Insight into the Interaction of Humulus lupulus L. Specialized Metabolites and Gastrointestinal Bitter Taste Receptors: In Vitro Study in STC-1 Cells and Molecular Docking.

Bitter taste receptors, also known as taste 2 receptors (T2R), are expressed throughout the body and are involved in regulating different physiological processes. T2R expression in the intestinal tract regulates orexigenic and anorexigenic peptide secretion, thus becoming potential a potential target for controlling food intake and the prevalence of obesity and overweight. The present study aims to investigate the implication of hop bitter compounds such as α-acids, ß-acids, and xanthohumol in the secretion of anorexigenic hormones and T2R expression in intestinal STC-1 cells. The tested bitter compounds induced the secretion of the anorexigenic hormones glucagon-like peptide 1 and cholecystokinin concurrently with a selective increase of murine Tas2r expression. Xanthohumol and α-acids selectively increase Tas2r138 and Tas2r130-Tas2r138 expression, respectively, in STC-1 cells, while ß-acids increased the expression of all bitter receptors studied, including Tas2r119, Tas2r105, Tas2r138, Tas2r120, and Tas2r130. Increased intracellular calcium levels confirmed this activity. As all investigated bitter molecules increased Tas2r138 expression, computational studies were performed on Tas2r138 and its human orthologue T2R38 for the first time. Molecular docking experiments showed that all molecules might be able to bind both bitter receptors, providing an excellent basis for applying hop bitter molecules as lead compounds to further design gastrointestinal-permeable T2R agonists.

Gut microbiota metabolically mediate intestinal helminth infection in Zebrafish.

Intestinal helminth parasite (IHP) infection induces alterations in the composition of microbial communities across vertebrates, although how gut microbiota may facilitate or hinder parasite infection remains poorly defined. In this work we utilized a zebrafish model to investigate the relationship between gut microbiota, gut metabolites, and IHP infection. We found that extreme disparity in zebrafish parasite infection burden is linked to the composition of the gut microbiome, and that changes in the gut microbiome are associated with variation in a class of endogenously-produced signaling compounds, N-acylethanolamines, that are known to be involved in parasite infection. Using a statistical mediation analysis, we uncovered a set of gut microbes whose relative abundance explains the association between gut metabolites and infection outcomes. Experimental investigation of one of the compounds in this analysis reveals salicylaldehyde, which is putatively produced by the gut microbe Pelomonas, as a potent anthelmintic with activity against Pseudocapillaria tomentosa egg hatching, both in vitro and in vivo. Collectively, our findings underscore the importance of the gut microbiome as a mediating agent in parasitic infection and highlights specific gut metabolites as tools for the advancement of novel therapeutic interventions against IHP infection.

Specific Compounds Derived from Traditional Chinese Medicine Ameliorate Lipid-Induced Contractile Dysfunction in Cardiomyocytes.

Chronic lipid overconsumption, associated with the Western diet, causes excessive cardiac lipid accumulation, insulin resistance, and contractile dysfunction, altogether termed lipotoxic cardiomyopathy (LCM). Existing treatments for LCM are limited. Traditional Chinese Medicine (TCM) has been shown as beneficial in diabetes and its complications. The following compounds-Resveratrol, Quercetin, Berberine, Baicalein, and Isorhamnetin-derived from TCM and often used to treat type 2 diabetes. However, virtually nothing is known about their effects in the lipid-overexposed heart. Lipid-induced insulin resistance was generated in HL-1 cardiomyocytes and adult rat cardiomyocytes by 24 h exposure to high palmitate. Upon simultaneous treatment with each of the TCM compounds, we measured myocellular lipid accumulation, insulin-stimulated fatty acid and glucose uptake, phosphorylation levels of AKT and ERK1/2, plasma membrane appearance of GLUT4 and CD36, and expression of oxidative stress-/inflammation-related genes and contractility. In lipid-overloaded cardiomyocytes, all the selected TCM compounds prevented lipid accumulation. These compounds also preserved insulin-stimulated CD36 and GLUT4 translocation and insulin-stimulated glucose uptake in an Akt-independent manner. Moreover, all the TCM compounds prevented and restored lipid-induced contractile dysfunction. Finally, some (not all) of the TCM compounds inhibited oxidative stress-related SIRT3 expression, and others reduced inflammatory TNFα expression. Their ability to restore CD36 trafficking makes all these TCM compounds attractive natural supplements for LCM treatment.

Considerable differences in management of cytomegalovirus infection in patients with biliary atresia.

Objectives: Patients with biliary atresia (BA) and ongoing cytomegalovirus (CMV) infection may have poorer outcomes after Kasai portoenterostomy than uninfected patients. Still, there is no consensus on the usefulness of viral testing and antiviral treatment (AVT). This study aims to explore the need for future research on AVT for CMV infection by assessing how CMV infection in BA patients is managed in different centers. Methods: An online questionnaire with 10 questions was offered to participants at an international congress on BA, organized in collaboration with the European Reference Network for rare liver diseases in 2022. Answers to questions were either dichotomic or multiple choices of different numeric intervals. Ongoing CMV infection was defined by detecting cytomegalovirus-immunoglobulin M (CMV-IgM) in serum or cytomegalovirus-deoxyribonucleic acid (CMV-DNA) by polymerase chain reaction in blood or urine. Results: There were 43 respondents from 36 centers in 26 countries. The total number of BA patients per year was between 208 and 380 from centers with 0-5 to >20 BA patients yearly (median 6-10). CMV infection was tested in 27 centers (75%), of which 18 (67%) use AVT. The rate of CMV infection varied between 0%-5% and 40%-50% (median 5%-10%). Willingness to treat the infection did not differ between centers with low and high rates of CMV infection. Conclusions: Most centers test for CMV infection, and a considerable proportion use AVT despite the lack of evidence of its benefits. A future randomized study on treating CMV infection in BA patients is necessary and feasible.

Comparison of 5-year cup and stem migration between ceramic-on-ceramic and ceramic-on-polyethylene bearing in press-fit total hip arthroplasty: a randomised controlled trial using radiostereometric analysis.

INTRODUCTION: The inelasticity of ceramic bearings might affect primary stability and migration of implants in press-fit total hip arthroplasty (THA). This randomised controlled trial compares migration patterns of the uncemented Delta-TT cup and H-MAX S stem between ceramic and polyethylene liners, up to 5 years follow-up. METHODS: Patients receiving primary press-fit THA were randomly allocated to a ceramic (n = 28) or polyethylene (n = 25) liner. Migration was measured using model-based radiostereometric analysis (RSA) at baseline and 1.5, 3, 6, 12, 24 and 60 months postoperatively and compared between groups using mixed models statistical analysis. The focus of this study is on the 2- to 5-year migration of the Delta-TT cup and migration during complete follow-up of the H-MAX S stem up to 5-years. RESULTS: At 5-year follow-up, mean (95% CI) proximal cup translation was 0.56 (0.37-0.74) mm in ceramic and 0.58 (0.25-0.90) mm in polyethylene (p = 0.729). The mean change in adduction was 1.05° (0.27-1.82°) in ceramic and 0.78° (-0.16-1.71°) in polyethylene. Mixed modelling showed that all between-group effects were ⩽0.20 mm for translation and ⩽0.22° for rotation at 5 years postoperatively (p ⩾ 0.23). Mean cup migration between 2 and 5 years was limited (all parameters <0.17 mm and <0.30°). At 5-year follow-up, mean stem subsidence was 2.09 mm (0.89-3.29 mm) in ceramic and 2.55 (0.97-4.12) mm in polyethylene. The mean change in internal rotation was 3.69° (1.98-5.40°) in ceramic and 4.01° (2.20-5.81°) in polyethylene. Most stem migration occurred up to 1.5 months, stabilising afterwards. All between-group effects were ⩽0.75 mm for translations and ⩽1.41° for rotations (p ⩾ 0.26). CONCLUSIONS: 5-year migration patterns of press-fit cups and stems were similar between ceramic and polyethylene liners. The Delta-TT cup and H-MAX S stem showed secondary stabilisation and remained stable up to 5 years in both groups, which is promising for long-term survival with both liner types. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03093038).

The core microbiome of cultured Pacific oyster spat is affected by age but not mortality.

The Pacific oyster is the most widely cultured shellfish worldwide, but production has been affected by mortality events, including in hatcheries that supply the seed for growers. Several pathogens cause disease in oysters, but in many cases, mortality events cannot be attributed to a single agent and appear to be multifactorial, involving environmental variables and microbial interactions. As an organism's microbiome can provide resilience against pathogens and environmental stressors, we investigated the microbiomes in cohorts of freshly settled oyster spat, some of which experienced notable mortality. Deep sequencing of 16S rRNA gene fragments did not show a significant difference among the microbiomes of cohorts experiencing different mortality levels, but revealed a characteristic core microbiome comprising 74 taxa. Irrespective of mortality, the relative abundance of taxa in the core microbiomes changed significantly as the spat aged, yet remained distinct from the microbial community in the surrounding water. The core microbiome was dominated by bacteria in the families Rhodobacteraceae, Nitrosomonadaceae, Flavobacteriaceae, Pirellulaeceae, and Saprospiraceae. Within these families, 14 taxa designated as the "Hard-Core Microbiome" were indicative of changes in the core microbiome as the spat aged. The variability in diversity and richness of the core taxa decreased with age, implying niche occupation. As well, there was exchange of microbes with surrounding water during development of the core microbiome. The shift in the core microbiome demonstrates the dynamic nature of the microbiome as oyster spat age.IMPORTANCEThe Pacific oyster (Magallana gigas, also known as Crassostrea gigas) is the most widely cultivated shellfish and is important to the economy of many coastal communities. However, high mortality of spat during the first few days following metamorphosis can affect the seed supply to oyster growers. Here, we show that the microbiome composition of recently settled oyster spat experiencing low or high mortality was not significantly different. Instead, development of the core microbiome was associated with spat aging and was partially driven by dispersal through the water. These findings imply the importance of early-stage rearing conditions for spat microbiome development in aquaculture facilities. Furthermore, shellfish growers could gain information about the developmental state of the oyster spat microbiome by assessing key taxa. Additionally, the study provides a baseline microbiome for future hypothesis testing and potential probiotic applications on developing spat.

Liquid chromatography-mass spectrometry quantification of phytochemicals in Withania somnifera using data-dependent acquisition, multiple-reaction-monitoring, and parallel-reaction-monitoring with an inclusion list.

Characterization of botanical extracts by mass spectrometry-based metabolomics analysis helps in determining the phytochemical composition that underlies their bioactivity and potential health benefits, while also supporting reproducibility of effects in clinical trials. The quantification of seven withanolides in Withania somnifera using three mass-spectrometry methods was evaluated using Deming regression. Two high-resolution time-of-flight mass spectrometry methods were used, one operating in data-dependent acquisition mode and the other in parallel-reaction-monitoring mode with an inclusion list. The two high-resolution time-of-flight mass spectrometry methods were compared to a multiple-reaction-monitoring method. We evaluated in-source fragmentation of steroidal glycosides and optimized the methods accordingly. A novel software approach to integrating parallel-reaction-monitoring data acquired with an inclusion list was developed. Combining and comparing quantitative results allowed for quantitative specificity, good precision, and adjustment of instrument source conditions for optimal quantification by multiple-reaction-monitoring mass spectrometry, an analytical method that is widely accessible in analytical and phytochemical laboratories.

Acute Myocardial Injury in Spontaneous Intracerebral Hemorrhage: A Secondary Observational Analysis of the FAST Trial.

BACKGROUND: Acute myocardial injury is associated with poor outcomes in patients with acute ischemic stroke, but its prognostic significance in patients with spontaneous intracerebral hemorrhage remains unclear. We investigated whether acute myocardial injury and the direction of the cardiac troponin I (cTnI) change (rising versus falling) affect post-intracerebral hemorrhage outcomes. METHODS AND RESULTS: We re-analyzed the FAST (Factor-Seven-for-Acute-Hemorrhagic-Stroke) trial. Acute myocardial injury was defined as at least 1 cTnI value above the upper reference limit with a rise/fall of >20%. Logistic regression tested for associations (1) between acute myocardial injury (presence versus absence) and poor outcome (modified Rankin Scale 4-6) and mortality at 15 and 90 days; (2) among 3 groups (rising versus falling versus no acute myocardial injury) and outcomes. Among the 841 FAST participants, 785 patients were included. Acute myocardial injury was detected in 29% (n=227); 170 had rising cTnI. At 15 and 90 days, respectively, those with acute myocardial injury had higher odds of poor outcome (adjusted odds ratio) ([aOR] 2.3 [95% CI, 1.3-3.9]); and adjusted odds ratio 2.5 [95% CI, 1.6-3.9];, and higher odds of mortality (adjusted odds ratio 2.4 [95% CI, 1.4-4.3]; and adjusted odds ratio 2.2 [CI, 1.3-3.6]) than patients without. There was no interaction between FAST group assignment and myocardial injury, and associations between myocardial injury and outcomes were consistent across group assignments. Rising cTnI was associated with the highest risk of poor outcomes and mortality. CONCLUSIONS: In this secondary analysis of the FAST trial, acute myocardial injury was common and associated with poor outcomes. The direction of the cTnI change might provide additional risk stratification after intracerebral hemorrhage.

Gut microbiota metabolically mediate intestinal helminth infection in zebrafish.

Intestinal helminth parasite (IHP) infection induces alterations in the composition of microbial communities across vertebrates, although how gut microbiota may facilitate or hinder parasite infection remains poorly defined. In this work, we utilized a zebrafish model to investigate the relationship between gut microbiota, gut metabolites, and IHP infection. We found that extreme disparity in zebrafish parasite infection burden is linked to the composition of the gut microbiome and that changes in the gut microbiome are associated with variation in a class of endogenously produced signaling compounds, N-acylethanolamines, that are known to be involved in parasite infection. Using a statistical mediation analysis, we uncovered a set of gut microbes whose relative abundance explains the association between gut metabolites and infection outcomes. Experimental investigation of one of the compounds in this analysis reveals salicylaldehyde, which is putatively produced by the gut microbe Pelomonas, as a potent anthelmintic with activity against Pseudocapillaria tomentosa egg hatching, both in vitro and in vivo. Collectively, our findings underscore the importance of the gut microbiome as a mediating agent in parasitic infection and highlight specific gut metabolites as tools for the advancement of novel therapeutic interventions against IHP infection. IMPORTANCE: Intestinal helminth parasites (IHPs) impact human health globally and interfere with animal health and agricultural productivity. While anthelmintics are critical to controlling parasite infections, their efficacy is increasingly compromised by drug resistance. Recent investigations suggest the gut microbiome might mediate helminth infection dynamics. So, identifying how gut microbes interact with parasites could yield new therapeutic targets for infection prevention and management. We conducted a study using a zebrafish model of parasitic infection to identify routes by which gut microbes might impact helminth infection outcomes. Our research linked the gut microbiome to both parasite infection and to metabolites in the gut to understand how microbes could alter parasite infection. We identified a metabolite in the gut, salicylaldehyde, that is putatively produced by a gut microbe and that inhibits parasitic egg growth. Our results also point to a class of compounds, N-acyl-ethanolamines, which are affected by changes in the gut microbiome and are linked to parasite infection. Collectively, our results indicate the gut microbiome may be a source of novel anthelmintics that can be harnessed to control IHPs.

Electrocatalysis of CO2 Reduction by Immobilized Formate Dehydrogenase without a Metal Redox Center.

Nicotinamide adenine dinucleotide-dependent formate dehydrogenase from Candida boidinii was immobilized in a 1,2-dimyristoyl-sn-glycero-3-phosphocholine/cholesterol floating lipid bilayer on the gold surface as a biocatalyst for electrochemical CO2 reduction. We report that, in contrast to common belief, the enzyme can catalyze the electrochemical reduction of CO2 to formate without the cofactor protonated nicotinamide adenine dinucleotide. The electrochemical data indicate that the enzyme-catalyzed reduction of CO2 is diffusion-controlled and is a reversible reaction. The orientation and conformation of the enzyme were investigated by surface-enhanced infrared reflection absorption spectroscopy. The α-helix of the enzyme adopts an orientation nearly parallel to the surface, bringing its active center close to the gold surface. This orientation allows direct electron transfer between CO2 and the gold electrode. The results in this paper provide a new method for the development of enzymatic electrocatalysts for CO2 reduction.

A clinically compatible in vitro drug-screening platform identifies therapeutic vulnerabilities in primary cultures of brain metastases.

PURPOSE: Brain metastases represent the most common intracranial tumors in adults and are associated with a poor prognosis. We used a personalized in vitro drug screening approach to characterize individual therapeutic vulnerabilities in brain metastases. METHODS: Short-term cultures of cancer cells isolated from brain metastasis patients were molecularly characterized using next-generation sequencing and functionally evaluated using high-throughput in vitro drug screening to characterize pharmacological treatment sensitivities. RESULTS: Next-generation sequencing identified matched genetic alterations in brain metastasis tissue samples and corresponding short-term cultures, suggesting that short-term cultures of brain metastases are suitable models for recapitulating the genetic profile of brain metastases that may determine their sensitivity to anti-cancer drugs. Employing a high-throughput in vitro drug screening platform, we successfully screened the cultures of five brain metastases for response to 267 anticancer compounds and related drug response to genetic data. Among others, we found that targeted treatment with JAK3, HER2, or FGFR3 inhibitors showed anti-cancer effects in individual brain metastasis cultures. CONCLUSION: Our preclinical study provides a proof-of-concept for combining molecular profiling with in vitro drug screening for predictive evaluation of therapeutic vulnerabilities in brain metastasis patients. This approach could advance the use of patient-derived cancer cells in clinical practice and might eventually facilitate decision-making for personalized drug treatment.

Identification of biological signatures of cruciferous vegetable consumption utilizing machine learning-based global untargeted stable isotope traced metabolomics.

In recent years there has been increased interest in identifying biological signatures of food consumption for use as biomarkers. Traditional metabolomics-based biomarker discovery approaches rely on multivariate statistics which cannot differentiate between host- and food-derived compounds, thus novel approaches to biomarker discovery are required to advance the field. To this aim, we have developed a new method that combines global untargeted stable isotope traced metabolomics and a machine learning approach to identify biological signatures of cruciferous vegetable consumption. Participants consumed a single serving of broccoli (n = 16), alfalfa sprouts (n = 16) or collard greens (n = 26) which contained either control unlabeled metabolites, or that were grown in the presence of deuterium-labeled water to intrinsically label metabolites. Mass spectrometry analysis indicated 133 metabolites in broccoli sprouts and 139 metabolites in the alfalfa sprouts were labeled with deuterium isotopes. Urine and plasma were collected and analyzed using untargeted metabolomics on an AB SCIEX TripleTOF 5,600 mass spectrometer. Global untargeted stable isotope tracing was completed using openly available software and a novel random forest machine learning based classifier. Among participants who consumed labeled broccoli sprouts or collard greens, 13 deuterium-incorporated metabolomic features were detected in urine representing 8 urine metabolites. Plasma was analyzed among collard green consumers and 11 labeled features were detected representing 5 plasma metabolites. These deuterium-labeled metabolites represent potential biological signatures of cruciferous vegetables consumption. Isoleucine, indole-3-acetic acid-N-O-glucuronide, dihydrosinapic acid were annotated as labeled compounds but other labeled metabolites could not be annotated. This work presents a novel framework for identifying biological signatures of food consumption for biomarker discovery. Additionally, this work presents novel applications of metabolomics and machine learning in the life sciences.

Comparative Analysis of Mitochondria Surrounding the Intercalated Discs in Heart Diseases-An Ultrastructural Pilot Study.

BACKGROUND: Mitochondria play a crucial role in adapting to fluctuating energy demands, particularly in various heart diseases. This study investigates mitochondrial morphology near intercalated discs in left ventricular (LV) heart tissues, comparing samples from patients with sinus rhythm (SR), atrial fibrillation (AF), dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM). METHODS: Transmission electron microscopy was used to analyze mitochondria within 0-3.5 µm and 3.5-7 µm of intercalated discs in 9 SR, 10 AF, 9 DCM, and 8 ICM patient samples. Parameters included mean size in µm2 and elongation, count, percental mitochondrial area in the measuring frame, and a conglomeration score. RESULTS: AF patients exhibited higher counts of small mitochondria in the LV myocardium, resembling SR. DCM and ICM groups had fewer, larger, and often hydropic mitochondria. Accumulation rates and percental mitochondrial area were similar across groups. Significant positive correlations existed between other defects/size and hydropic mitochondria and between count/area and conglomeration score, while negative correlations between count and size/other defects and between hydropic mitochondria and count could be seen as well. CONCLUSION: Mitochondrial parameters in the LV myocardium of AF patients were similar to those of SR patients, while DCM and ICM displayed distinct changes, including a decrease in number, an increase in size, and compromised mitochondrial morphology. Further research is needed to fully elucidate the pathophysiological role of mitochondrial morphology in different heart diseases, providing deeper insights into potential therapeutic targets and interventions.

Potential biomarkers for multiple sclerosis stage from targeted proteomics and microRNA sequencing.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system. There is a need for new circulating biomarkers for multiple sclerosis, in particular, markers that differentiate multiple sclerosis subtypes (relapsing-remitting, secondary progressive and primary progressive multiple sclerosis), as this can help in making treatment decisions. In this study, we explore two classes of potential multiple sclerosis biomarkers-proteins and microRNAs-circulating in the cerebrospinal fluid and serum. Targeted medium-throughput proteomics (92 proteins) and microRNA sequencing were performed on serum samples collected in a cross-sectional case-control cohort (cohort I, controls n = 30, multiple sclerosis n = 75) and a prospective multiple sclerosis cohort (cohort II, n = 93). For cohort I, we also made these measurements in paired cerebrospinal fluid samples. In the cohort I cerebrospinal fluid, we observed differences between multiple sclerosis and controls for 13 proteins, including some previously described to be markers for multiple sclerosis [e.g. CD27, C-X-C motif chemokine 13 (CXCL13) and interleukin-7 (IL7)]. No microRNAs were significantly differentially expressed between multiple sclerosis and controls in the cerebrospinal fluid. In serum, 10 proteins, including angiopoietin-1 receptor (TIE2), and 16 microRNAs were significantly different between relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis after performing a meta-analysis combining both cohorts. In the prospective part of the study, participants with relapsing-remitting multiple sclerosis were followed for around 3 years, during which time 12 participants converted to secondary progressive multiple sclerosis. In these longitudinally collected serum samples, we observed a peak in granzyme B, A and H proteins around the time of conversion. Single-sample enrichment analysis of serum microRNA profiles revealed that the peak in granzyme B levels around conversion coincides with enrichment for microRNAs that are enriched in CD4+, CD8+ and natural killer cells (e.g. miRNA-150). We identified several proteins and microRNAs in serum that represent potential biomarkers for relapsing-remitting and secondary progressive multiple sclerosis. Conversion to secondary progressive disease is marked by a peak in granzyme B levels and enrichment for immune-related microRNAs. This indicates that specific immune cell-driven processes may contribute to the conversion of relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis.

Cardiac Development and Factors Influencing the Development of Congenital Heart Defects (CHDs): Part I.

The traditional description of cardiac development involves progression from a cardiac crescent to a linear heart tube, which in the phase of transformation into a mature heart forms a cardiac loop and is divided with the septa into individual cavities. Cardiac morphogenesis involves numerous types of cells originating outside the initial cardiac crescent, including neural crest cells, cells of the second heart field origin, and epicardial progenitor cells. The development of the fetal heart and circulatory system is subject to regulatation by both genetic and environmental processes. The etiology for cases with congenital heart defects (CHDs) is largely unknown, but several genetic anomalies, some maternal illnesses, and prenatal exposures to specific therapeutic and non-therapeutic drugs are generally accepted as risk factors. New techniques for studying heart development have revealed many aspects of cardiac morphogenesis that are important in the development of CHDs, in particular transposition of the great arteries.

The Loss of Estradiol by Androgen Deprivation in Prostate Cancer Patients Shows the Importance of Estrogens in Males.

The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical consequences of E2 deficiency in men and discuss the effects of restoration of levels of this reproductive steroid hormone. In men with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT), E2 is suppressed along with testosterone, leading to side effects affecting the quality of life. These include hot flashes, arthralgia, fatigue, mood changes, cognition problems, weight gain, bone loss, and increased risk of cardiovascular disease. Transdermal E2 alone for ADT has shown equivalent testosterone suppression compared to gonadotropin-releasing hormone (GnRH) agonists while also preventing estrogen-deficiency side effects, including hot flashes and bone loss. Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public.

Preparation and evaluation of functional cocoa-free spread alternatives from different sources.

Spread products have an important market share as they have high nutritional value and they are increasingly consumed, especially by children as a source of energy. The purpose of this work was to evaluate the potential use of powdered chickpea, black rice, carob, doum, date seeds, and beetroot to produce novel functional spreadable products as cocoa-free alternatives. Additionally, to avoid the side effects of cocoa-based products and to assess the cocoa replacement effects on the sensory properties, chemical composition, texture analysis, viscosity, antioxidant, peroxide stability, and microbial quality during storage periods were compared to the ones of cocoa spread. Sensory evaluation revealed that most formulated spreads were accepted as chocolate spread alternatives since there was no significant difference in overall acceptability among cocoa, chickpea, black rice, carob, and doum, while date seeds and beetroot spreads were significantly less acceptable. A variation was observed in the proximate chemical analysis of the produced functional spreads, as the alternative spreads had different characteristics to each other in their physicochemical, texture, and rheological properties. Results indicated a wide variation in the total phenolic content (TPC) of the different spread extracts. The highest amount of TPC was obtained for beetroot spread (455.84 mg GAE/100 g) followed by black rice spread (436.08 mg GAE/100 g). The obtained results indicated that the antioxidant activity of different spreads was significantly different (p < .05) while based on their microbiological analysis, they could have a shelf life of up to 9 months. According to the results, chickpea, carob, doum, black rice, date seeds, and beetroot powders could be used for the production of cocoa-free alternatives as they were highly acceptable and they showed antioxidant and antimicrobial activity.

Interference of gastrointestinal barriers with antibiotic susceptibility of foodborne pathogens: an in vitro case study of ciprofloxacin and tetracycline against Salmonella enterica and Listeria monocytogenes.

Minimum inhibitory concentrations (MIC) assays are often questioned for their representativeness. Especially when foodborne pathogens are tested, it is of crucial importance to also consider parameters of the human digestive system. Hence, the current study aimed to assess the inhibitory capacity of two antibiotics, ciprofloxacin and tetracycline, against Salmonella enterica and Listeria monocytogenes, under representative environmental conditions. More specifically, aspects of the harsh environment of the human gastrointestinal tract (GIT) were gradually added to the experimental conditions starting from simple aerobic lab conditions into an in vitro simulation of the GIT. In this way, the effects of parameters including the anoxic environment, physicochemical conditions of the GIT (low gastric pH, digestive enzymes, bile acids) and the gut microbiota were evaluated. The latter was simulated by including a representative consortium of selected gut bacteria species. In this study, the MIC of the two antibiotics against the relevant foodborne pathogens were established, under the previously mentioned environmental conditions. The results of S. enterica highlighted the importance of the anaerobic environment when conducting such studies, since the pathogen thrived under such conditions. Inclusion of physicochemical barriers led to exactly opposite results for S. enterica and L. monocytogenes since the former became more susceptible to ciprofloxacin while the latter showed lower susceptibility towards tetracycline. Finally, the inclusion of gut bacteria had a bactericidal effect against L. monocytogenes even in the absence of antibiotics, while gut bacteria protected S. enterica from the effect of ciprofloxacin.

Protocol for the MS-CEBA study: an observational, prospective cohort study identifying Cognitive, Energetic, Behavioural and Affective (CEBA) profiles in Multiple Sclerosis to guide neuropsychological treatment choice.

BACKGROUND: Neuropsychological symptoms in the Cognitive, Energetic, Behavioural, and Affective (CEBA) domains are common in people with multiple sclerosis (PwMS) and can negatively affect societal participation. The current study aims to investigate whether there are combinations of symptoms in the different CEBA domains that consistently occur together, that is, if there are CEBA profiles that can be identified. If so, this study aims to develop a screening instrument identifying CEBA profiles in PwMS to select the most suitable neuropsychological rehabilitation treatment for a given CEBA profile and consequently improve the societal participation of PwMS. METHODS: This study is an observational, prospective cohort study consisting of 3 phases. Phase 1 focuses on the identification of CEBA profiles in a large sample of PwMS (n = 300). Phase 2 focuses on validating these CEBA profiles through replication of results in a new sample (n = 100) and on the development of the screening instrument. Phase 3 focuses on qualitatively evaluating in a small group of PwMS whether the selected treatment is suitable for the given CEBA profile or whether existing neuropsychological treatments should be adapted to meet the needs of PwMS suffering from symptoms in multiple CEBA domains simultaneously. Primary outcome is the CEBA profile, which will be derived from performance on neuropsychological assessment consisting of tests and questionnaires regarding the CEBA domains using a latent profile analysis. Inclusion criteria include MS diagnosis, sufficient ability in the Dutch language, and an age between 18 and 70 years. DISCUSSION: The results of the current study will contribute to a more comprehensive understanding of the entire spectrum of neuropsychological symptoms in PwMS. Identification of possible CEBA profiles, and accordingly, the development of a screening instrument determining the CEBA profile of PwMS in clinical practice, contributes to the timely referral of PwMS to the most suitable neuropsychological rehabilitation treatment. If necessary, adjustments to existing treatments will be suggested in order to sufficiently meet the needs of PwMS. All of this with the ultimate aim to improve societal participation, and thereby quality of life, of PwMS. TRIAL REGISTRATION: Dutch Central Committee on Research Involving Human Subjects (CCMO) NL83954.042.23; ClinicalTrials.gov NCT06016309.

Type 1 Myocardial Infarction in Patients With Acute Ischemic Stroke.

Importance: Elevated values of high-sensitivity cardiac troponin (hs-cTn) are common in patients with acute ischemic stroke and are associated with poor prognosis. However, diagnostic and therapeutic implications in patients with ischemic stroke remain unclear. Objective: To identify factors indicative of myocardial infarction (MI) in patients with acute ischemic stroke and hs-cTn elevation. The primary hypothesis was that a dynamic change of hs-cTn values (>50% change) in patients with acute ischemic stroke indicates MI. Design, Setting, and Participants: This cross-sectional study was a prospective, observational study with blinded end-point assessment conducted across 26 sites in Germany. Patients were included if they had acute ischemic stroke within 72 hours and either (1) highly elevated hs-cTn values on admission (>52 ng/L) or (2) hs-cTn levels above the upper limit of normal and a greater than 20% change at repeated measurements. Patients were enrolled between August 2018 and October 2020 and had 1 year of follow-up. Statistical analysis was performed between April 2022 and August 2023. Exposure: Standardized electrocardiography, echocardiography, and coronary angiography. Main Outcome and Measures: Diagnosis of MI as adjudicated by an independent end-point committee based on the findings of electrocardiography, echocardiography, and coronary angiography. Results: In total, 254 patients were included. End points were adjudicated in 247 patients (median [IQR] age, 75 [66-82] years; 117 were female [47%] and 130 male [53%]). MI was present in 126 of 247 patients (51%) and classified as type 1 MI in 50 patients (20%). Dynamic change in hs-cTn value was not associated with MI in univariable (32% vs 38%; χ2 P = .30) or adjusted comparison (odds ratio, 1.05; 95% CI, 0.31-3.33). The baseline absolute hs-cTn value was independently associated with type 1 MI. The best cutoffs for predicting type 1 MI were at hs-cTn values 5 to 10 times the upper limit normal. Conclusions and Relevance: This study found that in patients with acute ischemic stroke, a dynamic change in hs-cTn values did not identify MI, underscoring that dynamic changes do not identify the underlying pathophysiological mechanism. In exploratory analyses, very high absolute hs-cTn values were associated with a diagnosis of type 1 MI. Further studies are needed how to best identify patients with stroke who should undergo coronary angiography.