Normal Population Research Articles

Role of chirping in pulsed single-photon spectroscopy

We investigate the precision of estimating the interaction strength between a two-level system (TLS) and a single-photon pulse when the latter is subject to chirping. We consider linear, quadratic, and sinusoidal temporal phases applied to Gaussian and exponential temporal profiles. At the asymptotic time, when the TLS has fully decayed to its ground state, the fundamental precision depends solely on the magnitude of its spectral amplitude. For quadratically phase-modulated Gaussian pulses, this is entirely determined by the spectral bandwidth. We provide expressions for evaluating the fundamental precision for general temporal profiles and phase modulations. Finally, we show that experimentally feasible mode-resolved measurements are optimal, or close to it, for chirped, pulsed single-photon spectroscopy. Published by the American Physical Society 2024

Combining mathematical modeling, in vitro data and clinical target expression to support bispecific antibody binding affinity selection: a case example with FAP-4-1BBL

The majority of bispecific costimulatory antibodies in cancer immunotherapy are capable of exerting tumor-specific T-cell activation by simultaneously engaging both tumor-associated targets and costimulatory receptors expressed by T cells. The amount of trimeric complex formed when the bispecific antibody is bound simultaneously to the T cell receptor and the tumor-associated target follows a bell-shaped curve with increasing bispecific antibody exposure/dose. The shape of the curve is determined by the binding affinities of the bispecific antibody to its two targets and target expression. Here, using the case example of FAP-4-1BBL, a fibroblast activation protein alpha (FAP)-directed 4-1BB (CD137) costimulator, the impact of FAP-binding affinity on trimeric complex formation and pharmacology was explored using mathematical modeling and simulation. We quantified (1) the minimum number of target receptors per cell required to achieve pharmacological effect, (2) the expected coverage of the patient population for 19 different solid tumor indications, and (3) the range of pharmacologically active exposures as a function of FAP-binding affinity. A 10-fold increase in FAP-binding affinity (from a dissociation constant [KD] of 0.7 nM–0.07 nM) was predicted to reduce the number of FAP receptors needed to achieve 90% of the maximum pharmacological effect from 13,400 to 4,000. Also, the number of patients with colon cancer that would achieve 90% of the maximum effect would increase from 6% to 39%. In this work, a workflow to select binding affinities for bispecific antibodies that integrates preclinical in vitro data, mathematical modeling and simulation, and knowledge on target expression in the patient population, is provided. The early implementation of this approach can increase the probability of success with cancer immunotherapy in clinical development.

Urban Patterns from Space: A Remote Sensing Based Comparison Between France and Germany

AbstractThis article presents two novel methods on how to derive and visualise settlement patterns from space: a non-parametric approach called multi-scale homogeneity and a parametric, unsupervised approach known as hierarchical multi-scale clustering that models the urban clusters with the help of Gaussian bell curves. The main advantage of remote sensing based acquisition and fully automated evaluation methods is their consistency over large coverages. The Global Urban Footprint-Density (GUF-DenS) indicating the degree of impervious surfaces worldwide serves as database. The geographical focus lies on the neighbouring central-European countries France and Germany. Assuming that the centralist and federal administrative systems resulting from the individual history show a certain impact on the urban patterns, both countries are first examined separately, then together as union. The numerical comparison proofs the expected differences: the settlement pattern of the capital Paris as the largest metropolitan region in France is dominating, whereas several economic clusters of more of less similar size like Rhine–Ruhr and Rhine–Main characterise the German urban landscape. The most interesting and unexpected findings are located along the border, where neighbouring urban ellipses overlay in the separate processing and form transnational clusters when processed as union. One can interpret that the national border does not play a role in the urban development (any longer). The temporal change of the settlement patterns as effect of the regional planning strategies or the opening of the inner-European border cannot be derived from the mono-temporal GUF-DenS and thus, will be subject to future studies.

Predicting Microbial Protein Synthesis in Cattle: Evaluation of Extant Equations and Steps Needed to Improve Accuracy and Precision of Future Equations

Predictions of microbial crude protein (MCP) synthesis for beef cattle generally rely on empirical regression equations, with intakes of energy and protein as key variables. Using a database from published literature, we developed new equations based on the intake of organic matter (OM) and intakes or concentrations of crude protein (CP) and neutral detergent fiber (NDF). We compared these new equations to several extant equations based on intakes of total digestible nutrients (TDN) and CP. Regression fit statistics were evaluated using both resampling and sampling from a simulated multivariate normal population. Newly developed equations yielded similar fit statistics to extant equations, but the root mean square error of prediction averaged 155 g (28.7% of the mean MCP of 540.7 g/d) across all equations, indicating considerable variation in predictions. A simple approach of calculating MCP as 10% of the TDN intake yielded MCP estimates and fit statistics that were similar to more complicated equations. Adding a classification code to account for unique dietary characteristics did not have significant effects. Because MCP synthesis is measured indirectly, most often using surgically altered animals, literature estimates are relatively few and highly variable. A random sample of individual studies from our literature database indicated a standard deviation for MCP synthesis that averaged 19.1% of the observed mean, likely contributing to imprecision in the MCP predictions. Research to develop additional MCP estimates across various diets and production situations is needed, with a focus on developing consistent and reliable methodologies for MCP measurements. The use of new meta-omics tools might improve the accuracy and precision of MCP predictions, but further research will be needed to assess the utility of such tools.

T-cell engagers: model interrogation as a tool to quantify the interplay of relative affinity and target expression on trimer formation

T-cell engagers (TCEs) represent a promising therapeutic strategy for various cancers and autoimmune disorders. These bispecific antibodies act as bridges, connecting T-cell receptors (TCRs) to target cells (either malignant or autoreactive) via interactions with specific tumour-associated antigens (TAAs) or autoantigens to form trimeric synapses, or trimers, that co-localise T-cells with target cells and stimulate their cytotoxic function. Bispecific TCEs are expected to exhibit a bell-shaped dose-response curve, with a defined optimal TCE exposure for maximizing trimer formation. The shape of the dose-response is determined by a non-trivial interplay of binding affinities, exposure and antigens expression levels. Furthermore, excessively low binding to the TCR may reduce efficacy, but mitigate risk of over-stimulating cytokine secretion or induce effector cell exhaustion. These inevitable trade-off highlights the importance of quantitatively understanding the relationship between TCE concentration, target expression, binding affinities, and trimer formation. We utilized a mechanistic target engagement model to show that, if the TCE design parameters are close to the recommended ranges found in the literature, relative affinities for TCR, TAA and target expression levels have qualitatively different, but predictable, effects on the resulting dose-response curve: higher expression levels shift the curve upwards, higher antigen affinity shifts the curve to the left, and higher TCR affinity shifts the curve upwards and to the left.

Five-year changes in retinal nerve fibre layer thickness in the adult population: a population-based cohort study.

Distinguishing between the pathological thinning of the retinal nerve fibre layer (RNFL) and age-related reduction requires a comprehensive understanding of the longitudinal changes in RNFL thickness within a healthy population. To determine five-year changes in RNFL thickness and associated factors in people aged 45-69 years. This report pertains to the second and third phases of the Shahroud Eye Cohort Study. Participants were recruited by a multi-stage cluster sampling in Shahroud, Iran. Data on demographic details, visual acuity, non-cycloplegic refraction, and slit-lamp biomicroscopy were collected. High-definition optical coherence tomography was employed for retinal imaging. A total of 1,524 eyes from 908 participants were examined. The average RNFL thickness was 92.2 ± 8.5 (95% CI: 91.6 to 92.8) and 93.1 ± 8.7 μm (95% CI: 92.5 to 93.7) in the first and second phases with a five-year mean change of 0.95 ± 4.15 μm (95% CI: 0.70 to 1.20). The RNFL thickness mean changes in the superior, inferior, nasal, and temporal quadrants were 2.51 ± 7.86 (95% CI: 2.01 to 3.02), 2.93 ± 7.39 (95% CI: 2.56 to 3.29), -0.53 ± 6.15 (95% CI: -0.84 to -0.21), and -1.01 ± 4.67 μm (95% CI: -1.27 to -0.75), respectively. The five-year changes in average RNFL thickness were inversely correlated with axial length (β = -0.69, p < 0.001), mean keratometry (β = -0.37, p = 0.017), and baseline RNFL thickness (β = -0.617, p < 0.001). In hyperopic individuals, the increase in average RNFL thickness (β = 0.65, p = 0.012) was significantly greater than in those with emmetropia. Macular volume (β = 1.65, p < 0.001) showed a direct association with five-year changes in average RNFL thickness. Over 5 years, RNFL thickness changes were clinically insignificant in the normal population. The mean RNFL thickness seems to remain stable unless there is ocular disease. However, increased axial length and steeper keratometric readings were linked to RNFL thinning. Those with thicker RNFL measurements were at higher risk of thinning over time.

Applicability of epigenetic age models to next-generation methylation arrays

BackgroundEpigenetic clocks are mathematical models used to estimate epigenetic age based on DNA methylation at specific CpG sites. As new methylation microarrays are developed and older models discontinued, existing epigenetic clocks might become obsolete. Here, we explored the effects of the changes introduced in the new EPICv2 DNA methylation array on existing epigenetic clocks.MethodsWe tested the performance of four epigenetic clocks on the probeset of the EPICv2 array using a dataset of 10,835 samples. We developed a new epigenetic age prediction model compatible across the 450 k, EPICv1, and EPICv2 microarrays and validated it on 2095 samples. We estimated technical noise and intra-subject variation using two datasets with repeated sampling. We used data from (i) cancer survivors who had undergone different therapies, (ii) breast cancer patients and controls, and (iii) an exercise-based interventional study, to test the ability of our model to detect alterations in epigenetic age acceleration in response to theoretically antiaging interventions.ResultsThe results of the four epiclocks tested are significantly distorted by the EPICv2 probeset, causing an average difference of up to 25 years. Our new model produced highly accurate chronological age predictions, comparable to a state-of-the-art epiclock. The model reported the lowest epigenetic age acceleration in normal populations, as well as the lowest variation across technical replicates and repeated samples from the same subjects. Finally, our model reproduced previous results of increased epigenetic age acceleration in cancer patients and in survivors treated with radiation therapy, and no changes from exercise-based interventions.ConclusionExisting epigenetic clocks require updates for full EPICv2 compatibility. Our new model translates the capabilities of state-of-the-art epigenetic clocks to the EPICv2 platform and is cross-compatible with older microarrays. The characterization of epigenetic age prediction variation provides useful metrics to contextualize the relevance of epigenetic age alterations. The analysis of data from subjects influenced by radiation, cancer, and exercise-based interventions shows that despite being good predictors of chronological age, neither a pathological state like breast cancer, a hazardous environmental factor (radiation), nor exercise (a beneficial intervention) caused significant changes in the values of the “epigenetic age” determined by these first-generation models.

7618 Thyroid Nodules, Normal Thyroid Levels, and Chronic Anxiety: A Case for Sub-Clinical Toxic Multinodular Goiter

Abstract Disclosure: C.M. Barrera: None. Introduction: Chronic anxiety and panic disorders, as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), are the most common psychiatric conditions. Hyperthyroidism is a known cause of both chronic anxiety and panic disorder. Case 1: A 36-year-old overweight Latin female is referred for evaluation of multiple thyroid nodules. The thyroid ultrasound was heterogeneous, with multiple bilateral nodules. In her history, the patient has chronic anxiety with panic attacks resulting in frequent emergency room visits. The TSH and T4 levels were TSH 0.59 mIU/L (0.40-4.5) and T4 10.7 mcg/dL (5.1-11.9). An I[1]23- Thyroid Scan showed a hot nodule with mild suppression and an uptake of 31.8% (The top limit is 35%). The patient started methimazole 2.5 mg daily, and after two months, her chronic anxiety and panic attacks resolved. Post-methimazole TSH rose to 1.18 mIU/L, and T4 10.0 mcg/dL and she has weaned off anxiety medications. Case 2: A 49-year-old overweight Latin female is referred for increased thyroid nodules. She complained of six months of tachycardia and anxiety. The TSH and T4 levels were TSH of 0.828 mIU/L (0.40-4.5) and T4 of 7.9 mcg/dl (4.5-12.0). An I[1]23-Thyroid Scan showed no dominant hot or cold nodules, with an uptake of 36.4% (The top limit is 35%, within normal error limits). She started methimazole 5 mg daily, resolving her tachycardia and anxiety within five weeks. Post-methimazole TSH was 1.64 mIU/L (0.45-4.5), and T4 6.7 mcg/dL (4.5-12.0). Case 3: A 60-year-old overweight Latin female is referred for evaluation of multiple thyroid nodules of ten years. She complained of chronic anxiety and panic attacks for two years. The TSH and T4 were normal at TSH 0.36 mIU/L (0.35- 5.50) and T4 9.7 mcg/dL (4.5-10.9). The thyroid ultrasound showed multiple bilateral nodules. An I[1]23-Thyroid Scan showed a suspected hot nodule without appreciable suppression and an uptake of 33% (The top limit is 35%). The patient started methimazole 5 mg daily. After eight weeks, she reported the resolution of most of her chronic anxiety with post-methimazole TSH 2.39 mIU/L and T4 7.1 mcg/dL (4.5-12.0). Discussion: The normal range of TSH, typically from 0.4-4.5 mIU/L, is calculated by measuring the TSH levels among a normal population. The group range then determines the laboratory reference range. This contrasts with individual values, which have a narrower range, suggesting that each person has a unique thyroid level. This suggests that TSH levels at the extremum, associated with hyperfunctioning nodules contributing to a rise in uptake, may not be normal for that patient and may explain the anxiety and other symptoms. Learning Points: Evolving multiple autonomous thyroid nodules lowers TSH levels while raising thyroid uptake. Symptoms of chronic anxiety and panic attacks can predate abnormal thyroid levels and resolve with low-dose methimazole. Presentation: 6/1/2024

8488 Sex-Specific Differences in an Alstrom Syndrome Mouse Model

Abstract Disclosure: Y. Carcamo-Bahena: None. J. Youn: None. E. Lartigue: None. S. Sisley: None. Background: Alström syndrome is a monogenic autosomal recessive disorder caused by loss of the ALMS1 gene that affects 1 in 1 million. Loss of a functional ALMS1 protein leads to global disorganization of microtubules. Patients are affected by progressive vision and hearing loss and are at risk of developing obesity and type 2 diabetes. Aside from reproductive system anomalies, no clinical reports have identified sex-specific difference in patients with Alström syndrome. Methods: Male and female Alms1tvrm[1]02/tvrm[1]02 (null), Alms1tvrm[1]02/+ (heterozygous) and wildtype littermate mice were weaned onto standard chow diet. At 16 weeks of age, they were changed to a 45% high fat diet (HFD). Weekly body weights were collected and intraperitoneal glucose tolerance tests (GTTs, 1.5 g/kg D20W) were performed at three different time points (11, 16, 25 weeks of age). Results:Alms1 null mice were heavier than wildtype and heterozygous mice on standard chow diet. In males, significant changes in weight gain in null mice occurred by 10 weeks compared to wildtype and heterozygous mice (p&amp;lt;0.05). In females, compared to null, this change was observed by 13 weeks (p&amp;lt;0.05). Although female mice are typically protected from diet-induced obesity, the null females weighed the same as the null males (65.0 ± 2.0 vs 67.7 ± 2.8 g) after 9 weeks on HFD. We observed sex and diet specific differences in GTT outcomes. On chow diet, Alms1 deficiency did not affect glucose levels during a GTT in female mice. However, after 9 weeks of HFD (25 weeks of age), baseline fasting glucose levels were higher in the null females compared to wildtype (p&amp;lt;0.05) and heterozygotes (p&amp;lt;0.01). Additionally, the GTT curve was monophasic, indicating onset of diabetes whereas wildtype and heterozygotes (p&amp;lt;0.0001) had normal curves. Null male mice showed an impaired glucose response at 11 weeks of age on chow diet compared to wildtype and heterozygous males (p&amp;lt;0.001) and by 16 weeks, the GTT glucose curve for Alms1 null mice was monophasic. After 9 weeks of HFD, no differences were observed in glucose levels during a GTT. Conclusions: We observed sex-specific differences in this Alms1 null mouse model related to body weight and glucose tolerance with male null mice exhibiting earlier obesity and impaired glucose tolerance and female mice showing more pronounced effects on a HFD. Future research should investigate if these sex-specific effects alter responses to dietary or pharmaceutical interventions. Presentation: 6/1/2024

Investigation of the risk factors associated with prediabetes in normal-weight Qatari adults: a cross-sectional study

Type 2 diabetes is one of the most prevalent chronic diseases in the world, and more people than ever before have impaired glucose tolereance, or prediabetes. Many patients with impaired glucose tolerance and undiagnosed diabetes do not know that their glucose metabolism system has been in a state of disorder. Every year, about 5-10% of prediabetics develop diabetes. One of the important achieving factors may be the increase in blood lipids. However, it is not clear whether triglyceride is associated with impaired glucose tolerance and prediabetes in the Qatari population. Therefore, we investigated the relationship between the first several clinical variables and prediabetes status in normal and overweight populations. We conducted a cross-sectional study using data from the Qatar Biobank program. The study included 5,996 participants who were adults over the age of 20. We collected information about participants’ fasting blood glucose levels with other clinical measurements and used various machine learning models and logistic regression to study the association between the clinical measurements and prediabetes for normal and overobese weight groups. The use of several machine learning models showed that, after adjusting the potential confounding factors such as age and sex, Triglyceride has been demonstrated to be positively correlated with prediabetes, and there was a special population dependence phenomenon. Among them, nonobese people (p < 0.05). The effect value and 95% confidence interval and OR of triglyceride on prediabetes was 2.79 and (e0.78, e1.28), respectively.

A-048 Reference Interval and Clinical Performance Studies for Vitros® Immunodiagnostic Products Intact PTH II Assay to Aid in Diagnosis of Calcium and Parathyroid Disorders and Intraoperative Testing

Abstract Background Intact parathyroid hormone (iPTH) measurements aid in the differential diagnosis of hypercalcemia, hypocalcemia, and parathyroid disorders. The National Academy of Clinical Biochemistry has established guidelines for intraoperative PTH testing to monitor surgical success during parathyroidectomies. Studies were conducted to define the reference interval and clinical performance of the Vitros Immunodiagnostic Products Intact PTH II (Vitros iPTH II) assay, using samples from healthy individuals and patients with conditions commonly requiring iPTH testing, including intraoperative cases. Methods The reference interval study was conducted in accordance with Clinical and Laboratory Standards Institute (CLSI) guideline EP28-A3c in serum samples from 134 healthy individuals. For the clinical performance study, serum samples from individuals with hypoparathyroidism, primary hyperparathyroidism, chronic renal failure (secondary or tertiary hyperparathyroidism), hypercalcemia, hypercalcemia of malignancies, and hypocalcemia were tested. Intraoperative samples used were collected from parathyroidectomy patients in series at each surgical timepoint along with the standard plasma samples used to determine surgical success. Results The reference samples were composed of 134 serum donors that met all inclusion/exclusion criteria for healthy donors and had a normal test result on calcium, TSH, alkaline phosphatase, creatinine, and phosphate assays. The reference interval for iPTH was determined to be 14.2-75.2 pg/mL. The results in various disease states demonstrated the clinical performance of the Vitros iPTH II assay. Of 32 intraoperative sample series included in the study, three samples demonstrated no intraoperative decrease in iPTH due to surgical failures. Consistent with the goal of the parathyroidectomy procedure, at least a 50% decrease in iPTH was observed between the presurgical and post-excision samples in all other sample series. The clinical concordance with the Roche PTH assay used intraoperatively in these procedures was 100%. Conclusions Defining the reference interval for a normal healthy population and results from the intended use population demonstrated that the Vitros iPTH II assay can be used as an aid in the diagnosis of calcium and parathyroid disorders and intraoperative testing.

A-108 Re-evaluation of reference intervals for circulating albumin, total calcium, and magnesium levels among subjects in Dallas County

Abstract Background Reference intervals are either directly established from normal volunteers, adopted from assay manufactures and verified as transferable to the normal population, or indirectly derived using patients’ archived laboratory data. This study describes indirect derivation of reference intervals for albumin, total calcium, and magnesium appropriate to the patient population of Dallas County. The tests were selected due to their often combine measurement in the assessment of calcium and bone mineral metabolism Methods Retrospective reported laboratory results during May 2022 for albumin (n=1342), total calcium (n=1945), and magnesium (n=2148) were obtained. Values were subjected to statistical analysis for nature of distribution, mean, and standard deviation as well as stratified for patients’ characteristics (gender, race, and age). Statistical analysis applied were Hoffman regression analysis, one-way ANOVA, and Tukey-Kramer tests. Results Following removal of outliers, statistically suggested reference intervals for albumin, total calcium, and magnesium were 5.5 to 2.4 g/dL, 10.5 to 7.5 mg/dL, and 2.6 to 1.6 mg/dL respectively. Although there was race specific differences in albumin and calcium levels (p=0.032) and (p=0.002) respectively, differences for magnesium were slightly nonsignificant (p=0.06). Similarly, significant differences due to age were observed for albumin, total calcium, and magnesium (P &amp;lt;0.00 for all). The data suggests that albumin, magnesium, and calcium levels are unequivocally dependent on age and race for patients in Dallas County. The upper limits of population derived, and manufacturer verified reference intervals were 5.45 and 5.2 g/dL for albumin, 10.5 and 10.2 mg/dL for calcium, and 4.6, and 2.6 mg/dL for magnesium respectively, the lower limits were 2.4 and 3.5, 7.5 and 8.4, 1.4, and 1.6 mg/dL respectively. Conclusions Reference intervals for albumin, total calcium, and magnesium appropriate to the patient population of Dallas County were derived. Derived values were statistically different from the manufacturer verified values in use. The study although limited by the small number of acceptable samples, highlights the need for laboratories to derive their respective population-based reference intervals. The study will be expanded to other biochemical parameters utilizing much larger sample volume.

Calculation of continuous reference intervals for biological parameters exhibiting strong age‐dependent level changes: Its application to glycosaminoglycans and sialic acid in urine

AbstractGlycosaminoglycan (GAG) and sialic acid (total and free) assays are used as first‐line screening tests for the diagnosis of mucopolysaccharidoses and glycoproteinoses, respectively. There is a pronounced age‐dependent variation in the urinary concentrations of these metabolites in the normal population, and the stratification of the reference values into discrete age ranges may lead to an undesirably high number of false‐positive or false‐negative results. The aim of this study was to design a method for calculating continuous reference intervals as a function of age and its application to the analysis of GAGs and sialic acid (total, free, and conjugated) in urine. In the postpubertal period, concentrations of urinary GAGs and sialic acid have reached a plateau, so a traditional calculation of the reference range in this specific age group was considered appropriate. In the prepubertal period, a nonlinear regression performed with the Excel add‐in Solver was used to fit the logarithmized concentrations of the controls to a curve that represents the mean values as a function of age. A uniform distribution of the residuals was obtained, which allowed the calculation of the reference intervals by adding the values of their 2.5 and 97.5 percentiles to the independent variable of the regression curve to calculate the upper and lower reference curves. The main advantages of the developed method are (1) a reduction in the number of control samples needed to obtain adequate reference intervals and (2) an improvement in the reliability of diagnostic screening by reducing the uncertainty generated by the gaps in the traditional age‐stratified method.

Effect of body mass index on semen quality, sperm chromatin integrity and sperm DNA methylation

Obesity represents a growing problem due to its impacts on human health and reproduction. In this study, we analysed semen quality, sperm DNA integrity and gene-specific CpG methylation in 116 healthy men from normal population. The men were divided into three groups according to their body mass index (BMI), and their ejaculates were analysed using standard methods, sperm chromatin structure assay (SCSA), methylation next generation sequencing (NGS) and amplicon sequencing. The sperm methylation NGS revealed six significantly differentially methylated regions (DMRs). Using subsequent targeted amplicon sequencing in 116 men, two of the DMRs were proved as differentially methylated in sperm of men with normal BMI vs. BMI ≥ 25. The DMRs were located in the EPHA8 and ANKRD11 gene. Also, we detected a significant decline in the EPHA8, ANKRD11 and CFAP46 gene methylation in association with increasing BMI values. The genes EPHA8 and ANKRD11 are involved in the nervous system and brain development; the CFAP46 gene plays a role in a flagellar assembly and is associated with sperm motility. Significantly lower rates of motile and progressive motile sperm were observed in men with BMI ≥ 30. Our results show that excess body weight can modify CpG methylation of specific genes, affect sperm motility, and compromise sperm chromatin integrity. These factors can stand behind the observed reduced fertility in men with obesity. The methylation changes might be transmitted to their offspring through sperm, and become a basis for possible developmental and reproductive issues in the next generation.

Impaired motor-to-sensory transformation mediates auditory hallucinations.

Distinguishing reality from hallucinations requires efficient monitoring of agency. It has been hypothesized that a copy of motor signals, termed efference copy (EC) or corollary discharge (CD), suppresses sensory responses to yield a sense of agency; impairment of the inhibitory function leads to hallucinations. However, how can the sole absence of inhibition yield positive symptoms of hallucinations? We hypothesize that selective impairments in functionally distinct signals of CD and EC during motor-to-sensory transformation cause the positive symptoms of hallucinations. In an electroencephalography (EEG) experiment with a delayed articulation paradigm in schizophrenic patients with (AVHs) and without auditory verbal hallucinations (non-AVHs), we found that preparing to speak without knowing the contents (general preparation) did not suppress auditory responses in both patient groups, suggesting the absent of inhibitory function of CD. Whereas, preparing to speak a syllable (specific preparation) enhanced the auditory responses to the prepared syllable in non-AVHs, whereas AVHs showed enhancement in responses to unprepared syllables, opposite to the observations in the normal population, suggesting that the enhancement function of EC is not precise in AVHs. A computational model with a virtual lesion of an inhibitory inter-neuron and disproportional sensitization of auditory cortices fitted the empirical data and further quantified the distinct impairments in motor-to-sensory transformation in AVHs. These results suggest that "broken" CD plus "noisy" EC causes erroneous monitoring of the imprecise generation of internal auditory representation and yields auditory hallucinations. Specific impairments in functional granularity of motor-to-sensory transformation mediate positivity symptoms of agency abnormality in mental disorders.

Skyrmion dynamics in attractive and repulsive local magnetic fields

The study of the behavior of magnetic skyrmions in local magnetic fields’ nanometric length-scale has gained increasing interest in recent years due to the theoretical proposal of magnetic skyrmion–superconducting vortex pairs as potential hosts for topologically protected bound states, which hold high promise for applications in quantum computing. From a magnetic interaction point-of-view, the key interest lies in understanding the skyrmion dynamics triggered by the magnetic energy landscape generated by the superconducting vortex. Here, we present a micromagnetic study of the dynamics of nanometric skyrmions inside a Gaussian magnetic field profile, which is used as a simplified version of the vortex magnetic flux. On the one hand, our calculations show that local non-linear magnetic fields can be very effective in controlling the dynamics of magnetic skyrmions; in particular, they offer the appealing possibility to manipulate skyrmions in a two dimensional space. On the other hand, they also show that the dynamics of a skyrmion in a local magnetic field can be manipulated via a uniform external magnetic field without any change in the magnetic field gradient. An analytical expression for the skyrmion velocity is given, and the corresponding microscopic dynamics are confirmed by the micromagnetic simulations. This work is expected to motivate more theoretical and experimental studies of the behavior of magnetic skyrmions in proximity to superconducting vortices.

A study on normal reference values of the left ventricular strain parameters in young adults

Background: The left ventricular (LV) function is an important prognostic determinant of cardiopulmonary pathologies in adult. Clinical application of cardiac strain by two-dimensional speckle tracking echocardiography to measure LV function requires knowledge of the range of normal values. Reference values and associated variations of the deformation measures need to be “firmly established before routine clinical adoption” of LV strain measurements can be implemented in Indian population. Aims and Objectives: This study aims to establish normal values of LV strain parameters in normal Indian population. Materials and Methods: An observational, cross-sectional, single-center, hospital-based study. The study period October 2021–October 2022 in Nil Ratan Sircir Medical College, Kolkata. Cardiologically healthy adult subjects (sample size 250) both male and female, aged 18–45 years who were healthcare professionals of this medical college and hospital were included in the study. Routine history taking and investigations were done. Echodoppler was done with special emphasis on LV strain parameters. Results: Distribution of mean LV circumferential strain (LVCS) with age in years was statistically not significant (P=0.8068). The mean value in male and female were −18.9574(±0.9049) and −19.0257(±0.8908) respectively. In the current study, LVCS did not vary in statistically significant a way among different age groups too. The mean values in male and female were −22.5887(±1.8065) and −22.3312(±1.9007) respectively. Conclusion: This current study failed to show significant differences in LV strain parameters between age groups or male and female in Eastern India Population.

Testing for normality: a user's (cautionary) guide.

The normality assumption postulates that empirical data derives from a normal (Gaussian) population. It is a pillar of inferential statistics that enables the theorization of probability functions and the computation of p-values thereof. The breach of this assumption may not impose a formal mathematical constraint on the computation of inferential outputs (e.g., p-values) but may make them inoperable and possibly lead to unethical waste of laboratory animals. Various methods, including statistical tests and qualitative visual examination, can reveal incompatibility with normality and the choice of a procedure should not be trivialized. The following minireview will provide a brief overview of diagrammatical methods and statistical tests commonly employed to evaluate congruence with normality. Special attention will be given to the potential pitfalls associated with their application. Normality is an unachievable ideal that practically never accurately describes natural variables, and detrimental consequences of non-normality may be safeguarded by using large samples. Therefore, the very concept of preliminary normality testing is also, arguably provocatively, questioned.

New model for evaluating the impact response of steel fiber reinforced concrete subjected to the repeated drop-weight

The investigation of available experimental results obtained in the non-instrumented drop weight test recommended by American Concrete Institute on the steel-fiber-reinforced concrete reveals that the data distribution does not match a normal distribution. For this reason, logarithmic scales of the first-crack (number of blows to cause the first visible crack) and failure strengths (number of blows to spread the cracks sufficiently) are adopted to increase the fitness of the normal curve to the frequency histogram. The authors propose a novel model to predict the failure strength and evaluate the steel fiber effect on the post-cracking behavior of steel-fiber-reinforced concrete. The new model improves the prediction of the experimental results obtained in literature review for the various ranges of volume fraction of steel fiber analyzed. The proposed model is compared with other models using statistical parameters and the comparison shows a significant improvement considering different failure states. To verify the performance of the proposed model, in addition to results from another research, an experimental impact test was conducted. Besides, a reliable regression model is developed to validate experimental results. The findings underscore the potential of the proposed model to significantly enhance predictive accuracy, thereby proposing valuable insights for optimizing steel-fiber-reinforced concrete.

Evaluation of the clinical significance of lymphocyte subsets and myeloid suppressor cells in patients with renal carcinoma

PurposeThe purpose of this study was to analyze the expression patterns of immune cells in renal cancer patients, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), CD3 + /CD4 + T cells, CD3 + / CD8 + T cells, and CD3- CD16 + CD56 + cells. In addition, this study will explore the correlation between these immune markers and the progression of renal cell carcinoma and evaluate their potential application in predicting the therapeutic effect of renal cell carcinoma.MethodsIn this study, 80 renal cancer patients who received treatment in our hospital from October 2022 to December 2023 were selected as the research object and 50 healthy people who underwent a physical examination at the same time were selected as the control group. All participants had a 3 ml venous blood sample taken in the morning on an empty stomach. All patients with renal cell carcinoma have been confirmed by histopathological diagnosis. Clinicopathological data including age, gender, BMI, clinical stage, tumor size and pathological type were collected.MDSC, Treg, CD3 + /CD4 + T cells, CD3 + /CD8 + T cells, the ratio of CD3 + /CD4 + T cells/CD3 + /CD8 + T cell and the expression level of CD3-CD16 + CD56 + cells were detected by flow cytometry.ResultsThrough the detection of flow cytometry, we observed that there was no significant difference in gender, age, BMI and other baseline characteristics between renal cancer patients and healthy controls, and the P value was greater than 0.05. However, in the analysis of peripheral blood immune cell subsets, including CD3 + /CD4 + , CD3 + /CD8 + , CD3 + /CD4 + /CD3 + /CD8 + ratio, NK cells, regulatory T cells (T-reg), polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and mononuclear myeloid-derived suppressor cells (M-MDSC) were significantly different between renal cell carcinoma group and normal control group (P < 0.05). Specifically, the expression levels of CD3 + /CD4 + and CD3 + /CD8 + cells in renal cancer patients were lower than those in normal subjects, while the expression levels of T-reg, PMN-MDSC and M-MDSC were relatively high. (2) In the flow cytometry analysis, the expression level of immune cell subsets in the peripheral blood of renal cancer patients was detected.The results showed that there was no significant correlation between the expression of CD3 + /CD4 + , CD3 + /CD8 + , CD3 + /CD4 + /CD3 + /CD8 + ratio, NK cells, T-reg cells, PMN-MDSC and M-MDSC and the sex, age, BMI and pathological type of the patients. These differences were not statistically significant (P > 0.05).At the same time, CD3 + /CD8 + T cells, the ratio of CD3 + /CD4 + /CD3 + /CD8 + and the expression level of NK cells were not significantly correlated with tumor size and clinical stage (P > 0.05). However, the expression levels of CD3 + /CD4 + cells, M-MDSC, PMN-MDSC, and T-reg cells were statistically significantly different with tumor size and clinical stage (P < 0.05).There was a significant difference between these indexes and lymph node metastasis (P < 0.05). (3) The results of Logistic regression analysis showed that the low expression of CD3 + /CD4 + lymphocytes and the high expression of T-reg, PMN-MDSC and M-MDSC in peripheral blood may be related to the clinical stage of renal cell carcinoma.Conclusion(1) Compared with healthy individuals, patients with renal cell carcinoma showed a significant decrease in CD3 + /CD4 + T cells, CD3 + /CD8 + T cells and CD3-CD16 + CD56 + cells, while the CD4 + /CD8 + ratio increased. In addition, the number of PMN-MDSC, M-MDSC and T-reg cells was significantly increased compared with the normal population, indicating that the immune system function of patients was impaired. (2) The expression levels of CD3 + /CD4 + , PMN-MDSC, M-MDSC and T-reg were different in tumor size and clinical stage. Specifically, the expression levels of PMN-MDSC, M-MDSC, and T-reg increased correspondingly with the increase in tumor diameter and the progression of the clinical stage.