Sex and aging signatures of proteomics in human cerebrospinal fluid identify distinct clusters linked to neurodegeneration.

Sex and age are major risk factors for chronic diseases. Recent studies examining age-related molecular changes in plasma provided insights into age-related disease biology. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and neurodegeneration. By comprehensively examining 7,006 aptamers targeting 6,139 proteins in CSF obtained from 660 healthy individuals aged from 43 to 91 years old, we subsequently identified significant sex and aging effects on 5,097 aptamers in CSF. Many of these effects on CSF proteins had different magnitude or even opposite direction as those on plasma proteins, indicating distinctive CSF-specific signatures. Network analysis of these CSF proteins revealed not only modules associated with healthy aging but also modules showing sex differences. Through subsequent analyses, several modules were highlighted for their proteins implicated in specific diseases. Module 2 and 6 were enriched for many aging diseases including those in the circulatory systems, immune mechanisms, and neurodegeneration. Together, our findings fill a gap of current aging research and provide mechanistic understanding of proteomic changes in CSF during a healthy lifespan and insights for brain aging and diseases.

Unraveling diabetes complexity through natural products, miRNAs modulation, and future paradigms in precision medicine and global health.

BACKGROUND AND AIMS: The challenge posed by diabetes necessitates a paradigm shift from conventional diagnostic approaches focusing on glucose and lipid levels to the transformative realm of precision medicine. This approach, leveraging advancements in genomics and proteomics, acknowledges the individualistic genetic variations, dietary preferences, and environmental exposures in diabetes management. The study comprehensively analyzes the evolving diabetes landscape, emphasizing the pivotal role of genomics, proteomics, microRNAs (miRNAs), metabolomics, and bioinformatics. RESULTS: Precision medicine revolutionizes diabetes research and treatment by diverging from traditional diagnostic methods, recognizing the heterogeneous nature of the condition. MiRNAs, crucial post-transcriptional gene regulators, emerge as promising therapeutic targets, influencing key facets such as insulin signaling and glucose homeostasis. Metabolomics, an integral component of omics sciences, contributes significantly to diabetes research, elucidating metabolic disruptions, and offering potential biomarkers for early diagnosis and personalized therapies. Bioinformatics unveils dynamic connections between natural substances, miRNAs, and cellular pathways, aiding in the exploration of the intricate molecular terrain in diabetes. The study underscores the imperative for experimental validation in natural product-based diabetes therapy, emphasizing the need for in vitro and in vivo studies leading to clinical trials for assessing effectiveness, safety, and tolerability in real-world applications. Global cooperation and ethical considerations play a pivotal role in addressing diabetes challenges worldwide, necessitating a multifaceted approach that integrates traditional knowledge, cultural competence, and environmental awareness. CONCLUSIONS: The key components of diabetes treatment, including precision medicine, metabolomics, bioinformatics, and experimental validation, converge in future strategies, embodying a holistic paradigm for diabetes care anchored in cutting-edge research and global healthcare accessibility.

Safety of soy leghemoglobin from genetically modified Komagataella phaffii as a food additive.

The EFSA Panel on Food Additive and Flavourings (FAF Panel) provides a scientific opinion on the safety of soy leghemoglobin from genetically modified Komagataella phaffii as a food additive in accordance with Regulation (EC) No 1331/2008. The proposed food additive, LegH Prep, is intended to be used as a colour in meat analogue products. The yeast Komagataella phaffii strain MXY0541 has been genetically modified to produce soy leghemoglobin; the safety of the genetic modification is under assessment by the EFSA GMO Panel (EFSA-GMO-NL-2019-162). The amount of haem iron provided by soy leghemoglobin from its proposed uses in meat analogue products is comparable to that provided by similar amounts of different types of meat. The exposure to iron from the proposed food additive, both at the mean and 95th percentile exposure, will be below the 'safe levels of intake' established by the NDA Panel for all population groups. Considering that the components of the proposed food additive will be digested to small peptide, amino acids and haem B; the recipient (non GM) strain qualifies for qualified presumption of safety status; no genotoxicity concern has been identified and no adverse effects have been identified at the highest dose tested in the available toxicological studies, the Panel concluded that there was no need to set a numerical acceptable daily intake (ADI) and that the food additive does not raise a safety concern at the proposed use in food category 12.9 and maximum use level. The Panel concluded that the use of soy leghemoglobin from genetically modified Komagataella phaffii MXY0541 as a new food additive does not raise a safety concern at the proposed use and use level. This safety evaluation of the proposed food additive remains provisional subject to the ongoing safety assessment of the genetic modification of the production strain by the GMO Panel (EFSA-GMO-NL-2019-162).

Professional experiences of spanish advanced practice nurses: qualitative research.

BACKGROUND: Advanced practice nursing has emerged as a result of the evolution of healthcare systems, the changing needs of the population and the academic development of nursing, as well as sociodemographic and epidemiological changes. The aim of this study is to describe the professional experiences of Spanish advanced practice nurses in specific positions within the healthcare system in order to better understand the development and characteristics of this specialised nursing role. METHODS: A descriptive qualitative study was conducted. Fourteen advanced practice nurses from healthcare centres participated. Semi-structured interviews were carried out. Braun and Clarke's method for reflexive thematic analysis was followed. The Atlas. Ti version 22 program was used for technological support. The COREQ checklist was used to optimise the reporting of this qualitative study. RESULTS: From the analysis of the data collected, three themes and six subthemes were extracted: 1) Advanced practice nursing on the rise: (a) The driving forces in the development of advanced practice nursing, (b) Barriers to the development of advanced practice nursing; 2) Advanced practice nurses as a response to the population's needs: (a) The development of a new professional nursing role, (b) The patient at the centre of care in advanced practice nursing; 3) Training as the foundation for advanced practice nursing: (a) Expert nurses in a specific context, (b) Differences in the level of training depending on the context. CONCLUSION: Advanced practice nurses have faced countless barriers and difficulties that have impeded them from demonstrating their importance and effectiveness within the healthcare system. A stable regulatory framework for the functions of advanced practice nurses is required to promote care, training and research in the field of advanced practice nursing. Health institutions need to promote the role of advanced practice nurses, facilitate the employment of new professionals, and establish new areas of practice. TRIAL REGISTRATION: Not applicable.

Fall assessment and intervention among community-dwelling older people in a primary health care center in Spain: a best practice implementation project.

INTRODUCTION: The implementation of fall prevention programs in the community is complex. Although there is solid scientific evidence that supports the effectiveness of such programs, there are multiple barriers that should be addressed using multifaceted strategies. AIMS: The aim of this project was to increase compliance with evidence-based recommendations regarding fall risk screening and preventive interventions among older adults in a primary health care setting. METHODS: This project used a pre-/post-implementation clinical audit based on the JBI Evidence Implementation Framework. Eight audit criteria were derived from JBI evidence summaries. The sample size was 62 patients aged 70 years or older. Data collection methods included a review of medical records and a questionnaire. A baseline audit was conducted and five barriers to best practice were identified. Strategies were then developed to increase compliance with the evidence-based recommendations, guided by JBI's Getting Research into Practice (GRiP) analysis. A follow-up audit was conducted in July 2022 to evaluate changes in compliance with best practices. RESULTS: The baseline audit showed 0% compliance with best practice recommendations for seven out of eight audit criteria. Five barriers were identified: (1) absence of fall risk screening tools, (2) lack of fall prevention intervention protocols, (3) insufficient reporting of fall episodes in the records, (4) need for staff training, and (5) high staff turnover. Following the implementation of a fall risk assessment and intervention protocol, along with staff training, seven out of eight audit criteria increased from 0% to between 22.6% and 100%. CONCLUSIONS: This evidence-based implementation project improved nursing practice in relation to compliance with best practice interventions to prevent falls. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A229.

Competitive oxidation of key pentose phosphate pathway enzymes modulates the fate of intermediates and NAPDH production.

The oxidative phase of the pentose phosphate pathway (PPP) involving the enzymes glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconolactonase (6PGL), and 6-phosphogluconate dehydrogenase (6PGDH), is critical to NADPH generation within cells, with these enzymes catalyzing the conversion of glucose-6-phosphate (G6P) into ribulose-5-phosphate (Ribu5-P). We have previously studied peroxyl radical (ROO•) mediated oxidative inactivation of E. coli G6PDH, 6PGL, and 6PGDH. However, these data were obtained from experiments where each enzyme was independently exposed to ROO•, a condition not reflecting biological reality. In this work we investigated how NADPH production is modulated when these enzymes are jointly exposed to ROO•. Enzyme mixtures (1:1:1 ratio) were exposed to ROO• produced from thermolysis of 100 mM 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH). NADPH was quantified at 340 nm, and protein oxidation analyzed by liquid chromatography with mass spectrometric detection (LC-MS). The data obtained were rationalized using a mathematical model. The mixture of non-oxidized enzymes, G6P and NADP+ generated ∼175 µM NADPH. Computational simulations showed a constant decrease of G6P associated with NADPH formation, consistent with experimental data. When the enzyme mixture was exposed to AAPH (3 h, 37 ºC), lower levels of NADPH were detected (∼100 µM) which also fitted with computational simulations. LC-MS analyses indicated modifications at Tyr, Trp, and Met residues but at lower concentrations than detected for the isolated enzymes. Quantification of NADPH generation showed that the pathway activity was not altered during the initial stages of the oxidations, consistent with a buffering role of G6PDH towards inactivation of the oxidative phase of the pathway.

Ultrasound Cut-Off Values for Rectus Femoris for Detecting Sarcopenia in Patients with Nutritional Risk.

BACKGROUND: A nationwide, prospective, multicenter, cohort study (the Disease-Related caloric-protein malnutrition EChOgraphy (DRECO) study) was designed to assess the usefulness of ultrasound of the rectus femoris for detecting sarcopenia in hospitalized patients at risk of malnutrition and to define cut-off values of ultrasound measures. METHODS: Patients at risk of malnutrition according to the Malnutrition Universal Screening Tool (MUST) underwent handgrip dynamometry, bioelectrical impedance analysis (BIA), a Timed Up and Go (TUG) test, and rectus femoris ultrasound studies. European Working Group on Sarcopenia in Older People (EWGSOP2) criteria were used to define categories of sarcopenia (at risk, probable, confirmed, severe). Receiver operating characteristic (ROC) and area under the curve (AUC) analyses were used to determine the optimal diagnostic sensitivity, specificity, and predictive values of cut-off points of the ultrasound measures for the detection of risk of sarcopenia and probable, confirmed, and severe sarcopenia. RESULTS: A total of 1000 subjects were included and 991 of them (58.9% men, mean age 58.5 years) were evaluated. Risk of sarcopenia was detected in 9.6% patients, probable sarcopenia in 14%, confirmed sarcopenia in 9.7%, and severe sarcopenia in 3.9%, with significant differences in the distribution of groups between men and women (p < 0.0001). The cross-sectional area (CSA) of the rectus femoris showed a significantly positive correlation with body cell mass of BIA and handgrip strength, and a significant negative correlation with TUG. Cut-off values were similar within each category of sarcopenia, ranging between 2.40 cm2 and 3.66 cm2 for CSA, 32.57 mm and 40.21 mm for the X-axis, and 7.85 mm and 10.4 mm for the Y-axis. In general, these cut-off values showed high sensitivities, particularly for the categories of confirmed and severe sarcopenia, with male patients also showing better sensitivities than women. CONCLUSIONS: Sarcopenia in hospitalized patients at risk of malnutrition was high. Cut-off values for the better sensitivities and specificities of ultrasound measures of the rectus femoris are established. The use of ultrasound of the rectus femoris could be used for the prediction of sarcopenia and be useful to integrate nutritional study into real clinical practice.

Baroreflex and chemoreflex interaction in high-altitude exposure: possible role on exercise performance.

The hypoxic chemoreflex and the arterial baroreflex are implicated in the ventilatory response to exercise. It is well known that long-term exercise training increases parasympathetic and decreases sympathetic tone, both processes influenced by the arterial baroreflex and hypoxic chemoreflex function. Hypobaric hypoxia (i.e., high altitude [HA]) markedly reduces exercise capacity associated with autonomic reflexes. Indeed, a reduced exercise capacity has been found, paralleled by a baroreflex-related parasympathetic withdrawal and a pronounced chemoreflex potentiation. Additionally, it is well known that the baroreflex and chemoreflex interact, and during activation by hypoxia, the chemoreflex is predominant over the baroreflex. Thus, the baroreflex function impairment may likely facilitate the exercise deterioration through the reduction of parasympathetic tone following acute HA exposure, secondary to the chemoreflex activation. Therefore, the main goal of this review is to describe the main physiological mechanisms controlling baro- and chemoreflex function and their role in exercise capacity during HA exposure.

Deep Learning-Based Glucose Prediction Models: A Guide for Practitioners and a Curated Dataset for Improved Diabetes Management.

Accurate short- and mid-term blood glucose predictions are crucial for patients with diabetes struggling to maintain healthy glucose levels, as well as for individuals at risk of developing the disease. Consequently, numerous efforts from the scientific community have focused on developing predictive models for glucose levels. This study harnesses physiological data collected from wearable sensors to construct a series of data-driven models based on deep learning approaches. We systematically compare these models to offer insights for practitioners and researchers venturing into glucose prediction using deep learning techniques. Key questions addressed in this work encompass the comparison of various deep learning architectures for this task, determining the optimal set of input variables for accurate glucose prediction, comparing population-wide, fine-tuned, and personalized models, and assessing the impact of an individual's data volume on model performance. Additionally, as part of our outcomes, we introduce a meticulously curated dataset inclusive of data from both healthy individuals and those with diabetes, recorded in free-living conditions. This dataset aims to foster research in this domain and facilitate equitable comparisons among researchers.

Optimizing Nodal, Wnt and BMP signaling pathways for robust and efficient differentiation of human induced pluripotent stem cells to intermediate mesoderm cells.

Several differentiation protocols have enabled the generation of intermediate mesoderm (IM)-derived cells from human pluripotent stem cells (hPSC). However, the substantial variability between existing protocols for generating IM cells compromises their efficiency, reproducibility, and overall success, potentially hindering the utility of urogenital system organoids. Here, we examined the role of high levels of Nodal signaling and BMP activity, as well as WNT signaling in the specification of IM cells derived from a UCSD167i-99-1 human induced pluripotent stem cells (hiPSC) line. We demonstrate that precise modulation of WNT and BMP signaling significantly enhances IM differentiation efficiency. Treatment of hPSC with 3 µM CHIR99021 induced TBXT+/MIXL1+ mesoderm progenitor (MP) cells after 48 h of differentiation. Further treatment with a combination of 3 µM CHIR99021 and 4 ng/mL BMP4 resulted in the generation of OSR1+/GATA3+/PAX2+ IM cells within a subsequent 48 h period. Molecular characterization of differentiated cells was confirmed through immunofluorescence staining and RT-qPCR. Hence, this study establishes a consistent and reproducible protocol for differentiating hiPSC into IM cells that faithfully recapitulates the molecular signatures of IM development. This protocol holds promise for improving the success of protocols designed to generate urogenital system organoids in vitro, with potential applications in regenerative medicine, drug discovery, and disease modeling.

Morbidity and neurodevelopmental outcomes at 2 years in preterm infants undergoing percutaneous transcatheter closure vs. surgical ligation of the PDA.

OBJECTIVE: Review a cohort of preterm infants ≤29 weeks of gestation at birth and compare morbidities and neurodevelopmental outcomes based on PDA status and type of PDA closure. STUDY DESIGN: Single center observational retrospective-prospective case control study of premature infants who had no hsPDA, underwent surgical ligation or percutaneous transcatheter closure of the PDA. Neurodevelopmental testing was done using the Bayley Scales of Infant Development 3rd ed. RESULTS: The percutaneous transcatheter closure group had an older post menstrual age and greater weight at the time of procedure, and started enteral feeds and achieved room air status at an earlier post procedure day. Infants in the surgical ligation group were more likely to experience vocal cord paralysis. There was no difference in neurodevelopmental outcomes between groups. CONCLUSION: Waiting for infants to achieve the appropriate size for percutaneous transcatheter closure of the PDA may lead to reduced short-term complications without increasing the risk of neurodevelopmental impairment.

[Diagnostic significance of C4d in membranous nephropathy]. / Importancia diagnóstica del C4d en la nefropatía membranosa.

INTRODUCTION: Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome in adults (20-30%). Light microscopy shows thickening of glomerular basement membrane with appearance of spikes. These histological findings are not evident in early forms, in which case the granular deposition pattern of IgG and/or C3 in the basement membrane by immunofluorescence (IF) constitutes the diagnostic tool that allows to differentiate it from minimal change disease (MCD). Complement system plays a key role in the pathophysiology of MN. C4d is a degradation product and a marker of the complement system activation. C4d labelling by immunohistochemical (HI) technique can help in the differential diagnosis between both glomerulopathies NM and MCD when the material for IF is insufficient and light microscopy is normal. Our objective was to explore the discrimination power of C4d to differentiate between MN and MCD in renal biopsy material. METHODS: Paraffin-embedded samples were recovered from renal biopsies with a diagnosis of MN and MCD performed between 1/1/2008 and 4/1/2019. IH staining was performed by immunoperoxidase technique using a rabbit anti-human C4d polyclonal antibody. RESULTS: In all cases with MN (n = 27, 15 males) with a median age of 63 (range: 18-87) years, C4d deposits were detected. In 21 cases with MCD (12 males) with a median age of 51 (range: 18-87) years, the C4d marking was negative in every samples. CONCLUSION: The results indicate that the marking of the renal biopsy with C4d is a useful tool for the differential diagnosis between NM and MCD.

Introducción: La nefropatía membranosa (NM) es la causa más frecuente de síndrome nefrótico primario en adultos (20-30%). En la microscopia óptica se observa engrosamiento de membrana basal glomerular con aparición de espigas. Estos hallazgos histológicos no son evidentes en formas tempranas, en cuyo caso el patrón de depósito granular de IgG y/o C3 en la membrana basal por inmunofluorescencia (IF) permite diferenciarla de enfermedad por cambios mínimos (ECM). El sistema del complemento juega un papel central en la fisiopatología de la NM. C4d es producto de degradación y un marcador de la activación del complemento. La marcación con C4d en muestras de biopsias renales, por técnica de inmunohistoquímica (IH) puede colaborar en el diagnóstico diferencial entre ambas glomerulopatías. Nuestro objetivo fue explorar el poder de discriminación del C4d para diferenciar NM de ECM en material de biopsias renales. Métodos: Se recuperaron muestras en parafina de biopsias renales con diagnóstico de NM y ECM realizados entre 1/1/2008 y 1/4/2019. Se realizaron tinciones de IH por técnica de inmunoperoxidasa con C4d usando un anticuerpo policlonal antihumano de conejo. Resultados: En todos los casos con NM (n = 27, 15 hombres) con mediana de edad de 63 (rango: 18-86) años se detectaron depósitos de C4d. En los 21 casos con ECM (12 hombres) con mediana de edad de 51 (rango: 18-87) años la marcación de C4d fue negativa. Conclusión: Los resultados indican que la marcación de la biopsia renal con C4d es una herramienta útil para el diagnóstico diferencial entre NM y ECM.

Disruption of the mitochondrial network in a mouse model of Huntington's disease visualized by in-tissue multiscale 3D electron microscopy.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is still available, thus urging the identification of potential therapeutic targets. While evidence of mitochondrial structural alterations in HD exists, previous studies mainly employed 2D approaches and were performed outside the strictly native brain context. In this study, we adopted a novel multiscale approach to conduct a comprehensive 3D in situ structural analysis of mitochondrial disturbances in a mouse model of HD. We investigated MSSNs within brain tissue under optimal structural conditions utilizing state-of-the-art 3D imaging technologies, specifically FIB/SEM for the complete imaging of neuronal somas and Electron Tomography for detailed morphological examination, and image processing-based quantitative analysis. Our findings suggest a disruption of the mitochondrial network towards fragmentation in HD. The network of interlaced, slim and long mitochondria observed in healthy conditions transforms into isolated, swollen and short entities, with internal cristae disorganization, cavities and abnormally large matrix granules.

Use of Self-Efficacy Scale in Mass Casualty Incidents During Drill Exercises.

INTRODUCTION: Medical First Responders (MFRs) in the emergency department SUMMA 112 are tasked with handling the initial management of Mass Casualty Incidents (MCI) and building response capabilities. Training plays a crucial role in preparing these responders for effective disaster management. Yet, evaluating the impact of such training poses challenges since true competency can only be proven amid a major event. As a substitute gauge for training effectiveness, self-efficacy has been suggested. OBJECTIVE: The purpose of this study is to employ a pre- and post-test assessment of changes in perceived self-efficacy among MFRs following an intervention focused on the initial management of MCI. It also aimed to evaluate a self-efficacy instrument for its validity and reliability in this type of training. METHOD: In this study, we used a pretest (time 1 = T1) - post-test (time 2 = T2) design to evaluate how self-efficacy changed after a training intervention with 201 MFRs in initial MCI management. ANOVA within-subjects and between subjects analyses were used. RESULTS: The findings reveal a noteworthy change in self-efficacy before and after training among the 201 participants. This suggests that the training intervention positively affected participants' perceived capabilities to handle complex situations like MCI. CONCLUSION: The results allow us to recommend a training program with theory components together with practical workshops and live, large-scale simulation exercises for the training of medical first responders in MCI, as it significantly increases their perception of the level of self-efficacy for developing competencies associated with disaster response.

Stability of Multicomponent Antidote Parenteral Formulations for Autoinjectors against Chemical War Agents (Neurotoxics).

Combinations of different drugs are formulated in autoinjectors for parenteral administration against neurotoxic war agents. In this work, the effects on the chemical stability of the following three variables were studied: (i) type of drug combination (pralidoxime, atropine, and midazolam versus obidoxime, atropine, and midazolam); (ii) pH (3 versus 4); and (iii) type of elastomeric sealing material (PH 701/50 C BLACK versus 4023/50 GRAY). Syringes were stored at three different temperatures: 4, 25, and 40 °C. Samples were assayed at different time points to study the physical appearance, drug sorption on the sealing elastomeric materials, and drug content in solution. Midazolam was unstable in all tested experimental conditions. Drug adsorption was observed in both types of sealing elastomeric materials and was significantly (p < 0.01) dependent on the lipophilicity of the drug. The most stable formulation was the combination of pralidoxime and atropine at pH 4 with the elastomeric sealing material 4023/50 GRAY.

Cross-cultural evaluation of the Michigan Hand Outcomes Questionnaire: a systematic review.

This systematic review aims to provide a comprehensive synthesis and in-depth analysis of the quality of the different cross-cultural versions of the MHQ. This study was conducted using Pubmed, Web of Science, CINAHL and SCOPUS databases to identify cross-cultural validation studies of the MHQ. Methodological quality, quality of evidence and criteria for good measurement properties of these studies were applied for each psychometric property. Quality assessment and data extraction were performed independently by two reviewers according to the COnsensus-based Standards for selection of health Measurement INstruments (COSMIN) guidelines. A total of 493 articles were identified, of which 22 were included and 20 were analysed.Of the six properties analysed, responsiveness and hypothesis testing for construct validity had the highest methodological quality and quality of evidence, and met the criteria for good measurement properties. The lowest quality properties were measurement error and internal consistency. The different cross-cultural versions of the MHQ were found to be reliable, valid and able to detect clinical change. The lack of development of measurement error, formulation of an a priori hypothesis or structural validity affects the detection of small clinical changes and their discriminative capacity.

Identification of epigenetic silencing of the SFRP2 gene in colorectal cancer as a clinical biomarker and molecular significance.

BACKGROUND: Several studies have suggested secreted frizzled-related protein 2 (SFRP2) gene as a potential clinical biomarker in colorectal cancer (CRC). However, its diagnostic role remains unclear. In this study, we aimed to investigate the significance of SFRP2 methylation levels in a large cohort of biological specimens (including blood, adipose and colonic tissues) from patients with CRC, thereby potentially identifying new biomarker utility. METHODS: We examined the expression (by qPCR) and methylation status (by 450 K DNA array and DNA pyrosequencing) of the SFRP2 gene in healthy participants (N = 110, aged as 53.7 (14.2), 48/62 males/females) and patients with CRC (N = 85, aged 67.7 (10.5), 61/24 males/females), across different biological tissues, and assessing its potential as a biomarker for CRC. Additionally, we investigated the effect of recombinant human SFRP2 (rhSFRP2) as a therapeutic target, on cell proliferation, migration, and the expression of key genes related to carcinogenesis and the Wnt pathway. RESULTS: Our findings revealed that SFRP2 promoter methylation in whole blood could predict cancer stage (I + II vs. III + IV) (AUC = 0.653), lymph node invasion (AUC = 0.692), and CRC recurrence (AUC = 0.699) in patients with CRC (all with p < 0.05). Furthermore, we observed a global hypomethylation of SFRP2 in tumors compared to the adjacent area (p < 0.001). This observation was validated in the TCGA-COAD and TCGA-READ cohorts, demonstrating overall hypermethylation (both with p < 0.001) and low expression (p < 0.001), as shown in publicly available scRNA-Seq data. Notably, neoadjuvant-treated CRC patients exhibited lower SFRP2 methylation levels compared to untreated patients (p < 0.05) and low promoter SFRP2 methylation in untreated patients was associated with poor overall survival (p < 0.05), when compared to high methylation. Finally, treatment with 5 µg of rhSFRP2 treatment in CRC cells (HCT116 cells) inhibited cell proliferation (p < 0.001) and migration (p < 0.05), and downregulated the expression of AXIN2 (p < 0.01), a gene involved in Wnt signaling pathway. CONCLUSIONS: These findings establish promoter methylation of the SFRP2 gene as a prognostic candidate in CRC when assessed in blood, and as a therapeutic prognostic candidate in tumors, potentially valuable in clinical practice. SFRP2 also emerges as a therapeutic option, providing new clinical and therapeutical avenues.

The impact of experimental diabetes on intracerebral haemorrhage. A preclinical study.

Although diabetes mellitus negatively affects post-ischaemic stroke injury and recovery, its impact on intracerebral haemorrhage (ICH) remains uncertain. This study aimed to investigate the effect of experimental diabetes (ED) on ICH-induced injury and neurological impairment. Sprague-Dawley rats were induced with ED 2 weeks before ICH induction. Animals were randomly assigned to four groups: 1)Healthy; 2)ICH; 3)ED; 4)ED-ICH. ICH and ED-ICH groups showed similar functional assessment. The ED-ICH group exhibited significantly lower haemorrhage volume compared with the ICH group, except at 1 mo. The oedema/ICH volume ratio and cistern displacement ratio were significantly higher in the ED-ICH group. Vascular markers revealed greater expression of α-SMA in the ED groups (ED and ED-ICH) compared with ICH. Conversely, the ICH groups (ED-ICH and ICH) exhibited higher levels of VEGF compared to the healthy and ED groups. An assessment of myelin tract integrity showed an increase in fractional anisotropy in the ED and ED-ICH groups compared with ICH. The ED group showed higher cryomyelin expression than the ED-ICH and ICH groups. Additionally, the ED groups (ED and ED-ICH) displayed higher expression of MOG and Olig-2 than ICH. As for inflammation, MCP-1 levels were significantly lower in the ED-ICH groups compared with the ICH group. Notably, ED did not aggravate the neurological outcome; however, it results in greater ICH-related brain oedema, greater brain structure displacement and lower haemorrhage volume. ED influences the cerebral vascularisation with an increase in vascular thickness, limits the inflammatory response and attenuates the deleterious effect of ICH on white matter integrity.

Flavouring Group Evaluation 413 (FGE.413): Naringenin.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of naringenin [FL-no: 16.132] as a new flavouring substance, in accordance with Regulation (EC) No 1331/2008. No other substances with sufficient structural similarity have been identified in existing FGEs that could be used to support a read-across approach. The information provided on the manufacturing process, the composition and the stability of [FL-no: 16.132] was considered sufficient. From studies carried out with naringenin, the Panel concluded that there is no concern with respect to genotoxicity. The use of naringenin as a flavouring substance at added portions exposure technique (APET) exposure levels is unlikely to pose a risk for drug interaction. For the toxicological evaluation of naringenin, the Panel requested an extended one-generation toxicity study on naringenin, in line with the requirements of the Procedure and to investigate the consequence of a possible endocrine-disrupting activity. The Panel considered that changes in thymus weight, litter size, post-implantation loss and a consistent reduced pup weight in the high-dose F2 generation could not be dismissed and selected therefore, the mid-dose of 1320 mg/kg body weight (bw) per day for the parental males as the no observed adverse effect level (NOAEL) of the study. The exposure estimates for [FL-no: 16.132] (31,500 and 50,000 µg/person per day for children and adults, respectively) were above the threshold of toxicological of concern (TTC) for its structural class (III). Using the NOAEL of 1320 mg/kg bw per day at step A4 of the procedure, margins of exposure (MoE) of 1590 and 630 could be calculated for adults and children, respectively. Based on the calculated MoEs, the Panel concluded that the use of naringenin as a flavouring substance does not raise a safety concern.

Engagement and factors associated with annual anal human papillomavirus screening among sexual and gender minority individuals.

Objectives: Annual screening with a provider has been recommended for groups at highest risk for anal cancer. Anal self-sampling could help address screening barriers, yet no studies have examined annual engagement with this method. Methods: The Prevent Anal Cancer Self-Swab Study recruited sexual and gender minority individuals 25 years and over who have sex with men in Milwaukee, Wisconsin to participate in an anal cancer screening study. Participants were randomized to a home or clinic arm. Home-based participants were mailed an anal human papillomavirus self-sampling kit at baseline and 12 months, while clinic-based participants were asked to schedule and attend one of five participating clinics at baseline and 12 months. Using Poisson regression, we conducted an intention-to-treat analysis of 240 randomized participants who were invited to screen at both timepoints. Results: 58.8% of participants completed annual (median=370 days) anal screening. When stratified by HIV status, persons living with HIV had a higher proportion of home (71.1%) versus clinic (22.2%) annual screening ( p <0.001). Non-Hispanic Black participants had a higher proportion of home-based annual anal screening engagement (73.1%) compared to annual clinic screening engagement (31.6%) ( p =0.01). Overall, annual screening engagement was significantly higher among participants who had heard of anal cancer from an LGBTQ organization, reported "some" prior anal cancer knowledge, preferred an insertive anal sex position, and reported a prior cancer diagnosis. Annual screening engagement was significantly lower for participants reporting a medical condition. Conclusions: Annual screening engagement among those at disproportionate anal cancer risk was higher in the home arm.