Interindividual Variations Research Articles

Evaluation of species thermal sensitivity with individual-based physiological performance

Ignoring intraspecific variations can prevent us from accurately assessing species' thermal sensitivity to global warming. Individual-based physiological performance provides a feasible solution to depict species' thermal sensitivity using a bottom-up approach. We measured the cardiac performance of intertidal bivalves (1159 individuals from multiple populations of six bivalves), determined the upper thermal limit of each individual, calculated the proportions of individuals suffering sublethal/lethal heat stress, and mapped sensitive regions to high temperatures. Results showed that high inter-individual variations of physiological performance existed in levels of populations and species, and species’ thermal sensitivity was positively related to the intraspecific variations of heat tolerance. This bottom-up approach scaled up from individual, population to species emphasizes the importance of individual-based physiology performance in assessing thermal sensitivity across different hierarchical levels and enables better evaluating and forecasting of species responses to global warming.

Impact of Hypoxia-Hyperoxia Exposures on Cardiometabolic Risk Factors and TMAO Levels in Patients with Metabolic Syndrome.

Along with the known risk factors of cardiovascular diseases (CVDs) constituting metabolic syndrome (MS), the gut microbiome and some of its metabolites, in particular trimethylamine-N-oxide (TMAO), are actively discussed. A prolonged stay under natural hypoxic conditions significantly and multi-directionally changes the ratio of gut microbiome strains and their metabolites in feces and blood, which is the basis for using hypoxia preconditioning for targeted effects on potential risk factors of CVD. A prospective randomized study included 65 patients (32 females) with MS and optimal medical therapy. Thirty-three patients underwent a course of 15 intermittent hypoxic-hyperoxic exposures (IHHE group). The other 32 patients underwent sham procedures (placebo group). Before and after the IHHE course, patients underwent liver elastometry, biochemical blood tests, and blood and fecal sampling for TMAO analysis (tandem mass spectrometry). No significant dynamics of TMAO were detected in both the IHHE and sham groups. In the subgroup of IHHE patients with baseline TMAO values above the reference (TMAO ≥ 5 μmol/l), there was a significant reduction in TMAO plasma levels. But the degree of reduction in total cholesterol (TCh), low-density lipoprotein (LDL), and regression of liver steatosis index was more pronounced in patients with initially normal TMAO values. Despite significant interindividual variations, in the subgroup of IHHE patients with MS and high baseline TMAO values, there were more significant reductions in cardiometabolic and hepatic indicators of MS than in controls. More research is needed to objectify the prognostic role of TMAO and the possibilities of its correction using hypoxia adaptation techniques.

NKG2A discriminates natural killer cells with a suppressed phenotype in pediatric acute leukemia.

Natural killer (NK) cells are important for early tumor immune surveillance. In patients with hematological cancers, NK cells are generally functional deficient and display dysregulations in their receptor repertoires. Acute leukemia is the most common cancer in children, and we here performed a comparative phenotypic profiling of NK cells from B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients to identify aberrant NK cell phenotypes. NK cell phenotypes, maturation, and function were analyzed in matched bone marrow and blood NK cells from BCP-ALL patients at diagnosis, during treatment, and at end of treatment and compared with age-matched pediatric control subjects. Expression of several markers were skewed in patients, but with large interindividual variations. Undertaking a multiparameter approach, we found that high expression levels of NKG2A was the single predominant marker distinguishing NK cells in BCP-ALL patients compared with healthy control subjects. Moreover, naïve CD57-NKG2A NK cells dominated in BCP-ALL patients at diagnosis. Further, we found dysregulated expression of the activating receptor DNAM-1 in resident bone marrow CXCR6+ NK cells. CXCR6+ NK cells lacking DNAM-1 expressed NKG2A and had a tendency for lower degranulation activity. In conclusion, high expression of NKG2A dominates NK cell phenotypes from pediatric BCP-ALL patients, indicating that NKG2A could be targeted in therapies for this patient group.

Preferred temperature in the warmth of cities: Body size, sex and development stage matter more than urban climate in a ground-dwelling spider

Most ectotherms rely on behavioural thermoregulation to maintain body temperatures close to their physiological optimum. Hence, ectotherms can drastically limit their exposure to thermal extremes by selecting a narrower range of temperatures, which includes their preferred temperature (Tpref). Despite evidence that behavioural thermoregulation can be adjusted by phenotypic plasticity or constrained by natural selection, intraspecific Tpref variations across environmental gradients remain overlooked as compared to other thermal traits like thermal tolerance. Here, we analyzed Tpref variation of spider populations found along a gradient of urban heat island (UHI) which displays large thermal variations over small distances. We measured two components of the thermal preference, namely the mean Tpref and the Tpref range (i.e., standard deviation) in 557 field-collected individuals of a common ground-dwelling spider (Pardosa saltans, Lycosidae) using a laboratory thermal gradient. We determined if Tpref values differed among ten populations from contrasting thermal zones. We showed that endogenous factors such as body size or sex primarily determine both mean Tpref and Tpref range. The Tpref range was also linked to the UHI intensity to a lesser extent, yet only in juveniles. The absence of relationship between Tpref metrics and UHI in adult spiders suggests a Bogert effect according to which the ability of individuals to detect and exploit optimal microclimates weakens the selection pressure of temperatures (here driven by UHI) on their thermal physiology. Alternatively, this lack of relationship could also indicate that temperature patterns occurring at the scale of the spiders' micro-habitat differ from measured ones. This study shows the importance of considering both inter-individual and inter-population variations of the Tpref range when conducting Tpref experiments, and supports Tpref range as being a relevant measure to inform on the strength of behavioural thermoregulation in a given population.

Unicorn, Hare, or Tortoise? Using Machine Learning to Predict Working Memory Training Performance.

People differ considerably in the extent to which they benefit from working memory (WM) training. Although there is increasing research focusing on individual differences associated with WM training outcomes, we still lack an understanding of which specific individual differences, and in what combination, contribute to inter-individual variations in training trajectories. In the current study, 568 undergraduates completed one of several N-back intervention variants over the course of two weeks. Participants' training trajectories were clustered into three distinct training patterns (high performers, intermediate performers, and low performers). We applied machine-learning algorithms to train a binary tree model to predict individuals' training patterns relying on several individual difference variables that have been identified as relevant in previous literature. These individual difference variables included pre-existing cognitive abilities, personality characteristics, motivational factors, video game experience, health status, bilingualism, and socioeconomic status. We found that our classification model showed good predictive power in distinguishing between high performers and relatively lower performers. Furthermore, we found that openness and pre-existing WM capacity to be the two most important factors in distinguishing between high and low performers. However, among low performers, openness and video game background were the most significant predictors of their learning persistence. In conclusion, it is possible to predict individual training performance using participant characteristics before training, which could inform the development of personalized interventions.

Depicting the anatomy of the gyral white matter: ubi sumus? quo vadimus?

Abstract A cerebral gyrus is made up of an external layer of folded cortex and an inner core of white matter. The architecture of the core has specific features that make it distinct from the white matter of the deep brain regions. Limited externally by the grey matter that covers the top of the gyrus and the neighbouring sulci, this gyral white matter is made up of a mix of fibre populations with multiple directions and destinations. The presence of densely packed fibres with multiple crossings, the proximity to the cortex and the existence of inter-regional and inter-individual variations make the task of depicting this microanatomy extremely challenging. The topic is, however, of paramount relevance for both fundamental and applied neurosciences. This fibre colocalization is crucial for the functional role of each cerebral region and is key to clinical manifestations in cases of parenchymal damage. As track tracing, imaging and dissection are based on different biological or physical principles, it is natural for their results to sometimes be different, but they are often complementary. As the amount of available information increases, it becomes fragmented due to the multiplicity of methods, target phenomena and studied species. In this scoping review, we present the key concepts and map the primary sources of evidence regarding identifying the fibre pathways that compose the gyral white matter, enabling the discussion of avenues for future research. The general pattern in which these pathways are distributed in the gyral white matter was detailed, and the main variations as a function of brain topography were explained and illustrated with typical examples.

Dynamic Instrumental and Sensory Methods Used to Link Aroma Release and Aroma Perception: A Review.

Perception of flavor is a dynamic process during which the concentration of aroma molecules at the olfactory epithelium varies with time as they are released progressively from the food in the mouth during consumption. The release kinetics depends on the food matrix itself but also on food oral processing, such as mastication behavior and food bolus formation with saliva, for which huge inter-individual variations exist due to physiological differences. Sensory methods such as time intensity (TI) or the more-recent methods temporal dominance of sensations (TDS) and temporal check-all-that-apply (TCATA) are used to account for the dynamic and time-related aspects of flavor perception. Direct injection mass spectrometry (DIMS) techniques that measure in real time aroma compounds directly in the nose (nosespace), aimed at obtaining data that reflect the pattern of aroma release in real time during food consumption and supposed to be representative of perception, have been developed over the last 25 years. Examples obtained with MS operated in chemical ionization mode at atmospheric or sub-atmospheric pressure (atmospheric pressure chemical ionization APCI or proton-transfer reaction PTR) are given, with emphases on studies conducted with simultaneous dynamic sensory evaluation. Inter-individual variations in terms of aroma release and their relevance for understanding flavor perception are discussed as well as the evidenced cross-modal interactions.

Interindividual variations in associative visual learning: Exploration, description, and partition of response characteristics

Relying on existing literature to identify suitable techniques for characterizing individual differences presents practical and methodological challenges. These challenges include the frequent absence of detailed descriptions of raw data, which hinders the assessment of analysis appropriateness, as well as the exclusion of data points deemed outliers, or the reliance on comparing only extreme groups by categorizing continuous variables into upper and lower quartiles. Despite the availability of algorithmic modeling in standard statistical software, investigations into individual differences predominantly focus on factor analysis and parametric tests. To address these limitations, this application-oriented study proposes a comprehensive approach that leverages behavioral responses through the use of signal detection theory and clustering techniques. Unlike conventional methods, signal detection theory considers both sensitivity and bias, offering insights into the intricate interplay between perceptual ability and decision-making processes. On the other hand, clustering techniques enable the identification and classification of distinct patterns within the dataset, allowing for the detection of singular behaviors that form the foundation of individual differences. In a broader framework, these combined approaches prove particularly advantageous when analyzing large and heterogeneous datasets provided by data archive platforms. By applying these techniques more widely, our understanding of the cognitive and behavioral processes underlying learning can be expedited and enhanced.

Endothelial AHR activity prevents lung barrier disruption in viral infection.

Disruption of the lung endothelial-epithelial cell barrier following respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises vital gas exchange function1. Endothelial dysfunction can exacerbate tissue damage2,3, yet it is unclear whether the lung endothelium promotes host resistance against viral pathogens. Here we show that the environmental sensor aryl hydrocarbon receptor (AHR) is highly active in lung endothelial cells and protects against influenza-induced lung vascular leakage. Loss of AHR in endothelia exacerbates lung damage and promotes the infiltration of red blood cells and leukocytes into alveolar air spaces. Moreover, barrier protection is compromised and host susceptibility to secondary bacterial infections is increasedwhenendothelialAHR is missing. AHR engages tissue-protective transcriptional networks in endothelia, including the vasoactive apelin-APJ peptide system4, to prevent a dysplastic and apoptotic response in airway epithelial cells. Finally, we show that protective AHR signalling in lung endothelial cells is dampened by the infection itself. Maintenance of protective AHR function requires a diet enriched in naturally occurring AHR ligands, which activate disease tolerance pathways in lung endothelia to prevent tissue damage. Our findings demonstrate the importance of endothelial function in lung barrier immunity. We identify a gut-lung axis that affects lung damage following encounters with viral pathogens, linking dietary composition and intake to host fitness and inter-individual variations in disease outcome.

Single-subject cortical morphological brain networks across the adult lifespan.

Age-related changes in focal cortical morphology have been well documented in previous literature; however, how interregional coordination patterns of the focal cortical morphology reorganize with advancing age is not well established. In this study, we performed a comprehensive analysis of the topological changes in single-subject morphological brain networks across the adult lifespan. Specifically, we constructed four types of single-subject morphological brain networks for 650 participants (aged from 18 to 88 years old), and characterized their topological organization using graph-based network measures. Age-related changes in the network measures were examined via linear, quadratic, and cubic models. We found profound age-related changes in global small-world attributes and efficiency, local nodal centralities, and interregional similarities of the single-subject morphological brain networks. The age-related changes were mainly embodied in cortical thickness networks, involved in frontal regions and highly connected hubs, concentrated on short-range connections, characterized by linear changes, and susceptible to connections between limbic, frontoparietal, and ventral attention networks. Intriguingly, nonlinear (i.e., quadratic or cubic) age-related changes were frequently found in the insula and limbic regions, and age-related cubic changes preferred long-range morphological connections. Finally, we demonstrated that the morphological similarity in cortical thickness between two frontal regions mediated the relationship between age and cognition measured by Cattell scores. Taken together, these findings deepen our understanding of adaptive changes of the human brain with advancing age, which may account for interindividual variations in behaviors and cognition.

Enterotypes of the human gut mycobiome

BackgroundThe fungal component of the human gut microbiome, also known as the mycobiome, plays a vital role in intestinal ecology and human health. However, the overall structure of the gut mycobiome as well as the inter-individual variations in fungal composition remains largely unknown. In this study, we collected a total of 3363 fungal sequencing samples from 16 cohorts across three continents, including 572 newly profiled samples from China.ResultsWe identify and characterize four mycobiome enterotypes using ITS profiling of 3363 samples from 16 cohorts. These enterotypes exhibit stability across populations and geographical locations and significant correlation with bacterial enterotypes. Particularly, we notice that fungal enterotypes have a strong age preference, where the enterotype dominated by Candida (i.e., Can_type enterotype) is enriched in the elderly population and confers an increased risk of multiple diseases associated with a compromised intestinal barrier. In addition, bidirectional mediation analysis reveals that the fungi-contributed aerobic respiration pathway associated with the Can_type enterotype might mediate the association between the compromised intestinal barrier and aging.ConclusionsWe show that the human gut mycobiome has stable compositional patterns across individuals and significantly correlates with multiple host factors, such as diseases and host age.CJ96cDD7W-mAM3Q8ovNQ4eVideo

Economic analysis of allogeneic hematopoietic stem cell transplantation in the Bone Marrow Transplant Center of Tunisia

ABSTRACT Introduction: New procedures and diagnostic tests in hematopoietic stem cell transplantation (HSCT) are associated with a significant increase in costs. The last cost estimate of allogeneic HSCT done in Tunisia was in 1996 and concerned only direct medical costs. Therefore, an updated cost analysis is needed. Objective: Analysis of direct costs during the first-year post-allogeneic HSCT in two groups of patients: Bone Marrow Transplant (Allo-BMT) and Peripheral Blood Stem Cell Transplant (Allo-PBSCT) and identification of factors leading to interindividual variations in costs in order to compare these costs with the budget allocated by the payer (CNAM). Methods: Pharmacoeconomic retrospective study, concerning patients who underwent allogeneic HSCT in 2013. Clinical and unit cost data were obtained from medical and administration records. Results:This study showed that the average direct cost of allogeneic HSCT in the population during the first year reached 56 638€. The average cost of Allo-BMT was 63 612€, and Allo-PBSCT was 45 966€ (p > 0.05). The initial hospitalization counted for 88% of total direct cost with an average cost of 41 441€ in Allo-BMT and 24 672€ in Allo-PBSCT (p < 0.05). Direct medical costs represented more than 70% of total direct costs, drugs, and laboratory tests occupied the largest share. Antifungals, antitumors, and antiviral drugs were the most expensive pharmaceutical classes with a mean cost, respectively, of 4 526€; 3 737€ and 3 268€. Some clinical criteria were significantly related to total direct costs like length of aplasia (p < 0.01) and GVHD (p < 0.05). However, the type of blood disease, its risk, length of mucositis, and the treatment protocol have no effect on the costs for all allogeneic patients. Conclusion: Our results showed that the costs of Allo HSCT have exceeded by far the budget allocated by the CNAM to the center, since the 90s to this day. That’s why the total reimbursement mechanism should be revised.

Inter-individual variations in internal noise correlate with visual attention but not with post-perceptual processes

Inter-individual variations in internal noise correlate with visual attention but not with post-perceptual processes

Raman Spectroscopy Profiling of Splenic T-Cells in Sepsis and Endotoxemia in Mice.

Sepsis is a life-threatening condition that results from an overwhelming and disproportionate host response to an infection. Currently, the quality and extent of the immune response are evaluated based on clinical symptoms and the concentration of inflammatory biomarkers released or expressed by the immune cells. However, the host response toward sepsis is heterogeneous, and the roles of the individual immune cell types have not been fully conceptualized. During sepsis, the spleen plays a vital role in pathogen clearance, such as bacteria by an antibody response, macrophage bactericidal capacity, and bacterial endotoxin detoxification. This study uses Raman spectroscopy to understand the splenic T-lymphocyte compartment profile changes during bona fide bacterial sepsis versus hyperinflammatory endotoxemia. The Raman spectral analysis showed marked changes in splenocytes of mice subjected to septic peritonitis principally in the DNA region, with minor changes in the amino acids and lipoprotein areas, indicating significant transcriptomic activity during sepsis. Furthermore, splenocytes from mice exposed to endotoxic shock by injection of a high dose of lipopolysaccharide showed significant changes in the protein and lipid profiles, albeit with interindividual variations in inflammation severity. In summary, this study provided experimental evidence for the applicability and informative value of Raman spectroscopy for profiling the immune response in a complex, systemic infection scenario. Importantly, changes within the acute phase of inflammation onset (24 h) were reliably detected, lending support to the concept of early treatment and severity control by extracorporeal Raman profiling of immunocyte signatures.

Analysis of Intestinal Microbiota and Metabolic Pathways before and after a 2-Month-Long Hydrolyzed Fish and Rice Starch Hypoallergenic Diet Trial in Pruritic Dogs.

Intestinal microbiota alterations were described in allergic individuals and may improve with diets. Farmina Ultra Hypo (FUH), a hydrolyzed fish/rice starch hypoallergenic diet, is able to improve clinical signs in allergic dogs. Study objectives were to determine microbiota differences in allergic dogs before and after feeding with FUH for eight weeks. Forty skin allergic dogs were evaluated clinically before and after the diet. Unresponsive dogs were classified as canine atopic dermatitis (CAD); responsive dogs relapsing after challenge with previous foods were classified as being food reactive (AFR), and those not relapsing as doubtful (D). Sequencing of feces collected pre- and post-diet was performed, with comparisons between and within groups, pre- and post-diet, and correlations to possible altered metabolic pathways were sought. Microbiota in all dogs was dominated by Bacteroidota, Fusobacteriota, Firmicutes and Proteobacteria, albeit with large interindividual variations and with some prevalence changes after the diet. In general, bacteria producing short-chain fatty acids were increased in all samples. CAD dogs showed pre-and post-diet microbiota patterns different from the other two groups. Bacteria taxa were enriched post-diet only in the AFR group. Changes in metabolic pathways were observed mainly in the CAD group. FUH may be able to improve intestinal microbiota and thus clinical signs of skin allergy.

Pinus halepensis and P. brutia provenances present similar resilience to drought despite contrasting survival, growth, cold tolerance and stem quality: Insights from a 45 year-old common garden experiment

To improve forest management strategies in the context of ongoing climate change, a better understanding of the inter- and intra-specific variability of tree performance is needed. Pinus halepensis and Pinus brutia, two major Mediterranean species providing crucial ecosystem services to human populations, have attracted increasing attention as potential candidates for assisted migration in the last decades for their growth performance and adaptation to drought. In this study, we compared 12 provenances of P. halepensis and 13 provenances of P. brutia originating from all around the Mediterranean basin in a common garden experiment established in 1976 in southeast France to identify the best species and provenances. Tree survival, circumference and height, as well as stem straightness and the presence of defects were measured and estimated based on forest inventories conducted in 1983, 1988, 1996 and 2021–22. In 2021, 427 trees were also cored and the resulting tree-ring width series were used to assess radial growth resistance, recovery and resilience to drought. Inter-individual variations in competition intensity were taken into account using a distance-dependent competition index, and did not show any significant relationship with tree resilience to drought, while it was negatively related with tree growth and positively with stem quality. We found only marginal differences among species and provenances in terms of growth response to drought. In contrast, there were strong inter- and intra-specific differences in terms of survival, cold tolerance, growth, and stem quality with P. brutia performing better than P. halepensis on average. Interestingly, provenances performances were not related to the climatic conditions at their origins suggesting that the observed inter- and intra-specific variability was not shaped by climatic gradients. This study is the first to compare P. halepensis and P. brutia resilience to drought and provides insights for the assisted migration of those species.

Effect of metabolic rate on time-lags change in otolith microchemistry - An experimental approach using Salmo trutta.

Over decades ecologists have long been interested in relevant techniques to track the field movement patterns of fish. Elemental composition of otolith represents a permanent record of the growing habitats experienced by the fish throughout its entire lifetime that is increasingly used in the literature. The lack of a predictive and mechanistic understanding of the individual kinematics underlying ion incorporation/depletion still limits our fine-scale temporal interpretation of the chemical signal recorded in the otolith. In particular, the rate at which elements are incorporated into otoliths is hypothesized to depend on fish physiology. However, to date, time-lags have mostly been quantified at a population scale. Here, we report results from controlled experiments (translocation and artificially enriched environment) on individual trace element incorporation/depletion rates in Salmo trutta (Salmonidae). We reported significant lags (i.e. weeks to months) between changes in water chemistry and subsequent change in otolith composition and highlighted substantial inter-individual variations in the timing and magnitude of Sr/Ca and Ba/Ca responses. These differences are partially linked to the energetic status (i.e. metabolic rate) of the individuals. It, therefore, appears that individuals with the highest metabolic rate are more likely to record detailed (i.e. brief) temporal changes than individuals having lower metabolic values. The time taken for environmental changes to be reflected in the growing otolith thus can no longer be assumed to remain a constant within populations. Results from the current study are a step towards fine reconstructing environmental histories in dynamic environments.

P22-053-23 An “N-of-1” Study Protocol for Investigating Inter-Individual Variations in Glycemic Responses to Popular Diets in Healthy Male Participants

P22-053-23 An “N-of-1” Study Protocol for Investigating Inter-Individual Variations in Glycemic Responses to Popular Diets in Healthy Male Participants

Integrating Microbiome Analysis, Metabolomics, Bioinformatics, and Histopathology to Elucidate the Protective Effects of Pomegranate Juice against Benzo-alpha-pyrene-Induced Colon Pathologies.

Polycyclic aromatic hydrocarbons, e.g., benzo[a]pyrene (BaP), are common dietary pollutants with potential carcinogenic activity, while polyphenols are potential chemopreventive antioxidants. Although several health benefits are attributed to polyphenol-rich pomegranate, little is known about its interaction with BaP. This study integrates histochemical, microbiomic, and metabolomic approaches to investigate the protective effects of pomegranate juice from BaP-induced pathologies. To this end, 48 Sprague-Dawley rats received, for four weeks, either pomegranate, BaP, both, or neither (n = 12 rats per group). Whereas histochemical examination of the colon indicated tissue damage marked by mucin depletion in BaP-fed animals, which was partially restored by administration of pomegranate juice, the fecal microbiome and metabolome retained their resilience, except for key changes related to pomegranate and BaP biotransformation. Meanwhile, dramatic microbiome restructuring and metabolome shift were observed as a consequence of the elapsed time (age factor). Additionally, the analysis allowed a thorough examination of fecal microbiome-metabolome associations, which delineated six microbiome clusters (marked by a differential abundance of Lactobacillaceae and Prevotellaceae, Rumincococcaceae, and Erysipelotrichaceae) and two major metabolome clusters (a sugar- and amino-acids-dominated metabotype vs. a cluster of fatty acids and hydrocarbons), with sugar alcohols maintaining a unique signature. In conclusion, using paired comparisons to minimize inter-individual animal variations allowed the dissection of temporal vs. treatment-derived variations. Microbiome-metabolome association clusters may be further exploited for metabotype prediction and gut-health biomarker discovery.

18F]DPA-714: Effect of co-medications, age, sex, BMI and TSPO polymorphism on the human plasma input function.

We aimed to assess the effect of concomitant medication, age, sex, body mass index and 18-kDa translocator protein (TSPO) binding affinity status on the metabolism and plasma pharmacokinetics of [18F]DPA-714 and their influence on the plasma input function in a large cohort of 201 subjects who underwent brain and whole-body PET imaging to investigate the role of neuroinflammation in neurological diseases. The non-metabolized fraction of [18F]DPA-714 was estimated in venous plasma of 138 patients and 63 healthy controls (HCs; including additional arterial sampling in 16 subjects) during the 90min brain PET acquisition using a direct solid-phase extraction method. The mean fraction between 70 and 90min post-injection ([18F]DPA-71470-90) and corresponding normalized plasma concentration (SUV70-90) were correlated with all factors using a multiple linear regression model. Differences between groups (arterial vs venous measurements; HCs vs patients; high- (HAB), mixed- (MAB) and low-affinity binders (LAB); subjects with vs without co-medications, females vs males were also assessed using the non-parametric Mann-Whitney or Kruskal-Wallis ANOVA tests. Finally, the impact of co-medications on the brain uptake of [18F]DPA-714 at equilibrium was investigated. As no significant differences were observed between arterial and venous [18F]DPA-71470-90 and SUV70-90, venous plasma was used for correlations. [18F]DPA-71470-90 was not significantly different between patients and HCS (59.7 ± 12.3% vs 60.2 ± 12.9%) despite high interindividual variability. However, 47 subjects exhibiting a huge increase or decrease of [18F]DPA-71470-90 (up to 88% or down to 23%) and SUV70-90 values (2-threefold) were found to receive co-medications identified as inhibitors or inducers of CYP3A4, known to catalyse [18F]DPA-714 metabolism. Comparison between cortex-to-plasma ratios using individual input function (VTIND) or population-based input function derived from untreated HCs (VTPBIF) indicated that non-considering the individual metabolism rate led to a bias of about 30% in VT values. Multiple linear regression model analysis of subjects free of these co-medications suggested significant correlations between [18F]DPA-71470-90 and age, BMI and sex while TSPO polymorphism did not influence the metabolism of the radiotracer. [18F]DPA-714 metabolism fell with age and BMI and was significantly faster in females than in males. Whole-body PET/CT exhibited a high uptake of the tracer in TSPO-rich organs (heart wall, spleen, kidneys…) and those involved in metabolism and excretion pathways (liver, gallbladder) in HAB and MAB with a strong decrease in LAB (-89% and -85%) resulting in tracer accumulation in plasma (4.5 and 3.3-fold increase). Any co-medication that inhibits or induces CYP3A4 as well as TSPO genetic status, age, BMI and sex mostly contribute to interindividual variations of the radiotracer metabolism and/or concentration that may affect the input function of [18F]DPA-714 and consequently its human brain and peripheral uptake. INFLAPARK, NCT02319382, registered December 18, 2014, retrospectively registered; IMABIO 3, NCT01775696, registered January 25, 2013, retrospectively registered; INFLASEP, NCT02305264, registered December 2, 2014, retrospectively registered; EPI-TEP, EudraCT 2017-003381-27, registered September 24, 2018.