Significant Interindividual Variability Research Articles

Prediction of vancomycin plasma concentration in elderly patients based on multi-algorithm mining combined with population pharmacokinetics

The pharmacokinetics of vancomycin exhibit significant inter-individual variability, particularly among elderly patients. This study aims to develop a predictive model that integrates machine learning with population pharmacokinetics (popPK) to facilitate personalized medication management for this demographic. A retrospective analysis incorporating 33 features, including popPK parameters such as clearance and volume of distribution. A combination of multiple algorithms and Shapley Additive Explanations was utilized for feature selection to identify the most influential factors affecting drug concentrations. The performance of each algorithm with popPK parameters was superior to that without popPK parameters. Our final ensemble model, composed of support vector regression, light gradient boosting machine, and categorical boosting in a 6:3:1 ratio, included 16 optimized features. This model demonstrated superior predictive accuracy compared to models utilizing all features, with testing group metrics including an R2 of 0.656, mean absolute error of 3.458, mean square error of 28.103, absolute accuracy within ± 5 mg/L of 81.82%, and relative accuracy within ± 30% of 76.62%. This study presents a rapid and cost-effective predictive model for estimating vancomycin plasma concentrations in elderly patients. The model offers a valuable tool for clinicians to accurately determine effective plasma concentration ranges and tailor individualized dosing regimens, thereby enhancing therapeutic outcomes and safety.

Chronotropic incompetence predictors in a Cardiac Rehabilitation Program following myocardial infarction

Abstract Background Chronotropic incompetence (CI) has been described in many patients after myocardial infarction (MI) and can negatively affect physical capacity, especially if negative chronotropic therapy (NCT) is prescribed. Prediction of CI after MI could be useful for tailored medical therapy and exercise training prescription. Purpose We aim to predict CI on initial exercise ECG testing (ExECG) in MI patients submitted to a Cardiac Rehabilitation Program (CRP). Methods Patients with ST-segment elevation MI (STEMI) or occlusion MI (OMI) submitted to our CRP were prospectively included. After an initial follow-up phase of clinical stabilization and medical therapy optimization, ExECG (conventional or cardiopulmonary) was performed. Peak VO2 and chronotropic reserve index [(maximum heart rate – resting heart rate) / ([220-age] – resting heart rate)] were measured. Chronotropic incompetence was defined as <80% chronotropic reserve index (≤62% in patients treated with NCT). Pharmacological therapy with NCT was registered in absolute and equivalent doses per bisoprolol 2.5mg units (B2.5EU). The effect of NCT on CI was studied by ANOVA test, and predictors of CI by binary logistic regression analysis. The model was tested by area under the curve (AUC) analysis in receiver operating characteristic curves. A p<0.05 was considered statistically significant. Results The cohort comprised 143 patients, mostly middle-aged (mean 60.3±15.8 years) males (85.3%) with anterior or inferior MI (44.8% and 44.8%, respectively). Mean left ventricular ejection fraction (LVEF) was 52.4±10.6% and 36.4% depicted LVEF<50%. NCT was prescribed in most patients (n=125, 87.4%), and median equivalent dose was 1 [0.5-1] B2.5EU. CI was noted on more than half of the population on initial ExECG (n=75, 52.4%). Higher NCT doses per B2.5EU associated with worse mean chronotropic reserve indexes: 72.8±24.4% in patients without NCT; 71.7±18.7% in patients with 0.5 B2.5EU; 62.8±18.2% in patients with 1 B2.5EU; and 58.7±16.9% in patients with ≥2 B2.5EU (ANOVA p=0.04). On binary logistic regression analysis, only two variables were independent predictors of CI: diabetes mellitus (HR 3.02 [1.26-7.23], p=0.01) and LVEF (0.97 [0.94-0.99] per increased %, p=0.04). However, the predictive power of the model was poor (AUC 0.62 [0.53-0.71], p=0.01). Conclusions Chronotropic incompetence after a MI is associated with lower LVEF, diabetes mellitus, and higher doses of NCT. Although significant interindividual variability exists in chronotropic response in the post-infarction period, these factors could be taken into consideration for tailored prescription (or deprescription), especially in patients who may not derive any prognostic benefit from NCT.Chronotropic incompetence in CRP

Inter-individual differences in muscle damage following a single bout of high-intense whole-body electromyostimulation.

This brief report aimed to characterize inter-individual training responses following a single session of high-intense whole-body electromyostimulation (WB-EMS) using markers of muscle damage over a period of 72 h. Twelve healthy individuals (5 men, 7 women; 32.0 ± 7 years) participated in a single 20-minute high-intensity WB-EMS training session. Markers of muscle damage, creatine kinase (CK) and myoglobin (Mb), were assessed before and immediately after training, as well as at 1.5, 3, 24, 48 and 72 h post-exercise. Lactate levels were determined pre- and post-exercise. Overall, WB-EMS induced significant CK elevations, peaking at 72 h (18.358 ± 21.380 U/L; p < 0.01), and correlating Mb levels peaking at 48 h (1.509 ± 1.394 ng/dl, p < 0.01). Despite significant inter-individual variability in CK levels, both slow (SR) and fast responders (FR) were identified. FR showed significant increases in CK at all time points post WB-EMS (p < 0.05), whereas CK in SR significantly elevated after 48 h. Post-WB-EMS lactate concentration was identified to predict peak CK and Mb levels (r ≥ 0.65, both p < 0.05). High-intensity WB-EMS has the potential to induce severe muscle damage, as indicated by elevated levels of CK and Mb. We identified two distinct groups of individuals, SR and FR, indicating variability in response to WB-EMS. Furthermore, we suggest that individual responses to WB-EMS can be predicted based on post-WB-EMS lactate concentration.

Enlarged brain perivascular spaces correlate with blood plasma osmolality in the healthy population: A longitudinal study

Enlarged perivascular spaces (EPVS) are increasingly recognized as an MRI detectable feature of neuroinflammatory processes and age-related neurodegenerative changes. Understanding perivascular characteristics in healthy individuals is crucial for their applicability as a reference for pathological changes. Limited data exists on the EPVS load and interhemispheric asymmetry in distribution among young healthy subjects. Despite the known impact of hydration on brain morphometric studies, blood plasma osmolality's effect on EPVS remains unexplored.This study investigated the influence of age, total intracranial volume (TIV), and blood plasma osmolality on EPVS characteristics in 59 healthy adults, each undergoing MRI and osmolality assessment twice within 14.8 months (mean ± 4 months). EPVS analysis was conducted in the centrum semiovale using high-resolution automated segmentation, followed by an optimization algorithm to enhance EPVS segmentation accuracy. Linear Mixed Effects model was used for the statistical analysis, which unveiled significant inter-individual variability in EPVS load and inter-hemispheric asymmetry. EPVS volume increased with age, higher TIV and lower blood plasma osmolality levels. Our findings offer valuable insights into EPVS characteristics among the healthy population, establishing a foundation to further explore age-related and pathological changes.

Targeting Calcitriol Metabolism in Acute Vitamin D Toxicity-A Comprehensive Review and Clinical Insight.

High-dose vitamin D supplementation is common in the general population, but unsupervised high-dose supplementation in vitamin D-replete individuals poses a risk of severe toxicity. Susceptibility to vitamin D toxicity shows a significant inter-individual variability that may in part be explained by genetic predispositions (i.e., CYP24A1 polymorphism). The classic manifestation of vitamin D toxicity is hypercalcemia, which may be refractory to conventional therapy. Its causes include the endogenous overaction of 1α-hydroxylase, monogenic alterations affecting vitamin D metabolizing enzymes and exogenous vitamin D intoxication. In this manuscript, we include a literature review of potential pharmacological interventions targeting calcitriol metabolism to treat vitamin D intoxication and present a case of severe, exogenous vitamin D intoxication responding to systemic corticosteroids after the failure of conventional therapy. Systemic glucocorticoids alleviate acute hypercalcemia by inhibiting enteric calcium absorption and increasing the degradation of vitamin D metabolites but may cause adverse effects. Inhibitors of 1α-hydroxylase (keto/fluconazole) and inducers of CYP3A4 (rifampicin) may be considered steroid-sparing alternatives for the treatment of vitamin D intoxication.

Looking for the ideal medication for heart failure with reduced ejection fraction: a narrative review.

The main goals of the pharmacological treatment of Heart failure with reduced ejection fraction (HFrEF) are the reduction of mortality and the prevention of hospitalizations. However, other outcomes such as improvements in cardiac remodeling and clinical status, functional capacity and quality of life, should be taken into account. Also, given the significant inter-individual and intra-individual variability of HF, and the fact that patients usually present with comorbidities, an appropriate treatment for HFrEF should exert a clinical benefit in most patient profiles irrespective of their characteristics or the presence of comorbidities, while providing organ protection beyond the cardiovascular system. The aim of this narrative review is to determine which are the proven effects of the guideline-directed treatments for HFrEF on five key clinical outcomes: cardiovascular mortality and hospitalization due to HF, sudden death, reverse cardiac remodeling, renal protection and evidence in hospitalized patients. Publications that fulfilled the pre-established selection criteria were selected and reviewed. Renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a benefit in terms of mortality and hospitalization rates. ARNI, BB, and MRA have demonstrated a significant positive effect on the incidence of sudden death. ARB, ARNI, BB and SGLT2i have been associated with clear benefits in reverse cardiac remodeling. Additionally, there is consistent evidence of renal protection from ARB, ARNI, and SGLT2i in renal protection and of benefits for hospitalized patients from ARNI and SGLT2i. In conclusion, the combination of drugs that gather most beneficial effects in HFrEF, beyond cardiovascular mortality and hospitalization, would be ideally pursued.

Prevalence of actionable pharmacogenetic variants and high-risk drug prescriptions: A Swiss hospital-based cohort study.

Drug type and dosing recommendation have been designed and optimized based on average response in the general population. Yet, there is significant inter-individual variability in drug response, which results in treatment inefficacy or adverse drug reactions in a subset of patients. This is partly due to genetic factors that typically affect drug metabolism or clearance. To verify the relevance and applicability of international pharmacogenetic guidelines in the Swiss population, we genotyped 1533 patients from a hospital-based biobank who received at least 30 different drugs, as documented in their electronic health record. We then assessed the prevalence of clinically actionable variants in 13 high-risk pharmacogenes. We compared the allele frequencies obtained in the hospital-based cohort with those of a Swiss population-based cohort of 4791 individuals. The prevalence of clinically actionable variants was comparable between the two cohorts, with most study participants (97.3%) carrying at least one actionable pharmacogenetic variant. We then assessed the frequency of high-risk prescriptions due to actionable gene-drug interactions and observed that 31% of patients in the hospital-based cohort were prescribed at least one drug for which they carried a high-risk variant, and for which international guidelines recommend a change of drug or dosage. Our analysis confirms the high prevalence of actionable pharmacogenetic variants in the Swiss population. It also shows that a substantial minority of patients are exposed to drugs for which they carry potentially problematic variants. Implementing a genetically informed approach to drug prescribing could have a positive impact on the quality of healthcare delivery.

Analysis of Circadian Clock Gene Expression in Human Skin Explants

Many aspects of skin biochemistry and physiology are known to vary over the course of the 24-hour day. Traditional approaches to study circadian rhythms in the skin have employed rodents or human subjects, which limit the experimental variables that can be studied. Although explants derived from discarded surgical skin are a commonly used model in the skin biology field, circadian rhythms have yet to be examined exvivo. In this study, using human panniculectomy skin, we used RT-qPCR to monitor the epidermal expression of 4 core circadian clock genes over the course of 1 day exvivo. Although significant interindividual variability in overall gene expression profiles was observed, robust circadian oscillations were observed in many of the genes and individual explants. Comparison of our gene expression data with microarray data from 2 previous human-subject studies involving primarily young adult White males revealed both similarities and differences, including greater distribution in the time of day of peak expression in the skin explants. This increased variability appears to be due in part to the increased age and altered sex distribution of the donated skin. Nonetheless, our results indicate that skin explants offer an additional experimental system for studying circadian skin biology.

The Common Marmoset as a Translational Model for Longitudinal Studies of Cognitive Aging and Individual Vulnerability to Decline.

In humans, cognitive aging is highly variable, with some individuals experiencing decline while others remain stable, and different cognitive domains exhibiting uneven vulnerability to aging. The neural mechanisms driving this intra- and inter-individual variability are not fully understood, making longitudinal studies in translational models essential for elucidating the timelines and processes involved. The common marmoset (Callithrix jacchus), a short-lived nonhuman primate, offers an unprecedented opportunity to conduct longitudinal investigations of aging and age-related disease over a condensed time frame, in a highly translatable animal model. The potential of the marmoset as a model for cognitive aging is indisputable, but a comprehensive cognitive battery tailored for longitudinal aging studies has not yet been developed, applied, or validated. This represents a critical missing piece for evaluating the marmoset as a model and understanding the extent to which marmoset cognitive aging mirrors the patterns found in humans, including whether marmosets have individual variability in their vulnerability to age-related cognitive decline. To address this, we developed a comprehensive touchscreen-based neuropsychological test battery for marmosets (MarmoCog), targeting five cognitive domains: working memory, stimulus-reward association learning, cognitive flexibility, motor speed, and motivation. We tested a large cohort of marmosets, ranging from young adults to geriatrics, over several years. We found significant variability in cognitive aging, with the greatest decline occurring in domains dependent on the prefrontal cortex and hippocampus. Additionally, we observed significant inter-individual variability in vulnerability to age-related cognitive decline: some marmosets declined across multiple domains, others in just one, and some showed no decline at all. This pattern mirrors human cognitive aging, solidifies the marmoset as an advantageous model for age-related cognitive decline, and provides a strong foundation for identifying the neural mechanisms involved.

Precision medicine for obesity: current evidence and insights for personalization of obesity pharmacotherapy.

Obesity is a chronic and complex disease associated with increased morbidity, mortality, and financial burden. It is expected that by 2030 one of two people in the United States will have obesity. The backbone for obesity management continues to be lifestyle interventions, consisting of calorie deficit diets and increased physical activity levels, however, these interventions are often insufficient to achieve sufficient and maintained weight loss. As a result, multiple patients require additional interventions such as antiobesity medications or bariatric interventions in order to achieve clinically significant weight loss and improvement or resolution of obesity-associated comorbidities. Despite the recent advances in the field of obesity pharmacotherapy that have resulted in never-before-seen weight loss outcomes, comorbidity improvement, and even reduction in cardiovascular mortality, there is still a significant interindividual variability in terms of response to antiobesity medications, with a subset of patients not achieving a clinically significant weight loss. Currently, the trial-and-error paradigm for the selection of antiobesity medications results in increased costs and risks for developing side effects, while also reduces engagement in weight management programs for patients with obesity. The implementation of a precision medicine framework to the selection of antiobesity medications might help reduce heterogeneity and optimize weight loss outcomes by identifying unique subsets of patients, or phenotypes, that have a better response to a specific intervention. The detailed study of energy balance regulation holds promise, as actionable behavioral and physiologic traits could help guide antiobesity medication selection based on previous mechanistic studies. Moreover, the rapid advances in genotyping, multi-omics, and big data analysis might hold the key to discover additional signatures or phenotypes that might respond better to a certain intervention and might permit the widespread adoption of a precision medicine approach for obesity management.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P≤ 5 × 10-6). While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

The potential for therapeutic drug monitoring of belatacept and other biologicals in solid organ transplantation.

In solid organ transplantation (SOT), biologicals such as recombinant therapeutic proteins, monoclonal antibodies, fusion proteins and conjugates are increasingly used for immunosuppression, desensitization, ABO (blood group) incompatibility, antibody-mediated rejections and atypical haemolytic uremic syndrome. In this paper, we review the medical evidence available for biologicals used in SOT and the potential for improvement by the application of therapeutic drug monitoring (TDM) and model-informed precision dosing. Biologicals are used for off-label indications within the field of SOT, building on the experience from their use on labelled indications. Dosing is currently mostly standard, and experience vs. effect and toxicity is limited. Pharmacokinetic characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules. Individualization by concentration measurements and modelling has mostly been proof-of-concept or feasibility studies that lack the power to provide evidence for improvement in clinical outcome. For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in pharmacokinetics. Variability in absorption from subcutaneous administration may increase interindividual variability. There is also an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, but trials of adequate size to document the usefulness of TDM and MIPD are scarce. Collaboration within the TDM community seems mandatory to establish studies of sufficient strength to provide evidence for the use of biologicals that are currently used off-label in SOT and furthermore to identify the settings where TDM may be beneficial.

Study of Radiosensitivity and Induction of Radiation Adaptive Response in Peripheral Blood Lymphocytes of Patients with Oncological Diseases Using the Micronuclear Test.

Radiosensitivity to low and medium doses of X-ray radiation and the ability to induce a radiation adaptive response (RAR) of lymphocytes during in vitro irradiation of peripheral blood of patients with cancer were studied. The criterion for cytogenetic damage was the frequency of micronuclei (MN) in cytochalasin-blocked binucleate lymphocytes in culture. It was found that the spontaneous level of cytogenetic damage in the lymphocytes of patients was 2.6 times higher than in healthy volunteers, and there was also significant interindividual variability in values compared to the control cohort. There were no differences in mean values for radiosensitivity to low and medium doses of X-ray between the study groups. There was no correlation between the spontaneous level of MN in lymphocytes and the radiosensitivity of individuals in both groups. RAR was induced with the same frequency and to the same extent in lymphocytes from both patients and healthy individuals.

High Frequency of CYP2C19*3 Heterozygotes Among Patients Under Clopidogrel Treatment in Ouagadougou, Burkina Faso.

&lt;b&gt;Background and Objective:&lt;/b&gt; Despite its widespread use in cardiology, patient's response to clopidogrel exhibits significant interindividual variability, often leading to persistent thromboembolic complications. The hepatic Cytochrome P450 2C19 (CYP2C19) superfamily plays a pivotal role in clopidogrel's conversion to its active form and CYP2C19 polymorphisms significantly contribute to this variability. This study aimed to evaluate the prevalence and impact of the CYP2C19 rs4986893 polymorphism on clopidogrel treatment response. &lt;b&gt;Materials and Methods:&lt;/b&gt; Seventy-three patients with Cardiovascular Diseases (CVD) undergoing clopidogrel antiplatelet therapy for a minimum of six months were recruited from Centre Hospitalier Universitaire Yalgado Ouédraogo (CHU-YO). Sociodemographic data were collected and DNA was extracted from blood samples for CYP2C19 rs4986893 genotyping using PCR-RFLP. &lt;b&gt;Results:&lt;/b&gt; The patient's mean age was 62.56±13.45 years, ranging from 23 to 94 years, with a male-to-female sex ratio of 1.28. Most patients came from the informal sector, primarily of Mossi ethnicity and residing in Ouagadougou. Acute coronary syndromes (ACS) and hypertension were the predominant reasons for consultation, with clopidogrel showing efficacy in 97.3% of cases. While 72.6% had no family history of CVD, hypertension was prevalent among those with familial cardiovascular conditions. Genetic analysis revealed a 65.8% frequency of heterozygotes CYP2C19*1/*3, with no mutant homozygotes CYP2C19*3/*3 detected. The results of the present study underscore a high prevalence of heterozygotes CYP2C19*1/*3 among patients with cardiovascular diseases. &lt;b&gt;Conclusion:&lt;/b&gt; This intermediate metabolic phenotype, along with a good response to clopidogrel, suggests that CYP2C19*1/*3 genotype promotes a favourable response to clopidogrel therapy.

Optimizing vancomycin dosing in pediatrics: a machine learning approach to predict trough concentrations in children under four years of age.

Vancomycin trough concentration is closely associated with clinical efficacy and toxicity. Predicting vancomycin trough concentrations in pediatric patients is challenging due to significant inter-individual variability and rapid physiological changes during maturation. This study aimed to develop a machine learning model to predict vancomycin trough concentrations and determine optimal dosing regimens for pediatric patients < 4years of age using ML algorithms. A single-center retrospective observational study was conducted from January 2017 to March 2020. Pediatric patients who received intravenous vancomycin and underwent therapeutic drug monitoring were enrolled. Seven ML models [linear regression, gradient boosted decision trees, support vector machine, decision tree, random forest, Bagging, and extreme gradient boosting (XGBoost)] were developed using 31 variables. Performance metrics including R-squared (R2), mean square error (MSE), root mean square error (RMSE), and mean absolute error (MAE) were compared, and important features were ranked. The study included 120 eligible trough concentration measurements from 112 patients. Of these, 84 measurements were used for training and 36 for testing. Among the seven algorithms tested, XGBoost showed the best performance, with a low prediction error and high goodness of fit (MAE = 2.55, RMSE = 4.13, MSE = 17.12, and R2 = 0.59). Blood urea nitrogen, serum creatinine, and creatinine clearance rate were identified as the most important predictors of vancomycin trough concentration. An XGBoost ML model was developed to predict vancomycin trough concentrations and aid in drug treatment predictions as a decision-support technology.

Symptoms of a feather flock together? An exploratory secondary dynamic time warp analysis of 11 single case time series of suicidal ideation and related symptoms

Suicidal ideation fluctuates over time, as does its related risk factors. Little is known about the difference or similarities of the temporal patterns. The current exploratory secondary analysis examines which risk symptoms have similar time dynamics using a mathematical algorithm called dynamic time warping (DTW). Ecological momentary assessment data was used of 11 depressed psychiatric outpatients with suicidal ideation who answered three daytime surveys at semi-random sampling points for a period of three to six months. Patients with 45 assessments or more were included. Results revealed significant inter-individual variability in symptom dynamics and clustering, with certain symptoms often clustering due to similar temporal patterns, notably feeling sad, hopelessness, feeling stuck, and worrying.The directed network analyses shed light on the temporal order, highlighting entrapment and worrying as symptoms strongly related to suicide ideation. Still, all patients also showed unique directed networks. While for some patients changes in entrapment directly preceded change in suicide ideation, the reverse temporal ordering was also found. Relatedly, within some patients, perceived burdensomeness played a pivotal role, whereas in others it was unconnected to other symptoms. The study underscores the individualized nature of symptom dynamics and challenges linear models of progression, advocating for personalized treatment strategies.

Microplastic presence in dog and human testis and its potential association with sperm count and weights of testis and epididymis.

The ubiquitous existence of microplastics and nanoplastics raises concerns about their potential impact on the human reproductive system. Limited data exists on microplastics within the human reproductive system and their potential consequences on sperm quality. Our objectives were to quantify and characterize the prevalence and composition of microplastics within both canine and human testes and investigate potential associations with the sperm count, and weights of testis and epididymis. Using advanced sensitive pyrolysis-gas chromatography/mass spectrometry, we quantified 12 types of microplastics within 47 canine and 23 human testes. Data on reproductive organ weights, and sperm count in dogs were collected. Statistical analyses, including descriptive analysis, correlational analysis, and multivariate linear regression analyses were applied to investigate the association of microplastics with reproductive functions. Our study revealed the presence of microplastics in all canine and human testes, with significant inter-individual variability. Mean total microplastic levels were 122.63 µg/g in dogs and 328.44 µg/g in humans. Both humans and canines exhibit relatively similar proportions of the major polymer types, with PE being dominant. Furthermore, a negative correlation between specific polymers such as PVC and PET and the normalized weight of the testis was observed. These findings highlight the pervasive presence of microplastics in the male reproductive system in both canine and human testes, with potential consequences on male fertility.

Past, Present, and Future of Noninvasive Tests to Assess Gluten Exposure, Celiac Disease Activity, and End-Organ Damage

Although many biomarkers have been proposed and several are in widespread clinical use, there is no single readout or combination of readouts that correlates tightly with gluten exposure, disease activity or end-organ damage in treated celiac disease patients. Challenges to developing and evaluating better biomarkers include significant interindividual variability related to immune amplification of gluten exposure and how effects of immune activation are manifest. Furthermore, the current “gold standard” for assessment of end-organ damage, small intestinal biopsy, is itself highly imperfect, such that a marker that is actually a better reflection of the “ground truth” may indeed appear to perform poorly. The goal of this review is to review past and present efforts to establish robust non-invasive tools for monitoring treated celiac disease patients and to highlight emerging tools that may prove to be useful in clinical practice.

Population-level insights into temporal interference for focused deep brain neuromodulation.

The ability to stimulate deep brain regions in a focal manner brings new opportunities for treating brain disorders. Temporal interference (TI) stimulation has been suggested as a method to achieve focused stimulation in deep brain targets. Individual-level knowledge of the interferential currents has permitted personalizing TI montage via subject-specific digital human head models, facilitating the estimation of interferential electric currents in the brain. While this individual approach offers a high degree of personalization, the significant intra-and inter-individual variability among specific head models poses challenges when comparing electric-field doses. Furthermore, MRI acquisition to develop a personalized head model, followed by precise methods for placing the optimized electrode positions, is complex and not always available in various clinical settings. Instead, the registration of individual electric fields into brain templates has offered insights into population-level effects and enabled montage optimization using common scalp landmarks. However, population-level knowledge of the interferential currents remains scarce. This work aimed to investigate the effectiveness of targeting deep brain areas using TI in different populations. The results showed a trade-off between deep stimulation and unwanted cortical neuromodulation, which is target-dependent at the group level. A consistent modulated electric field appeared in the deep brain target when the same montage was applied in different populations. However, the performance in terms of focality and variability varied when the same montage was used among populations. Also, group-level TI exhibited greater focality than tACS, reducing unwanted neuromodulation volume in the cortical part by at least 1.5 times, albeit with higher variability. These results provide valuable population-level insights when considering TI montage selection.

The influence of sentence focus on mental simulation: A possible cause of ACE instability.

Recent studies have revealed the instability of the action-sentence compatibility effect (ACE). The current study was designed to demonstrate the hypothesis that the instability of the ACE may be attributed to the instability of focused information in a sentence. A pilot study indicated that the focused information of sentences was relatively stable in the sentence-picture verification task but exhibited significant interindividual variability in the action-sentence compatibility paradigm in previous studies. Experiments 1 and 2 examined the effect of sentence focus on the shape match effect and the ACE by manipulating the focused information of sentences using the focus marker word "" (is). Experiment 1 found that the shape match effect occurred in the original sentence, while it disappeared when the word "" (is) was used to make an object noun no longer the focus of a sentence. Experiment 2 failed to observe the ACE regardless of whether the sentence focus was on the action information. Experiment 3 modified the focus manipulation to observe its impact on the ACE using different fonts and underlines to highlight the focused information. The results indicated that the ACE only occurred when the action information was the sentence focus. These findings suggest that sentence focus influences mental simulation, and the instability of the ACE is likely to be associated with the instability of sentence focus in previous studies. This outcome highlights the crucial role of identifying specific information as the critical element expressed in the current linguistic context for successful simulation.