Gene expression and cellular changes in injured myocardium of Ciona intestinalis.

Ciona intestinalis is an invertebrate animal model system that is well characterized and has many advantages for the study of cardiovascular biology. The regulatory mechanisms of cardiac myocyte proliferation in Ciona are intriguing since regeneration of functional tissue has been demonstrated in other organs of Ciona in response to injury. To identify genes that are differentially expressed in response to Ciona cardiac injury, microarray analysis was conducted on RNA from adult Ciona hearts with normal or damaged myocardium. After a 24- or 48-h recovery period, total RNA was isolated from damaged and control hearts. Initial results indicate significant changes in gene expression in hearts damaged by ligation in comparison to control hearts. Ligation injury shows differential expression of 223 genes as compared to control with limited false discovery (5.8%). Among these 223 genes, 117 have known human orthologs of which 68 were upregulated and 49 were downregulated. Notably, Fgf9/16/20, insulin-like growth factor binding protein and Ras-related protein Rab11b were significantly upregulated in injured hearts, whereas expression of a junctophilin ortholog was decreased. Histological analyses of injured myocardium were conducted in parallel to the microarray study which revealed thickened myocardium in injured hearts. Taken together, these studies will connect differences in gene expression to cellular changes in the myocardium of Ciona, which will help to promote further investigations into the regulatory mechanisms of cardiac myocyte proliferation across chordates.

Modulation of mGlu5 reduces rewarding associative properties of nicotine via changes in mesolimbic plasticity: Relevance to comorbid cigarette smoking in psychosis.

RATIONALE: Antipsychotic medications that are used to treat psychosis are often limited in their efficacy by high rates of severe side effects. Treatment success in schizophrenia is further complicated by high rates of comorbid nicotine use. Dopamine D2 heteroreceptor complexes have recently emerged as targets for the development of more efficacious pharmaceutical treatments for schizophrenia. OBJECTIVE: The current study sought to explore the use of the positive allosteric modulator of the mGlu5 receptor 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) as a treatment to reduce symptoms related to psychosis and comorbid nicotine use. METHODS: Neonatal treatment of animals with the dopamine D2-like receptor agonist quinpirole (NQ) from postnatal day (P)1-21 produces a lifelong increase in D2 receptor sensitivity, showing relevance to psychosis and comorbid tobacco use disorder. Following an 8-day conditioning paradigm, brain tissue in the mesolimbic pathway was analyzed for several plasticity markers, including brain derived neurotrophic factor (BDNF), phosphorylated p70 ribosomal S6 kinase (phospho-p70S6K), and cadherin-13 (Cdh13). RESULTS: Pretreatment with CDPPB was effective to block enhanced nicotine conditioned place preference observed in NQ-treated animals. Pretreatment was additionally effective to block the nicotine-induced increase in BDNF and sex-dependent increases in cadherin-13 in the ventral tegmental area (VTA), as well as increased phospho-p70S6K in the nucleus accumbens (NAcc) shell found in NQ-treated animals. CONCLUSION: In conjunction with prior work, the current study suggests positive allosteric modulation of the mGlu5 receptor, an emerging target for schizophrenia therapeutics, may be effective for the treatment of comorbid nicotine abuse in psychosis.

Sensitivity of Pharmacokinetics to Differences in the Particle Size Distribution for Formulations of Locally Acting Mometasone Furoate Suspension-Based Nasal Sprays.

To assess bioequivalence of locally acting suspension-based nasal sprays, the U.S. FDA currently recommends a weight-of-evidence approach. In addition to in vitro and human pharmacokinetic (PK) studies, this includes a comparative clinical endpoint study to ensure equivalent bioavailability of the active pharmaceutical ingredient (API) at the site of action. The present study aimed to assess, within an in vitro/in vivo correlation paradigm, whether PK studies and dissolution kinetics are sensitive to differences in drug particle size for a locally acting suspension-based nasal spray product. Two investigational suspension-based nasal formulations of mometasone furoate (MF-I and MF-II; delivered dose: 180 µg) differed in API particle size and were compared in a single-center, double-blind, single-dose, randomized, two-way crossover PK study in 44 healthy subjects with oral charcoal block. Morphology-directed Raman spectroscopy yielded volume median diameters of 3.17 µm for MF-I and 5.50 µm for MF-II, and dissolution studies showed that MF-II had a slower dissolution profile than MF-I. The formulation with larger API particles (MF-II) showed a 45% smaller Cmax and 45% smaller AUC0-inf compared to those of MF-I. Systemic bioavailability of MF-I (2.20%) and MF-II (1.18%) correlated well with the dissolution kinetics, with the faster dissolving formulation yielding the higher bioavailability. This agreement between pharmacokinetics and dissolution kinetics cross-validated both methods and supported their use in assessing potential differences in slowly dissolving suspension-based nasal spray products.

Mepolizumab in Patients With Severe Asthma and Comorbidities: 1-Year REALITI-A Analysis.

BACKGROUND: Severe asthma is complex; comorbidities may influence disease outcomes. OBJECTIVE: To assess mepolizumab effectiveness in patients with severe asthma and comorbidities. METHODS: REALITI-A was a 2-year international, prospective study enrolling adults with asthma newly prescribed mepolizumab (100 mg subcutaneously) at physician's discretion. This post hoc analysis assessed 1-year outcomes stratified by comorbidities at enrollment: chronic rhinosinusitis with nasal polyps (CRSwNP), gastroesophageal reflux disease (GERD), depression/anxiety, and chronic obstructive pulmonary disease (COPD). Outcomes included the rate of clinically significant asthma exacerbations (CSEs; requiring systemic corticosteroids and/or hospital/emergency room admission) between the 12 months pre- and post-mepolizumab treatment and changes from baseline in daily maintenance oral corticosteroid dose (mo 12), Asthma Control Questionnaire-5 score (mo 12) and forced expiratory volume in 1 second (FEV1; mo 9-12). RESULTS: At enrollment (n = 822), 321 of 822 (39%), 309 of 801 (39%), 203 of 785 (26%), and 81 of 808 (10%) patients had comorbid CRSwNP, GERD, depression/anxiety, and COPD, respectively. Post- versus pre-treatment across all comorbidity subgroups: the rate of CSEs decreased by 63% or more; among 298 (39%) patients on maintenance oral corticosteroids at baseline, median dose decreased by 50% or more; Asthma Control Questionnaire-5 score decreased by 0.63 or more points; FEV1 increased by 74 mL or more. Patients with versus without CRSwNP had the greatest improvements (eg, rate of CSEs decreased by 75%). Patients without GERD, depression/anxiety, or COPD had greater improvements than those with the respective comorbidities, except for FEV1 in patients with COPD. CONCLUSIONS: Mepolizumab improved disease outcomes in patients with severe asthma irrespective of comorbidities, with additional benefit for patients with CRSwNP.

Utilisation and valorisation of distillery whisky waste streams via biomass electrolysis: electrosynthesis of hydrogen.

Fuel-flexible hydrogen generation methods, such as electrochemical conversion of biomass, offer a route for sustainable production of hydrogen whilst valorising feedstocks that are often overlooked as waste products. This work explores the potential of a novel, two-stage electrolysis process to convert biomass-containing solid (draff/spent barley) and liquid (pot ale and spent lees) whisky co-products, from the Isle of Raasay Distillery, into hydrogen, using a phosphomolybdic acid (H3[PMo12O40] or PMA) catalyst. Characterisation results for whisky distillery co-products will be presented, including thermogravimetric, differential scanning calorimetric, CHN elemental, total organic carbon and chemical oxygen demand analysis data. The results indicated that the characteristics of these co-products align well with those reported across the Scotch whisky distillation sector. Subsequently, the concept of thermal digestion of each co-product type, using the Keggin-type polyoxometalate PMA catalyst to abstract protons and electrons from biomass, will be outlined. UV-visible spectrophotometry was employed to assess the extent of reduction of the catalyst, after digestion of each co-product, and indicated that draff and pot ale offer the largest scope for hydrogen production, whilst digestion and electrolysis of spent lees is not viable due to the low biomass content of this distillation co-product. Finally, details of electrolysis of the PMA-biomass solutions using a proton-exchange membrane electrolysis cell (PEMEC) will be provided, including electrochemical data that help to elucidate the performance-limiting processes of the PEMEC operating on digested biomass-PMA anolytes.

New perspectives in application of kidney biomarkers in mycotoxin induced nephrotoxicity, with a particular focus on domestic pigs.

The gradual spread of Aspergilli worldwide is adding to the global shortage of food and is affecting its safe consumption. Aspergillus-derived mycotoxins, including aflatoxins and ochratoxin A, and fumonisins (members of the fusariotoxin group) can cause pathological damage to vital organs, including the kidney or liver. Although the kidney functions as the major excretory system in mammals, monitoring and screening for mycotoxin induced nephrotoxicity is only now a developmental area in the field of livestock feed toxicology. Currently the assessment of individual exposure to mycotoxins in man and animals is usually based on the analysis of toxin and/or metabolite contamination in the blood or urine. However, this requires selective and sensitive analytical methods (e.g., HPLC-MS/MS), which are time consuming and expensive. The toxicokinetic of mycotoxin metabolites is becoming better understood. Several kidney biomarkers are used successfully in drug development, however cost-efficient, and reliable kidney biomarkers are urgently needed for monitoring farm animals for early signs of kidney disease. ß2-microglobulin (ß2-MG) and N-acetyl-ß-D-glucosaminidase (NAG) are the dominant biomarkers employed routinely in environmental toxicology research, while kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are also emerging as effective markers to identify mycotoxin induced nephropathy. Pigs are exposed to mycotoxins due to their cereal-based diet and are particularly susceptible to Aspergillus mycotoxins. In addition to commonly used diagnostic markers for nephrotoxicity including plasma creatinine, NAG, KIM-1 and NGAL can be used in pigs. In this review, the currently available techniques are summarized, which are used for screening mycotoxin induced nephrotoxicity in farm animals. Possible approaches are considered, which could be used to detect mycotoxin induced nephropathy.

Remission outcomes in severe eosinophilic asthma with mepolizumab therapy: Analysis of the REDES study.

Introduction: Clinical remission as a multicomponent treatment goal in severe asthma is being explored in clinical practice. This post hoc analysis used data from the REDES study to assess the proportion of patients with severe eosinophilic asthma achieving our multicomponent definitions of clinical remission after 1 year of mepolizumab treatment. Methods: The real-world, retrospective observational REDES study enrolled patients with severe eosinophilic asthma who were newly prescribed mepolizumab and with ≥12 months of medical records pre-enrolment. Multicomponent clinical remission was defined as: oral corticosteroid (OCS)-free; exacerbation-free; asthma control test (ACT) score ≥20; and with or without post-bronchodilator forced expiratory volume in 1 second ≥80%. Baseline characteristics were also assessed in those who did/did not achieve clinical remission. Results: 37% and 30% of patients with severe eosinophilic asthma met our proposed three- and four-component on-treatment clinical remission definitions; an increase from 2% and 3% at baseline. Most frequently achieved individual components of clinical remission were: OCS-free; ACT score ≥20. For patients fulfilling the multicomponent clinical remission definitions, at baseline we observed higher blood eosinophil counts, better ACT scores and lung function, lower maintenance OCS use, and a slightly lower rate of prior exacerbations versus those who did not. Discussion: Clinical remission is a realistic target in clinical practice for a subset of patients with severe eosinophilic asthma receiving mepolizumab. Further studies are required to elucidate whether features linked to the underlying endotype can help predict treatment outcomes, increase rates of clinical remission, and potentially modify disease progression.

2D IMRT QA passing rate dependency on coronal plane.

Intensity modulated radiation therapy (IMRT) delivery involves a complex series of beam angles and multileaf collimator (MLC) arrangements, requiring quality assurance to be performed to validate delivery before treatment. The purpose of this work is to investigate the effect of dose gradient on quality assurance (QA) passing rate. Many (n = 40) IMRT plans were delivered and measured using a 2D planar array of ion chambers; additionally, eleven plans were measured at several coronal planes. For each measurement, dose gradient was assessed using a number of metrics and passing rate assessed at both 3%/3 mm and 3%/2 mm criteria. The passing rates of the various IMRT plans were shown to be generally correlated to gradient, with an average distance correlation of 0.54 ± 0.04 for the lateral dose gradient. The passing rate for an individual plan was shown to vary with coronal slice, though the correlation to dose gradient was not predictable. Even though the passing rate was strongly related to dose gradient for many of the plans, the signs of the correlations were not always negative, as hypothesized. The coronal plane at which QA is performed affects passing rate, though dose gradient may not easily be used to predict slices at which passing rate is higher.

A new target localization method for image-guided radiation therapy of prostate cancer.

In imaged-guided radiation therapy (IGRT), target localization is usually done with rigid-body registration based on anatomy matching. Problems arise when the target volume can only be matched partially due to inter-fractional organ motion and deformation, resulting in deteriorated target coverage and critical structure sparing. A new target localization method is investigated in which the treatment target volume is aligned with the prescription isodose surface. Our study included 15 prostate patients previously treated with intensity-modulated radiation therapy (IMRT). Patient setup and target localization were performed using a CT-on-rails system before and after the IMRT treatment. IMRT plans were generated on the original simulation CTs (15) and the same MUs and leaf sequences were used to compute the dose distributions on post-treatment CTs (98) with the isocenter adjustments based on either anatomical structure matching or prescription isodose surface alignment. When patients were aligned with the traditional anatomy matching method, the dose to 95% of the CTV, D95, received 74.0 - 77.6 Gy and the minimum CTV dose, Dmin, was 61.9 - 71.6 Gy, respectively, in the cumulative dose distributions. The rectal dose-volume constraints were violated in 35.7% of the treatment fractions. When patients were aligned using the new localization method, the dose to 95% of the CTV, D95, received 74.0 - 78.2 Gy and the minimum CTV dose, Dmin, was 68.4 - 71.6 Gy, respectively, in the cumulative dose distributions. The rectal dose-volume constraints were violated in 17.3% of the treatment fractions. Traditional IGRT target localization based on anatomy matching is effective for population-based PTV margins but not ideal for those patients with large inter-fractional prostate rotation/deformation due to large rectal and bladder volume variation. The new method using the prescription isodose surface to align the target volume could improve the target coverage and rectal sparing for these patients, which can be implemented clinically to improve target dose delivery accuracy.

Long-Term Results of a Phase 3 Randomized Prospective Trial of Erectile Tissue-Sparing Intensity-Modulated Radiation Therapy for Men With Clinically Localized Prostate Cancer.

PURPOSE: The objective of this study was to determine whether limiting the doses delivered to the penile bulb (PB) and corporal bodies with intensity modulated radiation therapy (IMRT) preserves erectile function compared with standard IMRT in men with prostate cancer. METHODS AND MATERIALS: A total of 117 patients with low- to intermediate-risk, clinical T1a-T2c prostate adenocarcinoma were enrolled in a single-institution, prospective, single-blind, phase 3 randomized trial. All received definitive IMRT to 74 to 80 Gy in 37 to 40 fractions and standard IMRT (s-IMRT) or erectile tissue-sparing IMRT (ETS-IMRT), which placed additional planning constraints that limited the D90 to the penile bulb and corporal bodies to ≤15 Gy and ≤7 Gy, respectively. Erectile potency was assessed with components of the International Index of Erectile Function and phosphodiesterase type 5 inhibitor (PDE5) medication records. RESULTS: Sixty-two patients received ETS-IMRT, and 54 received s-IMRT; 1 patient did not receive radiation therapy. Before treatment, all patients reported erectile potency. No patients received androgen deprivation therapy. In the intention-to-treat analysis, treatment arms did not differ in potency preservation at 24 months (37.1% ETS-IMRT vs 31.5% s-IMRT, P = .53). Of 85 evaluable patients with International Index of Erectile Function and PDE5 medication follow-up, erectile potency was seen in 47.9% of patients in the ETS-IMRT arm and 46.0% of patients in the s-IMRT arm (P = .86). PDE5 inhibitors were initiated in 41.7% of ETS-IMRT patients and 35.1% of s-IMRT patients (P = .54). Among all patients enrolled, there was no difference in freedom from biochemical failure between those treated with ETS-IMRT and s-IMRT (5-year 91.8% vs 90.7%, respectively, P = .77), with a median follow-up of 7.4 years. There were no differences in acute or late gastrointestinal or genitourinary toxicity. An unplanned per-protocol analysis demonstrated no differences in potency preservation or secondary endpoints between patients who exceeded erectile tissue-sparing constraints and those who met constraints, although power was limited by attrition and unplanned dosimetric crossover. CONCLUSIONS: ETS-IMRT that strictly limits dose to the penile bulb and corporal bodies is safe and feasible. Use of this planning technique did not show an effect on potency preservation outcomes at 2 years, though power to detect a difference was limited.

Stress combined with loss of the Candida albicans SUMO protease Ulp2 triggers selection of aneuploidy via a two-step process.

A delicate balance between genome stability and instability ensures genome integrity while generating genetic diversity, a critical step for evolution. Indeed, while excessive genome instability is harmful, moderated genome instability can drive adaptation to novel environments by maximising genetic variation. Candida albicans, a human fungal pathogen that colonises different parts of the human body, adapts rapidly and frequently to different hostile host microenvironments. In this organism, the ability to generate large-scale genomic variation is a key adaptative mechanism triggering dangerous infections even in the presence of antifungal drugs. Understanding how fitter novel karyotypes are selected is key to determining how C. albicans and other microbial pathogens establish infections. Here, we identified the SUMO protease Ulp2 as a regulator of C. albicans genome integrity through genetic screening. Deletion of ULP2 leads to increased genome instability, enhanced genome variation and reduced fitness in the absence of additional stress. The combined stress caused by the lack of ULP2 and antifungal drug treatment leads to the selection of adaptive segmental aneuploidies that partially rescue the fitness defects of ulp2Δ/Δ cells. Short and long-read genomic sequencing demonstrates that these novel genotypes are selected via a two-step process leading to the formation of novel chromosomal fragments with breakpoints at microhomology regions and DNA repeats.

SARS-CoV-2 Seroprevalence at an Urban Hospital in Haiti.

BACKGROUND: Much to the surprise of the global community, Haiti has had far fewer COVID-19 cases and deaths than initially expected. In this study, we sought to estimate the seroprevalence of COVID-19 in a convenience cohort based in Port-au-Prince, Haiti, to elucidate potential reasons for the apparently low burden of COVID-19 in Haiti. METHODS: We performed a cross-sectional analysis of SARS-CoV-2 antibody prevalence in patients aged one to 89 years old who were seen at the Haiti Adventist Hospital (HAH) laboratory between December 17, 2020, and July 3, 2021, with an order requiring a blood draw. We excluded patients outside of the age range and those who did not verbally consent to the study. We tested residual patient serum samples using the Biosys PlusTM COVID-19 IgM/IgG Rapid Test. FINDINGS: Of 9,740 patients seen by the HAH laboratory from December 2020 to July 2021, 538 consented to have antibody testing and answer survey questions. 529 were included in the final analysis. We excluded nine participants who were aged greater than 89 (n=3), aged less than one (n=2), or had results that were not properly recorded (n=4). Three of the tested patients were repeat testers, with one who had been tested three times. These repeat results were included for a final seroprevalence analysis of 533 samples. In the final participant pool, 142 (26.6%) of 533 samples tested positive for either IgM, IgG, or both antibodies to the SARS-CoV-2 virus. Adjustment for test sensitivity resulted in an estimated seroprevalence of 28.7% (95% CI 24.9-32.9). We observed significant differences in seroprevalences among age groups, with seroprevalence increasing with age. INTERPRETATION: The SARS-CoV-2 antibody seroprevalence in Haiti appears to be greater than the publicly reported statistics by several orders of magnitude. Furthermore, a reduced fatality rate relative to high-income countries points to uncertain factors that may confer immunologic resistance in the Haitian population.

5-Fluorouracil disrupts skeletal muscle immune cells and impairs skeletal muscle repair and remodeling.

5-Fluorouracil (5FU) remains a first-line chemotherapeutic for several cancers despite its established adverse side effects. Reduced blood counts with cytotoxic chemotherapies not only expose patients to infection and fatigue, but can disrupt tissue repair and remodeling, leading to lasting functional deficits. We sought to characterize the impact of 5FU-induced leukopenia on skeletal muscle in the context of remodeling. First, C57BL/6 mice were subjected to multiple dosing cycles of 5FU and skeletal muscle immune cells were assessed. Second, mice given 1 cycle of 5FU were subjected to 1.2% BaCl2 intramuscularly to induce muscle damage. One cycle of 5FU induced significant body weight loss, but only three dosing cycles of 5FU induced skeletal muscle mass loss. One cycle of 5FU reduced skeletal muscle CD45+ immune cells with a particular loss of infiltrating CD11b+Ly6cHi monocytes. Although CD45+ cells returned following three cycles, CD11b+CD68+ macrophages were reduced with three cycles and remained suppressed at 1 mo following 5FU administration. One cycle of 5FU blocked the increase in CD45+ immune cells 4 days following BaCl2; however, there was a dramatic increase in CD11b+Ly6g+ neutrophils and a loss of CD11b+Ly6cHi monocytes in damaged muscle with 5FU compared with PBS. These perturbations resulted in increased collagen production 14 and 28 days following BaCl2 and a reduction in centralized nuclei and myofibrillar cross-sectional area compared with PBS. Together, these results demonstrate that cytotoxic 5FU impairs muscle damage repair and remodeling concomitant with a loss of immune cells that persists beyond the cessation of treatment.NEW & NOTEWORTHY We examined the common chemotherapeutic 5-fluorouracil's (5FU) impact on skeletal muscle immune cells and skeletal muscle repair. 5FU monotherapy decreased body weight and muscle mass, and perturbed skeletal muscle immune cells. In addition, 5FU decreased skeletal muscle immune cells and impaired infiltration following damage contributing to disrupted muscle repair. Our results demonstrate 5FU's impact on skeletal muscle and provide a potential explanation for why some patients may be unable to properly repair damaged tissue.

Nephrotoxic Biomarkers with Specific Indications for Metallic Pollutants: Implications for Environmental Health.

Environmental and occupational exposure to heavy metals and metalloids is a major global health risk. The kidney is often a site of early damage. Nephrotoxicity is both a major consequence of heavy metal exposure and potentially an early warning of greater damage. A paradigm shift occurred at the beginning of the 21st century in the field of renal medicine. The medical model of kidney failure and treatment began to give way to a social model of risk factors and prevention with important implications for environmental health. This development threw into focus the need for better biomarkers: markers of exposure to known nephrotoxins; markers of early damage for diagnosis and prevention; markers of disease development for intervention and choice of therapy. Constituents of electronic waste, e-waste or e-pollution, such as cadmium (Cd), lead (Pb), mercury (HG), arsenic (As) and silica (SiO2) are all potential nephrotoxins; they target the renal proximal tubules through distinct pathways. Different nephrotoxic biomarkers offer the possibility of identifying exposure to individual pollutants. In this review, a selection of prominent urinary markers of tubule damage is considered as potential tools for identifying environmental exposure to some key metallic pollutants.

The role of urinary N-acetyl-ß-D-glucosaminidase in early detection of acute kidney injury among pediatric patients with neoplastic disorders in a retrospective study.

BACKGROUND: The 1-year cumulative incidence of AKI reportedly is high (52%) in pediatric neoplastic disorders. About half of these events occur within 2 weeks. However, subclinical AKI episodes may remain unrecognized by the conventional creatinine-based approaches. We investigated the diagnostic value of urinary N-acetyl-ß-D-glucosaminidase (uNAG) as an early marker of acute kidney injury (AKI). METHODS: In our retrospective study, 33 children with neoplastic disorders were inculded who had serial uNAG tests (at least 5 samples/patient) with a total of 367 uNAG measurements. Renal function was determined by cystatin-C and creatinine based GFR, and relative increase of uNAG index (uNAGRI). We focused on detecting both clinical and subclinical AKI episodes (according to Biomarker-Guided Risk Assessment using pRIFLE criteria and /or elevated uNAG levels) and the incidence of chronic kidney damage. RESULTS: Sixty episodes in 26 patients, with positivity at least in one parameter of kidney panel, were identified during the observation period. We detected 18/60 clinical and 12/60 subclinical renal episodes. In 27/60 episodes only uNAG values was elevated with no therapeutic consequence at presentation. Two patients were detected with decreased initial creatinine levels with 3 "silent" AKI. In 13 patients, modest elevation of uNAG persisted suggesting mild, reversible tubular damage, while chronic tubuloglomerular injury occurred in 5 patients. Based on ROC analysis for the occurence of AKI, uNAGRI significantly indicated the presence of AKI, the sensitivity and specificity are higher than the changes of GFRCreat. Serial uNAG measurements are recommended for  the reduction of the great amount of false positive uNAG results, often due to overhydratation. CONCLUSION: Use of Biomarker-guided Risk Assessment for AKI identified 1.5 × more clinical and subclinical AKI episodes than with creatinine alone in our pediatric cancer patients. Based on the ROC curve for the occurence of AKI, uNAGRI has relatively high sensitivity and specificity comparable to changes of GFRCysC. The advantage of serial uNAG measurements is to decrease the number of false positive results. TRIAL REGISTRATION: The consent to participate is not applicable because it was not reqired for ethical approval and it is a retrospectiv study.

Evaluating suggested stricter gamma criteria for linac-based patient-specific delivery QA in the conventional and SBRT environments.

PURPOSE: To evaluate AAPM TG-218 recommended tolerances for IMRT QA for conventional and SBRT delivery. METHODS: QA analysis was repeated for 150 IMRT/VMAT patients with varying gamma criteria. True composite delivery was utilized, corrected for detector and output variation. Universal tolerance (TLuniv) and action limits (ALuniv) were compared with statistical process control (SPC) TLSPC and ALSPC values. Analysis was repeated as a function of plan complexity for 250 non-stereotactic body radiotherapy (SBRT) VMAT patients at 3%/2mm and a threshold of 10% and for 75 SBRT VMAT patients at 2%/2 mm and a threshold of 50% with results plotted as a function of PTV volume. Regions of failure were dose-scaled on the planning CT data sets based on delivery results. RESULTS: The IMRT/VMAT TLSPC and ALSPC for gamma criteria of 3%/3 mm were 96.5% and 95.6% and for 3%/2 mm were 91.2% and 89.2%, respectively. Correlation with plan complexity for conventional fractionation VMAT was "low" for all sites with pelvis having the highest r value at -0.35. The equivalent SBRT PTV diameter ranged from 2.0 cm to 5.6 cm. Negative low correlation was found for 38 of 75 VMAT cases below ALuniv. CONCLUSIONS: The ALuniv and ALSPC are similar for 3%/2 mm. However, our 5% failure rate for ALuniv, may result in treatment start delays approximately 2 times/month, given 40 new cases/month. VMAT QA failure at stricter criteria did not correlate strongly with plan complexity. Site-specific action limits vary less than 3% from the average. SBRT QA results do not strongly correlate with target size over the range studied.