Corneal Epithelial Changes in Diabetic Patients: A Review.

The relationship between diabetes mellitus and ocular complications has been extensively studied by many authors. Diabetic keratopathy has already been well characterized and defined as a clinical entity. This review focuses on exploring corneal epithelial changes in diabetic patients, aiming to provide a pragmatic overview of the existing knowledge on this topic. The paper systematically examines alterations in corneal epithelial structure and their impact on diabetic patients. Advanced imaging techniques are also discussed for their role in precise characterization and improved diagnostics. Additionally, the paper explores the mechanisms behind corneal epithelial changes in diabetes, looking at factors such as hyperglycemia, oxidative stress, and Advanced Glycation End-Products. The impact of altered corneal epithelial integrity on barrier function and susceptibility to external issues is considered, addressing potential links to heightened proteolytic enzyme activities and delayed wound healing observed in diabetic individuals. The review also covers the practical implications of corneal epithelial changes, including the association with corneal erosions, persistent epithelial defects, and an increased risk of dry eye syndrome in diabetic patients.

Diagnostic Performance of Diastolic Hyperemia-Free Ratio Compared With Invasive Fractional Flow Reserve for Evaluation of Coronary Artery Disease.

Hyperemic and nonhyperemic pressure ratios are frequently used to assess the hemodynamic significance of coronary artery disease and to guide the need for myocardial revascularization. However, there are limited data on the diagnostic performance of the diastolic hyperemia-free ratio (DFR). We evaluated the diagnostic performance of the DFR compared with invasive fractional flow reserve (FFR). We performed a prospective, single-center study of 308 patients (343 lesions) who underwent DFR and FFR for evaluation of visually estimated 40% to 90% stenoses. Diagnostic performance of the DFR compared with FFR was evaluated using linear regression, Bland-Altman analysis, and receiver operating characteristic curves. The overall diagnostic accuracy of the DFR was 83%; the accuracy rates were 86%, 40%, and 95% when the DFR was <0.86, 0.88 to 0.90, and >0.93, respectively. The sensitivity, specificity, positive predicative value, and negative predictive value were 60%, 91%, 71%, and 87%, respectively. The Pearson correlation coefficient was 0.75 (p <0.05). The Bland-Altman analysis showed a mean difference of 0.09, and the area under the receiver operating characteristic curve was 0.88 (95% confidence interval 0.84 to 0.92, p <0.05). In conclusion, the DFR has a good diagnostic performance compared with FFR but 17% of the measurements were discordant. The diagnostic accuracy of the DFR was only 40% when the DFR was 0.88 to 0.90, suggesting that FFR may be useful in these arteries.

Idiopathic Subglottic Stenosis Is Associated With More Frequent and Abnormal Squamous Metaplasia.

OBJECTIVES: Gain insights into the pathophysiology of idiopathic subglottic stenosis (iSGS) by investigating differences in transcriptome of subglottic mucosal tissue between patients with iSGS and controls, and between tracheal and subglottic tissue within patients. METHODS: RNA sequencing was conducted on biopsied mucosal samples collected from subglottic and tracheal (in-patient control) regions in iSGS patients, and from subglottis in controls. The gene expression differences were validated on a protein level by (1) staining the tissue samples obtained from a second cohort of patients and controls; and (2) in vitro functional assays using primary subglottic epithelial cells from both iSGS patients and healthy donors. RESULTS: We found 7 upregulated genes in the subglottic region of iSGS patients relative to both the tracheal mucosa and subglottic region of controls. A gene ontology enrichment analysis found that the epithelial cell differentiation and cornification pathways are significant, involving specifically 3 of the genes: involucrin (IVL), small proline rich protein 1B (SPRR1B), and keratin 16 (KRT16). Involvement of these pathways suggests squamous metaplasia of the epithelium. Histological analyses of epithelium in subglottic mucosal biopsies revealed squamous metaplasia in 41% of the samples from iSGS patients and in 25% from controls. Immunohistochemical evaluation of the samples presented with squamous epithelium revealed increased expression of the protein encoded by SPRR1B, hyperproliferative basal cells, shedding of apical layers, and accompanying lesions in iSGS compared to CTRL. Cultured primary subglottic epithelial cells from iSGS patients had higher proliferation rates compared to healthy donors and squamous metaplastic differentiation formed thinner epithelia with increased expression proteins encoded by INV, SPRR1B, and KRT16, suggesting intrinsic dysfunction of basal cells in iSGS. CONCLUSIONS: Abnormal squamous differentiation of epithelial cells may contribute to the pathogenesis of iSGS. Patients having metaplastic epithelial phenotype may be sensitive to drugs that reverse it to a normal phenotype.

Genome-Wide Association Study of Gallstone Disease Identifies Novel Candidate Genomic Variants in a Latino Community of Southwest USA.

Gallstone disease (GSD) is a prevalent health condition that impacts many adults and is associated with presence of stones in gallbladder cavity that results in inflammation, pain, fever, nausea and vomiting. Several genome-wide association studies (GWAS) in the past have identified genes associated with GSD but only a few were focused on Latino population. To identify genetic risk factors for GSD in Latino population living in the Southwest USA we used self-reported clinical history, physical and lab measurements data in Sangre Por Salud (SPS) cohort and identified participants with and without diagnosis of GSD. We performed a GWAS on this phenotype using GSD cases matched to normal controls based on a tight criterion. We identified several novel loci associated with GSD as well as loci that were previously identified in past GWAS studies. The top 3 loci (MATN2, GPRIN3, GPC6) were strongly associated with GSD phenotype in our combined analysis and a sex stratified analysis results in females were closest to the overall results reflecting a general higher disease prevalence in females. The top identified variants in MATN2, GPRIN3, and GPC6 remain unchanged after local ancestry adjustment in SPS Latino population. Follow-up pathway enrichment analysis suggests enrichment of GO terms that are associated with immunological pathways; enzymatic processes in gallbladder, liver, and gastrointestinal tract; and GSD pathology. Our findings suggest an initial starting point towards better and deeper understanding of differences in gallstone disease pathology, biological mechanisms, and disease progression among Southwest US Latino population.

Coronary Revascularization in Patients With Cancer.

Purpose of review: The treatment of coronary artery disease (CAD) in cancer patients is an evolving landscape. Recent data emphasizes the importance of aggressive management of cardiovascular risk factors and diseases in improving cardiovascular health in this unique group of patients regardless of cancer type or stage. Recent findings: Novel cancer therapeutics such as immune therapies and proteasome inhibitors have been associated with CAD. Recent stent technologies may safely allow for shorter duration (< 6 months) of dual antiplatelet therapy post-percutaneous coronary interventions. Intracoronary imaging may be useful in the decision making process in terms of stent positioning and healing. Summary: Large registry studies have partially filled a gap left by the lack of randomized controlled trials in the treatment of CAD in cancer patients. Cardio-oncology is gaining traction as a major sub-specialty in the cardiology field given the release of the first European Society of Cardiology - Cardio-oncology guidelines in 2022.

Precision Medicine as a New Frontier in Speech-Language Pathology: How Applying Insights From Behavior Genomics Can Improve Outcomes in Communication Disorders.

PURPOSE: Precision medicine is an emerging intervention paradigm that leverages knowledge of risk factors such as genotypes, lifestyle, and environment toward proactive and personalized interventions. Regarding genetic risk factors, examples of interventions informed by the field of medical genomics are pharmacological interventions tailored to an individual's genotype and anticipatory guidance for children whose hearing impairment is predicted to be progressive. Here, we show how principles of precision medicine and insights from behavior genomics have relevance for novel management strategies of behaviorally expressed disorders, especially disorders of spoken language. METHOD: This tutorial presents an overview of precision medicine, medical genomics, and behavior genomics; case examples of improved outcomes; and strategic goals toward enhancing clinical practice. RESULTS: Speech-language pathologists (SLPs) see individuals with various communication disorders due to genetic variants. Ways of using insights from behavior genomics and implementing principles of precision medicine include recognizing early signs of undiagnosed genetic disorders in an individual's communication patterns, making appropriate referrals to genetics professionals, and incorporating genetic findings into management plans. Patients benefit from a genetics diagnosis by gaining a deeper and more prognostic understanding of their condition, obtaining more precisely targeted interventions, and learning about their recurrence risks. CONCLUSIONS: SLPs can achieve improved outcomes by expanding their purview to include genetics. To drive this new interdisciplinary framework forward, goals should include systematic training in clinical genetics for SLPs, enhanced understanding of genotype-phenotype associations, leveraging insights from animal models, optimizing interprofessional team efforts, and developing novel proactive and personalized interventions.

A data-fusion approach to identifying developmental dyslexia from multi-omics datasets.

This exploratory study tested and validated the use of data fusion and machine learning techniques to probe high-throughput omics and clinical data with a goal of exploring the etiology of developmental dyslexia. Developmental dyslexia is the leading learning disability in school aged children affecting roughly 5-10% of the US population. The complex biological and neurological phenotype of this life altering disability complicates its diagnosis. Phenome, exome, and metabolome data was collected allowing us to fully explore this system from a behavioral, cellular, and molecular point of view. This study provides a proof of concept showing that data fusion and ensemble learning techniques can outperform traditional machine learning techniques when provided small and complex multi-omics and clinical datasets. Heterogenous stacking classifiers consisting of single-omic experts/models achieved an accuracy of 86%, F1 score of 0.89, and AUC value of 0.83. Ensemble methods also provided a ranked list of important features that suggests exome single nucleotide polymorphisms found in the thalamus and cerebellum could be potential biomarkers for developmental dyslexia and heavily influenced the classification of DD within our machine learning models.

Analysis of Kerf Quality Characteristics of Kevlar Fiber-Reinforced Polymers Cut by Abrasive Water Jet.

Abrasive water jet machining has become an indispensable process for cutting Kevlar fiber-reinforced polymers used in applications such as ballistics protection, race cars, and protective gloves. The complex and diffuse action of a large number of input parameters leads to the need to evaluate the quality characteristics of the technological transformation as a result of the deployment of experimental studies adapted to the specific processing conditions. Thus, the paper focuses on identifying the influence of different factors and modeling their action on the characteristics that define the quality of the cut parts, such as the kerf taper angle and the Ra roughness parameter, by applying statistical methods of design and analysis of experiments.

Ocular Complications of Radiotherapy in Uveal Melanoma.

Uveal melanoma is the most common primary malignant intraocular tumor in adults. Radiation therapy has replaced enucleation and is now the preferred treatment in most cases. Nonetheless, around 70% of patients develop radiation-related complications, some of which are vision-threatening. The objective of this review is to present the most important complications associated with radiotherapy in the treatment of uveal melanoma and their pathogenesis, incidence, risk factors, and available preventive and therapeutic measures. The most common complications are cataracts, with a reported incidence ranging from 4% to 69%, and radiation retinopathy, reported in 5-68% of cases. Radiation-related complications are responsible for approximately half of secondary enucleations, the leading cause being neovascular glaucoma. A poor visual outcome is mainly associated with the presence of radiation retinopathy and radiation optic neuropathy. Therapeutic options are available for the majority of complications with the notable exception of optic neuropathy. However, many studies report a final visual acuity of less than 20/200 in more than 60% of treated eyes. Reducing complication rates can be achieved by lowering the dose of radiation, with the use of eccentric, customized plaques and careful planning of the irradiation delivery in order to protect structures vital to vision and by associating radiation therapy with other methods with the aim of reducing tumor volume.

Photoactivated Chromophore Corneal Collagen Cross-Linking for Infectious Keratitis (PACK-CXL)-A Comprehensive Review of Diagnostic and Prognostic Factors Involved in Therapeutic Indications and Contraindications.

Infectious keratitis is a severe infection of the eye, which requires urgent care in order to prevent permanent complications. Typical cases are usually diagnosed clinically, whereas severe cases also require additional tools, such as direct microscopy, corneal cultures, molecular techniques, or ophthalmic imaging. The initial treatment is empirical, based on the suspected etiology, and is later adjusted as needed. It ranges from topical administration of active substances to oral drugs, or to complex surgeries in advanced situations. A novel alternative is represented by Photoactivated Chromophore Corneal Collagen Cross-Linking (PACK-CXL), which is widely known as a minimally invasive therapy for corneal degenerations. The purpose of this review is to identify the main diagnostic and prognostic factors which further outline the indications and contraindications of PACK-CXL in infectious keratitis. Given the predominantly positive outcomes in the medical literature, we ponder whether this is a promising treatment modality, which should be further evaluated in a systematic, evidence-based manner in order to develop a clear treatment protocol for successful future results, especially in carefully selected cases.

Choroidal Thickness Increase after Subliminal Transscleral Cyclophotocoagulation.

Background: The purpose of this study is to estimate the success rate of subliminal transscleral cyclophotocoagulation for refractory glaucoma and to determine the correlation between the decrease in intraocular pressure and the variation in choroidal thickness. Methods: A pre−post study was conducted over a period of 3 years, including 81 eyes from 67 patients with different types of drug-refractory glaucoma who underwent subliminal transscleral cyclophotocoagulation. The variables included best-corrected visual acuity, intraocular pressure and choroidal thickness. Results: We observed the following success rates (defined as IOP < 21 mmHg): 80% at 1 month (65 patients), 74% at 3 months (60 patients), 64% at 6 months (52 patients) and 50.6% at 1 year (41 patients). A strong correlation was noted between the decrease in intraocular pressure and the increase in the average choroidal thickness at 1 year (318.42 µm) compared to the average preoperative thickness (291.78 µm). A correlation of increased choroidal thickness at 1-month with the success rate of the procedure was also observed. Conclusions: We observed a statistically significant correlation between the success rate, decrease in intraocular pressure and choroidal thickness. The correlation of increased choroidal thickness at 1-month with the success rate of the procedure could be used clinically as a predictive factor for the final outcome of patients. Further experimental research is warranted to determine whether the increase in choroidal thickness after subliminal transscleral cyclophotocoagulation is indeed evidence of increased uveoscleral drainage.

Accurate Identification of Subclones in Tumor Genomes.

Understanding intratumor heterogeneity is critical for studying tumorigenesis and designing personalized treatments. To decompose the mixed cell population in a tumor, subclones are inferred computationally based on variant allele frequency (VAF) from bulk sequencing data. In this study, we showed that sequencing depth, mean VAF, and variance of VAF of a subclone are confounded. Without considering this effect, current methods require deep-sequencing data (>300× depth) to reliably infer subclones. Here, we present a novel algorithm that incorporates depth-variance and mean-variance dependencies in a clustering error model and successfully identifies subclones in tumors sequenced at depths of as low as 30×. We implemented the algorithm as a model-based adaptive grouping of subclones (MAGOS) method. Analyses of computer simulated data and empirical sequencing data showed that MAGOS outperformed existing methods on minimum sequencing depth, decomposition accuracy, and computation efficiency. The most prominent improvements were observed in analyzing tumors sequenced at depths between 30× and 200×, whereas the performance was comparable between MAGOS and existing methods on deeply sequenced tumors. MAGOS supports analysis of single-nucleotide variants and copy number variants from a single sample or multiple samples of a tumor. We applied MAGOS to whole-exome data of late-stage liver cancers and discovered that high subclone count in a tumor was a significant risk factor of poor prognosis. Lastly, our analysis suggested that sequencing multiple samples of the same tumor at standard depth is more cost-effective and robust for subclone characterization than deep sequencing a single sample. MAGOS is available at github (https://github.com/liliulab/magos).

Prematurity-Risk Factor or Coincidence in Congenital Glaucoma?

Background and Objective: To correlate the intraocular pressure with the postconceptional age and identify a statistically significant connection between congenital glaucoma and prematurity. Materials and Methods: The current paper is a retrospective, comparative, case-control study. Data collection featured maternal age, gestational age at birth, birth weight, and intraocular ocular pressure (IOP) measurements. Results: Forty-two eyes of 21 children underwent examination. The participants were assigned into two groups. The Preterm-Glaucoma (PG) group included eight preterm-born children diagnosed with glaucoma, whereas the Preterm (P) group was comprised of premature newborns without the aforementioned condition. There was no statistically relevant difference in birth weight (p = 0.691078) nor in mean gestational age (p = 0.752623) between the two groups. The mean IOP in the PG group was 23.813 ± 4.5493, whereas in the P group, it ranged around 13.231 ± 1.0699, p < 0.0001. Using mixed-effects models, we obtained a reduction in IOP of 0.45 mmHg per week in the first month of life. A further weekly reduction of 0.36 mmHg was achieved in the next two months. Conclusions: The mean IOP of prematurely born children decreased with age. Our findings correlate with previously conducted studies, however, the drop in IOP values exceeded any data published so far. We found no correlation between prematurity and the incidence of congenital glaucoma.

Bioprosthetic valve monitoring in patients with carcinoid heart disease.

Background: Carcinoid heart disease (CnHD) is a frequent cause of morbidity and mortality in patients with neuroendocrine tumors and carcinoid syndrome. Although valve replacement surgery appears to decrease all-cause mortality in patients with advanced CnHD, few studies have investigated the outcomes of patients after valve replacement. Methods: We conducted a multi-institution retrospective registry of patients who received both tricuspid and pulmonic bioprosthetic valve (TV/PV) replacements for advanced CnHD from November 2005 to March 2021. Patients were followed post-operatively with echocardiographic studies every 3 months. Carcinoid valvular heart disease scores were used to monitor valve degeneration. Neuroendocrine tumor treatment, their administration times, and associations with echocardiographic findings were recorded. Results: Of 87 patients with CnHD, 22 patients underwent simultaneous surgical TV and PV replacement. In 6 patients (27.3%), increased PV Vmax was the first echocardiographic manifestation of valve degeneration in the setting of occult neurohormonal release. Post-operative telotristat ethyl and peptide receptor radionuclide therapy appeared to stabilize PV Vmax. The PV Vmax showed consistent elevation in the entire patient population when compared to baseline, while bioprosthetic TV echocardiographic parameters were relatively unchanged throughout. Post-operative warfarin therapy did not affect the rate of PV degeneration, and no major bleeding was recorded during or after post-operative anticoagulation therapy. Conclusion: Bioprosthetic valve degeneration is common in CnHD. Monitoring with echocardiographic studies every 3 months, focusing on PV velocities, could identify patients with occult disease that very likely promotes valve degeneration. Novel neuroendocrine tumor therapies may have a beneficial impact on valve degeneration.

Coronary Stent Healing in Cancer Patients-An Optical Coherence Tomography Perspective.

Objective: This study assessed stent healing patterns and cardiovascular outcomes by optical coherence tomography (OCT) in cancer patients after drug-eluting stent (DES) placement. Background: Cancer treatment, owing to its cytotoxic and antiproliferative effects, could delay stent healing and increase stent thrombosis risk, especially when dual antiplatelet therapy (DAPT) is discontinued early for oncological treatment. OCT can assess stent endothelialization and other healing parameters, which may provide clinical guidance in these challenging scenarios. Methods: This single-center retrospective study enrolled all cancer patients who underwent OCT for assessment of vascular healing patterns after prior DES placement from November 2009 to November 2018. Primary study endpoints were stent healing parameters, including stent coverage, apposition, degree of expansion, neointimal hyperplasia heterogeneity, in-stent restenosis, stent thrombosis, and overall survival (OS). Results: A total of 67 patients were included in this study. Mean time between DES placement and OCT evaluation was 154 ± 82 days. Stent healing matched published values for DES in non-cancer patients (P ≥ 0.063). At 1 year, the OS was 86% (95% confidence interval [CI]: 78-96%) with 0% incidence of acute coronary syndrome. Advanced cancers and active chemotherapies were associated with inferior OS (P = 0.024, hazard ratio [HR]: 3.50, 95% CI: 1.18-10.42 and P = 0.026, HR: 2.65, 95% CI: 1.13-6.22, respectively), while stent healing parameters were unassociated with OS. Forty-one patients (61%) had DAPT duration ≤6 months. Conclusions: Stent healing of contemporary DES appears similar in cancer and non-cancer patients. Cardiovascular risk of cancer patients after DES placement can be managed to facilitate timely cancer therapies, as the underlying malignancy and active chemotherapy ultimately determine survival.

Family Rank: a graphical domain knowledge informed feature ranking algorithm.

MOTIVATION: When designing prediction models built with many features and relatively small sample sizes, feature selection methods often overfit training data, leading to selection of irrelevant features. One way to potentially mitigate overfitting is to incorporate domain knowledge during feature selection. Here, a feature ranking algorithm called 'Family Rank' is presented in which features are ranked based on a combination of graphical domain knowledge and feature scores computed from empirical data. RESULTS: A simulated dataset is used to demonstrate a scenario in which family rank outperforms other state-of-the-art graph based ranking algorithms, decreasing the sample size needed to detect true predictors by 2- to 3-fold. An example from oncology is then used to explore a real-world application of family rank. AVAILABILITY AND IMPLEMENTATION: An implementation of Family Rank is freely available at https://cran.r-project.org/package=FamilyRank. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Transcatheter and surgical aortic valve replacement impact on outcomes and cancer treatment schedule.

BACKGROUND: Recent data suggest that transcatheter aortic valve replacement (TAVR) for the treatment of severe aortic stenosis (AS) is viable in cancer patients. TAVR may be preferred in cancer patients due to its minimally invasive nature and smaller impact on oncologic therapies compared to SAVR. Objectives We sought to determine if TAVR is an acceptable alternative to SAVR in cancer patients and whether TAVR allows for earlier initiation or resumption of anti-cancer therapies. METHODS: Cancer patients in a tertiary cancer center diagnosed with severe AS were retrospectively included. Patients accepted by the heart team underwent either TAVR or SAVR, while remaining patients received medical therapy alone. Time intervals to initiation of cancer treatment and the impact of cancer treatment on the replaced valves were recorded. Logistic regression was performed to determine the impact of treatment strategy on overall survival (OS) in all 3 subgroups. RESULTS: One hundred and eighty-seven cancer patients diagnosed with severe AS were identified. AVR was associated with better OS compared to medical therapy alone (p < 0.0001). TAVR was associated with better OS at 72 months (HR = 0.468, p < 0.001) compared to medical therapy alone, with no difference in OS observed between SAVR and TAVR. Time intervals to initiation of cancer treatments were shorter in the TAVR group, with no valve deterioration or infection observed in all groups. CONCLUSION: Cancer patients with severe AS benefit from AVR. TAVR is a viable alternative to SAVR in high-risk cancer patients to prolong survival and allow for earlier administration or resumption of anti-neoplastic therapies.

Cancer treatment resumption in patients with new-generation drug-eluting stents.

OBJECTIVE: Percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (DESs) may provide survival benefits to the cancer population undergoing PCI by expediting cancer treatment due to improved safety profile. We aimed to assess the safety of starting or resuming cancer treatment within 6 months of DES placement. We also compared the impact of different DES types on the overall survival (OS) in cancer patients and to identify a safe threshold for dual antiplatelet therapy (DAPT) discontinuation. METHODS: Cancer patients at our institution undergoing PCI with DES from December 2014 to June 2017 were included. Baseline demographics, DAPT duration, malignancy type, stage, and treatment were retrospectively analyzed. Univariate Cox regression was used to pinpoint baseline characteristics that correlated with OS. Survivorship was determined by Kaplan-Meier analysis, and the log-rank test was used to compare OS among DES types. RESULTS: Seventy-five patients were included. Of these, 45 had biodegradable polymer DES (Synergy) and 30 patients had durable polymer DES (Resolute Integrity, Xience, Ion, or Promus). Mean duration of follow-up was 1367 ± 334 days. There were two minor bleeding complications. No statistically significant differences in OS were found among different stent brands. Discontinuation of aspirin, early P2Y12 inhibitor discontinuation, and advanced cancer were significantly associated with OS. DAPT discontinuation <6 months after PCI was not associated with stent thrombosis or in-stent restenosis. There were two major adverse cardiac events: one in-stent restenosis while on DAPT for >12 months (attributed to radiation-induced heart disease) and one myocardial infarction and death. Of patients who resumed or started cancer treatment (chemotherapy, radiation therapy, or surgery) after PCI, all but one did so within 6 months of PCI, and most of them as early as 2 weeks. CONCLUSION: Patients may resume cancer treatment <6 months after PCI. We suggest that DAPT may be safely interrupted as early as 6 months, but additional longitudinal studies are needed.