Tackling the Antimicrobial Resistance "Pandemic" with Machine Learning Tools: A Summary of Available Evidence.

Antimicrobial resistance is recognised as one of the top threats healthcare is bound to face in the future. There have been various attempts to preserve the efficacy of existing antimicrobials, develop new and efficient antimicrobials, manage infections with multi-drug resistant strains, and improve patient outcomes, resulting in a growing mass of routinely available data, including electronic health records and microbiological information that can be employed to develop individualised antimicrobial stewardship. Machine learning methods have been developed to predict antimicrobial resistance from whole-genome sequencing data, forecast medication susceptibility, recognise epidemic patterns for surveillance purposes, or propose new antibacterial treatments and accelerate scientific discovery. Unfortunately, there is an evident gap between the number of machine learning applications in science and the effective implementation of these systems. This narrative review highlights some of the outstanding opportunities that machine learning offers when applied in research related to antimicrobial resistance. In the future, machine learning tools may prove to be superbugs' kryptonite. This review aims to provide an overview of available publications to aid researchers that are looking to expand their work with new approaches and to acquaint them with the current application of machine learning techniques in this field.

The Predictors of Early Treatment Effectiveness of Intravitreal Bevacizumab Application in Patients with Diabetic Macular Edema.

The aim of this study was to establish whether multiple blood parameters might predict an early treatment response to intravitreal bevacizumab injections in patients with diabetic macular edema (DME). Seventy-eight patients with non-proliferative diabetic retinopathy (NPDR) and DME were included. The treatment response was evaluated with central macular thickness decrease and best corrected visual acuity increase one month after the last bevacizumab injection. Parameters of interest were the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), vitamin D, and apolipoprotein B to A-I ratio (ApoB/ApoA-I). The NLR (2.03 ± 0.70 vs. 2.80 ± 1.08; p < 0.001), MLR (0.23 ± 0.06 vs. 0.28 ± 0.10; p = 0.011), PLR (107.4 ± 37.3 vs. 135.8 ± 58.0; p = 0.013), and SII (445.3 ± 166.3 vs. 675.3 ± 334.0; p < 0.001) were significantly different between responder and non-responder groups. Receiver operator characteristics analysis showed the NLR (AUC 0.778; 95% CI 0.669-0.864), PLR (AUC 0.628; 95% CI 0.511-0.735), MLR (AUC 0.653; 95% CI 0.536-0.757), and SII (AUC 0.709; 95% CI 0.595-0.806) could be predictors of response to bevacizumab in patients with DME and NPDR. Patients with severe NPDR had a significantly higher ApoB/ApoA-I ratio (0.70 (0.57-0.87) vs. 0.61 (0.49-0.72), p = 0.049) and lower vitamin D (52.45 (43.10-70.60) ng/mL vs. 40.05 (25.95-55.30) ng/mL, p = 0.025). Alterations in the NLR, PLR, MLR, and SII seem to provide prognostic information regarding the response to bevacizumab in patients with DME, whilst vitamin D deficiency and the ApoB/ApoA-I ratio could contribute to better staging.

The Role of the Gap Junction Protein Connexin in Adrenal Gland Tumorigenesis.

Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible role of connexins (Cxs), as major GJ proteins, under both physiological and pathological conditions in the adrenal gland, were evaluated in this review. The databases Web of Science, PubMed and Scopus were searched. Studies were evaluated if they provided data regarding the connexin expression pattern in the adrenal gland, despite current knowledge of this topic not being widely investigated. Connexin expression in the adrenal gland differs according to different parts of the gland and depends on ACTH release. Cx43 is the most studied connexin expressed in the adrenal gland cortex. In addition, Cx26, Cx32 and Cx50 were also investigated in the human adrenal gland. Cx50 as the most widespread connexin, along with Cx26, Cx29, Cx32, Cx36 and Cx43, has been expressed in the adrenal medulla with distinct cellular distribution. Considerable effort has recently been directed toward connexins as therapeutically targeted molecules. At present, there exist several viable strategies in the development of potential connexin-based therapeutics. The differential and hormone-dependent distribution of gap junctions within adrenal glands, the relatively large gap junction within this gland and the increase in the gap junction size and number following hormonal treatment would indicate that gap junctions play a pivotal role in cell functioning in the adrenal gland.

Growth differentiation factor-15 serum concentrations reflect disease severity and anemia in patients with inflammatory bowel disease.

BACKGROUND: Population of patients with inflammatory bowel disease (IBD) is burdened by various extraintestinal manifestations which substantially contribute to greater morbidity and mortality. Growth-differentiation factor-15 (GDF-15) is often over-expressed under stress conditions, such as inflammation, malignancies, heart failure, myocardial ischemia, and many others. AIM: To explore the association between GDF-15 and IBD as serum concentrations of GDF-15 were shown to be an independent predictor of poor outcomes in multiple diseases. An additional aim was to determine possible associations between GDF-15 and multiple clinical, anthropometric and laboratory parameters in patients with IBD. METHODS: This cross-sectional study included 90 adult patients diagnosed with IBD, encompassing both Crohn's disease (CD) and ulcerative colitis (UC), and 67 healthy age- and sex-matched controls. All patients underwent an extensive workup, including colonoscopy with subsequent histopathological analysis. Disease activity was assessed by two independent gastroenterology consultants specialized in IBD, employing well-established clinical and endoscopic scoring systems. GDF-15 serum concentrations were determined following an overnight fasting, using electrochemiluminescence immunoassay. RESULTS: In patients with IBD, serum GDF-15 concentrations were significantly higher in comparison to the healthy controls [800 (512-1154) pg/mL vs 412 (407-424) pg/mL, P < 0.001], whereas no difference in GDF-15 was found between patients with CD and UC [807 (554-1451) pg/mL vs 790 (509-956) pg/mL, P = 0.324]. Moreover, multiple linear regression analysis showed that GDF-15 levels predict CD and UC severity independent of age, sex, and C-reactive protein levels (P = 0.016 and P = 0.049, respectively). Finally, an association between GDF-15 and indices of anemia was established. Specifically, negative correlations were found between GDF-15 and serum iron levels (r = -0.248, P = 0.021), as well as GDF-15 and hemoglobin (r = -0.351, P = 0.021). Accordingly, in comparison to IBD patients with normal hemoglobin levels, GDF-15 serum levels were higher in patients with anemia (1256 (502-2100) pg/mL vs 444 (412-795) pg/mL, P < 0.001). CONCLUSION: For the first time, we demonstrated that serum concentrations of GDF-15 are elevated in patients with IBD in comparison to healthy controls, and the results imply that GDF-15 might be involved in IBD pathophysiology. Yet, it remains elusive whether GDF-15 could serve as a prognostic indicator in these patients.

Discontinuation of therapy in inflammatory bowel disease: Current views.

The timely introduction and adjustment of the appropriate drug in accordance with previously well-defined treatment goals is the foundation of the approach in the treatment of inflammatory bowel disease (IBD). The therapeutic approach is still evolving in terms of the mechanism of action but also in terms of the possibility of maintaining remission. In patients with achieved long-term remission, the question of de-escalation or discontinuation of therapy arises, considering the possible side effects and economic burden of long-term therapy. For each of the drugs used in IBD (5-aminosalycaltes, immunomodulators, biological drugs, small molecules) there is a risk of relapse. Furthermore, studies show that more than 50% of patients who discontinue therapy will relapse. Based on the findings of large studies and meta-analysis, relapse of disease can be expected in about half of the patients after therapy withdrawal, in case of monotherapy with aminosalicylates, immunomodulators or biological therapy. However, longer relapse-free periods are recorded with withdrawal of medication in patients who had previously been on combination therapies immunomodulators and anti-tumor necrosis factor. It needs to be stressed that randomised clinical trials regarding withdrawal from medications are still lacking. Before making a decision on discontinuation of therapy, it is important to distinguish potential candidates and predictive factors for the possibility of disease relapse. Fecal calprotectin level has currently been identified as the strongest predictive factor for relapse. Several other predictive factors have also been identified, such as: High Crohn's disease activity index or Harvey Bradshaw index, younger age (< 40 years), longer disease duration (> 40 years), smoking, young age of disease onset, steroid use 6-12 months before cessation. An important factor in the decision to withdraw medication is the success of re-treatment with the same or other drugs. The decision to discontinue therapy must be based on individual approach, taking into account the severity, extension, and duration of the disease, the possibility of side adverse effects, the risk of relapse, and patient's preferences.

Metabolic Crossroads: Unveiling the Complex Interactions between Obstructive Sleep Apnoea and Metabolic Syndrome.

Obstructive sleep apnoea (OSA) and components of metabolic syndrome (MetS) are inextricably connected. Considering the increasing burden of MetS and OSA, in the present review, we aimed to collate and summarise the potential pathophysiological mechanisms linking these pathologies. In short, obesity appears to promote OSA development via multiple pathways, some of which are not directly related to mass but rather to metabolic complications of obesity. Simultaneously, OSA promotes weight gain through central mechanisms. On the other hand, diabetes mellitus contributes to OSA pathophysiology mainly through effects on peripheral nerves and carotid body desensitization, while intermittent hypoxia and sleep fragmentation are the principal culprits in OSA-mediated diabetes. Apart from a bidirectional pathophysiological relationship, obesity and diabetes mellitus together additively increase cardiovascular risk in OSA patients. Additionally, the emergence of new drugs targeting obesity and unequivocal results of the available studies underscore the need for further exploration of the mechanisms linking MetS and OSA, all with the aim of improving outcomes in these patients.

Quality of life in postmenopausal women with osteoporosis and osteopenia: associations with bone microarchitecture and nutritional status.

PURPOSE: Primary aim of the study was to investigate the status of different health-related quality of life (HRQoL) domains in postmenopausal women with osteoporosis and osteopenia, and to explore possible associations with bone microarchitecture and nutritional status. METHODS: This was a single-center cross-sectional study that included 232 postmenopausal women, from which they were divided into three groups-osteoporosis (OP, N = 63), osteopenia (OPIA, N = 123), and control group (N = 46). Detailed medical history data and anthropometric measurements were taken from all women. Bone structure parameters were taken with DXA device, with additional analysis of bone microarchitecture status with Trabecular Bone Score (TBS). Nutritional status was assessed with Mini Nutritional Assessment (MNA) questionnaire, and HRQoL with Medical Outcomes Study Short Form-36 (SF-36) questionnaire. RESULTS: Nutrition evaluation analysis have shown that patients in OP group had significantly lower values of MNA score compared to the OPIA group and control group (P = 0.005). Furthermore, a significant positive correlation was found between all of the SF-36 domains and MNA scores, while significant positive correlation was found between TBS values and Physical functioning (P < 0.001), Bodily pain (P = 0.027), Social functioning (P = 0.029), and Vitality domains (P = 0.041) in total investigated population. Further analyses were performed only in OP and OPIA groups, and TBS score showed significant positive correlation with Physical functioning (r = 0.248, P < 0.001) and Bodily pain domains as well (r = 0.180, P = 0.014), while MNA score positively correlated with each of the SF-36 domains. Multiple regression models have shown that MNA score retained significant association with each SF-36 domains, and TBS value with Physical functioning (P = 0.003), Social functioning (P = 0.012), and Vitality domains (P = 0.014). CONCLUSION: This study highlights the associations that TBS has with some domains of HRQoL in postmenopausal women with osteoporosis and osteopenia. Moreover, nutritional status could play a role in the complex interplay between TBS and HRQoL.

Temporomandibular Disorder Prevalence and Its Association with Lifestyle Habits in Biomedicine Students-A Cross-Sectional Study.

This study aimed to examine the frequency of temporomandibular disorder among biomedical students and relate its occurrence to lifestyle habits. A cross-sectional collection of data was carried out and included a total of 676 examinees through a questionnaire that had 73 questions: general information and lifestyle habits, the Fonseca Anamnestic index (FAI), the Jaw Function Limitation Scale (JFLS), and the Perceived Stress Questionnaire (PSQ). The statistical analyses between three or more groups were conducted using the one-way analysis of variance (ANOVA) with post hoc Scheffé test or Kruskal-Wallis test with post hoc Dunn's test for quantitative variables. The comparison of qualitative variables was conducted using the Chi-square test, while the correlations were determined using Spearman's correlation test. The analysis showed that a higher frequency of moderate or severe TMD was observed in subjects who were smokers (p < 0.001) compared to non-smokers. Subjects who consumed more coffee had moderate to severe TMD compared to subjects who consumed a lesser amount (p < 0.001). Furthermore, a positive correlation between the amount of stress and the severity of TMD was found. Our study implies that students of biomedical studies have an increased risk for TMD and that there is a link with their lifestyle habits.

Effects of CBD supplementation on ambulatory blood pressure and serum urotensin-II concentrations in Caucasian patients with essential hypertension: A sub-analysis of the HYPER-H21-4 trial.

HYPER-H21-4 was a randomized crossover trial that aimed to determine if cannabidiol (CBD), a non-intoxicating constituent of cannabis, has relevant effects on blood pressure and vascular health in patients with essential hypertension. In the present sub-analysis, we aimed to elucidate whether serum urotensin-II concentrations may reflect hemodynamic changes caused by oral supplementation with CBD. The sub-analysis of this randomized crossover study included 51 patients with mild to moderate hypertension that received CBD for five weeks, and placebo for five weeks. After five weeks of oral CBD supplementation, but not placebo, serum urotensin concentrations reduced significantly in comparison to baseline (3.31 ± 1.46 ng/mL vs. 2.08 ± 0.91 ng/mL, P < 0.001). Following the five weeks of CBD supplementation, the magnitude of reduction in 24 h mean arterial pressure (MAP) positively correlated with the extent of change in serum urotensin levels (r = 0.412, P = 0.003); this association was independent of age, sex, BMI and previous antihypertensive treatment (ß ± standard error, 0.023 ± 0.009, P = 0.009). No correlation was present in the placebo condition (r = -0.132, P = 0.357). In summary, potent vasoconstrictor urotensin seems to be implicated in CBD-mediated reduction in blood pressure, although further research is needed to confirm these notions.

Serum Urotensin II Levels Are Elevated in Patients with Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) has become major public concern and is continuously investigated in new aspects of pathophysiology and management. Urotensin II (UII) is a powerful vasoconstrictor with a role in cardiovascular diseases. The main goal of this study was to evaluate serum UII levels in OSA patients and matched controls. A total of 89 OSA patients and 89 controls were consecutively enrolled. A medical history review and physical examination of the participants was conducted, with polysomnography performed in the investigated group. UII levels and other biochemical parameters were assessed according to the standard laboratory protocols. The median AHI in the OSA group was 39.0 (31.4-55.2) events/h, and they had higher levels of hsCRP when compared to control group (2.87 ± 0.71 vs. 1.52 ± 0.68 mg/L; p < 0.001). Additionally, serum UII levels were significantly higher in the OSA group (3.41 ± 1.72 vs. 2.18 ± 1.36 ng/mL; p < 0.001), while positive correlation was found between UII levels and hsCRP (r = 0.450; p < 0.001) and systolic blood pressure (SPB) (r = 0.317; p < 0.001). Finally, multiple regression analysis showed significant association of UII levels with AHI (0.017 ± 0.006, p = 0.013), SBP (0.052 ± 0.008, p < 0.001) and hsCRP (0.538 ± 0.164, p = 0.001). As UII levels were associated with blood pressure and markers of inflammation and OSA severity, it might play an important role in the complex pathophysiology of OSA and its cardiometabolic complications.

Differences in Plasma Cannabidiol Concentrations in Women and Men: A Randomized, Placebo-Controlled, Crossover Study.

The potential therapeutic benefits of cannabidiol (CBD) require further study. Here, we report a triple-blind (participant, investigator, and outcome assessor) placebo-controlled crossover study in which 62 hypertensive volunteers were randomly assigned to receive the recently developed DehydraTECH2.0 CBD formulation or a placebo. This is the first study to have been conducted using the DehydraTECH2.0 CBD formulation over a 12-week study duration. The new formulation's long-term effects on CBD concentrations in plasma and urine, as well as its metabolites 7-hydroxy-CBD and 7-carboxy-CBD, were analyzed. The results of the plasma concentration ratio for CBD/7-OH-CBD in the third timepoint (after 5 weeks of use) were significantly higher than in the second timepoint (after 2.5 weeks of use; p = 0.043). In the same timepoints in the urine, a significantly higher concentration of 7-COOH-CBD was observed p < 0.001. Differences in CBD concentration were found between men and women. Plasma levels of CBD were still detectable 50 days after the last consumption of the CBD preparations. Significantly higher plasma CBD concentrations occurred in females compared to males, which was potentially related to greater adipose tissue. More research is needed to optimize CBD doses to consider the differential therapeutic benefits in men and women.

Obesity and Clonal Hematopoiesis of Indeterminate Potential: Allies in Cardiovascular Diseases and Malignancies.

The clonal hematopoiesis of indeterminate potential (CHIP) is a term used to describe individuals who have detectable somatic mutations in genes commonly found in individuals with hematologic cancers but without any apparent evidence of such conditions. The mortality rate in individuals with CHIP is remarkably higher than the influence ascribed to hematologic malignancies, and it is plausible that cardiovascular diseases (CVD) could elucidate the apparent disparity. Studies have shown that the most frequently altered genes in CHIP are associated with the increased incidence of CVDs, type 2 diabetes mellitus (T2DM) and myeloid malignancies, as well as obesity. Additionally, multiple research studies have confirmed that obesity is also independently associated with these conditions, particularly the development and progression of atherosclerotic CVD. Considering the shared pathogenetic mechanisms of obesity and CHIP, our objective in this review was to investigate both preclinical and clinical evidence regarding the correlation between obesity and CHIP and the resulting implications of this interaction on the pathophysiology of CVDs and malignancies. The pro-inflammatory condition induced by obesity and CHIP enhances the probability of developing both diseases and increases the likelihood of developing CVDs, T2DM and malignancies, suggesting that a dangerous vicious loop may exist. However, it is vital to conduct additional research that will suggest targeted treatment options for obese individuals with CHIP in order to reduce harmful effects connected to these conditions.

The Role of AI in Breast Cancer Lymph Node Classification: A Comprehensive Review.

Breast cancer is a significant health issue affecting women worldwide, and accurately detecting lymph node metastasis is critical in determining treatment and prognosis. While traditional diagnostic methods have limitations and complications, artificial intelligence (AI) techniques such as machine learning (ML) and deep learning (DL) offer promising solutions for improving and supplementing diagnostic procedures. Current research has explored state-of-the-art DL models for breast cancer lymph node classification from radiological images, achieving high performances (AUC: 0.71-0.99). AI models trained on clinicopathological features also show promise in predicting metastasis status (AUC: 0.74-0.77), whereas multimodal (radiomics + clinicopathological features) models combine the best from both approaches and also achieve good results (AUC: 0.82-0.94). Once properly validated, such models could greatly improve cancer care, especially in areas with limited medical resources. This comprehensive review aims to compile knowledge about state-of-the-art AI models used for breast cancer lymph node metastasis detection, discusses proper validation techniques and potential pitfalls and limitations, and presents future directions and best practices to achieve high usability in real-world clinical settings.

Obesity, Gut Microbiota, and Metabolome: From Pathophysiology to Nutritional Interventions.

Obesity is a disorder identified by an inappropriate increase in weight in relation to height and is considered by many international health institutions to be a major pandemic of the 21st century. The gut microbial ecosystem impacts obesity in multiple ways that yield downstream metabolic consequences, such as affecting systemic inflammation, immune response, and energy harvest, but also the gut-host interface. Metabolomics, a systematized study of low-molecular-weight molecules that take part in metabolic pathways, represents a serviceable method for elucidation of the crosstalk between hosts' metabolism and gut microbiota. In the present review, we confer about clinical and preclinical studies exploring the association of obesity and related metabolic disorders with various gut microbiome profiles, and the effects of several dietary interventions on gut microbiome composition and the metabolome. It is well established that various nutritional interventions may serve as an efficient therapeutic approach to support weight loss in obese individuals, yet no agreement exists in regard to the most effective dietary protocol, both in the short and long term. However, metabolite profiling and the gut microbiota composition might represent an opportunity to methodically establish predictors for obesity control that are relatively simple to measure in comparison to traditional approaches, and it may also present a tool to determine the optimal nutritional intervention to ameliorate obesity in an individual. Nevertheless, a lack of adequately powered randomized trials impedes the application of observations to clinical practice.

Trial of a Novel Oral Cannabinoid Formulation in Patients with Hypertension: A Double-Blind, Placebo-Controlled Pharmacogenetic Study.

Cannabidiol (CBD) is a non-psychoactive cannabinoid, and available evidence suggests potential efficacy in the treatment of many disorders. DehydraTECH™2.0 CBD is a patented capsule formulation that improves the bioabsorption of CBD. We sought to compare the effects of CBD and DehydraTECH™2.0 CBD based on polymorphisms in CYP P450 genes and investigate the effects of a single CBD dose on blood pressure. In a randomized and double-blinded order, 12 females and 12 males with reported hypertension were given either placebo capsules or DehydraTECH™2.0 CBD (300 mg of CBD, each). Blood pressure and heart rate were measured during 3 h, and blood and urine samples were collected. In the first 20 min following the dose, there was a greater reduction in diastolic blood pressure (p = 0.025) and mean arterial pressure MAP (p = 0.056) with DehydraTECH™2.0 CBD, which was probably due to its greater CBD bioavailability. In the CYP2C9*2*3 enzyme, subjects with the poor metabolizer (PM) phenotype had higher plasma CBD concentrations. Both CYP2C19*2 (p = 0.037) and CYP2C19*17 (p = 0.022) were negatively associated with urinary CBD levels (beta = -0.489 for CYP2C19*2 and beta = -0.494 for CYP2C19*17). Further research is required to establish the impact of CYP P450 enzymes and the identification of metabolizer phenotype for the optimization of CBD formulations.

Emerging Therapies for the Treatment of Atherosclerotic Cardiovascular Disease: From Bench to Bedside.

Primarily a consequence of sedentary lifestyle, atherosclerosis has already reached pandemic proportions, and with every year the burden of it is only increasing. As low-density lipoprotein cholesterol (LDL-C) represents a crucial factor in atherosclerosis formation and progression, stringent lipid-lowering therapy could conceivably be the key to preventing the unfavorable outcomes that arise as a consequence of atherosclerosis. The use of statins in lipid-lowering is often burdened by adverse events or is insufficient to prevent cardiovascular events as a monotherapy. Therefore, in the present review, the authors aimed to discuss the underlying mechanisms of dyslipidemia and associated atherosclerotic cardiovascular disease (ASCVD) and preclinical and clinical trials of novel therapeutic approaches to its treatment, some of which are still in the early stages of development. Apart from novel therapies, a novel change in perspective is needed. Specifically, the critical objective in the future management of ASCVD is to embrace emerging evidence in the field of atherosclerosis, because clinicians are often burden by common practice and personal experience, both of which have so far been shown to be futile in the setting of atherosclerosis.

Nutritional Management of Patients with Head and Neck Cancer-A Comprehensive Review.

While surgical therapy for head and neck cancer (HNC) is showing improvement with the advancement of reconstruction techniques, the focus in these patients should also be shifting to supportive pre and aftercare. Due to the highly sensitive and anatomically complex region, these patients tend to exhibit malnutrition, which has a substantial impact on their recovery and quality of life. The complications and symptoms of both the disease and the therapy usually make these patients unable to orally intake food, hence, a strategy should be prepared for their nutritional management. Even though there are several possible nutritional modalities that can be administrated, these patients commonly have a functional gastrointestinal tract, and enteral nutrition is indicated over the parenteral option. However, after extensive research of the available literature, it seems that there is a limited number of studies that focus on this important issue. Furthermore, there are no recommendations or guidelines regarding the nutritional management of HNC patients, pre- or post-operatively. Henceforth, this narrative review summarizes the nutritional challenges and management modalities in this particular group of patients. Nonetheless, this issue should be addressed in future studies and an algorithm should be established for better nutritional care of these patients.

Chronic Effects of Oral Cannabidiol Delivery on 24-h Ambulatory Blood Pressure in Patients with Hypertension (HYPER-H21-4): A Randomized, Placebo-Controlled, and Crossover Study.

Background: Recent data indicate that cannabidiol (CBD), a nonintoxicating constituent of cannabis, is involved in several aspects of cardiovascular regulation, including blood pressure (BP). However, the impact of chronic CBD administration on 24-h BP and vascular health has not been previously examined in patients with hypertension. The primary aim of this randomized, triple-blind, placebo-controlled, and crossover study was to examine the influence of chronic CBD on 24-h ambulatory BP and arterial stiffness in hypertensive patients. Methods: Seventy patients with mild or moderate primary hypertension, who were untreated or receiving standard of care therapy, were randomly assigned to receive either 5 weeks of oral CBD or placebo-matched controls. Following a >2-week washout period, patients were crossed over to alternate therapy. The primary outcome of the study was dynamic in 24-h ambulatory BP and was assessed using two-way repeated measure analysis of variance. Results: Administration of CBD reduced average 24 h mean, systolic, and diastolic BP after 2.5 weeks (-3.22±0.90 mmHg [95% confidence interval -1.01 to -5.44 mmHg], -4.76±1.24 mmHg [-1.72 to -7.80 mmHg], and -2.25±0.80 mmHg [-0.30 to -6.01 mmHg], respectively (all p<0.05); however, these values largely remained stable following the uptitration of CBD dosing. There were no changes in liver enzymes or serious adverse events (AEs). There was no significant difference in pulse wave velocity (group×factor interaction: F=1.50, p=0.226) at different time points, regardless of the intervention arm. Conclusions: In conclusion, chronic administration of CBD reduces ambulatory BP in those with untreated and treated hypertension. In addition, lack of serious AEs implies safety and tolerability of the above-noted CBD formulation. ClinicalTrials.gov ID: NCT05346562, Registered April 6th 2022.

The Association between the Level of Advanced Glycation End Products and Objective Skin Quality Parameters.

Advanced glycation end products (AGEs) represent an endogenously produced or exogenously derived group of compounds derived from nonenzymatic glycation. Recent experimental studies are suggesting that AGEs could play an important role in the skin's quality and its aging process. Hence, the aim of this study was to clinically evaluate the AGEs and skin quality parameters across different age groups in the general population. The study included 237 participants. Melanin, erythema, hydration, friction and transepidermal water loss (TEWL) were evaluated using noninvasive probes, while AGEs were evaluated using a skin autofluorescence reader. There was a significant positive correlation between AGEs and the amount of melanin (p < 0.001), erythema (p < 0.001) and TEWL (p < 0.001), while there was a significant negative correlation between AGEs and hydration (p < 0.001) and friction (p < 0.001). After dividing the sample into three groups depending on their age, in all three groups, there was a significant positive correlation between AGEs and the melanin count (p < 0.001) and TEWL (p < 0.001), while there was a significant negative correlation between AGEs and skin hydration (p < 0.001). Multiple linear regression analysis showed that the level of AGEs as a dependent variable retained a significant association with age (p < 0.001), melanin (p < 0.001), erythema (p = 0.005) and TEWL (p < 0.001) as positive predictors. Moreover, AGEs retained a significant association with skin hydration (p < 0.001) and friction (p = 0.017) as negative predictors. These outcomes imply that AGEs could be linked with the complex physiology of the skin and its aging process.

Applying Explainable Machine Learning Models for Detection of Breast Cancer Lymph Node Metastasis in Patients Eligible for Neoadjuvant Treatment.

BACKGROUND: Due to recent changes in breast cancer treatment strategy, significantly more patients are treated with neoadjuvant systemic therapy (NST). Radiological methods do not precisely determine axillary lymph node status, with up to 30% of patients being misdiagnosed. Hence, supplementary methods for lymph node status assessment are needed. This study aimed to apply and evaluate machine learning models on clinicopathological data, with a focus on patients meeting NST criteria, for lymph node metastasis prediction. METHODS: From the total breast cancer patient data (n = 8381), 719 patients were identified as eligible for NST. Machine learning models were applied for the NST-criteria group and the total study population. Model explainability was obtained by calculating Shapley values. RESULTS: In the NST-criteria group, random forest achieved the highest performance (AUC: 0.793 [0.713, 0.865]), while in the total study population, XGBoost performed the best (AUC: 0.762 [0.726, 0.795]). Shapley values identified tumor size, Ki-67, and patient age as the most important predictors. CONCLUSION: Tree-based models achieve a good performance in assessing lymph node status. Such models can lead to more accurate disease stage prediction and consecutively better treatment selection, especially for NST patients where radiological and clinical findings are often the only way of lymph node assessment.