Targeting Neutrophil Extracellular Trap Formation: Exploring Promising Pharmacological Strategies for the Treatment of Preeclampsia.

Neutrophils, which constitute the most abundant leukocytes in human blood, emerge as crucial players in the induction of endothelial cell death and the modulation of endothelial cell responses under both physiological and pathological conditions. The hallmark of preeclampsia is endothelial dysfunction induced by systemic inflammation, in which neutrophils, particularly through the formation of neutrophil extracellular traps (NETs), play a pivotal role in the development and perpetuation of endothelial dysfunction and the hypertensive state. Considering the potential of numerous pharmaceutical agents to attenuate NET formation (NETosis) in preeclampsia, a comprehensive assessment of the extensively studied candidates becomes imperative. This review aims to identify mechanisms associated with the induction and negative regulation of NETs in the context of preeclampsia. We discuss potential drugs to modulate NETosis, such as NF-κß inhibitors, vitamin D, and aspirin, and their association with mutagenicity and genotoxicity. Strong evidence supports the notion that molecules involved in the activation of NETs could serve as promising targets for the treatment of preeclampsia.

Is Cryocide an Ethically Feasible Alternative to Euthanasia?

While some countries are moving toward legalization, euthanasia is still criticized on various fronts. Most importantly, it is considered a violation of the medical ethics principle of non-maleficence, because it actively seeks a patient's death. But, medical ethicists should consider an ethical alternative to euthanasia. In this article, we defend cryocide as one such alternative. Under this procedure, with the consent of terminally-ill patients, their clinical death is induced, in order to prevent the further advance of their brain's deterioration. Their body is then cryogenically preserved, in the hope that in the future, there will be a technology to reanimate it. This prospect is ethically distinct from euthanasia if a different criterion of death is assumed. In the information-theoretic criterion of death, a person is not considered dead when brain and cardiopulmonary functions cease, but rather, when information constituting psychology and memory is lost.

LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review.

LOX-1, ORL-1, or lectin-like oxidized low-density lipoprotein receptor 1 is a transmembrane glycoprotein that binds and internalizes ox-LDL in foam cells. LOX-1 is the main receptor for oxidized low-density lipoproteins (ox-LDL). The LDL comes from food intake and circulates through the bloodstream. LOX-1 belongs to scavenger receptors (SR), which are associated with various cardiovascular diseases. The most important and severe of these is the formation of atherosclerotic plaques in the intimal layer of the endothelium. These plaques can evolve into complicated thrombi with the participation of fibroblasts, activated platelets, apoptotic muscle cells, and macrophages transformed into foam cells. This process causes changes in vascular endothelial homeostasis, leading to partial or total obstruction in the lumen of blood vessels. This obstruction can result in oxygen deprivation to the heart. Recently, LOX-1 has been involved in other pathologies, such as obesity and diabetes mellitus. However, the development of atherosclerosis has been the most relevant due to its relationship with cerebrovascular accidents and heart attacks. In this review, we will summarize findings related to the physiologic and pathophysiological processes of LOX-1 to support the detection, diagnosis, and prevention of those diseases.

Ocular manifestations of Monkeypox virus (MPXV) infection with viral persistence in ocular samples - a case series.

OBJECTIVE: We describe the clinical presentation and ocular viral dynamics in patients with Monkeypox virus-related ophthalmic disease (MPXROD). METHODS: In this case series, we investigated five consecutive patients with confirmed mpox, diagnosed through a positive Monkeypox virus (MPXV) Polymerase Chain Reaction (PCR) test and presenting with ocular symptoms. They were referred from the Reference Center for Sexually Transmitted Infections in São Paulo (CRT) to the Uveitis Sector at the Federal University of São Paulo, between August and December 2022. We performed PCR testing on ocular samples and culture supernatants for MPXV in all patients. Viral sequencing was conducted in one of the cases. RESULTS: Replicating MPXV was identified in at least one ocular sample of all patients, between day 31 and day 145 after the onset of skin lesions. All patients presented with keratitis, 3 with uveitis (60%) and two exhibited hypopyon (40%). The onset of ocular symptoms occurred at a mean of 21,2 days after the appearance of the first skin lesion and persisted, on average, for 61,6 days, with a worsening trend observed until the initiation of tecovirimat treatment. Tecovirimat treatment was administered to all patients, with initiation occurring between 31 and 145 days after the onset of skin lesions. MPXV genome sequencing of an isolate from one patient classified it as belonging to lineage B1 in clade IIb. CONCLUSION: This study reveals a late onset and persistence of sight threatening ocular disease, along with potential viral infectivity even after systemic resolution in mpox cases. These findings highlight the risk of ongoing transmission from individuals with prolonged ocular manifestations, particularly through ocular discharge.

Hand hygiene knowledge, attitude, and practice before, during and post COVID-19: a cross-sectional study among university students in the United Arab Emirates.

Aims: Hand hygiene (HH) is an essential practice to evade the transmission of germs and minimize community-acquired infections. This study assesses the knowledge, attitude and practice (KAP) of HH and other health and safety measures before, during, and after the COVID-19 pandemic. in university students in the United Arab Emirates (UAE). Methods: A cross-sectional questionnaire study was conducted between December 2022 and March 2023, targeting university students from all disciplines and study levels. A 44-item questionnaire was used which included student demographics, knowledge, attitude, and practice of HH, as well as the anticipated risk of COVID-19 morbidity and mortality. Participants consented before commencing the questionnaire, and the collected data were analysed using the student's t-test and ANOVA test, as required. Results: A total of 378 responses were received nationwide, with a valid response rate of 98%. The HH knowledge revealed an average score of 62%, which was significantly higher in students with moderate family income. Additionally, the average attitude score was 74.7%, as measured on the Likert scale, and the score lacked any correlation with the other variables. HH practice showed an average score of 86.8%, which was correlated with the students' gender and field of study. Conclusions: This study showed a moderate level of knowledge, a good attitude, and good practice around HH and other safety measures among the UAE's university students. Socioeconomic status, gender, and field of study influenced the study outcomes. This study highlights the need for effective awareness campaigns to reinforce students' health and safety, especially for male and non-health science students, in order to protect against communicable diseases.

Evaluation of the impact of COVID-19 on stress and burnout among Ajman university (AU) medical students.

This study was conducted at AU to estimate the prevalence of stress and burnout among medical students during the COVID-19 pandemic. This study aimed to provide insights into the levels of stress and burnout experienced by medical students at AU and identify potential risk factors. The research methodology involved a cross-sectional survey using a self-administered questionnaire among 215 College of Medicine AU students. The findings indicated that many participants experienced moderate stress levels, as revealed by data collected on a Likert scale. No significant differences in stress scores were found based on sex, but variations were observed among years of study and living status. An analysis of burnout using the Copenhagen Burnout Inventory showed that over half of the participants experienced moderate levels of burnout. No significant differences in burnout were found based on gender, marital status, residence, GPA, motivation for enrolment, or nationality; however, variations were observed among different age groups and years of study. These findings highlight the need for targeted interventions and support systems to address stress and burnout among AU students by focusing on the identified risk factors. By implementing evidence-based strategies, AU can promote the well-being and resilience of medical students, thereby contributing to their overall success and the future of the healthcare workforce.

The discovery of novel noncoding RNAs in 50 bacterial genomes.

Structured noncoding RNAs (ncRNAs) contribute to many important cellular processes involving chemical catalysis, molecular recognition and gene regulation. Few ncRNA classes are broadly distributed among organisms from all three domains of life, but the list of rarer classes that exhibit surprisingly diverse functions is growing. We previously developed a computational pipeline that enables the near-comprehensive identification of structured ncRNAs expressed from individual bacterial genomes. The regions between protein coding genes are first sorted based on length and the fraction of guanosine and cytidine nucleotides. Long, GC-rich intergenic regions are then examined for sequence and structural similarity to other bacterial genomes. Herein, we describe the implementation of this pipeline on 50 bacterial genomes from varied phyla. More than 4700 candidate intergenic regions with the desired characteristics were identified, which yielded 44 novel riboswitch candidates and numerous other putative ncRNA motifs. Although experimental validation studies have yet to be conducted, this rate of riboswitch candidate discovery is consistent with predictions that many hundreds of novel riboswitch classes remain to be discovered among the bacterial species whose genomes have already been sequenced. Thus, many thousands of additional novel ncRNA classes likely remain to be discovered in the bacterial domain of life.

Medical school origins of award-winning physicians; analysis of a complete national dataset.

BACKGROUND: Educators and medical students share the same objective of achieving success in medical practice. Both groups consider doctors' successes to include optimum patient care outcomes and positive career progressions. Accordingly, identifying common educational features of such high-achieving doctors facilitates the generation of excellence amongst future medical trainees. In this study we use data from the British clinical merit award schemes as outcome measures in order to identify medical school origins of doctors who have achieved national or international prominence. METHODS: Britain has Clinical Excellence Awards/Distinction Awards schemes that financially reward all National Health Service doctors in England, Scotland and Wales who are classified as high achievers. We used these outcome measures in a quantitative observational analysis of the 2019-20 dataset of all 901 national award-winning doctors. Where appropriate, Pearson's Chi-Square test was applied. RESULTS: The top five medical schools (London university medical schools, Glasgow, Edinburgh, Oxford and Cambridge) were responsible for 51.2% of the physician merit award-winners in the 2019-20 round, despite the dataset representing 85 medical schools. 91.4% of the physician merit award-winners were from European medical schools. The lowest national award-winners (tier 3) originated from 61 medical schools representing six continents. International medical graduates comprised 11.4% of all award-winners. CONCLUSIONS: The majority of physicians who were national merit award-winners originated from only five, apparently overrepresented, UK university medical schools. In contrast, there was a greater diversity in medical school origin among the lower grade national merit awards; the largest number of international medical graduates were in these tier 3 awards (13.3%). As well as ranking educationally successful university medical schools, this study assists UK and international students, by providing a roadmap for rational decision making when selecting physician and non-physician medical education pathways that are more likely to fulfil their career ambitions.

Medical school origins of award-winning psychiatrists; analysis of a complete national dataset.

BACKGROUND: Britain attracts doctors from all over the world to work in the National Health Service. Elucidating the educational backgrounds of award-winning doctors working in the country is potentially an important medical education issue and a merit award audit. Using the British clinical merit award schemes as outcome measures, we identify medical school origins of award-winning doctors who have been identified as having achieved national or international prominence. METHODS: The Clinical Excellence Awards/Distinction Awards schemes select doctors in Britain who are classified as high achievers, with categories for national prominence and above. We used this outcome measure in a quantitative observational analysis of the 2019-20 dataset of all 901 award-winning doctors. Pearson's Chi-Square test was used where appropriate. RESULTS: Five university medical schools (London university medical schools, Glasgow, Edinburgh, Aberdeen and Cambridge) accounted for 59.1% of the psychiatrist award-winning doctors in the 2019 round, despite the dataset representing 85 medical schools. 84.1% of the psychiatrist award-winners were from European medical schools, compared to 92.1% of the non-psychiatrist award-winners. International medical graduates accounted for 22.7% of the award-winning psychiatrists. Psychiatrists with the lower grade national awards came from a more diverse educational background of 17 medical schools. IMGs represented diverse medical schools from five continents and were most represented in the lowest grade of national merit awards at 24.2%. CONCLUSIONS: The majority of the award-winning psychiatrists originated from only five medical schools. A greater diversity of medical school origin existed for the lowest grade national psychiatrist award-winners. International medical graduates contributed substantially to these award-winners; psychiatrist award-winners were more likely to be international medical graduates (22.7%) than non-psychiatrist award-winners (10.8%). This study not only indicates educational centres associated with the production of award-winners but also provides students with a roadmap for rational decision making when selecting medical schools.

The Potential of Wood Vinegar to Replace Antimicrobials Used in Animal Husbandry-A Review.

The indiscriminate use of antimicrobials in animal husbandry can result in various types of environmental contamination. Part of the dose of these products is excreted, still active, in the animals' feces and urine. These excreta are widely used as organic fertilizers, which results in contamination with antimicrobial molecules. The impacts can occur in several compartments, such as soil, groundwater, and surface watercourses. Also, contamination by antimicrobials fed or administrated to pigs, chickens, and cattle can reach the meat, milk, and other animal products, which calls into question the sustainability of using these products as part of eco-friendly practices. Therefore, a search for alternative natural products is required to replace the conventional antimicrobials currently used in animal husbandry, aiming to mitigate environmental contamination. We thus carried out a review addressing this issue, highlighting wood vinegar (WV), also known as pyroligneous acid, as an alternative antimicrobial with good potential to replace conventional products. In this regard, many studies have demonstrated that WV is a promising product. WV is a nontoxic additive widely employed in the food industry to impart a smoked flavor to foods. Studies have shown that, depending on the WV concentration, good results can be achieved using it as an antimicrobial against pathogenic bacteria and fungi and a valuable growth promoter for poultry and pigs.

Moral approval of xenotransplantation in Egypt: associations with religion, attitudes towards animals and demographic factors.

Xenotransplantation has great potential as an alternative to alleviate the shortage of organs for donation. However, given that the animal most suited for xenotransplantation is the pig, there are concerns that people in Muslim countries may be more hesitant to morally approve of these procedures. In this study, the moral approval of xenotransplantation was assessed in a group of 895 participants in Egypt. The results showed that religiosity itself does not predict moral approval of xenotransplantation, but religious identity does, as Muslims are less likely to approve of xenotransplantation than Christians. However, the strongest predictor of moral approval of xenotransplantation was gender, with women displaying less approval. A partial mediating factor in this association was concern for animal welfare. Based on these results, some implications for public policy are discussed.

Ethical Shortcomings of QALY: Discrimination Against Minorities in Public Health.

Despite progress, discrimination in public health remains a problem. A significant aspect of this problem relates to how medical resources are allocated. The paradigm of quality-adjusted-life-year (QALY) dictates that medical resources should be allocated on the basis of units measured as length of life and quality of life that are expected after the implementation of a treatment. In this article, I discuss some of the ethical shortcomings of QALY, by focusing on some of its flawed moral aspects, as well as the way it relates to discrimination on the basis of age, race, and disability status. I argue that while this approach seeks to maximize efficiency, it does not place sufficient value on the preservation of life itself. Even more concerning is the fact that the use of QALY disproportionately harms minorities. While QALY is a well-intentioned approach to the allocation of scarce healthcare resources, new alternatives must be sought.

Nightmare experiences and perceived ethnic discrimination amongst female university students in the United Arab Emirates: a cross-sectional study.

Perceived ethnic discrimination is known to be associated with anxiety and depression, and in turn, anxiety and depression are known to be associated with nightmare frequency and distress. This elicits a question: is perceived ethnic discrimination associated with nightmare frequency and distress? In this study, 179 female university students from the United Arab Emirates were assessed to answer that question. Results showed that while anxiety and depression were related to nightmare experiences, perceived ethnic discrimination was a stronger predictor of nightmare experiences. We posit two explanations for this finding: one based on psychoanalytical insights, and the other based on the Disposition-Stress model with neurobiological correlates. No significant differences were found across ethnicity when it comes to nightmare experiences or perceived ethnic discrimination. This is an encouraging sign of optimal societal integration in the United Arab Emirates.

Urinary biomarkers associated with acute kidney injury in pediatric mechanical circulatory support patients.

BACKGROUND: In patients requiring mechanical circulatory support (MCS), the incidence of acute kidney injury (AKI) is between 37 and 63%. In this study, we performed an exploratory analysis evaluating the relationship of multiple urine biomarkers with AKI development in pediatric MCS patients. METHODS: This is a single center retrospective study in a pediatric cohort receiving MCS from August 2014 to November 2020. We measured 14 urine biomarkers of kidney injury on day 1 following MCS initiation and analyzed their association with development of AKI in the first 7 days of MCS initiation. RESULTS: Sixty patients met inclusion criteria. Patients with AKI were more likely to be supported by venoarterial extracorporeal membrane oxygenation (65% vs. 8.3%, p < 0.001), compared to the no AKI group and less likely to have ventricular assist devices (10% vs. 50%, p < 0.001). There was a significant increase in the median urine albumin and urine osteoactivin in the AKI group, compared to the no AKI group (p = 0.020 and p = 0.018, respectively). When normalized to urine creatinine (UCr), an increased log osteoactivin/UCr was associated with higher odds of AKI development (OR: 2.05; 95% CI: 1.07, 4.44; p = 0.028), and higher log epidermal growth factor (EGF)/UCr (OR: 0.41; 95% CI: 0.15, 0.96) was associated with decreased odds of AKI. CONCLUSIONS: Early increase in urine osteoactivin is associated with AKI development within 7 days of MCS initiation in pediatric patients. Contrary, an increased urine EGF is associated with kidney protection. A higher resolution version of the Graphical abstract is available as Supplementary information.

Tubular mitochondrial pyruvate carrier disruption elicits redox adaptations that protect from acute kidney injury.

OBJECTIVE: Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity. METHODS: We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI. RESULTS: MPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival. CONCLUSIONS: Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.

Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy.

PURPOSE: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as an additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLT nephrotoxicity. METHODS: A bifunctional cyclic peptide, melanocortin 1 ligand (MC1L), labeled with [203Pb]Pb-MC1L, was used for [212Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [212Pb]Pb-MC1L in a dose-escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. RESULTS: Biodistribution analysis identified [212Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [212Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [212Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. CONCLUSION: Urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Impact of Pendent Ammonium Groups on Solubility and Cycling Charge Carrier Performance in Nonaqueous Redox Flow Batteries.

The synthesis, characterization, electrochemical performance, and theoretical modeling of two base-metal charge carrier complexes incorporating a pendent quaternary ammonium group, [Ni(bppn-Me3)][BF4], 3', and [Fe(PyTRENMe)][OTf]3, 4', are described. Both complexes were produced in high yield and fully characterized using NMR, IR, and UV-vis spectroscopies as well as elemental analysis and single-crystal X-ray crystallography. The solubility of 3' in acetonitrile showed a 283% improvement over its neutral precursor, whereas the solubility of complex 4' was effectively unchanged. Cyclic voltammetry indicates an ∼0.1 V positive shift for all waves, with some changes in reversibility depending on the wave. Bulk electrochemical cycling demonstrates that both 3' and 4' can utilize the second more negative wave to a degree, whereas 4' ceases to have a reversible positive wave. Flow cell testing of 3' and 4' with Fc as the posolyte reveals little improvement to the cycling performance of 3' compared with its parent complex, whereas 4' exhibits reductions in capacity decay when cycling either negative wave. Postcycling CVs indicate that crossover is the likely source of capacity loss in complexes 3, 3', and 4' because there is little change in the CV trace. Density functional theory calculations indicate that the ammonium group lowers the HOMO energy in 3' and 4', which may impart stability to cycling negative waves while making positive waves less accessible. Overall, the incorporation of a positively charged species can improve solubility, stored electron density, and capacity decay depending on the complex, features critical to high energy density redox flow battery performance.

Phone addiction, cyberbullying, and mental health amongst young adults in the United Arab Emirates: a cross-sectional study.

BACKGROUND: Smartphone addiction is a common phenomenon worldwide and within the UAE. It is related to many factors, including gender and ethnicity, and can lead to mental health disorders, such as anxiety and depression. This study investigates these factors concerning smartphone addiction among young adults in the UAE. METHODS: 421 participants answered a questionnaire of validated and reliable scales measuring smartphone addiction, cyberbullying experiences, mental health, and demographic information. The average age of the participants was 21 years, and the age groups were divided into two groups. Group 1 consists of participants who are 20 years or younger, and group 2 consists of participants aged 21 or older. RESULTS: There was a positive correlation between smartphone addiction with both anxiety and depression. A positive correlation was also found between cyberbullying victims, anxiety, and depression. Females were found to have higher levels of anxiety and smartphone addiction in comparison to males. CONCLUSION: Smartphone addiction is a problem that connects to disorders like anxiety and depression. Conversely, cyberbullying is not directly related to smartphone addiction but is also strongly related to anxiety and depression.

Pre-clinical Evaluation of Biomarkers for Early Detection of Nephrotoxicity Following Alpha-particle Radioligand Therapy.

Purpose: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLTs nephrotoxicity. Methods: A bifunctional cyclic peptide, melanocortin ligand-1(MC1L), labeled with [ 203 Pb]Pb-MC1L, was used for [ 212 Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [ 212 Pb]Pb-MC1L in a dose escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. Results: Biodistribution analysis identified [ 212 Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [ 212 Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary Neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [ 212 Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. Conclusion: urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Engineered Extracellular Vesicle-Based Therapies for Valvular Heart Disease.

Introduction: Valvular heart disease represents a significant burden to the healthcare system, with approximately 5 million cases diagnosed annually in the US. Among these cases, calcific aortic stenosis (CAS) stands out as the most prevalent form of valvular heart disease in the aging population.  CAS is characterized by the progressive calcification of the aortic valve leaflets, leading to valve stiffening. While aortic valve replacement is the standard of care for CAS patients, the long-term durability of prosthetic devices is poor, calling for innovative strategies to halt  or reverse disease progression. Here, we explor the potential use of novel extracellular vesicle (EV)-based nanocarriers for delivering molecular payloads to the affected valve tissue. This approach aims to reduce inflammation and potentially promote resorption of the calcified tissue. Methods: Engineered EVs loaded with the reprogramming myeloid transcription factors, CEBPA and Spi1, known to mediate the transdifferentiation of committed endothelial cells into macrophages. We evaluated the ability of these engineered EVs to deliver DNA and transcripts encoding CEBPA and Spil into calcified aortic valve tissue obtained from patients undergoing valve replacement due to aortic stenosis. We also investigated whether these EVs could induce the transdifferentiation of endothelial cells into macrophage-like cells. Results: Engineered EVs loaded with CEBPA + Spi1 were successfully derived from human dermal fibroblasts. Peak EV loading was found to be at 4 h after nanotransfection of donor cells.  These CEBPA + Spi1 loaded EVs effectively transfected aortic valve cells, resulting in the successful induction of transdifferentiation, both in vitro with  endothelial cells and ex vivo with valvular endothelial cells, leading to the development of anti-inflammatory macrophage-like cells. Conclusions: Our findings highlight the potential of engineered EVs as a next generation nanocarrier to target aberrant calcifications on diseased heart valves. This development holds promise as a novel therapy for high-risk patients who may not be suitable candidates for valve replacement surgery. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-023-00783-x.