The effect of adsorbent textural and functional properties on model naphthenic acid adsorption.

Naphthenic acids, NAs, are a major contaminant of concern and a focus of much research around remediation of oil sand process affected waters, OSPW. Using activated carbon adsorbents are an attractive option given their low cost of fabrication and implementation. A deeper evaluation of the effect NA structural differences have on uptake affinity is warranted. Here we provide an in-depth exploration of NA adsorption including many more model NA species than have been assessed previously with evaluation of adsorption kinetics and isotherms at the relevant alkaline pH of OSPW using several different carbon adsorbents with pH buffering to simulate the behaviour of real OSPW. Uptake for the NA varied considerably regardless of the activated carbon used, ranging from 350 mg/g to near zero highlighting recalcitrant NAs. The equilibrium data was explored to identify structural features of these species and key physiochemical properties that influence adsorption. We found that certain NA will be resistant to adsorption when hydrophobic adsorbents are used. Adsorption isotherm modelling helped explore interactions occurring at the interface between NA and adsorbent surfaces. We identified the importance of NA hydrophobicity for activated carbon uptake. Evidence is also presented that indicates favorable hydrogen bonding between certain NA and surface site hydroxyl groups, demonstrating the importance of adsorbent surface functionality for NA uptake. This research highlights the challenges associated with removing NAs from OSPW through adsorption and also identifies how adsorbent surface chemistry modification can be used to increase the removal efficiency of recalcitrant NA species.

Association Between the Decipher Genomic Classifier and Prostate Cancer Outcome in the Real-world Setting.

BACKGROUND AND OBJECTIVE: Although the prognostic significance of the Decipher prostate cancer genomic classifier (GC) has been established largely from analyses of archival tissue, less is known about the associations between the results of Decipher testing and oncologic outcomes among patients receiving contemporaneous testing and treatment in the real-world practice setting. Our objective was to assess the associations between the Decipher GC and risks of metastasis and biochemical recurrence (BCR) following prostate biopsy and radical prostatectomy (RP) among patients tested and treated in the real-world setting. METHODS: A retrospective cohort study was conducted using a novel longitudinal linkage of transcriptomic data from the Decipher GC and real-world clinical data (RWD) aggregated from insurance claims, pharmacy records, and electronic health record data across payors and sites of care. Kaplan-Meier and Cox proportional hazards regressions were used to examine the associations between the GC and study outcomes, adjusting for clinical and pathologic factors. KEY FINDINGS AND LIMITATIONS: Metastasis from prostate cancer and BCR after radical prostatectomy, Decipher GC continuous score, and risk categories were evaluated. We identified 58 935 participants who underwent Decipher testing, including 33 379 on a biopsy specimen and 25 556 on an RP specimen. The median age was 67 yr (interquartile range [IQR] 62-72) at biopsy testing and 65 yr (IQR 59-69) at RP. The median GC score was 0.43 (IQR 0.27-0.66) among biopsy-tested patients and 0.54 (0.32-0.79) among RP-tested patients. The GC was independently associated with the risk of metastasis among biopsy-tested (hazard ratio [HR] per 0.1 unit increase in GC 1.21 [95% confidence interval {CI} 1.16-1.27], p < 0.001) and RP-tested (HR 1.20 [95% CI 1.17-1.24], p < 0.001) patients after adjusting for baseline clinical and pathologic risk factors. In addition, the GC was associated with the risk of BCR among RP-tested patients (HR 1.12 [95% CI 1.10-1.14], p < 0.001) in models adjusted for age and Cancer of the Prostate Risk Assessment postsurgical score. CONCLUSIONS AND CLINICAL IMPLICATIONS: This real-world study of a novel transcriptomic linkage conducted at a national scale supports the external prognostic validity of the Decipher GC among patients managed in contemporary practice. PATIENT SUMMARY: This study looked at the use of the Decipher genomic classifier, a test used to help understand the aggressiveness of a patient's prostate cancer. Looking at the results of 58 935 participants who underwent testing, we found that the Decipher test helped estimate the risk of cancer recurrence and metastasis.

Deep Learning Segmentation of Infiltrative and Enhancing Cellular Tumor on Pre- and Posttreatment Multishell Diffusion MRI of Glioblastoma.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To develop and validate a deep learning (DL) method to detect and segment enhancing and nonenhancing cellular tumor on pre- and posttreatment MRI scans of patients with glioblastoma and to predict overall survival (OS) and progression-free survival (PFS). Materials and Methods This retrospective study included 1397 MRIs in 1297 patients with glioblastoma, including an internal cohort of 243 MRIs (January 2010-June 2022) for model training and cross-validation and four external test cohorts. Cellular tumor maps were segmented by two radiologists based on imaging, clinical history, and pathology. Multimodal MRI with perfusion and multishell diffusion imaging were inputted into a nnU-Net DL model to segment cellular tumor. Segmentation performance (Dice score) and performance in detecting recurrent tumor from posttreatment changes (area under the receiver operating characteristic curve [AUC]) were quantified. Model performance in predicting OS and PFS was assessed using Cox multivariable analysis. Results A cohort of 178 patients (mean age, 56 years ± [SD]13; 121 male, 57 female) with 243 MRI timepoints, as well as four external datasets with 55, 70, 610 and 419 MRI timepoints, respectively, were evaluated. The median Dice score was 0.79 (IQR:0.53-0.89) and the AUC for detecting residual/recurrent tumor was 0.84 (95% CI:0.79- 0.89). In the internal test set, estimated cellular tumor volume was significantly associated with OS (hazard ratio [HR] = 1.04/mL, P < .001) and PFS (HR = 1.04/mL, P < .001) when adjusting for age, sex and gross total resection status. In the external test sets, estimated cellular tumor volume was significantly associated with OS (HR = 1.01/mL, P < .001) when adjusting for age, sex and gross total resection status. Conclusion A DL model incorporating advanced imaging could accurately segment enhancing and nonenhancing cellular tumor, classify recurrent/residual tumor from posttreatment changes, and predict OS and PFS in patients with glioblastoma. ©RSNA, 2024.

Longitudinal registration of T1-weighted breast MRI: A registration algorithm (FLIRE) and clinical application.

PURPOSE: MRI is commonly used to aid breast cancer diagnosis and treatment evaluation. For patients with breast cancer, neoadjuvant chemotherapy aims to reduce the tumor size and extent of surgery necessary. The current clinical standard to measure breast tumor response on MRI uses the longest tumor diameter. Radiologists also account for other tissue properties including tumor contrast/pharmacokinetics in their assessment. Accurate longitudinal image registration of breast tissue is critical to properly compare response to treatment at different timepoints. METHODS: In this study, a deformable Fast Longitudinal Image Registration (FLIRE) algorithm was optimized for breast tissue. FLIRE was then compared to the publicly available software packages with high accuracy (DRAMMS) and fast runtime (Elastix). Patients included in the study received longitudinal T1 weighted MRI without fat saturation at two to six timepoints as part of asymptomatic screening (n = 27) or throughout neoadjuvant chemotherapy treatment (n = 32). T1 weighted images were registered to the first timepoint with each algorithm. RESULTS: Alignment and runtime performance were compared using two-way repeated measure ANOVAs (P < 0.0 5). Across all patients, Pearson's correlation coefficient across the entire image volume was slightly higher with statistical significance and had less variance for FLIRE (0.98 ±â€¯0.01 stdev) compared to DRAMMS (0.97 ±â€¯0.03 stdev) and Elastix (0.9 5 ±â€¯0.03 stdev). Additionally, FLIRE runtime (10.0 mins) was 9.0 times faster than DRAMMS (89.6 mins) and 1.5 times faster than Elastix (14.5 mins) on a Linux workstation. CONCLUSION: FLIRE demonstrates promise for time-sensitive clinical applications due to its accuracy, robustness across patients and timepoints, and speed.

Variation in surgical approach and postoperative complication among older adults undergoing ventral hernia repair.

BACKGROUND: Surgical decision-making for preference-sensitive operations among older adults is understudied. Ventral hernia repair (VHR) is one operation where granular data are limited to guide preoperative decision-making. We aimed to determine risk for VHR in older adults given clinically nuanced data including surgical and hernia characteristics. METHODS: We performed a retrospective analysis of the Michigan Surgical Quality Collaborative Core Optimization Hernia Registry from January 2020 to March 2023. The primary outcome was postoperative complication across age groups: 18-64, 65-74, and ≥ 75 years, with secondary outcome of surgical approach. Mixed-effects logistic regression evaluated association between minimally invasive surgery (MIS) and 30-day complications, controlling for patient and hernia characteristics. RESULTS: Among 8,659 patients, only 7% were 75 or older. MIS rates varied across hospitals [Median = 31.4%, IQR: (14.8-51.6%)]. The overall complication rate was 2.2%. Complication risk for undergoing open versus MIS approach did not vary between age groups; however, patients over age 75 undergoing laparoscopic repair had increased risk (aOR = 4.58, 95% CI 1.13-18.67). Other factors associated with risk included female sex (aOR = 2.10, 95% CI 1.51-2.93), higher BMI (aOR = 1.18, 95% CI 1.03-1.34), hernia width ≥ 6 cm (aOR = 3.15, 95% CI 1.96-5.04), previous repair (aOR = 1.44, 95% CI 1.02-2.05), and component separation (aOR = 1.98, 95% CI 1.28-3.05). Patients most likely to undergo MIS were female (aOR = 1.21, 95% CI 1.09-1.34), black (aOR = 1.30, 95% CI 1.12-1.52), with larger hernias: 2-5.9 cm (aOR = 1.76, 95% CI 1.57-1.97), or intraoperative mesh placement (aOR = 14.4, 95% CI 11.68-17.79). There was no difference in likelihood to receive MIS across ages when accounting for hospital (SD of baseline likelihood = 1.53, 95% CI 1.14-2.05) and surgeon (SD of baseline likelihood = 2.77, 95% CI 2.46-3.11) variation. CONCLUSIONS: Our findings demonstrate that hernia, intraoperative, and patient characteristics other than age increase probability for complication following VHR. These findings can empower surgeons and older patients considering preoperative risk for VHR.

Concurrent and longitudinal neurostructural correlates of irritability in children.

Irritability, or an increased proneness to frustration and anger, is common in youth; however, few studies have examined neurostructural correlates of irritability in children. The purpose of the current study was to examine concurrent and longitudinal associations between brain structure and irritability in a large sample of 9-10-year-old children. Participants included 10,647 children from the Adolescent Brain Cognitive Developmentsm Study (ABCD Study®). We related a latent irritability factor to gray matter volume, cortical thickness, and surface area in 68 cortical regions and to gray matter volume in 19 subcortical regions using structural equation modeling. Multiple comparisons were adjusted for using the false discovery rate (FDR). After controlling for age, sex, race/ethnicity, scanner model, parent's highest level of education, medication use, and total intracranial volume, irritability was associated with smaller volumes in primarily temporal and parietal regions at baseline. Longitudinal analyses showed that baseline gray matter volume did not predict irritability symptoms at the 3rd-year follow-up. No significant associations were found for cortical thickness or surface area. The current study demonstrates inverse associations between irritability and volume in regions implicated in emotional processing/social cognition, attention allocation, and movement/perception. We advance prior research by demonstrating that neurostructural differences associated with irritability are already apparent by age 9-10 years, extending this work to children and supporting theories positing socioemotional deficits as a key feature of irritability.

Progressive Paracentral Visual Field Loss at Low Intraocular Pressures Following LASIK.

Intraocular pressure is currently the only known reliable, modifiable risk factor for the development and progression of glaucoma. Other risk factors for glaucoma include increasing age, myopia, decreased central corneal thickness, and low corneal hysteresis (CH) measurements. Photoablative keratorefractive surgery including laser assisted in situ keratomileusis (LASIK) has become a common way to treat refractive error, with over 25 million procedures performed in the United States alone. Though myopic LASIK has been associated with a decrease in CH measurements, relatively little is known about the risk of LASIK on glaucoma onset and progression. Here we present an observational study of 4 consecutive relatively young and otherwise healthy glaucoma patients with a history of myopic LASIK who showed progression of paracentral visual field deficits at intraocular pressures of 12 mm Hg or less while being carefully monitored. Therefore, these patients required lower targets of intraocular pressure, in the single-digit range, to slow or halt progression. In this cohort, the average corneal hysteresis was more than 2 standard deviations below normal values. This series suggests that additional study into the association of LASIK and glaucoma is warranted, including the potential risk contribution of diminished CH. These studies may be particularly relevant as patients who underwent LASIK procedures in the early 2000s may now be at increased risk of glaucoma due to the risk factor of age.

Associations Between Prostate Magnetic Resonance Imaging, Genomic Testing, and Treatment for Localized Prostate Cancer.

INTRODUCTION: Although prostate MRI and tissue-based gene expression (genomic) tests improve staging and estimates of prostate cancer prognosis, their association with the intensity of treatment patients receive is not well understood. METHODS: We performed a retrospective cohort study of Medicare beneficiaries diagnosed with clinically localized prostate cancer in 2013 through 2017 in the Surveillance, Epidemiology, and End Results database. The primary study outcome was the receipt of treatment intensification in the first 12 months after diagnosis (defined as the addition of androgen deprivation therapy among patients receiving radiation or pelvic lymphadenectomy among those undergoing radical prostatectomy). We assessed associations between the receipt of prostate MRI and genomic testing and treatment intensification, adjusting for clinical and sociodemographic factors and further stratifying the analyses by risk status. RESULTS: We identified 37,064 patients with clinically localized prostate cancer, including 6,398, 22,011, and 5976 with low, intermediate, and high D'Amico-risk disease, respectively. Among all treated patients, receipt of prostate MRI was associated with increased odds of treatment intensification (odds ratio 1.76, 95% CI 1.65-1.88, P < .001). In contrast, genomic testing was not significantly associated. Among treated patients with high-risk disease, genomic testing was associated with decreased odds of intensified treatment (odds ratio 0.59, 95% CI 0.35-1.00, P = .05). CONCLUSIONS: Prostate MRI was associated with intensified treatment across risk strata, while genomic testing was associated with lower intensity of treatment among high-risk disease. Additional study is needed to determine whether use of imaging and risk stratification tools leads to improved long-term patient outcomes.

Surprise Billing Is Common in Total Joint Arthroplasty and Negatively Impacts Patient Satisfaction.

BACKGROUND: Patients undergoing total joint arthroplasty (TJA) may receive unexpected medical bills. Such "surprise" bills may cause financial hardship for patients, which prompted policymakers to pass the No Surprises Act. The purpose of this study was to determine the incidence of surprise bills for patients undergoing TJA and the effect of surprise billing on patient satisfaction. MATERIALS AND METHODS: This was a retrospective study of patients who underwent a primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) at a large multi-state institution. Patients completed a questionnaire regarding the incidence of surprise bills after their surgery, details of those bills, and how the bills affected their surgical satisfaction. Independent predictors for receiving a surprise bill were assessed through a multivariate regression analysis. RESULTS: Twelve percent of participants received at least one surprise bill after their TJA. The most common surprise bill came from the surgical facility (48%), followed by anesthesia (36%). Multivariate logistic regression analysis identified older age and Black race to be independent predictors of surprise billing. Furthermore, surgery occurring after the No Surprises Act bill enforcement on January 1, 2022, was found to increase a patient's likelihood of receiving a surprise bill (P=.039, effect size=0.18). Patients who received a surprise bill reported being significantly less satisfied with their surgery (P=.002, effect size=0.45). Forty-nine percent of patients with a surprise bill felt their billing negatively affected their surgical satisfaction. CONCLUSION: Surprise billing continues to occur after TJA and can negatively affect patient satisfaction. Although surgeons may be unable to limit the amount of bills patients receive postoperatively, increased communication and education regarding the perioperative billing process may prove to be beneficial for both patient satisfaction and the physician-patient relationship. [Orthopedics. 20XX;4X(X):XXX-XXX.].

Comparative Analysis of Mechanical Thrombectomy Outcomes of Middle Cerebral Artery M1, M2 Superior, and M2 Inferior Occlusion Strokes.

BACKGROUND: The M1 middle cerebral artery (MCA) commonly bifurcates into M2 superior and M2 inferior segments. However, MCA anatomy is highly variable rendering classification for mechanical thrombectomy trials difficult. This study explored safety and effectiveness of M2 MCA stroke thrombectomy stratified by M2 MCA anatomy. METHODS: Cases of large vessel occlusion strokes treated by mechanical thrombectomy between February 2016 and August 2022 were reviewed (N = 784). M1 (n = 431) and M2 (n = 118) MCA occlusions were assessed. Among M2 MCA occlusions, only prototypical MCA bifurcation anatomy cases were included (n = 99). Dominance was assessed based on angiography. Procedural and outcome data were compared between M1, M2 superior, and M2 inferior MCA occlusions. RESULTS: Baseline demographics and periprocedural criteria of M2 superior (n = 56) and M2 inferior (n = 43) occlusion mechanical thrombectomies were comparable. The occluded branch was dominant in 41/43 (95.3%) M2 inferior cases, but in only 37/56 (66.1%) M2 superior cases (P < 0.001). The 90-day favorable functional outcome (modified Rankin Scale score 0-2) and mortality (modified Rankin Scale score 6) rates were 60.0% and 8.9% in M2 superior, 42.9% and 32.6% in M2 inferior, and 44.1% and 26.0% in M1 (n = 431) cases. Compared with M2 superior cases, in M2 inferior cases, favorable outcome rates were lower (P = 0.094) and mortality rates were higher (P = 0.003) and resembled M1 rates (P = 0.750 and P = 0.355, respectively). CONCLUSIONS: In the setting of prototypical MCA bifurcation anatomy, thrombectomy of dominant M2 inferior occlusions had outcome rates similar to M1 occlusions. In contrast, M2 superior occlusions had significantly lower mortality rates and a trend toward better favorable functional outcome rates.

Risk of Pancreatitis After Endoscopic Ultrasound-Guided Fine-Needle Aspiration of Pancreatic Cystic Lesions: A Systematic Review and Meta-Analysis.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is frequently used to risk-stratify pancreatic cystic lesions (PCLs). Rising PCL incidence and developments in tissue acquisition and specimen analysis necessitate updated appraisal of EUS-FNA safety, particularly the risk of postprocedure pancreatitis, the most common EUS-FNA-related adverse event. Our systematic review aims to accurately quantify the risk of EUS-FNA-related pancreatitis to best inform decisions regarding EUS-FNA's optimal role in PCL workup. METHODS: We performed systematic searches in 4 databases from inception to April 2024 for original English-language studies investigating EUS-FNA-related pancreatitis. We extracted data on demographics and EUS-FNA-related pancreatitis risk, severity, and risk factors. These were meta-analyzed through the DerSimonian Laird Method using a random-effects model. Meta-regression of pancreatitis risk was performed to delineate associations with clinical and procedural characteristics. RESULTS: Sixty-four studies comprised 8,086 patients and reported 110 EUS-FNA-related pancreatitis events. Pooled risk of EUS-FNA-related pancreatitis was 1.4% (95% confidence intervals, -0.8% to 3.5%; I2 = 0.00), which was predominantly of mild severity (67%) and uniformly nonfatal. Pancreatitis risk lacked significant association with sample size, age, sex, cyst size, needle caliber, or passes, although we noted trends toward higher risk in studies published after 2015, those using higher gauge needles (19 G vs 22 G/25 G), and those performing EUS-guided through-the-needle biopsy. DISCUSSION: We note with high certainty that pancreatitis after EUS-FNA of PCLs is infrequent and mild in severity with no mortality in the included cohort. EUS-guided through-the-needle biopsy may serve as a significant risk factor for EUS-FNA-related pancreatitis risk; however, further studies are needed to delineate other predisposing characteristics.

Identification of plant transcriptional activation domains.

Gene expression in Arabidopsis is regulated by more than 1,900 transcription factors (TFs), which have been identified genome-wide by the presence of well-conserved DNA-binding domains. Activator TFs contain activation domains (ADs) that recruit coactivator complexes; however, for nearly all Arabidopsis TFs, we lack knowledge about the presence, location and transcriptional strength of their ADs1. To address this gap, here we use a yeast library approach to experimentally identify Arabidopsis ADs on a proteome-wide scale, and find that more than half of the Arabidopsis TFs contain an AD. We annotate 1,553 ADs, the vast majority of which are, to our knowledge, previously unknown. Using the dataset generated, we develop a neural network to accurately predict ADs and to identify sequence features that are necessary to recruit coactivator complexes. We uncover six distinct combinations of sequence features that result in activation activity, providing a framework to interrogate the subfunctionalization of ADs. Furthermore, we identify ADs in the ancient AUXIN RESPONSE FACTOR family of TFs, revealing that AD positioning is conserved in distinct clades. Our findings provide a deep resource for understanding transcriptional activation, a framework for examining function in intrinsically disordered regions and a predictive model of ADs.

Influence of Surface Chemistry on Metal Deposition Outcomes in Copper Selenide-Based Nanoheterostructure Synthesis.

The use of nanoparticle surface chemistry to direct metal deposition has been well-studied in the modification of metal nanoparticle substrates but is not yet well-established for metal chalcogenide particle substrates, although integration of these particles into nanoheterostructures is of high interest. In this report, we investigate the effect of Cu2-xSe surface chemistry on the morphology of metal deposition on these plasmonic semiconductor nanoparticles. Specifically, we functionalize Cu2-xSe nanoparticles with a suite of 12 different ligands and investigate how different aspects of the ligand structure do or do not impact the morphology and extent of subsequent metal deposition on the Cu2-xSe surface. Surprisingly, our results indicate that the morphology of the resulting metal deposits and the extent of metal deposition onto the existing Cu2-xSe particle substrate are indistinguishable for the majority of ligands tested. An exception to these findings is observed for particles functionalized by quaternary alkylammonium bromides, which exhibit statistically distinct metal deposition patterns compared to all other ligands tested. We hypothesize that this unique behavior is due to a cooperative binding mechanism of the quaternary alkylammonium bromides to the surface of copper selenide. Taken together, these results yield both new strategies for controlling postsynthetic modification of copper selenide nanoparticles and also reveal limitations of surface chemistry-based approaches for this system.

Classification of Suicide Attempt Risk Using Environmental and Lifestyle Factors in 3 Large Youth Cohorts.

Importance: Suicide is the third-leading cause of death among US adolescents. Environmental and lifestyle factors influence suicidal behavior and can inform risk classification, yet quantifying and incorporating them in risk assessment presents a significant challenge for reproducibility and clinical translation. Objective: To quantify the aggregate contribution of environmental and lifestyle factors to youth suicide attempt risk classification. Design, Setting, and Participants: This was a cohort study in 3 youth samples: 2 national longitudinal cohorts from the US and the UK and 1 clinical cohort from a tertiary pediatric US hospital. An exposome-wide association study (ExWAS) approach was used to identify risk and protective factors and compute aggregate exposomic scores. Logistic regression models were applied to test associations and model fit of exposomic scores with suicide attempts in independent data. Youth from the Adolescent Brain Cognitive Development (ABCD) study, the UK Millennium Cohort Study (MCS), and the Children's Hospital of Philadelphia emergency department (CHOP-ED) were included in the study. Exposures: A single-weighted exposomic score that sums significant risk and protective environmental/lifestyle factors. Main Outcome and Measure: Self-reported suicide attempt. Results: A total of 40 364 youth were included in this analysis: 11 564 from the ABCD study (3 waves of assessment; mean [SD] age, 12.0 [0.7] years; 6034 male [52.2%]; 344 attempted suicide [3.0%]; 1154 environmental/lifestyle factors were included in the ABCD study), 9000 from the MCS cohort (mean [SD] age, 17.2 [0.3] years; 4593 female [51.0%]; 661 attempted suicide [7.3%]; 2864 environmental/lifestyle factors were included in the MCS cohort), and 19 800 from the CHOP-ED cohort (mean [SD] age, 15.3 [1.5] years; 12 937 female [65.3%]; 2051 attempted suicide [10.4%]; 36 environmental/lifestyle factors were included in the CHOP-ED cohort). In the ABCD discovery subsample, ExWAS identified 99 risk and protective exposures significantly associated with suicide attempt. A single weighted exposomic score that sums significant risk and protective exposures was associated with suicide attempt in an independent ABCD testing subsample (odds ratio [OR], 2.2; 95% CI, 2.0-2.6; P < .001) and explained 17.6% of the variance (based on regression pseudo-R2) in suicide attempt over and above that explained by age, sex, race, and ethnicity (2.8%) and by family history of suicide (6.3%). Findings were consistent in the MCS and CHOP-ED cohorts (explaining 22.6% and 19.3% of the variance in suicide attempt, respectively) despite clinical, demographic, and exposure differences. In all cohorts, compared with youth at the median quintile of the exposomic score, youth at the top fifth quintile were substantially more likely to have made a suicide attempt (OR, 4.3; 95% CI, 2.6-7.2 in the ABCD study; OR, 3.8; 95% CI, 2.7-5.3 in the MCS cohort; OR, 5.8; 95% CI, 4.7-7.1 in the CHOP-ED cohort). Conclusions and Relevance: Results suggest that exposomic scores of suicide attempt provided a generalizable method for risk classification that can be applied in diverse samples from clinical or population settings.

Sports Endocrinology.

Sports endocrinology holds a unique importance in understanding and optimizing an active and healthy lifestyle. Active patients with diabetes will need to consider modifying medications, especially insulin. The use of the dual energy x-ray absorptiometry and Fracture Risk Assessment Tool scores is important as both initiate and monitor bone health treatment. Menstrual disorders and energy imbalances are some special concerns when treating female athletes, calling for a multidisciplinary treatment team. Performance agents are popular and have made their way into recreational sports.

Nucleolytic processing of abasic sites underlies PARP inhibitor hypersensitivity in ALC1-deficient BRCA mutant cancer cells.

Clinical success with poly (ADP-ribose) polymerase inhibitors (PARPi) is impeded by inevitable resistance and associated cytotoxicity. Depletion of Amplified in Liver Cancer 1 (ALC1), a chromatin-remodeling enzyme, can overcome these limitations by hypersensitizing BReast CAncer genes 1/2 (BRCA1/2) mutant cells to PARPi. Here, we demonstrate that PARPi hypersensitivity upon ALC1 loss is reliant on its role in promoting the repair of chromatin buried abasic sites. We show that ALC1 enhances the ability of the abasic site processing enzyme, Apurinic/Apyrimidinic endonuclease 1 (APE1) to cleave nucleosome-occluded abasic sites. However, unrepaired abasic sites in ALC1-deficient cells are readily accessed by APE1 at the nucleosome-free replication forks. APE1 cleavage leads to fork breakage and trapping of PARP1/2 upon PARPi treatment, resulting in hypersensitivity. Collectively, our studies reveal how cells overcome the chromatin barrier to repair abasic lesions and uncover cleavage of abasic sites as a mechanism to overcome limitations of PARPi.

Comparison of synthesized and acquired high b-value diffusion-weighted MRI for detection of prostate cancer.

BACKGROUND: High b-value diffusion-weighted images (DWI) are used for detection of clinically significant prostate cancer (csPCa). This study qualitatively and quantitatively compares synthesized DWI (sDWI) to acquired (aDWI) for detection of csPCa. METHODS: One hundred fifty-one consecutive patients who underwent prostate MRI and biopsy were included in the study. Axial DWI with b = 0, 500, 1000, and 2000 s/mm2 using a 3T clinical scanner using a 32-channel phased-array body coil were acquired. We retrospectively synthesized DWI for b = 2000 s/mm2 via extrapolation based on mono-exponential decay, using b = 0 and b = 500 s/mm2 (sDWI500) and b = 0, b = 500 s/mm2, and b = 1000 s/mm2 (sDWI1000). Differences in signal intensity between sDWI and aDWI were evaluated within different regions of interest (prostate alone, prostate plus 5 mm, 30 mm and 70 mm margin and full field of view). The maximum DWI value within each ROI was evaluated for prediction of csPCa. Classification accuracy was compared to Restriction Spectrum Imaging restriction score (RSIrs), a previously validated biomarker based on multi-exponential DWI. Discrimination of csPCa was evaluated via area under the receiver operating characteristic curve (AUC). RESULTS: Within the prostate, mean ± standard deviation of percent mean differences between sDWI and aDWI signal were -46 ± 35% for sDWI1000 and -67 ± 24% for sDWI500. AUC for aDWI, sDWI500, sDWI1000, and RSIrs within the prostate 0.62[95% confidence interval: 0.53, 0.71], 0.63[0.54, 0.72], 0.65[0.56, 0.73] and 0.78[0.71, 0.86], respectively. CONCLUSION: sDWI is qualitatively comparable to aDWI within the prostate. However, hyperintense artifacts are introduced with sDWI in the surrounding pelvic tissue that interfere with quantitative cancer detection and might mask metastases. In the prostate, RSIrs yields superior quantitative csPCa detection than sDWI or aDWI.

Recovery kinetics of dual AAV-mediated human otoferlin expression.

Deafness-causing deficiencies in otoferlin (OTOF) have been addressed preclinically using dual adeno-associated virus (AAV)-based approaches. However, timing of transduction, recombination of mRNA, and protein expression with dual hybrid AAV methods methods have not previously been characterized. Here, we have established an ex vivo assay to determine the kinetics of dual-AAV mediated expression of OTOF in hair cells of the mouse utricle. We utilized two different recombinant vectors that comprise DB-OTO, one containing the 5' portion of OTOF under the control of the hair cell-specific Myo15 promoter, and the other the 3' portion of OTOF. We explored specificity of the Myo15 promoter in hair cells of the mouse utricle, established dose response characteristics of DB-OTO ex vivo in an OTOF-deficient mouse model, and demonstrated tolerability of AAV1 in utricular hair cells. Furthermore, we established deviations from a one-to-one ratio of 5' to 3' vectors with little impact on recombined OTOF. Finally, we established a plateau in quantity of recombined OTOF mRNA and protein expression by 14 to 21 days ex vivo with comparable recovery timing to that in vivo model. These findings demonstrate the utility of an ex vivo model system for exploring expression kinetics and establish in vivo and ex vivo recovery timing of dual AAV-mediated OTOF expression.