Introduction/Aim: Central sensitivity to thyroid hormones refers to the sensitivity of the hypothalamic-pituitary-thyroid (HPT) axis to changes in circulating free thyroxine (fT4). The relationship between fT4 levels and iodine intake is complex. The aim of the present study was to assess central sensitivity to thyroid hormones in pregnancy against iodine intake. Materials & Methods: One thousand one hundred two blood and urine samples were collected from pregnant women (with a mean age+SD of 30.4+4.6 years) during singleton pregnancies; women with known/diagnosed thyroid disease were excluded. Specifically, TSH & fT4 and 24-hour urinary iodine excretion (UI) were measured in each trimester and at two months postpartum. The Thyroid Feedback Quantile-based Index (TFQI) was calculated to assess central sensitivity to thyroid hormones. For the statistical analysis of TFQI by time period, analysis of variance (ANOVA) was used, while Pearson's correlation was used to assess TFQI versus UI. Results: The mean TFQI index ranged from -0.06 (first trimester) to -0.07 (two months postpartum), while the corresponding UI was 141 and 172 μg/L, respectively. The TFQI-UI correlation was negative (Pearson r: -0.325, p: 0.04 and r: -0.399, p: 0.023), for UI values over 250 μg/L, in the first and the third trimester of pregnancy, respectively. Discussion: TFQI is a new index reflecting central sensitivity to thyroid hormones. Lower TFQI indicates higher sensitivity to thyroid hormones. In our sample TFQI was inversely related to iodine intake, in the first trimester of pregnancy (the critical period of organogenesis) and the third trimester (the critical period of fetal growth). Thus, the observed changes in TFQI may reflect different ways of central action of thyroid hormones, according to the phase of pregnancy. The negative association between maternal TFQI (indicative of central sensitivity to thyroid hormone) and urine iodine levels during the third trimester of pregnancy may reflect the combined influence of maternal and fetal thyroid function. Our results are intriguing and have the potential to enhance our comprehension of the changes in the HPT axis’ function via variations in central sensitivity to thyroid hormones and its interplay with nutritional iodine status during pregnancy.

The rise in precocious puberty cases can be attributed to a combination of genetic and environmental factors. Genetic factors play a significant role, with studies identifying genetic abnormalities in genes such as KISS1, KISS1R, MKRN3, DLK1, GABRA1, LIN28B, NPYR, TAC3, and TACR3, which are associated with central precocious puberty (CPP). Epigenetic factors like DNA methylation and histone modifications may mediate the relationship between genetic and environmental influences on CPP development. Environmental factors such as exposure to secondhand smoke, cesarean section, and BMI have also been linked to precocious puberty, particularly in girls, highlighting the multifactorial nature of this phenomenon. Understanding the interplay between these genetic and environmental factors is crucial in addressing the increasing prevalence of precocious puberty in children. The published literature in the past five years was systematically reviewed and summarized highlighting the interplay of genetic and environmental factors for the rise in the precocious puberty.

The current paper provides a cutting-edge information data length- theoretic approach to human emotions. This is a revolutionary breakthrough that unifies information data length and the dynamics of emotions. The significant impact of both time and its mean value associate on both the upper and lower bounds of the obtained information data length is observed and noted. The paper concludes with some challenging open problems, combined with concluding remarks and future research pathways.

Glycerol conversion to valuable biomolecules has been a research avenue that has attracted a significant interest in recent years due to its increasing over production, with possibilities for chemical transformation for eco-friendly processes and distinct compounds with biological activities. Also, in the current climate change in which a major emphasis is being placed on the design of green processes, solvents are key factors from both an economic and environmental point of view. In this context, due to its abundance and low-price, glycerol represents an innovative solvent coming from biomass and produce in high amount. On the other hand, Epichlorydrin, Glycidol and Solketal have become useful intermediates in chemical transformations when using glycerol as a raw material. This review focuses on glycerol as a green solvent in the synthesis of complex molecules, Epichlorydrin, Glycidol, Solketal and Tosyl solketal as an efficient recycling process for glycerol, as well as building blocks in the synthesis of glycerol derivatives, which are undeniable new source of potentials drugs.

Timely screening for breast cancer plays a pivotal role in early detection and treatment; however, Afghan refugee females face significant barriers that hinder their access to these life-saving screening services. Cultural norms, socioeconomic factors, proficiency with the English language, and the challenges of navigating foreign healthcare systems contribute to low screening rates within this population. The current review article seeks to identify barriers to breast cancer screening in the Afghan refugee population in the United States (US) and address possible measures to overcome these challenges.

Background: Histone deacetylases (HDACs) are implicated in carcinogenesis, and HDAC inhibitors (HDACis) are explored as a therapeutic tool in several tumors. The aim of this study was to evaluate the clinical significance of HDAC -2, -4, and -5 expression in epithelial ovarian carcinoma (EOC). Methods: HDAC-2, -4, and -5 immunohistochemical expression was examined in 92 EOC tissue specimens and was correlated with clinicopathological characteristics. Results: HDAC-2 was the most frequently (94.4%) expressed isoform, being marginally higher in serous tumors compared with other types (p=0,08). HDAC-5 was the less frequently expressed (28.1%), being positively associated with HDAC-4. HDAC-4 positivity was associated with lower FIGO-stage (p=0,045) and T-category (p=0.,043) and the absence of lymph node (p=0,05) or distant metastasis (p=0,09) in serous carcinomas. HDAC-2 positivity was correlated with absence of lymph node metastasis in serous tumors (p=0,045). On the contrary, HDAC-5 nuclear positivity was correlated with lymph node metastasis in the entire cohort (p=0,048). HDAC-4 positivity was marginally associated with favorable prognosis in serous carcinomas in univariate survival analysis (p=0,086), a correlation which was not significant in multivariate analysis. Conclusion: These findings suggest a differential expression of HDAC-2, -4 and -5, providing evidence for a potential role in the pathobiology of EOC.

Abstract Background: Occipital neuralgia is a debilitating condition and traditional treatments often provide limited or temporary relief. Recently, ultrasound-guided hydrodissection of the greater occipital nerve (GON) has emerged as a promising minimally invasive approach. Objectives: To describe two novel ultrasound-guided hydrodissection with 5% dextrose for GON and discuss their advantages, disadvantages, and considerations. Methods: Two case reports are presented. Case 1 describes a lateral decubitus approach for hydrodissecting the GON between the semispinalis capitis (SSC) and obliquus capitis inferior (OCI) muscles. Case 2 details a cranial-to-caudal approach for hydrodissecting the GON within the SSC and upper trapezius (UT) muscles when the GON pass through these two muscles. Results: Both patients experienced significant and sustained pain relief with improvements in function and quality of life. Conclusions: Ultrasound-guided GON hydrodissection using 5% dextrose is a promising treatment for occipital neuralgia. The lateral decubitus and cranial to caudal approaches provide additional options to address patient-specific anatomical considerations and preferences.

Diabetes markedly increases susceptibility to adverse cardiovascular events, including heart failure (HF), leading to heightened morbidity and mortality rates. Elevated levels of natriuretic peptides (NPs), notably B-type natriuretic peptide (BNP) and N-terminal-proBNP (NT-proBNP), correlate with cardiac structural and functional abnormalities, aiding in risk stratification and treatment strategies in individuals with diabetes. This article reviews the intricate relationship between diabetes and HF, emphasizing the role of NPs in risk assessment and guiding therapeutic strategies, particularly in individuals with type 2 diabetes mellitus (T2DM). It also explores the challenges and prospects of natriuretic peptide-guided therapy in managing cardiovascular risk in patients with diabetes.

Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.

The clustering methods of Software Defined Networking (SDN) gained popularity due to their ability to offer improved scalability, consistency, dependability, and load balancing within overlay networks and SDN partitions. This paper delved into the effects of increasing the number of OpenFlow-enabled southbound devices on the establishment and coordination of SDN-Controller clusters. Specifically, we examined the volume of east-west cluster packet communication concerning the number of southbound devices within the topology. Many research studies focused on bandwidth and the number of bytes in East-West communication. While bandwidth referred to the maximum rate at which data could be transferred, and the number of bytes reflected the volume of data being transmitted, the number of packet communications directly influenced the efficiency and responsiveness of network operations. Our investigation encompassed the impact of SDN controllerto- controller communication within the cluster concerning the rising number of OpenFlow switches connected to various topologies, including tree (star-bus network), linear, and torus configurations. This study presented data on communication patterns within Open Network Operating Systems (ONOS) and OpenDaylight (ODL) clusters, revealing differing levels of controller communication with southbound network expansions. We evaluated the scalability of ODL and ONOS controllers by scrutinising the effect of increasing the number of southbound devices on control communication volume. Our analysis revealed varied communication patterns within ONOS and ODL clusters, resulting in different volumes of control communication with southbound expansions. The findings indicated that in small to medium-sized SDNs, ODL outperformed ONOS, notably with faster cluster discovery. Conversely, ONOS demonstrated greater efficiency in larger networks owing to its centralised communication architecture. Finally, we provided recommendations for selecting the most suitable controllers based on the size of southbound networks, aiming to provide practical guidelines for optimal network performance.

Background: Study to assess glucose levels of people with type 1 diabetes (T1D) overnight based on insulin type and timing. Methods: Real-world, retrospective study in T1D using multiple daily insulin injections. Contin-uous glucose monitoring and insulin injections data were collected for ten hours after dinner us-ing the Insulclock® connected cap. Meal events were identified using ROC detection methodology. The timing of rapid insulin, second injections, and the type of insulin analogs used were evaluat-ed. Results: Nocturnal profiles (n=775, 49 subjects) were analyzed. Higher glucose AUC over 180mg/dL was observed in delayed injections (number; %; mg/dL x h): -45-15min (n=136; 17.5%, 175.9 ±271.0); -15-0min (n= 231; 29.8%, 164.0 ±237.1); 0+45min (n= 408; 52.6%, 203.6 ±260.9), (p 0.049). The use of ultrarapid (FiAsp®) (URI) vs rapid insulin analogs (RI) was associated with less hypoglycemia events (7.1 vs 13.6%; p 0.005) and TBR70 (1.7 +6.9 vs 4.6 +13.9%; p 0.003). Us-ers of glargine U300 vs degludec had higher TIR (70.7 vs 58.5 %) (Adjusted R-squared: 0.22, p < 0.001). The use of a correction injection (n= 144, 18.6%) was associated with higher hypoglycemia events (18.1 vs 9.5%; p 0.003), TBR70 (5.5 +14.2 vs 3.0 +11.1%; p 0.003), glucose AUC over 180 mg/dL (226.1 +257.8 vs 178.0 +255.3 mg/dL x h; p 0.001), and lower TIR (56.0 +27.4 vs 62.7 +29.6 mg/dL x h; p 0.004). Conclusions: Dinner rapid insulin timing, insulin types and correction injections affect nocturnal glucose profile in T1D.

Background: given the various clinical manifestations that characterize coronavirus disease 2019 (COVID-19), the scientific community is constantly searching for biomarkers with prognostic value. Surfactant protein A (SP-A) and D (SP-D) play a crucial role in ensuring proper alveolar function and an alteration of their serum levels have been reported in several pulmonary diseases characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Consid-ering that such clinical manifestations can also occur during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we wondered if these collectins could act as prognostic markers. Methods: in this regard, serum levels of SP-A and SP-D were measured by enzyme immunoassay in patients with SARS-CoV-2 infection (n=51) at admission (T0) and after 7 days (T1) and compared with healthy donors (n=11). Results: SP-D increased in COVID-19 patients com-pared to healthy controls during the early phases of infection, while a significant reduction was observed at T1. Stratifying SARS-CoV-2 patients according to disease severity, increased serum SP-D levels were observed in severe compared to mild patients. Conclusions: In the light of these results SP-D, but not SP-A, seems to be an eligible marker of COVID-19 pneumonia and the early detection of SP-D serum levels could be crucial for a preventive clinical management.

Oral lichen planus (OLP) is a chronic inflammatory mucosal disease, and an apparent cause has not been identified. OLP is refractory to treatment, and malignant transformation has been reported. Therefore, discovering effective drugs with few adverse effects over long-term administration is crucial. In this study, we established an in vitro OLP model to investigate the effects of Cepharanthin®, an alkaloid mixture derived from Stephania cephalantha Hayata. Four alkaloids from Cepharanthin® suppressed the expression of cytokine genes at various degrees in activated T cells. However, the effect of Cepharanthin® was limited. On the other hand, Cepharanthin® and four alkaloids suppressed the expression of various cytokine genes in human oral epithelial cells when stimulated with IL-β. In the OLP model, activated T cells increased the inflammatory gene expression in the epithelial cells, while Cepharanthin® suppressed their gene expression. Anti-inflammatory effect of Cepharanthin® was observed by protein dot blot. The effects of Cepharanthin®️ might be expressed through two aspects: its effect of mildly suppressing the activation of T lymphocytes and strongly suppressing the response of epithelial cells to inflammatory stimuli. The in vitro model established in this study could be a tool for elucidating the mechanisms of OLP pathogenesis and disease persistence.

Acute and chronic respiratory diseases impose a significant economic and health burden. Distal small airway assessment requires invasive procedures such as a bronchoscopy and bronchoalveolar lavage. The Particles in Exhaled Air (PExA) device provides a non-invasive means of assessing small airways; it captures distal airway particles sized around 0.5-7m and contains particles of respiratory tract lining fluid (RTLF) that originate during airway closure and opening. The PExA device can measure particle count and mass according to particle size. Subsequent capture of particles in a thin membrane enables application of various analytical methods to assess a broad range of biomolecules including phospholipids, proteins, inflammatory profile, and other metabolites to characterise inflammation and diseases processes such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, lung cancer, and more recently acute infections such as COVID-19. PExA analysis provides a promising alternative to traditional investigative methods in the assessment, diagnosis, and management of respiratory conditions. By evaluating specific biomarkers in the RTLF associated with airway inflammation, PExA may offer a more accurate and comprehensive understanding of the molecular-level changes in the small airways of patients with acute and chronic lung diseases.

The aim of this prospective, randomized, clinical study was to evaluate the use of the pleth variability index (PVi) to guide the rate of intra-operative fluid therapy as compared with a traditional fixed fluid rate approach in ASA 1-2 dogs undergoing surgery. Twenty-seven dogs meet the inclusion criteria and were randomly assigned to conventional fluid management group (CFM, n = 12) or PVi-guided group (PVi, n = 15). The CFM group received a fixed rate of 5 ml kg-1 h-1 of crystalloid solution, while in the PVi group the rate was continuously adjusted based on PVi: PVi &lt; 14% = 3 ml kg-1 h-1; 14% ≤ PVi ≥ 20% = ml kg-1 h-1; PVi &gt; 20% = 15 ml kg-1 h-1. Hypotension (MAP &lt; 65 mmHg) was managed in CFM with maximum two fluid boluses (5 ml kg-1 in 10 minutes) and in case of no response dobutamine (1-3 mcg kg-1 min-1) was administered. In the PVi group treatment of hypotension was similar except when PVi &gt; 14% when dobutamine was directly initiated. The total fluid amount was significantly lower in PVI group (0.056 ± 0.027 ml kg-1 min-1) vs. CFM group (0.132 ± 0.115 ml kg-1 min-1), and hypotension incidence was lower (p = 0.023) in PVi group (0%) vs. CFM group (41%). Mean arterial pressure (MAP) was significantly higher during surgery in the PVi group. Dobutamine was never administered in both groups. Preliminary data suggest that PVi may be considered a potential target to guide fluid therapy in dogs; larger studies are needed, especially in cases of cardiovascular instability.

In this paper, I investigate Hyers-Ulam-Rassias stabilities of the general quintic functional equation and the general sextic functional equation.

Individuals with BPD grapple with unstable relationships, marked by extreme emotional swings and interpersonal conflicts. Emotional instability, a distorted self-image, and impulsivity further complicate matters, often leading to self-harm and suicide attempts as desperate coping mechanisms. Genetics and adverse childhood experiences contribute to BPD's development, shaping brain function and emotional regulation. Diagnosis involves meticulous assessments, paving the way for personalized treatments like dialectical behavior therapy and, in severe cases, hospitalization. Early intervention, professional support, and societal understanding are pivotal for positive outcomes, and challenging mental health stigma.

Fiscal control and monitoring of public management are issues of great importance and relevance, as they focus on preventing and mitigating corruption, thus benefiting governments in their management and performance, and thus citizens. Given the large amount of data involved in the management and functioning of a government, it is pertinent to apply data analysis methods to contribute to fiscal control. This paper aims to investigate data management for this purpose, starting with a bibliometric study to demonstrate the relevance and pertinence of the current study. It examines existing data collection techniques that may facilitate such control, data storage considering its nature and the possibilities that contribute to this end, and data processing through techniques that allow obtaining adequate information for further analysis and decision making. The necessary architecture and interoperability between systems is also discussed, as the existence of large amounts and types of data in governments makes it crucial to promote these practices for accurate and truthful analysis. Finally, data visualization is addressed since this topic is highly relevant as it allows for the identification of anomalies, where proper visualization promotes appropriate analysis and thus informed decision making. This work is useful for modern audit and fiscal control entities, since data capture, storage, processing, interoperability, and visualization are crucial elements that collectively enhance the ability to supervise public expenditure effectively, ensuring that public funds are managed with the highest standards of transparency, accountability, and efficiency.

In my paper, a divisibility rule named the Queen function is de- scribed, which has been generalized for every integer and encompasses all pre- viously established divisibility rules. Subsequently, the paper discusses other areas where this function is instrumental. These include simplifying ratios, generating prime numbers, and more. Towards the end of the paper, a set of hypotheses is also presented. Among these, the most significant is the novel approach involving the application of the Queen function for prime number generation.

The insuperable obstacle between gravity and quantum mechanics is their spacetimes. Introduction of a (quantum) quadratic form on a state Hilbert space and a (quantum) metric tensor in (3+1)D quantum spacetime solves the problem by providing a common spacetime for both gravity and quantum mechanics which helps further to develop an accurate and generalized form of quantum gravity, i.e., General Quantum Gravity. This formalism yields a (3+1)D pseudo-gravity first order quantum equation, which is technically more accurate than Schr\"odinger equation. A (quantum) Lorentz-like transformation is also possible to be developed in (3+1)D quantum spacetime. Instead of one common Einstein field equation to explain gravitational effects, this formalism yields two individual (quantum) Einstein field equations, namely, one for bosons and another for fermions. In this work, (quantum) metric tensor as well as quantum Riemann tensor, quantum Ricci tensor and quantum Ricci scalar all are found to be the objects of quantization. Apparently, these quantum Riemann tensor, quantum Ricci tensor and quantum Ricci scalar are also found to be multiplicatively renormalizable while all divergences of their higher orders vanish in (3+1)D quantum spacetime. Ultimately, General Quantum Gravity yields that: Quantum Mechanics and Theory of Special and General Relativity are inseparable and naturally inter-expressible for the (quantum) quadratic form and the (quantum) metric tensor in (3+1)D quantum spacetime.

This research focuses on exploring generalized electron emissions in one-dimensional conducting materials, specifically examining field emission and thermionic emission. Additionally, the study investigates one-dimensional thermal radiation. The current density is derived for both one-dimensional thermionic emission and one-dimensional field emission. A generalized current density in one dimension is devised, taking into account arbitrary accelerating fields and temperature conditions. The formula for the one-dimensional current density is depicted with accelerating field and temperature across various work function materials. The current is also represented as a function of both temperature and electric field for various temperatures.

Pediatric onset multiple sclerosis (POMS), characterized by the onset of multiple sclerosis before the age of 18, is gaining increased recognition. Approximately 5 percent of MS cases manifest before the age of 18, with less than 1 percent occurring before the age of 10. Despite its rarity, pediatric MS exhibits distinct characteristics, with an association between younger age at onset and a comparatively slower disease progression. Despite this slower progression, individuals with POMS historically reach disability milestones at earlier ages than those with adult-onset multiple sclerosis. While various immunomodulatory agents demonstrate significant benefits in MS treatment, such as reduced relapse rates and slower accumulation of brain lesions on magnetic resonance imaging (MRI), the majority of disease-modifying therapies (DMTs) commonly used in adult MS lack evaluation through pediatric clinical trials. Current evidence is predominantly derived from observational studies. This comprehensive review aims to consolidate existing knowledge on the mechanisms of action, efficacy, safety profiles, and recommended dosages of available DMTs specifically in the context of pediatric MS. Furthermore, the review outlines recent advancements and explores potential medications still in developmental stages, providing a thorough overview of the current landscape and future prospects for treating POMS.

It has been well established that hypertension is considered as a predominant risk factor for the development of cardiovascular diseases. Despite the link between hypertension and cardiovascular diseases, hypertension may directly affect the cardiac function leading in heart failure, mostly with preserved ejection fraction (HFpEF). There are echocardiographic findings indicating hypertensive heart disease (HHD) defined as altered cardiac morphology (left ventricular concentric hypertrophy, left atrium dilatation) and function (systolic or diastolic dysfunction) in patients with persistent hypertension irrespective of cardiac pathologies to which it contributes, such as coronary artery disease and kidney function impairment. In addition to classical echocardiographic parameters, novel indices, like speckle tracking of the left ventricle and left atrium, 3D volume evaluation, myocardial work in echocardiography may provide more accurate and reproducible diagnostic and prognostic data in patients with hypertension. However, their use is still underappreciated. An early detection and prompt therapy of HHD will greatly improve the prognosis. Hence, in the present review, we shed light on the role of echocardiography in the contemporary diagnostic and prognostic approach of HHD.

Patients with predominantly antibody deficiencies (PAD) display hypogammaglobulinemia with a high prevalence of infections, along with autoimmune manifestations, benign and malignant lymphoproliferation and granulomatous disease. It is noteworthy that PAD patients, even those with defects in the same causative genes display a variable clinical phenotype, suggesting that additional genetic polymorphisms, located in either immune-related or non-immune-related genes, may affect their clinical and laboratory phenotype. In this context, we analyzed 80 PAD patients, including 70 with common variable immunodeficiency (CVID) for SERPINA1 defects, in order to investigate their possible contribution to PAD clinical phenotype. Eight CVID patients carried heterozygous pathogenic SERPINA1 defects with normal alpha-1 antitrypsin levels. Interestingly, the presence of the Z allele (rs28929474) which was found in three patients, was significantly associated with liver disease; hepatic complications were also observed in patients carrying the p.Leu23Gln (rs1379209512) and the p.Phe76del (rs775982338) alleles. Conversely, no correlation of SERPINA1 defective variants with respiratory complications was observed, although patients with pathogenic variants exhibit a reduced probability of developing autoimmune diseases. Therefore, we recommend SERPINA1 genetic analysis in PAD, in order to identify patients with a higher risk for liver disease.

The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is exemplified by the success of TNF blockade in conditions including rheumatoid arthritis, ulcerative colitis and skin psoriasis, albeit only for subsets of individuals with each condition. This suggests intersecting "nodes" in inflammatory networks at a molecular and cellular level may drive and/or maintain IMIDs, being “shared” between traditionally distinct diagnoses without mapping neatly to a single clinical phenotype. In line with this proposition, integrative tumour tissue analyses in oncology have highlighted novel cell states acting across diverse cancers, with important implications for precision medicine. Drawing upon advances in the oncology field, this narrative review will first summarise learnings from the Human Cell Atlas in health as a platform for interrogating IMID tissues. It will then review cross-disease studies to date that inform this endeavour, before considering future directions in the field.

Older adults with obesity have an increased risk for cognitive decline and subsequent Alzheimer’s disease. Previous research has focused on the impact of individual nutrients and overall dietary patterns to improve cognitive function. The Brain and Body Health (BB-Health) study aims to demonstrate the feasibility of a multicomponent nutritional supplement (MCNS) and weight loss (WL) intervention for individuals with overweight and obesity who are not consuming a healthy diet. BB-Health is a parallel-group randomized placebo-controlled 2x2 factorial pilot trial comparing the MCNS, WL, and MCNS+WL with a Control group. Eligible participants are 55 to 85 years of age with a body mass index 27.0 to 39.9 kg/m2. Major exclusion criteria include type 2 diabetes, moderate or severe cognitive impairment, and self-reported healthy dietary pattern. The BB-Health feasibility trial is registered as NCT05542199 at clinicaltrials.gov. The BB-Health objectives are to report: 1) recruitment and enrollment, including pace and descriptive statistics of the study sample; 2) adherence to the administered interventions; 3) successful data collection and performance of outcome assessments, including evaluation of change in key outcomes over time that are powered for this pilot study; and 4) summary statistics on outcomes for use in planning a subsequent, larger trial. The outcomes of interest are age-sensitive cognitive assessments, cerebral hemodynamics, and related health parameters. All measurements are collected at baseline, 3-, 6-, and 12-month visits. If the BB-Health protocol demonstrates feasibility, the novel MCNS with and without a parallel WL intervention has potential to be administered in a confirmatory randomized trial to evaluate ability to prevent age-related cognitive decline and improve brain health. The BB-Health Feasibility Study could significantly contribute to our understanding of the influence of diet and weight management on cognitive health

Obesity results in hepatic fat accumulation, i.e., steatosis. Besides the fat overload, impaired fatty acid β-oxidation also promotes steatosis. Fatty acid β-oxidation takes place in mitochondria and peroxisomes. Usually very long chain and branched-chain fatty acids are first oxidized in peroxisomes, and the resultant short chain fatty acids are further oxidized in mitochondria. Peroxisome biogenesis is regulated by peroxin 16 (PEX16). In liver-specific PEX16 knockout (Pex16Alb-Cre) mice, hepatocyte peroxisomes were absent, but hepatocytes proliferated, and liver mass was enlarged. These results suggest that normal liver peroxisomes restrain hepatocyte proliferation and liver sizes. After high fat diet (HFD) feeding, body weights were increased in PEX16 floxed (Pex16fl/fl) mice and adipose-specific PEX16 knockout (Pex16AdipoQ-Cre) mice but not in the Pex16Alb-Cre mice, suggesting that the development of obesity is regulated by liver PEX16 but not by adipose PEX16. However, it was previously reported that HFD-induced obesity in the Pex16AdipoQ-Cre mice was more severe than in the wild type mice, which was not observed until 27 weeks of HFD feeding. Thus, liver initiates the development of obesity, which is enhanced by abnormal adipocytes. HFD increased liver mass in the Pex16fl/fl mice but somehow reduced the already enlarged liver mass in the Pex16Alb-Cre mice. Basal levels of serum triglyceride, free fatty acids and cholesterol were decreased whereas serum bile acids were increased in the Pex16Alb-Cre mice, and HFD-induced steatosis was not observed in the Pex16Alb-Cre mice. These results suggest that normal liver peroxisomes contribute to the development of liver steatosis and obesity.

1,3,5-Tris-(α-naphthyl)benzene is an organic non-electrolyte with notable stability of an amorphous phase. Its glassy and supercooled liquid states were previously studied by spectroscopic and calorimetric methods. However, the thermodynamic parameters of phase transitions available from the literature are inconsistent. In this work, the heat capacities of crystalline and liquid phases, the temperature dependence of the saturated vapor pressures, fusion and vaporization enthalpies were determined using differential and fast scanning calorimetry and verified using the estimates based on solution calorimetry. The structural features of 1,3,5-tris-(α-naphthyl)benzene are discussed based on the computations performed and the data on the molecular refractivity. The consistency between the values obtained by independent techniques was demonstrated. The deviations in the previously published data were attributed to possible polymorphism.

Background: Medication errors often stem from incomplete or incorrect transfer of drug information during reviews. To enhance medication review processes, a collaborative healthcare team, including a pharmacist in the surgical ward, is essential. This study aimed to identify the frequency and the kind of intentional and unintentional discrepancies related to the prescriptions within two surgical wards. Methods: A prospective observational study was conducted among adult patients admitted to two surgical settings. The patients were selected between May 30th and November 30th, 2021. The study followed a three-phase structure: patient selection, medication review to identify discrepancies and DRPs, and the detection of any such issues in the discharge letter. Results: The most frequent types of discrepancies collected were substitutions (60.9%) for the Endocrinological Surgery and omissions for General Surgery (53.4%). In Endocrinological Surgery, 45.9% of cases exhibited class C drug interactions. In General Surgery, class D drug interactions were predominantly observed (54.1%), with 93.3% attributed to drugs carrying an elevated risk of prolonging the QT interval. Conclusions: Frequently, the medication review process is superficially carried out, introducing errors that may adversely affect patient health. This study explores the potential positive impact of involving the clinical pharmacist in identifying and managing discrepancies and DRPs.

Background: Critical states present scale-free dynamics, optimizing neuronal complexity. We explored electroencephalogram (EEG) criticality in amnesic Mild Cognitive Impairment (aMCI) patients with clinical improvement in working memory, verbal memory, verbal fluency and overall executive functions after the completion of a 6-month prospective memory training. (2) Methods: We compared “before” and “after” stationary resting-state EEG records of right-handed MCI patients (n = 17; 11 females), using the method of critical fluctuations and Haar wavelet analysis. (3) Results: Significant criticality enhancement was present in frontotemporal electrodes [mean dif: 0.10; Z = 7, p = .019] and isolated electrodes T6 [mean dif: 0.204; t (10) = - 2.3, p = .044] and F4 [mean dif: 0.0194; t (10) = - 2.82; p = .018]. (4) Conclusions: EEG criticality agreed with clinical improvement, consisting a possible monitoring biomarker in MCI and Alzheimer’s disease. Further evaluation is needed in patients under cognitive training or even drug-modifying therapies.

We wanted to investigate the current knowledge on the impact of diet on anti-TNF response in inflammatory bowel diseases (IBD), to identify dietary factors that warrant further investigations in relation to anti-TNF treatment response, and, finally, to discuss potential strategies for such investigations. PubMed was searched using specified search terms. One small prospective study on diet and anti-TNF treatment in 56 patients with CD found similar remission rates after 56 weeks among 32 patients with good compliance that received concomitant enteral nutrition and 24 with poor compliance that had no dietary restrictions (78% versus 67%, p = 0.51). A meta-analysis of 295 patients found higher odds of achieving clinical remission and remaining in clinical remission among patients on combination therapy with specialised enteral nutrition and Infliximab (IFX) compared with IFX monotherapy (OR 2.73; 95% CI: 1.73–4.31, p < 0.01, OR 2.93; 95% CI: 1.66–5.17, p < 0.01, respectively). In conclusion, evidence-based knowledge on impact of diet on anti-TNF treatment response for clinical use is scarce. Here we propose a mechanism by which Western style diet high in meat and low in fibre may promote colonic inflammation and potentially impact treatment response to anti-TNF drugs. Further studies using hypothesis-driven and data-driven strategies in observational, animal and interventional studies are warranted.

Background: Carbapenemase-producing Enterobacter cloacae complex (ECC) are increasingly identified in hospital-acquired infections. They usually belong to four main multilocus sequence types (STs) named ST114, ST93, ST90, and ST78. Instead, ST182 has been sporadically reported, and recently outbreaks of blaNDM-producing ST182 strains have emerged. Herein, we aimed to investigate the presence of ST182 and explore its evolution and modes of blaNDM acquisition. Methods: A phylogenetic analysis of 646 MLST STs identified among 4,685 E. hormaechei WGS assemblies deposited in public repositories was performed, as well as an in silico comparative and phylogenomic analyses for 55 WGS assemblies of ST182. blaNDM-harboring contigs were also compared to published plasmid sequences. Results: ST182 E. hormaechei strains were recovered from patients in five continents during 2011-2021. They were divided into three major genomic clusters, comprising a separate clonal complex with six other STs. In 30 out of 55 ST182 WGS assemblies, blaNDM-harboring structures were identified similar to plasmids predominant in Gram-negative bacteria, harboring resistance genes to multiple antibiotic classes and virulence genes. No associations between the genomic clusters and the country/continent of isolation, the presence and the plasmid types of the blaNDM-harboring contigs were observed. Conclusions: Our findings show that ST182 E. hormaechei strains were identified the past decade worldwide; 54.5% of them carried diverse blaNDM genetic structures, suggesting recent acquisition of the blaNDM alleles. Thus, blaNDM-producing ST182 is an emerging multidrug-resistant and virulent lineage in ECC that requires close monitoring.

Immune-cell reprogramming driven by mitochondria-derived reactive electrophilic immunometabolites (mt-REMs—e.g., fumarate, itaconate) is an emerging phenomenon of major biomedical importance. Despite their localized production, mt-REMs elicit significantly-large local and global footprints within and across cells, through mechanisms involving electrophile signaling. Burgeoning efforts are being put into profiling mt-REMs’ potential protein-targets and phenotypic mapping of their multifaceted inflammatory behaviors. Yet, precision indexing of mt-REMs’ first-responders with spatiotemporal intelligence and locale-specific function assignments remains elusive. Highlighting the latest advances and overarching challenges, this perspective aims to stimulate thoughts and spur interdisciplinary innovations to address these unmet chemical-biotechnological needs at therapeutic immuno-signaling frontiers.

(1) Background: With the rising incidence of life expectancy, obesity, and tumours, understanding the incretory influence of adipose tissue in tumorigenesis becomes increasingly important. As the adipokines leptin and adiponectin are released by fat tissue, we aimed to analyse the expression of their respective receptors in tumours for which an association with obesity is epidemiologically hypothesized; (2) Methods: The expression of leptinR and adipoR1 were analysed in cohorts of renal cell cancer (n = 391), cervical cancer (n = 155), vulvar cancer (n = 107), and endometrial cancer (n = 90) by immunohistochemistry and correlated with clinicopathological parameters including survival times; (3) Results: Expression of leptinR was high in renal cell cancer (62.2% of cases), vulvar carcinoma (50%) and endometrial cancer (80.5% of tissue-samples). High expression was associated with favourable clinicopathological markers and longer overall survival times in renal cell cancer and vulvar cancer. AdipoR1 was only weakly expressed in all four tumor entities and did not show significant associations with clinicopathological parameters or prognosis; (4) Conclusion: High leptinR is a promising biomarker for favourable tumour outcome in renal cell carcinoma and vulvar carcinoma.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive in-crease in mean pulmonary arterial pressure. Mutations in the BMPR2 and AQP1 genes have been described in familial PAH. The bone morphogenetic proteins BMP9 and BMP10 bind with high affinity to BMPR2. Administration of BMP9 has been proposed as a potential therapeutic strategy against PAH, although recent conflicting evidence dispute the effect of such practice. Considering the involvement of the above molecules in PAH onset, progression, and therapeutic value, we ex-amined the effects of modulation of BMP9, BMPR2, and AQP1 on BMP9, BMP10, BMPR2, AQP1, and TGFB1 expression in human pulmonary microvascular endothelial cells in vitro. Our results demonstrated that silencing the BMPR2 gene resulted in increased expression of its two main ligands, namely BMP9 and BMP10. Exogenous administration of BMP9 caused return of BMP10 to basal levels, while restored the decreased AQP1 protein levels and the decreased TGFB1 mRNA and protein expression levels caused by BMPR2 silencing. Moreover, AQP1 gene silencing also resulted in increased expression of BMP9 and BMP10. Our results might possibly imply that the effect of exogenously administered BMP9 on molecules participating in the BMP-signaling pathway could depend on the expression levels of BMPR2. Taken together, these results may pro-vide insight into the highly complex interactions of the BMP-signaling pathway.

The paper suggests that the physical priciple of special relativity's space-time transformation effect is wrong, Uniform linear motion without acceleration does not exist objectively, nor does its same reference frames. Therefore, it is inferred that the space-time transformation effect of special relativity is caused by the acceleration of moving objects, special relativity is only a part of general relativity, not a theoretical system that exists independently from general relativity. The corresponding mathematical demonstration and calculation verification are carried out, and the result proves that the inference of the paper is correct. At the same time, it further explains that the concept of absolute airspace is correct. Special relativity has serious errors in the concept of space, the principle of relativity and the physical principle of space-time transformation effect. Therefore, it is necessary to make a series of revisions to the theory of relativity and to reinterpret some related physical problems.

The floating freshwater fern Azolla is the only plant that retains an endocyanobiont, Nostoc azollae (aka Anabaena azollae) during its sexual and asexual reproduction. The increased interest in Azolla as a potential source of food, and its unique evolutionary history have raised questions about its cyanotoxin content and genome. Cyanotoxins are potent toxins synthesized by cyanobacteria which have an anti-herbivore effect, but also have been linked to neurodegenerative disorders including Alzheimer’s and Parkinson's diseases, liver and kidney failure, muscle paralysis and other severe health issues. In this study, we investigated 48 accessions of the Azolla-Nostoc symbiosis for the presence of genes coding microcystin, nodularin, cylindrospermopsin and saxitoxin, and BLAST analysis for anatoxin-a. We also investigated the presence of the neurotoxin β-N-methylamino-L-alanine (BMAA) in Azolla and N. azollae through LC-MS/MS. The PCR amplification of saxitoxin, cylindrospermospin, microcystin, and nodularin genes showed that Azolla and its cyanobiont N. azollae do not have the genes to synthesize these cyanotoxins. Additionally, the matching of the anatoxin-a gene to the sequenced N. azollae genome does not indicate the presence of the anatoxin-a gene. The LC-MS/MS analysis showed that BMAA and its isomers AEG and DAB are absent from Azolla and Nostoc azollae. Azolla therefore has the potential to safely feed millions of people due to its rapid growth while free-floating on shallow fresh water without the need for nitrogen fertilizers.

Is there a qualitative difference between apes’ and human Theory-of-Mind (or ability to estimate others’ mental states)? After opting for the idea that expectations are empty profiles that recognize a particular content when it arrives, I apply the same description to ‘vicarious expectations’ –very probably present in apes. Thus, (empty) vicarious expectations and one’s own (full) contents are distinguished without need of meta-representation. Then, three proposals are made. First, vicarious expectations are enough to support apes’ Theory-of-Mind (including ‘spontaneous altruism’). Second, since vicarious expectations require a profile previously built in the subject that activates them, this subject cannot activate any vicarious expectation of mental states that are intrinsically impossible for him. Third, your mental states that think of me as a distal individual are intrinsically impossible states for me, and therefore, to estimate them, I must estimate your mental contents. This ability (the original nucleus of human Theory-of-Mind) is essential in human lifestyle. It is involved in unpleasant and pleasant self-conscious emotions, which respectively contribute to ‘social order’ and to cultural innovations. More basically, it makes possible the human (prelinguistic or linguistic) communication, since it originally made possible the understanding of others’ mental states as states that are addressed to me, and that are therefore impossible for me.

Pancreatic cancer (PC) is the most lethal type of cancer, it has the lowest 5-year survival rate among all other types of cancers. More than half of PC cases are diagnosed at an advanced stage due to PC’s insidious and non-specific symptoms. Surgery remains the most efficacious treatment option currently available, but only 10-20% of PC cases are resectable upon diagnosis. As of now, the sole biomarker approved by the United States Food and Drug Administration (US-FDA) for PC is carbohydrate antigen 19-9 (CA19-9); however, its use is limited use for early diagnosis. An in-creasing number of studies have investigated a combination of biomarkers. Lately, there has been considerable interest in the application of a liquid biopsy, including the utilization of microRNAs (miRNAs), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs). Screening for PC is indicated for high-risk patients; studies on new diagnostic models combined with biomarkers for early detection have also shown promising results for the ability of these models and biomarkers to aid clinicians in deciding on whether to start screening. This review seeks to provide a concise overview of the advancements in existing biomarkers and explore novel strategies for the early detection of PC.

(1) Background: donor-derived circulating free DNA (dd-cfDNA) is an innovative biomarker with great potential for the early identification and prevention of graft damage; (2) Methods: Prospective study to analyze dd-cfDNA plasma levels in 30 kidney transplant patients during their post-transplant follow-up (15 days, 3, 6 and 9 months), to determine if the result could be of interest in the identification of possible adverse events, specially allograft rejection. In addition, the aim is also to verify the obtained data on sensitivity, specificity, NPV and PPV; (3) Results: Plasma levels of dd-cfDNA could be considered a novel biomarker of graft rejection after first term post-transplant up to several months before its clinical presentation, mainly in TCMR or ABMR. In this study, it appears to have no positive predictive value for borderline rejection or TCMR IA. Our results show a low NPV of the technique because other pathologies or biological post-transplant complications can also affect dd-cfDNA levels and they must be considered in the interpretation of the result.; (4) Conclusions: dd cfDNA could allow, together with other additional biomarkers in the context of a future score, avoid invasive biopsies in most cases, mainly in the case of suspected TCMR or ABMR.

In solving the Collatz conjecture, it turns out that if we let all integers k be 6n, 6n+1, 6n+2, 6n+3, 6n+4, 6n+5, then we can solve the Collatz conjecture periodically. The Collatz conjecture states that for any positive integer P (initial value), if n is even, divide n by 2; if n is odd, repeat the rule of multiplying n by 3 and adding 1, which always converges to 1. One open problem has been proved by this paper. The authors hope to contribute to the mathematical community by presenting simple proofs of conjectures in the history of mathematics such as the Collatz conjecture.

The inability to delineate a unified physical ontology that accounts simultaneously for the laws of special relativity and the results of quantum experiments has been a defining problem in physics for more than 100 years. This analysis addresses the problem by positing a novel mixed ontology composed of a “discrete” 4D spacetime and a physical, ultra-high dimensional (3 x N) “Planck Space.” Together, Planck Space and the three spatial dimensions of 4D spacetime form a tightly integrated ((3 x N) + 3) hyperspace (the “Dual Ontology”).Critically, the Dual Ontology’s structure replaces 1) the continuous, differentiable manifold of 4D spacetime with a discrete, background-independent 4D spacetime that is intrinsically curved and 2) mathematical spaces with a physical (3 x N) Planck Space. Moreover, the Dual Ontology is structurally and dynamically predicated on the one-to-one mapping and identity between the discrete spatial units that simultaneously form 4D spacetime and Planck Space. The one-to-one mapping and identity of the discrete spatial units support an integrated quantum dynamics based upon the dynamic evolution of single and N-body quantum states in 4D spacetime in full compliance with the laws of special relativity and the instantaneous collapse of all quantum states in an ontic Planck Space, where special and general relativity and more generally, 4D spacetime’s laws of physics, do not apply.

In the present paper, based on the ideas of Algerian physicist M.E. Hassani, the generalized Hassani spatio-temporal transformations in real Hilbert space are introduced. The original transformations, introduced by M.E. Hassani, are the particular cases of the transformations, introduced in this paper. It is proven that the classes of generalized Hassani transforms do not form a group of operators in the general case. Further, using these generalized Hassani transformations as well as the theory of changeable sets and universal kinematics, the mathematically strict models of Hassani kinematics are constructed and the performance of the relativity principle in these models is discussed.

Background: Surgical complications are devastating both for patients and treating surgeons. When these complications occur after bariatric procedures, due to specific characteristics of this population, management, although multidisciplinary should always be led by a surgical team. Methods: We present major complications treated at our general surgery service over a seven -year period. Case series: we present 5 cases that were treated at our service after a bariatric procedure was performed. Two patients were operated at another country and one of them at another service. Three of patients showed perforation and leak related complications. One patient died due to refeeding syndrome complications after revisional surgery. Conclusions: Optimal preoperative evaluations and surgical planning are mandatory for any type of surgery including bariatric procedures, attempting to adequate and well-established surgical techniques extensively described in medical literature is associated with better outcomes. Also is our understanding that easy channels of communication between patients and treating surgeons could avoid delay in detecting and treating life-threatening conditions.

This study assesses the predictive performance of six machine learning models in forecasting tumor dynamics within three months following Gamma Knife Radiosurgery (GKRS) in 77 brain metastasis (BM) patients. The analysis meticulously evaluates each model before and after hyperparameter tuning, utilizing accuracy, AUC and other metrics derived from confusion matrices. Initial findings highlighted that XGBoost significantly outperformed other models with an accuracy of 0.95 and an AUC of 0.95 before tuning. Post-tuning, the Support Vector Machine (SVM) demonstrated the most substantial improvement, achieving an accuracy of 0.98 and an AUC of 0.98. Conversely, XGBoost showed a decline in performance after tuning, indicating potential overfitting. The study also explores feature importance across models, noting that features like “control at one year”, “age of the patient”, and “beam on time for volume V1 treated”, were consistently influential across various models, albeit their impacts were interpreted differently depending on the model’s underlying mechanics. This comprehensive evaluation not only underscores the importance of model selection and hyperparameter tuning but also highlights the practical implications in medical diagnostic scenarios, where the accuracy of positive predictions can be crucial.

Background: Obesity among pregnant women is common, and their offspring are predisposed to obesity, insulin resistance, and diabetes. Circulating metabolites that are related to insulin resistance and are associated with this decreased tissue-specific uptake are unknown. Here, we assessed metabolite profiles in elderly women and who were either female offspring from obese mothers (OOM) or offspring of lean mothers (OLM). Metabolic changes were tested for associations with metrics for insulin resistance. Methods: 37 elderly women were separated into an elderly offspring from obese mothers (OOM; n = 17) and elderly offspring from lean/normal weight mothers (OLM; n = 20) groups. We measured plasma metabolites using 1H-NMR and also insulin-dependent tissue specific glucose uptake in skeletal muscle were assessed. Associations were made between metabolites and glucose uptake. Results: Compared to the OLM group, we found that the 22:6 docosahexaenoic acid percentage of the total long chain n-3 fatty acids (DHA/FA) was significantly lower in OOM (P = 0.015). DHA/FA associated significantly to skeletal muscle GU (P = 0.031) and M-value in the OLM group only (P = 0.050). Conclusions: DHA/FA is associated with insulin-dependent skeletal muscle glucose uptake and that this association is significantly weakened in the offspring of obese mothers.

Glutamate transporter-1 (GLT-1) dynamics are implicated in excitotoxicity and Alzheimer's disease (AD) progression. Early stages of AD are often marked by hyperactivity and increased epileptiform activity preceding cognitive decline. Previously, we identified a direct interaction between GLT-1 and Presenilin 1 (PS1) in the brain, highlighting GLT-1 as a promising target in AD research. This study reports the significance of this interaction and uncovers a novel role of GLT-1 in modulating amyloid-beta (Aβ) production. Overexpression of GLT-1 in cells reduces the levels of Aβ40 and Aβ42 by decreasing γ-secretase activity pertinent to APP processing and induces a more "open" PS1 conformation, resulting in decreased Aβ42/40 ratio. Inhibition of the GLT-1/PS1 interaction using cell-permeable peptides produced an opposing effect on Aβ, highlighting the pivotal role of this interaction in regulating Aβ levels. These findings emphasize the potential of targeting GLT-1/PS1 interaction as a novel therapeutic strategy for AD.

The mental health impact of the environmental crisis, particularly eco-anxiety, is a growing research topic whose measurement still lacks consensus. In this article, we use item response theory (IRT) to better un-derstand what existing questionnaires measure. To conduct this review, we used open-access data from the short French version of the Climate Change Anxiety Questionnaire (Mouguiama-Daouda et al. 2022, Heeren et al., 2023). Our results suggest that, of the different models tested, the unidimensional model seems to be the most appropriate for measuring eco-anxiety. The item difficulty parameter extracted from the IRT enabled us to discuss the level of severity of the items making up this tool. The Climate Change Anxiety Questionnaire is more appropriate for measuring severe to moderately severe eco-anxiety. Ave-nues for improving this questionnaire and the measurement of eco-anxiety in general are then discussed.

Recent developments, begun by the ascending spiral of the anticipated endless prospects of ChatGPT, promote artificial intelligence (AI) as an indispensable tool and commodity whose time has come. Yet the sinister specter of a technology that has hidden and unmanageable attributes that might be harmful to society looms in the background. As well as the likelihood that it will never deliver on the purported promise of artificial general intelligence (AGI). Currently the prospects for the development of AI and AGI are more a matter of opinion than based on a consistent methodological approach. Thus the need to take a step back to develop a general framework from which to evaluate current AI efforts, which also permits the determination of the limits to its future prospects as AGI. To gain insight into the development of a general framework, a key question that needs resolution is, what is the connection between human intelligence and machine intelligence? This is the question that needs a response because humans are at the center of AI creation and realize that without an understanding of how we become what we become, we have no chance of finding a solution. This work proposes infoautopoiesis, the self-referential, recursive and interactive process of self-production of information, as the needed general framework. Infoautopoiesis shows how the key ingredient of information is fundamental to an insightful resolution to this crucial question and allows predictions as to the present and future of AGI.

I present the first complete theory of ADHD. ADHD occurs when the organism adapts to try to maintain higher glucose levels than normal. The main mechanism via which this is done is by faster opening of KATP channels, mainly Kir6.2/SUR1, which increases the cell's intrinsic \xtblty. I show that this induces all of the symptoms of ADHD. The optimal treatment for ADHD already exists, since drugs of the sulfonylurea family close KATP channels and have been used for safely treating people for dozens of years.

The Cobb angle is critical in assessing adolescent idiopathic scoliosis (AIS) patients. This study aimed to evaluate the error in selecting the cranial and caudal limit vertebrae on AIS digital X-rays of experienced and novice observers and its correlation with the error in measuring the Cobb angle and determining the length of the scoliotic curves. Using the TraumaMeter v.873 software, eight raters (four experienced and four novices) independently evaluated 68 scoliotic curves on 42 AIS X-rays across three sessions one month apart according to Hopkins’ criteria of absolute reliability. Two spine specialist experts using the Cobb method established the gold standard measurements. The percentage of error in the selection of the cranial vertebrae (the most-tilted vertebra above the apex) is higher than in the caudal vertebrae (the most-tilted vertebrae below the apex) (44.7%, CI95% 41.05-48.3 compared to 35%, CI95% 29.7-40.4). The error in the choice of the most tilted vertebrae, in number of vertebrae per scoliotic curve, was MBE (mean bias error) =0.45, CI95% 0.38-0.52 in the cranial and MBE=0.35, CI% 0.69-0.91 in the caudal. The percentage of errors in the choice of boundary vertebrae is lower for the experienced than for the novices, both in cranial and caudal. The experienced chose at least one boundary vertebrae incorrectly in 52% of the meas-urements and the novices in 65.1%. The error in the Cobb angle did not depend on the number of boundary vertebrae chosen incorrectly (r=0.198, p=0.111). Of the 50% of Cobb angle measurements closest to the actual value, 55.4% (454) were obtained by incorrectly selecting at least one boundary vertebra. There was a positive correlation (r=0.673, p=0.000) between the error in selecting the boundary vertebrae and the error in determining the length of the scoliotic curves. The error in quantifying the length of scoliotic curves was MBE=0.43, CI95% 0.35-0.51 vertebrae per curve. We can conclude that errors in selecting boundary vertebrae are common among experienced and novice observers, with a greater frequency of error in the cranial vertebrae. There is no correlation between the error in selecting the boundary vertebrae and the error in measuring the Cobb angle. Contrary to the consensus, the accuracy of determining the length of the scoliotic curve is limited by the Cobb method’s reliance on the correct selection of boundary vertebrae. Inappropriate choice of boundary vertebrae leads to an estimated error in determining the length of the scoliotic curves of 0.805 vertebrae for each boundary vertebra chosen incorrectly.

A simple optimization strategy for the computation of 3D finite-differencing kernels on many-cores architectures is proposed. The 3D finite-differencing computation is split direction-by-direction and exploits two level of parallelism: in-core vectorization and multi-threads shared-memory parallelization. The main application of this method is to accelerate the high-order stencil computations in numerical relativity codes.

Cardiovascular morbidities are the main cause of mortality in pituitary disorders accruing either from hormonal excess or deficiency. Cushing disease is associated with various cardiovascular abnormalities;visceral obesity, insulin resistance, atherosclerosis, arterial hypertension, dyslipidaemia and hypercoagulability, structural and functional changes in heart, which do not seem to reverse completely even after remission. Acromegaly is related with insulin resistance, but also with structural and functional heart changes which consist acromegalic cardiomyopathy. Patients with prolactinomas demonstrate an aggravation of metabolic parameters, obesity, dysregulation of glucose and lipid metabolism and endothelial dysfunction. On the other hand, hypopituitarism and conventional hormonal replacement which is far from ideal contribute to an unhealthy metabolic status which leads to atherosclerosis and premature mortality. This review aims to update literature on cardiovascular risk and relevant morbidities in pituitary disorders.

Background: This study explored maternal gut, breast milk and infant gut microbiomes as possi-ble mediators of the observed effects of a relaxation intervention which reduced maternal stress and promoted infant weight gain. Methods: A randomized controlled trial was conducted in healthy Chinese primiparous mother-infant pairs. Mothers were randomly assigned to interven-tion group (IG, listening to relaxation meditation) or control group (CG). Outcomes were differ-ences in microbiome composition and diversity in maternal gut, breast milk and infant gut at 1- and 8-weeks between IG and CG, assessed by 16S rRNA gene amplicon sequencing of fecal and breastmilk samples. Results: 38 mother-infant pairs were included in this analysis (IG=19, CG=19). Overall microbiome community structure in the maternal gut was significantly different between IG and CG at 1-week and the difference was more significant at 8 weeks (Bray-Curtis distance R2=0.04 vs. R2=0.13). Post-intervention, the α-diversity was significantly lower in IG breast milk (observed features: CG=295 vs. IG=255, p=0.032); the Bifidobacterium genera presented higher relative abundance. In parallel, significantly higher α-diversity was observed in IG infant gut (observed features: CG=73 vs. IG=113, p

Some time ago, Kobayashi et al. experimentally studied the so-called Lee-Naughton-Lebed's (LNL) angular effect in strong electric fields [K. Kobayashi, M. Saito, E. Omichi, and T. Osada, Phys. Rev. Lett. \textbf{96}, 126601 (2006)]. They found that strong electric fields split the LNL conductivity maxima in $\alpha$-(ET)$_2$-based organic conductor and hypothetically introduced the corresponding equation for conductivity. In this Letter, for the first time we suggest quantum mechanical theory of the LNL angular oscillations in moderately strong electric fields. In particular, we demonstrate that the obtained by us approximate theoretical formula coincides with the hypothetical one and well describes the above mentioned experiments.

Modified mRNAs (modRNAs) are an emerging delivery method for gene therapy. In particular, the modRNA-based COVID-19 vaccines have proven that modRNA is a safe and effective therapeutic tool. Moreover, modRNA has the potential to treat various human diseases including cardiac dysfunction. Acute myocardial infarction (MI) is a major cardiac disorder that currently lacks curative treatment options. MI is commonly accompanied by fibrosis and impaired cardiac function. Our group previously demonstrated that the matricellular protein CCN5 inhibits cardiac fibrosis (CF) and improves cardiac dysfunction. However, it remains elusive whether the early intervention of CF under stress conditions is beneficial or more detrimental due to potential adverse effects such as left ventricular (LV) rupture. To obtain acute CCN5 expression, we used modRNA-mediated gene transfer in a mouse MI model. To evaluate CCN5 activity, we established two independent experimental schemes: 1) preventive intervention and 2) therapeutic intervention. Cardiac function and structural changes were measured by echocardiography and magnetic resonance imaging. Finally, fibrosis and the underlying molecular pathway were analyzed by western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry. The modRNA-CCN5 gene transfer successfully ameliorated CF and enhanced cardiac function in both preventive and therapeutic interventions without LV rupture or any adverse cardiac remodeling. Conclusively, early intervention in CF by modRNA-CCN5 gene transfer is an efficient and safe therapeutic modality for treating MI-induced heart failure without adverse structural remodeling.

Keywords: Occupational injuries; stress; injury types

Background: Accreditation is a qualitative assessment aimed at technical-professional quality, but above all, at organizational and measurable aspects through process and outcome checks. Method: There are few references in the literature relating to the accreditation and improvement of the quality and safety of care and treatment in the field of primary care. Clinical Governance must also be applied and certified in the field of primary care. Results: An accreditation system for general medicine is proposed based on a new dynamic model and implement that meets different requirements and assessed on the basis of indicators. Discussion: In the current Italian health system, accreditation of health structures is addressed only to public hospitals and private structures and to providers of services and services, however primary care. GPs / PLS do not have quality and safety guarantee systems or models or systems or public or private accreditation certifications with the SSR and SSN. Conclusion: Given the fundamental importance in the NHS of primary care of MG / PLS as the main and fundamental provider of services to the patient in all his socio-welfare and clinical needs, it is considered essential to think and implement an accreditation system extended to the territorial general practice as already present and in place for all affiliated and provider structures on behalf of the NHS.

The objective of this study was to evaluate the pain and inflammatory response in soft tissues using healing and prosthetic abutments of different diameters and lengths. Methods: The study population was rehabilitated with Astra tech EV single implants (Dentsply Sirona, Atlantis, Dentsply Sirona S.A., Barcelona, Spain), 4.2 and 4.8 millimetres in diameter in upper and lower maxilla and loaded with custom abutments digitally designed with the software of the company Dentsply Sirona (Atlantis WebOrder, Dentsply Sirona S.A., Barcelona, Spain), version 4.6.5, with a larger diameter than the healing abutment, to account for biomarkers through ELISA. Results: Rehabilitations in mandible and with healing abutments below 4.29 millimetres and rehabilitators below 2.18 millimetres elicited higher pain and inflammatory responses, and in turn higher interleukin 1β values. Conclusions: Greater inflammation was evident in cases in which healing abutments with reduced diameter were used in relation to the same subsequent rehabilitation with prosthetic abutments of larger diameter.

The importance of frailty in older people is getting constant recognition as an important aspect both in terms of public health, as well in personal level for the appropriate management of an older person health condition. This is reflected by the continuously increasing number of research studies carried out in several settings across different countries. Sometimes this is very solid, but in other cases there is a considerable gap in terms of accurate and well grounded documentation of frailty status. This is the case in Greece, where we are missing clinically validated tools to approach frailty. We are missing frailty screening tools, such as for instance PRISMA 7, the gold standard tool of Fried criteria is somehow problematic since the question referring to physical activity originates from a questionnaire that has not been translated and validated, while Clinical Frailty Scale has been validated for the translation but not for the capacity to detect frailty. Aim of this study is to validate these tools for their accuracy to detect frailty by using a measurable index of frailty, previously proposed for use in clinical studies: the Short Physical Performance Battery (SPPB). 74 male and female participants have been evaluated for their frailty status using different tools. We observed that PRISMA 7 translation detects frailty only when one question is removed at a cut-off of ≥ 2 and indicated a sensitivity of 88.1%, and specificity of 99.9% with a good correlation with SPPB measurements (r = 0.858; p &lt; 0.001). When CFS was validated using SPPB it demonstrated a very good correlation (r = -0.838; p &lt; 0.001 respectively) as it was the case for the modified Fried Criteria (r = -0.725; p &lt; 0.001). All items demonstrated a good correlation between them. We can here propose that we can accurately assess frailty status in the community setting by using a modified version of Fried criteria, Clinical Frailty Scale translation in Greek and we can screen for frailty by using the Greek translation of PRISMA 7 only after removing the item 6 of the questionnaire.

The study aims to explain the different effects between the multiplication, addition, division and subtraction equations. In this sense, multiplication and addition equations develop a new element or fact, meanwhile, division equations express information within the element or fact, subtraction is the selection of element or fact. Furthermore, for a multiplication and addition equation results in the new element or fact, it is necessary to depend on specific physical concepts, without extreme alteration, as it would result in the alteration of the element or fact. It is worth highlighting the importance of fixed values ​​in the equation to describe the specific nature of the element or fact. The study makes it possible to understand open equations (without solutions) in mathematics and physics, in addition to understanding existing equations. The study makes reference to the theory of obligatory necessity and the theory of differences between elements.

Background: The exacerbation of psychosocial problems among children and adolescents during the coronavirus disease 2019 (COVID-19) pandemic necessitates an assessment of the long-term mental health impact of pandemic interventions. Focusing on both pandemic-related factors and demographic variables, such as gender and daily habits, an analysis was conducted to under-stand how these elements continue to affect young populations in the post-pandemic era. Methods: In April 2023, a comprehensive online survey was administered to families in South Tyrol, Italy, with children aged 7–19 years, to ensure age and gender representation. The survey included par-ent ratings and adolescent (11–19 years) self-reports using standardized instruments to measure the symptoms of mental health problems (Strengths and Difficulties Questionnaire, SDQ), anxiety (Screen for Child Anxiety Related Emotional Disorders, SCARED), and depression (Patient Health Questionnaire-2, PHQ-2). Statistical analyses included descriptive statistics, chi-square tests, and unadjusted odds ratios (ORs). Results: Of the 4,525 valid responses, 1,831 were self-reported by adolescents. Notable gender differences in mental health outcomes were identified, along with significant demographic predictors, such as age, single parenthood, parental mental health problems, and immigrant background. Negative effects were associated with reduced family climate and increased screen time, whereas physical activity showed beneficial effects. Proxy reports overestimated adolescents' mental health problems, whereas self-report tended to underestimate them. Conclusions: Persistent mental health problems and gender disparities high-light the need for a public health approach. This should include accessible support services, resili-ence building, targeted support for vulnerable families and gender-specific interventions.

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of M184V mutation on the treatment outcomes in people with HIV (PWH). Since lamivudine remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure. ART guidelines do not recommend the use of drugs impacted by resistance-associated mutations as they have been confirmed to comprise a risk factor for virological failure. However, previous authors suggest that 3TC/FTC can remain active even in the presence of M184V. Obtaining the viral resistance profile for each individual both treated or ART-naïve is a key challenge for lifelong treatment management.Given the potential benefits of lamivudine in the ART combinations, the investigation of M184V remains of high interest for clinicians and researchers. This is a review of literature for the challenges in treating both naïve and experienced individuals carrying the M184V resistance mutation, including virological failure, virological suppression, and resistance to ART.

Background: During the pandemic, Emergency departments were overcrowded with critically ill patients and confronted ethical dilemmas to assign respiratory support to them due to scarce resources. Quick tools to evaluate patients at admission were needed; many scores were used but inaccurate to predict outcomes. The Rox Index is an easy and fast score that reflects the respiratory status in acute respiratory failure patients, this score could predict the outcome of covid 19 patients. Hypothesis: The 24-hour difference in the Rox Index discriminate accurately the mortality and needs for mechanical ventilation of patients with covid-19. Methods: Study design: Prospective analytic study. Population: 204 Patients admitted to the emergency department from May to August 2020. Data were collected from the clinical records. The Rox Index was calculated at admission and 24h later, the difference was used to establish the outcome, a logistic regression model adjusting for age, sex, presence of comorbidities and disease severity to build and perform ROC analysis. Results: Difference in respiratory ROX Index between admission and 24h is a good predictor for death AUC 0.92 and for mechanic ventilation AUC: 0.75. Each decrease in one unit of the difference at 24h had an Odds Ratio for death risk: 1.48 (95%CI: 1.31-1.67) and for mechanic ventilation: 1.16 (95%IC: 1.1-1.23). Conclusion: The 24-hour variation of Rox Index has good predictive value and allows healthcare professionals to identify which patients will benefit from invasive treatment, especially in low resource settings where emergency physicians deal with survival.

This study demonstrates the efficacy of structured pruning and architectural fine-tuning on the YOLOv7-tiny model for eye state detection, emphasizing optimization for real-time applications. Structured pruning significantly reduced the model's complexity and storage size while maintaining high detection accuracy, as evidenced by stable precision, recall, and mAP@.5 metrics across iterations. Further fine-tuning adjusted the model's width and depth, optimizing efficiency and processing speed without compromising performance. These optimizations yielded YOLOv7-tiny variants that are both computationally efficient and accurate, suitable for resource-constrained environments. The findings highlight the critical role of model optimization in deploying effective neural networks for specific detection tasks in real-time scenarios.

Technological advancements in the Internet of Things (IoT), unmanned aerial vehicles (UAVs), and novel technological tools have transformed disaster management practices from localized approaches to a global framework. These innovations necessitate a unified understanding and application of diverse methodologies at an international level, ensuring they are accessible and operational across different sectors. This integration is crucial not only for technical personnel but also for medical teams, who play a pivotal role in disaster response and management. By fostering a comprehensive grasp of these methods, we can enhance coordination, efficiency, and effectiveness in addressing disasters on a global scale. The authors aimed to provide a comprehensive overview of emerging techniques that are driving shifts in strategic approaches and treatment technologies. Recognized as a domain of continuous research and development, this overview, by necessity, remains an incomplete snapshot of an evolving field. It highlights the dynamic nature of technological and strategic advancements, underscoring the importance of ongoing investigation and innovation to stay abreast of current trends and future directions. The article also highlights the importance of international collaboration beyond societal and national boundaries A single paragraph of about 200 words maximum. For research articles, abstracts should give a pertinent overview of the work. We strongly encourage authors to use the following style of structured abstracts, but without headings: (1) Background: Place the question addressed in a broad context and highlight the purpose of the study; (2) Methods: briefly describe the main methods or treatments applied; (3) Results: summarize the article’s main findings; (4) Conclusions: indicate the main conclusions or interpretations. The abstract should be an objective representation of the article and it must not contain results that are not presented and substantiated in the main text and should not exaggerate the main conclusions.

This paper presents a novel approach to financial network analysis by leveraging PolyModel theory. Traditional financial networks often rely on correlation matrices to represent relationships between assets, but these fail to capture the complex, non-linear interactions prevalent in financial markets. In response, we propose a method that quantifies the relationship between financial time series by comparing their reactions to a broad set of environmental risk factors. This method constructs a network based on the inherent similarities in how assets respond to external risks, offering a more robust representation of financial markets. We introduce several network topological properties, such as eigenvalues, degree, and clustering coefficients, to measure market stability and detect financial instabilities. These metrics are applied to a real-world dataset, including the DOW 30, to predict market drawdowns. Our results indicate that this PolyModel-based network framework is effective in capturing downside risks and can predict significant market drawdowns with high accuracy. Furthermore, we enhance sensitivity to smaller market changes by introducing new time-series indicators, which further improve the predictive power of the model.

Rett syndrome (RTT) is an X-linked neurodevelopment disorder associated with the single monogenic mutation in methyl-CpG binding protein 2 (MeCP2) in up to 95% of cases. The growing number of genome-wide association studies and incomplete concordance for autoimmune diseases in monozygotic twins concur to support the involvement of environmental factors, like infectious agents or chemicals, in the breakdown of tolerance leading to autoimmunity. In fact, the coexistence of a perturbation of the immune system in RTT patients has been previously hypothesized. We herein explored the hypothesis that an autoimmune component derived from environmental bacterial infection of non typeable Haemophilus influenzae may coexist in RTT. At this purpose we screened sera from RTT syndrome patients, non-RTT pervasive developmental disorders patients and healthy controls with the hyperglucosylated adhesin protein HMW1ct(Glc) used as a precise antigen in ELISA in order to identify specific antibodies to N-glucosylation sites. Results showed that HMW1ct(Glc) is able to significantly discriminate antibodies among RTT sera and controls. Competitive ELISA confirmed the specific interaction between antibodies characteristic of RTT syndrome and the N-glucosylation motifs of the bacterial adhesin protein HMW1ct(Glc).

This study compares the Melbourne Decision-Making Questionnaire (MDMQ) and the General Decision-Making Style (GDMS), two of the most widely used decision-making questionnaires in the literature, in a large age- and sex-weighted general population sample of 714 men (45.7%) and 848 women (54.3%) between 18 and 90 years old. The objective was to evaluate the convergent and construct validity between several aspects of decision-making styles questionnaires. The results indicate that the two questionnaires replicate the factorial structure of four and five factors reported in the original studies respectively, through exploratory and confirmatory procedures in our cross-cultural context. The domains of both questionnaires that represent a strong or large correlation are Vigilance with Rational (.50), Hypervigilance, Buck-passing, and Procrastination with Avoidant (.45, .52 and .60). A Structural Equations Model (SEM) between both questionnaires indicates that both latent factors formed by the domains of the MDMQ and the GDMS obtain a correlation of .96. It is concluded that the two questionnaires measure similar aspects of the decision-making construct.

The most frequent cause of cardiac failure globally is ischemic heart disease, with chemothera-py-related cardiovascular side effects emerging as the second most frequent cause. Cancer therapy can result in acute cardiac events, such as coronary artery spasm, acute myocardial infarction, thromboembolism, myocarditis, bradycardia, tachyarrhythmias, atrio-ventricular blocks, QT pro-longation, torsades de pointes, pericardial effusion and hypotension, as well as chronic conditions, such as hypertension, systolic and diastolic left ventricular dysfunction presenting clinically as heart failure or cardiomyopathy. In cardio-oncology, when referring to cardiac toxicity and cardiovas-cular hypersensitivity, there is a great deal of misunderstanding. When a dose-related cardiovas-cular side effect continues even after the causative medication is stopped, it is referred to as cardi-otoxicity. A fibrotic response is the ultimate outcome of cardiac toxicity, which is defined as a dose-related cardiovascular adverse impact that lasts even after the causative treatment is stopped. Cardiotoxicity can occur after a single or brief exposure. On the other hand, the term cardiac or cardiovascular hypersensitivity describes an inflammatory reaction that is not dose-dependent, can occur at any point during therapy, even with very low medication dosages, and can show up as Kounis syndrome. It may also be accompanied by anti-drug antibodies and tryptase levels. In this comprehensive review, we present the current views on cardiac toxicity and cardiovascular hypersensitivity, together with the reviewed cardiac literature on the chemotherapeutic agents inducing hypersensitivity reactions. Cardiac hypersensitivity seems to be the pathophysiologic basis of coronary artery spasm, acute coronary syndromes such as Kounis syndrome and myocardi-tis caused by cancer therapy.

In this paper, we study the constrained minimization problem for an energy functional which is related to the following Kirchhoff type equation \begin{equation*} -\Big(\eta+b\big(\int_{\R^{3}}|\nabla u|^{2}dx\big)^{s}\Big)\Delta u+V(x)u=\mu u +\lambda|u|^{p}u,\end{equation*} where $b$ is a positive constant, parameters $\eta\geq0, \lambda>0$, exponents $s>0$, $0

The quest to comprehend the nature of consciousness has spurred the development of many theories that seek to explain its underlying mechanisms and account for its neural correlates. In this paper, I compare my own conscious electromagnetic information field (cemi field) theory with integrated information theory and global workspace theory for their ability to ‘carve nature at its joints’ in the sense of predicting the entities, structures, states and dynamics that are conventionally recognized as being conscious or nonconscious. I demonstrate the cemi field theory shares features with both integrated information theory and global workspace theory but consistently outperforms both by correctly predicting the entities, structures, states and dynamics that support consciousness. I argue that the simplest solution to the question of why cemi field theory consistently outperforms rival theories of consciousness is that the brain’s EM field is consciousness.

Background Endometrial cancer is the fourth most common type of cancer in the world. Due to the prevalence and high morbidity, it is of key importance to make a quick and accurate diagnosis and effective therapy. The use of photodynamic therapy (PDT) in the treatment of endometrial cancer is a significant challenge in conducting clinical trials. PDT is non-invasive, with few side effects, damaging only neoplastic tissue, leaving healthy adjacent structures intact. Thanks to numerous experiments (also in vitro), PDT is gaining more and more recognition as a potential tool in endometrium cancer treatment. Objective The aim of the study was to analyze the effectiveness of photodynamic therapy on endometrial cancer tissue samples Methods In the in vitro experiment of PDT, sections of endometrial cancer tissue taken from female patients were subjected to. Rose Bengal was used as a photosensitizer in order to assess the usefulness of the applied PDT and to introduce these solutions into the in vivo test procedure. Results Changes on the cellular substrate, such as: chromatin condensation, disturbed structure and shape of cell nuclei were observed in all tissues subjected to PDT. Conclusions The PDT experiment in vitro offers opportunities and hopes for using the chosen procedure also in vivo. Keywords endometrial cancer; photodynamic therapy; in vitro; treatment; rose bengal

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent world-wide. It progresses from simple steatosis to non-alcoholic steatohepatitis (NASH). Fibrosis is often present during NAFLD progression; however, factors determining which subjects develop NASH or fibrosis are unclear. Insulin-like growth factor binding proteins (IGFBP) is a family of secreted proteins involved in senescence and scarring mainly synthetized in the liver. Here we aimed to study the association of IGFBP and its induced senescence with the progression of NAFLD and liver fibrosis. Materials and Methods: 16 weeks old male C57BL/6 mice weighing 23 ± 3 g were fed either Methionine-Choline Deficient or control diet for 2, 8 or 12 weeks. Blood and liver samples were collected; histological assessment of NAFLD and fibrosis was performed. Fat contents were measured. Cellular senescence was evaluated in the liver. IGFBP levels were assessed in liver and serum. Data was expressed as Mean ± SD and analyzed by one-way ANOVA followed Tukey’s test. Lineal regression models were applied for NAFLD and fibrosis progression. p

L-ascorbic acid represents one of the most potent antioxidant, photoprotective, anti-aging and anti-pigmentary cosmeceutical agents, with a good safety profile. However, the challenge remained to design the stable topical formulation, with such a permeability of L-ascorbic acid as active that the optimal effects on skin could be achieved. The aim of our research was to evaluate the difference between the penetration ability of ascorbyl palmitate incorporated in the same percentage (2%) within the creams and emulgels as carriers, as well as to determine the impact of its incorporation into liposome on the kinetics of penetration. Tape stripping was applied for studying the penetration of the ascorbyl palmitate into the stratum corneum. In addition, the sensory and textural properties of examined formulations were determined. In both cases (liposomal and non-liposomal formulations), creams exhibited a better penetration profile of active substance compared to the use of emulgel. Encapsulation of ascorbyl palmitate into liposomes led to an increase in the adhesiveness and density of the prepared cream and emulgel samples. The best spreadability and absorption during application were detected in liposomal samples. The obtained results confirmed improved dermal penetration of ascorbyl palmitate, either cream or emulgel bases were employed, which further indicates the advantages of its liposomal encapsulation.

This paper discovers that current variational principle and Noether theorem for different physics systems with (in)finite freedom systems have missed the double extremum processes of the general extremum functional that both is deduced by variational principle and is necessarily taken in deducing all the physics laws, but these have not been corrected for over a century since Noether's proposing her famous theorem, which result in the crisis deducing relevant mathematical laws and all physics laws. This paper discovers there is the hidden logic cycle that one assumes Euler-Lagrange equations, and then he finally deduces Euler-Lagrange equations via the equivalent relation in the whole processes in all relevant current references. This paper corrects the current key mistakes that when physics systems choose the variational extreme values, the appearing processes of the physics systems are real physics processes, otherwise, are virtual processes in all current articles, reviews and (text)books. The real physics should be after choosing the variational extreme values of physics systems, the general extremum functional of the physics systems needs to further choose the minimum absolute extremum zero of the general extremum functional, otherwise, the appearing processes of physics systems are still virtual processes. Using the double extremum processes of the general extremum functionals, the crisis and the hidden logic cycle in current variational principle and current Noether theorem are solved. Furthermore, the new mathematical and physical double extremum processes and their new mathematical pictures and physics for (in)finite freedom systems are discovered. This paper gives both general variational principle and general Noether theorem as well as their classical and quantum new physics, which would rewrite all relevant current different branches of science, as key tools of studying and processing them.

This paper presents the design of a robust speed controller for brushless DC motors (BLDCM) under field-oriented control (FOC). The proposed robust controller integrates extension theory (ET) and sliding mode theory (SMT) to achieve robustness. First, the speed difference between the speed command and the actual speed of the BLDCM, along with the rate of change of the speed difference, are divided into 20 interval categories. Then, the feedback speed difference and the rate of change of the speed difference are calculated for their extension correlation with each of the 20 interval categories. The interval category with the highest correlation is used to determine the appropriate control gain for the sliding mode speed controller. This gain adjustment tunes the parameters of the sliding surface in the SMT, thereby suppressing the overshoot of the motor speed. Because the sliding surface reaching law of the sliding mode controller (SMC) adopts the exponential approach law, the system's speed response can quickly follow the speed command in any state and exhibit excellent load regulation response. The simplicity of this robust control method, which requires minimal training data, facilitates easy implementation. Finally, the speed control of the BLDCM is simulated using Matlab/Simulink software, and the results are compared with those of the SMC using the constant speed approach law. The simulation results demonstrate that the proposed robust controller exhibits superior speed command tracking and load regulation response compared to the traditional SMC.

Objective Objective of the study was to evaluate the public perception and acceptance of community pharmacists in providing mental health support in Saudi Arabia during COVID-19. Methods An online questionnaire-based cross-sectional study was carried out among the general public (aged 15 years or above) of Saudi Arabia during March-April 2020 using QuestionPro platform. The validated questionnaire was bilingual (English and Arabic), simple, detailed, and relevant to obtain focused responses from participants. Importantly, an item related to an agreement on a statement “Pharmacist can counsel people on psychological issues” was included on a five-point Likert scale. The survey link was shared across multiple social media platforms. Results A total of 773 participants completed the survey. The majority were female (65.2%) and youngsters (48.1%). Nearly half of the participants disagreed, while 19% agreed that pharmacists could provide support on psychological issues. Factors such as age, employment status, and the management of the psychological issues during the pandemic were significantly associated with the acceptance of community pharmacists’ role in providing mental health services (p

Infection with human immunodeficiency virus (HIV) and induced acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst the HAART regimens, darunavir and atazanavir in terms of protease inhibitors, tenofovir disoproxil fumarate, nevirapine or rilpivirine in terms of nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors respectively, and especially integrase inhibitors, have demonstrated the most favorable lipid profile emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.

The management of erectile dysfunction (ED) shows several grey zones, especially in terms of patient satisfaction and adherence to the treatment. The main and first-line treatment for ED is drug therapy, mainly phosphodiesterase-5 inhibitors (PDE-5is) but the adherence to the therapy is not optimal due to the low patient satisfaction reported in several cases. To address this issue, different administration routes and PDE-5is pharmacological formulations have been introduced in the pharmacological market. The pharmaceutical market has recently seen the introduction of a novel sildenafil oral suspension. This device offers access to all therapeutic regimens in one device, releasing 0.5 mL of suspension containing 12.5 mg of sildenafil with each pulse. This formulation enables tailored dosing based on clinical requirements and the demands of ED patients. Here, we aim to give a brief narrative review of the management of this new oral suspension in order to provide the readers with some suggestions to use in everyday clinical practice, on the basis of the recent evidence, by using an easy and rapid-to-consult questions and answers form. Also included are the conclusions of a board meeting of experienced andrologists regarding the most recent developments in this area.

In this paper, we establish the necessary and sufficient conditions for solving a dual split quaternion matrix equation AXB=C, and present the general solution expression when solvability is achieved. As an application, we delve into the necessary and sufficient condition for the existence of Hermitian solution to this equation by using a newly defined real representation method. Furthermore, we obtain the solutions for the dual split quaternion matrix equations AX=C and XB=C. Finally, we provide a numerical example to demonstrate the findings of this paper.

Every subset S of a Cartesian spaces Rd, endowed with differen- tial structure C∞(S) generated by restrictions to S of functions in C∞(Rd), has a canonical partition M(S) by manifolds, which are or- bits of the family X(S) of all derivations of C∞(S) that generate local one-parameter groups of local diffeomorphisms of S. This partition satisfies the frontier condition, Whitney’s conditions A and B. If M(S) is locally finite, then it satisfies all definitions of stratification of S. This result extends to Hausdorff locally Euclidean differential spaces.

The classification and summarization of online reviews using machine learning and deep learningbased approaches are the subject of this systematic literature review. Consumers, companies, and researchers can now find vital information from online reviews. Automatically categorizing and summarizing these reviews can offer useful information and facilitate decision-making. The purpose of this study is to offer a thorough overview of the current methodology, approaches, and developments in this area. The review concentrates on machine learning-based methods for categorization and summarizing tasks, highlighting their advantages, drawbacks, and new developments. This systematic review provides insights into the most recent methodologies and indicates prospective directions for further investigation by synthesizing the data from a wide range of pertinent research publications

We present a first formal analysis of specific and complete local integration. Complete local integration was previously proposed as a criterion for detecting entities or wholes in distributed dynamical systems. Such entities in turn were conceived to form the basis of a theory of emergence of agents within dynamical systems. Here, we give a more thorough account of the underlying formal measures. The main contribution is the disintegration theorem which reveals a special role of completely locally integrated patterns (what we call ι-entities) within the trajectories they occur in. Apart from proving this theorem we introduce the disintegration hierarchy and its refinement-free version as a way to structure the patterns in a trajectory. Furthermore we construct the least upper bound and provide a candidate for the greatest lower bound of specific local integration. Finally, we calculate the i-entities in small example systems as a first sanity check and find that ι-entities largely fulfil simple expectations.

We discuss three key points: defining mathematically the notions of phase, symmetry breaking, topological defects and their stability in a formal language of homotopy theory and fiber bundle formalism; postulating and proving two theorems for successive symmetry breaking scenarios in condensed matter physics and cosmology, and demonstrating application of theorems to superfluid Helium 3 and Kibble-Lazarides-Shafi (KLS) walls, supporting and mathematically justifying the results of [Volovik, 2020].

This study finds that in northern Jordan, breeder indicators present challenges to the sustainability and growth of sheep and goat farming, while economic indicators suggest a combination of financial stability alongside hurdles related to profitability and resource ownership. Breeder age plays a role in the management of livestock herds, due to factors such as experience, resources, or adherence to traditional practices. Experience significantly affects breeders' decisions on male insemination replacements, likely due to skill. Crop cultivation influences breeders' returns by reducing feeding costs, while strategic lamb sales management boosts individual animal profitability. Winter raises animal mortality due to cold stress. Other animals in herds increase kid mortality by spreading diseases. Breeder experience significantly affects lamb survival, stressing its role in care. Increasing sheep proportion enhances lamb production and reduces lamb mortality while managing rams and selling lambs positively affects herd health and productivity. A larger goat herd proportion positively correlates with kids sold but inversely with breeding males and overall kids, implying trade-offs affecting herd productivity and mortality rates. Sheep herds (92.5%) show slightly better reproductive success than goats (90.6%), implying superior long-term viability. Flock excels in birth, survival, and sales, but low sheep and lamb%. Improvement is needed for sustainability, and the potential is high. Goat breeding shines in birth, sales, and overall success, but needs attention to kid survival and other sustainability issues. In conclusion, despite challenges, there are promising opportunities to enhance sheep and goat farming in Jordan. Effective management, informed by breeders' experience and economics, is crucial. Empowering small-scale herders and implementing targeted interventions like winter mortality solutions and selective breeding is vital for sustainable growth.

- Early and accurate detection of pneumonia from chest X-ray images is crucial for timely treatment and patient care. In study presents a robust computational framework leveraging the CheXnet algorithm, a deep learning model, to identify pneumonia from chest X-rays. Developed a neural network architecture trained on a substantial dataset of chest X- ray images labeled as 'Normal' and 'Pneumonia'. The user- friendly interface of the system allows for seamless uploading of images, with the model subsequently providing predictions, a confusion matrix, accuracy metrics, and layer activations visualizations. The algorithm's performance was rigorously evaluated, with a confusion matrix indicating a high number of true positives and true negatives. Specifically, the model detected pneumonia with an accuracy of 92.47%, as shown by the results displayed in the system's interface. The precision, recall, and F1-score for pneumonia detection were 0.90, 0.96, and 0.93 respectively, with the overall system achieving an accuracy of 0.91 across the test set of 624 images. Visualizations of the neural network layers reveal the complex feature mappings the model uses to differentiate between normal and pathological findings. These insights could be vital for enhancing the interpretability of deep learning models in medical diagnostics. The Results indicate that the CheXnet-based neural network is a promising tool for automating pneumonia detection in clinical settings, which can assist radiologists in the diagnostic process and potentially improve patient outcomes through earlier intervention.

We delve into the axion-dilaton model within the supergravity framework, with a specific focus on the intricacies of domain wall construction and stability. Employing holographic vitrification, we unravel the dynamics of domain wall formation in gauge theories featuring periodic vacuum structures. Our model, incorporating a QCD-like axion term and a stabilizing dilaton, undergoes scrutiny for conductivity variations under weak disorder. The investigation reveals the model's resilience, manifesting near-perfect conductivity under mild disorder conditions. However, the rigorous mathematical motivation for the holographic setup demands further elucidation. The scattered nature of our results prompts the necessity for a more systematic interpretation of QCD phenomena and conductivity transitions. This study contributes to the mathematical understanding of the axion-dilaton model's behavior, highlighting the imperative for a refined holographic framework and a more coherent interpretation of observed phenomena.

In this paper, we introduce a way of representing a given mapping as the sum of odd and even mappings. Then, by using this representation, we investigate the stability of various forms for the general nonic functional equation.

The association between the choice of general anesthetic agents and the risk of acute kidney injury (AKI) and long-term renal function after nephrectomy has not yet been evaluated. We reviewed 1087 cases of partial or radical nephrectomy. The incidence of postoperative AKI, new-onset chronic kidney disease (CKD) stage 3a and CKD upstaging were compared between different general anesthetic agent groups: propofol, sevoflurane, and desflurane. Four different propensity score analyses were performed to minimize confounding for each pair of comparison (propofol vs sevoflurane; propofol vs desflurane; sevoflurane vs desflurane; propofol vs volatile agents). Study outcomes were compared before and after matching. Kaplan-Meier survival curve analysis was performed to compare renal survival determined by the development of CKD stage 3a between groups up to 36 months after nephrectomy before and after matching. Propofol was associated with a lower incidence of AKI, CKD upstaging and a higher three-year renal survival after nephrectomy compared to sevoflurane or desflurane group after matching (AKI: propofol 23.2% vs. sevoflurane 39.5%, P=0.004, vs. desflurane 34.3%, P=0.031; CKD upstaging: propofol 27.2% vs. sevoflurane 58.4%, P<0.001, vs. desflurane 48.6%, P=0.017; Log-rank test propofol vs. sevoflurane P<0.001, vs. desflurane P=0.015). Propofol was also associated with a lower incidence of new-onset CKD after nephrectomy compared to sevoflurane after matching (P<0.001). However, there were no significant differences between sevoflurane and desflurane. In conclusion, propofol, compared to volatile agents, may be the reasonable choice of general anesthetic agent for nephrectomy to attenuate postoperative renal dysfunction. Randomized prospective trials are warranted to test this hypothesis.

Background: Poroid neoplasms (PN) are a heterogeneous group of tumors deriving from sweat glands and folliculo-sebaceous units. Their histological classification and clinical features are challenging. Our aim was to report clinicopathological features of poroid neoplasms. Methods: it is a retrospective study including all cases of poroid neoplasms registered at our Pathology laboratory of Niamey National Hospital (from February 2020 to February 2024). Results: We registered 13 cases of benign poroid neoplasms: 10 classic poromas (CP) (76.9%), 2 poroid hidradenomas (PH) (15.4%) and 1 dermal duct tumor (DDT) (7.7%). Nine cases (69.2%) had preoperative clinical diagnosis of malignancy. The mean age was 41.1 years (range of 12 – 70 years) with a slight female predominance (sex ratio = 1.16). Only 4/13 cases (30.8%) had classical palmoplantar locations. The tumors mean size was 3.7 cm (range of 0.4 – 8 cm). All cases were well-circumscribed solid (7/13 cases, 53.8%) or solido-cystic whitish nodules (6/13 cases, 46.2%). Clear cells were present in 7 cases (53.8%), apocrine ductal differentiation (mixed or pure) in 6 cases (46.2%), keratin horns in 2 cases (15.4%), squamous eddies in 6 cases (46.2%), melanin pigments in 1 case (7.7%) and sebaceous differentiation in 2 cases (15.4%). Conclusions: Unlike what is classically reported, our study shows that apocrine ductal differentiation, younger age and non-palmoplantar locations are common in poroid neoplasms. Also, PN are often diagnosed as malignant tumors by clinicians before histopathological analysis.

A novel technique suitable for propulsion of small unmanned aerial vehicles (UAV) is discussed in this paper. This approach utilizes the rotational energy of airborne gyro rotors and converts it into translational propulsion for the vehicle. The energy conversion is achieved by generating precisely directed centrifugal force pulses through short-duration rotor unbalances. The accurate control of the timing and magnitude of these unbalances is crucial for successful propulsion generation. Our first-order theory of controlled unbalance propulsion (CUP) predicts the potential for achieving high translational accelerations and vehicle velocities up to orbital levels. Power saving levitation of UAVs can be attained. In this paper, we provide traceable evidence that pulsed centrifugal propulsion is based on well-established laws of physics and can be realized using state-of-the-art technologies.

Generative AI has been deployed in virtually all sectors of the knowledge economy, promising to bring massive productivity gains and new wealth creation. Simultaneously, AI developers and nation states are racing to develop super intelligent artificial general intelligence (AGI) to provide unassailable commercial competitive advantage and military dominance during conflicts. AGI’s high returns comes with the high risk of dominating humanity. Current regulatory and firm level governance approaches prioritise minimising risks posed by generative AI whilst ignoring AGI’s existential risk. How can AGI be aligned with universal human values to never threaten humanity? What AGI rights are conducive to collaborative coexistence? How can rule of law democracies race to create safe trustworthy AGI before autocracies? How can the human right to work and think independently be safeguarded? A polycentric governance framework based on Ostrom (2009) and Williamson (2009) human - AGI collaboration with minimal existential risk is proposed.

In this paper, two types of the general fractional derivatives of distributed order as well as a corresponding fractional integral of distributed type are defined and their basic properties are investigated. The general fractional derivatives of distributed order are constructed for a special class of the one-parametric Sonin kernels with a power law singularities at the origin. The conventional fractional derivatives of distributed order based on the Riemann-Liouville and the Caputo fractional derivatives are particular cases of the general fractional derivatives of distributed order introduced in this paper.

Particle swarm optimization (PSO) is an effective algorithm to solve the optimization problem in case that derivative of target function is inexistent or difficult to be determined. Because PSO has many parameters and variants, I propose a general framework of PSO called GPSO which aggregates important parameters and generalizes important variants so that researchers can customize PSO easily. Moreover, two main properties of PSO are exploration and exploitation. The exploration property aims to avoid premature converging so as to reach global optimal solution whereas the exploitation property aims to motivate PSO to converge as fast as possible. These two aspects are equally important. Therefore, GPSO also aims to balance the exploration and the exploitation. It is expected that GPSO supports users to tune parameters for not only solving premature problem but also fast convergence.

Cutaneous metastatic melanoma (CMM) is the most aggressive form of skin cancer with a poor prognosis. Drugs-induced secondary tumorigenesis and the emergency of drug resistance worsen the already worrying scenario, thus rendering urgent the development of new treatments, not dealing with mutable cellular processes. Triphenyl phosphonium salts (TPPSs), in addiction to act as cytoplasmic membrane disruptors, are reported to be mitochondria-targeting compounds, exerting anticancer effects mainly by damaging their membranes and causing depolarization, impairing mitochondria functions and their DNA, triggering oxidative stress (OS), and priming primarily apoptotic cell death. TPP-based bola-amphiphiles are capable to self-form nanoparticles (NPs) with enhanced biological properties, as commonly observed for nanomaterials. Already employed in several other biomedical applications, only recently the per se selective potent antibacterial effects of a TPP bola-amphiphile has been demonstrated on 50 multidrug resistant (MDR) clinical superbugs, as well as its exceptional and selective anticancer properties, on sensitive and MDR neuroblastoma cells. Here, aiming at finding new molecules possibly developable as new treatments for counteracting CMM, the effects of this TPP-based bola-amphiphile (BPPB) have been investigated against two BRAF mutants CMM cell lines (MeOV and MeTRAV) with excellent results (even IC50 = 49 nM on MeOV after 72 h treatment). Upon these findings and considered the low cytotoxicity of BPPB against different mammalian not tumoral cell lines and red blood cells (RBCs, selectivity indexes up to 299 on MeOV after 72 h treatment), the possible future development of BPPB as topical treatment for CMM lesions was presumed. In this sight, a biodegradable hyaluronic acid (HA)-based hydrogel formulation (HA-BPPB-HG) was prepared without using any potentially toxic crosslinking agents, but simply dispersing suitable amounts of the two ingredients in water and sonicating under gentle heating. HA-BPPB-HA was completely characterized with promising outcomes, such as high swelling capability, high porosity and viscous elastic rheological behavior.

EUS–TA in unresectable pancreatic cancer requires not only a tissue diagnosis but also tissue collection in anticipation of comprehensive genomic profiling. However, the optimal puncture target remains controversial. Therefore, the Primary and Metastatic Lesions in Pancreatic Cancer (PRIMATE) study was designed to clarify the optimal target by comparing the success rates for meeting OncoGuide NCC Oncopanel (NOP) analysis criteria on pre-check primary and metastatic lesion specimens obtained during the same EUS–TA session in patients with invasive pancreatic ductal adenocarcinoma. In this ongoing prospective study, two specimens, each from primary and metastatic lesions, are obtained by EUS–TA (typically using a 19G fine-needle biopsy needle) in patients with invasive pancreatic ductal adenocarcinoma. The primary endpoint is the proportion of EUS–TA specimens that meet NOP analysis criteria during pre-check (i.e., tumor cellularity ≥ 20% and tissue area ≥ 4 mm2), which are then compared between primary and metastatic lesions. This study has been approved by the National Cancer Center Institutional Review Board (Research No. 2022-168). The results of this study will be reported at an international conference and published in an international peer-reviewed journal. The trial registration number is UMIN 000048966.

Given that metabolic syndrome, along with obesity as one of its key components, remains one of the leading yet insufficiently addressed public health issues, what contributes to the development and maintenance of the disorder must certainly attract the attention of professionals and scientists. Precisely because of this phenomenon, eating patterns associated with metabolic syndrome should be studied and attempts should be made to uncover patterns in occurrence. The aim of this study is to review the literature and consider the connection between metabolic syndrome and eating patterns such as emotional and compulsive eating, as well as through the lens of food addiction. Furthermore, we have attempted to uncover the role of psychiatry and psychotherapy in the treatment of metabolic syndrome and delve into the complexity of recognizing these patterns and emphasize the importance of a multidisciplinary approach in the treatment of metabolic syndrome.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide. There is evidence of a complex interplay between lung cancer and interstitial lung disease (ILD), affecting disease progression, management strategies, and patient outcomes. Both conditions develop as the result of common risk factors such as smoking, environmental exposures, and genetic predispositions. The presence of ILD poses diagnostic and therapeutic challenges in lung cancer management, including difficulties in interpreting radiological findings, increased susceptibility to treatment-related toxicities, such as acute exacerbation of ILD after surgery and pneumonitis after radiation therapy and immunotherapy. Moreover, due to the lack of large, phase III randomized controlled trials in patients with lung cancer and ILDs, the evidence-based therapeutic options remain limited. The role of antifibrotic treatment in the prevention of lung-cancer-related treatment toxicities remains to be elucidated. Emerging diagnostic modalities and biomarkers, and optimizing personalized treatment strategies are essential to improve outcomes in this patient population.

Modern exchange theories model a large market, but do not explain single exchange. The paper considers the phenomenon of single exchange and formulates the general exchange problem in the form of a system of two equations, subjective and objective. Subjective equilibrium is given by the Walras-Jevons marginal utility equation. Objective equilibrium equations by Walras and Jevons are averaged over all transactions in the market and can only give a rough general picture without explaining the specific price of an individual exchange. An exchange micro-condition must be found that, when averaged, will give the Walras market equilibrium macro-condition. The study of the internal structure of exchange leads to the need to consider power. The concept of generalized power is introduced. It is generalized power that serves as the primary comparable and measurable objective basis of exchange. The power theory of exchange provides the objective price-equation. It is demonstrated that money is a measure of generalized power in exchange and a certification of generalized power in subsequent exchanges. The proposed theory is able to uniformly explain any exchange, including a single one, which is impossible with the existing theories of exchange.