Search Results (98)

The cannabinoid 1-receptor (CB1R) is found in particularly high levels in the hippocampus (HPC). Increased CB1R density and binding are observed in patients with schizophrenia, and epidemiological studies suggest that regular cannabis use during adolescence is a risk factor for the disease. CB1R was shown to interfere with neuronal network oscillations and to impair sensory gating and memory function. Neuronal oscillations are essential in multiple cognitive functions, and their impairment was documented in neurological and psychiatric diseases. The aim of this study was to investigate how adolescent pre-treatment with the CB1R-selective agonist CP-55940 may lead to abnormalities in theta synchronization in adulthood. Rats were pre-treated with CP-55940 or vehicle during adolescence (daily injections in PND 32–36 or PND 42–46). They were then tested in adulthood (PND over 70) under urethane anesthesia. Hippocampal theta rhythm was elicited by brainstem stimulation at five intensity levels 1 hour before and up to 5 h after injection. We found a significant decrease in elicited theta power after CP-55940 in adult rats, which was aggravated further in rats pre-treated in adolescence with the CB1R agonist. The effect was significantly larger in rats pre-treated during early adolescence (PND 32–36) compared to the group pre-treated during late adolescence (PND 42–46). We conclude that (1) exposure to cannabis during adolescence leads to increased sensitivity to CB1R agonist in adulthood, and (2) early adolescence, a critical period for development of HPC networks generating theta rhythms, is particularly prone to this sensitivity. Full article

An overview of seasonal variations in glycaemic patterns in children and young adults with type 1 diabetes has been addressed in a previous work, which paved the way for an in-depth study involving not only traditional Multiple Dose Injection (MDI) therapy, but also a comparative analysis with the use of Advanced Hybrid Closed-Loop (AHCL) insulin pumps. The widespread use of Flash Glucose Monitoring (FGM) and Continuous Glucose Monitoring (CGM) systems, as well as dedicated platforms for synchronizing and storing CGM reports, has facilitated an efficient approach to analyzing glycaemic patterns. The effect of environmental parameters on glycemic trends undoubtedly has a clinical relevance, which however can be appropriately managed by knowing the responses in patients treated with different therapeutic approaches. In this sense, it is possible to evaluate how the glycemic trend in diabetic patients, in relation to external temperatures, responds differently to therapies. In this work, the response, in terms of glucose level, in diabetic patients was analyzed, according to the different therapeutic approaches and in relation to variations in external temperature. For the same period of the previous work (one year: Autumn 2022–Summer 2023), seasonal variations in CGM metrics (i.e., Time In Range—TIR, Time Above Range—TAR, Time Below Range—TBR and Coefficient of Variation—CV) were analyzed. The results show a better metabolic control, linked to the effect of the algorithm on the trend of glycaemia. However, the analysis focused on the heatwave of July 2023 highlights the role of extreme temperatures as a stress factor in the insulin pumps performance. A further focus was carried out on the comparison of glycaemic patterns during the school and non-school period for all patients until 21 years old. Results suggest that during the school period, glycaemic patterns, in patients treated with MDI, show a greater onset of hyperglycaemia. From all that has emerged, it appears clear that structured education on diabetes self-management for patients and their families is fundamental and must take into account multiple factors (type of therapy, daily activities, atmospheric temperature) in order to keep their effects under control. Full article

Background/Objectives: Postprandial glucose variability is a key challenge in diabetes management for patients receiving multiple daily insulin injections (MDI). This study evaluated transformer-based machine-learning models for predicting post-prandial glucose peaks and nadirs using pre-meal glucose, insulin dose, and nutritional input. Methods: In this observational study, 58 adults with diabetes provided dietary records, insulin logs, and continuous glucose monitoring data. After preprocessing and participant-level splitting (64:16:20), model-ready datasets comprised 6155/1449/1805 (train/validation/test) meal events for the Full-Nutrition model and 6299/1484/1849 for the Carbohydrate and Available-Carbohydrate models. We evaluated three transformer-based models and assessed performance using MAE, R², and the Clarke error grid. Results: The Full Nutrition Model achieved MAEs of 32.2 mg/dL (peak) and 21.8 mg/dL (nadir) with R² values of 0.58 for both. Carbohydrate-based models showed similar accuracy. Most predictions fell within Clarke error grid Zones A and B. Conclusions: Transformer-based machine-learning models can accurately predict postprandial glucose variability in MDI-treated patients. Carbohydrate-only inputs performed comparably to full-nutrient data, supporting the feasibility of simplified dietary inputs in clinical applications. Full article

Thick-lipped grey mullet (Chelon labrosus) has important characteristics that make it a promising candidate species for diversifying Mediterranean aquaculture. However, spontaneous spawning in captivity has not been documented, mainly due to failure of females to spawn, highlighting the need for further research on reproduction control. This study evaluated the efficacy of GnRHa administration, using repeated intramuscular injections or slow-release Ethylene–Vinyl Acetate (EVAc) implants combined with a dopamine antagonist (metoclopramide, Met), in terms of spawning performance and egg quality. Three groups were established: (a) saline injection (0.9% NaCl; Saline-INJ), (b) GnRHa [Des-Gly¹⁰, D-Ala⁶-ProNEth⁹-mGnRHa] injection at 10 μg kg⁻¹ BW (GnRHa-INJ), and (c) EVAc implant containing GnRHa at 50 μg kg⁻¹ bw (GnRHa-IMP). Over four weeks, Saline-INJ and GnRHa-INJ females received weekly saline or GnRHa, respectively. GnRHa-INJ and GnRHa-IMP females also received weekly Met (15 mg kg⁻¹ bw). GnRHa induced 11 spawns (1,768,680 eggs), nearly triple the Saline-INJ group (4 spawns, 394,400 eggs). Daily relative fecundity (DRF) and fertilization success were highest in GnRHa-INJ (56,982 eggs kg⁻¹ day⁻¹; 59.7%), followed by GnRHa-IMP (20,375; 18.8%) and Saline-INJ (13,061; 9.1%). Multiple injections showed a trend toward higher spawning performance and egg quality compared to implants, although variability was high and further replication is needed. Nevertheless, optimizing both GnRHa delivery methods could further enhance their effectiveness while maintaining operational benefits for aquaculture. Full article

Background and Objectives: Automated insulin delivery (AID) systems represent a major advancement in type 1 diabetes (T1D) management, particularly in pediatric populations. However, real-world evidence comparing their effectiveness to conventional multiple daily injection (MDI) therapy in youth remains limited. This study aimed to evaluate the impact of transitioning from MDI therapy to AID systems on glycemic control in children and adolescents with T1D, and to explore potential differences based on baseline HbA1c levels and device type. Materials and Methods: In this single-center, retrospective observational study, 76 children and adolescents with T1D were evaluated before and after switching from MDI to either the Medtronic MiniMed™ 780G or Tandem t:slim X2™ Control-IQ system. Glycemic control was assessed using continuous glucose monitoring (CGM)-derived metrics at three time points: the last 15 days of MDI therapy (T0), 15 days after (T1), and 6 months after (T2) AID initiation. Statistical comparisons were conducted across time points and between subgroups stratified by baseline HbA1c and AID system. Results: Significant improvements in glycemic control were observed as early as 15 days after AID initiation, with sustained benefits at 6 months. Time in range (TIR) increased from 62.0% at baseline to 76.7% at 15 days and 75.8% at 6 months, and time in tight range (TITR) from 39.8% to 53.9% at T1 and 52.1% at T2 (both p < 0.001). Improvements were more pronounced in participants with higher baseline HbA1c (+16.9% for TITR and +22.3% for TIR). No significant differences in glycemic outcomes were observed between device groups, although algorithm-driven differences in insulin delivery patterns were noted. Total daily insulin dose and BMI increased significantly over time (p < 0.001 and p = 0.008, respectively). Conclusions: AID therapy leads to rapid and sustained improvements in glycemic control among youth with T1D, particularly in those with suboptimal baseline control. These benefits highlight the clinical value of AID systems, while also emphasizing the need for monitoring potential metabolic impacts. Full article

Background/Objectives: Type 1 diabetes mellitus (T1D) is the most common metabolic disorder in children, with significant physical and emotional impacts. Achieving optimal glucometric control is challenging due to the complex management and limitations of insulin therapy. Advances in pharmacology and technology, including continuous glucose monitoring (CGM) systems, offer new options for diabetes management. We developed Andiacare, an open-source platform for macro/micro-management of diabetes and analyzed its application in a pediatric T1D cohort to evaluate glucometric control patterns. Methods: A retrospective cohort study was conducted in a pediatric population (<18 years old) in Andalusia, Spain. Patients treated with Multiple Daily Injections of Insulin (MDI) and FreeStyle Libre 2 System (Abbott, Spain) were included. The patient data were analyzed using the Andiacare platform, which categorizes patients based on the Advanced Technologies and Treatments for Diabetes (ATTD) panel’s targets for glucometric control. Results: The study included 2215 patients from 18 pediatric hospitals. The Andiacare platform categorized patients into four groups based on glucometric control parameters, enabling patient stratification based on their glucometric control. Only 25.8% of the cohort achieved the recommended Time in Range (TIR), and 9.5% of the patients achieved all target parameters of glucometric control. Age is a determinant factor in adherence and achievement of set goals. Conclusions: This study offers insights into glucometric control in a large pediatric population with T1D in Andalusia. Few patients achieved the recommended glucometric control targets, highlighting the need for improved management strategies. The use of digital platforms such as Andiacare might contribute to facilitating the management of large pediatric cohorts. New algorithms integrating glucometric and non-glucometric parameters are required for improved individual and cohort categorization to optimize therapeutic interventions. Full article

Background and Objectives: Eating disorders are one of the most widespread health concerns, mainly among adolescents. Children and adolescents with type 1 diabetes mellitus (T1DM) have been reported to have a high prevalence of eating disorders. The aim of our study is to evaluate the risk of diabetes-specific eating disorders in children with T1DM using continuous subcutaneous insulin infusion (CSII), with real-time glycemic data from continuous glucose monitoring (CGM). Materials and Methods: Sixty-four patients (aged 7–18 years) completed the Diabetes Eating Problem Survey-Revised (DEPS-R). The DEPS-R is a diabetes-specific self-report questionnaire to assess diabetes-specific compensatory behaviors. Auxological findings, sex, age, age at diagnosis, hemoglobin A1c (HbA1c) levels, and all CGM data were obtained from their medical records. Results: Although the median DEPS-R score was higher in children and adolescents using CSII compared to those using multiple daily injections (MDIs) (14 vs. 11), the difference was not statistically significant (p = 0.302). The risk of diabetes-specific eating disorders was identified in six patients (30%) using CSII and in nine patients (20.4%) using multiple daily injections (p = 0.403). Interestingly, in the subgroup with poor glycemic control (HbA1c > 9%), DEPS-R scores were significantly lower among those using CSII compared to the MDI group. Pearson correlation analysis demonstrated positive associations between DEPS-R scores and diabetes duration, weight SDS, body mass index (BMI), BMI SDS, HbA1c, mean glucose, Glucose Management Indicator (GMI), time above range (TAR) (very high), and coefficient of variation (CV), while a moderate negative correlation was observed with time in range (TIR). Conclusions: This study showed that the treatment of CSII had a beneficial effect on the risk of eating disorders in patients with poor glycemic control. As well, from this perspective, CSII maintains its status as a potentially beneficial therapeutic approach in diabetes management. Full article

The primary contradiction in mature oilfields during the high water-cut stage is the uneven vertical water drive, which prevents the effective utilization of residual oil in the upper part of thick sand bodies at small scales. To address this issue, ultra-short-radius horizontal wells are employed to establish large-diameter oil flow channels within the reservoir, thereby achieving precise exploitation of this type of residual oil. Optimizing the length of the horizontal section is a critical issue in the development of small-scale residual oil, but conventional methods for optimizing the length of horizontal sections cannot be directly applied to ultra-short-radius horizontal wells (USRHWs). Therefore, utilizing reservoir seepage mechanics theory, the reservoir numerical simulation method was employed to investigate variations in daily and cumulative oil production for different horizontal section lengths. The theoretical upper limit of the optimal horizontal section length for actual injection and production well patterns was determined. Considering the coupled flow characteristics in the bottom water drive reservoir formation and wellbore, as well as the impact of friction losses caused by the relative roughness of the pipe wall under turbulent flow conditions on productivity, a mathematical model was established for the optimal length of the horizontal section of USRHWs, and the technological optimal value was determined. On this basis, fully accounting for the influence of drilling costs and oil prices on the optimization of the horizontal section length, an economic model for optimizing horizontal section length was established, and we comprehensively determine the optimal length of horizontal sections from multiple perspectives, including simulation, technology, and economics. The effectiveness of this method was validated by the processing results of actual reservoir parameters and the production performance after drilling. Full article

Breast cancer (BC) is the most common malignancy and the second-leading cause of cancer-related mortalities in women. Epidemiological studies suggested the reduced BC incidence in Mediterranean populations due to the daily consumption of diets rich in extra-virgin olive oil (EVOO). EVOO secoiridoid phenolics are widely known for their positive outcomes on multiple cancers, including BC. The current study investigates the suppressive effects of individual and combined EVOO phenolics for BC progression and motility. Screening of a small library of EVOO phenolics at a single dose of 10 µM against the viability of the BC cell lines ZR-75-1 (luminal A) and MDA-MB-231 (triple negative BC, TNBC) identified oleocanthal (OC) and ligstroside aglycone (LA) as the most active hits. Screening of EVOO phenolics for BC cells migration inhibition identified OC, LA, and the EVOO lignans acetoxypinoresinol and pinoresinol as the most active hits. Combination studies of different olive phenolics showed that OC combined with LA had the best synergistic inhibitory effects against the TNBC MDA-MB-231 cells migration. A combination of 5 µM of each of OC and LA potently suppressed the migration and invasion of the MDA-MB-231 cells versus LA and OC individual therapies and vehicle control (VC). Animal studies using the ZR-75-1 BC cells orthotopic xenografting model in female nude mice showed significant tumor progression suppression by the combined OC-LA, 5 mg/kg each, ip, 3X/week treatments compared to individual LA and OC treatments and VC. The BC suppressive effects of the OC-LA combination were associated with the modulation of SMYD2–EZH2–STAT3 signaling pathway. A metastasis–clonogenicity animal study model using female nude mice subjected to tail vein injection of MDA-MB-231-Luc TNBC cells also revealed the effective synergy of the combined OC-LA, 5 mg/kg each, compared to their individual therapies and VC. Thus, EVOO cultivars rich in OC with optimal LA content can be useful nutraceuticals for invasive hormone-dependent BC and TNBC progression and metastasis. Full article

In the Kelameili volcanic gas reservoir, primary hydraulic fracturing treatments in some wells take place on a limited scale, resulting in a rapid decline in production post stimulation and necessitating re-fracturing operations. However, prolonged production has led to a significant evolution in the in situ stress field, which complicates the design of re-fracturing parameters. To address this, this study adopts an integrated geology–engineering approach to develop a formation-specific geomechanical model, using rock mechanical test results and well-log inversion to reconstruct the reservoir’s initial stress field. The dynamic stress field simulations and re-fracturing parameter optimization were performed for Block Dixi-14. The results show that stress superposition effects induced by multiple fracturing stages and injection–production cycles have significantly altered the current in situ stress distribution. For Well K6, the optimized re-fracturing parameters comprised a pump rate of 12 m³/min, total fluid volume of 1200 m³, prepad fluid ratio of 50–60%, and proppant volume of 75 m³, and the daily gas production increased by 56% correspondingly, demonstrating the effectiveness of the optimized re-fracturing design. This study not only provides a more realistic simulation framework for fracturing volcanic rock gas reservoirs but also offers a scientific basis for fracture design optimization and enhanced gas recovery. The geology–engineering integrated methodology enables the accurate prediction and assessment of dynamic stress field evolution during fracturing, thereby guiding field operations. Full article

Umbilical cord mesenchymal stem cells (UCMSCs)-derived small extracellular vehicles (sEVs) are reported to offer therapeutic effects in regenerative medicine, but they lack safety and biodistribution profiles to support smooth translation at the clinical stage and regulatory requirements. Our study aimed to determine the safety and biodistribution profile in a healthy animal model before application in the metabolic syndrome model. Method: Healthy male Sprague Dawley (SD) rats were given an intravenous (IV) injection of normal saline (control group) or pooled fetal UCMSCs-derived sEVs (treated group) every three weeks for 90 days. Morbidity and mortality observation (daily), physical measurements (weekly), selected serum biochemistry (every three weeks), and hematology (every three weeks) were performed for 90 days. Acute toxicity (on day 14) and sub-chronic toxicity (on day 90) were assessed for gross necropsy, relative organ weight, and histopathological assessment of lungs, liver, spleen, kidney, and lymph nodes. Separately, a biodistribution study was conducted with the sEVs preparations labeled with PKH26 fluorescent dye, given intravenously to the rats. The organs were harvested 24 h post-injection. There were no drastic changes in either group’s morbidity or mortality, physical, hematological, and biochemistry evaluation. The histopathological assessment concluded moderate (focal) inflammation in the treated group’s kidneys and signs of recovery from the inflammation and vascular congestion in the liver. A biodistribution study revealed a higher accumulation of sEVs in the spleen. Multiple IV injections of the pooled fetal UCMSCs-derived sEVs in healthy male SD rats were deemed safe. The sEVs were abundantly distributed in the spleen 24 h post-injection. Full article

Background/Objectives: The association between sexual dysfunction and diabetes is well known, but few studies have investigated its prevalence in type 1 diabetes (T1D). The aim of this study was to evaluate the prevalence of sexual dysfunction in a group of women with T1D, regardless of their age, and to compare its different prevalences in women treated with different insulin regimens. Methods: The population included 77 women affected by T1D, of which 16 were on Multiple Daily Injections (MDI) and 61 on Continuous Subcutaneous Insulin Infusion (45 on Advanced Hybrid Closed Loop System with catheter and 16 on patch pump). All participants completed the Female Sexual Function Index (FSFI), a questionnaire that evaluates several aspects of sexual function. Another questionnaire that evaluated general features, diabetes-specific features and sexual-specific features was proposed to every participant. Results: The overall prevalence of female sexual dysfunction was 49.3%. A correlation was demonstrated between the prevalence of female sexual dysfunction and age; another correlation was found between the prevalence of female sexual dysfunction and dyadic status. No correlation between glycemic control and sexual dysfunction was found. Conclusions: Women with T1D presented a high prevalence of sexual dysfunction, independently from glycometabolic disease control and insulin regimens; on the other hand, a significant correlation was demonstrated with age and dyadic status. Evaluation of sexual function in women with T1D appears to be important in clinical settings independently from disease control. Full article

This study investigated the prevalence of cystic fibrosis-related diabetes (CFRD) in the Croatian cystic fibrosis (CF) population, the age at diagnosis, insulin requirements, and the relationship between age at diagnosis and other clinical parameters. Medical records from 152 patients with genetically and laboratory-confirmed CF were reviewed through to 2025. The American Diabetes Association criteria were used to diagnose CFRD. Anthropometric and clinical data were collected from the latest medical records. A total of 17 out of 152 patients had CFRD, with a prevalence of 4.8% in the paediatric population (4/84) and 19.1% in adults (13/68). The median age of CFRD diagnosis was 14 years (range 9–22 years, SD = 3.95). Thirteen patients used insulin: one used bolus only, seven used basal-bolus multiple daily injections, and five used insulin pumps. The average total daily insulin (TDI) per kilogram (kg) body weight was 0.447 U/kg (SD = 0.429). The age at CFRD diagnosis was positively correlated with the body mass index (BMI) (p = 0.029). Patients requiring insulin by age 15 had higher TDI and were more likely to have CF liver disease (p = 0.027, p = 0.037, respectively). The prevalence of CFRD and age at diagnosis aligned with previous studies. Patients diagnosed at a younger age and requiring insulin earlier had lower BMIs, likely due to a faster decline in beta cell function and earlier onset of insulinopenia. Full article

Background/Objectives: The association between sexual dysfunctions and diabetes is largely known, but few studies investigated its prevalence in Type 1 Diabetes (T1D). The aim of this study was to evaluate the prevalence of sexual dysfunction in a group of men with T1D regardless of their age and to compare the prevalence in men treated with different intensive insulin regimens. Methods: The study population included 68 men affected by T1D, of whom 17 were on Multiple Daily Injections (MDI) and 51 were on Continuous Subcutaneous Insulin Infusion (41 on Advanced Hybrid Closed Loop System with catheters and 10 on patch pumps). All participants completed the International Index of Erectile Function (IIEF-15), which evaluates several domains of sexual function. Another questionnaire that evaluated general features, diabetes-specific features, and sexual-specific features was proposed to every participant. Results: The overall prevalence of erectile dysfunction was 48.5%, and the overall prevalence of a severe grade of erectile dysfunction was 26.5%. Correlations were demonstrated between the prevalence of erectile dysfunction and age and between the prevalence of erectile dysfunction and dyadic status. Age and dyadic status were also correlated with lower scores in several other domains of the IIEF-15 questionnaire. Conclusions: Men with Type 1 Diabetes present a high prevalence of erectile dysfunction, independent of glycometabolic control of the disease and insulin regimens; on the contrary, a great correlation is demonstrated with age and dyadic status. Full article

Background and Clinical Significance: Orofacial granulomatosis is a rare but often disabling condition potentially associated with inflammatory bowel disease (IBD). Pathogenesis is not well understood, and no disease-specific approved treatment exists to date. Case Presentation: A 26-year-old woman with pan-enteric Crohn’s disease developed buccal swelling and deep oral ulcers histologically confirmed as associated orofacial granulomatosis. Multiple therapies were attempted during her life, including systemic steroids and immunomodulator drugs as Thalidomide, Adalimumab, and Ustekinumab in combination with topical steroid injections and Cyclosporin application, with no or minimal benefit. Only Infliximab showed good efficacy, but it was suspended due to side effects. Following secondary loss of response to Ustekinumab, compassionate treatment with Upadacitinib, a recently developed oral Jak-1 selective inhibitor, resulted in the complete resolution of the oral ulcers. Moreover, after the 12-week induction phase and the transition to 30 mg/daily maintenance dosage, the oral disease remained controlled. Due to the clinical recurrence of Crohn’s disease, Vedolizumab was added as associated treatment, resulting in complete clinical benefit after six months of follow-up. Conclusions: This is a unique case of orofacial granulomatosis associated with pan-enteric Crohn’s disease successfully treated with Upadacitinib. More data are needed to explore its potential benefits in this clinical condition. Full article