Citations

Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic kidney disease, nephrolithiasis, and transplant rejection. This validation study uses the KIT Assay to investigate the clinical utility of the non-invasive detection of IgAN and predicting the progression of renal damage over time. The study design benefits from longitudinally collected urine samples from an investigator-initiated, multicenter, prospective study, evaluating the efficacy of corticosteroids versus Rituximab for preventing progressive IgAN. A total of 131 urine samples were processed for this study; 64 urine samples were collected from 34 IgAN patients, and urine samples from 64 demographically matched healthy controls were also collected; multiple urinary biomarkers consisting of cell-free DNA, methylated cell-free DNA, DMAIMO, MAMIMO, total protein, clusterin, creatinine, and CXCL10 were measured by the microwell-based KIT Assay. An IgA risk score (KIT-IgA) was significantly higher in IgAN patients as compared to healthy control (87.76 vs. 14.03, p < 0.0001) and performed better than proteinuria in discriminating between the two groups. The KIT Assay biomarkers, measured on a spot random urine sample at study entry could distinguish patients likely to have progressive renal dysfunction a year later. These data support the pursuit of larger prospective studies to evaluate the predictive performance of the KIT-IgA score in both screening for non-invasive diagnosis of IgAN, and for predicting risk of progressive renal disease from IgA and utilizing the KIT score for potentially evaluating the efficacy of IgAN-targeted therapies.

Abstract MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN–PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN–PA2G4 protein–protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. Significance: Competitive chemical inhibition of the PA2G4–MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

Abstract Black women in the United States are disproportionately affected by early-onset, triple-negative breast cancer. DNA methylation has shown differences by race in healthy and tumor breast tissues. We examined associations between genome-wide DNA methylation levels in breast milk and breast cancer risk factors, including race, to explain how this reproductive stage influences a woman's risk for, and potentially contributes to racial disparities in, breast cancer. Breast milk samples and demographic, behavioral, and reproductive data, were obtained from cancer-free, uniparous, and lactating U.S. black (n = 57) and white (n = 82) women, ages 19–44. Genome-wide DNA methylation analysis was performed on extracted breast milk DNA using the Infinium HumanMethylation450 BeadChip. Statistically significant associations between breast cancer risk factors and DNA methylation beta values, adjusting for potential confounders, were determined using linear regression followed by Bonferroni Correction (P &lt; 1.63 × 10−7). Epigenetic analysis in breast milk revealed statistically significant associations with race and lactation duration. Of the 284 CpG sites associated with race, 242 were hypermethylated in black women. All 227 CpG sites associated with lactation duration were hypomethylated in women who lactated longer. Ingenuity Pathway Analysis of differentially methylated promoter region CpGs by race and lactation duration revealed enrichment for networks implicated in carcinogenesis. Associations between DNA methylation and lactation duration may offer insight on its role in lowering breast cancer risk. Epigenetic associations with race may mediate social, behavioral, or other factors related to breast cancer and may provide insight into potential mechanisms underlying racial disparities in breast cancer incidence.

Background: The variability of throwing metrics, particularly elbow torque and ball velocity, during structured long-toss programs is unknown. Hypotheses: (1) Elbow torque and ball velocity would increase as throwers progressed through a structured long-toss program and (2) intrathrower reliability would be high while interthrower reliability would be variable. Study Design: Descriptive laboratory study. Level of Evidence: Level 3. Methods: Sixty healthy high school and collegiate pitchers participated in a structured long-toss program while wearing a validated inertial measurement unit, which measured arm slot, arm velocity, shoulder rotation, and elbow varus torque. Ball velocity was assessed by radar gun. These metrics were compared within and between all pitchers at 90, 120, 150, and 180 ft and maximum effort mound pitching. Intra- and interthrower reliabilities were calculated for each metric at every stage of the program. Results: Ball velocity significantly changed at each progressive throwing distance, but elbow torque did not. Pitching from the mound did not place more torque on the elbow than long-toss throwing from 120 ft and beyond. Intrathrower reliability was excellent (intraclass correlation coefficient >0.75) throughout the progressive long-toss program, especially on the mound. Ninety-one percent of throwers had acceptable interthrower reliability (coefficient of variation <5%) for ball velocity, whereas only 79% of throwers had acceptable interthrower reliability for elbow torque. Conclusion: Based on trends in elbow torque, it may be practical to incorporate pitching from the mound earlier in the program (once a player is comfortable throwing from 120 ft). Ball velocity and elbow torque do not necessarily correlate with one another, so a degree of caution should be exercised when using radar guns to estimate elbow torque. Given the variability in elbow torque between throwers, some athletes would likely benefit from an individualized throwing program. Clinical Relevance: Increased ball velocity does not necessarily equate to increased elbow torque in long-toss. Some individuals would likely benefit from individualized long-toss programs for rehabilitation.

Background: There are many risk factors for shoulder and elbow injuries in professional baseball pitchers. The elbow carrying angle has not been studied as a potential risk factor. Purpose/Hypothesis: The aim of this study was to determine whether elbow carrying angle is a risk factor for shoulder or elbow injuries in professional baseball pitchers. We hypothesized that pitchers with a higher elbow carrying angle would be less likely to sustain an injury during the season than pitchers with a lower elbow carrying angle. Study Design: Cohort study; Level of evidence, 2. Methods: All professional pitchers for a single baseball club during the 2018 season had the carrying angle of both elbows measured at spring training by a single examiner. The pitchers were followed prospectively throughout the season. Shoulder and elbow injuries were recorded prospectively. Results: A total of 52 pitchers (21 [40%] Major League Baseball and 31 [60%] Minor League Baseball) were included. During the season, 23 (44%) pitchers became injured. The mean carrying angle in the throwing arm was 12.5° ± 4.2° versus 9.9° ± 2.8° in the nonthrowing arm ( P < .001). Comparing the injured and noninjured groups, there were no differences in level of play ( P = .870), throwing hand dominance ( P = .683), batting hand dominance ( P = .554), throwing-side carrying angle ( P = .373), nonthrowing-side carrying angle ( P = .773), or side-to-side difference in carrying angle ( P = .481). Conclusion: The elbow carrying angle was not associated with an injury risk during a single season in professional baseball pitchers.

Abstract Objective The quality of all clinical MRI is dependent on B0 homogeneity, which is optimized during the shimming part of a prescan or preparatory phase before image acquisition. The purpose of this study was to assess shimming techniques clinically employed for breast MRI across our practice, and to determine factors that correlate with higher image quality for contrast-enhanced breast MRI at 1.5T. Methods One hundred consecutive female patients were retrospectively collected with Institutional Review Board approval. Shimming-related parameters, including shim-box placement and shimming gradient offsets were extracted from prior contrast-enhanced 3D fat-suppressed T1-weighted gradient echo image acquisitions. Three breast radiologists evaluated these images for fat saturation, breast density, overall image quality, and artifacts. Technologist experience was also evaluated for variability of shimming. Generalized linear mixed models were used to compare acquisition parameters between fat saturation. P &lt; 0.05 was considered as statistical significance. Results The percentage of soft tissue inside the field of view (FOV) (ie, Tissue/FOV) in the good fat-saturation group (0.37 ± 0.06) was significantly lower (P &lt; 0.01) than that in the poor fat-saturation group (0.39 ± 0.06). Other shimming-related parameters were found not significantly affecting the fat-saturation outcomes. Technologists with more experience tended to have less variable shimming performance than junior technologists did. Conclusions The quality of clinical MRI and especially breast MRI is highly dependent on shimming. Decreasing Tissue/FOV was associated with good image quality (good fat saturation). Optimization of shimming may require manual shimming or higher-order field-correction strategies.

Background: Ulnar collateral ligament (UCL) reconstruction of the elbow is commonly performed on professional baseball pitchers. Recent reports have suggested that revision rates are on the rise and may be higher than previously thought. Purpose: To provide a comprehensive report on current trends, surgical techniques, and outcomes of revision UCL reconstructions performed on professional baseball pitchers between 2010 and 2016. Study Design: Case series; Level of evidence, 4. Methods: The Major League Baseball Health and Injury Tracking System (HITS) was used to compile records of all revision UCL reconstructions performed on professional baseball pitchers between 2010 and 2016. Player data and outcomes were obtained from HITS, and surgical details were obtained from operative reports. Descriptive statistical analysis was performed on epidemiologic data. Outcomes (return to play [RTP] rates, RTP times, subsequent injuries, and subsequent surgeries) were compared across the most common surgical techniques (docking vs modified Jobe) and graft sources (palmaris longus autograft vs hamstring autograft). Results: A total of 69 professional baseball pitchers underwent revision UCL reconstruction from 2010 to 2016 at an average of 1424 days (47 months) after their primary surgery. A trend was seen toward increasing numbers of revision surgeries over time ( R 2 = 0.441; P = .104). The most commonly used tunnel configuration was the modified Jobe technique (n = 41; 59.4%), and the most commonly used graft was hamstring autograft (n = 34; 49.3%). A majority (76.6%) of pitchers achieved RTP, and 55.3% were able to return to the same level of play. Mean time to RTP was 436 days (14.5 months) for players with a palmaris longus autograft versus 540 days (18 months) for those with a hamstring autograft ( P = .108). Further, the mean time to RTP was 423 days (14 months) for the docking technique versus 519 days (17 months) for the modified Jobe technique ( P = .296). Similar rates of subsequent injuries and surgeries were noted between the 2 revision techniques and 2 most commonly used graft constructs. Conclusion: Revision UCL reconstruction showed relatively high RTP rates (77%), but only 55% of players returned to their same level of play. Mean time to RTP was shorter than that found in other, smaller investigations. Although general trends were seen toward decreased time to RTP for the docking technique and palmaris longus autograft, these differences did not reach statistical significance.

Objectives: The variability of throwing metrics, particularly elbow torque and ball velocity, during structured long-toss programs is yet to be fully elucidated. The primary aims of this study were to assess various throwing metrics through a structured long-toss program using wearable technology and to quantify the intra and inter thrower variability of these metrics at each stage of throwing. Methods: This was a descriptive laboratory study in which 60 high school and collegiate pitchers participated in a predetermined, structured, progressive long-toss program. All players wore a motusBASEBALL sleeve (Motus Global, Inc.; Rockville Centre, NY), which measured arm slot, arm velocity, shoulder rotation, and elbow varus torque. Radar guns were used to measure ball velocity. These metrics were compared within and between all pitchers at each of the following throwing distances: 90 ft, 120 ft, 150 ft, 180 ft, and maximum effort mound pitching. Intra- and inter- thrower reliabilities were calculated for each throwing metric at every stage of the program. Excellent intra-thrower reliability was defined by an Intra-class coefficient (ICC) >0.750. Acceptable inter-thrower reliability was defined by a Coefficient of Variation (CV) <5%. Results: Ball velocity significantly changed at each progressive throwing distance, but this did not consistently correlate with an increase in elbow torque. Pitching from the mound did not place more torque on the elbow than throwing from 120 ft and beyond. Intra-thrower reliability was excellent throughout the progressive long-toss program for each throwing metric. Ninety-one percent of throwers had acceptable inter-thrower reliability for ball velocity, whereas only 79% of throwers had acceptable inter-thrower reliability for elbow torque. Conclusion: Based on trends in elbow torque, it may be practical to incorporate pitching from the mound earlier in the program (once a player is comfortable throwing from 120 ft). Ball velocity and elbow torque do not necessarily correlate with one another, so a degree of caution should be exercised when using radar guns to estimate elbow torque. Given the variability in elbow torque between throwers, some athletes would likely benefit from an individualized throwing program.