Browse Articles

Comparison of orbital structures between age-related distance esotropia and acute acquired concomitant esotropia

Purpose To compare orbital magnetic resonance imaging (MRI) findings of age-related distance esotropia (ARDE) with those of age-matched healthy controls and acute acquired concomitant esotropia (AACE) patients. Methods Coronal MRI scans of 16 ARDE cases, 15 AACE cases, 26 elderly controls cases, and 22 young controls cases were analyzed to measure (1) the displacement angles of the lateral rectus (LR) and medial rectus (MR), (2) the LR tilting angle, (3) the ratio of the MR-to-LR cross-sectional areas (CSAs), and (4) the superior rectus (SR) downward displacement ratio (SDR). Results ARDE patients showed significant LR sagging relative to elderly controls, by 5.1° (p = 0.048), while there was no significant LR displacement in AACE relative to young controls. ARDE patients also exhibited marked LR tilting relative to all other groups. Additionally, the MR-to-LR CSA ratios were 26% (p = 0.002) and 27% (p = 0.001) higher in the ARDE and AACE groups than in the controls, respectively, indicating imbalance in the horizontal rectus (HR). Additionally, SDR values were higher in ARDE and elderly controls, suggesting that a closer proximity of the SR muscle to the globe is an age-related alteration. Conclusion The findings demonstrate that ARDE is characterized by unique orbital changes, particularly in the LR, that distinguish it from AACE. The observed increase in the MR-to-LR CSA ratio among the esotropia groups points to an imbalance of HR tension. These MRI-based insights enhance our comprehension of the unique pathophysiology of these conditions, helping to distinguish ARDE from AACE in acquired esotropia and guiding customized treatments strategies.

Individualized calibration of estimated glomerular filtration rate for serial renal function determination: a pilot study

Understanding shell coating effects to overcome quenching in single anisotropic upconversion nanoparticles

A mixed-integer linear programming method for time-dependent line planning in passenger railway systems

This paper addresses a line planning problem (LPP) that simultaneously optimizes both train and passenger times in passenger railway systems, considering time-dependent origin-destination-period demand and passenger train choice. The problem is clearly and flexibly modeled in a physical infrastructure-based directed graph, which efficiently integrates the train operation choice and the passenger train choice. The problem is first formulated as a mixed-integer, non-concave, and non-linear programming model aimed at minimizing both the total operating cost of trains and the total travel cost of passengers. To solve the problem, an extended time-dimension method is proposed to transform the non-concave and non-linear model into a mixed-integer linear programming (MILP) model that can be solved using a commercial solver. Additionally, a set of simplification strategies is introduced to reduce the computational complexity while ensuring the global optimality of the linear model. A case study of a busy Chinese railway line demonstrates that the optimized time-dependent line plan enhances operational efficiency and accommodates the diversified travel preferences driven by time-dependent demand.

Effects of mallotus furetianus extract on CYP3A activities in rats

Regulating orbital interaction to construct quasi-covalent bond networks in Pt intermetallic alloys for high-performance fuel cells

Risk factors for early suspected ventilator-associated pneumonia in severe thoracic blunt trauma patient: A French national cohort study

Background Ventilator-associated pneumonia (VAP) is the most common infection in severely injured patients requiring mechanical ventilation. Chest trauma has been identified as a significant risk factor for VAP. This study aimed to describe the risk factors for early VAP in patients with severe blunt thoracic trauma admitted to the intensive care unit (ICU) and receiving mechanical ventilation. Materials and Methods A retrospective cohort study was conducted using data from a national registry including data from 17 French trauma centers during a period of seven years. The study included patients with severe blunt thoracic trauma requiring invasive mechanical ventilation. Data analysis focused on identifying independent risk factors for early suspected VAP (occurring within 48 hours to 5 days after ICU admission) using two models of logistic regression. Results From 31700 patients screened 712 patients were analyzed. Early suspected VAP occurred in 192 (27%) patients. The study identified several independent risk factors associated with early suspected VAP in patients with severe blunt thoracic trauma: male gender (OR= 2.77, 95%CI: 1.68–4.77, p < 0.001), ASA score >1 (OR= 1.64, 95%CI: 1.08–2.50, p = 0.019), injury severity score (ISS) >15 (OR=3.15, 95%CI: 1.13–11.99, p = 0.025), initial Glasgow Coma Scale (GCS) score <9 (OR=2.71, 95%CI: 1.88–3.96, p < 0.001), absolute thoracic abbreviated injury scale (AIS) (OR=1.51, 95%CI: 1.14–1.99, p = 0.003), and the number of packed red blood cells (PRBCs) transfused within the first 24 hours (OR=1.04, 95%CI: 1.00–1.08, p = 0.027). Prehospital antibiotic administration was identified as a protective factor (OR=0.54, 95%CI: 0.29–0.94, p = 0.028). Conclusion In patients with severe blunt chest trauma receiving invasive mechanical ventilation, male gender, ASA score, ISS > 15, GCS < 9, thoracic AIS and number of PRBCs transfused were independent risk factors for early suspected VAP. Prehospital antibiotic therapy was a protective factor, suggesting potential strategies for VAP prevention.

Postpartum administration of eplerenone to mitigate vascular dysfunction in mice following a preeclampsia-like pregnancy

Abstract Preeclampsia is a severe pregnancy complication associated with substantial injury to systemic vasculature, major organs, and the feto-placental unit, with an approximate mortality rate of 76,000 pregnant women and 500,000 babies each year. Preeclampsia results in up to five-fold increased risk of cardiovascular disease. There is currently no cure and limited treatment options for preeclampsia and its long-term effects. In this study, we modelled preeclampsia in the mouse via nitric oxide blockade and examined the effect of therapeutic intervention during pregnancy (esomeprazole) and postpartum (eplerenone) on indices of cardiovascular health. Pregnant CBA x C57BL/6 mice received 50 mg/kg/day N(ω)-nitro-L-arginine methyl ester to induce a preeclampsia-like phenotype. Mice were treated with either 12.5 mg/kg/day esomeprazole during pregnancy, 55.5 mg/kg/day eplerenone during the postpartum period, or both esomeprazole and eplerenone in sequence. Mice were hypertensive during pregnancy, fetal growth was restricted by 10%, and maternal vasoactivity was impaired at 5-weeks postpartum. Eplerenone treatment (± esomeprazole) reduced vasoconstriction at 5-weeks postpartum and enhanced vasorelaxation at 5- and 10-weeks postpartum, supporting improved cardiovascular indices in the medium to long term postpartum period. Postpartum eplerenone treatment may be beneficial in mitigating consequent cardiovascular disease risk following a pregnancy complicated by preeclampsia.

Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling

Abstract Mechanical forces of the tumor microenvironment change dynamically during key events of tumorigenesis such as invasion and metastasis. These changes in compressive forces often affect the breast cancer cell phenotype. However, it is lesser known how these dynamic mechanical forces in the tumor microenvironment affect the phenotypes of tumor infiltrated leukocytes (TIL) and their subsequent anticancer activities. Here we find, in primary patient-derived explant cultures (PDEC) containing resident TILs, that low compression promotes a change in the original identity of breast cancer cells from luminal to a more mesenchymal and undifferentiated state. These altered tumor cells induce an upregulation of immunosuppressive cytokines such as interleukin-10 (IL-10) and Transforming Growth Factor Beta (TGF-β), as well as polarization of macrophages towards pro-tumor M2(Gc)-type and depletion of CD8+ effector memory T-cells. These immunosuppressive events are mediated by tumor cell derived fibroblast growth factor 2 (FGF2) and prostaglandin E2 (PGE2). We also find that FGF2 rich areas in primary tumors show enrichment in M2-like-macrophages and diminished numbers of CD8 + T and B-cells. Our results suggest that low compressive forces in the tumor microenvironment induce local immunosuppression via FGF2 secretion arising from phenotypic plasticity of tumor cells.

A measure of event-related potentials (ERP) indices of motivation during cycling

Although motivation is a central aspect of the practice of a physical activity, it is a challenging endeavour to predict an individual’s level of motivation during the activity. The objective of this study was to assess the feasibility of measuring motivation through brain recording methods during physical activity, with a specific focus on cycling. The experiment employed the Effort Expenditure for Reward Task (EEfRT), a decision-making task based on effort and reward, conducted under two conditions: one involving cycling on an ergometer at moderate intensity and the other without cycling. The P300, an event-related potential linked to motivation, was recorded using electroencephalography. A total of 20 participants were recruited to complete the EEfRT, which involved making effort-based decisions of increasing difficulty in order to receive varying levels of monetary reward. The results demonstrated that the P300 amplitude was influenced by the act of cycling, exhibiting a reduction during the cycling session. This reduction may be explained by a reallocation of cognitive resources due to the exertion of physical effort, which is consistent with the transient hypofrontality theory. In terms of behaviour, participants demonstrated a tendency to make more challenging choices when the potential rewards were higher or the probability of gaining them was lower. This pattern was observed in both the cycling and non-cycling conditions. A positive correlation was identified between P300 amplitude and the proportion of difficult choices, particularly under conditions of low reward probability. This suggests that P300 may serve as a neural marker of motivation. The study demonstrates the feasibility of using electroencephalography to monitor motivation during exercise in real-time, with potential applications in rehabilitation settings. However, further research is required to refine the design and explore the effects of different exercise types on motivation.

MCTP2 is a novel biomarker promoting tumor progression and nodal metastasis in oral squamous cell carcinoma

Generating dermatopathology reports from gigapixel whole slide images with HistoGPT

Abstract Histopathology is the reference standard for diagnosing the presence and nature of many diseases, including cancer. However, analyzing tissue samples under a microscope and summarizing the findings in a comprehensive pathology report is time-consuming, labor-intensive, and non-standardized. To address this problem, we present HistoGPT, a vision language model that generates pathology reports from a patient’s multiple full-resolution histology images. It is trained on 15,129 whole slide images from 6705 dermatology patients with corresponding pathology reports. The generated reports match the quality of human-written reports for common and homogeneous malignancies, as confirmed by natural language processing metrics and domain expert analysis. We evaluate HistoGPT in an international, multi-center clinical study and show that it can accurately predict tumor subtypes, tumor thickness, and tumor margins in a zero-shot fashion. Our model demonstrates the potential of artificial intelligence to assist pathologists in evaluating, reporting, and understanding routine dermatopathology cases.

“If he returns, receive him because he has realized that he needs assistance”: A qualitative study exploring preferences for retention on antiretroviral therapy support in Malawi among Lighthouse Clinic clients

Introduction Retention of people living with HIV (PLHIV) on antiretroviral therapy (ART) is critical. Retention is not static: clients cycle in and out of care over the course of treatment. Retention support is also evolving, with interventions like mobile health (mHealth) gaining traction. We aimed to explore ART clients’ perspectives and recommend strategies for improved retention support including a two-way-texting (2wT) mHealth intervention in two clinics in Malawi. Materials and methods We conducted focus group discussions (FGDs) with PLHIV on ART receiving 2wT or standard of care (SoC) retention support to understand client perspectives. FGDs were audio-recorded in Chichewa, translated and transcribed into English. We used the RE-AIM implementation science framework to report findings on the reach, effectiveness, adoption, implementation, and maintenance potential of retention interventions considering individual, clinic/organization, and community factors. Through rapid qualitative analysis, we identified key themes and subthemes. Results Ten FGDs were conducted with 89 ART clients (aged ≥18 years; 55% female): four FGDs among 2wT participants and six among SoC participants. Few differences were observed between 2wT and SoC clients. All clients appreciated accessing at least one form of support and recommended continuous assistance, regardless of age, sex, or duration on ART. Clients wished to be encouraged by other PLHIV to allay common fears. Groups discussed the need for intensified support to retain young clients or those out of care longer. Individual responsibility was identified as necessary, but insufficient, to improve retention: respondents desired a more positive clinic environment to encourage persistence in care. Fear of stigma, unintended status disclosure, and negative interactions with clinic staff prevent some clients from returning to care. Conclusion PLHIV want differentiated, continuous retention support from other PLHIV coupled with a positive clinic environment to promote retention and reengagement in care. As differentiated retention support is expensive, consideration of cost, feasibility, and sustainability is needed.

Anti-osteoporotic potential of a probiotic mixture containing Limosilactobacillus reuteri and Weissella cibaria in ovariectomized rats

Phase separation in mitochondrial fate and mitochondrial diseases

Mitochondria are central metabolic organelles that control cell fate and the development of mitochondrial diseases. Traditionally, phase separation directly regulates cell functions by driving RNA, proteins, or other molecules to concentrate into lipid droplets. Recent studies show that phase separation regulates cell functions and diseases through the regulation of subcellular organelles, particularly mitochondria. In fact, phase separation is involved in various mitochondrial activities including nucleoid assembly, autophagy, and mitochondria-related inflammation. Here, we outline the key mechanisms through which phase separation influences mitochondrial activities and the development of mitochondrial diseases. Insights into how phase separation regulates mitochondrial activities and diseases will help us develop interventions for related diseases.

Depletion-dependent activity-based protein profiling using SWATH/DIA-MS detects serine hydrolase lipid remodeling in lung adenocarcinoma progression

Abstract Systematic inference of enzyme activity in human tumors is key to understanding cancer progression and resistance to therapy. However, standard protein or transcript abundances are blind to the activity status of the measured enzymes, regulated, for example, by active-site amino acid mutations or post-translational protein modifications. Current methods for activity-based proteome profiling (ABPP), which combine mass spectrometry (MS) with chemical probes, quantify the fraction of enzymes that are catalytically active. Here, we describe depletion-dependent ABPP (dd-ABPP) combined with automated SWATH/DIA-MS, which simultaneously determines three molecular layers of studied enzymes: i) catalytically active enzyme fractions, ii) enzyme and background protein abundances, and iii) context-dependent enzyme-protein interactions. We demonstrate the utility of the method in advanced lung adenocarcinoma (LUAD) by monitoring nearly 4000 protein groups and 200 serine hydrolases (SHs) in tumor and adjacent tissue sections routinely collected for patient histopathology. The activity profiles of 23 SHs and the abundance of 59 proteins associated with these enzymes retrospectively classified aggressive LUAD. The molecular signature revealed accelerated lipoprotein depalmitoylation via palmitoyl(protein)hydrolase activities, further confirmed by excess palmitate and its metabolites. The approach is universal and applicable to other enzyme families with available chemical probes, providing clinicians with a biochemical rationale for tumor sample classification.

Finite-time analysis of epidemic reaction-diffusion models: Stability, synchronization, and numerical insights

This study presents an innovative approach to analyzing finite-time stability (FTS) and synchronization (FTSYN) in integer-order reaction-diffusion systems (RDs), particularly in the context of epidemiological modeling. By integrating Gronwall’s inequality, Lyapunov functionals (LFs), and linear control strategies, a comprehensive framework is developed to address transient dynamics within finite time frames. The proposed methodology advances the theoretical understanding of FTS and FTSYN by addressing the relatively unexplored dynamics of spatially extended systems. MATLAB simulations validate the theoretical findings, demonstrating the effectiveness of the control schemes and their practical applicability in modeling real-world disease transmission. Integrating spatial diffusion and disease dynamics provides critical insights into the influence of parameters such as diffusion rates and mortality on system behavior. This work contributes a robust framework for enhancing the analysis and management of nonlinear systems, with significant implications for epidemiology and other fields requiring rapid convergence and synchronization.

Harnessing algae oil as a sustainable DHA source for parenteral nutrition in vegan patients

Abstract Parenteral nutrition (PN) is a life-saving intervention for patients unable to meet their nutritional needs through oral or enteral routes. However, long-term PN therapy is often associated with complications, including intestinal failure-associated liver disease (IFALD), largely attributed, among other factors, to oxidative stress induced by pro-inflammatory unsaturated fatty acids. To mitigate the risk of developing IFALD, NEs have been optimized by increasing the content of Ω-3 fatty acids, particularly docosahexaenoic acid (DHA). This study aimed to develop a novel NE utilizing algae oil as a sustainable source of DHA, along with soybean lecithin as an emulsifier, to create a fully animal-free alternative to commercial intravenous NEs. The formulated algae oil-based NEs met pharmacopeial and physicochemical standards for intravenous administration, achieving a mean droplet diameter below 166.2 nm, a narrow polydispersity index, and a minimal percentage of fat globules larger than 5 μm, capped at a maximum of 0.01%. They demonstrated excellent compatibility with commercial PN admixtures, biocompatibility with red blood cells, and stability over six months of storage. Among the formulations, NE P100, prepared using non-GMO soybean-derived phospholipids containing over 90% phosphatidylcholine, exhibited the most favorable properties, indicating its potential for further development. These findings highlight algae oil as a sustainable and effective source of DHA, offering a viable option for PN-dependent patients, including those following vegan diets, while reducing the risk of IFALD. Further in vitro and in vivo research is warranted to expand applications and refine this vegan alternative in PN therapy.

NXPE1 alters the sialoglycome by acetylating sialic acids in the human colon

Abstract Mild periodic acid Schiff staining (mPAS) of human colonic tissue has been used to answer a variety of fundamental questions in germline and somatic genetics. mPAS stains sialic acids except when these glycans are modified by O-acetylation, but a full accounting of the genes contributing to sialoglycan acetylation is incomplete. Using haplotypes derived from whole genome sequencing, we identify a region on chromosome 11 that is associated with inherited differences in mPAS staining. Of the genes in this region, only haplotypes containing NXPE1 correlate perfectly with mPAS staining in the original cohort used for whole genome sequencing, as well as in a validation cohort. Transcriptomic analysis indicates that linked haplotypes are associated with altered expression of NXPE1 suggesting a possible genetic mechanism. Genetic manipulation of a common single nucleotide polymorphism observed in the haplotype region and located in NXPE1’s promoter alters expression and causes changes to modified sialic acid levels supporting this mechanism. Finally, high-performance liquid chromatography (HPLC) confirms that enzymatically active NXPE1 is capable of transferring an acetyl group from acetyl coenzyme A to sialic acid in vitro. These findings suggest that NXPE1 is the long-sought gene responsible for differences in colon mPAS staining and may be the prototype of a new family of sialic acid O-acetylation-modifying genes.

The impact of VUS reclassification on reproductive decision making

Introduction Laboratories will occasionally reclassify a VUS to pathogenic (P) or likely pathogenic (LP), making it clinically actionable. Here, we aim to characterize the frequency of this reclassification in genes tested routinely during preconception counseling in order to help guide reproductive decision making. Design Utilizing the American College of Medical Genetics (ACMG) 113-gene pre-conception panel, we conducted data analysis from ClinVar Miner (https://clinvarminer.genetics.utah.edu/). The numbers of VUS’s reported for each gene were recorded over a 3-year period (2019, 2021, & 2022). In addition, data on the number of VUS’s in conflict (VUS/P and VUS/LP) were recorded. The 10 genes with the most VUS’s and the genes with the most frequent reporting discordance were compared over the 3 years, Results There was a 103% increase in the number of VUS’s reported (2019: 13,278, 2021: 22,434, 2022: 26,965) and a 235% increase in the number of VUS’s in conflict (2019:387, 2021: 946, 2022:1297). The overall percent conflict increased significantly (2019: 2.9% vs. 2022: 4.8%). Nine genes among the top 10 with the most frequent VUS’s remained the same over the 3-year period, while five out of the ten most frequent genes with VUS’s in conflict remained the same. Conclusions The rate of conflicting reporting of a VUS has increased in 3 years and is currently at 4.8%. A potential upgrade of a VUS to pathogenic or likely pathogenic may turn the variant “actionable,” justifying testing embryos for the variant through PGT-M.