Interindividual Variability Research Articles

A Simple HPLC-DAD Method for the Therapeutic Monitoring of Clozapine and Related Metabolites in Human Plasma and Urine Samples.

Clozapine and its metabolites require close therapeutic monitoring (TDM) in patients due to poor correlation between the administrated doses and resulting plasma concentrations, the narrow therapeutic interval, high inter-individual variability, and the risk of serious side effects once toxic levels are exceeded. The aim of the study was to develop a simple (relatively cheap) LC-UV method for the quantification of clozapine and its metabolites in plasma and urine samples. For sample preparation, liquid-liquid extraction (LLE) in n-octanol was more efficient and less limiting in injection volumes compared to the in-situ formation of SUPRAS. When analyzing urine, an alkalinization step before extraction was required. The proposed method produced linear concentration responses with/without internal standard (IS) for the target analytes, with LLOQs within the targeted range of 50 ppb and %RSD within the acceptable 15% range. Furthermore, sample stability studies proved that pre-extracted samples were stable for the short term at room temperature and long-term when frozen.

A replicate crossover trial on the inter-individual variability of sleep indices in response to acute exercise undertaken by healthy men.

Using the necessary replicate-crossover design, we investigated whether there is inter-individual variability in home-assessed sleep in response to acute exercise. Eighteen healthy men (mean(SD): 26(6) years) completed two identical control (8-h laboratory rest, 08:45-16:45) and two identical exercise (7-h laboratory rest; 1-h laboratory treadmill run [62(7)% peak oxygen uptake], 15:15-16:15) trials in randomised sequences. Wrist-worn actigraphy (MotionWatch 8) measured home-based sleep (total sleep time, actual wake time, sleep latency, sleep efficiency) two nights before (nights 1-2) and three nights after (nights 3-5) the exercise/control day. Pearson's correlation coefficients quantified the consistency of individual differences between the replicates of control-adjusted exercise responses to explore: (1) immediate (night 3 minus night 2); (2) delayed (night 5 minus night 2); and (3) overall (average post-intervention minus average pre-intervention) exercise-related effects. Within-participant linear mixed models and a random-effects between-participant meta-analysis estimated participant-by-trial response heterogeneity. For all comparisons and sleep outcomes, the between-replicate correlations were non-significant, ranging from trivial-to-moderate (r range = -0.44 to 0.41, P≥0.065). Participant-by-trial interactions were trivial. Individual differences SDs were small, prone to uncertainty around the estimates indicated by wide 95% confidence intervals and did not provide support for true individual response heterogeneity. Meta-analyses of the between-participant, replicate-averaged condition effect revealed that, again, heterogeneity (τ) was negligible for most sleep outcomes. Control-adjusted sleep in response to acute exercise was inconsistent when measured on repeated occasions. Inter-individual differences in sleep in response to exercise were small compared to the natural (trial-to-trial) within-subject variability in sleep outcomes.

Kidney and vascular involvement in Alagille syndrome.

Alagille syndrome (ALGS) is an autosomal dominant, multisystemic disease with a high interindividual variability. The two causative genes JAG1 and NOTCH2 are expressed during kidney development, can be reactivated during adulthood kidney disease, and Notch signalling is essential for vascular morphogenesis and remodelling in mice. Liver disease is the most frequent and severe involvement; neonatal cholestasis occurs in 85% of cases, pruritus in 74%, xanthomas in 24% of cases, and the cumulative incidences of portal hypertension and liver transplantation are 66% and 50% respectively at 18years of age. Stenosis/hypoplasia of the branch pulmonary arteries is the most frequent vascular abnormality reported in ALGS. Kidney involvement is present in 38% of patients, and can reveal the disease. Congenital anomalies of the kidney and urinary tract is reported in 22% of patients, hyperchloremic acidosis in 9%, and glomerulopathy and/or proteinuria in 6%. A decreased glomerular filtration rate is reported in 10% of patients and is more frequent after liver transplantation for ALGS than for biliary atresia. Kidney failure has been frequently reported in childhood and adulthood. Renal artery stenosis and mid aortic syndrome have also frequently been reported, often associated with hypertension and stenosis and/or aneurysm of other large arteries. ALGS patients require kidney assessment at diagnosis, long-term monitoring of kidney function and early detection of vascular complications, notably if they have undergone liver transplantation, to prevent progression of chronic kidney disease and vascular complications, which account for 15% of deaths at a median age of 2.2years in the most recent series.

Individualistic reward-seeking strategies that predict response to nicotine emerge among isogenic male mice living in a micro-society.

Individual animals differ in their traits and preferences, which shape their social interactions, survival, and susceptibility to disease, including addiction. Nicotine use is highly heterogenous and has been linked to the expression of personality traits. Although these relationships are well documented, we have limited understanding of the neurophysiological mechanisms that give rise to distinct behavioral profiles and their connection to nicotine susceptibility. To address this question, we conducted a study using a semi-natural and social environment called "Souris-City" to observe the long-term behavior of individual male mice. Souris-City provided both a communal living area and a separate test area where mice engaged in a reward-seeking task isolated from their peers. Mice developed individualistic reward-seeking strategies when choosing between water and sucrose in the test compartment, which, in turn, predicted how they adapted to the introduction of nicotine as a reinforcer. Moreover, the profiles mice developed while isolated in the test area correlated with their behavior within the social environment, linking decision-making strategies to the expression of behavioral traits. Neurophysiological markers of adaptability within the dopamine system were apparent upon nicotine challenge and were associated with specific profiles. Our findings suggest that environmental adaptations influence behavioral traits and sensitivity to nicotine by acting on dopaminergic reactivity in the face of nicotine exposure, potentially contributing to addiction susceptibility. These results further emphasize the importance of understanding interindividual variability in behavior to gain insight into the mechanisms of decision-making and addiction.

Subclinical hypothyroidism and plasma levels of commonly prescribed anti-seizure medications

Background: Epilepsy remains the most common neurological problem worldwide. Most commonly prescribed antiseizure medications (ASMs) like phenytoin, sodium valproate, and carbamazepine show high inter-individual variability in bioavailability due to genetic and epigenetic factors resulting in either therapeutic failure or toxicity. In our study, we aim to determine the association between subclinical hypothyroidism and the plasma levels of these commonly prescribed ASMs, leading to either therapeutic failure or adverse drug reactions. Methods: We collected demographic data, details about the antiepileptic medication, and plasma levels of ASMs (phenytoin, carbamazepine, and sodium valproate) from patients on antiseizure medications who came for routine therapeutic drug monitoring (TDM). High-performance liquid chromatography (HPLC) estimated plasma levels of the antiseizure medications as per the TDM laboratory standard operating procedure (SOP) and thyroid function test (TSH) by a standard enzyme-linked immune-sorbent assay (ELISA) kit. Results: Of the 158 patients who had TDM, 75.31% were taking sodium valproate, 15.18% were on phenytoin, and 9.49% were on carbamazepine monotherapy. In our study, we found that 12 patients (7.59%) had TSH levels between 4 to 10 mIU/l, indicating subclinical hypothyroidism (SCH). The plasma drug levels of all 12 patients who had SCH were found to be below the therapeutic range. Conclusions: This study has established a significant association between ASMs, particularly sodium valproate, and thyroid dysfunction, specifically SCH, in patients with epilepsy. Our findings suggest that prolonged ASM therapy can lead to thyroid disturbances, warranting careful monitoring of thyroid function in these patients.

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.

Rapid modulation in music supports attention in listeners with attentional difficulties

Background music is widely used to sustain attention, but little is known about what musical properties aid attention. This may be due to inter-individual variability in neural responses to music. Here we find that music with amplitude modulations added at specific rates can sustain attention differentially for those with varying levels of attentional difficulty. We first tested the hypothesis that music with strong amplitude modulation would improve sustained attention, and found it did so when it occurred early in the experiment. Rapid modulations in music elicited greater activity in attentional networks in fMRI, as well as greater stimulus-brain coupling in EEG. Finally, to test the idea that specific modulation properties would differentially affect listeners based on their level of attentional difficulty, we parametrically manipulated the depth and rate of amplitude modulations inserted in otherwise-identical music, and found that beta-range modulations helped more than other modulation ranges for participants with more ADHD symptoms. Results suggest the possibility of an oscillation-based neural mechanism for targeted music to support improved cognitive performance.

A Multivariate Phenotypical Approach of Sepsis and Septic Shock—A Comprehensive Narrative Literature Review

Despite medical advances, sepsis and septic shock remain some of the leading causes of mortality worldwide, with a high inter-individual variability in prognosis, clinical manifestations and response to treatment. Evidence suggests that pulmonary sepsis is one of the most severe forms of sepsis, while liver dysfunction, left ventricular dysfunction, and coagulopathy impact the prognostic. Sepsis-related hypothermia and a hypoinflammatory state are related to a poor outcome. Given the heterogeneity of sepsis and recent technological progress amongst machine learning analysis techniques, a new, personalized approach to sepsis is being intensively studied. Despite the difficulties when tailoring a targeted approach, with the use of artificial intelligence-based pattern recognition, more and more publications are becoming available, highlighting novel factors that may intervene in the high heterogenicity of sepsis. This has led to the devise of a phenotypical approach in sepsis, further dividing patients based on host and trigger-related factors, clinical manifestations and progression towards organ deficiencies, dynamic prognosis algorithms, and patient trajectory in the Intensive Care Unit (ICU). Host and trigger-related factors refer to patients’ comorbidities, body mass index, age, temperature, immune response, type of bacteria and infection site. The progression to organ deficiencies refers to the individual particularities of sepsis-related multi-organ failure. Finally, the patient’s trajectory in the ICU points out the need for a better understanding of interindividual responses to various supportive therapies. This review aims to identify the main sources of variability in clustering septic patients in various clinical phenotypes as a useful clinical tool for a precision-based approach in sepsis and septic shock.

Active CNS delivery of oxycodone in healthy and endotoxemic pigs

BackgroundThe primary objective of this study was to advance our understanding of active drug uptake at brain barriers in higher species than rodents, by examining oxycodone brain concentrations in pigs.MethodsThis was investigated by a microdialysis study in healthy and endotoxemic conditions to increase the understanding of inter-species translation of putative proton-coupled organic cation (H+/OC) antiporter-mediated central nervous system (CNS) drug delivery in health and pathology, and facilitate the extrapolation to humans for improved CNS drug treatment in patients. Additionally, we sought to evaluate the efficacy of lumbar cerebrospinal fluid (CSF) exposure readout as a proxy for brain unbound interstitial fluid (ISF) concentrations. By simultaneously monitoring unbound concentrations in blood, the frontal cortical area, the lateral ventricle (LV), and the lumbar intrathecal space in healthy and lipopolysaccharide (LPS)-induced inflammation states within the same animal, we achieved exceptional spatiotemporal resolution in mapping oxycodone transport across CNS barriers.ResultsOur findings provide novel evidence of higher unbound oxycodone concentrations in brain ISF compared to blood, yielding an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 2.5. This supports the hypothesis of the presence of the H+/OC antiporter system at the blood–brain barrier (BBB) in pigs. Despite significant physiological changes, reflected in pig Sequential Organ Failure Assessment, pSOFA scores, oxycodone blood concentrations and its active net uptake across the BBB remained nearly unchanged during three hours of i.v. infusion of 4 µg/kg/h LPS from Escherichia coli (O111:B4). Mean Kp,uu,LV values indicated active uptake also at the blood-CSF barrier in healthy and endotoxemic pigs. Lumbar CSF concentrations showed minimal inter-individual variability during the experiment, with a mean Kp,uu,lumbarCSF of 1.5. LPS challenge caused a slight decrease in Kp,uu,LV, while Kp,uu,lumbarCSF remained unaffected.ConclusionsThis study enhances our understanding of oxycodone pharmacokinetics and CNS drug delivery in both healthy and inflamed conditions, providing crucial insights for translating these findings to clinical settings.

Significant individual variation in cardiac-cycle-linked cerebrospinal fluid production following subarachnoid hemorrhage

BackgroundSpontaneous subarachnoid hemorrhage (SAH) often results in altered cerebrospinal fluid (CSF) flow and secondary hydrocephalus, yet the mechanisms behind these phenomena remain poorly understood. This study aimed to elucidate the impact of SAH on individual CSF flow patterns and their association with secondary hydrocephalus.MethodsIn patients who had experienced SAH, changes in CSF flow were assessed using cardiac-gated phase-contrast magnetic resonance imaging (PC-MRI) at the Sylvian aqueduct and cranio-cervical junction (CCJ). Within these regions of interest, volumetric CSF flow was determined for every pixel and net CSF flow volume and direction calculated. The presence of acute or chronic hydrocephalus was deemed from ventriculomegaly and need of CSF diversion. For comparison, we included healthy subjects and patients examined for different CSF diseases.ResultsTwenty-four SAH patients were enrolled, revealing a heterogeneous array of CSF flow alterations at the Sylvian aqueduct. The cardiac-cycle-linked CSF net flow in Sylvian aqueduct differed from the traditional figures of ventricular CSF production about 0.30–0.40 mL/min. In 15 out of 24 patients (62.5%), net CSF flow was retrograde from the fourth to the third and lateral ventricles, while it was upward at the cranio-cervical junction in 2 out of 2 patients (100%). The diverse CSF flow metrics did not distinguish between individuals with acute or chronic secondary hydrocephalus. In comparison, 4/4 healthy subjects showed antegrade net CSF flow in the Sylvian aqueduct and net upward CSF flow in CCJ. These net CSF flow measures also showed interindividual variability among other patients with CSF diseases.ConclusionsThere is considerable inter-individual variation in net CSF flow rates following SAH. Net CSF flow in the Sylvian aqueduct differs markedly from the traditional ventricular CSF production rates of 0.30–0.40 mL/min in SAH patients, but less so in healthy subjects. Furthermore, the cardiac-cycle-linked net CSF flow rates in Sylvian aqueduct and CCJ suggest an important role of extra-ventricular CSF production.

Regional Sensorimotor Effects of Chiropractic Spinal Manipulation: Preliminary Results From an Experimental Study.

The purpose of this study was to assess the effects of different spinal manipulation (SM) techniques and target segments on a specific dermatome and myotome, when compared with a remote spinal cord segment that served as a control location. Twenty-nine healthy volunteers were randomized to receive instrumental (Activator IV, Activator Methods International Ltd) or manual SM at the C6, C1, and T4 vertebral segments in 3 independent sessions. Pressure pain thresholds (PPTs) and muscle strength were examined at the C6 (test) and L4 (control) dermatomes and myotomes, at baseline and after intervention. Linear mixed-effects models were used to analyze changes over time and interindividual variability. Pressure pain thresholds significantly increased at both proximal and distal C6 dermatome locations (P < .05), irrespective of the technique and segment of application (P > .2). No significant changes were observed at the L4 dermatome. Muscle strength remained unchanged throughout the study. Multilevel modeling revealed significant associations between increased PPTs along the C6 dermatome (P < .001), whereas the combination of technique and target segment predicted PPT increases at the proximal C6 dermatome. These findings support regional, rather than segmental mechanisms underlying the sensory effects of SM. Specifically, significant increases in PPTs along the C6 dermatome suggest localized effects on pain sensitivity, which may depend on the target spinal region. Further investigation is needed to better understand these regional changes of SM and their potential clinical implications.

Multi-parametric thrombus profiling microfluidics detects intensified biomechanical thrombogenesis associated with hypertension and aging.

Arterial thrombosis is a leading cause of death and disability worldwide with no effective bioassay for clinical prediction. As a symbolic feature of arterial thrombosis, severe stenosis in the blood vessel creates a high-shear, high-gradient flow environment that facilitates platelet aggregation towards vessel occlusion. Here, we present a thrombus profiling assay that monitors the multi-dimensional attributes of thrombi forming in such biomechanical conditions. Using this assay, we demonstrate that different receptor-ligand interactions contribute distinctively to the composition and activation status of the thrombus. Our investigation into hypertensive and older individuals reveals intensified biomechanical thrombogenesis and multi-dimensional thrombus profile abnormalities, endorsing the diagnostic potential of the assay. Furthermore, we identify the hyperactivity of GPIbα-integrin αIIbβ3 mechanosensing axis as a molecular mechanism that contributes to hypertension-associated arterial thrombosis. By studying drug-disease interactions and inter-individual variability, our work reveals a need for personalized anti-thrombotic drug selection that accommodates each patient's pathological profile.

Urine Metabolomics during a Legume Diet Intervention Suggests Altered Metabolic Signatures and Potential New Intake Markers: First Insights.

Given the general increase in legume consumption worldwide, there is a need to characterize the resulting human metabolic adaptations in order to demonstrate potential legume diet/health relationships. A nuclear magnetic resonance (NMR) metabolomics urine study was carried out on a small cohort (n = 18) to characterize the excretory effects of a pilot longitudinal 8-week legume-based dietary intervention. Despite the expected high interindividual variability in the excreted metabolome, the results suggested a nonlinear metabolic response, with higher metabolic activity in the first 4 weeks and a tendency toward baseline at the end of the intervention. The excretion of isoleucine, leucine, and threonine increased, along with metabolite changes suggestive of activation of the tricarboxylic acid cycle (through anaplerosis), ketogenesis, fat catabolism, and glycoprotein biosynthesis. Gut microbiota adaptations were also suggested based on the increased excretion of 2-hydroxyisobutyrate, allantoin, and hippurate. Increased levels of trigonelline were consistent with its role as a legume intake marker, whereas malonate and pseudouridine were suggested as possible additional markers. Correlation of NMR data with nutritional parameters aided putative explanatory hypotheses to be advanced. Our results suggest a dynamic response to legume consumption, mainly through increased amino acid excretion and altered energy metabolism, while advancing potential new markers of legume intake. These results require confirmation in larger cohorts but pave the way for an informed interpretation of the effects of legume-based diets on human health.

Chimpanzees employ context-specific behavioral strategies within fission-fusion societies.

Fission-fusion social systems allow individuals to make flexible choices about where, with whom, and in what contexts to spend their time in response to competing social and ecological pressures. The ability for fission-fusion societies to support individual behavioral strategies that vary across contexts has been suggested, but the potential function of such context-specific social choices remains largely understudied. We adopted the concept of social niche construction to explore possible differences in social complexity at the individual and group level across feeding contexts. Specifically, we examined patterns of co-attendance across two common ecological contexts in wild Central African chimpanzees (Pan troglodytes troglodytes) in the Goualougo Triangle, Republic of Congo. From data compiled over 6years, we used multidimensional social network analysis to study the patterns of co-attendance generated from 436 group scans at Ficus and 4527 visits to termite mounds. These two contexts were chosen, because they are both fixed spatial features across the landscape that serve as well-defined points to compare association patterns. We identified context-specific social niche construction in a fission-fusion chimpanzee society that produce different patterns of relationships and social complexity that are consistent in their expression over many years, and offer functional benefits. While enhancing our understanding of chimpanzee behavioral strategies, culture, and conservation, our investigation also indicates that the social niche construction framework aids in elucidating the evolutionary advantages of fission-fusion sociality by accounting for intra- and interindividual variability, cognition, and choice in newfound ways.

The pericoronary adipose tissue attenuation in CT strongly depends on kernels and iterative reconstructions.

To investigate the influence of kernels and iterative reconstructions on pericoronary adipose tissue (PCAT) attenuation in coronary CT angiography (CCTA). Twenty otherwise healthy subjects (16 females; median age 52 years) with atypical chest pain, low risk of coronary artery disease (CAD), and without CAD in photon-counting detector CCTA were included. Images were reconstructed with a quantitative smooth (Qr36) and three vascular kernels of increasing sharpness levels (Bv36, Bv44, Bv56). Quantum iterative reconstruction (QIR) was either switched-off (QIRoff) or was used with strength levels 2 and 4. The fat-attenuation-index (FAI) of the PCAT surrounding the right coronary artery was calculated in each dataset. Histograms of FAI measurements were created. Intra- and inter-reader agreements were determined. A CT edge phantom was used to determine the edge spread function (ESF) for the same datasets. Intra- and inter-reader agreement of FAI was excellent (intra-class correlation coefficient = 0.99 and 0.98, respectively). Significant differences in FAI were observed depending on the kernel and iterative reconstruction strength level (each, p < 0.001), with considerable inter-individual variation up to 34 HU and intra-individual variation up to 33 HU, depending on kernels and iterative reconstruction levels. The ESFs showed a reduced range of edge-smoothing with increasing kernel sharpness, causing an FAI decrease. Histogram analyses revealed a narrower peak of PCAT values with increasing iterative reconstruction levels, causing aFAI increase. PCAT attenuation determined with CCTA heavily depends on kernels and iterative reconstruction levels both within and across subjects. Standardization of CT reconstruction parameters is mandatory for FAI studies to enable meaningful interpretations. Question Do kernels and iterative reconstructions influence pericoronary adipose tissue (PCAT) attenuation in coronary CT angiography (CCTA)? Findings Significant differences in fat-attenuation-index (FAI) were observed depending on the kernel and iterative reconstruction strength level with considerable inter- and intra-individual variation. Clinical relevance PCAT attenuation heavily depends on kernels and iterative reconstructions requiring CT reconstruction parameter standardization to enable meaningful interpretations of fat-attenuation differences across subjects.

Genome-Wide Search for Nonadditive Allele Effects Identifies PSKH2 as Involved in the Variability of Factor V Activity.

Factor V (FV) is a key molecular player in the coagulation cascade. FV plasma levels have been associated with several human diseases, including thrombosis, bleeding, and diabetic complications. So far, 2 genes have been robustly found through genome-wide association analyses to contribute to the inter-individual variability of plasma FV levels: structural F5 gene and PLXDC2. The authors used the underestimated Brown-Forsythe methodology implemented in the QuickTest software to search for non-additive genetic effects that could contribute to the inter-individual variability of FV plasma activity. QUICKTEST was applied to 4 independent genome-wide association studies studies (LURIC [Ludwigshafen RIsk and Cardiovascular Health Study], MARTHA [Marseille Thrombosis Association], MEGA [Multiple Environmental and Genetic Assessment], and RETROVE [Riesgo de Enfermedad Tromboembolica Venosa]) totaling 4505 participants of European ancestry with measured FV plasma levels. Results obtained in the 4 cohorts were meta-analyzed using a fixed-effect model. Additional analyses involved exploring haplotype and gene×gene interactions in downstream investigations. A genome-wide significant signal at the PSKH2 locus on chr8q21.3 with lead variant rs75463553 with no evidence for heterogeneity across cohorts was observed (P=0.518). Although rs75463553 did not show an association with mean FV levels (P=0.49), it demonstrated a robust significant (P=3.38x10-9) association with the variance of FV plasma levels. Further analyses confirmed the reported association of PSKH2 with neutrophil biology and revealed that rs75463553 likely interacts with two loci, GRIN2A and POM121L12, known for their involvement in smoking biology. This comprehensive approach identifies the role of PSKH2 as a novel molecular player in the genetic regulation of FV, shedding light on the contribution of neutrophils to FV biology.

Effects of altered contractile environment on muscle shape change in the triceps surae.

Skeletal muscles change shape when they contract. Current insights into the effects of shape change on muscle function have primarily come from experiments on isolated muscles operating at maximal activation levels. However, when muscles contract and change shape, the forces they apply onto surrounding muscles will also change. The impact of an altered contractile environment (i.e., mechanical behaviour of surrounding muscle) on muscle shape change, remains unknown. To address this, we altered the mechanical contributions of the gastrocnemii during isometric plantarflexion contractions [via changing knee angle] and determined if there were associated changes in how the muscles of the triceps surae bulged in thickness during a ramped contraction. We combined B-mode ultrasound imaging with surface electromyography to quantify the neuromechanical contributions of the medial (MG) and lateral gastrocnemius (MG) and soleus (SOL) muscles during isometric plantarflexion contractions. Our results demonstrated that at the same SOL activity levels, altering knee angle had no influence on the magnitude of muscle shape change (thickness) in the triceps surae muscles. We observed high levels of inter-individual variability in muscle bulging patterns, particularly in the knee flexed position, suggesting a complex relationship between muscle bulging and activation strategies in the triceps surae, which may be related to differences in muscle mechanical properties between participants or across muscles. Our findings highlight the dynamics of in vivo bulging interactions among muscles within the triceps surae and provide insights for future investigations into the impact of altered contractile environments on three-dimensional muscle deformations and force production.

Exome Sequence Data of Eight SLC Transporters Reveal That SLC22A1 and SLC22A3 Variants Alter Metformin Pharmacokinetics and Glycemic Control.

Background: Type 2 diabetes (T2D) is one of the leading causes of mortality and is a public health challenge worldwide. Metformin is the first-choice treatment for T2D; its pharmacokinetics (PK) is facilitated by members of the solute carrier (SLC) superfamily of transporters, it is not metabolized, and it is excreted by the kidney. Although interindividual variability in metformin pharmacokinetics is documented in the Mexican population, its pharmacogenomics is still underexplored. We aimed to identify variants in metformin SLC transporter genes associated with metformin PK and response in Mexican patients. Methods: Using exome data from 2217 Mexican adults, we identified 86 biallelic SNVs in the eight known genes encoding SLC transporters, with a minor allele frequency ≥ 1%, which were analyzed in an inadequate glycemic control (IGC) association study in T2D metformin treated patients. Metformin PK was evaluated in a pediatric cohort and the effect of associated SNVs was correlated. Results: Functional annotation classified two SNVs as pathogenic. The association study revealed two blocks associated with IGC. These haplotypes comprise rs622591, rs4646272, rs4646273, and rs4646276 in SLC22A1; and rs1810126 and rs668871 in SLC22A3. PK profiles revealed that homozygotes of the SLC22A1 haplotype reached lower plasma metformin concentrations 2 h post administration than the other groups. Conclusions: Our findings highlight the potential of pharmacogenomics studies to enhance precision medicine, which may involve dosage adjustments or the exploration of alternative therapeutic options. These hold significant implications for public health, particularly in populations with a high susceptibility to develop metabolic diseases, such as Latin Americans.

Non-alcohlic Fatty Liver Disease (NAFLD): Is it a Dormant Volcano or Tip of an Iceberg?

Non-alcoholic fatty liver disease (NAFLD), a major cause of chronic liver disease, is known to affect a quarter of the global adults. Natural history of NAFLD shows interindividual variation, traditionally it progresses from simple steatosis to steatohepatitis to fibrosis/cirrhosis and finally yet rarely to hepatocellular carcinoma. It is largely a lifestyle-related disease and is often labeled as the hepatic manifestation of metabolic syndrome. Both prevention and control of NAFLD include controlling risk factors (obesity, diabetes mellitus, hypertension and dyslipidemia), through lifestyle modification and medications. Drug therapy for NAFLD per se is still evolving and till date, no drugs are approved. It is clinically silent, especially in the early stages, and is a diagnosis of exclusion. Certain easily calculated indices can stratify cases into high or low risk for advanced fibrosis, thereby dictating appropriate monitoring and treatment measures. In addition to complications specific to liver disease in those who do progress to advanced fibrosis or cirrhosis, an increased risk of nonliver disease-related morbidity and mortality is also present. Challenges are manifold and include rising burden due to ever-growing epidemic of diabetes and obesity, low public awareness, fragmented healthcare, no approved drugs, and dearth of data on magnitude and epidemiology of the disease. The recent integration of NAFLD into the National Program for Prevention and Control of Non-Communicable Diseases (NPCDCS) by the Ministry of Health and Family Welfare of India is a welcome step in this direction as the contributory factors are mostly the same for all diseases and controlling any one or all of them will have a desired impact on the prevalence of all the diseases under this program.

Progression of cyclosporine A-blood levels in experimental cats receiving a high-dose treatment protocol.

Cyclosporine A (CsA) is used as a steroid-sparing or alternative immunosuppressing agent in cats with various immune-mediated diseases such as immune-mediated hemolytic anemia. Daily treatment dosages of 5-20 mg/kg have been described. Interindividual variations in CsA blood levels are known to occur. To determine when steady-state conditions are reached and thus the earliest advisable time for monitoring CsA blood levels during the course of treatment, a prospective experimental study was conducted in six healthy adult Domestic Shorthair cats. Cats were treated with an oral dosage of 7 mg/kg CsA q 12 h for 10 days. On days 1, 2, 3, 5, 7, and 10 after the start of CsA administration (i.e., after 1, 3, 5, 9, 13, and 19 CsA administrations), EDTA blood was collected to measure the CsA level 12 h after the CsA administration (trough values) using high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS/MS). Statistical analysis revealed a significant increase in mean CsA blood levels up to day 5 (2,050 ± 964.2 ng/mL [mean ± SD], 832-3,203 ng/mL [minimum-maximum]; repeated-measures ANOVA: p = 0.0021), while values on days 5 and 7 did not differ significantly from CsA concentrations on day 10. CsA concentrations showed markedly interindividual variability. Cyclosporine A blood levels reached a steady state on day 5 of high dosages of CsA q 12 h (i.e., after nine CsA administrations), indicating that this time point is suitable for monitoring blood levels in clinical patients. Results confirmed the well-known remarkable interindividual variability of CsA, indicating the need for treatment monitoring. The assessed treatment regime resulted in significantly higher mean CsA trough levels than the target range for immunosuppressive therapy (200-600 ng/mL).