Significant Interindividual Variability Research Articles

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 (Py-GC/MS), 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.

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.

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.

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.

3D anatomy of the supraorbital and greater occipital nerve trajectories.

This research aims to enhance understanding of the anatomy of the supraorbital nerve (SON) and greater occipital nerve (GON), focusing on their exit points, distal trajectories, and variability, utilizing a novel 3D representation. Ten cadaveric specimens underwent meticulous dissection, and 3D landmarks were registered. Models were generated from CT scans, and a custom 3D method was employed to visualize nerve trajectories. Measurements, including lengths and distances, were obtained for the SON and GON. The SON exhibited varied exit points, with the lateral branches being the longest. The GON showed distinct branching patterns, which are described relative to various anatomical reference points and planes. No systematic left-right differences were observed for either nerve. 3D analysis revealed significant interindividual variability in nerve trajectories. The closest approximation between the SON and GON occurred between lateral branches. The study introduces a novel 3D methodology for analyzing the SON and GON, highlighting considerable anatomical variation. Understanding this variability is crucial for clinical applications and tools targeting the skull innervation. The findings serve as a valuable reference for future research, emphasizing the necessity for personalized approaches in innervation-related interventions.

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.

Therapeutic drug monitoring of imatinib in patients with chronic myeloid leukaemia: Experience from Oran HUE

Imatinib, a first-line treatment for chronic myelogenous leukemia, presents significant interindividual pharmacokinetic variability. The correlation between the plasma exposure of Imatinib and its pharmacological effects makes this drug a good candidate for pharmacological therapeutic monitoring in addition to the usual monitoring tests. We introduced monitoring of Imatinib in 27 patients suffering from chronic myelogenous leukemia. According to the dosage results, dosage adaptation recommendations were proposed to clinicians in patients outside the targeted therapeutic range. The goal was to achieve an optimal response to Imatinib, prevent its adverse effects and improve adherence to treatment.

Second Wave, Late-Stage Neuroinflammation in Cleared Brains of Aged 5xFAD Alzheimer’s Mice Detected by Macrolaser Light Sheet Microscopy Imaging

This study leverages the innovative imaging capabilities of macrolaser light-sheet microscopy to elucidate the 3D spatial visualization of AD-associated neuropathologic networks in the transparent brains of 44-week-old 5xFAD mice. Brain samples from ten AD and seven control mice were prepared through a hydrophilic tissue-clearing pipeline and immunostained with thioflavin S (β-amyloid), anti-CD11b antibody (microglia), and anti-ACSA-2 antibody (astrocytes). The 5xFAD group exhibited significantly higher average total surface volumes of β-amyloid accumulation than the control group (AD, 898,634,368 µm3 [383,355,488–1,324,986,752]; control, 33,320,178 µm3 [11,156,785–65,390,988], p = 0.0006). Within the AD group, there was significant interindividual and interindividual variability concerning the number and surface volume of individual amyloid particles throughout the entire brain. In the context of neuroinflammation, the 5xFAD group showed significantly higher average total surface volumes of anti-ACSA-2-labeled astrocytes (AD, 59,064,360 µm3 [27,815,500–222,619,280]; control, 20,272,722 µm3 [9,317,288–27,223,352], p = 0.0047) and anti-CD11b labeled microglia (AD, 51,210,100 µm3 [15,309,118–135,532,144]; control, 23,461,593 µm3 [14,499,170–27,924,110], p = 0.0162) than the control group. Contrary to the long-standing finding that early-stage neuroinflammation precedes the subsequent later-stage of neurodegeneration, our data reveal that the second wave, late-stage active neuroinflammation persists in the aged AD brains, even as they continue to show signs of ongoing neurodegeneration and significant amyloid accumulation.

Determination of Treosulfan and Fludarabine in Plasma by Turbulent Flow Liquid Chromatography-Tandem Mass Spectrometry (TFLC-MS/MS).

Treosulfan is a structural analog of the alkylating agent busulfan which has been shown in clinical trials to exhibit comparable myeloablative activity while causing fewer serious side effects. Treosulfan is currently being considered for FDA approval in combination with fludarabine, one of the most commonly used myeloablative agents, as a conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Because plasma concentrations of both treosulfan and fludarabine exhibit significant interindividual variability, therapeutic drug monitoring (TDM) is indicated to ensure dosages are administered that maximize efficacy while minimizing toxicity. In this chapter, we describe a rapid, accurate assay to detect treosulfan and fludarabine simultaneously in human plasma using turbulent flow liquid chromatography coupled to electrospray ionization tandem mass spectrometry (TFLC-ESI-MS/MS). Treosulfan and fludarabine are extracted from only 100μL of acidified plasma via protein precipitation with methanol containing isotope-labeled internal standards. The extract is injected into the TFLC-ESI-MS/MS system, and the analytes are quantified using multiple reaction monitoring and a six-point calibration curve.

Pharmacokinetic Consideration of Venetoclax in Acute Myeloid Leukemia Patients: A Potential Candidate for TDM? A Short Communication.

Venetoclax (VNX)-based regimens have demonstrated significantly favorable outcomes in patients with acute myeloid leukemia (AML) and are now becoming the standard treatment. Tyrosine kinase inhibitors are administered at a fixed dose, irrespective of body surface area or weight. For such orally targeted therapies, real-world data have highlighted a larger pharmacokinetic (PK) interindividual variability (IIV) than expected. Even if VNX PKs have been well characterized and described in the literature, only 1 clinical trial-based PK study has been conducted in patients with AML. This study aimed to evaluate the PK of VNX in AML patients. We retrospectively analyzed all patients treated with a combination of VNX-azacitidine between January and July 2022 at our center, using at least 1 available VNX blood sample. Based on a previously published population PK model, individual PK parameters were estimated to evaluate the exposure and IIV. and Discussion. Twenty patients received VNX in combination with azacitidine, according to the PK data. A total of 93 plasma concentrations were collected. The dose of VNX was 400 mg, except in 7 patients who received concomitant posaconazole (VNX 70 mg). The patients' weight ranged from 49 kg to 108 kg (mean = 78 kg). Mean individual clearance was 13.5 ± 9.4 L/h with mean individual daily area under the concentration-time curves of 35.8 mg.h/L with significant IIV (coefficient of variation = 41.1%). Ten patients were still alive (8 in complete response), but all experienced at least 1 hematological toxicity of grade ≥ 3. Based on the observed large PK variability in the data from our real-world AML patients, the risk of drug interactions and the recommended fixed-dosage regimen of VNX therapeutic drug monitoring may be useful.

Pharmacogenomics of Dementia: Personalizing the Treatment of Cognitive and Neuropsychiatric Symptoms.

Dementia is a syndrome of global and progressive deterioration of cognitive skills, especially memory, learning, abstract thinking, and orientation, usually affecting the elderly. The most common forms are Alzheimer's disease, vascular dementia, and other (frontotemporal, Lewy body disease) dementias. The etiology of these multifactorial disorders involves complex interactions of various environmental and (epi)genetic factors and requires multiple forms of pharmacological intervention, including anti-dementia drugs for cognitive impairment, antidepressants, antipsychotics, anxiolytics and sedatives for behavioral and psychological symptoms of dementia, and other drugs for comorbid disorders. The pharmacotherapy of dementia patients has been characterized by a significant interindividual variability in drug response and the development of adverse drug effects. The therapeutic response to currently available drugs is partially effective in only some individuals, with side effects, drug interactions, intolerance, and non-compliance occurring in the majority of dementia patients. Therefore, understanding the genetic basis of a patient's response to pharmacotherapy might help clinicians select the most effective treatment for dementia while minimizing the likelihood of adverse reactions and drug interactions. Recent advances in pharmacogenomics may contribute to the individualization and optimization of dementia pharmacotherapy by increasing its efficacy and safety via a prediction of clinical outcomes. Thus, it can significantly improve the quality of life in dementia patients.

Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children (MIS-C).

Multisystem inflammatory syndrome in children (MIS-C) is a rare but life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes pediatric COVID-19 (pCOVID-19). The relationship of the systemic tissue injury to the pathophysiology of MIS-C is poorly defined. We leveraged the high sensitivity of epigenomic analyses of plasma cell-free DNA (cfDNA) and plasma cytokine measurements to identify the spectrum of tissue injury and glean mechanistic insights. Compared to pediatric healthy controls (pHC) and pCOVID-19, MIS-C patients had higher levels of cfDNA primarily derived from innate immune cells, megakaryocyte-erythroid precursor cells, and non-hematopoietic tissues such as hepatocytes, cardiac myocytes, and kidney cells. Non-hematopoietic tissue cfDNA levels demonstrated significant inter-individual variability, consistent with the heterogenous clinical presentation of MIS-C. In contrast, adaptive immune cell-derived cfDNA levels were comparable in MIS-C and pCOVID-19 patients. Indeed, the innate immune cells cfDNA in MIS-C correlated with levels of innate immune inflammatory cytokines and non-hematopoietic tissue-derived cfDNA, suggesting a primarily innate immunity-mediated response to account for multi-system pathology. These data provide insight into the pathogenesis of MIS-C and support the value of cfDNA as a sensitive biomarker to map tissue injury in MIS-C and likely other multi-organ inflammatory conditions.

Poor sleep hygiene practices are associated with a higher increase in sleep problems during the COVID-19 pandemic: A latent change score model.

The Coronavirus 2019 (COVID-19) pandemic significantly influenced physical and mental health worldwide. The present study aimed to investigate changes in sleep problems across three waves of the COVID-19 pandemic, and to identify potential predictors of the inter-individual variability around these changes, with a particular focus on the role of detrimental sleep hygiene practices. A total of 352 participants completed an online survey of self-report questionnaires at three different waves of the COVID-19 pandemic: T1 (Spring 2020); T2 (Autumn-Winter 2020); and T3 (Spring 2021). The questionnaires collected information on socio-demographic and COVID-19-related variables, psychological distress (i.e. the Depression Anxiety Stress Scale-21), sleep hygiene (i.e. the Sleep Hygiene Index) and sleep problems (i.e. the Medical Outcomes Study-Sleep Scale). Latent change score modelling revealed an average increase in sleep problems between T1 and T2 with significant inter-individual variability. No substantial changes were observed on average between T2 and T3. Notably, poorer sleep hygiene practices were associated with a more pronounced increase in sleep problems between T1 and T2 (β = 0.191, p = 0.013), even after controlling for relevant confounders such as demographic factors, COVID-19-related information and psychological distress. These findings expand on previous research regarding the detrimental effects of the pandemic on mental health, suggesting that interventions targeting sleep hygiene practices may be beneficial for mitigating its negative impact on sleep disruptions.

A comprehensive review of machine learning algorithms and their application in geriatric medicine: present and future.

The increasing access to health data worldwide is driving a resurgence in machine learning research, including data-hungry deep learning algorithms. More computationally efficient algorithms now offer unique opportunities to enhance diagnosis, risk stratification, and individualised approaches to patient management. Such opportunities are particularly relevant for the management of older patients, a group that is characterised by complex multimorbidity patterns and significant interindividual variability in homeostatic capacity, organ function, and response to treatment. Clinical tools that utilise machine learning algorithms to determine the optimal choice of treatment are slowly gaining the necessary approval from governing bodies and being implemented into healthcare, with significant implications for virtually all medical disciplines during the next phase of digital medicine. Beyond obtaining regulatory approval, a crucial element in implementing these tools is the trust and support of the people that use them. In this context, an increased understanding by clinicians of artificial intelligence and machine learning algorithms provides an appreciation of the possible benefits, risks, and uncertainties, and improves the chances for successful adoption. This review provides a broad taxonomy of machine learning algorithms, followed by a more detailed description of each algorithm class, their purpose and capabilities, and examples of their applications, particularly in geriatric medicine. Additional focus is given on the clinical implications and challenges involved in relying on devices with reduced interpretability and the progress made in counteracting the latter via the development of explainable machine learning.

Population pharmacokinetics of oxcarbazepine active metabolite in Chinese children with epilepsy.

Oxcarbazepine (OXC) is an antiepileptic drug whose efficacy is largely attributed to its monohydroxy derivative metabolite (MHD). Nevertheless, there exists significant inter-individual variability in both the pharmacokinetics and therapeutic response of this drug. The objective of this study is to explore the impact of patients' characteristics and genetic variants on MHD clearance in a population pharmacokinetic (PPK) model of Chinese pediatric patients with epilepsy. The PPK model was developed using a nonlinear mixed effects modeling method based on 231 MHD plasma concentrations obtained from 185 children with epilepsy. The one-compartment model and combined residual model were established to describe the pharmacokinetics of MHD. Forward addition and backward elimination were employed to evaluate the impact of covariates on the model parameters. The model was evaluated using goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. In the two final PPK models, age, estimated glomerular filtration rate (eGFR), and a combined genotype of six variants (rs1045642, rs2032582, rs7668282, rs2396185, rs2304016, rs1128503) were found to significantly reduce inter-individual variability for MHD clearance. The inter-individual clearance equals to 1.38 × (Age/4.74)0.29 × (eGFR/128.66)0.25 × eθABCB-UGT-SCN-INSR for genetic variants included model and 1.30 × (Age/4.74)0.30 × (eGFR/128.66)0.23 for model without genetic variants. The precision of all parameters was deemed acceptable, and the model exhibited good predictability while remaining stable and effective. Conclusion: Age, eGFR, and genotype may play a significant role in MHD clearance in children with epilepsy. The developed PPK models hold potential utility in facilitating oxcarbazepine dose adjustment in pediatric patients. What is Known: • The adjustment of the oxcarbazepine regimen remains difficult due to the considerable inter- and intra-individual variability of oxcarbazepine pharmacokinetics. • Body weight and co-administration with enzyme-inducing antiepileptic drugs emerge as the most influential factors contributing to the pharmacokinetics of MHD. What is New: • A positive correlation was observed between eGFR and the clearance of MHD in pediatric patients with epilepsy. • We explored the influence of genetic polymorphisms on MHD clearance and identified a combined genotype (ABCB-UGT-SCN-INSR) that exhibited a significant association with MHD concentration.

Relationship of <i>SLCO1B1</i> and <i>ABCB1</i> gene polymorphisms with clinical variants of methotrexate toxicity in pediatric acute lymphoblastic leukemia therapy

Background. Despite the significant clinical efficacy of current treatment protocols for acute lymphoblastic leukemia (ALL) in children, high-dose methotrexate demonstrates significant interindividual variability in drug toxicity and disease outcomes due to polymorphisms of drug transporter genes and genes responsible for cytostatic metabolism, which makes pharmacogenetic studies increasingly relevant.Aim. To evaluate the association of ABCB1 (C3435T rs1045642, rs1128503, rs2032582, rs4148738), SLCO1B1 T521C rs4149056 gene polymorphisms with the main types of methotrexate toxicity and the onset of clinical events (death, recurrence, progression) during the treatment of childhood ALL.Materials and methods. The study enrolled 103 patients diagnosed with ALL who received therapy according to BFM group protocols (2002/2009), using high-dose (2000 and 5000 mg/m2) methotrexate. Laboratory methods using NCI toxicity scales (CTCAE v5.0 2018) were used to assess adverse reactions. Real-time polymerase chain reaction method was used to study ABCB1 and SLCO1B1 gene polymorphisms. The study material was peripheral blood. Material was sampled once, regardless of the duration of methotrexate therapy. SPSS Statistics 21.0 software was used for statistical processing of the results. Analysis of associations was performed using the χ2 criterion and Fisher’s exact test.Results. Development of infectious complications, oropharyngeal mucositis, delayed MTX elimination, events were significantly associated with polymorphisms of the studied genes: SLCO1B1 T521C rs4149056, ABCB1 rs4148738, ABCB1 rs1128503, which correlates with the data of world scientific literature.Conclusion. Determination of polymorphisms of genes responsible for the transport and metabolism of methotrexate is a promising and dynamically developing area of clinical oncology.

Role of Genetic Polymorphisms in the Efficacy and Adverse Effects of Metformin in the Treatment of Type 2 Diabetes Mellitus

Role of Genetic Polymorphisms in the Efficacy and Adverse Effects of Metformin in the Treatment of Type 2 Diabetes Mellitus

Pharmacogenomics and the Concept of Personalized Medicine for the Management of Hypertension

Pharmacogenomics and the Concept of Personalized Medicine for the Management of Hypertension

Long-term monitoring of clodronate in equine hair using liquid chromatography-tandem mass spectrometry

Given the potential for long-term inhibition of bone remodeling/healing and detrimental effects to horses in training, bisphosphonates are tightly regulated in horseracing. Hair has proven to be an effective matrix for detection of drug administration to horses and has been particularly effective in detecting drugs for a long period of time post administration. Thus, hair may prove to be a useful matrix for detection of administration of this class of drugs. The objective of the current study was to develop an assay and assess the usefulness of hair as a matrix for long-term detection of clodronate to horses. Seven horses received a single intramuscular administration of 1.8 mg/kg clodronate. Hair samples were collected prior to and up to 6 months post administration. A liquid chromatography-tandem mass spectrometry method was developed and concentrations of clodronate measured in hair samples. The drug was first detected on day 7 in 4/7 horses, and on days 14, 28 and 35 in the remaining three horses. In 4/7 horses, clodronate was still detectable 6 months post administration. Results of this study demonstrate that, although there was significant inter-individual variability in detection times (63 to 180 days) and several intermediate times where the drug could not be detected but was subsequently detected in later timepoints, clodronate administration was detectable in hair for a prolonged period in most of the horses (4/7) studied.

A time-course investigation of the human urinary excretion of the hydrogen sulfide biomarker trimethylsulfonium

Hydrogen sulfide is a toxic gas but also recognized as an endogenously produced metabolite in humans playing key roles. We previously identified trimethylsulfonium, which can be a methylation product of hydrogen sulfide but the stability in the production of trimethylsulfonium has not been investigated. In the present work, the intra- and inter-individual variability in the excretion of trimethylsulfonium over 2 months in a group of healthy volunteers was investigated. Urinary levels of trimethylsulfonium (mean: 56 nM, 95% CI: 48–68 nM) were > 100-fold lower than the conventional hydrogen sulfide biomarker thiosulfate (13 µM, 12–15 µM) and the precursor for endogenous hydrogen sulfide production cystine (47 µM, 44–50 µM). There was no correlation between urinary trimethylsulfonium and thiosulfate. Higher intra-individual variability in the excretion of trimethylsulfonium (generally 2-8 fold) than that for cystine (generally 2-3 fold) was found. Trimethylsulfonium displayed significant inter-individual variability with two concentration clusters at 117 nM (97−141) and 27 nM (22−34). In conclusion, the observed inter- and intra-individual variability must be considered when using urinary trimethylsulfonium as a biomarker.