also to modulate other cellular processes, such as actin polymerization and vesicle trafficking. Recently, we reported that centronuclear myopathy associated dynamin-2 mutations, p.A618T, and p.S619L, impair Ca2+-induced exocytosis of the glucose transporter GLUT4 containing vesicles in immortalized human myoblasts. As exocytosis and endocytosis occur within rapid timescales, here we applied high-temporal resolution techniques, such as patch-clamp capacitance measurements and carbon-fiber amperometry to assess the effects of these mutations on these two cellular processes, using bovine chromaffin cells as a study model. We found that the expression of any of these dynamin-2 mutants inhibits a dynamin and F-actin-dependent form of fast endocytosis triggered by single action potential stimulus, as well as inhibits a slow compensatory endocytosis induced by 500 ms square depolarization. Both dynamin-2 mutants further reduced the exocytosis induced by 500 ms depolarizations, and the frequency of release events and the recruitment of neuropeptide Y (NPY)-labeled vesicles to the cell cortex after stimulation of nicotinic acetylcholine receptors with 1,1-dimethyl-4-phenyl piperazine iodide (DMPP). They also provoked a significant decrease in the Ca2+-induced formation of new actin filaments in permeabilized chromaffin cells. In summary, our results indicate that the centronuclear myopathy (CNM)-linked p.A618T and p.S619L mutations in dynamin-2 affect exocytosis and endocytosis, being the disruption of F-actin dynamics a possible explanation for these results. These impaired cellular processes might underlie the pathogenic mechanisms associated with these mutations.

Increased Levels of Phosphorylated-P38α Induce WNT/ß-Catenin and NGF/P75NTR/TrkA Pathways Disruption and SN56 Cell Death following Single and Repeated Chlorpyrifos Treatment.

Chlorpyrifos (CPF) biocide, exposure to which is mainly produced in the human population through diet, induces several neurotoxic effects. CPF single and repeated exposure induces memory and learning disorders, although the mechanisms that produce these outcomes are complex and not well understood. CPF treatment (single and repeated) of cholinergic septal SN56 cells induced an increase in phosphorylated-P38α levels that led to WNT/ß-Catenin and NGF/P75NTR/TrkA pathways disruption and cell death. These results provide new knowledge on the mechanisms that mediate CPF basal forebrain cholinergic neuronal loss induced by CPF single and repeated exposure and can help unravel the way through which this compound produces cognitive decline and develop efficient treatments against these effects.

Clinical Analysis for Diagnosing Autism in Children Under Two: A Case Report.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with rising prevalence, necessitating early diagnosis and intervention. This case report examines the clinical diagnosis approach of ASD in children under two years, emphasizing motor developmental delay, chromosome 19 mutations, prematurity, macrocephaly, and false-negative Modified Checklist for Autism in Toddlers (MCHAT) results. This study identifies gross motor delays as a potential key indicator in the diagnosis of ASD, as all five cases (Patients A, B, C, D, and E) were observed to have such deficits. Two cases (Patients A and B) initially had negative MCHAT results but were later diagnosed with ASD. Patients C and E both had a chromosome 19 abnormality. Patient E had macrocephaly and an amino acid metabolism disorder. ASD atypical behaviors like hand flapping, wringing, and twirling were also noted. Our systematic review validated the key findings presented in this study, unveiling a consistent pattern throughout the existing literature about ASD diagnoses and the associated misconceptions. These cases highlight the significance of early motor delay, genetic factors, and the limitations of MCHAT in early ASD diagnosis. This case report underscores the need for improved screening tools, genetic investigations, and comprehensive assessments to enhance early detection and intervention for ASD. Early identification and personalized interventions hold a promise to improve the outcomes and quality of life for children with autism.

Full Validation and Application to Clinical Research of a High-Performance Liquid Chromatography Method for the Assessment of Urinary 3-Indoxyl Sulfate in Pediatric Patients with Hematopoietic Stem Cell Transplant.

3-indoxyl sulfate (3-IS) results from a hepatic transformation of indole, a tryptophan degradation product produced by commensal gut bacteria. The metabolite has shown promise as a biomarker of dysbiosis and clinical outcomes following hematopoietic stem cell transplant (HSCT) in adults. Nonetheless, there is a paucity of data regarding microbiome health and outcomes in the pediatric HSCT setting. We developed and thoroughly validated an affordable high-performance liquid chromatography/fluorescence detector (HPLC-FLD) method to quantify 3-IS in urine for use in the pediatric setting. Chromatographic separation was achieved on a C18 column (250 × 4.6 mm × 5 µm) with a mobile phase consisting of pH 4.0 acetic acid-triethylamine buffer and acetonitrile (88:12, v/v), eluted isocratically at 1 mL/min. 3-IS fluorescence detection was set at excitation/emission of 280 and 375, respectively. The method was fully validated according to FDA-specified limits including selectivity, linearity (0.10 to 10.00 mg/L, r2 > 0.997), intra- and inter-day accuracy, and precision. 3-IS stability was confirmed after three freeze-thaw cycles, for short- and medium-term on a benchtop and at 4 °C and for long-term up to 60 days at -20 °C. The validated method was used to quantify 3-IS in urine samples from HSCT pediatric patients.

Glycaemia and ischaemia-reperfusion brain injury in patients with ischaemic stroke treated with mechanical thrombectomy (GLIAS-MT): an observational, unicentric, prospective study protocol.

INTRODUCTION: Poststroke hyperglycaemia is an independent risk factor for poorer outcomes in patients treated with mechanical thrombectomy (MT) and is associated with a lower probability of functional recovery and higher mortality at 3 months. This study aims to evaluate the association between glucose levels during cerebral reperfusion with MT and functional recovery at 3 months, measured by subcutaneous continuous glucose monitoring (CGM) devices. METHODS: This prospective observational study aims to recruit 100 patients with ischaemic stroke and large anterior circulation vessel occlusion, in whom MT is indicated. CGM will be performed using a Freestyle Libre ProIQ device (FSL-CGM, Abbott Diabetes Care, Alameda, California, USA), which will be implanted on admission to the emergency department, to monitor glucose levels before, during and after reperfusion. The study's primary endpoint will be the functional status at 3 months, as measured by the dichotomised modified Rankin Scale (0-2 indicating good recovery and 3-6 indicating dependency or death). We will analyse expression profiles of microRNA (miRNA) at the time of reperfusion and 24 hours later, as potential biomarkers of ischaemic-reperfusion injury. The most promising miRNAs include miR-100, miR-29b, miR-339, miR-15a and miR-424. All patients will undergo treatment according to current international recommendations and local protocols for the treatment of stroke, including intravenous thrombolysis if indicated. ETHICS AND DISSEMINATION: This study (protocol V.1.1, dated 29 October 2021, code 6017) has been approved by the Clinical Research Ethics Committee of La Paz University Hospital (Madrid, Spain) and has been registered in ClinicalTrials.gov (NCT05871502). Study results will be disseminated through peer-reviewed publications in Open Access format and at conference presentations. TRIAL REGISTRATION NUMBER: NCT05871502.

Distance-dependent neuromodulation effect during thermal ablation for atrial fibrillation.

INTRODUCTION: Thermal atrial fibrillation (AF) ablation exerts an additive treatment effect on the cardiac autonomic nervous system (CANS). This effect is mainly reported during ablation of the right superior pulmonary vein (RSPV), modulating the right anterior ganglionated plexus (RAGP), which contains parasympathetic innervation to the sinoatrial node in the epicardial fat pad between RSPV and superior vena cava (SVC). However, a variable response to neuromodulation after ablation is observed, with little to no effect in some patients. Our objective was to assess clinical and anatomic predictors of thermal ablation-induced CANS changes, as assessed via variations in heart rate (HR) postablation. METHODS: Consecutive paroxysmal AF patients undergoing first-time PV isolation by the cryoballoon (CB) or radiofrequency balloon (RFB) within a 12-month time frame and with preprocedural cardiac computed tomography (CT), were evaluated. Preablation and 24-h postablation electrocardiograms in sinus rhythm were collected and analyzed to assess HR. Anatomic evaluation by CT included the measurement of the shortest distance between the SVC and RSPV ostium (RSPV-SVC distance). RESULTS: A total of 97 patients (CB, n = 50 vs. RFB, n = 47) were included, with similar baseline characteristics between both groups. A significant HR increase postablation (ΔHR ≥ 15 bpm) occurred in a total of 37 patients (38.1%), without difference in number of patients between both thermal ablation technologies (CB, 19 [51%]), RFB, 18 [49%]). Independent predictors for increased HR were RSPV-SVC distance (odds ratio [OR]: 0.49, CI: 0.34-0.71, p value < .001), and age (OR: 0.94, CI: 0.89-0.98, p value = .003). CONCLUSIONS: Thermal balloon-based PV isolation influences the CANS through its effect on the RAGP, especially in younger patients and patients with shorter RSPV-SVC distance.

Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: a plain language summary of the monarchE study.

WHAT IS THIS SUMMARY ABOUT?: This article summarizes the most recent results of the monarchE study. This study was completed in participants with a type of breast cancer called HR+, HER2-, node-positive, high-risk early breast cancer. In this study, abemaciclib, a non-chemotherapy treatment, was administered with standard of care endocrine therapy after curative surgery. Most participants had received prior chemotherapy and/or radiotherapy. The study investigated if abemaciclib helped participants live longer without their cancer returning compared with participants who only received standard of care endocrine therapy. The study participants were assigned to 1 of 2 treatment groups. Participants in Group A were assigned to receive standard of care endocrine therapy with abemaciclib for 2 years, followed by endocrine therapy for a total of at least 5 years. Participants in Group B were assigned to receive standard of care endocrine therapy only for at least 5 years. The effect of treatment was compared between these 2 groups. WHAT WERE THE RESULTS?: Overall, the results showed that the cancer was 34% less likely to come back after surgery in the participants in Group A (abemaciclib plus endocrine therapy) compared with those in Group B (endocrine therapy only). At 4 years since the start of the study treatment, more participants who received the combination of abemaciclib plus endocrine therapy remained free of cancer compared with participants who received endocrine therapy alone (86% versus 79%). Participants who received abemaciclib plus endocrine therapy had more side effects than those who received endocrine therapy alone, but most of these effects were mild to moderate and reversible upon the end of therapy. The most common side effects in the abemaciclib group were diarrhea, infections, low number of white blood cells, and tiredness. WHAT DO THE RESULTS MEAN?: This study found that administering abemaciclib in combination with standard endocrine therapy after curative breast surgery helped lower the risk of cancer returning in people with HR+, HER2-, node-positive, high-risk early breast cancer. Abemaciclib is a new treatment option for people with this diagnosis. People with high-risk early breast cancer should always talk to their doctors and nurses before making any decisions about their treatment.Clinical Trial Registration: NCT03155997 (monarchE study).

Impact of SARS-CoV-2 infection on the cognitive functioning of patients institutionalized in nursing homes.

BACKGROUND: COVID-19 disease affected the cognitive level of institutionalized patients in nursing homes, especially in the older subjects regardless of gender. This study aims to assess cognitive impairment using the Mini-Mental State Examination (MMSE) before and after COVID-19 infection, and to determine whether these changes varied based on gender. METHODS: A pre- and post-COVID-19 study was conducted, involving 68 geriatric patients (34 men and 34 women) from two nursing homes. Cognitive impairment was assessed using the MMSE. RESULTS: COVID-19 infection had a notable impact on the cognitive health of older adults residing in nursing homes, primarily attributed to the social isolation they experienced. This effect was more pronounced in older individuals. A comparison of the MMSE results by gender before and after contracting COVID-19 revealed significant differences in attention and calculation, with women obtaining the worst score before the virus. However, following their recovery from the virus, men demonstrated significantly lower scores in time and space orientation and evocation. CONCLUSION: COVID-19 has led to a decline in cognitive functioning, significantly worsening the mental state of older individuals, even after recovery from the virus. Consequently, it is crucial to implement proactive measures to prevent isolation and safeguard the cognitive well-being of this vulnerable population.

Influence of the pressure wire on the fractional flow reserve calculation: CFD analysis of an ideal vessel and clinical patients with stenosis.

BACKGROUND AND OBJECTIVE: Fractional Flow Reserve (FFR) is generally considered the gold standard in hemodynamics to assess the impact of a stenosis on the blood flow. The standard procedure to measure involves the displacement of a pressure guide along the circulatory system until it is placed next to the lesion to be analyzed. The main objective of the present study is to analyze the influence of the pressure guide on the invasive FFR measurements and its implications in clinical practice. METHODS: We studied the influence of pressure wires on the measurement of Fractional Flow Reserve (FFR) through a combination of Computational Fluid Dynamics (CFD) simulations using 45 clinical patient data with 58 lesions and ideal geometries. The analysis is conducted considering patients that were subjected to a computer tomography and also have direct measurements using a pressure guide. Influence of the stenosis severity, degree of occlusion and blood viscosity has also been studied. RESULTS: The influence of pressure wires specifically affects severe stenosis with a lumen diameter reduction of 50 % or greater. This type of stenosis leads to reduced hyperemic flow and increased coronary pressure drop. Thus, we identified that the placement of wires during FFR measurements results in partial obstruction of the coronary artery lumen, leading to increased pressure drop and subsequent reduction in blood flow. The severity of low FFR values associated with severe stenosis may be prone to overestimation when compared to stenosis without severe narrowing. These results have practical implications, particularly in the interpretation of lesions falling within the "gray zone" (0,75-0,80). CONCLUSIONS: The pressure wire's presence significantly alters the flow on severe lesions, which has an impact on the FFR calculation. In contrast, the impact of the pressure wire appears to be reduced when the FFR is larger than 0.8. The findings provide critical information for physicians, emphasizing the need for cautious interpretation of FFR values, particularly in severe stenosis. It also offers insights into improving the correlation between FFRct models and invasive measurements by incorporating the influence of pressure wires.

Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis.

BACKGROUND AND OBJECTIVES: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. METHODS: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. RESULTS: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. CONCLUSIONS: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.

The Role of Immunomodulatory Therapy with Oxiris in COVID-19 with Renal Failure and Immune Dysfunction.

INTRODUCTION: The main objective of this study was to evaluate the impact of hemoadsorption on the elimination of inflammatory mediators. METHODS: A prospective, bicenter, observational cohort study was conducted between March 2020 and February 2022 to explore the immunomodulatory response, demographic and clinical characteristics of individuals with COVID-19 admitted to the ICU with severe acute respiratory failure and in need of CRRT with Oxiris® with or without AKI. RESULTS: Sixty-four patients were analyzed. Statistically significant differences were observed between exposed and unexposed groups, in relation to the reduction in D-dimer levels -15,614 (24,848.9) versus -4,136.5 (9,913.47) (p 0.031, d: 1.59, 95% CI: -21,830, -1,126). An increase in PCT was observed 0.47 (2.08) versus -0.75 (2.3) (p 0.044 95% CI: 0.03, 2.44). No differences were found in a decrease in CRP -4.21 (7.29) versus -1.6 (9.02) (p 0.22) nor in the rest of inflammatory parameters fibrinogen, IL-6, ferritin, lymphocytes, and neutrophils. Subgroup analysis in patients exposed to therapy also showed a significant decrease in D-dimer of 55% from baseline: 6,000 (1,984.5-27,750) pre-therapy versus 2,700 (2,119.5-6,145) (95% CI: -23,000, -2,489) post-therapy with a strong effect size (p 0.001, d: 0.65). CONCLUSION: The hemoadsorptive therapy in COVID-19 was associated with a significant decrease in D-dimer parameters without showing decreases in the rest of the clinical, inflammatory parameters and severity scales analyzed.

Conception, pregnancy, and childbirth from the perspective of transgender men: A meta-ethnography.

BACKGROUND: Transgender men who decide to gestate biologically often face a health system that is highly feminized and discriminatory. In addition, the lack of preparation and knowledge among healthcare professionals leads to the provision of care that fails to meet their specific needs. AIM: To synthesise the experiences of transgender men with regard to conception, pregnancy, and childbirth. METHOD: Ten studies were included in a synthesis of qualitative studies, following the interpretive meta-ethnography method developed by Noblit and Hare and summarized in accordance with the eMERGe meta-ethnography reporting guidelines. RESULTS: The metaphor of a divergent matryoshka dealing with a constricted reality helps us to understand the experiences of conception, pregnancy, and childbirth of transgender men, who often face stigma, discrimination, and marginalization in society and healthcare. The metaphor also highlights the gender dysphoria that arises from the physical changes associated with these processes. Four key themes emerge from this metaphor: (1) The decision to conceive being a trans man; (2) The challenge of adjusting to a new body reality; (3) The significance of navigating in an environment of non-representation; and (4) The marked absence of transsexuality in mainstream healthcare. CONCLUSIONS: Actions should prioritize strengthening ethical sensitivities and improve the training of health professionals to address issues such as gender perspectives, equality, and communication skills. Additionally, social visibility policies need to be implemented.

Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center.

The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, and molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers have been recruited to participate in cognitive, neuropsychologic, imaging, fluid biomarkers, genomic and multi-omic studies. Tissue and longitudinal data collected to foster, facilitate, and support research on dementia and aging. The Genetics and high throughput -omics core (GHTO) have collected of more than 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include longitudinal DNA, RNA, non-fasted plasma, cerebrospinal fluid pellets, and peripheral blood mononuclear cells. The GHTO has performed deep molecular profiling (genomic, transcriptomic, epigenomic, proteomic, and metabolomic) from large number of brain (n = 2,117), CSF (n = 2,012) and blood/plasma (n = 8,265) samples with the goal of identifying novel risk and protective variants, identify novel molecular biomarkers and causal and druggable targets. Overall, the resources available at GHTO support the increase of our understanding of Alzheimer Disease.

Rapid and Simple Morphological Assay for Determination of Susceptibility/Resistance to Combined Ciprofloxacin and Ampicillin, Independently, in Escherichia coli.

Current antibiograms cannot discern the particular effect of a specific antibiotic when the bacteria are incubated with a mixture of antibiotics. To prove that this task is achievable, Escherichia coli strains were treated with ciprofloxacin for 45 min, immobilized on a slide and stained with SYBR Gold. In susceptible strains, the nucleoid relative surface started to decrease near the MIC, being progressively condensed as the dose increased. The shrinkage level correlated with the DNA fragmentation degree. Ciprofloxacin-resistant bacilli showed no change. Additionally, E. coli strains were incubated with ampicillin for 45 min and processed similarly. The ampicillin-susceptible strain revealed intercellular DNA fragments that increased with dose, unlike the resistant strain. Co-incubation with both antibiotics revealed that ampicillin did not modify the nucleoid condensation effect of ciprofloxacin, whereas the quinolone partially decreased the background of DNA fragments induced by ampicillin. Sixty clinical isolates, with different combinations of susceptibility-resistance to each antibiotic, were co-incubated with the EUCAST breakpoints of susceptibility of ciprofloxacin and ampicillin. The morphological assay correctly categorized all the strains for each antibiotic in 60 min, demonstrating the feasible independent evaluation of a mixture of quinolone and beta-lactam. The rapid phenotypic assay may shorten the incubation times and necessary microbial mass currently required for evaluation.

The Role of Fibroblasts in Skin Homeostasis and Repair.

Fibroblasts are typical mesenchymal cells widely distributed throughout the human body where they (1) synthesise and maintain the extracellular matrix, ensuring the structural role of soft connective tissues; (2) secrete cytokines and growth factors; (3) communicate with each other and with other cell types, acting as signalling source for stem cell niches; and (4) are involved in tissue remodelling, wound healing, fibrosis, and cancer. This review focuses on the developmental heterogeneity of dermal fibroblasts, on their ability to sense changes in biomechanical properties of the surrounding extracellular matrix, and on their role in aging, in skin repair, in pathologic conditions and in tumour development. Moreover, we describe the use of fibroblasts in different models (e.g., in vivo animal models and in vitro systems from 2D to 6D cultures) for tissue bioengineering and the informative potential of high-throughput assays for the study of fibroblasts under different disease contexts for personalized healthcare and regenerative medicine applications.

Gender-Based Dating Violence and Social Media among Spanish Young People: A Qualitative Study.

(1) Gender-based dating violence is common among adolescents. This violence has global repercussions and can have immediate and delayed consequences on health. Also, cases of dating violence and sexual abuse using technology are increasing. The aim of this research is to describe and understand the perceptions and experiences of Spanish university students aged 18 to 22, about gender-based dating violence and its perpetuation through social media. (2) A qualitative descriptive study was used, following the five consolidated criteria for reporting and publishing COREQ qualitative research. (3) The inductive analysis of the data obtained in the focus group session and the individual interviews of the twelve participants was organised into three major themes: the concept of gender violence that Spanish youth have, the education they have received on gender-based violence and whether they consider that social media are a way to exercise this type of violence. (4) Spanish youth have a broad vision of the attitudes and behaviours that make up gender-based dating violence in an affective relationship. The education received at home is of vital importance for young people, but not all receive it. Social media are frequent tools through which many young people perpetuate controlling partner violence and normalise aspects and situations of gender violence, making it necessary to stress them in prevention programs.