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AbstractBackgroundUrinary Tract Infections are the most common post‐transplant infection and can have varied presentations. This study aimed to describe the outcomes of kidney transplant recipients with asymptomatic histologic pyelonephritis on allograft biopsy. Histologic Pyelonephritis was defined as neutrophil cast or neutrophilic tubulitis, interstitial infiltrates with predominant neutrophils, and no evidence of rejection or glomerulonephritis on biopsy.MethodsThe study included 123 kidney transplant recipients, of whom 95 underwent protocol biopsies, and 28 had biopsies for elevated creatinine within the first 2 years of a kidney transplant.ResultsThe mean age of the cohort was 55.3 years, with 52% females and 78% deceased donor transplants. The risk factors for asymptomatic histologic pyelonephritis were recipient female sex (OR 1.89, 1.3–2.7, diabetes mellitus (OR 2.479, 1.687–3.645), and deceased donation (OR 1.69, 1.098–2.63). The incidence of asymptomatic pyelonephritis on protocol biopsy was 1.7%, with 52% having positive urine cultures and Escherichia coli being the most common bacteria. Subjects with asymptomatic pyelonephritis had inferior graft survival compared to the matched cohort HR 1.88 (1.06–3.35), p = .0281. In addition, of these 123 subjects, 68 (55%) subsequently developed pyelonephritis, and 34 subjects had pyelonephritis within 6 months after this episode. Subjects with recurrent infections exhibited lower survival HR 2.86 (1.36–6.02) and a trend toward higher rejection risk.ConclusionAsymptomatic histologic pyelonephritis can occur in kidney transplant recipients and is associated with inferior graft survival.

Background: Both valvular heart disease (VHD) and atrial fibrillation (AF) frequently coexist. AF is an important cause of arrhythmias with a definitive cardiovascular morbidity. The use of either vitamin K antagonists (VKAs/warfarin) or direct oral anticoagulants (DOACs) (also known as new oral anticoagulants (NOACs)) has been the mainstay for preventing stroke and systemic embolism in patients with VHD and/or AF, and this has been broadly discussed. However, there are limited studies on anticoagulation therapy for patients with valvular atrial fibrillation (VAF). The main aim of this meta-analysis was to evaluate the outcomes (stroke–vascular events and intracranial bleeding) following DOAC and VKA treatment amongst patients with VAF. Methods: We identified clinical trials and observational studies published in the last 10 years. A systematic review and a meta-analysis were performed to evaluate the outcomes of patients with valvular atrial fibrillation following DOAC vs. VKA treatment. Data evaluation was performed using Review Manager 5.4; the endpoints were stroke–vascular events and intracranial bleeding following DOAC and VKA treatment amongst VAF patients. Risk ratios (RR) were evaluated with 95% confidence intervals. Using random effects models, forest plots were obtained. Heterogeneity was assessed by using the I2 statistic. Results: Eight studies were included in this metanalysis, and a total of fifteen thousand two hundred and fifteen patients (DOAC (8732) and VKA (6483)) were pooled. We found a significant risk reduction in stroke–vascular events when using DOACs in comparison with using VKAs (pooled RR: 0.76; 95% CI: 0.64–0.90, p = 0.002). A total of 14862 patients (DOAC (8561) and VKA (6301)) were pooled from a total of six studies for intracranial bleeding. We found a significant risk reduction in terms of intracranial bleeding when using DOACs in comparison with using VKAs (pooled RR: 0.43; 95% CI: 0.24–0.77, p ≤ 0.05). Conclusions: When compared to VKAs, DOAC agents were found to have less risk of stroke–vascular events and intracranial bleeding. Further prospective studies are essential to establish the efficacy and safety of DOAC agents in patients with various subtypes of VAF.

Traumatic brain injury (TBI) remains a major cause of morbidity and death among the pediatric population. Timely diagnosis, however, remains a complex task because of the lack of standardized methods that permit its accurate identification. The aim of this study was to determine whether serum levels of brain injury biomarkers can be used as a diagnostic and prognostic tool in this pathology. This prospective, observational study collected and analyzed the serum concentration of neuronal injury biomarkers at enrollment, 24h and 48h post-injury, in 34 children ages 0–18 with pTBI and 19 healthy controls (HC). Biomarkers included glial fibrillary acidic protein (GFAP), neurofilament protein L (NfL), ubiquitin-C-terminal hydrolase (UCH-L1), S-100B, tau and tau phosphorylated at threonine 181 (p-tau181). Subjects were stratified by admission Glasgow Coma Scale score into two categories: a combined mild/moderate (GCS 9–15) and severe (GCS 3–8). Glasgow Outcome Scale-Extended (GOS-E) Peds was dichotomized into favorable (≤4) and unfavorable (≥5) and outcomes. Data were analyzed utilizing Prism 9 and R statistical software. The findings were as follows: 15 patients were stratified as severe TBI and 19 as mild/moderate per GCS. All biomarkers measured at enrollment were elevated compared with HC. Serum levels for all biomarkers were significantly higher in the severe TBI group compared with HC at 0, 24, and 48h. The GFAP, tau S100B, and p-tau181 had the ability to differentiate TBI severity in the mild/moderate group when measured at 0h post-injury. Tau serum levels were increased in the mild/moderate group at 24h. In addition, NfL and p-tau181 showed increased serum levels at 48h in the aforementioned GCS category. Individual biomarker performance on predicting unfavorable outcomes was measured at 0, 24, and 48h across different GOS-E Peds time points, which was significant for p-tau181 at 0h at all time points, UCH-L1 at 0h at 6–9 months and 12 months, GFAP at 48h at 12 months, NfL at 0h at 12 months, tau at 0h at 12 months and S100B at 0h at 12 months. We concluded that TBI leads to increased serum neuronal injury biomarkers during the first 0–48h post-injury. A biomarker panel measuring these proteins could aid in the early diagnosis of mild to moderate pTBI and may predict neurological outcomes across the injury spectrum.

Lung cancer is the most diagnosed cancer worldwide. Many non-malignant pulmonary lesions, such as tuberculosis, fungal infection, organizing pneumonia, inflammatory myofibroblastic tumor, and IgG4 disease, can mimic lung cancer due to their overlapping morphological appearance on imaging. These benign entities with minor differentiating imaging clues may go unnoticed in a high-volume cancer institution, leading to over-investigation that may result in repeated biopsies, pointless wedge resections, and related morbidities. However, with a thorough medical history, laboratory diagnostic work-up, and careful analysis of imaging findings, one can occasionally restrict the range of possible diagnoses or arrive at a definitive conclusion. When imaging features overlap, image-guided lung sampling is crucial since histopathological analysis is the gold standard.

(1) Background: Acute kidney injury (AKI) kidneys have high non-utilization rates due to concerns regarding unfavorable outcomes. In this paper, we aimed to review the past, present, and future opinions on AKI kidneys. (2) Methods: A PubMed search was conducted for topics relevant to AKI kidney transplantation. (3) Results: Current short- and long-term data on AKI kidneys have demonstrated good outcomes including favorable graft function and survival. The role of procurement biopsies is controversial, but they have been shown to be beneficial in AKI kidneys by allowing clinicians to differentiate between reversible tubular injury and irreversible cortical necrosis. Machine perfusion has also been applied to AKI kidneys and has been shown to reduce delayed graft function (DGF). The incidence of DGF increases with AKI severity and its management can be challenging. Strategies employed to counteract this have included early initiation of dialysis after kidney transplantation, early targeting of adequate immunosuppression levels to minimize rejection risk, and establishment of outpatient dialysis. (4) Conclusions: Despite good outcomes, there continue to be barriers that impact AKI kidney utilization. Successful strategies have included use of procurement biopsies or machine perfusion and expectant management of DGF. With increasing experience, better use of AKI kidneys can result in additional opportunities to expand the donor pool.

Background: There is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous Americans and Whites. This study aims to identify the frequency of recommended medication changes based on PGx results and compare the pharmacogenomic (PGx) results and patients’ perceptions of the findings between a cohort of Indigenous American and White kidney transplant recipients. Methods: Thirty-one Indigenous Americans and fifty White kidney transplant recipients were studied prospectively. Genetic variants were identified using the OneOme RightMed PGx test of 27 genes. PGx pharmacist generated a report of the genetic variation and recommended changes. Pre- and post-qualitative patient surveys were obtained. Results: White and Indigenous American subjects had a similar mean number of medications at the time of PGx testing (mean 13 (SD 4.5)). In the entire cohort, 53% received beta blockers, 30% received antidepressants, 16% anticoagulation, 47% pain medication, and 25% statin therapy. Drug–gene interactions that warranted a clinical action were present in 21.5% of patients. In 12.7%, monitoring was recommended. Compared to the Whites, the Indigenous American patients had more normal CYP2C19 (p = 0.012) and CYP2D6 (p = 0.012) activities. The Indigenous American patients had more normal CYP4F2 (p = 0.004) and lower VKORC (p = 0.041) activities, phenotypes for warfarin drug dosing, and efficacy compared to the Whites. SLC6A4, which affects antidepressant metabolism, showed statistical differences between the two cohorts (p = 0.017); specifically, SLC6A4 had reduced expression in 45% of the Indigenous American patients compared to 20% of the White patients. There was no significant difference in patient perception before and after PGx. Conclusions: Kidney transplant recipients had several drug–gene interactions that were clinically actionable; over one-third of patients were likely to benefit from changes in medications or drug doses based on the PGx results. The Indigenous American patients differed in the expression of drug-metabolizing enzymes and drug transporters from the White patients.

PURPOSE Radiation-associated cardiac disease is a major cause of morbidity/mortality among childhood cancer survivors. Radiation dose-response relationships for cardiac substructures and cardiac diseases remain unestablished. METHODS Using the 25,481 5-year survivors of childhood cancer treated from 1970 to 1999 in the Childhood Cancer Survivor Study, we evaluated coronary artery disease (CAD), heart failure (HF), valvular disease (VD), and arrhythmia. We reconstructed radiation doses for each survivor to the coronary arteries, chambers, valves, and whole heart. Excess relative rate (ERR) models and piecewise exponential models evaluated dose-response relationships. RESULTS The cumulative incidence 35 years from diagnosis was 3.9% (95% CI, 3.4 to 4.3) for CAD, 3.8% (95% CI, 3.4 to 4.2) for HF, 1.2% (95% CI, 1.0 to 1.5) for VD, and 1.4% (95% CI, 1.1 to 1.6) for arrhythmia. A total of 12,288 survivors (48.2%) were exposed to radiotherapy. Quadratic ERR models improved fit compared with linear ERR models for the dose-response relationship between mean whole heart and CAD, HF, and arrhythmia, suggesting a potential threshold dose; however, such departure from linearity was not observed for most cardiac substructure end point dose-response relationships. Mean doses of 5-9.9 Gy to the whole heart did not increase the risk of any cardiac diseases. Mean doses of 5-9.9 Gy to the right coronary artery (rate ratio [RR], 2.6 [95% CI, 1.6 to 4.1]) and left ventricle (RR, 2.2 [95% CI, 1.3 to 3.7]) increased risk of CAD, and to the tricuspid valve (RR, 5.5 [95% CI, 2.0 to 15.1]) and right ventricle (RR, 8.4 [95% CI, 3.7 to 19.0]) increased risk of VD. CONCLUSION Among children with cancer, there may be no threshold dose below which radiation to the cardiac substructures does not increase the risk of cardiac diseases. This emphasizes their importance in modern treatment planning.

TPS633 Background: Ovarian function suppression (OFS) when combined with tamoxifen or an aromatase inhibitor is the standard of care for premenopausal estrogen receptor positive (ER+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) based on SOFT (Francis 2022) and TEXT (Pagani 2022) clinical trials and confirmed in a metanalysis (EBCTCG 2022). However, estrogen deprivation in premenopausal women is associated with significant morbidity and up to 40% of premenopausal women with ER+/HER2- BC are intolerant of OFS. For these women, tamoxifen monotherapy is the only FDA approved option. Therefore, there is substantial room to improve endocrine therapy for premenopausal women with ER+/HER2- BC. (Z)-endoxifen is one of the most active anti-estrogen tamoxifen metabolites, with preclinical data demonstrating superiority to tamoxifen and letrozole in aromatase expressing xenograft models and evidence for antitumor activity in early phase clinical trials in patients with prior progression on endocrine therapy including tamoxifen. In addition to its ability to potently block ERa, (Z)-endoxifen at clinically achievable concentrations inhibits protein kinase C beta 1 (PKCβ1), resulting in downstream AKT inhibition and apoptosis. It is hypothesized that (Z)-endoxifen, when delivered as monotherapy at doses that dually target both ERα and PKCβ1, will potently inhibit BC proliferation while obviating the need for OFS in premenopausal women. If successful, this innovative approach could spare women with endocrine sensitive BC from the side effects of OFS. Methods: To further study (Z)-endoxifen in premenopausal women, a multicenter study in the United States, with possible expansion to other countries was designed (EVANGELINE; NCT05607004). This is a Phase 2, open-label, randomized, neoadjuvant study in premenopausal women with Stage IIA or IIB ER+/HER2- BC. Subjects are randomized 1:1 to either exemestane plus goserelin or (Z)-endoxifen. The primary objective is to determine whether the endocrine sensitive disease (ESD) rate (defined as Ki-67 ≤ 10% after 4 weeks of neoadjuvant therapy) with (Z)-endoxifen is non-inferior to exemestane plus goserelin. Subjects will be enrolled with the intent of surgical treatment in the involved breast(s) after completing 6 months of neoadjuvant treatment. Safety, tolerability, response rates and surgical outcomes will be assessed. Disease progression will be monitored throughout study participation. Paired tumor biopsies and blood sampling will allow for a robust biomarker evaluation. Prior to initiating the Treatment Cohort (162 subjects), up to 12 subjects will be enrolled in a pharmacokinetic (PK) Run-in Cohort to identify the optimal dose for the Treatment Cohort. Enrolment in the PK Run-in cohort began in February 2023. Clinical trial information: NCT05607004 .

Accurate prediction of progression in subjects at risk of Alzheimer's disease is crucial for enrolling the right subjects in clinical trials. However, a prospective comparison of state-of-the-art algorithms for predicting disease onset and progression is currently lacking. We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of a 5-year future time period, of three key outcomes: clinical diagnosis, Alzheimer's Disease Assessment Scale Cognitive Subdomain (ADAS-Cog13), and total volume of the ventricles. The methods used by challenge participants included multivariate linear regression, machine learning methods such as support vector machines and deep neural networks, as well as disease progression models. No single submission was best at predicting all three outcomes. For clinical diagnosis and ventricle volume prediction, the best algorithms strongly outperform simple baselines in predictive ability. However, for ADAS-Cog13 no single submitted prediction method was significantly better than random guesswork. Two ensemble methods based on taking the mean and median over all predictions, obtained top scores on almost all tasks. Better than average performance at diagnosis prediction was generally associated with the additional inclusion of features from cerebrospinal fluid (CSF) samples and diffusion tensor imaging (DTI). On the other hand, better performance at ventricle volume prediction was associated with inclusion of summary statistics, such as the slope or maxima/minima of patient-specific biomarkers. On a limited, cross-sectional subset of the data emulating clinical trials, performance of the best algorithms at predicting clinical diagnosis decreased only slightly (2 percentage points) compared to the full longitudinal dataset. The submission system remains open via the website https://tadpole.grand-challenge.org, while TADPOLE SHARE (https://tadpole-share.github.io/) collates code for submissions. TADPOLE's unique results suggest that current prediction algorithms provide sufficient accuracy to exploit biomarkers related to clinical diagnosis and ventricle volume, for cohort refinement in clinical trials for Alzheimer's disease. However, results call into question the usage of cognitive test scores for patient selection and as a primary endpoint in clinical trials.