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Abstract Purpose Skeletal muscle is the primary site for insulin-stimulated glucose disposal, and muscle insulin resistance is central to abnormal glucose metabolism in obesity. Whether muscle insulin signaling to the level of Akt/AS160 is intact in insulin-resistant obese humans is controversial. Methods We defined a linear range of insulin-stimulated systemic and leg glucose uptake in 14 obese and 14 nonobese volunteers using a 2-step insulin clamp (Protocol 1) and then examined the obesity-related defects in muscle insulin action in 16 nonobese and 25 obese male and female volunteers matched for fitness using a 1-step, hyperinsulinemic, euglycemic clamp coupled with muscle biopsies (Protocol 2). Results Insulin-stimulated glucose disposal (Si) was reduced by > 60% (P < 0.0001) in the obese group in Protocol 2; however, the phosphorylation of Akt and its downstream effector AS160 were not different between nonobese and obese groups. The increase in phosphorylation of Akt2 in response to insulin was positively correlated with Si for both the nonobese (r = 0.53, P = 0.03) and the obese (r = 0.55, P = 0.01) groups. Total muscle GLUT4 protein was 17% less (P < 0.05) in obese subjects. Conclusions We suggest that reduced muscle glucose uptake in obesity is not due to defects in the insulin signaling pathway at the level of Akt/AS160, which suggests there remain significant gaps in our knowledge of muscle insulin resistance in obesity. Our data imply that models of acute lipotoxicity do not replicate the pathophysiology of obesity.

Background Immunotherapy has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with immunotherapy naïve and exposed primary ccRCC tumors to better understand immunotherapy resistance. Results Spatial molecular imaging of tumor and adjacent stroma samples from 21 tumors suggests that viable tumors following immunotherapy harbor more stromal CD8 + T cells and neutrophils than immunotherapy naïve tumors. YES1 is significantly upregulated in immunotherapy exposed tumor cells. Spatial GSEA shows that the epithelial-mesenchymal transition pathway is spatially enriched and the associated ligand-receptor transcript pair COL4A1 - ITGAV has significantly higher autocorrelation in the stroma after exposure to immunotherapy. More integrin αV + cells are observed in immunotherapy exposed stroma on multiplex immunofluorescence validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV . Assessing bulk RNA expression and proteomic correlates in CPTAC databases reveals that collagen IV protein is more abundant in advanced stages of disease. Conclusions Spatial transcriptomics of samples of 3 patient cohorts with cRCC tumors indicates that COL4A1 and ITGAV are more autocorrelated in immunotherapy-exposed stroma compared to immunotherapy-naïve tumors, with high expression among fibroblasts, tumor cells, and endothelium. Further research is needed to understand changes in the ccRCC tumor immune microenvironment and explore potential therapeutic role of integrin after immunotherapy treatment.

Abstract Background Papillary renal cell carcinoma (pRCC) accounts for up to 15% of all kidney cancer cases, yet our understanding of its tumor immune microenvironment (TIME) remains limited. We utilized multiplex immunofluorescence (mIF) and spatial transcriptomics (ST) to evaluate immune cell spatial architecture in pRCC and compared to that of clear cell RCC (ccRCC). Methods Surgical tumor specimens were obtained from localized RCC tumors, followed by mIF using markers for T cells, B cells, and tumor-associated macrophages (TAMs). Spatial data were derived in regions of interest (ROIs) manually selected from spatially distinct tissue compartments of the TIME. Single-cell ST was performed on a subset of patient samples, utilizing probes against 960 transcripts. Cell abundance, cell spatial clustering, and spatially varying gene expression were analyzed to identify unique features of the TIME in pRCC. Results Sixteen pRCC and 70 ccRCC patient samples underwent mIF. Compared to ccRCC, global pRCC immune cell abundance was statistically lower amongst functional CD8 T cells, while global cell spatial clustering was higher amongst M2-like macrophages as measured by mIF, including PDL1+ subsets. Using ST, seven genes were significantly associated with spatial clustering of M2-like macrophages in pRCC. Three of seven genes (CCL18, GPNMB, CD9) are known markers of lipid-associated TAMs (LAMs) (adjusted p-value < 0.1). Conclusions Compared to ccRCC, pRCC has fewer T cells but greater M2-like macrophage spatial clustering. Using ST, we found that multiple LAM-associated genes are spatially enriched in pRCC. Additional resources should be dedicated to investigating myeloid biomarkers and the impact of myeloid modulating therapeutics in pRCC.

Background School victimization during adolescence is a multidimensional phenomenon that affects psychological well-being and social development. Understanding its underlying factors is essential for designing effective preventive strategies. Objective This study aims to analyze school victimization in adolescents from a psychosocial perspective, proposing an explanatory model that integrates individual variables (psychological distress, life satisfaction, and resilience) and social variables (community social support). Method The total of participants was 1,687 adolescents (46% male, 54% female) aged 12–17 years (M = 13.65, SD = 1.14), from 13 schools in Puerto Vallarta, Mexico. Results Psychological distress is positively associated with school victimization, while life satisfaction is negatively associated. Furthermore, community social support and resilience were found to indirectly influence school victimization through life satisfaction and, negatively, through psychological distress. Multigroup analysis revealed differences in victimization dynamics by gender, although the model is invariant. Conclusion The findings highlight the importance of adopting a multidimensional perspective in understanding and addressing school victimization. Promoting resilience and strengthening community social support could reduce the risk of victimization and improve students' psychological well-being. These results have practical implications for the development of comprehensive prevention and intervention strategies in school settings.

For decades, there has been ongoing discussion about whether centralized or decentralized wastewater management systems are better. Decision-makers need to define the best option but do not always have the necessary tools to develop, compare, and identify the most appropriate solution. To address this, studies have been conducted on a settlement level. In this study, the main focus was to develop and optimize wastewater management scenarios for a region containing rural areas, where data scarcity was an issue, by extracting scenario-relevant information from the region using a satellite image and its calibration using locally available data. We selected a study region in India containing 184 villages with a total population of around 210,000 and covering an area of around 400 km2. The study considered three different scenarios for the study area: centralized, decentralized, and an optimized scenario, which consists of a hybrid system involving partly decentralized and partly semi-centralized (clustered) infrastructure. The study developed a systematic approach for defining an optimized cluster of villages by considering the cost trade-off between the wastewater treatment plant (WWTP) capacity and sewer network layout. The results showed that the clustered and decentralized scenarios were nearly equal in terms of cost (around EUR 118 million), while the centralized scenario showed a relatively high cost of EUR 168 million. Potential applications and further development of the method were also considered. The proposed methodology may aid global wastewater management by estimating and optimizing infrastructure costs needed to fulfill Sustainable Development Goal 6 (SDG#6) in rural regions.

The implementation of a geriatric oncology service is challenging in both high-income and low-and-middle-income countries. The Octavio Frias de Oliveira Institute of Cancer of Sao Paulo (ICESP) is a tertiary healthcare complex of the Clinics Hospital of the University of Sao Paulo Medical School and is considered a model of excellence in oncology in Latin America. The objective of this manuscript is to describe 10 years of the geriatric oncology service at ICESP and the challenges for its implementation. We performed a narrative description of the ICESP’s geriatric oncology service and a general retrospective descriptive analysis of data collected from routine structured medical records of patients referred to the service from 2011 to 2021. This article highlights the different settings in which the service operates (outpatient, pre-operative and hospital follow-up). In this period, 1,700 patients were assessed for preoperative evaluation (median age 83.9, SD 4.95), 468 patients were evaluated for therapeutic decision (median age 79.4, SD 7.38), 968 in general geriatric oncology care outpatient clinics from 2012 to 2021 (median age 78.7, SD 7.91) and 1,391 inpatient evaluations. In the past 10 years, our geriatric oncology team has grown exponentially and changed its characteristics in order to adjust them to the hospital demands, raising awareness among the oncology teams about the benefit of using geriatric assessment and promoting multidisciplinary discussions.

Bovine mastitis is a major bioeconomic and animal health challenge in dairy systems and is traditionally managed with intensive antibiotic therapy, contributing to antimicrobial resistance (AMR). This study explored the therapeutic potential of essential oils (EOs) from two native species of the Valdivian temperate rainforest, Laureliopsis philippiana (Tepa; LP_EO) and Drimys winteri (Canelo; DW_EO), against priority mastitis pathogens. Gas Chromatography–Mass Spectrometry (GC–MS) was used to characterize EO composition, and in vitro antibacterial and antifungal activities were evaluated against clinical isolates of Staphylococcus aureus, Streptococcus uberis and the azole-resistant yeast Pichia kudriavzevii by disk diffusion and broth microdilution assays. Both EOs were dominated by monoterpenes; LP_EO was richer in oxygenated monoterpenes (eucalyptol, terpinen-4-ol), whereas DW_EO showed a pinene-rich profile (β-pinene, α-pinene). DW_EO produced significantly larger inhibition zones than LP_EO against S. aureus and P. kudriavzevii and exhibited lower MIC50/MIC90 values for S. aureus, S. uberis and P. kudriavzevii. Notably, DW_EO showed a higher inhibitory activity against P. kudriavzevii with a MIC90 of 4 mg/mL. These findings support DW_EO as a high-potential dual-action phytotherapeutic candidate for developing formulations and complementary tools within sustainable bovine udder health and antimicrobial stewardship frameworks.

Introduction: High-Intensity Interval Training (HIIT) involves developing exercises in short periods of time with high intensity, followed by periods of rest between the series of exercises performed, and is considered an important tool to combat obesity. Therefore, the present work aimed to identify the effects of high-intensity intermittent training on the lipid profile in overweight and obese university students. Materials and methods: quasi-experimental study, consisting of a sample of 30 students, who were randomly assigned into two groups of 15 students, thus leaving a control group (continuous training): 15 and an experimental group (intermittent exercise of high intensity: 15. Moreover, there were carried out Laboratory tests before and after training to find the lipid profile. Also, the realization of 20 training sessions, which were distributed three times a week, with an average duration of 50 minutes. Additionally, the performed of statistical tests with a level of statistical significance of p <0.05. Results: there is a statistically significant relationship in the HDL value of the control and experimental group. The Glucose values show statistically significant relationships in the experimental group (p = 0.001). Conclusions: Intermittent high-intensity training and continuous moderate-intensity work generate a decrease in LDL and Triglycerides variables and an increase in HDL. However, they are not statistically significant after 20 training sessions. However, high-intensity intermittent training results in glucose-lowering in overweight and obese people.

The brain requires a large amount of energy. Its function can be altered when energy demand exceeds supply or during metabolic disturbances such as diabetes mellitus. Diabetes, a chronic disease with a high incidence worldwide, is characterized by high glucose levels (hyperglycemia); however, hypoglycemic states may also occur due to insulin treatment or poor control of the disease. These alterations in glucose levels affect the brain and could cause epileptic seizures and status epilepticus . In addition, it is known that oxidative stress states emerge as diabetes progresses, contributing to the development of diseases secondary to diabetes, including retinopathy, nephropathy, cardiovascular alterations, and alterations in the central nervous system, such as epileptic seizures. Seizures are a complex of transient signs and symptoms resulting from abnormal, simultaneous, and excessive activity of a population of neurons, and they can be both a cause and a consequence of oxidative stress. This review aims to outline studies linking diabetes mellitus and seizures to oxidative stress, a condition that may be relevant to the development of severe seizures in diabetes mellitus patients.

We have previously shown that Environmental Enrichment (EE)-consisting of social support, novelty, and open spaces-decreased disease progression and anxiety in a rat model of endometriosis. We developed a novel EE intervention to be tested in a pilot randomized clinical trial (RCT) in patients with endometriosis, a painful, stressful disease. To translate and evaluate the feasibility and acceptability of an adapted EE intervention as an adjuvant to standard-of-care for endometriosis patients. Feasibility was assessed through recruitment, enrollment, and adherence rates. Acceptability was evaluated through a post-intervention survey and focus group discussion 3-months after the end of the intervention. Of the 103 subjects recruited, 64 were randomized to the intervention group and 39 to the control group. At the start of the intervention, the study groups consisted of 29 (intervention) and 27 (control) subjects. Enrollment rates were 45.3% and 69.2%, and adherence rates were 41.4% and 100% for the intervention and control groups, respectively. Delays resulting from natural events (earthquakes, the COVID-19 pandemic) impacted enrollment and adherence rates. The most common reasons for missing an intervention were period pain (39.1%) and work-study (34.8%). There was high acceptability (>80%) of the intervention's logistics. The majority (82.4%) of subjects would continue participating in support groups regularly, and 95.7% would recommend the intervention to other patients. We showed that EE could be translated into an acceptable integrative multi-modal therapy perceived as valuable among participants who completed the intervention. High attrition/low adherence indicates that additional refinements would be needed to improve feasibility. Acceptability data indicate that EE has the potential to be integrated into the clinical management of patients with endometriosis and other inflammatory, painful disorders. Studies are ongoing to assess the efficacy of EE in improving pain symptoms, mental health, and quality of life (QoL).