Exploring the Associated Genetic Causes of Diabetic Retinopathy as a Model of Inflammation in Retinal Diseases.

To investigate potential biomarkers and biological processes associated with diabetic retinopathy (DR) using transcriptomic and proteomic data. The OmicsPred PheWAS application was interrogated to identify genes and proteins associated with DR and diabetes mellitus (DM) at a false discovery rate (FDR)-adjusted p-value of <0.05 and also <0.005. Gene Ontology PANTHER analysis and STRING database analysis were conducted to explore the biological processes and protein interactions related to the identified biomarkers. The interrogation identified 49 genes and 22 proteins associated with DR and/or DM; these were divided into those uniquely associated with diabetic retinopathy, uniquely associated with diabetes mellitus, and the ones seen in both conditions. The Gene Ontology PANTHER and STRING database analyses highlighted associations of several genes and proteins associated with diabetic retinopathy with adaptive immune response, valyl-TRNA aminoacylation, complement activation, and immune system processes. Our analyses highlight potential transcriptomic and proteomic biomarkers for DR and emphasize the association of known aspects of immune response, the complement system, advanced glycosylation end-product formation, and specific receptor and mitochondrial function with DR pathophysiology. These findings may suggest pathways for future research into novel diagnostic and therapeutic strategies for DR.

Retinal Dystrophies Associated With Peripherin-2: Genetic Spectrum and Novel Clinical Observations in 241 Patients.

Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. Results: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. Conclusions: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.

Genomic analysis of the first multidrug-resistant ESBL-producing high-risk clonal lineage Klebsiella pneumoniae ST147 isolated from a cat with urinary tract infection.

Urinary tract infections (UTIs) are pervasive in human and veterinary medicine, notably affecting companion animals. These infections frequently lead to the prescription of antibiotics, contributing to the rise of antimicrobial-resistant bacteria. This escalating concern is underscored by the emergence of a previously undocumented case: a high-risk clone, broad-spectrum cephalosporin-resistant K. pneumoniae ST147 strain, denoted USP-275675, isolated from a cat with UTI. Characterized by a multidrug-resistant (MDR) profile, whole genome sequencing exposed several antimicrobial-resistance genes, notably blaCTX-M-15, blaTEM-1B, blaSHV-11, and blaOXA-1. ST147, recognized as a high-risk clone, has historically disseminated globally and is frequently associated with carbapenemases and extended-spectrum ß-lactamases. Notably, the core-genome phylogeny of K. pneumoniae ST147 strains isolated from urine samples revealed a unique aspect of the USP-276575 strain. Unlike its counterparts, it did not cluster with other isolates. However, a broader examination incorporating strains from both human and animal sources unveiled a connection between USP-276575 and a Portuguese strain from chicken meat. Both were part of a larger cluster of ST147 strains spanning various geographic locations and sample types, sharing commonalities such as IncFIB or IncR plasmids. This elucidates the MDR signature inherent in widespread K. pneumoniae ST147 strains carrying these plasmids, highlighting their pivotal role in disseminating antimicrobial resistance (AMR). Finally, discovering the high-risk clone K. pneumoniae ST147 in a domestic feline with a UTI in Brazil highlights the urgent need for thorough AMR surveillance through a One Health approach.

Measuring cfDNA integrity as a biomarker for predicting neoadjuvant chemotherapy response in breast cancer patients: a pilot study.

PURPOSE: Circulating cell-free DNA (cfDNA) is a promising biomarker for predicting treatment response and disease outcomes in Breast Cancer (BC) patients undergoing neoadjuvant chemotherapy (NAC). To determine if cfDNA originates from tumors, matching tumor and cfDNA gene mutations are necessary, often requiring tumor DNA sequencing. We assessed plasma cfDNA integrity by measuring concentrations and ratios of larger-to-smaller Alu DNA fractions as a potential biomarker, eliminating the need for prior tumor sequencing. METHODS: We included patients with localized and/or locally advanced BC receiving standard NAC alone or in combination with immunotherapy and/or anti-HER2 targeted therapy. Blood samples were collected before treatment, every 2 weeks during treatment, and before surgery. RESULTS: Of the 38 evaluated patients, only 28 completed the protocol and underwent surgery after NAC. Seven patients (25%) achieved a pathologic complete response (pCR). We found that cfDNA integrity (cfDNAI) levels at 15 days after starting NAC were significantly higher in patients who achieved pCR (p = 0.045) and correlated significantly with Disease-Free Survival (DFS) in univariate analysis (p = 0.0371). CONCLUSIONS: Evaluation of cfDNAI 2 weeks after NAC initiation appears to be an early biomarker for tumor pCR and DFS. Measuring Alu fragments of different lengths may replace techniques requiring prior tumor sequencing to measure ctDNA, reducing costs and complexity of cfDNA serial measurements in BC patients undergoing NAC.

Reactivities of acrylamide warheads toward cysteine targets: a QM/ML approach to covalent inhibitor design.

Covalent inhibition offers many advantages over non-covalent inhibition, but covalent warhead reactivity must be carefully balanced to maintain potency while avoiding unwanted side effects. While warhead reactivities are commonly measured with assays, a computational model to predict warhead reactivities could be useful for several aspects of the covalent inhibitor design process. Studies have shown correlations between covalent warhead reactivities and quantum mechanic (QM) properties that describe important aspects of the covalent reaction mechanism. However, the models from these studies are often linear regression equations and can have limitations associated with their usage. Applications of machine learning (ML) models to predict covalent warhead reactivities with QM descriptors are not extensively seen in the literature. This study uses QM descriptors, calculated at different levels of theory, to train ML models to predict reactivities of covalent acrylamide warheads. The QM/ML models are compared with linear regression models built upon the same QM descriptors and with ML models trained on structure-based features like Morgan fingerprints and RDKit descriptors. Experiments show that the QM/ML models outperform the linear regression models and the structure-based ML models, and literature test sets demonstrate the power of the QM/ML models to predict reactivities of unseen acrylamide warhead scaffolds. Ultimately, these QM/ML models are effective, computationally feasible tools that can expedite the design of new covalent inhibitors.

The Showcases of Dental History - A Time Machine in Miniature at the University of Puerto Rico: Part I.

The evolution of 20-year-old dental museum-like showcases located in the lobby and the main hallway of the School of Dental Medicine, Puerto Rico (PR) are described along with important professionals who impacted on this development.

The Showcases of Dental History - A time machine in miniature at the University of Puerto Rico: Part II - The Exhibits.

The University of Puerto Rico School of Dentistry was established in 1957. Over the years, it has played an important role in Puerto Rico's healthcare system. That legacy is displayed through the walls of the School of Dentistry. In Part 1, the evolution of 20-year-old dental museum-like showcases located in the lobby and the main hallway of the school were described along with important professions who impacted on this development. In this paper, we will describe in detail the items available at the museum.

Patient-reported outcomes after personalised dose-escalation for stage II-III non-small-cell lung cancer patients: Results from the randomised ARTFORCE PET-Boost trial.

BACKGROUND AND PURPOSE: The ultimate challenge in dose-escalation trials lies in finding the balance between benefit and toxicity. We examined patient-reported outcomes (PROs), including health-related quality of life (HRQoL) in patients with locally advanced non-small cell lung cancer (LA-NSCLC), treated with dose-escalated radiotherapy. MATERIALS AND METHODS: The international, randomised, phase 2 ARTFORCE PET-Boost study (NCT01024829) aimed to improve 1-year freedom from local failure rates in patients with stage II-III NSCLC, with a ≥ 4 cm primary tumour. Treatment consisted of an individualised, escalated fraction dose, either to the primary tumour as a whole or to its most FDG-avid subvolume (24 x 3.0-5.4 Gy). Patients received sequential or concurrent chemoradiotherapy, or radiotherapy only. Patients were asked to complete the EORTC QLQ-C30, QLQ-LC13, and the EuroQol-5D at eight timepoints. We assessed the effect of dose-escalation on C30 sum score through mixed-modelling and evaluated clinically meaningful changes for all outcomes. RESULTS: Between Apr-2010 and Sep-2017, 107 patients were randomised; 102 were included in the current analysis. Compliance rates: baseline 86.3%, 3-months 85.3%, 12-months 80.3%; lowest during radiation treatment 35.0%. A linear mixed-effect (LME) model revealed no significant change in overall HRQoL over time, and no significant difference between the two treatment groups. Physical functioning showed a gradual decline in both groups during treatment and at 18-months follow-up, while clinically meaningful worsening of dyspnoea was seen mainly at 3- and 6-months. CONCLUSION: In patients with LA-NSCLC treated with two dose-escalation strategies, the average patient-reported HRQoL remained stable in both groups, despite frequent patient-reported symptoms, including dyspnoea, dysphagia, and fatigue.

The HGF/Met Receptor Mediates Cytotoxic Effect of Bacterial Cyclodipeptides in Human Cervical Cancer Cells.

BACKGROUND: Human cervix adenocarcinoma (CC) caused by papillomavirus is the third most common cancer among female malignant tumors. Bioactive compounds such as cyclodipeptides (CDPs) possess cytotoxic effects in human cervical cancer HeLa cells mainly by blocking the PI3K/Akt/mTOR pathway and subsequently inducing gene expression by countless transcription regulators. However, the upstream elements of signaling pathways have not been well studied. METHODS: To elucidate the cytotoxic and antiproliferative responses of the HeLa cell line to CDPs by a transcriptomic analysis previously carried out, we identified by immunochemical analyses, differential expression of genes related to the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/MET) receptors. Furthermore, molecular docking was carried out to evaluate the interactions of CDPs with the EGF and MET substrate binding sites. RESULTS: Immunochemical and molecular docking analyses suggest that the HGF/MET receptor participation in CDPs cytotoxic effect was independent of the protein expression levels. However, protein modulation of downstream Met-targets occurred due to the inhibition of phosphorylation of the HGF/MET receptor. Results suggest that the antiproliferative and cytotoxicity of CDPs in HeLa cells involve the HGF/MET receptor upstream of PI3K/Akt/mTOR pathway; assays with the human breast cancer MCF-7 and MDA-MB-231cell lines supported the finding. CONCLUSION: Data provide new insights into the molecular mechanisms involved in CDPs cytotoxicity and antiproliferative effects, suggesting that the signal transduction mechanism may be related to the inhibition of the phosphorylation of the EGF/MET receptor at the level of substrate binding site by an inhibition mechanism similar to that of Gefitinib and foretinib anti-neoplastic drugs.

Histological Findings in the Eyes of Abcc6 Knockout Rat Model of Pseudoxanthoma Elasticum.

Purpose: To describe the ocular findings of murine pseudoxanthoma elasticum (PXE) models with ATP-binding cassette subfamily C member 6 (Abcc6) gene knockout. Methods: This experiment was conducted in four Abcc6-/- rats and compared with six wild-type Abcc6+/+ control rats. The animals underwent necropsy at 6 months of age. Histological examination of the eyes was performed. Results: Histological examination of eight eyes from four Abcc6-/- rats revealed multiple nodular foci of calcification in the uvea, sclera, and conjunctiva, focally in perivascular distribution, as well as linear and nodular calcification of Bruch's membrane. Calcific foci were not associated with inflammation in the knockout rats. There was no evidence of calcification in control eyes. Discussion: The Abcc6-/- rat model shows that PXE can affect multiple ocular tissues beyond the calcification in Bruch's membrane noted in human eyes. Nodular calcific foci probably correspond to comet lesions seen in patients with PXE. The presence of ectopic calcium without inflammation distinguishes it from inflammatory calcium deposition in atherosclerosis. Further studies are needed to determine why PXE does not cause inflammatory infiltration. Translational Relevance: The Abcc6-/- murine model may be suitable for studying ocular PXE pathophysiology and ectopic calcification and developing effective therapies.

Ising-like model replicating time-averaged spiking behaviour of in vitro neuronal networks.

We analyze time-averaged experimental data from in vitro activities of neuronal networks. Through a Pairwise Maximum-Entropy method, we identify through an inverse binary Ising-like model the local fields and interaction couplings which best reproduce the average activities of each neuron as well as the statistical correlations between the activities of each pair of neurons in the system. The specific information about the type of neurons is mainly stored in the local fields, while a symmetric distribution of interaction constants seems generic. Our findings demonstrate that, despite not being directly incorporated into the inference approach, the experimentally observed correlations among groups of three neurons are accurately captured by the derived Ising-like model. Within the context of the thermodynamic analogy inherent to the Ising-like models developed in this study, our findings additionally indicate that these models demonstrate characteristics of second-order phase transitions between ferromagnetic and paramagnetic states at temperatures above, but close to, unity. Considering that the operating temperature utilized in the Maximum-Entropy method is T o = 1 , this observation further expands the thermodynamic conceptual parallelism postulated in this work for the manifestation of criticality in neuronal network behavior.

Pseudoxanthoma elasticum-associated angioid streaks near a scleral buckle.

Purpose: We report a patient with pseudoxanthoma elasticum (PXE) with angioid streaks near a scleral buckle site. Observations: A 46-year-old male with PXE presented for evaluation of blurry vision and was found to have classic PXE findings in both eyes and angioid streaks adjacent to the site of a scleral buckle in his left eye. He underwent multimodal imaging, genetic testing, and intravitreal aflibercept in the right eye. Conclusions and importance: Bruch's membrane is known to be fragile in PXE, and patients are often counseled about the heightened risk of playing contact sports. This report raises the question of whether tension from a scleral buckle in the setting of a calcified and brittle BM may increase the likelihood of angioid streaks near the buckle site. In the setting of retinal detachment, it may be worthwhile to carefully weigh the pros and cons of vitrectomy versus buckle for PXE patients.

New forays into measurement of ocular biomechanics.

PURPOSE OF REVIEW: The field of corneal biomechanics has rapidly progressed in recent years, reflecting technological advances and an increased understanding of the clinical significance of measuring these properties. This review will evaluate in-vivo biomechanical properties obtained by current technologies and compare them regarding their relevance to established biomechanical properties obtained by gold-standard ex-vivo techniques normally conducted on elastic materials. RECENT FINDINGS: Several new technologies have appeared in recent years, including vibrational optical coherence tomography (VOCT) and the corneal indentation device (CID). These techniques provide promising new opportunities for minimally invasive and accurate measurements of corneal viscoelastic properties. SUMMARY: Alterations in corneal biomechanics are known to occur in several corneal degenerative diseases and after refractive surgical procedures. The measurement of corneal biomechanical properties has the capability to diagnose early disease and monitor corneal disease progression. Several new technologies have emerged in recent years, allowing for more accurate and less invasive measurements of corneal biomechanical properties, most notably the elastic modulus.

Neuroprotective effects of platinum nanoparticle-based microreactors in bicuculline-induced seizures.

Epilepsy designates a group of chronic brain disorders, characterized by the recurrence of hypersynchronous, repetitive activity, of neuronal clusters. Epileptic seizures are the hallmark of epilepsy. The primary goal of epilepsy treatment is to eliminate seizures with minimal side effects. Nevertheless, approximately 30% of patients do not respond to the available drugs. An imbalance between excitatory/inhibitory neurotransmission, that leads to excitotoxicity, seizures, and cell death, has been proposed as an important mechanism regarding epileptogenesis. Recently, it has been shown that microreactors composed of platinum nanoparticles (Pt-NP) and glutamate dehydrogenase possess in vitro and in vivo activity against excitotoxicity. This study investigates the in vivo effects of these microreactors in an animal model of epilepsy induced by the administration of the GABAergic antagonist bicuculline. Male Wistar rats were administered intracerebroventricularly (i.c.v.) with the microreactors or saline and, five days later, injected with bicuculline or saline. Seizure severity was evaluated in an open field. Thirty min after behavioral measurements, animals were euthanized, and their brains processed for neurodegeneration evaluation and for neurogenesis. Treatment with the microreactors significantly increased the time taken for the onset of seizures and for the first tonic-clonic seizure, when compared to the bicuculline group that did not receive the microreactor. The administration of the microreactors also increased the time spent in total exploration and grooming. Treatment with the microreactors decreased bicuculline-induced neurodegeneration and increased neurogenesis in the dorsal and ventral hippocampus. These observations suggest that treatment with Pt-NP-based microreactors attenuates the behavioral and neurobiological consequences of epileptiform seizure activity.

Facial trauma in the major league baseball.

OBJECTIVE: The objectives of this study were to identify and describe significant facial trauma present in Major League Baseball (MLB) that resulted in players missing games or being placed in the injury reserve list. STUDY DESIGN: This was a retrospective cohort study. The predictor variables were the player's age, height, weight, body mass index, position, team conference, and if played games took place in playoffs season. The outcome variables were injury location (upper, middle, and lower facial third) and type of injury (soft tissue, fracture). Chi-square and logistic regression were computed to determine associations between predictor and outcome variables. RESULTS: A total of 109 players missed games due to facial injuries, and a total of 115 injuries were identified. Of the 115 injuries, none occurred in the upper facial third, 96 (83%) were in the middle third, and 19 (17%) in the lower third. Most fractures occurred in fielders (45%), and most soft tissue injuries in basemen (40%). CONCLUSIONS: Significant facial trauma in the MLB has risen in recent years. The player's height, conference, and playoff season were the most associated factors. Most injuries occurred in the periorbital area. A recommendation for the use of protection goggles can be made to prevent them.

The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants.

We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.

Quantifying alcohol-attributable disability-adjusted life years to others than the drinker in Aotearoa/New Zealand: A modelling study based on administrative data.

BACKGROUND AND AIMS: Quantifying the health burden of alcohol has largely focused upon harm to drinkers, which is an underestimate. There is a growing literature on alcohol's harm to others (HTO), but it lacks the systematic transfer of HTO into a comparative risk assessment framework. This study calculated disability-adjusted life years (DALYs) for fetal alcohol spectrum disorder (FASD), interpersonal violence and traffic injury due to another's drinking. DESIGN: This study is a disease burden analysis, using modelling of DALYs for New Zealand in 2018. SETTING AND PARTICIPANTS: The study took place among the Aotearoa/New Zealand population in 2018. MEASUREMENTS: The involvement of others' drinking was obtained from prevalence, alcohol-attributable fraction studies and administrative data. Disability weights (DW) for FASD were adapted from fetal alcohol syndrome (FAS) weights using a Beta-Pert probability distribution; for interpersonal injury, DWs used hospital events linked with injury compensation; for traffic injury, DWs used hospital events. Populations were stratified by ethnicity, age group and gender. A descriptive comparison was made with a previous estimate of DALYs for drinkers. FINDINGS: In 2018, 78 277 healthy life years were lost in Aotearoa/New Zealand due to alcohol's HTO. The main contributor (90.3%) was FASD, then traffic crashes (6.3%) and interpersonal violence (3.4%). The indigenous population, Maori, was impacted at a higher rate (DALYs among Maori were 25 per 1000 population; among non-Maori 15 per 1000 population). The burden of HTO was greater than that to drinkers (DALYs HTO = 78 277; DALYs drinkers = 60 174). CONCLUSIONS: Disability from fetal alcohol spectrum disorder (FASD) appears to be a major contributor to alcohol's harm to others in Aotearoa/New Zealand. Taking FASD into account, the health burden of harm to others is larger than harm to the drinker in Aotearoa/New Zealand, and ethnicity differences show inequity in harm to others. Quantification of the burden of harm informs the value of implementing effective alcohol policies and should include the full range of harms.

Detection of TTR Amyloid in the Conjunctiva Using a Novel Fluorescent Ocular Tracer.

Background: Transthyretin amyloidosis (ATTR) is a significant cause of cardiomyopathy and other morbidities in the elderly and Black Americans. ATTR can be treated with new disease-modifying therapies, but large shortfalls exist in its diagnosis. The objective of this study was to test whether TTR amyloid can be detected and imaged in the conjunctiva using a novel small-molecule fluorescent ocular tracer, with the implication that ATTR might be diagnosable by a simple eye examination. Methods: Three approaches were used in this study. First, AMDX-9101 was incubated with in vitro aggregated TTR protein, and changes in its excitation and emission spectra were quantified. Second, a cadaver eye from a patient with familial amyloid polyneuropathy type II TTR mutation and a vitrectomy sample from an hATTR patient were incubated with AMDX-9101 and counterstained with Congo Red and antibodies to TTR to determine whether AMDX-9101 labels disease-related TTR amyloid deposits in human conjunctiva and eye. Last, imaging of in vitro aggregated TTR amyloid labeled with AMDX-9101 was tested in a porcine ex vivo model, using a widely available clinical ophthalmic imaging device. Results: AMDX-9101 hyper-fluoresced in the presence of TTR amyloid in vitro, labeled TTR amyloid deposits in postmortem human conjunctiva and other ocular tissues and could be detected under the conjunctiva of a porcine eye using commercially available ophthalmic imaging equipment. Conclusions: AMDX-9101 enabled detection of TTR amyloid in the conjunctiva, and the fluorescent binding signal can be visualized using commercially available ophthalmic imaging equipment. Translational Relevance: AMDX-9101 detection of TTR amyloid may provide a potential new and noninvasive test for ATTR that could lead to earlier ATTR diagnosis, as well as facilitate development of new therapeutics.

What Are We Eating? Surveying the Presence of Toxic Molecules in the Food Supply Chain Using Chromatographic Approaches.

Consumers in developed and Western European countries are becoming more aware of the impact of food on their health, and they demand clear, transparent, and reliable information from the food industry about the products they consume. They recognise that food safety risks are often due to the unexpected presence of contaminants throughout the food supply chain. Among these, mycotoxins produced by food-infecting fungi, endogenous toxins from certain plants and organisms, pesticides, and other drugs used excessively during farming and food production, which lead to their contamination and accumulation in foodstuffs, are the main causes of concern. In this context, the goals of this review are to provide a comprehensive overview of the presence of toxic molecules reported in foodstuffs since 2020 through the Rapid Alert System for Food and Feed (RASFF) portal and use chromatography to address this challenge. Overall, natural toxins, environmental pollutants, and food-processing contaminants are the most frequently reported toxic molecules, and liquid chromatography and gas chromatography are the most reliable approaches for their control. However, faster, simpler, and more powerful analytical procedures are necessary to cope with the growing pressures on the food chain supply.

Corrigendum to "Phytochemicals and bioactive constituents in food packaging - A systematic review" [Heliyon 9(11) (November 2023) e21196].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e21196.].