Characterizing the Contribution of Dependent Features in XAI Methods.

Explainable Artificial Intelligence (XAI) provides tools to help understanding how AI models work and reach a particular decision or outcome. It helps to increase the interpretability of models and makes them more trustworthy and transparent. In this context, many XAI methods have been proposed to make black-box and complex models more digestible from a human perspective. However, one of the main issues that XAI methods have to face especially when dealing with a high number of features is the presence of multicollinearity, which casts shadows on the robustness of the XAI outcomes, such as the ranking of informative features. Most of the current XAI methods either do not consider the collinearity or assume the features are independent which, in general, is not necessarily true. Here, we propose a simple, yet useful, proxy that modifies the outcome of any XAI feature ranking method allowing to account for the dependency among the features, and to reveal their impact on the outcome. The proposed method was applied to SHAP, as an example of XAI method which assume that the features are independent. For this purpose, several models were exploited for a well-known classification task (males versus females) using nine cardiac phenotypes extracted from cardiac magnetic resonance imaging as features. Principal component analysis and biological plausibility were employed to validate the proposed method. Our results showed that the proposed proxy could lead to a more robust list of informative features compared to the original SHAP in presence of collinearity.

Bone health, cardiovascular disease, and imaging outcomes in UK Biobank: a causal analysis.

This study examined the association of estimated heel bone mineral density (eBMD, derived from quantitative ultrasound) with: (1) prevalent and incident cardiovascular diseases (CVDs: ischemic heart disease (IHD), myocardial infarction (MI), heart failure (HF), non-ischemic cardiomyopathy (NICM), arrhythmia), (2) mortality (all-cause, CVD, IHD), and (3) cardiovascular magnetic resonance (CMR) measures of left ventricular and atrial structure and function and aortic distensibility, in the UK Biobank. Clinical outcomes were ascertained using health record linkage over 12.3 yr of prospective follow-up. Two-sample Mendelian randomization (MR) was conducted to assess causal associations between BMD and CMR metrics using genetic instrumental variables identified from published genome-wide association studies. The analysis included 485 257 participants (55% women, mean age 56.5 ± 8.1 yr). Higher heel eBMD was associated with lower odds of all prevalent CVDs considered. The greatest magnitude of effect was seen in association with HF and NICM, where 1-SD increase in eBMD was associated with 15% lower odds of HF and 16% lower odds of NICM. Association between eBMD and incident IHD and MI was non-significant; the strongest relationship was with incident HF (SHR: 0.90 [95% CI, 0.89-0.92]). Higher eBMD was associated with a decreased risk in all-cause, CVD, and IHD mortality, in the fully adjusted model. Higher eBMD was associated with greater aortic distensibility; associations with other CMR metrics were null. Higher heel eBMD is linked to reduced risk of a range of prevalent and incident CVD and mortality outcomes. Although observational analyses suggest associations between higher eBMD and greater aortic compliance, MR analysis did not support a causal relationship between genetically predicted BMD and CMR phenotypes. These findings support the notion that bone-cardiovascular associations reflect shared risk factors/mechanisms rather than direct causal pathways.

Noninvasive Techniques for Tracking Biological Aging of the Cardiovascular System: JACC Family Series.

Population aging is one of the most important demographic transformations of our time. Increasing the "health span"-the proportion of life spent in good health-is a global priority. Biological aging comprises molecular and cellular modifications over many years, which culminate in gradual physiological decline across multiple organ systems and predispose to age-related illnesses. Cardiovascular disease is a major cause of ill health and premature death in older people. The rate at which biological aging occurs varies across individuals of the same age and is influenced by a wide range of genetic and environmental exposures. The authors review the hallmarks of biological cardiovascular aging and their capture using imaging and other noninvasive techniques and examine how this information may be used to understand aging trajectories, with the aim of guiding individual- and population-level interventions to promote healthy aging.

Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

Cardiovascular Magnetic Resonance Reference Ranges From the Healthy Hearts Consortium.

BACKGROUND: The absence of population-stratified cardiovascular magnetic resonance (CMR) reference ranges from large cohorts is a major shortcoming for clinical care. OBJECTIVES: This paper provides age-, sex-, and ethnicity-specific CMR reference ranges for atrial and ventricular metrics from the Healthy Hearts Consortium, an international collaborative comprising 9,088 CMR studies from verified healthy individuals, covering the complete adult age spectrum across both sexes, and with the highest ethnic diversity reported to date. METHODS: CMR studies were analyzed using certified software with batch processing capability (cvi42, version 5.14 prototype, Circle Cardiovascular Imaging) by 2 expert readers. Three segmentation methods (smooth, papillary, anatomic) were used to contour the endocardial and epicardial borders of the ventricles and atria from long- and short-axis cine series. Clinically established ventricular and atrial metrics were extracted and stratified by age, sex, and ethnicity. Variations by segmentation method, scanner vendor, and magnet strength were examined. Reference ranges are reported as 95% prediction intervals. RESULTS: The sample included 4,452 (49.0%) men and 4,636 (51.0%) women with average age of 61.1 ± 12.9 years (range: 18-83 years). Among these, 7,424 (81.7%) were from White, 510 (5.6%) South Asian, 478 (5.3%) mixed/other, 341 (3.7%) Black, and 335 (3.7%) Chinese ethnicities. Images were acquired using 1.5-T (n = 8,779; 96.6%) and 3.0-T (n = 309; 3.4%) scanners from Siemens (n = 8,299; 91.3%), Philips (n = 498; 5.5%), and GE (n = 291, 3.2%). CONCLUSIONS: This work represents a resource with healthy CMR-derived volumetric reference ranges ready for clinical implementation.

Plasmonic Contact Lenses Based on Silver Nanoparticles for Blue Light Protection.

Constant exposure to blue light emanating from screens, lamps, digital devices, or other artificial sources at night can suppress melatonin secretion, potentially compromising both sleep quality and overall health. Daytime exposure to elevated levels of blue light can also lead to permanent damage to the eyes. Here, we have developed blue light protective plasmonic contact lenses (PCLs) to mitigate blue light exposure. Crafted from poly(hydroxyethyl methacrylate) (pHEMA) and infused with silver nanoparticles, these contact lenses serve as a protective barrier to filter blue light. Leveraging the plasmonic properties of silver nanoparticles, the lenses effectively filtered out the undesirable blue light (400-510 nm), demonstrating substantial protection (22-71%) while maintaining high transparency (80-96%) for the desirable light (511-780 nm). The maximum protection level reaches a peak of 79% at 455 nm, aligned with the emission peak for the blue light sourced from LEDs in consumer displays. The presence of silver nanoparticles was found to have an insignificant impact on the water content of the developed contact lenses. The lenses maintained high water retention levels within the range of 50-70 wt %, comparable to commercial contact lenses. The optical performance of the developed lenses remains unaffected in both artificial tears and contact lens storage solution over a month with no detected leakage of the nanoparticles. Additionally, the MTT assay confirmed that the lenses were biocompatible and noncytotoxic, maintaining cell viability at over 85% after 24 h of incubation. These lenses could be a potential solution to protect against the most intense wavelengths emitted by consumer displays and offer a remedy to counteract the deleterious effects of prolonged blue light exposure.

Leukocyte Telomere Length and Cardiac Structure and Function: A Mendelian Randomization Study.

BACKGROUND: Existing research demonstrates the association of shorter leukocyte telomere length with increased risk of age-related health outcomes including cardiovascular diseases. However, the direct causality of these relationships has not been definitively established. Cardiovascular aging at an organ level may be captured using image-derived phenotypes of cardiac anatomy and function. METHODS AND RESULTS: In the current study, we use 2-sample Mendelian randomization to assess the causal link between leukocyte telomere length and 54 cardiac magnetic resonance imaging measures representing structure and function across the 4 cardiac chambers. Genetically predicted shorter leukocyte telomere length was causally linked to smaller ventricular cavity sizes including left ventricular end-systolic volume, left ventricular end-diastolic volume, lower left ventricular mass, and pulmonary artery. The association with left ventricular mass (ß =0.217, Pfalse discovery rate=0.016) remained significant after multiple testing adjustment, whereas other associations were attenuated. CONCLUSIONS: Our findings support a causal role for shorter leukocyte telomere length and faster cardiac aging, with the most prominent relationship with left ventricular mass.

Multifunctional transition and temperature-responsive contact lenses.

Smart contact lenses have recently gained traction due to their functionalization as noninvasive diagnostic and therapeutic wearables that can address several ocular diseases. Herein, multifunctional contact lenses exhibiting UV-transition and temperature-responsive capabilities were developed utilizing chromogenic materials that were integrated simultaneously into poly(2-hydroxyethyl methacrylate) (pHEMA) contact lenses. The functionalities of the contact lenses were optically evaluated in both their activated and non-activated states. Transition contact lenses offered excellent UV and blue light blocking capabilities (~45%) at their inactive states. When activated via UV exposure, the transparent lenses darkened instantaneously and absorbed portions of the visible light spectrum. The absorption intensity and transient discoloration of the transition lenses relied primarily on the utilized photochromic material. Likewise, the temperature-responsive contact lenses exhibited distinct colorimetric variations in response to temperature changes within the physiological range (33-38 °C). The maximum sensitivity of the thermochromic lens was 8% transmitted light per Celsius degree shift. Physiochemical and morphological analysis indicated the adequacy of the contact lenses. Hence, the multifunctional contact lenses can be deployed as smart wearables to manage ophthalmic deficiencies that are deterred by UV radiations and variations in ocular surface temperature.

Radiomics of pericardial fat: a new frontier in heart failure discrimination and prediction.

OBJECTIVES: To use pericardial adipose tissue (PAT) radiomics phenotyping to differentiate existing and predict future heart failure (HF) cases in the UK Biobank. METHODS: PAT segmentations were derived from cardiovascular magnetic resonance (CMR) studies using an automated quality-controlled model to define the region-of-interest for radiomics analysis. Prevalent (present at time of imaging) and incident (first occurrence after imaging) HF were ascertained using health record linkage. We created balanced cohorts of non-HF individuals for comparison. PyRadiomics was utilised to extract 104 radiomics features, of which 28 were chosen after excluding highly correlated ones (0.8). These features, plus sex and age, served as predictors in binary classification models trained separately to detect (1) prevalent and (2) incident HF. We tested seven modeling methods using tenfold nested cross-validation and examined feature importance with explainability methods. RESULTS: We studied 1204 participants in total, 297 participants with prevalent (60 ± 7 years, 21% female) and 305 with incident (61 ± 6 years, 32% female) HF, and an equal number of non-HF comparators. We achieved good discriminative performance for both prevalent (voting classifier; AUC: 0.76; F1 score: 0.70) and incident (light gradient boosting machine: AUC: 0.74; F1 score: 0.68) HF. Our radiomics models showed marginally better performance compared to PAT area alone. Increased PAT size (maximum 2D diameter in a given column or slice) and texture heterogeneity (sum entropy) were important features for prevalent and incident HF classification models. CONCLUSIONS: The amount and character of PAT discriminate individuals with prevalent HF and predict incidence of future HF. CLINICAL RELEVANCE STATEMENT: This study presents an innovative application of pericardial adipose tissue (PAT) radiomics phenotyping as a predictive tool for heart failure (HF), a major public health concern. By leveraging advanced machine learning methods, the research uncovers that the quantity and characteristics of PAT can be used to identify existing cases of HF and predict future occurrences. The enhanced performance of these radiomics models over PAT area alone supports the potential for better personalised care through earlier detection and prevention of HF. KEY POINTS: •PAT radiomics applied to CMR was used for the first time to derive binary machine learning classifiers to develop models for discrimination of prevalence and prediction of incident heart failure. •Models using PAT area provided acceptable discrimination between cases of prevalent or incident heart failure and comparator groups. •An increased PAT volume (increased diameter using shape features) and greater texture heterogeneity captured by radiomics texture features (increased sum entropy) can be used as an additional classifier marker for heart failure.

Genome-Wide Association Study of Pericardial Fat Area in 28 161 UK Biobank Participants.

BACKGROUND Pericardial adipose tissue (PAT) is the visceral adipose tissue compartment surrounding the heart. Experimental and observational research has suggested that greater PAT deposition might mediate cardiovascular disease, independent of general or subcutaneous adiposity. We characterize the genetic architecture of adiposity-adjusted PAT and identify causal associations between PAT and adverse cardiac magnetic resonance imaging measures of cardiac structure and function in 28 161 UK Biobank participants. METHODS AND RESULTS The PAT phenotype was extracted from cardiac magnetic resonance images using an automated image analysis tool previously developed and validated in this cohort. A genome-wide association study was performed with PAT area set as the phenotype, adjusting for age, sex, and other measures of obesity. Functional mapping and Bayesian colocalization were used to understand the biologic role of identified variants. Mendelian randomization analysis was used to examine potential causal links between genetically determined PAT and cardiac magnetic resonance-derived measures of left ventricular structure and function. We discovered 12 genome-wide significant variants, with 2 independent sentinel variants (rs6428792, P=4.20×10-9 and rs11992444, P=1.30×10-12) at 2 distinct genomic loci, that were mapped to 3 potentially causal genes: T-box transcription factor 15 (TBX15), tryptophanyl tRNA synthetase 2, mitochondrial (WARS2) and early B-cell factor-2 (EBF2) through functional annotation. Bayesian colocalization additionally suggested a role of RP4-712E4.1. Genetically predicted differences in adiposity-adjusted PAT were causally associated with adverse left ventricular remodeling. CONCLUSIONS This study provides insights into the genetic architecture determining differential PAT deposition, identifies causal links with left structural and functional parameters, and provides novel data about the pathophysiological importance of adiposity distribution.

Anti- SARS-CoV-2 IgG and IgM Levels in Iraqi General Population.

BACKGROUND: Acquired immunity plays an important role in the prevention of viral infections. SARS-CoV-2 is an infection that leads to a pandemic. The development of specific anti-SARSCoV- 2 antibodies may play a vital role in disease prevention and control. Thus IgG antibody screening in the general population provides information on the immunological status of the community. AIM: To clarify the SARS-CoV-2 immune status in the general population. METHODS: A cross-sectional study was conducted in Kirkuk province during the period from 15 May 2022 to 11 September 2022. The samples were collected from voluntary subjects and informed consent was taken from each participant before their enrolment in the study. SARS-CoV-2 IgG, SARSCoV- 2 IgM, 25-OH Vitamin D, Vitamin B12, and Folate were determined using the Electrochemiluminescence Immunoassay (eCLIA) technique with the instrument NIPIGON-Robot R1Automated ECL Analyzer (Canada). RESULTS: The overall IgG mean concentration was 37.75 ± 23.18 COI, with a median of 39.99 COI and a range of 0.25 - 87.23 COI. Additionally, 93% of tested samples were with concentrations of more than 1 COI. The highest frequency (18.2%) was for the IgG concentration of 51 to 60 COI, while the lowest frequency (1.3%) was for the concentration of 81 - 90 COI. The IgG was significantly higher (P = 0.046) in males (39.87 ± 24.04 COI) than that in females (35.12 ± 21.89 COI). The IgM overall concentration was 0.569 ± 0.456 COI, with a median of 0.489 COI and a range of 0.17 - 6.40 COI. The mean serum level of folic acid concentration was 9.03 ± 5.72 ng/ml, with a median of 7.476 ng/ml and a range of 0.60 - 20.00 ng/ml. The mean serum concentration of vitamin B12 was 462.65 ± 349.18 pg/ml, with a median of 353 pg/ml and a range of 13.05 - 2000 pg/ml. The mean serum concentration of vitamin D was 18.29 ± 18.42 ng/ml with a median of 12.44 ng/ml and a range of 3 - 100 ng/ml. IgG and IgM serum levels did not show a significant correlation with serum levels of folic acid, vitamin D, and vitamin B12. However, there was a significant correlation between folic acid and vitamin D (r = 0.197; P = 0.012); vitamin B12 and vitamin D (r = 0.253, P = 0.001). While there was a non-significant correlation between folic acid and vitamin D serum levels (r = 0.129, P = 0.10). CONCLUSION: General population IgG antibody concentration reflects a high rate of herd immunity. Folic acid was with a mean value of about half of the upper normal limit and only 17.7% were with low values. Vitamin B12, only 6.3% of the population had values lower than normal. However, the range of vitamin B12 was wide. While vitamin D values were lower than the normal limit at 82.6%. However, a large scale well designed was warranted to evaluate COVID-19 national immune response.

Ischemic Heart Disease and Vascular Risk Factors Are Associated With Accelerated Brain Aging.

BACKGROUND: Ischemic heart disease (IHD) has been linked with poor brain outcomes. The brain magnetic resonance imaging-derived difference between predicted brain age and actual chronological age (brain-age delta in years, positive for accelerated brain aging) may serve as an effective means of communicating brain health to patients to promote healthier lifestyles. OBJECTIVES: The authors investigated the impact of prevalent IHD on brain aging, potential underlying mechanisms, and its relationship with dementia risk, vascular risk factors, cardiovascular structure, and function. METHODS: Brain age was estimated in subjects with prevalent IHD (n = 1,341) using a Bayesian ridge regression model with 25 structural (volumetric) brain magnetic resonance imaging features and built using UK Biobank participants with no prevalent IHD (n = 35,237). RESULTS: Prevalent IHD was linked to significantly accelerated brain aging (P < 0.001) that was not fully mediated by microvascular injury. Brain aging (positive brain-age delta) was associated with increased risk of dementia (OR: 1.13 [95% CI: 1.04-1.22]; P = 0.002), vascular risk factors (such as diabetes), and high adiposity. In the absence of IHD, brain aging was also associated with cardiovascular structural and functional changes typically observed in aging hearts. However, such alterations were not linked with risk of dementia. CONCLUSIONS: Prevalent IHD and coexisting vascular risk factors are associated with accelerated brain aging and risk of dementia. Positive brain-age delta representing accelerated brain aging may serve as an effective communication tool to show the impact of modifiable risk factors and disease supporting preventative strategies.

Computational approaches for evaluating morphological changes in the corneal stroma associated with decellularization.

Decellularized corneas offer a promising and sustainable source of replacement grafts, mimicking native tissue and reducing the risk of immune rejection post-transplantation. Despite great success in achieving acellular scaffolds, little consensus exists regarding the quality of the decellularized extracellular matrix. Metrics used to evaluate extracellular matrix performance are study-specific, subjective, and semi-quantitative. Thus, this work focused on developing a computational method to examine the effectiveness of corneal decellularization. We combined conventional semi-quantitative histological assessments and automated scaffold evaluations based on textual image analyses to assess decellularization efficiency. Our study highlights that it is possible to develop contemporary machine learning (ML) models based on random forests and support vector machine algorithms, which can identify regions of interest in acellularized corneal stromal tissue with relatively high accuracy. These results provide a platform for developing machine learning biosensing systems for evaluating subtle morphological changes in decellularized scaffolds, which are crucial for assessing their functionality.

Exploring the relationship between insomnia and depression: a cross-sectional prospective study.

This is a cross-sectional prospective study aimed to examine the association between insomnia and depression among individuals attending an outpatient psychiatric clinic. Methods: A total of 416 participants were recruited from the psychiatric and mental health outpatient clinic using a cross-sectional design. The participants completed the Pittsburgh Sleep Quality Index (PSQI) and the Beck Depression Inventory (BDI) to measure sleep disturbances and depressive symptoms, respectively. Ethical approval was obtained from the Institutional Review Board at Ninevah University. Descriptive statistics, bivariate correlations, and multivariate regression analysis were used to analyze the data. The data collected in the study was analyzed using SPSS v0.26. Results: A total of 416 participants were recruited from the psychiatric and mental health outpatient clinic in Iraq through convenience sampling. The sample included 227 (54.6%) females and 189 (45.4%) males, with a mean age of 35.4 years (SD=9.8, range=18-65). Participants had a mean PSQI score of 11.6 (SD=3.7, range=2-21) and a mean BDI score of 21.8 (SD=11.1, range=0-54). Bivariate correlations showed a significant positive relationship between sleep disturbances (as measured by the PSQI) and depressive symptoms (as measured by the BDI) (r=0.67, P<0.001). Conclusions: The study provides valuable insights into the relationship between insomnia and depression in a sample of individuals from Iraq. These findings could contribute to the development of interventions to improve mental health outcomes among this population.

3D Printing of Multimaterial Contact Lenses.

3D printing of multimaterial objects is an emerging field with promising applications. The layer-by-layer material addition technique used in 3D printing enables incorporation of distinct functionalized materials into the specialized devices. However, very few studies have been performed on the usage of multimaterial 3D printing for printable photonic and wearable devices. Here, we employ vat photopolymerization-based 3D printing to produce multimaterial contact lenses, offering enhanced multiband optical filtration, which can be valuable for tackling ocular conditions such as color blindness. A combination of hydroxyethyl methacrylate (HEMA) and polyethylene glycol diacrylate (PEGDA) was used as the base hydrogel for 3D printing. Atto565 and Atto488 dyes were added to the hydrogel for wavelength filtering, each dye suitable for a different type of color blindness. Multimaterial disks and contact lenses, with separate sections containing distinct dyes, were 3D-printed, and their optical properties were studied. The characteristics of multimaterial printing were analyzed, focusing on the formation of a uniform multimaterial interface. In addition, a novel technique was developed for printing multiple dyed materials in complex lateral geometrical patterns, by employing suitable variations in CAD models and the UV curing time. It was observed that the multimaterial printing process does not negatively affect the optical properties of the contact lenses. The printed multimaterial contact lenses offered a combined multi-band color blindness correction due to the two dyes used. The resulting optical spectrum was a close match to the commercially available color blindness correction glasses.

Phenazopyridine-Induced Methemoglobinemia in a Jehovah's Witness Treated with High-Dose Ascorbic Acid Due to Methylene Blue Contradictions: A Case Report and Review of the Literature.

Methemoglobinemia is an acute medical emergency that requires prompt correction. Physicians should have a high degree of suspicion of methemoglobinemia in cases that present with hypoxemia that does not resolve with supplemental oxygenation, and they should confirm this suspicion with a positive methemoglobin concentration on arterial blood gas. There are multiple medications that can induce methemoglobinemia, such as local anesthetics, antimalarials, and dapsone. Phenazopyridine is an azo dye used over-the-counter as a urinary analgesic for women with urinary tract infections, and it has also been implicated in causing methemoglobinemia. The preferred treatment of methemoglobinemia is methylene blue, but its use is contraindicated for patients with glucose-6-phosphatase deficiency or those who take serotonergic drugs. Alternative treatments include high-dose ascorbic acid, exchange transfusion therapy, and hyperbaric oxygenation. The authors report a case of a 39-year-old female who took phenazopyridine for 2 weeks to treat dysuria from a urinary tract infection and subsequently developed methemoglobinemia. The patient had contraindications for the use of methylene blue and was therefore treated with high-dose ascorbic acid. The authors hope that this interesting case promotes further research into the utilization of high-dose ascorbic acid for managing methemoglobinemia in patients who are unable to receive methylene blue.

Conceptual Overview of Biological Age Estimation.

Chronological age is an imperfect measure of the aging process, which is affected by a wide range of genetic and environmental exposures. Biological age estimates may be derived using mathematical modelling with biomarkers set as predictors and chronological age as the output. The difference between biological and chronological age is denoted the "age gap" and considered a complementary indicator of aging. The utility of the "age gap" metric is assessed through examination of its associations with exposures of interest and the demonstration of additional information provided by this metric over chronological age alone. This paper reviews the key concepts of biological age estimation, the age gap metric, and approaches to assessment of model performance in this context. We further discuss specific challenges for the field, in particular the limited generalisability of effect sizes across studies owing to dependency of the age gap metric on pre-processing and model building methods. The discussion will be centred on brain age estimation, but the concepts are transferable to all biological age estimation.

Derivation and comparison of formulae for the adjustment of total calcium.

Background: Free ionized calcium (Ca2+) is the biologically active component of total calcium (TCa) and hence responsible for its biological action. TCa is routinely adjusted for albumin using several formulae (e.g. James, Orell, Payne and Berry) to more closely reflect Ca2+. Here, we derive a novel formula to estimate Ca2+ and compare its performance to established formulae. Methods: Cohort for prediction of Ca2+: 2806 serum samples (TCa) taken contemporaneously with blood gas samples (Ca2+) at Imperial College Healthcare NHS Trust were used to derive formulae to estimate Ca2+ using multivariable linear regression. Cohort for prediction of PTH: Performance of novel and existing formulae to predict PTH in 5510 patients was determined by Spearman correlation. Results: Ca2+ prediction Cohort: Adjusted calcium (r2 = 0.269) was less strongly associated with Ca2+, than TCa (r2 = 0.314). Prediction of Ca2+ from a newly derived formula incorporating TCa, potassium, albumin, and hematocrit had an improved r2 of 0.327, whereas inclusion of all available parameters increased the r2 further to 0.364. Of the established formulae, James performed best in predicting Ca2+ (r2 = 0.27). PTH prediction cohort: Berry resulted in higher whereas Orell in lower adjusted calcium levels. Prediction of PTH was strongest in the setting of hypercalcemia, with James having the highest Spearman correlation coefficient (+0.496) similar to including all parameters (+0.499). Conclusion: Adjustment of calcium for albumin using established formulae does not always outperform unadjusted TCa in the reflection of Ca2+. Further prospective studies are needed to optimise adjustment of TCa and to establish bounds for validity.

A scalable corneal xenograft platform: simultaneous opportunities for tissue engineering and circular economic sustainability by repurposing slaughterhouse waste.

Introduction: Corneal disease is a leading cause of blindness globally that stems from various etiologies. High-throughput platforms that can generate substantial quantities of corneal grafts will be invaluable in addressing the existing global demand for keratoplasty. Slaughterhouses generate substantial quantities of underutilized biological waste that can be repurposed to reduce current environmentally unfriendly practices. Such efforts to support sustainability can simultaneously drive the development of bioartificial keratoprostheses. Methods: Scores of discarded eyes from the prominent Arabian sheep breeds in our surrounding region of the United Arab Emirates (UAE) were repurposed to generate native and acellular corneal keratoprostheses. Acellular corneal scaffolds were created using a whole-eye immersion/agitation-based decellularization technique with a widely available, eco-friendly, and inexpensive 4% zwitterionic biosurfactant solution (Ecover, Malle, Belgium). Conventional approaches like DNA quantification, ECM fibril organization, scaffold dimensions, ocular transparency and transmittance, surface tension measurements, and Fourier-transform infrared (FTIR) spectroscopy were used to examine corneal scaffold composition. Results: Using this high-throughput system, we effectively removed over 95% of the native DNA from native corneas while retaining the innate microarchitecture that supported substantial light transmission (over 70%) after reversing opacity, a well-established hallmark of decellularization and long-term native corneal storage, with glycerol. FTIR data revealed the absence of spectral peaks in the frequency range 2849 cm-1 to 3075 cm-1, indicating the effective removal of the residual biosurfactant post-decellularization. Surface tension studies confirmed the FTIR data by capturing the surfactant's progressive and effectual removal through tension measurements ranging from approximately 35 mN/m for the 4% decellularizing agent to 70 mN/m for elutes highlighting the effective removal of the detergent. Discussion: To our knowledge, this is the first dataset to be generated outlining a platform that can produce dozens of ovine acellular corneal scaffolds that effectively preserve ocular transparency, transmittance, and ECM components using an eco-friendly surfactant. Analogously, decellularization technologies can support corneal regeneration with attributes comparable to native xenografts. Thus, this study presents a simplified, inexpensive, and scalable high-throughput corneal xenograft platform to support tissue engineering, regenerative medicine, and circular economic sustainability.